ORAL DOSAGE FORM 24 Volume DRUG DEVELOPMENT SERIES

HANDBOOK OF PHARMACEUTICAL
GENERIC DEVELOPMENT

ORAL Immediate Release

T ablets

VOLUME I - Part ONE

Drug Development - Solid Oral Dosage Forms

GENERIC DEVELOPMENT
Handbook of Pharmaceutical
Generic Development Series

24 VOLUME DRUG DEVELOPMENT SERIES PRODUCT DEVELOPMENT

 ORAL DOSAGE FORM 24 Volume DRUG DEVELOPMENT SERIES

HPGD 24 Vol. SERIES - ORAL TABLETS - Part I

First International Edition - 01.
First published and distributed in UK, US, EU, RSA, Israel and Japan in November 1996:
by Locum International Publishing House (Houston, Israel, South Africa).
Second International Edition - 02 (First to Fourth Print).
Fourth printing published and distributed in UK, US, EU, Israel, Asia, and Japan in January
2000 by Locum International Publishing House (Houston, Israel, South Africa) in Hard
Cover; Soft and Spiral Cover; Electronic Diskette; and e-mail attachment versions. All print
and electronic versions identical in content and format.
Copyright © 1995 - 2000, Handbook of Pharmaceutical Generic Development.
Text Copyright © 1995 - 2000, Handbook of Pharmaceutical Generic Development.
Illustration copyright © 1995 - 2000, Handbook of Pharmaceutical Generic Development.
Locum International Publishing House PO Box 874, 50 Gilad Street Kochav Yair 44864
Israel. - All right reserved.
ISSN 0793 8632
ISSN 0793 8640 - Electronic Version (Diskette, CD ROM and e-mail attachment version)
Handbook Development 24 volume series
General Generic Development ISSN Series number 0793 7407
General Generic Development ISSN Series number 0793 7792 - Electronic Issue (Diskette
and e-mail attachment version are identical in size and content to the printed hard or soft
cover version.)
Duplication: No part of this publication may be reproduced, stored in a retrieval
system or transmitted in any form or by any means, electronic, mechanical,
photocopying, microfilming, recording or otherwise, without the prior written
permission of the copyright owner or subject to the following conditions:
Authorization to photocopy items for internal or personal use or internal or personal
use of specific company personnel, is granted by Locum International Publishing
House, provided that the base fee of $1 per page is paid directly to the Copyright
Clearance Center (CCC) 222 Rosewood Drive, Danvers, MA 01923 USA. For
organizations that have been granted a photocopy license by CCC, a separate
system of payment has been arranged.
For additional information, contact the Publications Department Locum International
Publishing House; PO Box 874, 50 Gilad Street, Kochav Yair, 44864 Israel.

UK Fax: +(44) 207-900 2096

US Fax: +(1) 435-408 1665
Fax: +972-97-494 532
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Handbook of
Pharmaceutical
Generic
Development

Part One
ORAL
Immediate Release

TABLETS
Drug D e v e l o p m e n t

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Inc. All Rights Reserved.

Neither this book nor any part may be

reproduced or transmitted in any form or
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including photocopying, microfilming and
recording, or by any information storage
and retrieval system, without the
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The Complete H a n d b o o k S e r i e s o f
Pharmaceutical Drug Development
ISBN 0793 8632 - Electronic Version
Handbook Development 24 Volume Series
ISSN Series Number 0793 761X - Electronic Version

Handbook of Pharmaceutical Generic Development

Vol. 1 - Tablets Oral
Part I (Development) & Part II (Development ANDA or EU Dossier)
Handbook of Pharmaceutical Generic Development
Vol. 2 - Capsules Oral
Part I (Development) & Part II (Development ANDA or EU Dossier)
Handbook of Pharmaceutical Generic Development
Vol. 3 - Semisolids
Part I (Development) & Part II (Development ANDA or EU Dossier)
Handbook of Pharmaceutical Generic Development
Vol. 4 - Liquids Oral
Part I (Development) & Part II (Development ANDA or EU Dossier)
Handbook of Pharmaceutical Generic Development
Vol. 5 - SG Capsules
Part I (Development) & Part II (Development ANDA or EU Dossier)
Handbook of Pharmaceutical Generic Development
Vol. 6 - e-SOPs / SOPs
Handbook of Pharmaceutical Generic Development
Vol. 7 - Suspensions
Part I (Development) & Part II (Development ANDA or EU Dossier)
Handbook of Pharmaceutical Generic Development
Vol. 8 - Eye & Nose
Part I (Development) & Part II (Development ANDA or EU Dossier)
Handbook of Pharmaceutical Generic Development
Vol. 9 - Aerosols MDI
Part I (Development) & Part II (Development ANDA or EU Dossier)
Handbook of Pharmaceutical Generic Development
Vol. 10 -Tablets CR/MR
Part I (Development) & Part II (Development ANDA or EU Dossier)
Handbook of Pharmaceutical Generic Development
Vol. 11 -Capsules ER
Part I (Development) & Part II (Development ANDA or EU Dossier)
Handbook of Pharmaceutical Generic Development
Vol. 12 - Tablets Oral DR
Part I (Development) & Part II (Development ANDA or EU Dossier)
Handbook of Pharmaceutical Generic Development
Vol. 13 - Analytical (Top
Part I (Method Validation) & Part II (Analytical Methods 1994-2003)
50 Generic Assay Methods)
Handbook of Pharmaceutical Innovative Development Vol. 14 - Tablets Oral
Handbook of Pharmaceutical Innovative Development Vol. 15 - Capsules Oral
Handbook of Pharmaceutical Innovative Development Vol.16 Suspensions Oral
Handbook of Pharmaceutical Drug Development Vol. 17 - MF and MMI
(Master Formula & Manufacturing Instructions Parts 1 - 5)
Handbook of Pharmaceutical Drug Development Vol. 18 - MF and MMI
(Master Formula & Manufacturing Instructions Parts 6 -10)
Handbook of Pharmaceutical Innovative Development Vol. 19-SOPs/PAI-Checklist
Part I, II & III (Development, Manufacturing & Engineering)
Handbook of Pharmaceutical Drug Development Vol. 20 - Sterile Injections
Part I (Development) & Part II (Development ANDA or EU Dossier)

Available as Print, Online, CD ROM or electronic mail attachment. Additional Drug Specific Volumes in Preparation.
An on-going electronic and print series. Available either as Hard Bound, Soft Bound or Soft Spiral Cover (for Updating).

For Drug Specific Handbooks refer to the 120+ Drug Development Series titled
READY-TO-GO™ DRUG DEVELOPMENT SERIES
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HPGD 24 Vol. SERIES - ORAL TABLETS - Part I

First International Edition - 01.
First published and distributed in UK, US, EU, RSA, Israel and Japan in November 1996:
by Locum International Publishing House (Houston, Israel, South Africa).
Second International Edition - 02 (First to Fourth Print).
Fourth printing published and distributed in UK, US, EU, Israel, Asia, and Japan in January
2000 by Locum International Publishing House (Houston, Israel, South Africa) in Hard
Cover; Soft and Spiral Cover; Electronic Diskette; and e-mail attachment versions. All print
and electronic versions identical in content and format.
Copyright © 1995 - 2000, Handbook of Pharmaceutical Generic Development.
Text Copyright © 1995 - 2000, Handbook of Pharmaceutical Generic Development.
Illustration copyright © 1995 - 2000, Handbook of Pharmaceutical Generic Development.
Locum International Publishing House PO Box 874, 50 Gilad Street Kochav Yair 44864
Israel. - All right reserved.
ISSN 0793 8632
ISSN 0793 8640 - Electronic Version (Diskette, CD ROM and e-mail attachment version)
Handbook Development 24 volume series
General Generic Development ISSN Series number 0793 7407
General Generic Development ISSN Series number 0793 7792 - Electronic Issue (Diskette
and e-mail attachment version are identical in size and content to the printed hard or soft
cover version.)
Duplication: No part of this publication may be reproduced, stored in a retrieval
system or transmitted in any form or by any means, electronic, mechanical,
photocopying, microfilming, recording or otherwise, without the prior written
permission of the copyright owner or subject to the following conditions:
Authorization to photocopy items for internal or personal use or internal or personal
use of specific company personnel, is granted by Locum International Publishing
House, provided that the base fee of $1 per page is paid directly to the Copyright
Clearance Center (CCC) 222 Rosewood Drive, Danvers, MA 01923 USA. For
organizations that have been granted a photocopy license by CCC, a separate
system of payment has been arranged.
For additional information, contact the Publications Department Locum International
Publishing House; PO Box 874, 50 Gilad Street, Kochav Yair, 44864 Israel.

UK Fax: +(44) 207-900 2096

US Fax: +(1) 435-408 1665
Fax: +972-97-494 532
E-mail: info@locum. co. il
http://www.locum.co.il
http://www.locumeuro.com
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Current Printing (last digit): 10 9 8 7 6 5 4 3.
SERIAL NUMBER - DO NO REMOVE! - REGISTERED WITH sales@l o c u m u s a . com
Ö PRINTED IN USA
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WARNING: THIS ISSUE A IS MULTIPLE PAGE UV ENCODED EDITION.
PRINTED IN IRELAND
PRINTED IN REPUBLIC OF SOUTH AFRICA

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Acknowledgments
I.A.G.I.M. (R&D) Foundation.
I.A.G.I.M. Members (1994 - 2000).
Contributions - Generic & Research Firms
Associate Universities, Technicons and Consultants.
Handbook Series Coordinating Committee.
International Journal of Drug Development.
Journal of Pharmaceutical Development.
International Journal of Generic Drugs.
I.A.G.I.M. Drug Development Archives
Locum International Archives.
FDA/OGD/CDER Maryland
Guides and Guidelines
Library of Congress.
AIC Conferences.
Editorial Board.
Pharm. Eur.
USP/NF.
USPC.
BP.
°

To Doribelle
for her years of support and help
to Sean for his expert knowledge on computerization
to David and Ari for running the project's computers
and lastly to Pat for his inestimable
contribution.

24 Volume Series
Handbook of Generic development
Third International Edition.

L O C U M P U B L I S H I N G H O U S E

Í °Î
Ï Ð
Í °Î

24 VOLUME DRUG DEVELOPMENT SERIES PRODUCT DEVELOPMENT

 ORAL DOSAGE FORM 24 Volume DRUG DEVELOPMENT SERIES

INTRODUCTION
Handbook of Generic Development - Oral Tablet Dosage Form

This handbook is the third international edition of the ongoing 24 volume series
under the cumulative title of Handbook of Generic Drug Development. It is a hands-
on, technical presentation that portrays the current drug requirement steps
necessary at the time of going to print, of the Abbreviated New Drug Application for
oral tablet dosage form, namely tablets and caplets. It is written in conjunction with
Part Two of the Handbook which models as a representative ANDA and as an
example of the drug development process required for solid oral dosage forms The
Handbook is available in electronic format (CD ROM) and e-format (on-line). The
Handbook is up-dated to current regulatory requirements once or occasionally under
exceptional circumstances twice annually. Complete updates are available without
charge to Association Members of the Drug Development Association - IAGIM.
This handbook provides a proven pathway to solid oral dosage form development.
Modern commercial formulations highlight the common tablet/caplet development
routes namely the classical wet granulation, spray granulation, dry granulation and
finally slugging and direct compression. Low active dosage (<10mg) and high
potency (>50%) examples are specially chosen to demonstrate the formulation steps
and process stages as a prerequisite to developing stable, elegant and rugged
formulas.
This Handbook edition includes additional data on analytical method validation has
been redesigned to meet the Guidance for Industry - Organization of an Abbreviated
New Drug Application and an Abbreviated Antibiotic Application as well as all FDA
guideline and requirements of the Center of Drug Evaluation and Research (CDER)
to date of publishing. Editor-in-Chief.

ISSN 0793 8632

An on-going series

Additional Volumes in Preparation

General Drug Development Series ISSN 0973 7601
Electronic Drug Development Series ISSN 0973 761X

ÓšÎ
© COPYRIGHT 1995-00
pÏ›Ðp

24 VOLUME DRUG DEVELOPMENT SERIES PRODUCT DEVELOPMENT

 ORAL TABLETS Table of Contents.

Contents
PHARMACEUTICAL DEVELOPMENT

Table of Contents VII

Acronyms - Abbreviations XIII
Introduction XIV
Preface XV
Forward XVI

Chapter 1
Regulatory 1.1
- Pre-formulation checklist 1.3
Documentation 1.4
- SOP Control checklist 1.5
Development Notebooks 1.6
- Development Notebooks checklist 1.7
- SOP Control and Development Notebooks SOPs 1.8

Chapter 2
Developing the Formula -an Overview 2.1
- Formulation checklist 2.2
- Development formulations 2.3
Drug Development Checklist 2.4
Development Formula SOPs 2.5
Developing the Formula 2.6
Product Development Flow Chart 2.11
Product Development Guide 2.13
Direct Compression Tablet Development 2.21
Direct Compression Flow Charts 2.26
Direct Compression Master Formula 2.29
Wet Granulation Development 2.31
Wet & Direct Compression Flow Charts 2.26
Wet Granulation Manufacturing Flow Charts 2.41
Wet Granulation Master Formula (aqueous granulation) 2.42
Wet Granulation Master Formula (alcoholic granulation) 2.44

HANDBOOK OF GENERIC DRUG DEVELOPMENT VII 24 VOLUME HANDBOOK SERIES

 ORAL TABLETS Table of Contents.

Contents
Chapter 2
Purified Water - an essential ingredient 2.45
Do and Don'ts in Development 2.48
Purified Water - Checklist 2.49

Chapter 3
Active Ingredients 3.1
-Do’s and Don’ts 3.2
-Active checklist 3.3
-Approved Suppliers Checklist 3.5
-Standard Operating Procedures, Actives 3.6

Chapter 4
Semi active ingredients 4.1
-Validating the Semi-active ingredients, Checklist 4.2
Qualifying the Antioxidant 4.4
Antioxidant Tabulations 4.5

Chapter 5
Non active materials (excipients) 5.1
-Checklist non active ingredient 5.2
-Standard Operating Procedures, Non actives 5.3

Chapter 6
Container closure systems 6.1
-Container-liner-closure systems, Checklist 6.2
-Container-liner-closure systems, SOPs 6.3
-Packaging Components 6.5
-Packaging Components Documentation Requirements SOP 6.6
-Packaging Characteristics 6.11
-Packaging Component Descriptions 6.12
-Packaging Component 6.16

Chapter 7
Manufacturing Instructions 7.1
- Manufacturing Instructions; Checklist 7.4
- The manufacturing Instructions and Controls 7.5
- Manufacturing Flow Charts 7.16
- Large scale manufacturing Instructions 7.20
- Large scale Master Formula 7.24
- Large scale Manufacturing Instructions 7.27

HANDBOOK OF GENERIC DRUG DEVELOPMENT VIII 24 VOLUME HANDBOOK SERIES

 ORAL TABLETS Table of Contents.

Contents
Chapter 8
In-process Quality Controls 8.1
-Manufacturing in-process controls; Checklist 8.3
-In-process Specifications 8.5
-Process yields 8.8
-In-process Control Specifications 8.9
-In-process Film Coating Specifications 8.10

Chapter 9
Finished Product Specifications 9.1
- Finished Product Specifications Tablet & Caplets 9.2
- Finished Product Specifications; Checklists 9.4
- Finished Product Specifications; Required SOPs 9.5

Chapter 10
Process Optimization and Procedures 10.1
Qualification of Antioxidant and Lubricant 10.2
Qualification of Loss on Drying Limits 10.3

Chapter 11
Scale-up Procedures 11.1
- Scale-up procedures; checklist 11.3
- Scale-up procedures; Aqueous Film Coating 11.6

Chapter 12
Cleaning Limits 12.1
Cleaning Limits Procedures; Checklist 12.6
Cleaning Validation Requirements; SOPs 12.8

Chapter 13
Analytical Validation Requirements 13.1
-Analytical Testing Out of Specification 13.21
-Analytical Testing Do's and Don'ts - Retesting Rules 13.23
-Out-of-Specifications Checklists 13.24
-Ruggedness and Robustness 13.37
-Impurities in Drug Substances 13.41
-Impurities Do's and Don'ts 13.50
-Impurities Glossary of terms 13.51
-Impurities Decision Trees 13.53
Analytical Post approval Changes - PAC/ALTS 13.55
PAC-ALTS Checklist 13.58

HANDBOOK OF GENERIC DRUG DEVELOPMENT IX 24 VOLUME HANDBOOK SERIES

 ORAL TABLETS Table of Contents.

Contents
Chapter 14
Process Qualification Batch 14.1
-Process Qualification Batch; Checklist 14.2
-Process Qualification Batch; SOPs 14.3
-Process Qualification Blend Analysis 14.7
-Process Qualification Blend Analysis - Do's and Don'ts 14.7
-Process Qualification Qualifying Tablet Hardness 14.8
Tablet Hardness Protocol 14.10

Chapter 15
Pivotal batch
-The Pivotal Batch 15.1
-Pivotal batch Checklist 15.2
-Pivotal batch SOPs 15.3
-Sampling and Testing the Pivotal Batch 15.3
-Auditing the Pivotal batch 15.4
-Auditing the Pivotal batch Checklist 15.9

Chapter 16
Bioequivalence vs. RLD 16.1
Test Designs - Overview 16.2
Statistical Bioequivalence 16.13
IBE Equation explained 16.14
IBE - Big Picture (Pros and Cons) 16.15
Comparing IBE and ABE 16.16
Dissolution Testing in IR Dosage Forms 16.18
Typical IVIVC Models 16.21
Choosing IVIVC levels 16.22
Dissolution Testing in IR Solid Dosage Forms 16.23
Similarity Factor in dissolution testing 16.30
Biowaivers 16.32
Overall Dissolution Picture 16.35
Biopharmaceutics Classification System 16.36
Evaluating Differences between Drug, Powder Blend, and Tablets 16.37
Performance Verification in Dissolution testing 16.39
Food-Effects in BA-BE Studies 16.52
Similarity Testing - Chow, Pitt and Others 16.60

HANDBOOK OF GENERIC DRUG DEVELOPMENT X 24 VOLUME HANDBOOK SERIES

 ORAL TABLETS Table of Contents.

Contents
Chapter 17
Technical Transfer Documentation 17.1
-Technical Transfer Documentation; Do's and Don'ts Checklist 17.5
-Technical Transfer Documentation; Pharmaceutical Part 17.7
-Technical Transfer Documentation; Analytical Part 17.10

Chapter 18
Process Validation Batches 18.1
-The Process Validation Batches - Essential know-how 18.2
-Process Validation Requirements; SOPs 18.4
-Process Validation Master Plans 18.5

Chapter 19
Pre--Approval Inspections 19.1
PAI Summary 19.8
Pre--Approval Inspection Audit - Team Set Up 19.9
Pre--Approval Inspection Audit - Team Activities 19.11

Chapter 20
Stability Testing of Drug Substance and Drug Product I 20.1
Stability Testing of Drug Substance and Drug Product II 20.15
Stability Testing of Drug Substance and Drug Product II 20.31
Stability Testing Significant Change 20.28
Stability Storage Conditions 20.29
Photostability in Drug Substances 20.31
Setting up a Functional Stability Unit 20.40
Stability SOPs Development 20.48

Chapter 21
Standard Operational Procedures
Development SOPs 21.1
Index of Pharmaceutical Standard Operating Procedures 21.3
Index of Analytical Standard Operating Procedures 21.10
Index of Microbiological Standard Operating Procedures 21.16
Index of Stability Standard Operating Procedures 21.20
Model Development Report 22.1
Experimental Development 22.2
Pre-formulation Development 22.7
Small scale Development 22.9
Scale-up 22.14
Pivotal Lot Manufacture 22.27
Model Development Report - Summary and Conclusion 22.41
HANDBOOK OF GENERIC DRUG DEVELOPMENT XI 24 VOLUME HANDBOOK SERIES
ORAL TABLETS Table of Contents.

ISSN 0793 8632

An on-going series
Additional Volumes in Preparation
ISBN 0793 8640 - Electronic Version
Handbook Development 24 Volume Series
ISSN Series Number 0793 7792 - Electronic Version

ISSN 0793 8632

An on-going series

Additional Volumes in Preparation

General Drug Development Series ISSN 0973 7601
Electronic Drug Development Series ISSN 0973 761X

ÓšÎ
International Print Edition
p20±00p
© COPYRIGHT 1995-00
Ï›Ð

HANDBOOK OF GENERIC DRUG DEVELOPMENT XII 24 VOLUME HANDBOOK SERIES

 ORAL TABLETS Table of Contents.

H P G D
Handbook of Pharmaceutical Generic Development
™

Drug Development - Part I

Electronic ANDA™ - Part II
© Copyright 1995 -2000 Locum International Ltd.

2000 Update Program

Part I and Part II : HandBook Generic Development Series
þ Volume 1 Edition 03 - 2000 þ Volume 13 Edition 03 - 2000
þ Volume 2 Edition 03 - 2000 þ Volume 14 Edition 03 - 2000
þ Volume 3 Edition 03 - 2000 þ Volume 15 Edition 03 - 2000
þ Volume 4 Edition 03 - 2000 þ Volume 16 Edition 03 - 2000
þ Volume 5 Edition 03 - 2000 þ Volume 17 Edition 03 - 2000
þ Volume 6 Edition 03 - 2000 þ Volume 18 Edition 03 - 2000
þ Volume 7 Edition 03 - 2000 þ Volume 19 Edition 03 - 2000
þ Volume 8 Edition 03 - 2000 þ Volume 22 Edition 03 - 2000
þ Volume 9 Edition 03 - 2000 þ Volume 21 Edition 03 - 2000
þ Volume 10 Edition 03 - 2000 þ Volume 22 Edition 03 - 2000
þ Volume 11 Edition 03 - 2000 þ Volume 23 Edition 03 - 2000
þ Volume 12 Edition 03 - 2000 þ Volume 24 Edition 03 - 2000

Update License No:

Initiation Date : January 2000 1.3.00-000
Expiration Date : January 2004
No of Years : FOUR (4)
Update Period : January 2001; January 2002; January 2003; January 2004.

This Print or CD ROM edition of the Drug Development series has been updated to June 2000 Office of Generic
Drug's requirements. Handbook clients requiring to continue this annual ONGOING service need only to
become members of the Drug Development Association (I.A.G.I.M.) for the period of the update service as
required by the firm, starting from date of purchase. The Drug Development Update Program is renewed in
December each year as a function of the firms requirements. New Drug Formula And Manufacturing Procedures
Are Added Annually All updates are on CD ROM in PDF™. Warning: Copyright © 1985 -2000 Locum
Publishing House Inc.-All Rights Reserved.

Neither this information or nor any part of the data contained therein may be reproduced, copied or transmitted
in any form, modification or merged portion or by any means, electronic or mechanical, including printing
photocopying, microfilming and recording, or by any information storage and retrieval system, without the prior
written permission of the publishers. ™ Trademark - Locum Corporation, ™ Locum International Group.

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[email protected] - [email protected]
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(See web site for IAGIM Application Membership Forms)
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HANDBOOK OF GENERIC DRUG DEVELOPMENT XIII 24 VOLUME HANDBOOK SERIES

ORAL TABLETS Table of Contents.

Additional Handbooks in preparation on drug specific dosage forms

in the title series 120+ Ready-To-Go Series
view at http://www.locumusa.com/2go
Available either on diskette, CD ROM or via electronic mail attachment.

An on-going electronic and print series

Additional Volumes in Preparation

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HANDBOOK OF GENERIC DRUG DEVELOPMENT XIV 24 VOLUME HANDBOOK SERIES

 Introduction

Introduction
T
he purpose of the Handbook Series is to illustrate generic drug development from pre-
formulation to regulatory submission. The Handbook Series on pharmaceutical dosage
forms deals with the US generic drug development process of the ANDA (Abbreviated
New Drug Application) and EU Dossier It is well suited to innovative development
processes for the Chemistry-Manufacturing-Controls (CMC) Section of an New Drug
Application (NDA).
Each book is devoted to a specific dosage form e.g. tablets, capsules, (immediate & modified
release), liquids, topical semi solids, suspensions, eye and nose preparations, inhalation
aerosols and so forth. It is an ongoing series that is reviewed and updated twice annually, as
new agency regulations, guides, guidelines and industry procedures are adopted or regulated.
The Handbook is a basic hands-on working approach to generic drug development and the
overall developmental process. The handbook ends with the requirements for manufacturing
the first three commercial product lots for distribution and marketing.
Each Handbook is presented in two volumes referred to as Part One and Part Two. These two
parts are supplementary and should be used and referenced together, as they complement
each other. Electronic templates for the full registration process are available for each dosage
form. These approximate +300 Word™ based templates consist of electronically completed
ANDA data where only the variable facts and figures need to be inserted into the prepared
data fields. Templates may be incorporated readily into any popular documentation system
Part One covers the development topics from pre-formulation of generic ANDAs to final FDA
filing with the Office of Generic Drugs. Each chapter details key development steps coupled
with a hands-on development checklists and specification that dovetail with a series of SOPs
on practical generic issues that the FDA review chemists and inspectors routinely address
during an ANDA file review and during pre-approval site inspections (PAIs). Agency site
inspections routinely cover the product development unit or R&D departments, QC and
Analytical Research laboratories, as well as the manufacturing facilities and production
warehouses. During a product-specific pre-approval inspection there is a concentration of
effort by the inspectorate to thoroughly review and evaluate the drug development process
from pre-formulation to pivotal batch.
Topics covered are real life examples from A (actives) to V (validation). Procedures are kept
as simple as possible in order that the checklists and SOPs can be understood by all
departmental personnel concerned. Specifications checklists and SOPs used emphasize
essential procedures or requirements meeting all the published FDA guides and guidelines at
the time of publication Thus the checklists become a first party audit or self-inspection format
for the Standard Operating Procedures.
Part Two is a complete real-life dosage form specific working model of a US (or EU) Generic
Application In the US, it is commonly known as an Abbreviated New Drug Application (ANDA).
In Part Two, the model ANDA (or a model EU dossier) meets the current agency expectations
on content, file assembly and format - the manufacturing data in chapters 11 and 12 are taken
from commercial processes currently in practice as presented in the Ready-to-Go™ 120+ Drug
development know-how series.
3

Handbook of Pharmaceutical xiv Generic Development

 Introduction

Preface
“… getting a generic drug to the market place on time….”

G
etting a generic drug to the market place at the right time is no easy task. The
generic drug product must be approved by the FDA close to the latest patent
and exclusivity expiration date of the innovator drug, if a firm wants to be the
first generic drug product on the retail shelves.
Furthermore the three commercial validation batches should be manufactured, filled
and packed via a full-scale standard production run. The now ready-to-launch generic
drug product must meet all its product specifications and the three commercial
validation lots should be on and real time stability evaluation for at least one to three
months. Should all this work have been completed on time and the manufacturing
facility is in full GMP compliance with all manufacturing and control documentation in
place - then the generic product has been developed ‘on time’.
Getting to this point is a long training and planning operation. That it can be done has
been shown by dedicated and well managed generic-innovative and generic
companies. This handbook is designed to show the key highlights of the essential
training and planning along the way.
It is not a manual on how to pre-formulate or formulate a specific dosage form, more
over it is a handbook on how to plan, manage and deliver all the key ingredients of a
successful generic drug product from pre-formulation to the marketed generic drug -
on time and without a delay in the drug product development process.
The length and breath and importance of preparing a successful long life generic
product for the market place requires much attention to detail. Development must stop
if the product fails an essential intermediate, finished product or stability specification
and continue only after the fault has been isolated and corrected - thus the essential
use of checklists and standard operating procedures in this Handbook. The SOPs are
generic in content, they simply highlight important principles and way points and are
suitable for editing and customizing for the firms own in-house needs.
The FDA file contents and review expectations of the drug product must be well
understood and controlled early in the development process in order to avoid problems
with the approval process and later with the quality and customer acceptance of the
marketed product.
This Handbook emphasizes ‘first party certification’ by in-house auditing and self
inspection programs exhibiting a past systematic QC track record that may help
streamline FDA’s enforcement of drug Good Manufacturing Practices (GMPs).
This handbook was designed to produce a rugged generic drug product - to rapidly
facilitate FDA and pre-approval review and reach the market place on time...
Editor

Handbook of Pharmaceutical xv Generic Development

 Forward

Clear statements, aims, objectives

FORWARD conclusions and results inform the
reviewer of where you are going.
Concise - a report that is succinct and
Thirteen Key Directives to the point is all that's needed.
on Drug Development. Compact, avoid any padding - period!
Controlled prospective protocols and
procedures can be written for most
Directive 1. "Write a clear SOP on drug studies or processes and will produce
development". The goal of drug well-controlled documents.
development is to present a quality Certify & check - review and audit
rugged drug in the overall shortest every document your development unit
development time. If your firm hasn't produces. Sign, date and stamp
clear, concise drug development documents that have passed a careful
procedures and objectives on file, and thorough audit review process.
backed-up with all the necessary
protocols, from cleaning, to process to Directive 5.
"Be innovative and creative"
analytical validation - don't start the
Get your research department to talk to
project until this is done.
the developers, the production people,
Directive 2.
regulatory affairs and lab. analysts. Do
"Run pilot studies - never uncontrolled
not compartmentalise your personnel.
studies" - uncontrolled studies like non-
validated assays may seem cheaper at Cross departmental communication
the time but generally give the wrong imparts development expertise and
guidance. A pilot study to evaluate a builds in genuine product value.
potential bioequivalent product with a Challenge SOPs and procedures with
fully validated analytical assay/ the aim of producing a better product.
metabolite/impurity procedure, prior to Documentation can always be made
the main study - often works out more more attractive and user friendly. Writing
cost effective than plunging into a high procedures using attractive fonts and
cost study without a pilot evaluation. point sizes often invite readership.
Never do uncontrolled studies! Directive 6.
Directive 3. "Be Open and Direct "
"Write and Report Facts Faithfully" Never hide a bad study or cover up a
A failed result is a positive endpoint as it poor result. All test results are valid
may well highlight a wrong development unless an appropriate investigation
route. If the result stays 'failed' after a procedures proves otherwise. Review
full investigation, then report its impact your firm's out-of-specification
and conclusions on the study or process operational procedure, and check that
faithfully. Never average results in order there are no organization omissions…
to bring an out-of-spec-result into Directive 7.
specification. "Investigate all abnormalities"
That's a GLP violation. Test results that are out-of-specification
Directive 4. need formal written investigations based
"Remember the 5C's of documentation” on a Out Of Specification Standard
Each documentation page of a report, Operating Procedure. The result may
protocol, method, or submission file well be a simple sampling or technician
should be like the 5C's of a flawless error. For example - an extraneous peak
diamond (cut, clarity, clear, carat, cost.) that suddenly appeared after many
production manufactured lots

Handbook of Pharmaceutical xvi Generic Development

 Forward

in an HPLC assay spectrum, was found That regulator won't forget you or your
on investigation to arise from a change product line up for review!
in an inactive dye vendor (a new Work with regulators - or they will work
supplier) and not as was anticipated a against you and your product may not
new product impurity or degradant. get to the market place on time.
Directive 8. Treat regulators with respect - as you
"Run a mock PAI against your would like to be treated. Agency official
Application just before submitting." are understanding, experienced
The Drug Application will eventually be professionals whose prime concern is
judged on the acceptability of the product quality and safety.
manufacture, control and testing In any regulatory meeting the only
facilities as documented in the agency
welcome outcome is a win-win scenario.
file and in-house supporting data. Audit
Both parties get what they want.
every facet of the development,
manufacture, control and stability Remember an agency never looses an
procedures of the drug product. Check argument - the product only suffers and
and cross-reference each possible gets delayed due to incomplete data or
submission document against the regulatory requirements.
manufacturing / control and laboratory Directive 11.
files and equipment logs. Build in routine "Talk to the regulators regularly."
self-inspection checks during the Allow regulators to review protocols prior
development process. Formulate this to starting the work. Get their opinion
quality development routine by SOPs and express your concerns openly.
and department audit checklists. Regulators like openness and honesty -
Directive 9. and work well with polite, respectful and
"Make your Application really clear, professional personnel.
concise and user friendly " Directive 12.
Well prepared and assembled print or "Take a hard look a your cGMP's "
electronic files and dossiers are a joy to
The absence of GMP compliance simply
read, review, and evaluate. Use all the
adulterates your drug development
desk top publishing tools to shape your
pipeline. GMP compliance is targeted to
firm's reports as attractive, stimulating,
play a more dynamic role in the drug
and interesting to read and review.
review and PAI process.
A document can entice or repel a reader (Establishment Evaluation System - FDA Drug Center and
simply by its construction - it can also be Office of Regulatory Affairs electronic data sharing)
made a scientific work-of-art. Directive 13.
Directive 10. "Audit everything enthusiastically".
"Treat regulators like your key Leave no audit stone unturned.
personnel treat you" Establish consistent in-house audit self-
Listen to regulators - they too have their inspection programs effective at each
story to tell and may know regulations stage of the drug development pathway.
that you don't. Listen to their concerns At the end of every development report
clearly - it's in your product's interest. submission stage, (refer development
There is no greater achievement in checklist chapter 15), audit the department
satisfying a PAI inspector's requests in and relevant steps concerned.
real-time and in producing the End-of-study auditing is quite ineffective
documentation/data requested - before as early errors or omissions can not be
he leaves the firms' premises. corrected promptly and on-time. 2

Handbook of Pharmaceutical xvii Generic Development

 TABLETS ORAL D o c u m e n t a t i o n CHAPTER 1

Regulatory
‘Sit and review with your regulatory department before you start’

D eveloping successful generic drugs in the least possible time and without
expensive mistakes, requires significant pre-planning with the regulatory affairs
department. Successful generic project managers can visualize all the key
sections of the ANDA submission file, before pre-formulation work has actually been
initiated.
The regulatory department must insure that the innovators’ drug or the reference
listed drug ( R L D ) is suitable for generic manufacture and marketing.
This purpose of this Handbook is to allow the reader to visualize the complete
generic development pathway in a concentrated rational picture.
Review the checklist titled Initial Regulatory Check Prior to Pre-formulation in order to obtain
an initial overview of the forensic regulatory elements.
An early decision on pack type and sizes is required from the marketing and sales
department in order to initiate the product's stability specifications.
Part Two
Part Two of the Handbook of Pharmaceutical Generic Development Series provides
a full scale development of a current US abbreviated new drug application (ANDA)
for the selected dosage form chosen (e.g. tablets, capsules, semisolids, liquids etc.)
In the development ANDA, pages and sections provide an example of each and
every document required to compile and assemble a complete regulatory file for
submission to the FDA’s Office of Generic Drugs (OGD).
The left hand side pages are designed for personal notes, summaries and
explanations on the submitted data forms and tables. These pages are designed for
side-by-side comparisons and ease of viewing. Essential tips and potential traps are
explained in the notes and summaries as well as the common do’s and don’ts
regularly addressed by the agency review chemists in a ANDA / AADA file
submission.
SUMMARY:
◊ Review the ANDA requirements and the relevant guides and guidelines
impacted by the dosage form with the Regulatory Affairs Department

◊ Know all the twenty two (22) ANDA sections in the registration file impacting on
the development, formulation, manufacturing procedures, all intermediate and
final product specifications, pivotal batch, stability requirements, as well as key
regulatory ANDA do’s and don’ts.

◊ Complete the pre-formulation regulatory checklist and discuss and review all
the paperwork required to complete this section successfully.

Handbook of Pharmaceutical Sect:1

1. 1 Generic Development
 TABLETS ORAL D o c u m e n t a t i o n CHAPTER 1

SECTION I
Section One of the ANDA file consists of three documents. A drug developer needs
to understand the information required to accurately compile these three documents
as the information impacts upon the development timeline. These three parts are:.
♦ Cover Letter and Field Letter
♦ Table of Contents
♦ Signed Application Form
Cover Letter
The cover letter should be on the letterhead of the Applicant or the Applicant's Agent
and should state the following particulars:

1. Purpose of Submission 3. Name of Applicant

2. Type of Submission 4. Title of Applicant
• (Original ANDA / AADA) 5. Signature of Applicant (ink)
• (Supplement) 6. Proprietary name (if any)
• (Re-submission) 7. Generic name of Drug
• (Amendment) 8. Number of volumes submitted.

A foreign company will have either a US agent or US subsidiary company to act as

the applicant, especially if the finished drug product is developed and manufactured
outside the US. There is nothing special about this application letter, required on a
standard applicant letterhead and an exact representation of the cover and field
letters are presented in Part II of the Handbook.

Table of Contents
Table of Contents laid-out to the FDA's CDER Guide to Industry Format, (Feb. 1999
Overall ANDA Guideline Requirements) needs to provide rapid access to the twenty
Two (22) sections of the ANDA submission file. A drug developer needs to
understand all 22 sections, in detail, as they contain the overall development,
manufacturing and control data that makes up the entire drug development project.
Careful review of each section and its required contents will aid significantly in the
pre-formulation to final pivotal processes. The overall development report can be
structured on each CMC section highlighting the choices made and work carried out
to fulfill each sectional requirement. The development report is a real-time ongoing
series of procedural reports that culminates in the final collated Development Report.
SIGNED APPLICATION FORM:
Signed Application Form (Form FDA 356h or 3439) with original ink signature
requires all DMF numbers of materials and containers used in the final product
presentation. Also no test results, analysis, or stability results may be submitted from
a QC / QA or R&D laboratory that has not received a FDA Plant DMF number (Note:
- New Revised Form FDA 356h became official from January 8, 1998).
Obtaining DMF numbers from suppliers on time requires advanced pre-planning (up
to three months or more) and scrupulous care should be taken that no Agency
deficiencies or FDA concerns of a recent or overdue nature are outstanding on the
materials or container components being used in the firm's generic formulation.

Handbook of Pharmaceutical Sect:1

1. 2 Generic Development
 TABLETS ORAL D o c u m e n t a t i o n CHAPTER 1

ØCHECK LIST×
CL # HPGD-03-01Y2K

INITIAL REGULATORY CHECK PRIOR TO

PRE-FORMULATION
‘…model examples of each form, report and document are prepared
in Part Two of the Handbook of Generic Drug development… ‘

1. Submission Cover Letter reviewed and draft prepared? qYes qNo

2. Revised Form FDA 356h reviewed (NB: all DMF #’s clearly noted.) qYes qNo
3. Basis for ANDA Submission prepared and reviewed? qYes qNo
4. Is the Patent Certification clear for a generic product development? qYes qNo
5. Patent Certification statement prepared? qYes qNo
6. Exclusivity period has expired and statement prepared? qYes qNo
7. Comparison of your Generic Drug with the chosen Reference Listed qYes qNo
Drug (Select from FDA Orange Book) or original Innovator's product ?
8. Innovators package insert obtained via FOI (insure latest edition)? qYes qNo
9. Innovators package insert has no exclusive indications? qYes qNo
10.Labeling statement on number of strengths and package sizes? qYes qNo
11. Proposed draft labeling for carton prepared (main & side panel) qYes qNo
12. Innovators Insert converted to a generic package insert (remove any qYes qNo
exclusive indications)?
13. Proposed ANDA Package Insert OK (your firm's details added)? qYes qNo
14. Side-by-Side comparison of your firm's and innovator's insert? qYes qNo
15.Repeat check that Innovators Insert is the latest edition and date? qYes qNo
(review FDA Web Site for model insert, check immediately before
ANDA file is submitted to OGD.)
16.Obtain a full set of Jacket Covers (specific colors for file types) from qYes qNo
FDA OGD Offices and review all FDA guidelines for specific dosage
form (IR & CR / MR and DR where appropriate)
17.Review and list all DMF #'s required for early vendor implementation qYes qNo
(Active material suppliers, special excipients, all container-closures specification &
coating materials,)
Footnote :
Footnote : Bold letter in first word indicate that this work must be checked and approved before pre-formulation
qYes qNo
work starts.

Handbook of Pharmaceutical Sect:1

1. 3 Generic Development
 TABLETS ORAL D o c u m e n t a t i o n CHAPTER 1

Do - have a SOP manual in a spiral

bound book form for all key
departments e.g. Pharmaceutical,
Documentation Analytical, Stability, Microbiology,
Quality Assurance and Regulatory
Affairs, for ease of updating and
removing superseded (old) editions.
‘If there is no documentation it’s a rumor; Do - write brief and to the point
If it’s well documented - it’s a fact. ’ SOPs so that they can be read and
understood quickly.
SOP CONTROL Use forms or checklists for extra

S
first
tandard operational procedures for
a generic development unit are the
essential documentation
information and attached to the SOP.
Don’t - have loose lying SOPs
gathering dust on the shelf.
requirements.
Without a functional set of standard Don’t - write a SOP that can not be
development procedures, developing followed - routinely, by all
generic drugs will follow a haphazard concerned.
non-reproducible process. SOPs are Don’t - write long SOPs (about 1 to
efficient and useful instructional and 3 pages is sufficient for the average
working tools. SOP).
Standard Operating Procedures Don’t - write SOPs just to comply
should meet six basic and functional with GMP - use them frequently as
requirements operational and training tools.

♦ SOP Index system Don’t - allow SOPs to become static

documents - review and amend them
♦ an intelligent numbering system regularly as procedures are
♦ standardized format optimized.
♦ approval signatures DEVELOPMENT SOPs
♦ a rapid distribution procedure A development SOP is a protocol or
♦ Annual or biannual reviews summary of the overall generic drug
development process. It acts as a
The SOP index is a list consisting of a guideline or road map for the
SOP reference numbers and the development team to follow to ensure
procedure titles. The SOP number complete product development.
ideally has four components, the
department code (P for pharmaceutics Development SOPs are not a CFR
etc.), the SOP number e.g. (001 to requirement. They are designed for
999), the edition number (01, 02) and rapid and complete generic drug
the last review or the editorial date. development and are significant aids
(e.g. HPGD-02-069Y). to agency staff during pre-approval
inspections (PAIs).
Do’s and Don’ts DEVELOPMENT NOTEBOOKS
Do - make the SOP index an actual Similar to SOPs, numbered and bound
Standard Operating Procedure and development notebooks are essential
change the edition # for each new tools for a structured generic or
SOP modification during the course of innovative development program to
the year. succeed.

Handbook of Pharmaceutical Sect:1

1. 5 Generic Development
 T ABLETS ORAL D o c u m e n t a t i o n CHAPTER 1

Ø CHECK LIST ×
CL # HPGD-02-01Y2K

SOP CONTROL.

‘…failure to follow your SOPs adulterates the product…’

1. Is there an Index for all the Pharmaceutical Development SOPs ? qYes qNo
2. Is this Index a Standard Operational Procedure itself ? qYes qNo
3. Are SOPs correctly organized according to this Index ? qYes qNo
4. Are the SOPs available in the community language(s) ? qYes qNo
5. Do the SOPs have a logical, intelligent SOP numbering system ? qYes qNo
6. Are all SOPs signed and is each signature dated ? qYes qNo
7. Check, if the circulation of SOPs is effective and on-time ? qYes qNo
8. Check that no SOP has a date older than two (2) years ? qYes qNo
9. Check that superseded SOP editions have all been removed ? qYes qNo
10. Check that all department personnel have signed the ‘Agreement to qYes qNo
Comply with SOPs’?
11. Is the effective date of the SOP about 21 days after the last qYes qNo
signature - to allow for SOP training ?
12. Has the SOP been signed by all authorizing parties within 14-21 qYes qNo
days of the first signature?
13. Are the department SOPs - brief, concise and to the point? (select qYes qNo
and review three examples.)
14. Are the ‘responsible persons’ clearly indicated in the SOP's qYes qNo
Responsibility section?
15. Has a product specific ‘Development SOP’ been prepared for each qYes qNo
dosage form under development (i.e. SOP for Tablets IR and Tablets
CR/MR etc.)?
16. Do these ‘Development SOPs’ acts as a blue print for the qYes qNo
development team to follow to ensure complete product development?
17. Does the development team regard ‘Development SOPs’ as qYes qNo
valuable working tools and fail-safe procedural mechanisms?

Footnote : Bold lettering in checklist indicate that this work must be checked and approved before pre-formulation work starts.

Handbook of Pharmaceutical Sect:1

1. 6 Generic Development
 T ABLETS ORAL D o c u m e n t a t i o n CHAPTER 1

signed by a supervisor and then dated.

Development Corrections to notebooks follow the

Correction SOP. All deletions must be
Notebooks readable and no correction fluids (Tipex
fluid or White-out) are permissible.
‘Record every trial formula,
every method used, every
All ingredient weights and measures
result obtained require a check signature at the time of
and every failure.’ measurement. Late signatures are invalid
and are neither GMP or professional.
DEVELOPMENT NOTEBOOKS Development of pre-formulation and
Pharmaceutical development notebooks are development lots do not require strict GMP
essential tools for successful generic drug procedures, however good GMP
development. The Development notebooks development practices enhance the
are bound, numbered, 100 page, hard cover scientific validity of results obtained.
notebooks suitable for a development
laboratory environment. Non-calibrated equipment and poor
process techniques produce questionable
The issue and control of the development
development reports and generic products.
notebooks and the signing procedures after
ANDAs derived from inadequate
each work section is complete is an
development procedures may certainly fail
important control check.
in the market place.
The development notebooks are used to
Development Quality Assurance
record all pre-formulation and product
A well documented, and controlled generic
development procedures. All failed
development unit permits for rapid generic
procedures must be recorded. No product
drug development at the lowest cost.
was ever developed without a number of
reject lots. Meticulously prepared development
Key data recorded in notebooks include : documentation aids in the timely
♦ All ingredient lot # and expiry dates production of rugged generic products
within the allocated development time
♦ Active and excipient sources (supplier) frame.
♦ all pre-formulation formula Good documentation is a cost-and-time
♦ all manufacturing methods used saver and allows for rapid data review
during pre-approval inspections (PAIs), a
♦ Equipment used, speeds and times blessing for agency inspectors, as well as a
♦ All in-process controls proven training record for further
successful generic product development.
♦ all results and observations
♦ all tentative specifications The development notebook is the raw data
source for the ‘Development Report’ and is
♦ All finished product controls an important review document from a pre-
♦ proposed stability specifications approval and regulatory viewpoint. Up to
10% of development and research time
♦ all failed data, and abnormal results should be allocated to fine-tuning
♦ investigations and conclusions development SOPs, notebooks, correct
documentation and team training in their
Each stage and page of the notebook is correct use. 3

Handbook of Pharmaceutical Sect:1

1. 7 Generic Development
 T ABLETS ORAL D o c u m e n t a t i o n CHAPTER 1

ØCHECK LIST×
CL # HPGD-02-01Y2K

DEVELOPMENT NOTEBOOKS.

‘…Sign every stage not every page - check every page and every stage….’

1. Does the R&D unit have bound & page numbered notebooks ? qYes qNo

2. Are the development notebooks signed on every stage & page ? qYes qNo

3. Has each completed section been signed with a check signature ? qYes qNo

4. Has correcting fluid been used to cover up data ? qYes qNo

5. Are data corrections performed according to the SOP ? qYes qNo

6. Are all pre-formulation and development formula numerically recorded ? qYes qNo

7. Do the notebooks record successful and failed development product formula ? qYes qNo

8. Do all calculations have check signatures which are dated. qYes qNo

9. Has the Product Development SOP been complied with during the product qYes qNo
development phase ?

10. Is a process of formula, specifications and process optimization evident ? qYes qNo

11. Do all specifications have an appropriate range, where absolutely needed? qYes qNo

12. Have critical upper and lower range limits been qualified ? qYes qNo

13. Are out-of-specification results investigated and documented ? qYes qNo

14. Are the lot #’s, expiration dates and source of each active and non-active qYes qNo
ingredient used during routinely recorded in workbooks ?

15. Does the development notebook appear suitable as a scientific basis for the qYes qNo
generic drug product ‘Product Development Report’?

Footnote : Bold numbers in checklist indicate that this work must be checked and approved before pre-formulation work starts.

Handbook of Pharmaceutical Sect:1

1. 8 Generic Development
 T ABLETS ORAL D o c u m e n t a t i o n CHAPTER 1

STANDARD OPERATING
PROCEDURE
SOP # HPGD-02-01Y2K

SOP CONTROL AND DEVELOPMENT

NOTEBOOKS
The following Standard Operating Procedures are recommended for a generic
development unit and should be in place prior to initiating product development:

SOP CONTROL
# HPGD-02-01Y2K Indexing procedure for pharmaceutical development SOPs
# HPGD-02-01Y2K Index for pharmaceutical development SOPs
# HPGD-02-01Y2K Signing procedures of pharmaceutical development SOPs
# HPGD-02-01Y2K Standard Operating Procedures - number and format
# HPGD-02-01Y2K Circulation of pharmaceutical development SOPs
# HPGD-02-01Y2K Annual review of pharmaceutical development SOPs
# HPGD-02-01Y2K List of FDA guides and Guidelines impacting on product
development dosage form and type (IR / CR)

DEVELOPMENT NOTEBOOKS
# HPGD-02-01Y2K Issue and use of pharmaceutical development notebooks.
# HPGD-02-01Y2K Signing procedures for development notebooks.
# HPGD-02-01Y2K Development notebooks - review and audit procedures.
# HPGD-02-01Y2K Standard procedures in generic product development.
# HPGD-02-01Y2K Pharmaceutical development notebooks - disposition.

ED. N0: 02 Effective Date: APPROVED:

Replaces Ed 01.
Ed. Status: MM/DD/2000
Operational Department R&D QC QA

Handbook of Pharmaceutical Sect:1

1. 9 Generic Development
 ORAL TABLETS DEVELOPMENT CHAPTER 2

AN OVERVIEW

Developing the Formula

‘…plan the development stages into a Development SOP
- then carefully work the plan of what you are going to do‘…

THE DEVELOPMENT SOP THE DEVELOPMENT REPORT

The development report documents all
T he development SOP is a document
that contains each stage of the
development process of the generic
the results of the development process
as highlighted from pre-formulation to
the pivotal batch filing in the ANDA
drug up to and including the pivotal
batch (submission batch). The development notebooks and
This document brings all the interacting reports provide the basic raw data/
departments, i.e. pharmaceutical, results to the development report.
analytical and stability units together to The development report is completed
form one development program. after the pivotal batch has been
packed, tested and placed on
The overall development procedure accelerated stability.
requires that the product formula, All product specifications and
manufacturing process and controls procedures and qualifications are
and final product specifications completed prior to the start of the
(including stability) are formulated, pivotal batch. Major development stops
optimized and qualified through a at the conclusion of this batch. This
series of upper and lower limit
batch is the ANDA demonstration batch
specification qualifications during the
for filing with the FDA that
overall product development phase.
demonstrates a well developed product
These validation qualifications are formula and process.
demonstrated again for regulatory Scale-Up and Post Approval Changes
purposes as a final single continuous (SUPAC-IR) are permissible after the
process during the manufacture of the pivotal batch but MUST follow the
pivotal batch and demonstrated in the SUPAC rules for each change made.
three validation batches. The three validation batches, - sold as
The validation process shows that all commercial products - demonstrate that
the ranges and limits in a manufactured the formula and process consistently
batch, produce the desired drug give the same product specifications
product according to the written and are comparable to the
specifications. bioequivalency batch (i.e. pivotal).
The development process simply
Optimizations and qualification of establishes the ruggedness or
specification limits and process robustness of the formula, the
parameters are developed before the manufacturing process, the product
pivotal batch manufacture in a specifications and the type of
development batches namely the equipment used. The pivotal and
process optimization and qualification validation batches demonstrate and
batch (PQ). The PQ batch is in fact the then prove the consistency of the
real end point of product development. overall drug product and process.

Handbook of Pharmaceutical Sect:2

2. 1 Generic Development
 ORAL TABLETS DEVELOPMENT CHAPTER 2

ØC H E C K L I S T ×
CL # HPGD-03-01Y2K

DEVELOPING THE FORMULA

‘…combine the development stages into an overall 'Development Report'
- what did you really do?…’

1. Is a ‘Development SOP’ for the specific dosage form available? qYes qNo
2. Does a SOP specifying the contents of a 'Product Development Report'? qYes qNo
3. Is the active ingredient characterized for particle size and bulk density for each qYes qNo
approved supplier (a least two suppliers should be evaluated and approved)?
4. Are the source and supply of the excipients characterized and listed? qYes qNo
5. Is the source and supply of the complete container-closure-system characterized qYes qNo
6. Does the SOP indicate that non-compendial active material assays requires a qYes qNo
validation and stability indicating assay?
7. Does the SOP required full analysis of the Reference Listed Drug (RLD), its qYes qNo
overall impurity and stability profile?
8. Is an historical listing and summary of all experimental batches manufactured qYes qNo
required?
9. Is a multipoint dissolution profile of the product formula at key stages required qYes qNo
and compared to the RLD?
10. Do the manufacturing procedures, process parameters and in-process controls qYes qNo
require optimization and challenges at either ends of the specification's limits?
11. Is a process of tightening and qualifying the product specifications, (based on qYes qNo
batch analysis) evident, as the development process undergoes optimization?
12. Does the development process identify the critical processing steps, for the qYes qNo
process validation protocol, with the potential to affect the product?
13. Are hardness vs. dissolution tests qualified (Tablet Hardness Qualification)? qYes qNo
14. Does the analytical development require a final validated assay and stability qYes qNo
indicating (SI) assay well before running the PQ and Pivotal batch?
15. Are stability study assays of the PO and PQ batch required to be tested by a qYes qNo
validated assay procedure and stability indicating (SI) analysis?

Footnote : Bold numbers in checklist indicate that this work must be checked and approved before formulation work starts.

Handbook of Pharmaceutical Sect:2

2. 2 Generic Development
 ORAL TABLETS DEVELOPMENT CHAPTER 2

Formula Development
‘…research and evaluate the reference listed drug thoroughly…'
ANDA Tablet Preparations Non-active ingredients (excipients)
The development of a single dosage The product formula of the generic
oral tablet requires six key decisions. single dose oral tablet do not have to
This evolves choosing the : - contain the same inactive ingredients
at the same quantities as the RLD as
♦ Reference listed drug (RLD) sterile or semi-solids dosage forms.
♦ Active material (source/supply) The qualitative ingredients are
♦ Non-active ingredients (source/supply) required to be in the OGD Inactive
Ingredient Guide (IIG).
♦ Container-closure system (as RLD) The FDA publish the Inactive
♦ Comparative dissolution procedure Ingredient Guide. Inactive ingredients
♦ Bioequivalence to the (RLD) found in approved oral tablets drug
The RLD is chosen from the FDA products in the US are listed in the IIG.
'Orange Guide' (now on the Internet). The strength (i.e. quantity) of the
(‘Approved Drug Products with Therapeutic inactive ingredient in the product
Equivalence Evaluations’ - Ed. 20th,2000) formula must not be greater than the
Active substance highest concentration previously
The active drug substance is chosen approved in an approved drug product
according to standard criteria. Correct for the same route of administration
choice of active ingredient is critical (i.e. oral route)
and time consuming. Key choosing Several SOP’s have been included to
parameters include :- clarify the choice of inactive
♦ Analytical profile - similar to RLB ingredients for pre-formulation and
under normal and stress conditions. formulation development.
♦ Impurity profile - similar to RLB The choice of a well known excipient
under normal and stress conditions. manufactures with an established
excipient range is very important as
♦ Approved supplier must meet all long term stability, dissolution and
ANDA regulatory documentation aging problems are minimized or
requirements. avoided. Thus source and supply of
♦ Active Material specifications inactive ingredients is paramount.
remain constant - batch-to-batch
Container-closure-systems
(not a R&D lot or non-commercial
The drug product container-closure
batch)
system should be a similar material
♦ Vendor able to supply for the next 8- composition as the RLD container-
10 years at similar specifications to closure system.
material used in actual pivotal The degree of product protection by
batch. the container-liner-closure system
Using the RLD’s Active Material must prevent physical, chemical and
Ideally the same supplier of the active microbiological changes on storage
drug substance as used by the RLD, is and during customer-consumer use.
the most cost-effective in the long (FDA final guidance for industry on container
closure is dated May 1999.)
term, as stability, impurity, and aging
profiles are similar.

Handbook of Pharmaceutical Sect:2

2. 3 Generic Development
 ORAL TABLETS DEVELOPMENT CHAPTER 2

ØC H E C K L I S T ×
CL # HPGD-02-01Y2K

FORMULA DEVELOPMENT
‘…Systematically compare your developing product to the chosen RLD
at all key stages…'

1. Has the Reference Listed Drug (RLD) been chosen from the Orange qYes qNo
Guide?
2. Has the RLD been purchased in all the proposed marketing sizes ? qYes qNo
3. Have different batch numbers (3 lot #’s) of the RLD been purchased? qYes qNo
4. Confirm if the RLD is of recent manufacture (analyze new samples)? qYes qNo
5. Conform that at least 10-20 samples of each RLD lot # and pack size qYes qNo
are available for physical, chemical (assay and impurities), dissolution
and stability testing?
6. Confirm if the RLD has been placed on stability at 40o C for 3 months qYes qNo
for evaluating potential degradation and impurity levels?
7. Confirm if the impurity profile of the RLD has been evaluated? qYes qNo
8. Has reverse engineering of the RLD formula been performed? qYes qNo
9. Have the chosen inactive and maximum strength been cross-checked qYes qNo
in the IIG? (for unique or unusual excipients)?
10. Are the in-actives qualitatively compatible with the RLD for oral use qYes qNo
(composition and strength)?
11 Have the RLD formula been reviewed in the International Drug qYes qNo
Compendia (Italian, French, Swiss) for formula composition data?
12. Has the FOI system been used to gather data on the Innovative qYes qNo
drug?
13. Has a full analytical profile range been determined from analysis of qYes qNo
the various batch lots of the RLD (at least 3 lots #’s for Assay; Content
Uniformity; Impurities; Dissolution)?
14. Has the chosen RLD undergone stress testing to establish the level qYes qNo
of its degradation products?
15. Has a multipoint dissolution of the several RLD batch lots been qYes qNo
evaluated to assess the consistency of the RLD dissolution parameters?
Footnote : Bold numbers in checklist indicate that this work must be checked and approved before formulation work starts.

Handbook of Pharmaceutical Sect:2

2. 4 Generic Development
 ORAL TABLETS DEVELOPMENT CHAPTER 2

STANDARD OPERATING Page 1 of 1.

PROCEDURES
SOP # HPGD-02-01Y2K

FORMULA DEVELOPMENT

The following selected model Standard Operating Procedures are recommended for
a generic development unit : Models of selected SOPs are provided.

DEVELOPMENT SOP
HPGD-02-01Y2K Setting up a General Development SOP.
HPGD-02-01Y2K Setting up a Product Specific Development SOP.
HPGD-02-01Y2K Contents of a Development SOP - (Oral Tablets)

DEVELOPMENT FORMULA
HPGD-02-01Y2K Vendor Certification Requirements for Product Development.
HPGD-02-01Y2K Formulation of ANDA (Oral Tablets) Preparations
HPGD-02-01Y2K Formulation of ANDA to Q & Q Status (Oral Tablets)
HPGD-02-01Y2K Standard Procedures for Generic Product Development

DEVELOPMENT REPORT
HPGD-02-01Y2K SOP for Development Reports.
HPGD-02-Y2K Contents of a Development Report - (Oral Tablets) - Single
dose.
HPGD-02-01Y2K Parameters for Process Optimization and Process
Qualification.

NOTE ON DEVELOPMENT
The intent and purpose of the pivotal batch is as a final demonstration that the
formula, process and controls are well developed and tested during development
stages and really need no significant changes or further process qualification.
However scale-up changes can take place within the SUPAC rules after
manufacturing the pivotal batch.
These SUPAC rules govern the Scale-Up from pivotal (10% or more) to commercial
(100%) and Post-Approval Changes i.e. changes after registration approval has
been given.
[End of Document]

ED. N0: 02 Effective Date: APPROVED:

Replaces Ed 01.
Ed. Status: MM/DD/200Y
Operational Department R&D QC QA

Handbook of Pharmaceutical Sect:2

2. 5 Generic Development
 ORAL TABLETS DEVELOPMENT CHAPTER 2

STANDARD OPERATING
PROCEDURES
SOP # HPGD-02-01Y2K Page 1 of 1

Biopharmaceutical Guidance
FDA Web site Listing of
In Vivo Bioequivalence and In Vitro Dissolution Testing
1. Alprazolam Tablets 19. Hydroxychloroquine Sulfate Tablets

2. Bumetanide Tablets 20. Indapamide Tablets

3. Buspirone Hydrochloride Tablets 21. Ketoprofen Capsules

4. Captopril Tablets 22. Leucovorin Calcium Tablets

5. Carbamazepine Tablets 23. Medroxyprogesterone Acetate Tablets

6. Carbidopa and Levodopa Tablets 24. Metaproterenol Sulfate and Albuterol

Metered Dose Inhalers In Vitro

7. Cefaclor Capsules and Suspension 25. Metoprolol Tartrate Tablets

8. Cholestyramine Powder 26. Nadolol Tablets

9. Cimetidine Tablets 27. Naproxen Tablets

10.Clozapine Tablets 28. Nortriptyline Hydrochloride Capsules

11.Diclofenac Sodium Tablets 29. Pentoxifylline (extended-release)

Tablets

12.Diflunisal Tablets 30. Phenytoin/Phenytion Sodium Capsules,

Tablets, Suspension)

13.Diltiazem Hydrochloride Tablets 31. Pindolol Tablets

14.Flurbiprofen Tablets 32. Piroxicam Capsules

15.Gemfibrozil Capsules or Tablets 33. Potassium Chloride - slow-release

Tablets and Capsules

16.Glipizide Tablets 34. Ranitidine Hydrochloride Tablets

17.Glyburide Tablets 35. Selegiline Hydrochloride Tablets

18.Guanabenz Acetate Tablets 36. Trazodone Hydrochloride Tablets

FDA WEBSITE PROTOCOLS AVAILABLE FROM 12/99

Strikethrough = Removed from FDA List
ED. N0: 02 Effective Date : APPROVED:
Replaces Ed 01.
Ed. Status: MM/DD/200Y
Operational Department R&D QC QA

Handbook of Pharmaceutical Sect:2

2. 6 Generic Development
TABLETS ORAL D E V E L O P M E N T CHAPTER 2

Developing the Formula

‘research and evaluate the generic formula thoroughly’

Product Development Stages for a US Generic

Literature Search: Drug Products with Therapeutic

Equivalence Evaluations " Edition 20
P reliminary activities in a drug
development project start with a
comprehensive review of
(2000) Under the section titled
'Prescription and OTC Drug Products -
authoritative reference books on the Patent and Exclusivity Data', the patent
pharmaceutical and analytical number and patent and exclusivity
parameters and attributes of the chosen expiration dates are obtained. The
drug. latest cumulative index to the Orange
Reference works such as the US Book may be viewed on the FDA home
Pharmacopoeia, (and supplements) page.
B.P., (and addenda) Ph. Eur.; Use patents (i.e. therapeutic uses) are
Pharmacopoeial Forum, Physician's indicated with the symbol "U" followed
Desk Reference; Martindale; Merck; by a number representing a specific
Florey; and Vidal are thoroughly therapeutic use. A corresponding list of
reviewed on physical and chemicals therapeutic uses are given.
aspects of the active ingredient and Exclusivity information for a specific
potential formulations. category is indicated by an abbreviation
An extensive computerized online followed by the date on which the
search relating to the specific drug exclusivity actually expires (NCE - Dec.
substance and the drug product is 30, 2000) NCE = New Chemical Entity.
conducted.
Sourcing of Raw Material:
The USP Supplements and BP Sourcing for a potential suppliers of the
Addenda are carefully screened for new active material.
monographs at regular intervals during At least two approved suppliers of
the ongoing drug development program active material should be qualified.
as a new active monograph may be Request samples from potential
published during the actual product suppliers. Exercised care that the
development stages.
active material samples received
Finally the Innovator's Summary Basis
always represent a production batch
of Approval is obtained via the Freedom
and are not from an experimental batch
of Information Services for data review.
lot where the specifications, physical
Patent Evaluation: (bulk density and particle size) and
The Innovator's overall patent situation chemical (impurity profile), may change
is thoroughly evaluated with special with time. Once a suitable active
reference to product and use patents. supplier has been located sufficient
Exclusivity and Patent data is reviewed material should be ordered to allow for
in the FDA's Orange Book "Approved preliminary pre- formulation
development to begin prior

Handbook of Pharmaceutical Sect:2

2. 7 Generic Development
TABLETS ORAL D E V E L O P M E N T CHAPTER 2

the full analytical testing of the Microscopic observation, although

suppliers sample. This is a time saving mainly used for capsule composition,
device as a full analytical profile (with can give valuable information on
BET, polymorphism evaluation etc.) particle size and crystal shapes.
may take one or two months to fully
Information on the presence of specific
appraise.
excipients can be obtained from
Testing of Active Material microscopic observation. For example,
Sample: the pharmacognosy of Avicel™ and
Initiate chemical evaluation with the different starches have very specific
analytical development laboratory as shapes and are thus easily identified.
per official pharmacopoeia monograph Dissolution Profile
(Pharmacopoeial Forum method, if Perform a 12 tablet dissolution profile
present at time), or alternatively by the using USP monograph and FDA
supplier's test method or a modified in- method or in-house method (which ever
house analytical method based on the is available at the time of testing)
supplier's method and specifications,
where no official monograph exists. First batch of Active Material:
Active Material Release
Marketing input requirements: This initial active material lot is
Based on the Innovator's product released by the Development (or plant
obtained from the market place the QC laboratory if the material is intended
following product presentation for pivotal batches), according to
information is acquired; pharmacopoeia, (or in-house methods
◊ tablet shape, (possible patent on a and specifications in the absence of a
special tablet or caplet shape.) pharmacopoeia monograph). Release
◊ tablet color - individual color for each of material without full monograph
dosage strength testing is allowable if the material is not
◊ proposed code / symbol or lettering intended for a Process Qualification
for punch embossing (PQ) and pivotal batch.
◊ proposed packaging sizes (smallest;
Physical Characterization of
intermediate; and largest pack sizes)
◊ Container - closure types. (glass, Active:
plastic securitainer, blister pack.) A full analytical evaluation of the
approved supplier active material is
Innovator's Tablet Testing: now undertaken that will finally end in a
Physical Testing comprehensive Analytical Development
Physical tests evaluating the Report.
innovator's product for tablet color, Standard physical parameters for
weight, thickness, hardness range, evaluation are:
friability, etc. as well as an evaluation of • Polymorphism
the tablet punch diameter (round) and
shape (caplet) are now undertaken. • B.E.T. surface analysis
Inactive Ingredient Identification • Particle size distribution
Evaluation of inactive ingredients as
used in innovator's product are
• Particle size distribution method
obtained from the package insert, and / development
or the PDR with supporting analytical • Bulk density
and microscopic tests confirming,
where possible, the identification of the • Microscopic observation
ingredients formulated.

Handbook of Pharmaceutical Sect:2

2. 8 Generic Development
TABLETS ORAL D E V E L O P M E N T CHAPTER 2

Chemical characterization: ⇒ Physical properties of tablets:

• Optical rotation
♦ Weight,
• Enantiomeric purity
• O.V.I. testing (organic volatiles) ♦ hardness,
• Impurity profile ♦ thickness,
Evaluation of raw material ♦ friability, dissolution etc.
supplier: Choice of Punch and Die Set:
• DMF availability Ordering of punches, (or dosing disks
• Compliance with USP monograph for capsule filling).
• Impurity profile and stability profile The Pivotal Batch as well as the
Process Qualification batch should be
• Commitment to maintain written compressed on a production (or
physical / chemical specifications production type) machine, e.g.
• Statement of non-patent infringement Manesty™ Fetta P1200™; Kilian
RTS™
Interim analytical and pre- Production supervisors are consulted
formulation development report: regarding the choice of the
The findings of the initial development compression machine. Avoid any
work are summarized and tabulated manufacture with worn-out punch and
into an interim development report, die sets. The Punch Supervisor initiates
covering the analytical and pre- the ordering of the embossed or scored
formulation findings that will eventually punch and die sets suitable for the
form part of the overall comprehensive proposed marketed product. Scoring is
product development report. important. Tablet shape and scoring
can affect the dissolution parameters.
DEVELOPMENT LOTS
Maintaining the proposed marketing
Developing the formula through a
tablet shape is an important factor at
series of mini experimental trials
the dissolution profile evaluation stage.
involves evaluating the type of
granulation process and the physical Analytical testing of tablets /
properties of the granules / tablets caplets:
formed. Steps for the choice of a Dissolution in USP medium and other
suitable process are: relevant media versus innovator's
♦ Evaluation of suitable excipients: product as well as the Uniformity of
♦ Excipient compatibility using DSC Content for low drug active
method and 55o C stability. concentrations are two critical
development parameters. Refer to the
♦ Dry mixing, slugging, milling (dry
USP requirements for Uniformity of
granulation procedures)
Content vs. uniformity of dosage units,
♦ Wet granulation (by low / high shear where the active content is above or
mixer or F/Bed sprayer), etc. below 50 mg.
♦ Determination of granule moisture Active Stability:
content (~1-2%) and temperature Ordering of raw material for Process
setting for testing LOD. (Mettler™,/ Qualification (PQ) and Pivotal Batches.
Computrac™ Infra Red Dryers etc.) On accepting the stability profile data
⇒ Physical properties of granulate: from the active material evaluation,
n Flow, coupled with the results the from the
development lots, the active supplier is
n density, now approved. Order sufficient material
n compressibility for the PQ and Pivotal Lot manufacture.

Handbook of Pharmaceutical Sect:2

2. 9 Generic Development
TABLETS ORAL D E V E L O P M E N T CHAPTER 2

It is important to use same batch of work are summarized in an interim

active material for the PQ and Pivotal process report, outlining the
batch, as these two batches are optimization data for final presentation
somewhat complementary to each other in the product development report.
and form the culmination of the formula PROCESS QUALIFICATION
and process development. (The PQ Batch)
An average of 2-3 months may be The process qualification batch is
required from date of order to receipt of manufactured in order to detect any
approved active material, during this problems that may arise during the
period process optimization batch(es) manufacture of production size batches,
and scale-up work is performed. permitting a timely solution before the
manufacture of a pivotal batch.
PROCESS OPTIMIZATION
The process qualification team and
Process optimization is the process of
production personnel should discuss
fine tuning the manufacturing process
formula and process instructions and
and making minor adjustments to the
decide on optimum batch size, and then
formula or process. It should be
define critical processing steps and test
performed on a larger batch size so that
parameters to be evaluated.
the potential problems of scale-up can
be addressed, as they arise with larger
Master Documentation:
size manufacturing equipment that use The project researcher finalizes the
the same operating principle. Fine tune Batch Formula and Manufacturing
the effects of granulation and Instructions documentation package for
compression parameters may include; signing by the authorizing personnel.
The process qualification team
♦ granulation speeds (i.e. blade prepares the PQ Protocol and consults
speeds (i.e. chopper 1 and II in high
with the analytical coordinator with
speed Granulators -e.g. Diosna™ ))
respect to the analytical testing
♦ number of mixing stages (one or two requirements of the many PQ samples.
for high shear mixing) Production personnel are present
♦ mixing times and overall mixing during the process qualification batch
run, as this process usually mimics
♦ solvent amounts and rate of addition production conditions and acts as a
♦ screen size of granulate (e.g. 0.6-0.8 precursor to the upcoming pivotal
mm) with respect to tablet properties. batch. The suitability of the process
♦ Drying temperature versus LOD documentation package is evaluated
obtained and its effect on granulate during this run. Amendments are added
and tablet properties (capping, flow, where necessary to effect practical
sticking, and hardness). documentation for the pivotal batch.
Upon completion of the process
♦ Blending times (short) - the effect on qualification batch testing, a Process
uniformity, lubricity and dissolution. Qualification Report is formulated.
♦ Effect of hardness on tablet ANALYTICAL TEST METHODS
properties (aging, dissolution,
friability, hardness limits ). FINALIZED
A fully validated stability indicating
♦ Qualify the Hardness Range Limits assay and impurity profile is finalized
♦ Final evaluation of stability profile. prior to executing the pivotal batch. The
analytical methods need to be
Process Optimization Report:
authorized and signed prior to the date
The findings of the process optimization
of the actual pivotal manufacture.

Handbook of Pharmaceutical Sect:2

2 . 10 Generic Development
TABLETS ORAL D E V E L O P M E N T CHAPTER 2

biostudy protocols on specific drug

PIVOTAL LOTS actives on the FDA CDER home page.
Based on the PQ batch results and Where possible consult these protocols
amended documentation, the pivotal lot with care prior to the bioequivalence
is now prepared. In the manufacture of evaluation.
the Pivotal Batch, a minimum of 100
000 (net) dosage units are required. Pivotal Sampling & Testing
Some firms prepare documentation for The sampling and testing procedures for
100 000 dosage units gross, ignoring the pivotal batch hold a special regulatory
significance. The pivotal batch represents
the fact that there may well be 2% to
the documented batch that is filed with
5% production losses. The net batch
the FDA's Office of Generic Drugs, as well
yield turns out to be 98 000 or 95 000
as being the batch representing the
dosage units well below the 100 therapeutic bioequivalence of the drug
thousand net required by FDA’s Office product when compared against the
of Generic Drugs (OGD). reference listed drug (RLD) or the
Capsules may have a greater innovator's own drug, during the biostudy.
manufacturing loss than tablets - thus it is Under these circumstances, the need
prudent to scale the pivotal batch for at for a fully representative sampling and
least 110 000 dosage units. Remember
testing procedure, as required by GMP,
the pivotal batch may range from 10% net
is achieved by a specific written
to 100% (i.e. full size) of the proposed
'sampling and testing' protocol. This
commercial batch size.
special batch has both legal and
Experienced Generic firms who do not
anticipate any problems with the pivotal regulatory aspects in the eyes of the
documentation often target the pivotal FDA - sampling must not only be done
quantity to 70% of the proposed but seen to be done (i.e. via a well
commercial lot thus achieving appropriate written protocol).
scale-up and pivotal in a single batch. DEVELOPMENT REPORTS
Packing the pivotal batch. Firms should have a well structured and
The Pivotal batch needs to be fully assembled Product Development Report.
packed in the proposed marketing packs Although not a FDA 21 CFR regulatory
(OGD rules). Frequently the pivotal batch requirement, a functional Development
is packed into 2, 3 or 4 different pack Report will certainly go a long way to
types and several different pack sizes convince the reviewers of a fully justified
and closure combinations. (combinations overall process that consistently produces
of glass, HDPE, Clicloc™, plastic, metal the desired end-product.
caps, or Al foil/blister packs etc.) The Development Report is the basis
The tablet / capsule trail documentation on which the validation protocol is
identifies the exact quantity packed into designed and structured, without it
each container-closure system. The validation may well be incomplete or
overall packaging should total to 100% of problematic.
the net pivotal batch. Development reports are required to be
At least 15-20 % of the exhibition (pivotal) seen by the site inspectors at the
batch should be packed into each product specific pre-approval inspection
container-closure category. (PAI visit). The preparation of a Product
BIOSTUDY Development Report should be based
Bioequivalence evaluation on all the interim reports prepared
The pivotal batch samples are used to during the development work, including
perform the bioequivalent study. The FDA analytical reports and where well
displays a list of about 30 - 40 model prepared, assembled and structured -
oil the review process - immeasurably.

Handbook of Pharmaceutical Sect:2

2 . 11 Generic Development
 TABLETS ORAL D E V E L O P M E N T CHAPTER 2

PRODUCT DEVELOPMENT FLOWCHART

Solid, Dosage Forms

APPROVE
STAGE 1 a minimum of
LITERATURE TWO
SEARCH SUPPLIERS

STAGE 2
ACTIVE SOURCING
Q3A
Impurities cf.
STAGE 3 innovator's profile
Do not evaluate ACTIVE EVALUATION
material while still
in a R&D
STAGE 4
stage.
ACTIVE PURCHASING
USE ONLY
PRODUCTION
ACTIVES
STAGE 5
Active testing

STAGE 6
Innovator Product Purchasing

Purchase a new
STAGE 7
lot number every 3 months
Innovator Product Testing
from the smallest to the
largest pack size
(in each dosage strength)
STAGE 8
Bulk Active Testing

STAGE 9 Q3C - Residual

Solvents Check
DRUG Excipient Evaluation

DEVELOPMENT
21 STAGES STAGE 10
Container Closure
System Choices

STAGE 11
Manufacturing Process Evaluation

STAGE 12
Bulk Active Purchase

Handbook of Pharmaceutical Sect:2

2 . 13 Generic Development
 TABLETS ORAL D E V E L O P M E N T CHAPTER 2

PRODUCT DEVELOPMENT
FLOWCHART
Solids Dosage Forms

STAGE 13
Analytical Evaluation

STAGE 14
Process Optimization
PO Batch

STAGE 15.
Prepare full Written SCALE - UP
Protocols for PO
Scale-Up & PQ STAGE 16
Batches PROCESS
(Future Q6A
QUALIFICATION
Requirements will impact
on this development)
STAGE 17
PIVOTAL BATCH
PRODUCTION

STAGE 18
ANDA PRE-SUBMISSION
AUDIT

Review all raw data

STAGE 19 Development & Lab Notebooks
ANDA SUBMISSION Evaluate all interim reports
that form part of the
Product Development Report
19B
PRODUCT
DEVELOPMENT
REPORT
STAGE 20
Process Validation &
Statistics
(3 commercial lots)
STAGE 21
Process Revalidation
after a major change
Process validation lots (Check SUPAC)
signify the first THREE
consecutive production
lots.
(Same Batch Size and
Active Lot No:)

Handbook of Pharmaceutical Sect:2

2 . 14 Generic Development
 ORAL TABLETS DEVELOPMENT CHAPTER 2

PRODUCT DEVELOPMENT GUIDE

PRE-FORMULATION - TABLETS
Introduction
Guidelines for the development of a ANDA product for the US market, Note: some tests or
procedures may be unnecessary. The order of performing the various stages may change
depending on the product under development. These guidelines may be modified for other
geographic zones.
Development Stage Scope of Product Development

Stage 1 Literature Search

Literature Research USP BP Pharm. Eur, PDR, Martindale, Merck, Florey, Vidal
FDA - FOI Summary Basis of Approval
On-linecomputerized Electronic Data Base (articles and publication on test methods,
search Dissolution synthesis procedures, drug impurities,
pharmacokinetics and dynamics)
FDA CDER Evaluation of Biostudy parameters, Dissolution methods.
Patent evaluation Orange Guide + FDA CDER WWW Patent Consultant
Stage 2 Active Sourcing
Sourcing for Active International Suppliers US, European, Asian, e.g. (ACIC-Canada)
Raw Material (AllChem-UK) (Lek-Czech), (Esteves; Moehs; Uquifa-Spain);
(Biopharma, S.I.M, Midy-Italy) (Chemcaps, Reddy; Tricon-India);
(Federa-Brussels) - Review suppliers catalogues & data critically.
Potential Suppliers List Request samples and C of A and Specifications
Evaluate at least two suppliers fully.
Stage 3 Active Evaluation
Evaluate Potential Evaluate at least two to three potential active suppliers
Actives • DMF availability
• Compliance with USP monograph
• Impurity profile and stability
• Potential Polymorphic forms
• Commitment for physical specifications
• Statement of non-patent infringement
Stage 4 Active Purchasing

Purchase (Potential) Evaluate at least two potential active material suppliers for
Active Material approved supplier status
Stage 5 Active Testing
Testing of Active Chemical testing by the R&D analytical lab as per
Material sample a. Pharmacopoeia monograph (if present)
b. Pharmacopoeia Forum (if available)
c. In-house method (based on manufacturer)
d. Supplier's test methods and specifications

Handbook of Pharmaceutical Sect:2

2 . 15 Generic Development
 ORAL TABLETS DEVELOPMENT CHAPTER 2

PRE-FORMULATION
Development Scope of Product Development
Stage
Stage 6 Innovator's Product Purchasing
DRUG PRODUCT Purchase at least 3 different lots in smallest and largest pack size
Innovator Samples for each product strength

Stage 7 Innovator's Product Testing

Innovator Testing Evaluate physical parameters:-
tablet shape, tablet color, code for punch embossing, pack sizes
containers materials, closure types; cotton and desiccants.
Innovator Physical Physical testing
Testing Weight; Thickness; Hardness; LOD; Friability; Disintegration:
Evaluation of tablet punch; size; score; embossing and shape
Evaluation of Innovator Summary Formula in PDR; International PDRs (Italian, French,
formula ingredients Swiss) and Innovators product's insert (obtain latest FOI -FDA)
Perform actual analytical testing on innovator's product.

Microscopic Particle/crystal information on

observation Particle size
Crystal shape, habit,
Differentiation on the presence of specific excipients can be
verified from microscopic observation. E.g., Cross-linked
cellulose's Starch and Avicel have a specific shapes and
morphology and maybe easily detected.
Evaluation of Biostudy Review FDA CDER Home page for listing and Biostudy
parameters parameters

Dissolution profile USP monograph and FDA method - (where present)

Dissolution; 12 unit Dissolution Profile.
Stage 8 Bulk Active Testing
FIRST BATCH FROM Physical characterization of bulk batch
APPROVED SUPPLIER • Polymorphism
Full Physical • B.E.T.
characterization • Particle size distribution (& method development)
• Bulk density;
• Microscopic observation

FULL CHEMICAL Chemical characterization

CHARACTERIZATION • Assay
• Stressed Analysis
• Degradants (Expected)
• Impurity profile
• Optical rotation
• Enantiomeric purity
• O.V.I. Testing

Handbook of Pharmaceutical Sect:2

2 . 16 Generic Development
 ORAL TABLETS DEVELOPMENT CHAPTER 2

DEVELOPMENT BATCHES
Development Stage Scope of Product Development
Stage 9 Excipients
Evaluation of formu-
Excipient compatibility using DSC methods and stability
lation with suitable
assessment
excipients
Stage 10 Container Closure System
Evaluation of suitable Choice of container-closure-liner system including:
Container-Closure • material composition,
System • type of thermoplastic resin and resin pigments,
• manufacturers and suppliers,
• liners and seals used by closure manufacturer,
• cotton and desiccants.
• manufacturer's DMF numbers for all component parts
• Letters of Access for regulatory authorities to view DMF dossiers
Stage 11 Manufacturing Process

EVALUATION • Wet granulation (aqueous or non aqueous)

SUITABLE high shear mixing / low shear mixing
MANUFACTURING • FBD spray procedure), or
PROCESSES • Dry mixing, dry granulation and/'or Slugging
• Determination of order of mixing
Wet Granulation • Determination of pre-mixing (in Granulator)
• Determination of fluid addition (if relevant)
Dry Granulation • Determination of granulation time (chopper I & II)
• Determination of torque end-point value
Slugging and Dry • Determination of Drying parameters
Granulation • Determination of LOD limits
• Determination of testing temperature for checking LOD limits
(State machine used e.g. Mettler™, Computrac™).
• Flow properties,
GRANULATION • Density,
Physical Properties of • Particle-size distribution
Granulate • Compressibility
Compression • Weight, • Hardness,
Physical Properties of • Thickness, • Friability
Compressed Tablets • Disintegration • Dissolution
Final Formula Assessment of Final Master Formula and accelerated 1-3 month
Established stability profile.
Stage 12 Bulk Active Purchased
Active material Ordering of Active material for Process Qualification (PQ) and
Bulk purchase Pivotal Batch(es).
On approval of final formula, order sufficient material for the PQ
(2) and Pivotal Lots (sufficient for all strengths and batch sizes).
NB: Never mix batch numbers in PQ and Pivotal Lots.

Handbook of Pharmaceutical Sect:2

2 . 17 Generic Development
 ORAL TABLETS DEVELOPMENT CHAPTER 2

FULL LABORATORY EVALUATION

Development Scope of Product Development
Stage 13 Analytical Evaluation
Analytical testing of • Dissolution - in USP medium (Multipoint profiles) and other
tablets/Caplets relevant media versus Innovator's product
• U of C-for low active concentrations. Refer to USP requirements
for uniformity of content vs. uniformity of dosage units.
• Validation of analytical package i.e. Assay; Dissolution ; Content
Uniformity completed prior to Process Qualification

PROCESS OPTIMIZATION
Development Scope of Product Development
Stage 14 Process Optimization
GRANULATION • Effect of granulation parameters
OPTIMIZATION
• Granulation time
• Speed of choppers (I & II) or mixer blades
• Solvent addition rate and overall amount
• Ratio of intra-granulate Disintegrant and binders agents
• Screen size for milling (e.g. 0.6 or 0.8mm)
• Adjusting mill screen size up or down to fine tune hardness
• Evaluation of optimized granulate and tablet attributes
DRYING • FB Drying temperature versus target LOD and range limits and
the effect on granulate and tablet properties (flow, capping,
sticking).

BLENDING ◊ Blending times

◊ Lubricant Split into two parts (pre-blending and final blending)
◊ The effect on Content Uniformity, Granule lubrication and
Dissolution profile.
◊ Evaluation of unit dose sampling vs. Content Uniformity

COMPRESSION ∗ Effect of hardness on tablet properties (aging, dissolution,

friability).
∗ Evaluation of Hardness Range Limits
∗ Evaluation of stability results of optimized mfg. process
PROCESS ∗ Prepare PO Report. This Process Optimization Report forms
OPTIMIZATION part of the product Development Report
REPORT

Handbook of Pharmaceutical Sect:2

2 . 18 Generic Development
 ORAL TABLETS DEVELOPMENT CHAPTER 2

ESTABLISHING AND INVITRO INVIVO CORRELATION

Development Scope of Product Development

Stage 15 Analytical Evaluation
IVIV Correlation • Dissolution - in USP medium (Multipoint profiles) and other
relevant media versus Innovator's product.
• Perform IVIV Bioavailability Study (where relevant)

Establish a Level A or C correlation without adjusting dissolution

parameters and time scale
• Adjust the dissolution parameters or time scale to achieve a
Level A or C correlation (adjust only if necessary)

SCALE UP
Development Scope of Product Development

Stage 16 SCALE UP
Scale-up Scale-up lot prepared if larger batch size scale up problems
anticipated.
Process Qualification batch and Scale-up batch may be
evaluated as a single batch.
Scale-up Report The preparation of a Scale-up Report. The Scale-up report forms
part of the overall Development Report

PROCESS QUALIFICATION
Development Scope of Product Development
Stage
Stage 17 Process Qualification

The process qualification batch is manufactured in order to detect any problems that may arise during
the manufacture of production size batches, allowing a solution prior the manufacture of the pivotal
demonstration batch. Scale-up to the pivotal batch size or 70% of the pivotal batch may be combined
with qualifying the manufacturing process At this stage full manufacturing documentation is prepared
alone standard procedures.
PRODUCTION Process Qualification batch should be compressed in a production
FACILITIES (or production type with same principle and operation) tabletting
machine

Size of pivotal and marketing batch confirmed (NLT 100 000 net/
packed at target parameters or 10% of proposed market batch).

BATCH Preparation of Master Formula and Processing Instructions

DOCUMENTATION
Discussion of formula, manufacturing process and control
parameters with production personnel and QA Staff

Handbook of Pharmaceutical Sect:2

2 . 19 Generic Development
 ORAL TABLETS DEVELOPMENT CHAPTER 2

PROCESS QUALIFICATION
Development Stage Scope of Product Development
Stage 17 (Cont) Process Qualification

FINAL REVIEW and Review of proposed formula, manufacturing process and control
AUTHORIZATION parameters with production personnel and QA Staff with
authorization signatures (RD; QA-QC; RA; and Production)

PROTOCOL PQ. protocol prepared

KEY STEPS Critical manufacturing steps designated and sampling and testing
parameters specified.

OPERATING Presence of production and control personnel during PQ

CONDITIONS manufacture

P.Q. REPORT Upon completion prepare Process Qualification Report. This P-Q
report forms part of the overall Development Report
PIVOTAL BATCH
Development Scope of Product Development

Stage 18 Pivotal Production

PRODUCTION Pivotal batch MUST be compressed in a production tabletting
FACILITIES machine (or production type with same principle and operation)
BATCH Preparation of FINAL Master Formula and Processing Instructions
DOCUMENTATION
REVIEW and Review of FINAL formula, manufacturing process and control
parameters with production personnel and QA Staff. Pivotal
AUTHORIZATION
authorization signatures (RD; QA-QC; RA; and Production)
attached.
OPERATING Operation of production and control personnel during Pivotal
CONDITIONS manufacture, aided by development team.
REPORT The preparation of a Pivotal Report. This pivotal report forms part
of the overall Development Report.

BIOEQUIVALENT STUDY
Stage Scope of Product Development
Stage 19 BIOSTUDY Evaluation
BIOSTUDY Fasted Perform Fasted / Food Effect Biostudy on Pivotal Lot Samples
BIOSTUDY Perform Food Effect Biostudy on Pivotal Lot Samples (See food
[Food Effect] effect guidelines, where appropriate)
HIGHEST DOSAGE Biostudy generally performed on highest strength of product
One or two studies Fasted AND Food Effect Study may be required
WAIVER For multiple strength products Invitro dissolution testing conducted
CONDITIONS in three different pH media on lower dosage forms
SIMILARITY TESTING Perform Similarity Test [F2 Test] on dissolution results.

Handbook of Pharmaceutical Sect:2

2 . 20 Generic Development
 ORAL TABLETS DEVELOPMENT CHAPTER 2

PRE-SUBMISSION AUDITING
Development Stage Scope of Product Development

Stage 20 ANDA Pre-Submission Auditing

Development Report Audit all raw data supporting Development Report

ANDA Regulatory File Audit Plant and Laboratory Documentation as per ANDA

SOPs Review SOP System and Update level

cGMP Review cGMP of Manufacturing Processes

Biostudy Report Evaluate and develop a IVIV correlation (Level A where possible.)

Validation Protocol Product Process Validation Protocol complete and signed

ANDA SUBMISSION
Development Stage Scope of Product Development
Stage 21 ANDA Submission

ANDA Submission Submit ANDA structured as Part Two of this Handbook

(9 Copies -as per Color system)

(1 Field Copy)

VALIDATION BATCHES
Development Scope of Product Development
Stage

Stage 22 Process Validation

Protocol Process Validation Protocol for 3 consecutive marketing lots

Execute validation Process Validation of 3 consecutive marketing lots

Report Process Validation Report

Similarity Show intra-batch similarity

Bio-Validation Show inter-batch similarity between Biobatch (Pivotal) and the

Similarity Commercial Validation Lots

Handbook of Pharmaceutical Sect:2

2 . 21 Generic Development
 ORAL TABLETS DEVELOPMENT CHAPTER 2

COMMERCIAL RE-VALIDATION
DUE TO MAJOR CHANGE
Development Scope of Product Development
Stage

Stage 23 Process Re-validation

Formula Change Revalidate procedure with new formula process or equipment with

Process Change a different operating principle

Equipment Change

Minor change Follow SUPAC Rules Level I II or III

IMPORTANT NOTE ON DEVELOPMENT

Developers are encouraged to develop IVIVC for IR dosage forms, where applicable
to the BCS, (Biopharmaceutical Classification System) in the expectation that the
information will be useful in establishing appropriate dissolution specifications and
thus permit certain post approval formulation and manufacturing changes to be
effected, - without additional bioequivalence studies.

The objective of developing an IVIVC is to establish a predictive mathematical

model describing the relationship between invitro dissolution settings and the actual
invivo drug-plasma parameters found, (such as AUC, Cmax, Tmax).

The invitro dissolution settings are adjusted (via media, pH agitation) until a I : I
correlation is achieved (Level A) or a single dissolution point and a plasma
parameter is shown to correlate (Level C).
When more than one point correlates a multiple Level C is obtained - which may
possibly be upgraded to a Level A with additional development work.

This matching of dissolution settings with plasma levels, that are derived from a
specific IR formula and its corresponding manufacturing process, is in fact simply an
arbitrary set of values that establish the so called 'predictive mathematical model'.

An IVIVC should be evaluated to demonstrate that predictability of the invivo

performance of the drug product (i.e. derived from the plasma parameters) from its in
vitro dissolution characteristics (e.g. equipment settings / and manufacturing
changes) is maintained over the product's dissolution profile

Handbook of Pharmaceutical Sect:2

2 . 22 Generic Development
ORAL TABLETS DEVELOPMENT CHAPTER 2.

DC TABLET DEVELOPMENT

D irect Compression
Tablet Development
‘…Developing low strength actives via direct compression
is often the preferred route…

OVERVIEW Wherever possible the use of

geometric proportioned DC mixtures
T ABLET DEVELOPMENT of low
strength drugs may follow two
processes, either by traditional
reduces the number of bioequivalent
studies necessary, as a waiver may be
obtained for the lower dosage
alcoholic or aqueous wet granulation
strengths.
techniques or via the simpler direct
compression mode with marginally DESIGNING DC FORMULATIONS
faster dissolution rates. Keeping direct compression
Dosage strengths with 1 to 10 mg per formulations simple and elegant
100 or 150 mg tablet are considered require four basic elements - namely.
suitable drug candidates for the direct n Choice of the Direct Compression
compression development route. excipient blend (SDL/MCC);(SDL/CM).
Where the tablet strength exists as
two strengths e.g. Bupirone 5 & 10 mg n Choosing geometrical proportioned
tablets, the ten milligram strength mixes for multiple tablet strengths.
tablet may be developed from the n Choice of ideal tablet weight
same direct compression blend where
n Designing and optimising the
a geometric proportioned amount
tablet's physical specifications, for
(double) is used for compressing the
weight, hardness, friability,
higher dosage strength.
disintegration, dissolution and film
Low tablet fill weight variations are coating for light protection).
easily obtained. Typical overall tablet
Table 2.
weights for 1 to 5mg active drug in DC
formula, range between 100 -150 mg. Direct Compression Design
and for 10mg actives up to 200mg. Parameter Decision Range
In geometrically scaled-up formula the
Key Standardise
tablet weight is doubled i.e. 200 to 300
Excipient blend for DC formula
mg per unit.
Tablet Weight 100 - 280 mg
Table 1. Multiple strength geometric design
Direct Compression Tablet Hardness 5-9 SCU
Tablet Strength Tablet Weight Disintegration <5 min
1 - 5 mg 100 - 140 mg Dissolution Rapid
6 - 10 mg 200 - 280 mg Thickness 2.5 - 4.0mm
20 mg ±300 mg Friability < 1.0%

Handbook of Pharmaceutical Sect:2

2 . 23 Generic Development
ORAL TABLETS DEVELOPMENT CHAPTER 2.

CHOOSING THE FORMULA DIRECT COMPRESSION MIXTURES

IDEAL PROPERTIES
n Choice of the Direct Compression
'excipient blend'. Directly compressible excipient blends
THE percentage of the active should have the following properties:-
ingredient in the overall direct Ü A directly compressible shape/size
compression formula for 1 - 10 mg Ü Produce low tablet ejection forces
strength tablets varies from 0.7% to
10% (see table 10 and 11). Ü Capable of a high dilution potential
The active material's particle size and Ü Free flowing and easy to handle
bulk / tapped density are significant Ü Lubricant insensitive
parameters in DC formulation. Ü Good dry blending properties
By reducing the percentage active per
tablet (i.e. increasing tablet weight) Ü Narrow particle size distribution
the surface phenomena of the Ü High water solubility
physical parameters of particle size Ü Non hygroscopic (or very low)
and density are fundamentally
reduced. This is an important factor
Ü Inert & chemically stable
when active materials have a low bulk The DC mixture should be readily
density or a particle shape that mixes compressible with a high dilution
poorly. potential (with and without) the active
However decreasing the percentage material producing a rapid
active per tablet requires optimum disintegrating tablet (less 3-5 minutes)
mixing and blending techniques. with an optimum target hardness of
Poorly flowing actives may be reverse about 6-9 SCU and showing a rapid
blended to improve flow properties. dissolution profile, almost equal to the
Reverse blending (formula A & B) solubility of the pure active material
required mixing the glidant, talc (and under the same dissolution conditions.
part lubricant) with the active and Tablet thickness and diameter
thereafter blending with the direct depend on the die chosen to meet a
compression excipients. thickness of between ± 2.5 and 4.0
The direct compression method mm.
involves mixing the drug substance Direct compression mixtures comprise
with the excipient blend so that the of three essential parts;
mixture on compression into tablets
will meet the desired finished product Ü Readily compressible excipient/
specifications as highlighted in table diluent with superior flow and
2. Homogeneity of the unlubricated compressible properties (e.g. SDL /
mannitol / lactilol etc.)
mixture, prior to the addition/blending
of the lubricant is usually qualified Ü DC dry binder and disintegrating
during the development stage. agent (e.g. MCC / CM)
This key process obviates the need
for excessive mixing after the addition Ü A lubricant / glidant package
of the lubricant which may impact on Spray dried lactose (SDL) or regular
the dissolution profile.
monohydrate lactose (100 or 200
Homogeneity testing prior to addition mesh) are diluting DC agents and
of the lubricant is omitted in routine perform well in mixing and blending
commercial production once this operations in amounts from 30 -60%
content uniformity step has been (used for lower cost of formulations).
qualified and validated.

Handbook of Pharmaceutical Sect:2

2 . 24 Generic Development
ORAL TABLETS DEVELOPMENT CHAPTER 2.

Finlac DC™ - Microcrystalline Lactilol (MCL)

Lactose, as spray dried lactose (SDL) Xyrofin UK)
or monohytrate lactose is one of the Mannitol DC™ - Mannitol USP granular (M)
most commonly used tablet diluents.
Avicel pH 101 / 102 compress well
For direct compression formulation
with superior disintegration abilities
spray dried lactose is preferred
(when used at either 15, 30, or 60% -
because of its superior flow and
but generally a higher unit cost).
compression properties. The table
Equivalent results are obtainable by
below shows the ratio of lactose types
substituting a 1:1 ratio (equal parts) of
to microcrystalline cellulose (MCC).
crystalline maltose and micro-
Table 3. crystalline cellulose.
Lactose : MCC Ratios Table 5.
Non-active : Cost % per tablet Binder/Disintegrant Excipients
SDL/MCC : High 30 : 60 Non-active % per tablet
Avicel pH 101 30 - 50
SDL/MCC : Low 60 : 30
Avicel pH 102 15 - 30 - 65
SDL/MCC : Medium 50 : 50 Advantose™ 100 30 - 65
MHL-100/MCC : Low 30 : 60 Advantose™ 100 15 - 30
Avicel pH 101 15 - 30
MHL-200/MCC : Low 60 : 30
Avicel pH101™ - microcrystalline cellulose (MCC)
Advantose™ - crystalline maltose (CM)
For 'fine particle-size actives', 200
Where necessary suitable additional
mesh monohytrate is more suitable
direct compression disintegrants such
and with 'granular actives' the 100
as sodium starch glycolate (2-4%) or
mesh monohytrate is generally
'dried' starch NF (~3% to 5%) promote
preferred for the blending stage.
rapid tablet disintegration and allows
Microcrystalline lactilol (a faster drug release. Where Mannitol
disaccharide sugar alcohol derived DC formulations tend to increase the
from lactose) may be substituted in dissolution time on ageing (shelf life
lieu of lactose. Marginally harder period), sodium starch glycolate
tablets are produced at the same (SSG) is recommended (at about
compression strength. Since 4.0%).
microcrystalline lactilol has a lower Table 6.
moisture pick up and lower Additional Disintegrant
hygroscopicity, shelf life extension is Non-active % per tablet
promoted when used with active
materials sensitive to moisture pick-up Sodium starch glycolate 2.0 - 4.0
over the shelf life testing period. Starch NF (dried) 3.0 - 5.0
Table 4.
DC Bulking Excipients Lubrication/Glidant
Magnesium stearate (MS) is the most
Non-active % per tablet
commonly used lubricant in direct
Lactose 100 NF 50 - 60 compression tablet formulations.
Lactose 200 NF 25 - 60 0.5% concentration is a typical level of
Spray dried lactose 30 - 65 lubrication. Since lubrication is a
surface phenomenon it is important to
Lactilol - Finlac™ DC 30 - 65
introduce a range of magnesium
Mannitol DC 30 - 65 stearate from 0.5 to 1.0% in the

Handbook of Pharmaceutical Sect:2

2 . 25 Generic Development
ORAL TABLETS DEVELOPMENT CHAPTER 2.

formulation. The 0.5% level is Note:- Vegetable grade magnesium

generally intended for routine stearate NF is a certified food grade
commercial production. However in vegetable derived stearic acid - 99.9%
certain atypical situations the passing 325 mesh (no BSE origin).
lubrication requirements of a specific Table 7.
batch lot may be higher due to the Lubricant Package
higher surface area of the component
Non-active % per tablet
powder ingredients.
Magnesium stearate 0.6 - 1.2
It is therefor important to allow for an
increased level of lubrication up to Aerosil 0.5 - 0.8
1.0%. The lubrication range must be Talc (glidant) 2.0 -2.5
qualified, i.e. not to alter/affect the
dissolution rate or any other tablet Magnesium stearate / 0.4 -0.5
specification parameter. Stability data Stearic acid (1:1 ratio) 0.4 -0.5
should show that the dissolution rate 1
Ferro Corporation Walton Hills Ohio
of tablets processed with 1.0% (Synpro®)
Magnesium stearate is no different to
tablets made with 0.5% lubricant at TARGET PROCESS PARAMETERS
target speeds. In the current climate of Directly compressible formulations
global marketing a vegetable grade of may require critical process
magnesium stearate should be used. qualification during the overall product
development phase.
In active materials with a low bulk
density (<0.4g/mL), talc (1-2%) may Ü Active particle size / bulk density
be used as a glidant and densifier. specifications (target values & limits)
Magnesium stearate NF (vegetable
grade1) and colloidal silicon dioxide Ü Optimum mixing time for the
(CSS - Aerosil) usually provide an 'unlubricated powder blend'
optimum lubrication package. Ü Optimum 'unlubricated blend'
Magnesium stearate may usually be content uniformity qualification
substituted for equal parts (1:1) of
magnesium stearate and stearic acid Ü % Lubricant range qualification
producing equivalent lubricant effects. Ü Lubricant blending time (content
Since lubrication is a surface uniformity qualification of end mix)
phenomenon, specific to the tablet
edges (i.e. die wall-effects on ejection) Ü Hardness range qualification with
lower levels of lubricant can be used dissolution tests results
when compressing smaller tablets of GEOMETRIC GRANULATES
100 to 160 mg weight especially when n Choosing geometrical proportioned
used with concave punches producing blends for multiple strengths
biconvex tablets. preparations is the recommended
Different vendor sources of excipients development strategy for direct
including the lubricant should be compression tablet formulations.
evaluated and found to be Bioequivalent waiver applications for
comparable, via end specifications the lower strength formulations is
and stability testing, especially when standard development procedure
commercial production may be while the highest strength preparation
effected at several non-related is evaluated for bioequivalency
manufacturing sites. against the reference listed drug.

Handbook of Pharmaceutical Sect:2

2 . 26 Generic Development
 ORAL TABLETS DEVELOPMENT CHAPTER 2.

DIRECT COMPRESSION ADVANTAGES PRODUCT SPECIFICATIONS

n Choice of physical tablet
n Direct compression dry blends are
specifications (e.g. hardness, friability,
generally superior in dissolution than
thickness, disintegration, dissolution).
the equivalent wet granulation
Choosing a DC blend based on tables
formula, that include wet granulation
10 and 11 will produce a compressed
preparations incorporating up to 4% of
tablet within the target specifications
the super-disintegrants
as indicated in table 2. Hardness 6-9
croscarmellose and crospovidone.
SCU (at low, target and high speeds),
This in conjunction with the Disintegration <1-3 minutes, friability
processing advantages offered by the <0.5%, thickness 2.5 - 4.0mm.
direct compression process, leads DC Formulations in table 10 & 11
most developers of low dosage produce tablet disintegration values at
strength formulations along the direct under 3 minutes, (formula A, B, G, H
compression route. less <1minute) while the dissolution
Where active ingredients are sensitive profile obtained was superior to the
to moisture gain microcrystalline equivalent wet granulation process
cellulose (Avicel™) should be which remained consistently close or
substituted in whole or in part (i.e. 1:1 similar to the pure active material's
ratio) with crystalline maltose dissolution profile. Active material
(Advantose™).
degradants during stability evaluation
Table 8. in the compressed dosage form
Moisture Pick-up of Tablets (where present) were similar to the
% weight gain at 6 months drug substance impurity profile - thus
DC Excipient 75% at 100oC the DC formulation of the eight actives
Crystalline maltose 1.0 did not impact or effect impurity or
Granular mannitol 1.2 degradant growth profiles. Aqueous
Microcrystalline cellulose 4.9 film coating was essential in formula
[H] Ketorolac 10mg DC tablets due to
TABLET WEIGHT discoloration of the active on exposure
n The choice of the optimum tablet to light / heat stress.
weight needs to be made early in the DISSOLUTION PROFILE
development process. Tablet weight Examining the dissolution profile SD
for low dose DC preparations seldom at each sampling interval may lead to
exceeds 300 mg. Tablet weight improvement and optimization the
uniformity variation should be qualified product formula. The object is to
for each choice of formulation. reduce the SD at the 10 and 20
The ideal target tablet weight to aim minutes interval to the lowest possible
for is about 140 - 160 mg, however the value using additional disintegrants
overall tablet weight range for most and optimum mixing / blending times.
active materials requiring 0.5 - 10mg Table 9.
of drug substance is in the confines of DISSOLUTION PROFILE
100 - 200mg. % Dissolved at (minutes)
6 tablets 10 20 30 45
Film coating for taste masking or light Development Formula [H]
sensitive material will add on an MEAN 83 90 95.4 98.7
additional 2-3% of the overall tablet SD1 15.5 10.1 6.4 3.5
weight (Refer to chapter 11). Optimised Formula + Process
Note:- Smaller tablets as a rule MEAN 84 92 94.6 99.8
SD2 8.1 5.3 3.9 2.9
require less percentage lubrication.

Handbook of Pharmaceutical Sect:2

2 . 27 Generic Development
 ORAL TABLETS DEVELOPMENT CHAPTER 2.

DIRECT COMPRESSION
Development Flowchart

Excipient Blend Decision Table

A B C D E
DC Filler Disintegrant Lubricant(s) Fine Tuning Fine Tuning
(Dissolution) Glidant / lubrication
e.g. SDL/L MCC MS SSG / CC / XP Talc / SA / CSD
KEY
CC Croscarmellose
CSD Colloidal Silicon Dioxide
L Lactose monohydrate Evaluate Active material
MS Magnesium stearate Dissolution ; Bulk Density ; Particle size,
MCC Microcrystalline cellulose
% in formula.
SA Stearic Acid
SDL Spray dried lactose
SSG Sodium starch glycolate EXAMPLE:
XP Crospovidone 60% L
30% MCC
CHOOSE DC BLEND 0.5% MS
Select A, B, or C
from table above
Fine Tune
Lactose type - (fine/coarse)
MCC type pH 101/102 Flat bevelled or
Lubricant package CHOOSE Biconvex
Based on above active Tablet weight & Shape Choose higher
properties ± 120 - 1-5% Active or lower % lubricant
± 200 - 10% Active
± 300 - 20% Active

EVALUATE
Weight uniformity
Content Uniformity
FORMULATE Hardness & Dissolution
Optimise Development Batches Profile
Dry blend mix A, B & C (compare active dissolution)
+ compare reference drug)

FINE TUNE
OPTIMIZATION A, B & C Repeat tests
Unlubricated blend - UoC Adjust D & E
lubricated blend - UoC
Lubrication range (0.5 - 1.0%)
Tablet Weight Uniformity
OPTIMIZATION
Formula & Process
Fine tune D & E

Tablet Hardness
Qualification (low & High) To Pivotal
with Dissolution Profile PROCESS QUALIFICATION

Handbook of Pharmaceutical Sect:2

2 . 28 Generic Development
ORAL TABLETS DEVELOPMENT CHAPTER 2.

DIRECT COMPRESSION
SUITABILITY:
Glibenclamide 5 mg
Selegiline 5 mg
Manufacturing Flowchart [I] Famotidine 10/20/40 mg
Bromhexine 8 mg
SDL(30%) - MCC(60%) Amitriphyline 10 mg

LACTOSE

Active Lubricant
Material and Glidant
MIX Y-cone

SIEVE
Mill FLUSH
50 MESH
Where necessary
0.6 -0.8 mm

MIX
MICROCRYSTALLINE
CELLULOSE rpm + time

SUPER
DISINTEGRANTS Lubricant coats
the lactose
MIX Y-cone providing
greater control
over final
blending stage

Development
Content Uniformity on
unlubricated blend to
establish mixing time

BLEND STEP IPQC

rpm + time ID
Assay
Content Uniformity

COMPRESS QC
Weight uniformity
Thickness
Hardness
AQUEOUS Roller mixer Disintegration
FILM COAT
RELEASE
ID
To printing COATED DC TABLETS Assay
Content Uniformity
Dissolution

Handbook of Pharmaceutical Sect:2

2 . 29 Generic Development
 ORAL TABLETS DEVELOPMENT CHAPTER 2.

DIRECT COMPRESSION
Manufacturing Flowchart [II]
SDL(60%) - MCC(30%)

Active LACTOSE
(65%)
Material (10%)

MICROCRYSTALLINE
35% CELLULOSE (15%)
Lubricant
(1%)
SODIUM STARCH
GLYCOLATE (2%)

SIEVE
AEROSIL (0.5%)
STARCH (6%)

MIX Y-cone 50 MESH

20 - 25 min
Aerosil mixed with either
starch (4), lactose (1+3)

Sieve
or lubricant (2)

(Where necessary)
0.8 mm Lubricant coats
final blend
in Y-Cone
directly for a

MIX Y-cone
short period
(3-5 min)
20 - 25 min

During
Development
Content Uniformity of
unlubricated blend to
establish mixing time
BLEND Y-cone IPQC
5 min ID
Assay
Content Uniformity

COMPRESS QC
Weight uniformity
Thickness
Hardness
AQUEOUS Roller mixer Disintegration
FILM COAT (See Chapter 11)

RELEASE
ID
To printing COATED DC TABLETS Assay
Content Uniformity
Dissolution

SUITABILITY: [Product suitable for either Wet or Dry Granulation]

1. Buspirone 5/10 mg
2. Tamoxifen 10/20/40 mg -

Handbook of Pharmaceutical Sect:2

2 . 30 Generic Development
 ORAL TABLETS DEVELOPMENT CHAPTER 2

DIRECT COMPRESSION FORMULA

Table 10

DIRECT COMPRESSION MASTER FORMULA

% EXCIPIENTS

STRENGTH Per TABLETÜ 1mg 2mg 5mg 5mg 8mg 10mg 5mg/ 10mg
10mg
ACTIVE Ü [A] [B] [C] [D] [E] [F] [G] [H]

% Active Material 0.7 1.4 3.6 5.0 5.5 10.0 3.55 5.0

Avicel pH 101 50.0 50.0 30.0 - - 60.0

Avicel pH 102 - - - 60.0 30.0 15.0 30.0 -

Lactose monohydrate - - - - 59.7 - - -

100 mesh NF

Lactose monohydrate 6.3 6.6 61.0 32.5 - - - -

200 mesh NF

Lactose Spray Dried NF 40.0 38.0 - - - 66.5 61.3 34.0

Sodium Starch Glycolate - - 4.0 2.0 - 2.0 4.0 -

Starch NF - - - - 3.0 5.0 - -

Aerosil - - 0.8 - 0.6 0.5 0.5 0.5

(Colloidal Silicon Dioxide NF)

Talc 2.5 2.5 - - - - - -

Magnesium Stearate 0.5 0.5 0.6 0.5 1.2 1.0 0.65 0.5

TOTAL PERCENTAGE 100 100 100 100 100 100 100 100

Tablet weight (mg) 140 140 140 100 150 100 140/ 200
280

Hardness SCU (target) 6 6 6 6-7 6 6 6 6-8

Disintegration <<15 MIN <5 <5 <5 <5 <5 <5 <5 <5
[A] Flunitrazepam DC Tablet [D] Selegiline DC Tablet [G]Buspirone DCTabs.
[B] Flunitrazepam DC Tablet [E] Bromhexine DC Tablet [H]Ketorolac DC Tabs.
[C] Glibenclamide DC Tablet [F] Amitriphyline DC Tablet

Handbook of Pharmaceutical Sect: 2 . 31 Generic Development

 ORAL TABLETS DEVELOPMENT CHAPTER 2

DIRECT COMPRESSION FORMULA

Table 11

DIRECT COMPRESSION MASTER FORMULA

% EXCIPIENTS % EXCIPIENTS

STRENGTH Per TABLETÜ 1mg 2mg 5mg 5mg 8mg 10mg 5mg 10mg
10mg
ACTIVE Ü [A] [B] [C] [D] [E] [F] [G] [H]

% Active Material 0.7 1.4 3.6 5.0 5.5 10.0 3.55 5.0

Avicel pH 101 25.0 25.0 15.0 - - 30.0

Avicel pH 102 - - - 30.0 30.0 15.0 30.0 -
Advantose™ 100 25.0 25.0 15.0 - - 15.0 - 30.0
Lactose monohydrate - - - - 30.0 - - -
100 mesh NF
Lactose monohydrate 6.3 6.6 61.0 - - - - -
200 mesh NF
Lactilol - Finlac™ DC - - - 32.0 30.0 - 30.0 -
Mannitol DC - - - 30.0 - - - -
Lactose Spray Dried NF 40.0 39.0 - - - 50.0 31.0 34.5
Sodium Starch Glycolate - - 4.0 2.5 - 3.0 4.0 -
Starch NF - - - - 3.0 5.5 - -
Aerosil - - 0.8 - 0.5 0.5 0.8 -
(Colloidal Silicon Dioxide NF)

Talc 2.5 2.5 - - - - - -

Magnesium Stearate 0.5 0.5 0.6 0.5 1.0 1.0 0.65 0.5
TOTAL PERCENTAGE 100 100 100 100 100 100 100 100
Tablet weight (mg) 140 140 140 140 150 120 140/ 200
280
Hardness SCU (target) 6 6 6 6-7 6 6 6 6-8
Disintegration <15 MIN <5 <5 <5 <5 <5 <5 <5 <5

[A] Flunitrazepam DC Tablet [D] Selegiline DC Tablet [G] Buspirone DC Tabs.

[B] Flunitrazepam DC Tablet [E] Bromhexine DC Tablet [H] Ketorolac DC Tabs.
[C] Glibenclamide DC Tablet [F] Amitriphyline DC Tablet

Handbook of Pharmaceutical Sect: 2 . 32 Generic Development

 ORAL TABLETS DEVELOPMENT CHAPTER 2

TABLET DEVELOPMENT

W et Granulation Development
OverView
Tablet Development
‘…Developing low & high strength actives via wet granulation
high shear techniques…

OVERVIEW Wherever possible the use of

geometric proportioned blends
T ABLET DEVELOPMENT of low
and high strength drugs may
follow two processes, either by
reduces the number of bioequivalent
studies necessary, as a waiver may be
obtained for the lower dosage
traditional alcoholic or aqueous wet
strengths.
granulation techniques via high shear
Common geometric proportion ratios
techniques.
shown in the formulation tables are
Dosage strengths with 0.5 to 850 mg 0.75, 1, 1.5, 1.7, 2 and 3. (i.e.
or more per tablet are considered tamoxifen coated tablets 10, 20, 30
suitable drug candidates for the high and 40 mg or metformin 500 and 850
shear development route. mg)
Where the tablet strength exists as
two strengths e.g. Nabumetone 500 & DESIGNING THE FORMULATION
750 mg tablets, higher strength tablet Keeping wet compression formulations
may be developed from the same simple cost effective and elegant
granule blend using a geometric require six basic elements - namely.
proportioned amount of common n Critical choice of either alcoholic
granulate (i.e. x 1.5) for compressing (95/99.5%) or aqueous granulation
the higher dosage strength. procedures (based on unit stability).
Low active fill weight are readily n Choice of the overall formulation
processed. Actives varying from 0.5 to excipient mixture (key parts).
50mg of drug substances give typical
n Choice of high shear granulator or a
tablet weights, ranging between 100 to
fluidized bed technique.
200 mg per compression. In designing
geometrically scaled-up formula, the n Choice of the actual wet granulation
common granulate is a simply multiple processing steps (see flow charts).
i.e. 200 to 400 mg per tablet. n Choosing geometrical proportioned
Table 1. mixes for multiple tablet strengths.
Wet Granulation n Designing and optimising the
tablet's physical specifications, for
Active Strength Tablet Weight
shape, weight, hardness, thickness,
0.5 - 50 mg 100 - 200 mg friability, disintegration, dissolution
100 - 250 mg 300 - 550 mg and film coating for light protection or
taste masking.
750 - 850 mg ± 850-980 mg

Handbook of Pharmaceutical Sect: 2 . 33 Generic Development

 ORAL TABLETS DEVELOPMENT CHAPTER 2

Table 2.
ALCOHOL / WATER GRANULATION
Wet Granulation Design Occasionally an appropriate ratio of
Parameter Decision Range alcohol / water mixtures from 60 : 40
Wet granulation Use a standardise (Nabumetone) to 95 : 5 (Mesalamine,
Excipient blend excipients range ISMN etc.) are appropriate and can
Multiple strength geometric design produce stable granulated material.
Tablet Weight 150 - 980 mg Table 4.
Individual weight ± 7.5% Alcoholic Granulation
Average weight ± 5.0% Active Alcohol/Water
Tablet Hardness 8-18 SCU
Nabumetone 500/750 60.0 : 40.0%
Thickness 2.5 - 8.0mm
Mesalamine 95.0 : 5.0%
Friability < 1.0%
Disintegration <10 -15 min AQUEOUS GRANULATION ACTIVES
Dissolution NLT 80 in 45 min Table 5.
Aqueous Granulation
CHOOSING THE FORMULA
Active % P. Water
n Choice of alcoholic (95% or 99.5%)
or aqueous granulation procedure. Carbidopa /Levodopa 100
The choice of the granulating solvent Clonazepam 100
whether pure alcohol or a water / Enalapril Maleate 100
alcohol mix is a critical early decision. Famotidine 100
ALCOHOLIC GRANULATION Frusemide 100
Many active materials do not produce Gemfibrozil 100
satisfactory stability profiles when Norfloxacin 100
granulated solely with purified water. Tamoxifen 100
Active degradation and overall Trazodone HCl 100
impurity growth is often accelerated
during wet granulation or during the n CHOICE of the wet granulation
shelf life period due to the presence of excipient mixture.
residual water in the compressed The percentage of the active
tablet. Hydrous (95%) or anhydrous ingredient in the overall formula may
alcohol (99.5%) is the granulating range from 0.5 mg (Clonazepam) to
solvent of choice in aqueous sensitive 850 mg (metformin) while excipient
active materials. Table 3. composition may vary from 99.5% to
less than 10% (see tables 15 to 17).
Alcoholic Granulation Where the active material exceeds
Active Alcohol % 90% with 10% or less of excipients the
Bupropion 99.5% process of choice often rests in
Carbamazepine 95.0% fluidized bed granulators / processors.
Diclofenac Na / K 99.5% (ref. Table 16).
Glipizide 95.0%
The active material's particle size and
ISMN 40mg 95.0%
bulk / tapped density are significant
Mesalamine 95.0%
parameters in wet formulation.
Naproxen 95.0%
Processing by high shear granulators
Omeprazole 99.5%
produce high density granules as
Simvastitin 95.0%
opposed to moderate density granules
Verapamil HCl 99.5%
produced in fluidized bed granulators.

Handbook of Pharmaceutical Sect: 2 . 34 Generic Development

 ORAL TABLETS DEVELOPMENT CHAPTER 2

Active's surface phenomena and properties. Improving general granule

parameters of particle size / bulk flow properties is the function of the
density are fundamentally important glidant(s). Dry glidants (dried starch or
when selected the type of high shear colloidal silica dioxide) are added and
granulating / processing equipment. blended immediately before the
This is of added importance when lubricant(s) is added.
active materials have a low bulk Homogeneity of the unlubricated
density due to particle shape and may blend, prior to the addition and
impact on blending and mixing. blending of the lubricant is usually
High density/coarse starting materials qualified during the development
perform poorly in high air/volume FBG stage. Qualifying this process obviates
as mixing and blending techniques are the need for excessive mixing after the
generally inadequate. addition of the lubricant, which may in
The selection of the granulator type certain formulations, impact on the
has a major influence on the dissolution profile. Homogeneity
characteristic of the final product. testing prior to addition of the lubricant
Poorly flowing actives should be is omitted in routine commercial
granulated via high shear Diosner™ production once this content
type granulators to improve flow uniformity step has been adequately
properties of the nucleated granule. qualified and validated.
SPECIAL GRANULATION CASES
Extra and intra-granular formulation
Placing the microcrystalline cellulose,
Occasionally the active dose may be
750 - 850 mg. This presents a special
disintegrants and/or starch either extra
set of granulation problems. In effect
or intra-granular may have a marked
these tablets require conversion of the
impact on the granule formation and
bulk active essentially into a 'direct
flow characteristics, as well as a
compressible active' using less than ±
technique for fine tuning dissolution
8 - 10% of the excipient material. The
profiles (see flow charts 2 to 4)
active granulation process requires a
Mixing the glidant (dry starch and standard fluidized bed granulator or
colloidal silicon dioxide) with a ± 50% /processor (FBG) - See flow chart 1.
part of the MCC in the unlubricated
granule blend may significantly A typical '92-94% active; 6-8%
enhance granule flow properties and excipient' formula consists of
further aid dissolution fine tuning. essentially only three non-active
ingredients (table 6). The super
ORDER of ADDITION
disintegrant, (usually croscarmellose)
The wet granulation method involves is fluidized with 50% intragranular and
granulating the drug substance and 50% extragranular material.
excipients in a specific order of
The process involves multiple spraying
addition so that the granulate on
of the active material with 50%
drying, blending and compression into
disintegrant in the FBG. Initially spraying
tablets will consistently meet the with the binding agent followed by 1 to 2
specifications as highlighted. (table 2). short water sprays. Thus the active
It is important in formula development material is nucleated and built up in the
to ensure that the unlubricated granule spray granulator with relatively small
blend is fully homogeneous and that amounts of super disintegrant. After
the addition of the lubricant, simply spraying, the FBG is charged with the
improves 'tablet-edge die wall' ejection remaining disintegrant and briefly air
and not general granule flow blended in the Granulator.

Handbook of Pharmaceutical Sect: 2 . 35 Generic Development

 ORAL TABLETS DEVELOPMENT CHAPTER 2

Alternatively after spraying and drying The ideal granulate should be readily
the 'granulated active' is transferred to compressible with superior flow
a Y-cone or tumble blender and the properties at high compression
remaining 50% disintegrant blended. speeds. Disintegration should be rapid
The final blending step requires the (5-15 minutes) at optimum target
addition of the lubricant and a brief hardness values that may range
blending (<5 min/10 rpm). Blending in between 8-18 SCU. The dissolution
a Y-cone via a 'two-stage blending profile should be designed to be just
process' is a common practice. marginally greater than the solubility
Table 6
of the pure active material under
Spray Dried Actives similar dissolution conditions.
Active % Excipients
Tablet/caplet thickness and
Material mg per tablet
dimensions depend on tablet weight
Famotidine 750 Strong Binder 2-5 and die chosen to meet a thickness of
Metformin 850 Super Disintegrant ±4
between ±2.5 and 8.0 mm.
Lubricant ± 0.8

Essentially only three excipients Wet granulation formulae comprise of

five essential excipient processes in 3
ADVANTAGES: to 4 distinct manufacturing steps.
High Shear Granulator have the These stages are;
following ADVANTAGES:- Ü Diluent or bulking agent (e.g.
Ü Process a broad range of starting lactose / mannitol / lactilol etc.)
materials
Ü Potential for high density granules. Ü Granulating solution with or with
Ü Shorter processing times. out the binder (e.g. Povidone K-30/90
Ü Granulation end-points may be (PVP), / Hydroxypropyl Cellulose)
fixed by torque value end-points. Ü Disintegrating agent - intragranular
Ü Narrow particle size distribution. (e.g. MCC / SSG)
DISADVANTAGES:
Ü Higher batch-to-batch variation. Ü Extragranular glidant / disintegrant
Ü Product handling between steps. or super disintegrant

ADVANTAGES:
Ü Single or dual Lubricant
Fluidized Bed Processors have the Regular lactose, tricalcium Phosphate
following properties. and the various dried starches are
Ü Capable of producing granules with common diluting and bulking agents
90-93% active and 7-10% non-actives and perform well in wet mixing and dry
Ü Narrow particle size distribution blending operations in amounts from
Ü Granulation end-points may be 2-20% (used in lower cost drug
fixed by controlled spraying formulations).
DISADVANTAGES: For high shear granulators, 200 mesh
Ü Process a narrower range of lactose is preferred due to its superior
starting materials flow and granulating properties. Table
Ü Produces moderate density 7 shows common diluents used in
granules aqueous and alcoholic granulation.
Ü Problems with low density or high Dried starch NF (DS), pregelatinised
density actives and excipients starch (STA-RX-1500) and sodium
starch glycolate are frequently used.

Handbook of Pharmaceutical Sect: 2 . 36 Generic Development

 ORAL TABLETS DEVELOPMENT CHAPTER 2

Table 7.
Avicel pH 101 / 102 /105 /112 when
Bulking Excipients blended in approximately equal parts
Non-active % / tablet 50 : 50% intra and extra-granularly,
Microcrystalline Cellulose 10 - 30 form compressible granules with
101/105 /102/112 superior disintegration abilities (when
Lactose MH-200 35 - 75 used at quantities that range from 15,
to 30, or 60%.
Tricalcium Phosphate 10 - 50
Equivalent results are obtainable by
Dried starch 5 - 25 substituting a 1:1 ratio (equal parts) of
Maltose - Advantose™100 35 - 75 crystalline maltose and micro-
crystalline cellulose.
For 'fine particle-size actives', 200 Table 10.
mesh lactose monohytrate is more Granulating Agents / Binders
suitable. With 'granular actives' the Excipient % per tablet
100 mesh lactose monohytrate is
Povidone K30 2-4
generally preferred during the
blending stage. Povidone K90 2 - 3.5
Microcrystalline lactilol (a Hydroxypropyl Cellulose 1 - 1.5 - 2.5
disaccharide sugar alcohol derived Hydroxypropyl 1 - 1.5 - 2.5
from lactose) may be substituted in Methylcellulose
lieu of lactose. Marginally harder Pregelatinized Starch 1 - 5 - 10
tablets are produced at the same (Starch 1551™)
compression strength. Since
microcrystalline lactilol has a lower Where necessary suitable additional
moisture pick up and lower disintegrants such as sodium starch
hygroscopicity, shelf life extension is glycolate (2-5%) or 'dried' starch NF
promoted when used with active (~3% to 6%) promote rapid tablet
materials sensitive to moisture pick-up disintegration and allows faster drug
over the shelf life testing period. release. Where Mannitol formulations
0rganic acids may significantly tend to increase the dissolution time
improve the overall stability profile of on ageing (shelf life period), sodium
certain actives (e.g. Bupropion HCl). starch glycolate (SSG) is
Table 8. recommended (at about 3.0 - 5.0%).
pH adjusters /Organic Acids Table 11
Non-active % / tablet Extragranular Disintegrants
Citric Acid 2-4
Excipient % per tablet
Maleic Acid 1-2
Sodium starch glycolate 2.0 - 4.0
Glutamic Acid HCl 10 - 20 Croscarmellose Na 3.0 - 5.0
Avicel pH101™ - microcrystalline cellulose (MCC) Starch NF (dried) 3.0 - 5.0
Advantose™ - crystalline maltose (CM)
Microcrystalline 5.0 - 15.0
Table 9. Cellulose 102
Super Disintegrants Microcrystalline 5.0 - 10.0
Non-active % / tablet Cellulose 105
Croscarmellose Na 2-5 Common splitting ratios between intragranular:
extragranular disintegrants are in the order of 1:1
Crospovidone 2-4 and 1.5 : 1

Finlac™ - Microcrystalline Lactilol (MCL) Xyrofin

UK); Mannitol ™ - Mannitol USP (M)

Handbook of Pharmaceutical Sect: 2 . 37 Generic Development

 ORAL TABLETS DEVELOPMENT CHAPTER 2

Lubrication/Glidant when compressing smaller tablets of

100 to 160 mg weight especially when
Magnesium and at times calcium used with concave punches producing
stearate are frequently used lubricants biconvex tablets.
in tablet formulations. 0.5 - 0.75%
concentration is a typical level of Different vendor sources of excipients
lubrication. Na Stearyl Fumarate may including the lubricant should be
be substituted when alkali stearates evaluated and found to be comparable
interact or retard dissolution. Since especially when commercial
lubrication is a surface phenomenon it production may be effected at several
is important to introduce a range of different manufacturing sites.
magnesium stearate from 0.5 to 1.0% Note:- Vegetable grade magnesium
in the formulation. The 0.5% level is stearate NF is a certified food grade
generally intended for routine vegetable derived stearic acid - 99.9%
commercial production. However in < 325 mesh (no BSE origin).
certain atypical situations the Table 12.
lubrication requirements of a specific Lubricant Package
batch lot may be higher due to the Non-active % per tablet
higher surface area of the component
Mg/Ca stearate 0.6 - 1.5
powder ingredients.
Na Stearyl Fumarate NF* 1.5 - 2.0
It is therefor important to allow for an
increased level of lubrication up to Aerosil 0.5 - 1.2
1.0%. The lubrication range must be Talc (glidant) 2.0 -3.0
qualified, i.e. not to alter or affect the
dissolution rate or any other tablet Magnesium stearate / 0.4 -0.6
specification parameter. Stability data Stearic acid (1:1 ratio) 0.4 -0.6
should show that the dissolution rate
of tablets processed with 1.0% TARGET PROCESS PARAMETERS
Magnesium stearate is no different to Wet granulation formulations may
tablets made with 0.5% lubricant at require critical process qualification
target speeds. In the current climate of during the overall product
global marketing a vegetable grade of development phase.
magnesium stearate should be used. Ü Active particle size / bulk density
In active materials with a low bulk specifications (target values & limits)
density (<0.4g/mL), talc (1-3%) may Ü Optimum mixing time for the
be used as a glidant and densifier. 'unlubricated powder blend'
Magnesium stearate NF (vegetable
1 Ü Optimum 'unlubricated blend'
grade ) and colloidal silicon dioxide content uniformity qualification
(CSS - Aerosil) usually provide an
optimum lubrication package. Ü % Lubricant range qualification
Magnesium stearate may usually be Ü Lubricant blending time (content
substituted for equal parts (1:1) of uniformity qualification of end mix)
magnesium stearate and stearic acid Ü Hardness range qualification with
producing equivalent lubricant effects. dissolution tests results.
Since lubrication is a surface
phenomenon, specific to the tablet Note:- Smaller tablets as a rule require less
1
edges (i.e. die wall-effects on ejection) percentage lubrication. *PRUV™ Ferro
lower levels of lubricant can be used Corporation Walton Hills Ohio (Synpro®)

Handbook of Pharmaceutical Sect: 2 . 38 Generic Development

 ORAL TABLETS DEVELOPMENT CHAPTER 2

GEOMETRIC GRANULATES TABLET WEIGHT

n Choosing geometrical proportioned n The choice of the optimum tablet
blends for multiple strengths weight needs to be made early in the
preparations is the recommended development process.
development strategy to be used in Tablet weight for low dose
tablet formulations. preparations seldom exceeds 300 mg.
Bioequivalent waiver applications for Tablet weight uniformity variation
the lower strength formulations is should be qualified for each choice of
standard development procedure formulation. Average weight variation
while the highest strength preparation is ±5.0% while individual weight
is evaluated for bioequivalency variation is ±7.5%.
against the reference listed drug. Very high dose actives have special
SOME DISADVANTAGES tablet weight considerations when
processed in fluidized bed granulators
n Wet granulation formula, including i.e. 6 - 10% total excipients.
wet granulation preparations
incorporating up to 4% of the super- Very low dose tablet weight ranges for
disintegrants croscarmellose and most active materials requiring 0.5 -
crospovidone have generally lower 20mg of drug substance is in the
dissolution assays at similar sampling confines of 100 - 200mg. Aqueous film
points than equivalent direct coating for either taste masking or
compression dry blends. light sensitive material will add on an
additional 2-3% of the overall tablet
The ability to processing a broad weight.
range of active materials especially
the process advantages offered by PRODUCT SPECIFICATIONS
very high dose actives (i.e. metformin n Choice of physical tablet
850 mg per 970mg tablet) leads most specifications (e.g. hardness, friability,
tablet developers for the more thickness, disintegration, dissolution).
complicated drug formulations along Choosing a formula blend based on
the wet granulation route such as tables 15 - 17 will generally produce
processing via a fluidized bed an elegant compressed tablet within
granulator. acceptable target specifications as
Where active ingredients are indicated in table 2.
sensitive to moisture gain Uniform weights, Content Uniformity,
microcrystalline cellulose (Avicel™) Hardness 8-18 SCU (at low, target
should be substituted in whole or in and high speeds), Disintegration <10-
part (i.e. 1:1 ratio) with crystalline 15 minutes, friability <0.5-1.0%,
maltose (Advantose™). thickness 2.5 - 8.0mm.
Table 13. Formulations in tables 15 & 17 should
Moisture Pick-up of Tablets produce tablet dissolution profiles only
% weight gain at 6 months marginally greater than the pure active
Excipient 75% at 100oC material's dissolution profile.
Active material degradants during
Crystalline maltose 1.0
stability evaluation in the compressed
Granular mannitol 1.2 dosage form (where present) were
Microcrystalline cellulose 4.9 similar to the drug substance impurity
profile - thus the formulation of the

Handbook of Pharmaceutical Sect: 2 . 39 Generic Development

 ORAL TABLETS DEVELOPMENT CHAPTER 2

actives did not impact or effect

impurity or degradant growth profiles. FLUIDIZED BED PROCESSOR
Aqueous film coating was essential in
certain formulas due to taste masking
or discoloration of the active on
exposure to light / heat stress.
Water
DISSOLUTION PROFILE LOAD Active
Load #3
+
Examining the dissolution profile 50% Super Disintegrant
Standard Deviation (SD) at each Water
sampling interval may lead to Load #2
improvement and optimization the
Spray
product formula. The object is to
Parameters PVP
reduce the SD at the 10 and 20 K90 Soln
minutes interval to the lowest possible #1
value using additional disintegrants
and optimum mixing / blending times . Triple nozzle 1.8mm
Table 14 . 1.5 - 2.5 Liters/ min
DISSOLUTION PROFILE
% Dissolved at (minutes)
6 tablets 10 20 30 45 SPRAY PRESSURE
Development Formula [H] 3 - 4 ATM
MEAN 72 93 96.6 99.7
SD1 15.7 9.3 5.9 3.4
Optimised Formula + Process
MEAN 74 95 97.6 99.8 Inlet Air 60oC
SD2 8.7 5.9 3.8 2.7
CHECK
LOD

DRYING
FLOW Range from Stage
CHART 1 1.5 - 4.5%

50% Super Disintegrant Transfer to 15 min

+glidant (Dried Starch NF) 10 RPM
Tumbler/Y-cone

0.5% Lubricant 5 min

(Add to blender) Tumbler/Y-cone 10 RPM

Blend
Uniformity testing
COMPRESS
COAT (Target speed Rpm)

Handbook of Pharmaceutical Sect: 2 . 40 Generic Development

 ORAL TABLETS DEVELOPMENT CHAPTER 2

Flow Chart 2

WET GRANULATION
Development Flowchart
EXCIPIENT MIX - DECISION TABLE
A B C D E
Filler Intragranular Granulating Agent Extra disintegrant Fine Tuning
Disintegrant (Fine Tuning Glidant / lubrication
Dissolution)
e.g. L/MCC MCC/SSG / CC PVP/HPMC/HPC SSG / CC / XP Talc / SA /
CSD/MS
KEY
CC Croscarmellose
CSD Colloidal Silicon Dioxide
L Lactose monohydrate Evaluate Active material
MS Magnesium stearate Dissolution ; Bulk Density ; Particle size, EXAMPLE:
MCC Microcrystalline cellulose
% Active in formula. 22% SRx
SA Stearic Acid Wet
PVP Povidone K30 /K90 35% MCC
HPC Hydroxypropyl cellulose 1.0% HPC
S Starch NF 11% S
SRx Pregelatinized Starch
10% MCC
SSG Sodium starch glycolate CHOOSE GRANULE EXCIPIENTS Dry 0.8 CSD
XP Crospovidone
Select A, B, C, D & E 1.0% MS
from table above & refer to tables 15-17
Fine Tune
MCC type pH 101/102/105
Disintegrant - (SSG/MCC) Flat, bevelled or
Lubricant package CHOOSE Biconvex
Based on the active Tablet Weight & Shape Choose higher
material's properties ± 200 for 1-10% Active or lower % lubricant
± 550 for 50% Active
± 750 for 80% Active

EVALUATE
Weight uniformity
Content Uniformity
FORMULATE Hardness & Dissolution
Optimise Development Batches Profile
blended mix A, B, C, D & E (compare active dissolution)
+ compare reference drug)

FINE TUNE
OPTIMIZATION A, B & C Repeat tests
Unlubricated blend - UoC Adjust D & E
lubricated blend - UoC
Lubrication range (0.5 - 1.0%)
Tablet Weight Uniformity
OPTIMIZATION
Formula & Process
Fine tune D & E
To Pivotal Process
Tablet Hardness
Qualification (low & High)
with Dissolution Profile
PROCESS QUALIFICATION

Handbook of Pharmaceutical Sect: 2 . 41 Generic Development

 ORAL TABLETS DEVELOPMENT CHAPTER 2

Flow Chart 3

WET GRANULATION
Manufacturing Flowchart [I]

LMH
and/or
MCC

Active Material Lubricant

and Glidant
(bulk density check)
Wet Granulator

SIEVE
DRYING FLUSH
50 MESH
LOD CHECK

Mill MIX
Where necessary
0.6 -0.8 mm
rpm + time
EXTRAGRANULAR
MCC and / or SSG
Lubricant coats
glidant
SUPER
providing
DISINTEGRANTS
greater control
MIX Y-cone over final
blending stage
rpm (10) + time (20 min)

During
Development
Content Uniformity on BLEND STEP IPQC
unlubricated blend to ID
establish mixing time rpm (10) + time (5 min)
Assay
Content Uniformity

QC
COMPRESS Weight uniformity
Thickness
Hardness
Friability
AQUEOUS Roller mixer Disintegration
FILM COAT
RELEASE
ID
To printing COATED TABLETS Assay
Content Uniformity
Dissolution

Courtesy of: International Journal of Generic Drugs

Vol. 02. Edition 07., (1998); Locum Press.

Handbook of Pharmaceutical Sect: 2 . 42 Generic Development

 ORAL TABLETS DEVELOPMENT CHAPTER 2

Flow Chart 4
WET GRANULATION
Manufacturing Flowchart [2]
ALCOHOLIC - (Product Specific Chart)

Active Lactose 200

Material (25%) (50%)
(usual range 35-75%)
SODIUM STARCH
GLYCOLATE (5%)
Lubricant
(±1%)
PVP K30 (3%)
in alcohol

SIEVE
50 MESH
During GRANULATOR
Development 3 - 5 min
Establish
Content Uniformity of
unlubricated blend to DRY
fix the mixing time
LOD CHECK
Lubricant coats
Sieve final blend
Aerosil mixed with (Where necessary) in Y-Cone
either lubricant or 0.6 - 0.8 - 1.0 mm directly for a
starch short period
MIXING (3-5 min)

Tumbler/Y-cone
AEROSIL (0.5%)
STARCH (6%)

MICROCRYSTALLINE 20 - 25 min
CELLULOSE (18%)

IPQC
BLEND Y-cone ID
rpm (10) + time (5 min) Assay
Content Uniformity

SUITABILITY: QC
Diclofenac Na 50 mg
Weight uniformity
COMPRESS Thickness
Hardness
Friability
AQUEOUS Roller mixer Disintegration
FILM COAT
RELEASE
ID
To printing COATED TABLETS Assay
Content Uniformity
Dissolution

Courtesy of: International Journal of Generic Drugs

Vol. 02., Edition 07., (1998); Locum Press.

Handbook of Pharmaceutical Sect: 2 . 43 Generic Development

ORAL TABLETS DEVELOPMENT CHAPTER 2

AQUEOUS GRANULATION FORMULA

Table:15 HIGH SHEAR GRANULATOR

AQUEOUS MASTER FORMULA

GRANULATION % EXCIPIENTS
27+
STRENGTH Per TABLETÜ 100 2.0 20 10 20 40 400 20
mg mg mg mg mg mg mg mg
ACTIVE Ü [A] [B] [C] [D] [E] [F] [G] [H]

ÜACTIVE MATERIAL %Ü 50.8 1.14 10.0 5.0 10.0 27.3 58.8 10.9*

Avicel pH 101 - - - - - 20.0 - -

Avicel pH 102 20.0 15.0 - 42.0 41.0 - 20.0 -
Avicel pH 105 - 10.0 10.0 - -
Avicel pH 112 - - -
Lactose monohydrate100 - - - - - - - -
Lactose Spray Dried NF - - - - - - - -
Lactose monohydrate - 61.4 76.6 - - 44.0 - 60.0
200 mesh NF
Sodium Starch Glycolate - - - - 5.0 - 2.0
Croscarmellose Sodium 5.0 3.5
Starch STA-RX-1500 - - - 25.0 25.0 - - -
Starch NF 15 13.4 10.0 15.2 12.2 - 14.3 19.6
PVP K-30 (Povidone USP) - 2.1 - - - 1.8 2.1 1.0
Pregelatinized Starch NF 10.0 - 1.0 - - - - 5.0

%
Hydroxypropyl Cellulose NF - - - 1.0 1.0 - - -
Color/Dye 3.5 1.4 0.2 - - 0.1 - -
Sodium Bicarbonate USP - - 1.5 - - - - -
Aerosil - - - 0.8 0.8 0.8 0.5 0.5
(Colloidal Silicon Dioxide NF)
Magnesium Stearate 0.5 0.6 0.5 1.0 1.0 1.0 0.8 1.0
Purified Water USP qs qs qs qs qs qs qs qs

TOTAL PERCENTAGE Ü 100 100 100 100 100 100 100 100

Tablet weight (mg) Ü 250 180 200 210 210 150 680 280
Hardness SCU (target) 9 8 8 7-9 9 9 10 9-11
Disintegration <15 MIN 5-15 5-15 5-15 5-15 5-15 5-15 5-15 5-15
KEY:-
[A] Carbidopa/Levodopa [B] Clonazepam [C] Enalapril Maleate [D] Famotidine USP
[E] Famotidine USP [F] Frusemide BP [G] Norfloxacin USP [H] Tamoxifen Citrate*

Handbook of Pharmaceutical Sect: 2 . 45 Generic Development

ORAL TABLETS DEVELOPMENT CHAPTER 2

AQUEOUS GRANULATION FORMULA

Table:16 HIGH SHEAR GRANULATOR & FLUIDIZED BED GRANULATOR

AQUEOUS MASTER FORMULA

GRANULATION % EXCIPIENTS

STRENGTH Per TABLETÜ 275 40 150 400 450 250 500 200
mg mg mg mg mg mg mg mg
ACTIVE Ü [I] [J] [K] [L] [M] [N] [O] [P]

Ü ACTIVE MATERIAL %Ü 72.0 36.0 37.5 59.7 69.0 90.9 90.9 52.6

Avicel pH 101 - - - - - - - -
Avicel pH 102/105 7.0 - - 18.3 15 - - -
Lactose monohydrate 100 mesh - - - - - - - -
Processed in
Lactose monohydrate - 36.0 49.0 - - -
Fluidized Bed 36.6
200 mesh NF Granulator
Lactose Spray Dried NF - - - - - - - -
Sodium Starch Glycolate - - 10.0 - - 6.0 6.0 -
Croscarmellose Sodium 2.0
Starch STA-RX-1500 - - - - 8.5 - - 5.0
Starch NF - 25.0 - 4.2 - 0.3 0.3 -
PVP K-30/90 (Povidone) 3.5 3.0 2.5 - - 2.2 2.2 -
Pregelatinized Starch NF - - - 15.0 - - 5.0
Hydroxypropyl Cellulose NF
Na lauryl sulfate/
Polysorbate 80
Sodium Bicarbonate USP
Aerosil
(Colloidal Silicon Dioxide NF)
-
-

-
0.3
-
-

-
-
-
-
-

0.5
% -
-

-
-
3.0
1.0

-
2.0
-
-

-
-
-
-

-
-
-
-

-
-

Magnesium/Calcium stearate 0.8 - 0.5 0.8 1.0 0.5 0.4 0.8

Talc 4.0 - - - - - - -
Purified Water USP qs qs qs qs qs qs qs qs

TOTAL PERCENTAGE Ü 100 100 100 100 100 100 100 100

Tablet weight (mg) Ü 380 300 400 660 650 275 550 380
Hardness SCU (target) 8-11 9 9 8-11 9 8-11 8-11 8-11
Disintegration <15 MIN 5-15 5-15 5-15 5-15 5-15 5-15 5-15 5-15
KEY:-
[I] Naproxen Na [J] Verapamil [K] Trazodone [L] Norfloxacin
[M] Norfloxen [N] Naproxen [O] Naproxen [P] Labetalol

Handbook of Pharmaceutical Sect: 2 . 46 Generic Development

ORAL TABLETS DEVELOPMENT CHAPTER 2

ALCOHOLIC GRANULATION FORMULA

Table:17 HIGH SHEAR GRANULATOR

ALCOHOLIC MASTER FORMULA

GRANULATION EXCIPIENTS mg/tab

STRENGTH Per TABLETÜ 50 10 750 75 50 100 / 20 20

mg mg mg mg mg 75 mg mg
ACTIVE Ü [A] [B] [C] [D] [E] [F] [G] [H]

ÜACTIVE MATERIAL %Ü 20.0 4.0 77.0 25.0 25.0 22.0 10.0 10.0

Avicel pH 101 - - - 30.0 20.0 - 10.0 30.0

Avicel pH 102 / 112 15.0 15.0 50 - - 65.2 - -
Advantose™ 100 15.0 15.0 50 - - - - -
Lactose Spray Dried NF - - - - - - - -
Lactose monohydrate
200 mesh NF
Tricalcium Phosphate NF
Sodium Starch Glycolate
Starch STA-RX-1500
Starch NF
mg/tab
62.0

50.0
20.0
-
30.0
60.0

10.0
20.0
-
30.0
-
-

85.0
-
-
140

-
25.0
-
15.5
98.5

-
10.0
-
12.5
-

-
-
-
141

-
-
20.0
-
34.2

-
20.0
-
-
PVP K-30 (Povidone USP) 4.2 4.0 - 12.0 7.5 - 4.5
Hydroxypropyl Cellulose NF
- - 3.6 - 5.0 1.5 - -
Hydroxypropyl Methylcellulose
ALCOHOL 95% 32.0 32.0 85.0 28.0 18.0 25 10.0 20.0
Aerosil 1.0 1.0 5.0 1.0 0.5 0.5 0.5 0.5
(Colloidal Silicon Dioxide NF)
Talc 3.2
Sodium lauryl sulphate NF - - - - - - - -
Antioxidant - - - - - 0.1 - -
Solubilizing Agent - - - - - 0.2 - -
Citric acid : Ascorbic (2:1) - - - - - - 7.5 -
Organic Acids (15:1) 6.5
Magnesium Stearate 2.8 2.5 - 1.5 1.0 0.8 1.0 0.8
TOTAL PERCENTAGE 100 100 100 100 100 100 100 100
Tablet weight (mg) 250 250 970 300 200 480 200 200
Hardness SCU (target) 8 8 9 7-9 7-9 8-11 8-11 8-11
Disintegration <15 MIN 5-15 5-15 5-15 5-15 5-15 5-15 5-15 5-15
KEY:-
[A] Diclofenac K Tab [B] Omeprazole Tab [C] Nabumetone Tab [D] Diclofenac Na Tab
[E]Diclofenac Na Tab [F] Bupropion [G] Simvastitin Tab [H] ISMN 20mg Tab
References: Handbook of Generic Development Tablets IR
Vol. 1 Edition II (1999), Locum Press

Handbook of Pharmaceutical Sect: 2 . 47 Generic Development

 TABLETS ORAL Development CHAPTER 2

Purified
problem becomes more acute.
The optimum scenario is for the R&D
department or development unit to be
connected, where possible to the same
Water water supply system as the commercial
production unit or alternatively install a
An Ingredient of Solid Dosage purified water system that mimics the
Form Development. proposed production quality, scheduled
for use in the full-size commercial lots.
‘develop all experimental batches This implies that the experimental
with batches, the scale-up lots, the process
Purified Water USP or Ph. Eur. -
similar or identical to the proposed qualification, pivotal and the initial three
commercial production quality.’ validation batches will all be prepared
and manufactured with commercial
production quality water.
T he use of appropriate water quality
as a non-active ingredient in the
development of pharmaceutical
The cleaning validation protocol
developed during the R&D phase
dosage forms, especially solid oral should use the same water quality.
granulating and coating solutions is
often realized at a late development
stage - occasional too late to be
Changing the
included in the product’s overall water quality during
development. product development
This section deals with the pitfalls of
failing to establishing strict criteria for may compromise
water quality both during pre- earlier results
formulation, formula development and
designing the cleaning validation Water quality for product development
protocol. should be at least purified water of
pharmacopoeial grade (USP / Ph. Eur)
Take a second look at and used from the very onset of the
development studies.
water as a key
The research or development water
non-active ingredient specifications should not change as the
for solid dosage form product develops and as the awareness
grows, that microbial parameters and
development pH are significant formula parameters,
to be evaluated in the development
Equivalent Commercial Quality process. Preparation of aqueous film
The development unit’s water quality coating solution during scale-up and
should be equivalent to the water early stability trials requires commercial
quality that is available for the quality purified water NF/BP
manufacture of the proposed Water-soluble semi-actives used (i.e.
commercial product. Where preservatives, anti-oxidants, chelating
development is separated from agents and coating dispersions) require
manufacture (in an overseas facility) formulation in a stable aqueous phase
the with standard and consistent
specifications.

Handbook of Pharmaceutical Sect: 2 . 49 Generic Development

 TABLETS ORAL Development CHAPTER 2

Using a higher than Similarly the use of a higher water

proposed water quality, (during the development stages
i.e. WFI) than the proposed plant
quality during commercial quality available, will result
product development in a commercial product with distorted
will simply bias pH parameters, as well as a biased
stability or impurity profile.
test results These products in special cases are
Using a lower water quality, which will prone to develop production problems
have a higher TOC (total organic resulting in greater microbial
carbon) level, will not necessary bioburdens or OOS chemical pH shifts
produce a more rugged product at the that frequently fail the product release
end of the development stage. specifications or worse still, fail the
annual commercial stability tests
The test results will simply be non- resulting in a drug product recall.
comparable with future, down the line,
test results where the water quality has
Many firms simply wonder why there is
been upgraded to a production quality, little correlation in the product quality,
for the manufacture of the exhibition as was so clearly demonstrated during
(pivotal) batch(es) required for the development, scale-up or pivotal
government agency registration batch lots. The answer may lie partly in
purposes. random ad-hoc water quality changes
that took place during the development
Specific microorganism, that are and scale-up procedures.
identified as an on-site contaminants in
a drug product ingredients may not be
Generic drug manufactures must
as significant as to the actual class and insure that the water quality remains
type of organism, it actually represents constant from pre-formulation to
in the manufacturing process or commercial validation and full scale
equipment configuration-layout that commercial batch manufacture. As a
allows for its continual survival, and non-active excipient, water quality
growth. Of special concern is the water specifications should not change once
used for granulation and preparing the formulation and drug product
coating solution (sugar, film or enteric). development stage is completed.
Pharmaceutical development units, Constant water quality
who upgrade water quality as the is required from
product nears final formation, may not
realize that the initial results based on a pre-formulation
lower water quality may have skewed to commercial
the early test results that now become validation
unsuitable for formula-to-formula
comparisons. Process qualification, pivotal and
Eventually the firm may not have a the commercial validation batches must
proper basis for developing a fully be manufactured with the same water
validated and optimized drug product or quality specification.
for that matter, an appropriate Most important, the physical, chemical
validation protocol without the need of and microbial specifications must be
repeating some of the initial constant from the pre-formulation lab-
developmental batch lots with the scale mini-batches to the commercial
applicable standardized commercial batch lots using on-site plant water.
water quality.

Handbook of Pharmaceutical Sect: 2 . 50 Generic Development

 TABLETS ORAL Development CHAPTER 2

equivalent to the proposed commercial

Overseas or remote batch quality.
R&D Do use the same microbiological
methods for bioburden evaluation (TMC
Development Units / MLT) as used at the commercial sites
must harmonize QC microbiological laboratory.

their water qualities Choosing the wrong

with commercial water quality
production during development
Remote Units:
and pilot work
Generic developers who are based in can seriously delay your
remote affiliations or research units (i.e. product launch.
overseas development units) that are
far removed from the commercial plant, Do inquire and obtain the commercial
where the proposed manufacturing will firms SOP / Policy, as to the use of
be effected by water quality changes. purified water in the commercial
Obtain batch-to-batch water quality product at the maximum alert limits.
analysis reports of the previous 6-12 Do research the proposed commercial
months manufactured lots (consecutive site’s water quality capability in the
batches) and carefully evaluate the early stages of product development.
physical,(pH) chemical ([salt]) and
especially microbial water specification
profiles.
Don’ts:
Note, the water bioburden is a function Don’t assume that the newly
of the purification process and the ad-
developed generic product will not be
hoc addition of an added carbon filter or
occasionally manufactured for
on-line membrane filter (0.2 micron) not
commercial use with a water quality
present in the proposed commercial
bioburden of 70 to 100 organisms per L
unit, may produce a higher water
quality, undesirable in development Don’t formulate blind if your
stages - that will certainly bias test development unit is remote from the
results. proposed commercial site and if you are
These deficiencies are the not given full and detailed water quality
development units concern; Should specifications and satisfactory replies to
your developmental SOPs omit the your water quality queries.
control of the water quality during the Don’t forget Good Manufacturing
generic development process and its Practices (GMP) in the development
synchronization with the water quality at unit are not a legal requirement in
the proposed manufacturing site. product development, but promote
formulation and scientific data validity.
Do’s and Don’ts - during solid
oral dosage form development: Don’t allow management resources or
new researchers to think 'water-is-just-
Do insure that the water quality used water ' - in drug development - it is not.
during product development is

Handbook of Pharmaceutical Sect: 2 . 51 Generic Development

 TABLETS ORAL Development CHAPTER 2

ØCHECK LIST ×
SOP # P-HGD-01-Y2K

PURIFIED WATER FOR DRUG DEVELOPMENT.

‘…without a full set of specifications and complete documentation

the purified water used is adulterated…’

Use Pharmacopeial Water Quality (from pre-formulation to validation):

1. The minimum water quality for development is purified water of qYesqNo

Pharmacopeial grade?

2. The latest Purified Water USP changes in the last Pharmacopeial qYesqNo
supplement has been checked for monograph changes?

3. The Purified Water used during the product development process qYesqNo
meets the requirements of the USP or Pharm Eur. monograph?

4. Each water test result falls within the USP/Pharm Eur. limits as qYesqNo
stated in the official monograph ?

5. The firms has a SOP requiring development to be performed using qYesqNo

water quality similar to the proposed commercial manufacturing site ?

6. Products being developed in R&D at the proposed commercial qYesqNo

manufacturing site use the same production water quality ?

7. Process Qualification, Pivotal and Validation batches actually use qYesqNo

purified water obtained from commercial production (where
geographically possible) and remote development sites mimic the
commercial production quality, at the same bioburden level?

8. The cleaning validation procedures and protocol is developed using qYesqNo

the same water quality?

9. No changes are permitted in water quality as the product qYesqNo

development procedures progress (prepare specific SOPs)?

10.Water quality higher than the commercial available quality is qYesqNo

prohibited in the drug development process ?

Handbook of Pharmaceutical Sect: 2 . 52 Generic Development

 TABLETS ORAL Development CHAPTER 2

ØCHECK LIST ×
SOP # P-HGD-01-Y2K

PURIFIED WATER FOR DRUG DEVELOPMENT.

‘…review water quality batch lots for microbial levels - in real time…’

11. Careful note is taken of the microbial alert and warning levels in force at the qYesqNo
proposed commercial site?

12. The firms water quality alert / action levels are set at NMT 30 qYesqNo
organisms/mL?

13. The firms water quality warning levels are set at NMT 70 organisms/mL? qYesqNo

14. The firms water quality used for granulating solutions or coating suspensions qYesqNo
are set at maximum level of NMT 100 organism / mL?

15. The presence of frequent found organisms at the proposed manufacturing qYesqNo
site are noted and incorporated during product development testing?

16. The indicator microbe pseudomonas statzeri is used during microbial qYesqNo
limit test Studies during the solid oral dosage form development stages?

17. Months of consecutive commercial quality water lots have been evaluated qYesqNo
for upper and lower bioburden parameters ?

18. The final end-formula when spiked with water quality at the alert or qYesqNo
maximum levels adequately meets the microbial limit test (if required)?

19. Bulk ingredient water is boiled (30 min) and cooled to the required qYesqNo
temperature immediately before use, when used in open type granulating kettles
for granulation fluid preparations?

20. Bulk water when not in immediate use, is maintained at around 80o C and qYesqNo
continually circulated in appropriate distribution piping (closed system)?

21. The company maintains a full batch-to-batch analysis profile (in real time) of qYesqNo
all water quality lots produced for product production use?

22. All alert/action and warning level results from the batch-to-batch analysis are qYesqNo
fully investigated and proper corrective action taken?

Handbook of Pharmaceutical Sect: 2 . 53 Generic Development

 ORAL TABLETS ACTIVES CHAPTER 3

Active Ingredients
‘Now think about the active ingredient, its source, its supply
and how to keep its specifications constant.’

Active Ingredients commercial validation batches must be

The active ingredient for your firms manufactured with the fully developed
generic drug must be cost-effective active drug substance. Most important
and freely available (for at least 8-10 the physical and chemical
years or even more). The active drug specifications must be constant from
substance should be a commercial batch to batch.
product batch and not a research or Generic developers should obtain a
development lot (as development batch-to-batch analysis report of the
specifications are still changing). last 6-10 manufacturing lots
Active ingredients for innovative drugs (consecutive batches) and carefully
still on patent with 2 or 3 years to go evaluate the impurity and degradative
are the active ingredients most analytical profiles.
interested to generic firms. Note, the impurity profile is a function
of the active drug synthesis
Changing specifications procedures. It should remain constant
Bulk pharmaceutical chemical firms
or improve with synthesis optimization.
(BPCs) synthesizing these active
substances may not have a fully However the degradative analytical
validated and optimized active product profile is a function of the stability and
and may supply generic firms with aging of the active drug substance that
developmental batch lots. can be evaluated analytically either
These R&D lots will most certainly under stress conditions (40oC/3
change in their drug substance months) alone or in combination with
specifications, especially particle size the formula excipients selected.
and bulk density as the process is Certain impurities from the actual drug
refined and optimized. The impurity synthesis may in fact increase in
profile will also change as the active percentage with drug product aging
firm optimizes the key synthesis steps under stressed conditions and may
and purification process. then be considered degradants in this
case.
Generic drug manufactures must
insure that the active drug Choose established actives
specifications do not change once the Ideally the active ingredient should be
formulation and drug product manufactured by an established and
development stage is reached. well known pharmaceutical bulk
Process qualification, pivotal and the chemical manufacturer (BPC).

Handbook of Pharmaceutical Sect: 3 . 1 Generic Development

 ORAL TABLETS ACTIVES CHAPTER 3

Active Ingredients
Remember, BPC companies are DMF or GMP deficiencies cited by the
inspected by the FDA and the bulk FDA?)
chemical manufacturer’ active drug Don’t use a firms active drug
substance your generic firm may substance it you are not given full and
require or the bulk firms GMP may be detailed specifications and satisfactory
cited for a series of regulatory or drug replies to your DMF and GMP queries
master file (DMF) deficiencies. (Request the firms last two EIRs from
These deficiencies are your concern, the FOI services.)
should you choose to use their active Don’t be the first to reference the
drug substance for generic active drug in your ANDA unless a
development. Any DMF deficiencies thorough investigation has been made
at the time of ANDA submission will and all the active drug specifications
affect and delay the approval process are satisfactory.
of your generic ANDA file.
Don’t forget to place two or more
It is essential for the generic developer active drug batches (different lots #’s)
to communicate with the BPC firms’ on stability (40oC/3 months) in order to
regulatory affairs department and obtain a complete stressed analytical
request a summary of outstanding profile (examine all extraneous HPLC
DMF and GMP deficiencies specific to peaks obtained and cross check
the particular active drug required for unidentified peak ID with the active
your generic drug product manufacturer).
development. Part two of the
Handbook contains model systems of Don’t ever mix two lot/batch numbers
all the vendor / developer of the active drug substance for a
documentation requirements. developmental, analytical, pivotal or
validation study, due to insufficient
Do’s and Don’ts:- material.
Do insure that the batch lots of active Don’t use active material older than
drug are commercial batches.
18 months to two years for analytical,
Do obtain the drug’s active analytical stability or impurity studies, as non-
profile from the manufacture (for representative and non-comparative
commercial batches). data will be obtained.
Do request and obtain the drug active Don’t forget to obtain a statement
physical specifications on bulk density
from the DMF holder (the active drug
and particle size, (obtain analytical
manufacturer) that all issues
methods used to determine these
communicated to the DMF holder by
parameters).
the FDA have been fully addressed i.e.
Do get a analytical batch analysis of all deficiencies in the active DMF have
the last 6-10 consecutive commercial been corrected and at the time of
batches. writing there are no outstanding
Do inquire about the regulatory status deficiencies. These corrections are
of the firms DMF (has the DMF been also specific to the samples of
referred to previously by other ANDA commercial batches your firm has
applicants and are there outstanding received for development studies.

Handbook of Pharmaceutical Sect: 3 . 2 Generic Development

 ORAL TABLETS ACTIVES CHAPTER 3

ØC H E C K L I S T ×
CL # P-HGD-02-Y2K

Active Ingredients Check - Approval of Supplier.

‘…without a full set of specifications and complete documentation

the active material is adulterated’…

For Pharmacopoeia Active Drug Substances - (from Approved Suppliers):

1. A full USP Certificate of Analysis has been supplied? qYes qNo.

2. Each analytical test falls within the USP/NF limits as stated in the official qYes qNo.
USP monograph?

3. If the USP active material monograph is in the BP as well then the active qYes qNo.
passes the BP ‘Related Substances’ monograph test?

4. IR and UV Identification spectra (as per the USP/NF Identification test) qYes qNo.
has been supplied by the manufacturer?

5. IR Identification Spectra of Official Reference Standards (see Forum) qYes qNo.

have been compared with the active drug substance?

6. All spectra are fully labeled and show the active materials lot # ? qYes qNo.

7. A letter of authorization obtained from the active supplier (DMF holder) qYes qNo.
addressed to the ANDA applicant referencing the active DMF #, as used in
the ANDA generic product?

8. The DMF holder (active manufacturer) has included a statement that all qYes qNo.
FDA issues / concerns communicated to the DMF holder i.e. deficiencies in
the active DMF have been fully addressed?

9. The active material safety data sheet has been provided by the approved qYes qNo.
supplier?

10. The latest USP supplement has been checked for monograph changes? qYes qNo.

Footnote : Checklist applies to non compendial (non USP) active drug substances - where applicable .

Handbook of Pharmaceutical Sect: 3 . 3 Generic Development

 ORAL TABLETS ACTIVES CHAPTER 3

Active Ingredients
‘…timeline for active materials from first look to Approved Supplier…’

An Approved Supplier of an active Five Aging parameters :

drug substance is the chosen vendor Stability studies emphasizing assay,
that consistently meets the impurity profile and degradants,
specifications and documentation dissolution, and possible changes in
requirements of the generic drug polymorphic/crystal habit forms.
developer. Analytical methods
Step 1 - The referenced listed drug The assay and stability indicating
(RLD) must be purchased immediately method should be well established
the project is authorized for formula during this stage of the vendor
evaluation. certification process.
Step 2 - Analytical know how : Step 3 - Candidate vendor samples :
Analytical assay and test procedures Once a potential candidate
must commence immediately in the manufacturer (active) has been
following key sections :- identified - obtain a minimum of three
Physical parameters different batch/lots for a full analytical
Bulk density and particle size are profile and batch-to-batch analysis.
essential QC parameters. The drug Step 4 - DMF and GMP issues :
solubility should be established in the Resolve any outstanding 'DMF & GMP'
intended dissolution media at the issues. (No FDA deficiencies or future
specification pH). changes in active specifications).
If the drug substance is a polymorph Step 5 - Full analytical profile :
then the type of polymorph must be Perform all test procedures to obtain a
established and the active polymorph full analytical profile. Analytical
stability evaluate with aging. Check for procedures should be well qualified at
crystal changes during aging and this time point.
stability testing. Step 6 - Batch-to-batch analysis:
(Remember: the manufacturing Perform a full batch-to-batch analysis
parameters may affect and change the with in-house and vendor supplied
polymorphic form and crystal habit data. Consult BSC classification1.
inadvertently.) Investigate all abnormal results and
Chemical parameters review with vendor to a satisfactory
Assay, impurity profile and degradants conclusion.
produced on aging (stability studies)
Step 7 - Stability Profile :
and dissolution are the standard
Conduct accelerated stability study on
stability tests. Hardness, thickness and
active drug substance alone and in the
disintegration are routine Quality
proposed formulation.
Control manufacturing tests.
Microbial parameters Step 8 - Approved Supplier :
Evaluate the microbial purity of the Approval of active supplier with all
active if a bioburden is suspected active specifications to purchasing
originating from the active preparation department.
1
or synthesis or if the active is derived Biopharmaceutics Classification System and potential In-
from a biological source. Vitro In-Vivo Correlations.

Handbook of Pharmaceutical Sect: 3 . 4 Generic Development

 ORAL TABLETS ACTIVES CHAPTER 3

ØC H E C K L I S T ×
CL # P-HGD-02-Y2K

Active Ingredients - Approved Suppliers.

‘…one approved active good - two approved suppliers better’…

1. Three different batch lots of RLD purchased? qYes qNo.

2. Candidate samples of active drug obtained? qYes qNo.

3. Bulk density and particle size evaluated ? qYes qNo.

4. Active solubility evaluated in proposed vehicle ? qYes qNo.

5. Can active drug exist as a polymorph ? qYes qNo.

6. If a potential polymorph, protocol for evaluation available? qYes qNo.

7. Protocol for active crystal habit studies available ? qYes qNo.

8. Vendor EIR reviewed and audited as satisfactory qYes qNo.

9. Vendor DMF and GMP issues have been fully resolved qYes qNo.

10. Vendor statement on final specification obtained ? qYes qNo.

11. A full batch-to-batch analysis with three lot #’s has been tested? qYes qNo.

12. All abnormal results from the batch-to-batch analysis qYes qNo.
investigated

13. Are the accelerated stability results of the active drug qYes qNo.
substance alone and in the proposed formulation approvable ?

14. Does the purchasing department have a full set of approved qYes qNo.
specifications ?

15. Has a vendor approval certificate for the approved active been qYes qNo.
issued (copy with purchasing department)

Handbook of Pharmaceutical Sect: 3 . 5 Generic Development

 ORAL TABLETS ACTIVES CHAPTER 3

STANDARD OPERATING
PROCEDURES
SOP # P-HGD-02-Y2K

Active Ingredients - Approved Suppliers.

The following selected model Standard Operating Procedures are recommended for a generic
development unit :

ACTIVE INGREDIENTS
P-000-02- Y2K Active Drug Substances for Generic Drugs.
P-000-02- Y2K Active Drug Substances specifications procedure prior to purchasing.
P-000-02-Y2K Vendor Certification Requirements for Approved Actives.
P-000-02-Y2K Decision tree for establishing impurity acceptance criteria.
P-000-02-Y2K Decision tree for establishing degradation acceptance criteria.
P-000-02-Y2K Decision tree for establishing particle size acceptance criteria.
.P-000-02-Y2K Decision tree for establishing polymorphism existence.
.P-000-02-Y2K Decision tree for establishing microbiological testing.
.P-000-02-Y2K Decision tree for evaluating chiral actives.
P-000-02-Y2K Developing Product Formula with Approved Actives.
P-000-02-Y2K Inventory Records for the Active Drug Substance.
P-000-02-Y2K Investigating and handling abnormal batch results.
1
Solid State Forms Some drug substances exist in different solid state forms
(polymorphs or solvates) which differ in their physical properties. Differences in
these forms have been shown to affect drug product performance, dissolution
bioavailability and stability.
1
Polymorphism: the occurrences of different crystalline forms of the same drug
substance. This may include solvation or hydration products (also known as
pseudopolymorphism) and amorphous forms.
Physico-chemical measurements and techniques are commonly used to determine
whether multiple forms exist. Examples of these procedures are:
n Melting point (including hot stage microscopy)
n Solid State Infra Red Common tests
n X-Ray Powder Diffraction in Generic
n Thermal Analysis (DSC ; TGA ; DTA) Actives
-------------------------------------------------------------
n Raman Spectroscopy
n Scanning Electron Microscopy Less
n Solid State NMR common
procedures
4
[End of Document]

ED. N0: 02 Effective Date APPROVED:

Replaces Ed 01. :
Ed. Status: MM/DD/2000
Operational Department R&D QC QA

Handbook of Pharmaceutical Sect: 3 . 6 Generic Development

 ORAL TABLETS SEMI-ACTIVES CHAPTER 4

'Semi Actives'
‘…Challenge each preservative and anti-oxidant system during
development and then optimize its formula concentration…’

Semi active ingredients Release specification: 85.0 -105.0%.

S emi active ingredients

preservative systems, antioxidants
are Check specification:
Tablet
55.0 -105.0%
formulations can and do
and chelating excipients. They are not
active ingredients nor are they fully consume the anti-oxidant system
inactive ingredients as they maintain during the product’s shelf life. Heavy
the quality, inhibit impurity / degradant metals may act a catalysts and
growth and enhance stability of the degrade active and semi-actives.
product formula. Specifications, as above have a very
Choosing semi active ingredients. limited value in a drug development
The evaluation of semi active program. Evaluating the total summed
ingredients requires thorough heavy metal content of the combined
optimization qualification for: excipients (from their Certificate of
◊ the anti-oxidant system Analyses) may provide a starting
◊ the chelating agent(s) baseline for the choice of a suitable
antioxidant.
These systems maintain an active role
by (a) minimizing the potency loss of The development formula optimization
the active ingredient(s) and (b) should tabulate the loss of assay
stabilizing the drug product's impurities potency and impurity / degradant
during aging. growth for the active substance over
an accelerated shelf life period of 0,1 2
The anti-oxidant system may well and 3 months at 400 C / 75% RH
degrade significantly with time and This formula optimization procedure
therefore does not require any simply eliminates any routine
qualification or testing of its upper and antioxidant testing in the future.
lower operational limits.
These antioxidant qualification studies
It is important to establish and validate are needed during the product
drug assay and impurity profiles during development stage and once
the formula development (optimization) performed, close the requirement for
stage. Following this development path any further testing. This important
the actual antioxidant loss need not be example shows how careful product
established or even qualified during development can result in reduced QC
the product development stage. routine finished product testing.
Formula Optimization:
A anti-oxidant optimization protocol
The first three commercial validation
(provided in this chapter) will enable lots do not require antioxidant release
drug developers to fully eliminate or stability check testing as their
antioxidant release and check formula inclusion was qualified during
specifications from routine product the development optimization phase.
release and stability testing Product release specifications must
requirements of the pivotal and not become, in part, a substitute for
subsequent commercial marketed incomplete development validation
batches of the type: testing.

Handbook of Pharmaceutical Sect: 4 . 1 Generic Development

 ORAL TABLETS SEMI-ACTIVES CHAPTER 4

ØC H E C K L I S T ×
CL # P-HGD-03-Y2K

Validating the Semi Active Ingredients

‘ don’t test a semi-active after it has been qualified...’

1. A full development validation/qualification study of the antioxidant has q Yes qNo

been performed during the development process ?

2. Has a range of antioxidant percentages been qualified by development q Yes qNo

optimization studies. (e.g. lower [0.05%] middle [0.1%] and upper [0.15%])?

3. Does the of the antioxidant percent chosen represent the lowest % value q Yes qNo
to minimize impurities and degradants during the inferred product shelf life?

4. Has the overall excipient formula been evaluated for total heavy metal q Yes qNo
content from the inactive C of As and product specification data sheets?

5. Have reducing agents, antioxidant synergist and sequestering agents that q Yes qNo
have not been appropriately validated, been excluded from the product
formula?

6. Does the active ingredient remain in the check specification range (90.0 - q Yes qNo
110.0 of labeled amount) at the end of accelerated stability testing?

7. Does the potency of the active ingredient decrease when the chelating q Yes qNo
agent is removed from the product formulation during normal and aging
studies?

8. Have range studies been performed to evaluate the optimum amount? qYes qNo
9. Has the product formula been evaluated at lower, middle and upper q Yes qNo
antioxidant percentages and evaluated against active assay values?

10. Has it been clearly established that the inclusion of chelating or an q Yes qNo
antioxidant synergist positively enhances the action of the antioxidant?

11. Has potency loss of the semi actives been fully demonstrated during the q Yes qNo
product development stages to establish valid specification ranges?

12. Does the stability testing protocol only evaluate formula specifications q Yes qNo
that are directly impacted by the aging process ?

13. Has a complete product development profile of the antioxidant been q Yes qNo
evaluated in order to eliminate routine release and stability testing of the
antioxidant agent during commercial manufacture ?

14. Is the stability testing protocol for the pivotal batch a logical q Yes qNo
development sequence from the product development work ?
Footnote :
Bold numbers in checklist indicate this work must be qualified and or validated before
manufacturing the Process Qualification Batch, which actually marks the end of the product
development stage.

Handbook of Pharmaceutical Sect: 4 . 2 Generic Development

 TABLETS ORAL S E M I - A C T I V E S CHAPTER 4

Qualifying
Observations and Results:
⇒ Batch P-04 manufactured without
Cremophor displayed, higher hardness, a
short disintegration time and good
the ANTIOXIDANT stability results compared with batches
manufactured with Cremophor™.
T he qualification of the antioxidant
concentration in the formula is shown
here as an example in order to
⇒ Observations during the tabletting
process showed that batches formulated
with Cremophor™ did not achieve the
evaluate the effect of increasing target hardness, thus the use of solubility
quantities of the antioxidant Butylated agent for BHA is thereby eliminated
Hydroxyanisole.
BHA ranging from zero (acting as a Stability tests demonstrated that:
control) to a maximum of 0.15 percent of ♦ Control Batch, P-05 manufactured
the tablet weight is incorporated into a without BHA showed an significant
250 mg immediate release oral tablet increase in the percent of impurities /
formulation (Ref. Table No. 01). degradation products after the one month
interval. (Refer Table 7 - shaded area)
The use of Cremophor™ RH40 (ranging
♦ Formulations containing BHA
from zero percent to a maximum of 0.5%
antioxidant quantities between 0.05%
of the tablet weight) is added to evaluate
(0.195mg) and 0.15% (0.580mg) of the
a possible improvement in the Butylated
tablet core weight, afforded adequate
Hydroxyanisole NF solubility during the
stability results for Assay and Impurities.
manufacturing stages.
♦ As thin layer chromatography and
The granulation is performed via a High supporting HPLC impurity analysis
Shear Granulator (Diosna P-10™) using demonstrates that similar results were
dry PVP K-30™ as the tablet binder and obtained, it is concluded that presence of
Purified Water USP as the granulation BHA serves as an antioxidant that inhibits
agent. Microcrystalline Cellulose is and retards the growth of impurities and
incorporated extra-granularly. degradants.
The tablet cores are coated in the Accela Based on the above antioxidant
Cota™ A10 and the film-coated tablets, qualification experiments the choice of
packaged in High Density Polyethylene formula, P-04 (0.1% BHA) was selected
containers, which are evaluated for for further in the optimization and
stability at accelerated stability conditions qualification batch development:
of 40°C / 75% RH for 3 months. Stability Chosen Formula:
Indicating tests methods (TLC and HPLC)
used for investigating Assay, Dissolution • Active material 250 mg
and known Impurities are fully validated.
• PVP K-30 - (Dry binder)
The physical parameters of the • Microcrystalline Cellulose NF - (Dry Filler)
granulates tested are shown in Table No.
02 and the granulates for all batches • Dry Starch NF (Disintegrant)
demonstrated adequate flow and • BHA (Antioxidant 0.1%)
compressibility characteristics. The • Purified Water USP (Granulation fluid)
physical test results for the tablet cores
are presented in Table No. 03. • Stearic Acid NF (~1.4 - 1.5%)
The optimization batch stability results • Magnesium Stearate NF (~0.25%)
are presented in Table No. 04 - 07
.

Handbook of Pharmaceutical Sect: 4 . 3 Generic Development

TABLETS ORAL S E M I - A C T I V E S CHAPTER 4

Qualification of Antioxidant
Oral Tablets 250 mg Active Material
Optimization Batch Stage
Table No. 01.
Formulae Ingredients Amount per tablet core (mg)
ò
P-01 P-02 P-03 P-04 P-05
Batch No. è
Part I - Pre-mix (dry) High shear mixing Control Control
Active Material 250.0 250.0 250.0 250.0 250.0
Microcrystalline Cellulose NF 30.0 30.0 30.0 30.0 30.0
(Avicel PH101™)
Povidone USP 8.0 8.0 8.0 8.0 8.0
PVP K-30™
Starch NF 40.0 40.0 40.0 40.0 40.0
Part II - Granulation solution Granulating Stage
Butylated Hydroxyanisole NF 0.195 0.580 0.390 0.390 -
(BHA). (0.05%) (0.15%) (0.1%) (0.1%) (Control)
Polyoxyl 40 Hydrogenerated 2.0 2.0 2.0 - 2.0
Caster Oil NF. (Control)
(Cremophor RH40™)
Alcohol USP (95%) Qs Qs Qs Qs Qs
Purified Water USP Qs Qs Qs Qs Qs
PART III - Extra-granule Dry Mixing
Microcrystalline Cellulose NF 52.8 52.4 52.6 50.6 53.0
(Avicel PH102™)
PART IV - Lubrication Rapid Dry Blending
Stearic Acid NF 6.0 6.0 6.0 6.0 6.0
Magnesium Stearate NF 1.0 1.0 1.0 1.0 1.0
Total Core Weight 390.0 390.0 390.0 390.0 390.0

AQUEOUS FILM COATING SUSPENSION

Opadry OY-S-345™ - Orange 10.0 10.0 10.0 10.0 10.0
Purified Water USP Qs Qs Qs Qs Qs
Total 400.0 400.0 400.0 400.0 400.0
Note: Qs = Processing aqueous and non-aqueous solvents only.
The tabulated data highlight the process optimization stage - once the correct formula has been decided
upon. All development work performed on the antioxidant and solubilizing agent (Cremophore™) are
evaluated at this stage, just prior to the Process Qualification Batch. Inclusion in this chapter is for
explanation purposes only.

Handbook of Pharmaceutical Sect: 4 . 4 Generic Development

TABLETS ORAL S E M I - A C T I V E S CHAPTER 4

Qualification of Antioxidant
Table No. 02.

Ø Optimization Batch Stage - Granulate Physical Characterization

Oral Tablets containing 250 mg of Active Material
BATCH NO. è P-01 P-02 P-03 P-04 P-05
Granulation Tests Results:
Bulk Density (BD) 0.59 0.60 0.61 0.60 0.62
(g/mL)
Tapped Bulk Density (TD) 0.73 0.74 0.75 0.72 0.74
(g/mL)
Carr’s Index - Compressibility (%) 14 14 15 16 14

Sieve Analysis Method Jet or Sonic Sifter

Percentage remaining
Sieve 20 Mesh 0.4 0.3 0.3 0.3 0.6
Sieve 40 Mesh 24.5 8.7 15.0 13.5 14.9
Sieve 60 Mesh 40.0 37.0 38.0 37.2 38.0
Sieve 80 Mesh 15.6 22.2 18.0 19.1 18.9
Sieve 100 mesh 5.6 9.2 7.3 7.1 6.7
Amount in PAN 13.4 22.2 20.5 22.5 21.3
LOD (%) 3.0 2.3 2.5 3.3 2.4

Table No. 03.

Ø Optimization Batch Stage - Physical Test Results

Physical Tests Oral Tablets 250 mg Active Material.

Batch No è P-01 P-02 P-03 P-04 P-05

TABLET CORES Control Control

Hardness 8 9 8 13 9
Average of 10 (SCU)
Disintegration Time 1:55 1:47 1:50 1:31 1:33
Average of 6 (min)
Friability (%) 0.21 0.16 0.2 0.15 0.15

COATED TABLET
Disintegration Time 2:55 2:50 2:35 2:26 3:05
Average of 6 (min)
P-04 &- P-05 Control Batches.
Reference:
Carr’s Index - Compressibility = (CVD-BD) / CVD×100) Wells, J.I. - Pharmaceutical Preformulation -
Chapter 7: Powder Flow Properties.)

Handbook of Pharmaceutical Sect: 4 . 5 Generic Development

 TABLETS ORAL S E M I - A C T I V E S CHAPTER 4

Qualification of Antioxidant
Oral Tablets 250 mg Active Material

Optimization Batch Stage - Stability studies

Container / closure system : HDPE container 110cc

Fill size : 150 tablets
Storage conditions : 40°C / 75% Relative Humidity
Table No. 04.

Assay and Impurities (%)

Batch P-01 Containing BHA 0.05% w/w

Parameters Thin Layer (TLC) HPLC

Storage Appearance Disint Assay Impurity Impurity Impurity ANY TOTAL Impurity ANY TOTAL
(months) Time I II III Impurity
I II Impurity Impurity
(min) TLC TLC TLC I HPLC II II

Specs. White to Off NMT 90.0 - NMT NMT NMT NMT NMT NMT NMT NMT
White 15 110.0 1.0 0.5 0.5 0.1 0.5 0.1
3.0 1.0
0 Conforms 2’54” 102.0 <0.1 <0.1 <0.1 <0.1 <0.3 <0.02 <0.02 <0.04
1 Conforms 3’09” 99.8 <0.1 <0.1 <0.1 <0.1 <0.3 <0.02 0.02 0.04
2 Conforms 2’46” 101.2 <0.1 <0.1 0.1 0.1 <0.3 0.05 0.05 0.10
3 Conforms 2’43” 100.8 <0.1 0.1 0.1 0.1 0.3 0.1 0.05 0.15

Table No. 05.

Assay and Impurities (%)
Batch P-02 - Containing BHA 0.15% w/w
Parameters Thin Layer (TLC) HPLC
Storage Appear Disint. Assay Impurity Impurity Impurity ANY TOTAL Impurity ANY TOTAL
(months) ance Time I II III Impurity I II Impurity Impurity
(min) TLC TLC TLC I HPLC II II
Specs White to NMT 90.0 - NMT NMT NMT NMT NMT NMT NMT NMT
Off 15 110.0 1.0 0.5 0.5 0.1 3.0 0.5 0.1 1.0
White
0 Conforms 2’46” 102.6 <0.1 <0.1 <0.1 <0.1 <0.3 <0.02 <0.02 <0.04
1 Conforms 2’45” 101.4 <0.1 <0.1 <0.1 <0.1 <0.3 <0.02 <0.02 <0.04
2 Conforms 2’55” 100.0 <0.1 <0.1 <0.1 <0.1 <0.3 <0.02 <0.05 <0.06
3 Conforms 2’45” 100.8 <0.1 <0.1 <0.1 0.1 0.3 <0.02 <0.05 <0.07

Key:
Assay % of Label Claim of Active BHA - Butylated Hydroxyanisole NF Dissolution % of Label Claim of Active
ANY I = Any other impurities (by TLC) TOTAL I = Total impurities (by TLC) ANY II = Any other impurities (HPLC)
TOTAL II = Total impurities (by HPLC)

Handbook of Pharmaceutical Sect: 4 . 6 Generic Development

 TABLETS ORAL S E M I - A C T I V E S CHAPTER 4

Qualification of Antioxidant
Oral Tablets 250 mg Active Material
Batch No: P01

Stability Studies I - Optimization Batch Stage

Container / closure system : HDPE container 110cc Fill size : 150 Tablets
Storage conditions : 40°C / 75% Relative Humidity Mfg. Date:
Packaging Date: Expiration: Date Stability Start Date:

Storage Appearance Disinte- Assay (%) Dissolution (%)

(months) gration (CV)
Time (min)
(Containing BHA 0.05% w/w)
Assay Impurity Impurity Impurity ANY TOTAL Impurity ANY TOT 10’ 20’ 30’
I II III I I II II
Impurity
TLC TLC TLC I HPLC

Specs. White to Off NMT 15 90.0- NMT NMT 0.5 NMT 0.5 NMT 0.1 NMT 3.0 NMT 0.5 NMT 0.1 NMT 1.0 NLT 75% (Q)
White 110.0 1.0 dissolved in 30’

0 Conforms 2'.45'' 102.8 <0.1 <0.1 <0.1 <0.1 <0.3 <0.02 <0.02 <0.04 92.6 98.1 96.9
(5.1) (3.0) (4.5)

1 Conforms 2'..34'' 100.9 <0.1 <0.1 <0.1 <0.1 <0.3 <0.02 <0.02 <0.04 98.0
(2.1)

2 Conforms 2'..45'' 100.9 <0.3 <0.1 <0.1 <0.1 <0.5 <0.02 <0.05 0.07 99.8
(2.2)

3 Conforms 2'':55'' 102.1 0.3 0.1 0.1 0.1 0.5 0.06 0.05 0.11 95.1 97.2 96.7
(3.2) (2.4) (1.4)
Table No. 05

Handbook of Pharmaceutical Sect: 4 . 7 Generic Development

 TABLETS ORAL S E M I - A C T I V E S CHAPTER 4

Qualification of Antioxidant
Oral Tablets 250 mg Active Material
0.15% Antioxidant - Test Batch
Batch No: P02

Stability Studies II - Optimization Batch Stage

Container / closure system : HDPE container 110cc Fill size : 150 Tablets QL Impurity I = 0.1%
Storage conditions : 40°C / 75% Relative Humidity Mfg. Date: QL Impurity II = 0.05%
Packaging Date : Expiration: Date Stability Start Date: QL Impurity III = 0.05%

Storage Appearance Disint. Assay (%) Dissolution (%)

Time
(months) (Containing BHA 0.15% W/W)
(min.)
& (CV)
Assay Impurity Impurity Impurity ANY TOTAL Impurity ANY TOTAL 10’ 20’ 30’
I II III Impurity Impurity HPLC HPLC HPLC
TLC TLC TLC
Specs. White to Off NMT 15 90.0- NMT 1.0 NMT 0.5 NMT 0.5 NMT 0.1 NMT 3.0 NMT 0.5 NMT 0.1 NMT 1.0 NLT 75% (Q)
White 110.0 dissolved in 30’
0 Conforms 2'.4.0'' 101.6 <0.1 <0.1 <0.1 <0.1 <0.3 <0.02 <0.02 <0.04 95.3 98.6 98.1
(2.1) (1.9) (0.8)
1 Conforms 2'.50'' 102.8 <0.1 <0.1 <0.1 <0.1 <0.3 <0.02 <0.05 <0.04 94.2
(3.2)
2 Conforms 2'.'45'' 99.8 <0.1 <0.1 <0.1 <0.1 <0.4 <0.02 <0.05 0.07 97.9
(2.0)
3 Conforms 2'.45'' 100.2 <0.1 <0.1 <0.1 <0.1 <0.3 <0.02 <0.05 <0.07 93.1 97.2 95.8
(3.5) (2.4) (1.8)
Tests
Table No. 06 not
State the Detection limit Required
for each impurity

Handbook of Pharmaceutical Sect: 4 . 8 Generic Development

 TABLETS ORAL S E M I - A C T I V E S CHAPTER 4

Qualification of Antioxidant
Oral Tablets 250 mg Active Material
No Antioxidant - Control Batch
Batch No: P05

Stability Studies II - Optimization Batch Stage

Container / closure system : HDPE container 110cc Fill size : 150 Tablets
Storage conditions : 40°C / 75% Relative Humidity Mfg. Date:
Packaging Date: Expiration: Date Stability Start Date:

Storage Appearance Disinte-

(months) gration. Assay (%)
Time
(min) WITHOUT BHA
Assay Impurity Impurity Impurity ANY TOTAL Impurity ANY TOTAL
I II III Impurity Impurity HPLC HPLC HPLC
TLC TLC TLC TLC TLC

Specs. White to NMT 15 90.0- NMT 1.0 NMT 0.5 NMT 0.5 NMT 0.1 NMT 3.0 NMT 0.5 NMT 0.1 NMT 1.0
Off White 110.0
0 Conforms 2’40” 100.8 <0.1 <0.1 <0.1 <0.1 0.1 <0.03 <0.02 <0.05
1 Conforms 2’50” 99.8 0.2 0.1 0.1 0.1 0.4 <0.03 <0.62 <0.65
2 Conforms 2.55” 101.8 0.6 <0.1 0.2 0.2 1.1 <0.02 <0.58 0.60
3 Conforms 2.40” 102.2 1.4 <0.2 0.2 0.21 2.0 <0.04 <0.84 <0.88
Table No. 07
Note: Control Batch - No dissolution studies necessary High Impurity Significant
value indicate Increase in
antioxidant impurities
requirements

Handbook of Pharmaceutical Sect: 4 . 9 Generic Development

 TABLETS ORAL S E M I - A C T I V E S CHAPTER 4

Qualification of Antioxidant
Oral Tablets 250 mg Active Material

REFERENCE LISTED DRUG

Batch No: RLD -0705

Stability Studies II - Optimization Batch Stage

Container / closure system : HDPE container 110cc Fill size : 150 Tablets
Storage conditions : 40°C / 75% Relative Humidity Mfg. Date:
Packaging Date: Expiration: Date Stability Start Date:

Storage Appearance Disinte-

(months) gration. Assay (%)
Time
(min) 0.1% - BHA
Assay Impurity Impurity Impurity ANY TOTAL Impurity ANY TOTAL
I II III Impurity Impurity HPLC HPLC HPLC
TLC TLC TLC TLC TLC

Specs. White to NMT 15 90.0- NMT 1.0 NMT 0.5 NMT 0.5 NMT 0.1 NMT 3.0 NMT 0.5 NMT 0.1 NMT 1.0
Off White 110.0
0 Conforms 2’55” 101.8 <0.1 <0.1 <0.2 <0.1 0.5 <0.03 <0.05 <0.08
1 Conforms 2’40” 100.7 0.2 0.1 0.1 0.1 05 <0.03 <0.05 <0.08
2 Conforms 2.50” 100.8 0.5 <0.2 0.2 0.05 0.95 <0.02 <0.05 0.07
3 Conforms 2.50” 103.9 0.6 <0.4 0.3 0.1 1.4 <0.04 <0.10 <0.14
Table No. 07B
Note: Reference Batch - Dissolution studies necessary
Impurities
serve as a
REFERENCE

Handbook of Pharmaceutical Sect: 4 . 10 Generic Development

TABLETS ORAL NON-ACTIVE - EXCIPIENTS CHAPTER 5

Non active Ingredients

‘…Each excipient must play its role - and all non active ingredients must be entirely
necessary.’

NON ACTIVE INGREDIENTS General Excipient Rules:

Non active ingredients for single dose The non-active should ideally be
oral tablet preparations are required to compendial (USP/NF; BP; EP; JP etc.)
meet certain minimum agency criteria: • The non-active should ideally be in
For ANDA submissions, the non active the Handbook of Pharmaceutical
must appear in the FDA’s Inactive Excipients (current 2nd Edition)
Ingredient Guide (IIG). This guide is a
list of inactive ingredients that have • The non-active must be in the FDA’s
been used in currently marketed OTC IIG-Inactive Ingredient Guide regarding
and prescription drug products for a ⇒ same dosage route only
specific route - in this case for oral ⇒ maximum percentage not
use. exceeded.
The second key condition for the non • If the non-active is for an OTC tablet
active ingredient is that the percentage product only (not an ANDA) then it
amount used in the product formula should be at least in the GRAS1 lists.
must not exceed the maximum • It is strongly recommended that non-
percentage for the specific route (e.g. actives selected for ANDA formula are
oral use) as stated in the Inactive subject to approved supplier procedures
Ingredient Guide. - similar to Active Ingredients.
The maximum quantity of a specific Inactive ingredients specifications
non active ingredient is generally Inactive ingredients with unspecified
determined by the FDA as the highest physical size parameters may require
amount of non active that is currently quality control in two critical physical
approved for an OTC or ANDA product specifications (e.g. Magnesium stearate):
for that specific dosage form or route ◊ particle size specification
of administration. ◊ bulk density specification
ANDA approvals may be OTCs or Uniformity of Content-Granulate studies
prescription products. The above It is important that generic
'quantitative control' apply only to ANDA
manufacturers correlate excipient
submissions and do not apply to OTC
specifications and evaluate the impact
non-ANDA products.
on the bulk granulate ‘uniformity of
Choosing non-active ingredients. content’ assay during in-process
Excipient-to-excipient interactions (color manufacture. Lubricated and un-
effects and incompatibilities) must be lubricated granulation studies evaluating
excluded early in development. mixing time for Content Uniformity and
Uniformity of Content for granule and dissolution profile are recommended.
tablet may be impacted by the physical Specifications for particle size and bulk
specifications of the excipients. density ranges should be clearly
Generic manufacturers who evaluate specified in order to prevent significant
the reference listed drug (RLD) and differences (< 5%) in batch-to-batch and
design a Q&Q formula may minimize intra-batch dissolution assay values.
fluctuations in dissolution and
bioequivalent testing.

Handbook of Pharmaceutical Sect: 5 . 1 Generic Development

 TABLETS ORAL NON-ACTIVE - EXCIPIENTS CHAPTER 5

ØC H E C K L I S T ×
CL # P-HPGD-03-Y2K

Non active ingredients

‘qualify the excipient performance at both ends of the given
specification range qualify the process performance with the chosen
excipients’

1. Has the RLD’s non active ingredients been qualitatively identified ? qYes qNo
2. Is the generic formulation a basic Q&Q formula of the RLD ? qYes qNo
3. Are the non actives referenced in the FDA’s IIG Guide qYes qNo
4. Has the maximum percentage not been exceeded for oral tablets? qYes qNo
5. Has the particle size and bulk density of key non actives (e.g. qYes qNo
lubricants) been specified with an appropriate range?
6. Is the dissolution profile of the proposed generic formula similar to qYes qNo
the RLD's profile?
7. Are the comparative 12 point dissolution values all within 5% of the qYes qNo
RLD dissolution profile under normal and accelerated testing?
8. Is the granulation uniformity of content spread less than 4.0 - 5.0% qYes qNo
with RSD ,6.0%?
9. Does the development protocol indicate that the final formula is qYes qNo
manufactures at the lower and upper tabletting speeds ?
10. Does the firm regularly review the Pharmacopoeial Forum for qYes qNo
proposed monographs and specifications for non-compendial
excipients ?
11. Has the firm reviewed all the suppliers for potential ‘Approved qYes qNo
Suppliers’ as listed the Handbook of Pharmaceutical Excipients ?
12. Is Purified Water USP used as an approved excipient granulating qYes qNo
agent and coating suspension ingredient?
13. Have the excipient specifications been reviewed in USP / NF, qYes qNo
Ph. Eur / BP, and JP and the latest supplements and addenda?
14. For compendial excipients has the latest supplement been qYes qNo
checked ?
15. Does your generic firm have a current ‘ Approved Supplier SOP ' qYes qNo
for non active ingredients?
Footnote : The words non active ingredient; inactive ingredient and excipient are all the same meaning and interchangeable in use.
1
GRAS - Generally Accepted As Safe (Ref. 21 Code FR )

Handbook of Pharmaceutical Sect: 5 . 2 Generic Development

TABLETS ORAL NON-ACTIVE - EXCIPIENTS CHAPTER 5

STANDARD OPERATING
PROCEDURES
CL # P-HPGD-03-Y2K

Non active Ingredients (excipients)

The following development Standard Operating Procedures are recommended.

NON ACTIVE INGREDIENTS

(EXCIPIENTS)
P-000-02-0Y2K Vendor Certification Requirements for Approved Non-actives.

P-000-02-0Y2K Non Actives Ingredients for ANDA formula development

P-000-02-0Y2K Qualifying Non-actives Ingredients for ANDA formulation

development

P-000-02-0Y2K Use of Purified Water USP in Product Development

P-000-02-0Y2K Checking Excipient in the FDA ‘Inactive Ingredient Guide’

P-000-02-0Y2K Developing specifications for Approved Non-active ingredients.

4
[End of Document]

ED. N0: 02 Effective Date APPROVED:

Replaces Ed 01. :
Ed. Status: MM/DD/2000
Operational Department R&D QC QA

Handbook of Pharmaceutical Sect: 5 . 3 Generic Development

 ORAL TABLETS Containers CHAPTER 6

Container-Closure Systems
‘…the container documentation is the key
dot every i and cross every t…’

CONTAINER CLOSURE SYSTEMS registration (pivotal and validation lots).

T he generic drug product container-

closure system should be of a
similar material composition to the
New stability studies are required.
Emphasis should be placed on the
routine QC container testing - often
reference listed drug (RLD) container- overlooked by development
liner-closure system. laboratories:
Product protection Documentation requirements
The degree of product protection must
be equal or better than the RLD’s
The documentation requirements of a
container and the container-closure suitable chosen container system
system must prevent physical, chemical requires careful auditing and review.
and microbiological changes of the drug Obtaining the correct documentation is
product, on storage and during time consuming and may take several
customer-consumer use. months before all supplier
documentation is complete, correct and
Oral tablets are generally packed in on file with the generic manufacturer.
glass or thermoplastic HDPE / HDPP
containers. Full specifications, Letters of Access
(LOAs) for components with DMF
Four principal rules apply to tablet numbers, Certificates of Analysis and
container-closure systems:-
21 CFR certification is required.
♦ All development stability testing
must be performed in the container-
The principal components in direct
closure in which the drug is to be contact with the tablet preparation are
marketed. most critical:
♦ All the manufacturers container-liner- Complete documentation is required:
closure documentation must be ♦ the securitainer™ - (thermoplastic)
obtained and checked for current ⇒ resin type and source for plastics
specifications. ⇒ color pigment used for plastics
♦ Container-liner-closure ⇒ additives used in the resin.
specifications must be compatible with
the production filling and packaging ♦ the closure liner or laminate
equipment where the commercial ♦ the closure (cap) - HDPP
batches will be produced.
All Container-liner-closure suppliers ♦ Cotton wool BP/USP fillers.
are approved with detailed technical ♦ Drying agents (enclosed Silica gel)
specifications and test methods.
Special emphasis must be placed on
Documentation specifications for each
component have been itemized in the
the type of thermoplastic resin used.
attached SOPs with actual model
Manufacturers who change the resin examples of the full container-liner-
automatically compromise the generic closure package in Part II of this
stability studies performed for ANDA Handbook.

Handbook of Pharmaceutical Sect: 6 . 1 Generic Development

 ORAL TABLETS Containers CHAPTER 6

ØC H E C K L I S T ×
CL # P-HGD-03-Y2K

Container-liner-closure Systems

‘…check that the suppliers specifications - always refer to the latest USP edition…’

1. The components of the thermoplastic tube complies with the 21 qYes qNo
CFR?

2. HDPE complies with the 21 CFR 177.1520 ? qYes qNo

3. HDPE complies with the USP requirements for HDPE ? qYes qNo

4. Polypropylene complies with the 21 CFR 177.1520 ? qYes qNo

5. The thermoplastic colorant complies with 21 CFR 17.300 ? qYes qNo

6. The inner seals in the cap complies with the 21 CFR 176.180 qYes qNo

(where relevant)? 21 CFR 172.280 qYes qNo

(where relevant) 21 CFR 175.300 qYes qNo

7. The vendor’s name & address of each component is identified ? qYes qNo

8. The manufacturer of the tube resin cap and liner etc. is identified? qYes qNo

9. The resin type and code number is fully identified ? qYes qNo

10. Specifications comply with the current USP requirements ? qYes qNo

11. Each pack size (e.g. 20, 50, 100 units) has a separate set of qYes qNo
component specifications (for container, resin, liner, cap, colorant etc.)

12. Letters of authorization (LOA) from the DMF holders obtained? qYes qNo

13. Certificates of Compliance identifying the materials used in the qYes qNo
component manufacture conform to 21 CFR 172-177 etc.?

14. Certificate of Analysis identifying component meets specific USP qYes qNo
Test Requirements (e.g. moisture permeability test etc.)?

15. GMP Certification statement indicating GMP status of component qYes qNo
manufacturing facility?
Footnote : Bold numbers in checklist indicate that this documentation must be on file with generic drug
developer prior to process qualification or pivotal batch manufacture.

Handbook of Pharmaceutical Sect: 6 . 2 Generic Development

 ORAL TABLETS Containers CHAPTER 6

ØC H E C K L I S T ×
CL # P-HGD-03-Y2K

Container-Liner-Closure Systems

‘ check the suppliers documentation thoroughly -

it impacts on your ANDA submission ’

16. GMP Certification of component manufacturing facilities indicate: qYes qNo

♦ All materials are manufactured in accordance with DMF # 1234 qYes qNo

♦ Manufacturing is in compliance to Good Manufacturing Practice cGMP 21 qYes qNo

CFR part 210-211)?

♦ No materials specification changes will be made without amendment to qYes qNo

component DMF # 1234 ?

♦ No materials specification changes will be made without full notification to all qYes qNo
ANDA holders ?

17. Technical data sheet and component drawings supplied by manufacturer qYes qNo
for each component (container, liner composite, closure, fillers)?

18. Separate component drawings and specifications for - container? qYes qNo

19. Separate component drawings and specifications for - liner/laminate? qYes qNo

20. Separate component drawings and specifications for - cap / closure? qYes qNo

21. Separate specifications and certificate of analysis for fillers (cotton wool) qYes qNo

22. Generic Developer has a LOA for every DMF File referenced to FDA? qYes qNo

23. All DMF #’s referenced in ANDA are identified on ANDA cover page? qYes qNo

24. Documentation has been sourced on time during product design phase ? qYes qNo

25. Documentation has been audited in-house for current pharmacopoeial qYes qNo
editions, latest Cert. of Analysis and updated component specifications ?

26. Packaging system complies with 'Guidance for Industry Application for qYes qNo
Container Closure Systems used for Packaging of Human Drugs' (Draft 6/1998)
Footnote : Insure that vendors and manufacturers have updated all their component specification and
documentation to the current year. Specifications must apply to actual batch lot supplied to developers.

Handbook of Pharmaceutical Sect: 6 . 3 Generic Development

 ORAL TABLETS Containers CHAPTER 6

STANDARD OPERATING
PROCEDURES
CL # P-HGD-03-Y2K Page 1 of 1.

Container-Liner-Closure Systems

The Attached SOP for a ANDA drug products highlights the components quality
control specifications and documentation requirements for filing an drug product
application. The following selected model Standard Operating Procedures are
recommended SOPs :

CONTAINER-LINER-CLOSURE SYSTEMS
# P-000-01-129Y Container-liner-closure systems for generic development.
# P-000-01-129Y Documentation requirements for Container-liner-closure systems .
21 CFR references:-
The Indirect Food Additive regulations in the 21 Code Federal Register (21 CFR)
that are applicable to solid oral dose container closure packaging components are:-

21 Code Federal Register (21 CFR 170 -199) - Food Additive Regulations
Indirect Food Additives General - Part 174
Indirect Food Additives Adhesives and Coatings - Part 175
Indirect Food Additives Paper & Cardboard - Part 176
Indirect Food Additives Polymers - Part 177
Indirect Food Additives Adjuvants / Sanitizers - Part 178
Indirect Food Additives GRAS - Part 186
Examples;
Colorant (in thermoplastic) - 175.300
Resinous & polymeric coatings - 175.300
Adhesives - 175.105
Paper and paperboard (contact aqueous/fatty) - 176.170
Inner seals (in closures/caps) - 176.180
Fluorocarbon resins - 177.1380
Olefin polymers - 177.1580
Polyethylene phthalate polymers - 177.1630
HDPP (Polypropylene)1 - 177. 1520
HDPE (Polyethylene) 2 - 177.1520
HDPE Resins (of thermoplastic) - 177.1520
- 177.280 (175.300)
1 High Density Polypropylene - HDPP
2 High Density Polyethylene - HDPE
4
[End of Document]

ED. N0: 02 Effective Date APPROVED:

Replaces Ed 01. :
Ed. Status: MM/DD/2000
Operational Department R&D QC QA

Handbook of Pharmaceutical Sect: 6 . 4 Generic Development

 ORAL TABLETS MANUFACTURE CHAPTER 7

Manufacturing
Instructions
'…start with the order of addition and the processing conditions...
end with process optimization and process qualification...'

The Product Formula manufactured at both the lower and

upper hardness values.
T he initial generic product formula
may, but not necessary, be Dissolution Testing
qualitatively based on the chosen Dissolution testing of the product must
Reference Listed Drug (RLD) as to the remain within 5% of the dissolution
type and grade of excipients present in parameters of the RLD. The reference
the RLD or innovators formulation. listed drug chosen should be
Non-active Ingredients evaluated for dissolution across at
Review of the PDR1 should provide least three to six different batch
sufficient confirmation of the numbers per tablet strength.
qualitative formula ingredients and Where possible the RLD batch lots
analytical evaluation some should be purchased over a period of
approximate quantitative percentages a six months to provide a spread in
of each active and non-active manufacturing dates.
ingredient used. Caution: Purchase recent
Semi actives, Colors manufactured stock. If RLD stock has
The antioxidants alone or with exceeded 50% of its shelf life - use
chelating agents are challenged to this lot to evaluate the dissolution
establish whether they maintain assay values of an aged reference lot to
potency and minimize impurity growth determine how the RLD dissolution
and the loss of active ingredient during profile changes with aging.
product aging.
Obtain from recent lots the mean
Colors may be changed or lighter dissolution curve as well as the upper
pastels used . The color / tablet shape and lower dissolution curves.
or dimensions chosen should be Target your generic drug dissolution
similar but not identical to the RLD. profile close to the RLD’s mean
Formula optimization requires that the dissolution curve.
excipient percentage amounts have Use twelve tablets for each
been chosen for maximum tablet determination. This will remove intra-
performance. Good dissolution profiles batch bias (i.e. variation between
(evaluated before and after stability) individual tablets of the same batch
should be achieved with tablets lot).
1
Physicians Desk Reference

Handbook of Pharmaceutical Sect: 7 . 1 Generic Development

 ORAL TABLETS MANUFACTURE CHAPTER 7

Altering the dissolution parameters: the lubricant volume and aid in the
Without formula changes dissolution uniform coating of the granules during
may be altered by several factors such blending.
as (a) the order of addition or (b) Over lubrication and non-uniform
varying the amount of intra-granular lubrication of the granules may not be
and extra granular disintegrant as well detected in the tabletting process but
as (c) controlled lubrication coating via will manifest itself in the consistency of
short or longer blending times of the the batch-to-batch dissolution analysis
finished granule with the lubricating which may impact on the
agent / glidant combination. The bioequivalency testing.
addition of Dry Starch NF at the Compress the final development
lubrication stage (in the blender) formula or the process qualification
improves the tablet dissolution by batch on the actual commercial
partial coating of the lubricant(s). machine at the highest tabletting
Granulating Agent - Dry or Solution speed to insure the absence of
The Addition of the binder (granulating compression problems (capping,
agent) e.g. PVP K30™ may be added screeching etc.)
as an initial dry mix with the active or
alternatively dissolved in solution with Factors impacting on dissolution
the granulating fluid (e.g. water or profile:
alcohol) an added (rate) to the ◊ Active particle size and bulk
granulating vessel.
density
Granule moisture range
The amount of moisture in the granule ◊ Excipient formulation of non-
when it exceeds the range 2.0 - 2.5% actives
results in harder tablets on aging with ◊ Order and stage of addition
longer dissolution times. Control of ◊ Intra-granular disintegrating agent
granule moisture and comparison of quantity and blending time (Y-
resulting tablet dissolution is a critical Cone).
development parameter. Improved ◊ Inter-granular disintegrating agent
dissolution can be obtained by quantity and blending time (Y-
reducing moisture to optimum levels cone).
that result in elegant cores or tablets.
◊ Granulation moisture content.
Granule blending times ◊ Quantity of lubricant in formula.
Control of the granule ‘coating’ ◊ Splitting blending amounts and
process of the lubricant (i.e. Mg blending times - for lubricants.
Stearate and/or Stearic Acid) may be
◊ Lubrication blending times - 3-5
achieved by a two stage lubricating
blend. When the lubricant blending
minutes generally (Y-cone)
times are reduced, the lubricant should The formula given in Chapter Five and
be bulked up (with a reserve a portion Charts 1 to 3 use most of the above
of cornstarch) to eliminate partial over- development parameters to produce a
coating of the granules in initial drug product comparative to the RLD
contact with resulting non-uniform that shows excellent stability and long
coating of the entire granulation term stable impurity profiles.
material. A premix of the glidant and
lubricant can be considered. Flow charts for Dry and wet
Lubricants may also be blended with granulation are given to highlight the
extragranular disintegrant to bulk-up various manufacturing techniques

Handbook of Pharmaceutical Sect: 7 . 2 Generic Development

 ORAL TABLETS MANUFACTURE CHAPTER 7

Process Validation
Developing the manufacturing process ♦ mixing speeds (rpm; chopper I / II)
and process parameters will result in a ♦ mixing times (start / stop)
rugged set of manufacturing
instructions and in-process controls. ♦ FBD parameters (drying times)
The end point of the process ♦ Granule LOD content.
optimization is a consistent batch-to- ♦ Addition of disintegrants to FDB or
batch product quality and uniform milling stage
finished product specifications.
♦ blending parameters and order of
In order to achieve consistent batch- addition of lubricants and glidants
to-batch analysis, the manufacturing
♦ Multiple lubricants (Mg Stearate
procedure requires individual process
0.25% and Stearic Acid 0.75%)
step optimization (i.e. process
validation). ♦ Short lubricant blending times
Manufacturing Instructions ♦ Partial coating of lubricants with
glidants and/or Disintegrants
Optimize the manufacturing process.
The process optimization procedure ♦ maximum processing times per step
requires individual process step Development and optimization
evaluation during the development of
From this development and
the process manufacturing
optimization procedures - key process
instructions.
steps can be identified with the
The end of the product development potential to affect the finished drug
phase will result in a regulatory product both in quality and
demonstration of the development specifications. It is these key
optimization procedure or development processing steps that are addressed
validation with the demonstration of and demonstrated in the validation
the pivotal generic batch and protocol for the initial three,
thereafter the three consecutive consecutive, full size, validation
validation batches for commercial batches.
sale. Upper and lower in-process controls
The manufacturing process requires are established for these critical
certain key steps to be evaluated for processing steps and these limits are
optimizing the process and producing individually challenged and qualified
a rugged end product. under the product development
These development steps are: program.
Addition of ingredients- The final regulatory demonstration of
all operating ranges and product
♦ Screening of bulk powders (size)
specification limits takes place with the
♦ Pre-blending procedures for small three commercial validation batches.
amounts (plastic bags prohibited) Only parameters that can impact on
♦ Order of addition of excipients the product quality are evaluated in a
validation program.
♦ Dry mixing the binder in Granulator This process of developmental
♦ Addition rates times for granulating validation and exhibition validation
fluids. results in a final validated process
Processing of the ingredient mix producing a rugged drug product
meeting the desired drug product
♦ High/low shear mixing settings
specifications.

Handbook of Pharmaceutical Sect: 7 . 3 Generic Development

 ORAL TABLETS MANUFACTURE CHAPTER 7

ØC H E C K L I S T ×
CL # P-HGD-03-Y2K

Manufacturing Instructions
(example of a wet granulation procedure)

‘ write the manufacturing instructions clearly - so they can be simply followed

one step at a time... ‘

1. The manufacturing instructions specify the exact equipment used ? qYes qNo
2. Major equipment is identified with an ID number ? qYes qNo

3. The words “use suitable / appropriate... etc. ” are not used ? qYes qNo

4. Mixer/granulator times have a ‘start and stop’ recording time ? qYes qNo

5. Mixer/granulator speeds and chopper settings are precisely stated ? qYes qNo
6. Instructions identify the mixing times and temperatures for preparing the qYes qNo
granulating solution?

7. Operator and check signatures are per individual step ? qYes qNo

8. No signature is for two operations documented as one step ? qYes qNo

9. Manufacturing steps are broken down to one action only ? qYes qNo
10. FBD temperatures are recorded as T0 C ( ± 2/3 0 C) - avoid ranges ? qYes qNo

11. FBD inlet, outlet and bed temperatures are recorded ? qYes qNo

12. Drying is continued until the target granulate moisture percentage qYes qNo
determined by LOD (± 0.2 - 0.4%) is reached ? Record overall drying time.
13. Dried granules are milled stating screen size and machine settings ? qYes qNo
14. Blender rpm and blending time recorded (with / without bar)? qYes qNo

15. The overall manufacturing time is indicated ? qYes qNo

16. Type of compression machine is documented ? qYes qNo

17. The maximum standing time before compression is indicated ? qYes qNo

18. Machine speed is stated (target, lower and upper rpm) ?. qYes qNo

19. The sample size, number of samples and sampling location (i.e. LHS and qYes qNo
RHS) is identified in batch sheets?
Footnote : Where possible transfer the lubricated granules into a double polyethylene lined drum. Close well and protect from light where
necessary using an inner transparent bag and an outer black bag. Obtain the granule net weight and calculate the yield.

Handbook of Pharmaceutical Sect: 7 . 4 Generic Development

 ORAL TABLETS MANUFACTURE CHAPTER 7

Manufacturing
Instructions
Manufacturing and Controls
BATCH MANUFACTURING INSTRUCTIONS
A DETAILED EXAMPLE

Product name: [Generic name] Tablets USP [000.0] mg.

Batch Number: AIG-0034
Department: ______________ Batch Size: 000000 units
Precautions: •‚ Sub-lot No: þ1 þ2 ý3
Caution: …† Manufacture Date: Month DD, 200?
Cat./Formula No: # C0020 Cores þ : Coated þ Tablets þ
Based on PQ: Batch # IAG-000-02 þ PIVOTAL BATCH
þ Validation Lot ý Commercial Lot
Change Control for this document: Original - No Change þ : Change ý Change made: -
none
KEY to :
Precautions: • Wear Mask and Gloves
‚ Wear disposable overalls
ƒ Use air stream face visor with AIR filter
„ Use Mask, Gloves and Safety glasses
Material causes extreme irritation to skin and eyes
Do not expose to skin or exposed areas.
Caution: … Avoid exposure to light / Protect form light
† Store in well closed containers and minimize or avoid
exposure to environmental air
‡ Raw material has to be stored at 5°°C - hold active material at 25o C for
one hour to reach room temperature before weighing, sampling or
processing
ˆ Potential danger to pregnant women, pregnant women are prohibited
in this area
‰ Do not heat above [00]øøC
• Maintain Room humidity below 50%
Note:
A modern real life commercial manufacturing process for film-coated tablets is provided as
an example of how to prepare and write the manufacturing and processing instructions.
This specific set of manufacturing instructions was chosen as it represents a complex
example and highlights numerous processing principles. The order of each process step is
critical and should follow the order that the ingredients appear in the master formula.
As actual values and numerical parameters are not significant in the example provided.
The figures are simply reported as [00] for ease of purpose.
Part Two of the Handbook Series provides actual operational values of commercial sized
batch lots. An example of a Film Coated Caplets is provided .

Handbook of Pharmaceutical Sect: 7 . 5 Generic Development

 ORAL TABLETS MANUFACTURE CHAPTER 7

Manufacturing Instructions and Controls

BATCH MANUFACTURING FORMULA
[Generic name] Tablets [USP] [000.0] mg.

Batch No: Weighing Date:

Page I of 2.
Per % RM. Sign
UNIT Exc Raw Material Names Lot per [0000 000] units weigh.
mg ess No Dept.
Kg g mg L mL A B
PART ONE - GRANULATION
SUBLOT ONE

00.0 [Excipient #1 NF] 00 000

00.0 [Excipient #2 NF] 00 000
00.0 [Excipient #3 NF] 00 000
00.0 [Excipient #4 NF] 00 000
00.0 [Active Ingredient Ph. Eur./ BP] 00 000 The ORDER
GRANULATING SOLUTION 1 of appearance
of the ingredients
00.0 [Granulating Agent USP 00 000
is the same
- [Purified Water USP] 00 000 ORDER of
- [Purified Water USP] q.s. 00 000 processing
000.0 Theoretical End Weight. 00 000

PART TWO - GRANULATION

SUBLOT TWO

00.0 [Excipient #1 NF] 00 000

00.0 [Excipient #2 NF] 00 000
00.0 [Excipient #3 NF] 00 000
00.0 [Excipient #4 NF] 00 000
00.0 [Active Ingredient Ph. Eur./BP] 00 000 The ingredients
are rewritten for
GRANULATING SOLUTION 2 each sub-lot. Up to
three sublots are
00.0 [Granulating Agent USP 00 000
common
- [Purified Water USP] 00 000
- [Purified Water USP] q.s. 00 000
000.0 Theoretical End Weight. 00 000

PART THREE - BLENDING

SUBLOTS: ONE + TWO
000.0 Combined Granulates - Sublots 1 +2 00 000 NOTE:
00.0 [Extra-granular Glidant NF] 00 000 The sublots are
00.0 [Extra-granular Disintegrant NF] 00 000 combined and
00.0 [Extra-granular Lubricant NF] 00 000 extragranular 'DRIES'
are added for both
000.0 Theoretical End Weight. 00 000 sublots

ED. N0: 02 Effective Date APPROVED:

Replaces Ed 01. :
Ed. Status: MM/DD/2000
Operational Department R&D QC QA

Handbook of Pharmaceutical Sect: 7 . 6 Generic Development

 ORAL TABLETS MANUFACTURE CHAPTER 7

Manufacturing Instructions and Controls

BATCH MANUFACTURING INSTRUCTIONS
[Generic name] Tablets [USP] [000.0] mg.

Batch No: Weighing Date:

Page 2 of 2.
Per % Raw Material Names RM. Sign
UNIT Exc Lot per [0 000 000] units weigh.
mg ess No Dept.
PART FOUR - AQUEOUS FILM COAT
SUSPENSION ¹
- 00 Aqueous Film Coating Suspension - -
- Purified Water USP 00 000
00.0 FILM-DRY OP-D-0000 [Color] 00 000
- Theoretical End Weight. 00 000
NOTE:
The quantity of the
'Commercial Color'
PART FIVE - FILM COATING, and amount of
diluting water
SUBLOT 1
000.0 [Name] Tablets [000] mg CORES 000
[Name] Tablets [000] mg CORES 000
00.0² Aqueous Film Coating Suspension
000.0 Theoretical End Weight. 000

PART SIX - FILM COATING,

SUBLOT 2 NOTE:
000.0 [Name] Tablets [000] mg CORES 000 The quantity of CORES
Name] Tablets [000] mg CORES 000 and the 'diluted' Coating
00.0² Aqueous Film Coating Suspension Suspension
000.0 Theoretical End Weight. 000

PART SEVEN - FILM COATING,

SUBLOT 3
000.0 [Name] Tablets [000] mg CORES 000 NOTE:
Name] Tablets [000] mg CORES 000 This process has TWO
00.0² Aqueous Film Coating Suspension granulation sublots into ONE
000.0 Theoretical End Weight. 000 Blending Process with
THREE coating sublots

NOTE:
The concept of a single batch
Edition Number: Effective Date: APPROVED
01
means;
Ed. Status MM/DD/199Y _____________ __________Granulation - Blend -_________/________
_______________ Coating
New Department R &D 1 - 3 RA : ONE : 1 - QC 4 / QA

¹ Aqueous film coat suspension contains 00.% solids

² Solids remaining in film coat

Handbook of Pharmaceutical Sect: 7 . 7 Generic Development

 ORAL TABLETS MANUFACTURE CHAPTER 7

Manufacturing Instructions and Controls

BATCH MANUFACTURING INSTRUCTIONS
[Generic name] Tablets [USP] [000.0] mg.

Batch No: MNF Date:

Page 1 of 8.
MANUFACTURING INSTRUCTIONS Machine Sign Date
A+B

1. IDENTIFY the room number and equipment and verify the JB LJ

cleanliness prior to use.

WET GRANULATION I SUBLOT I

PART 1
2. LOAD into the [High Shear Mixer 000] (Type & No) the ingredients
JB LJ
in the following order:

[INGREDIENT #1 NF]
[INGREDIENT #2NF]
[INGREDIENT #3 NF] NOTE:
[INGREDIENT #4 NF] The ingredients are written in
MIX for [ 0 ] minutes at mixer speed [I] or [II] and Chopper [I] or [II] the same order as they are
JB and
processed LJ also as they
appear in the 'Master
Formula'
3. Granulation Preparation - No. I

4. WEIGH [00] Kg [PURIFIED WATER USP] into a stainless steel

vessel fitted with a roller mixer. (#0) JB LJ

5. OPERATE the mixer and add the [GRANULATING AGENT USP] and
mix until fully dissolved. JB LJ

6. LOAD the [High Shear Mixer 000] (Type & No) with the following JB LJ
ingredient :

[ACTIVE INGREDIENT BP / Ph. Eur.]

7. MIX for [0] minutes at mixer speed [I / II] and Chopper [I / II]. JB LJ

8. ADD or SPRAY the granulating solution to the [High Shear Mixer JB LJ

000] (Type & No) while mixing at mixer speed [II] and chopper speed [II].

Total Mixing Time is 45 seconds. JB LJ

Time of adding Solution/SPRAYING - [40] seconds
Time of mixing - [ 5] seconds

ED. N0: 02 Effective Date APPROVED:

Replaces Ed 01. :
Ed. Status: MM/DD/2000
Operational Department R&D QC QA

Handbook of Pharmaceutical Sect: 7 . 8 Generic Development

 ORAL TABLETS MANUFACTURE CHAPTER 7

Manufacturing Instructions and Controls

BATCH MANUFACTURING INSTRUCTIONS
[Generic name] Tablets [USP] [000.0] mg.

Batch No: MNF Date:

Page 2 of 8.
MANUFACTURING INSTRUCTIONS Machine Sign Date
A+B
9. If necessary, ADD the [PURIFIED WATER USP]. q.s. and mix at the JB LJ
same conditions as in stage 8.
NOTE
Amount of additional [PURIFIED WATER USP]: _________ Kg. Each action
Additional mixing time: _________ Seconds is
CAPITALIZED
10. DISCHARGE the wet granulate into a FBD mobile bed (Type & No)
JB LJ
while mixing at mixer speed I.

11. DRY the wet granulate in the FBD (Type & No) under the following JB LJ
settings:
Time of Drying [00] min. Ñ 10%
Inlet Air Temperature NMT [00]º C (Target: [00]º C)
Outlet Air Temperature NMT [00]º C (Target: [00]º C)

12. ATTACH the temperature graph of the FBD (Type & No) to the JB LJ
manufacturing instructions.
Immediately ADD the batch number to the temperature graph and date JB LJ
and sign it.

13. MILL about 1Kg. 'check portion' the dried granulate through an JB LJ
OSCILLATING GRANULATOR (Type & No) fitted with a [0.0 mm] screen.

14. CHECK the milled granulate portion for Loss on Drying (LOD). JB LJ
Use (Type & No) IR machine with temperature set at temperature [00]º C
Record First result: __________[ 0.0%]
LOD Limits: [0.0 to 0.0%]

15. If necessary, CONTINUE to DRY the bulk granulate under the same JB LJ
conditions as stage 11, until the LOD is close to the midpoint of the given
range limits and check moisture again.
JB LJ
16. RECORD Second result: __________[ 0.0%]
17. PASS the Dried Granulate through the OSCILLATING JB LJ
GRANULATOR (Type & No) fitted with a [0.0 mm] screen into a [000]
liter container or bin.
JB LJ
18. WEIGH the milled granulate. ______Kg.
Immediately ADD the batch number to the scale print-out, attach to the JB LJ
manufacturing instructions, date and sign the print-out.
19. Theoretical Weight [00.0] Kg. Yield __________ %
(Yield Limits: NLT 95% of Theoretical Weight.) Bins __________

ED. N0: 02 Effective Date APPROVED:

Replaces Ed 01. :
Ed. Status: MM/DD/2000
Operational Department R&D QC QA

Handbook of Pharmaceutical Sect: 7 . 9 Generic Development

 ORAL TABLETS MANUFACTURE CHAPTER 7

Manufacturing Instructions and Controls

BATCH MANUFACTURING INSTRUCTIONS
[Generic name] Tablets [USP] [000.0] mg.

Batch No: MNF Date:

Page 3 of 8.
Sign
MANUFACTURING INSTRUCTIONS Machine A+B Date

PART TWO - SUBLOT- II

20. Granulation Preparation - No II

(i) WEIGH [00] Kg [PURIFIED WATER USP] into a stainless steel JB LJ

vessel fitted with a roller mixer. (NO [0])
(ii) OPERATE the mixer and add/spray the [GRANULATING AGENT JB LJ
USP] and mix until fully dissolved.

21. LOAD the [High Shear Mixer 000] (Type & No) with the following
JB LJ
ingredients in order of addition:
[ACTIVE INGREDIENT BP];
JB LJ
Mix for [ 0 ] minutes at mixer speed [I] or [II] and Chopper [I] or [II]
JB LJ
22. ADD the granulating solution to the [High Shear Mixer 000] (Type &
No) while mixing at mixer speed [II] and chopper speed [II].
Total Mixing Time is 45 seconds. JB LJ
Time of adding Solution/SPRAYING - [40] seconds
Time of mixing - [ 5] seconds
JB LJ
23. If necessary, ADD / SPRAY the [PURIFIED WATER USP]. q.s. and
mix at the same conditions as in stage 22.
Amount of additional [PURIFIED WATER USP]: __________ Kg. JB LJ
Additional mixing time __________ Seconds

24. DISCHARGE the wet granulate to the FBD mobile bed (Type & No) JB LJ
while mixing at mixer speed I.

25. DRY the wet granulate in the FBD (Type & No) under the following JB LJ
settings:
Time of Drying [00] min Ñ 10%
Inlet Air Temperature NMT [00]º C (Target: [00]º C)
JB LJ
Outlet Air Temperature NMT [00]º C (Target: [00]º C)
JB LJ
ATTACH the temperature graph of the FBD (Type & No) to the
manufacturing instructions. Immediately add the batch number to the
temperature graph and date and sign it.
JB LJ
26. MILL about a 1Kg. 'check portion' of dried granulate through a
OSCILLATING GRANULATOR (Type & No) fitted with a [0.0 mm] JB LJ
screen.
27. CHECK the milled granulate portion for Loss on Drying (LOD).
ED. N0: 02 Effective Date APPROVED:
Replaces Ed 01. :
Ed. Status: MM/DD/2000
Operational Department R&D QC QA

Handbook of Pharmaceutical Sect: 7 . 10 Generic Development

 ORAL TABLETS MANUFACTURE CHAPTER 7

Manufacturing Instructions and Controls

BATCH MANUFACTURING INSTRUCTIONS
[Generic name] Tablets [USP] [000.0] mg.

Batch No: MNF Date:

Page 4 of 8.
MANUFACTURING INSTRUCTIONS Machine Sign Date
A+B

USE (Type & No) IR machine with temperature set at temperature [00]º C JB LJ
RECORD First LOD result ________ [0.0%]
LOD Limits: - [0.0 to 0.0%]
28. If necessary, CONTINUE to DRY the bulk granulate under the same
JB LJ
conditions as stage 25, until the LOD is close to the midpoint of the given
range limits and check moisture again.

29. RECORD Second LOD result: __________ [0.0%] JB LJ

30. PASS the Dried Granulate through the OSCILLATING GRANULATOR
JB LJ
(Type & No) fitted with a [0.0 mm] screen into a [000] liter container or bin.
31. WEIGH the milled granulate. ______Kg. Immediately add the batch
number to the scale print-out, attach to the manufacturing instructions, JB LJ
date and sign the print-out.
Calculate Yield
32. Theoretical Weight [00.0] Kg. Yield ___________ % JB LJ
(Yield Limits: NLT 95% of Theoretical Weight.) No of Bins ______
33. TRANSFER the milled granulate from stage 31 of both sub lots to a
JB LJ
twin shell blender / Flow bin (Type & No).

PART THREE - FINAL BLENDING

PASS the [LUBRICANT NF] through a quick sieve
34. ADD to the twin shell blender / Flow bin (Type & No). the
JB LJ
[GLIDANT NF]
[DISINTEGRANT NF]
[LUBRICANT NF]
and blend / mix for [0] minutes. Speed: [00.0] rpm.
Mixing Start Time: _________
JB LJ
Mixing Stop Time: _________
35. COLLECT 10 samples, each equivalent to the approximate weight of
one tablet (000 mg) in labeled sample containers. Collect samples from JB LJ
upper, middle and lower part of the container. Send the samples to the QC
laboratory for Blend Uniformity Testing.
36. WEIGH the final blended material JB LJ
Actual weight: [00.0] Kg.
Theoretical Weight [00.0] Kg. Yield __________ %
No. of containers _____ .
(Yield Limits: NLT 98% of total actual weight from (1) & (2) sublots,
including the dry lubricant added at stage 34).
Edition Number: Effective Date APPROVED
01
Ed. Status: MM/DD/Y2K _____________ __________ _______________ _________/________
New Department R &D RA QC / QA

Handbook of Pharmaceutical Sect: 7 . 11 Generic Development

 ORAL TABLETS MANUFACTURE CHAPTER 7

Manufacturing Instructions and Controls

BATCH MANUFACTURING INSTRUCTIONS
[Generic name] Tablets [USP] [000.0] mg.

Batch No: MNF Date:

Page 5 of 8.
MANUFACTURING INSTRUCTIONS Machine Sign Date
A+B
COMPRESSION
Tablet core - Compression JB LJ
37. IDENTIFY and verify cleanliness of the tabletting equipment in use
COMPRESS the final blend according to the written product
specifications JB LJ
Tabletting machine: (Type & No).
Machine Speed _______ Tablets per hour
Limit of rpm NLT _______ rpm ; NMT _______ rpm

38. WEIGH the tablet cores: JB LJ

Actual production weight: [00.0] Kg.
Weight of Samples taken: [00.0] Kg.
Vacuum and rejects Weight: [00.0] Kg.
Total weight [00.0] Kg
No of Bulk Containers [0]
Theoretical Weight [00.0] Kg. Yield _________ %
(Yield Limits: NMT 2% unexplained loss compared to the final blend
weight from stage 16.

39. SEAL the double PE plastic bags (clear inner, black outer) with JB LJ
plastic ties then close all containers, and attach (bar coded) labels to the
Bulk Containers for transport to the holding area.

PART FOUR
FILM COATING SUSPENSION
JB LJ
40. IDENTIFY and verify the cleanliness of the coating equipment.
Weigh [00] Kg PURIFIED WATER USP into a stainless steel vessel
fitted with a roller mixer. (Vessel # 0) JB LJ
41. ADD gradually, while mixing the [FILM-DRY OD-P-0000 - Color] to
the PURIFIED WATER USP and mix to a uniform dispersion - about 45
minutes:
Mixing time ________minutes.
42. PASS the AQUEOUS FILM COATING SUSPENSION through a [00] JB LJ
mesh screen into a stainless steel container and close well.
JB LJ
PREVENT
43. SPLIT the AQUEOUS FILM COATING SUSPENSION into equal
Foaming of
sublots and label with (bar-coded) batch number and Sublot number. aqueous dispersion
(Allow to de-aerate)
44. NB: STIR the AQUEOUS FILM COATING SUSPENSION
continuously during the coating process.

Edition Number: Effective Date APPROVED

01
Ed. Status: MM/DD/Y2K _____________ __________ _______________ _________/________
New Department R &D RA QC / QA

Handbook of Pharmaceutical Sect: 7 . 12 Generic Development

 ORAL TABLETS MANUFACTURE CHAPTER 7

Manufacturing Instructions and Controls

BATCH MANUFACTURING INSTRUCTIONS
[Generic name] Tablets [USP] [000.0] mg.

Batch No: MNF Date:

Page 6 of 8.
MANUFACTURING INSTRUCTIONS Machine Sign Date
A+B
PART FIVE - COATING SUBLOT 1
Coating Procedure: JB LJ
45. IDENTIFY and verify cleanliness of the coating equipment in use
Sublot Size ________ Kg. Equal to ___________ tablets.
SUB LOT No 1.
PREHEATING OF CORES: JB LJ
Coating machine (Type & No) : Set parameters as follows :
Extraction Air Temperature: [00]º C - [00]º C
Incoming Air Temperature: [00]º C - [00]º C NOTE:
Total Warming time: [0] Minutes Each separate
Drum Speed: _________ rpm (minimum speed) 'operating step'
Jogging cycle: One cycle every [0] minutes. has a distinct set
Limit of rpm: NLT _[0]_ rpm: NMT _[0]_ rpm. of check initials

SPRAYING PARAMETERS
Pump type: Peristaltic
Spray rate: [000] - [000] g/min
Nozzles: [0] - [0.0] mm
INLET AIR
Angle of Guns to Bed: 90 degrees
Relative Humidity
Height above Bed: [00] cm
should be controlled
Incoming Air Temperature: [00]º C - [00]º C (Target: 00ºC) JBday-to-day
(to prevent LJ
Extraction Air Temperature: [00]º C - [00]º C (Target: 00ºC) environmental variation)

46. COAT tablet cores at a drum speed of [0] - [0] rpm and a spray rate JB LJ
of [000] - [000] g/min until the target COATED tablet weight of [000] mg
is obtained.
COATING COMPLETION PROCEDURE. JB LJ
47. REDUCE drum speed to minimum rpm and perform the following:
- Reduce set point of incoming air temperature to 00ºC
- on reaching this temperature - close the inlet air.
- continue drum speed until the Extraction Air Temperature reaches 00ºC
- 00ºC
48. TRANSFER coated tablets into containers lined with two PE plastic JB LJ
bags (clear inner, black outer). Seal bags with plastic ties and close
containers, and attach (bar coded) labels to the Bulk Containers for
transport to the holding area.
49. ATTACH the temperature graphs (Type & No) to the manufacturing JB LJ
instructions. Immediately add the batch / Sublot number to the
temperature graph(s) and date and sign graph.
JB LJ
50. WEIGH Coated tablets
Actual production weight: [00.0] Kg. No of Containers

Edition Number: Effective Date APPROVED

01
Ed. Status: MM/DD/Y2K _____________ __________ _______________ _________/________
New Department R &D RA QC / QA

Handbook of Pharmaceutical Sect: 7 . 13 Generic Development

 ORAL TABLETS MANUFACTURE CHAPTER 7

Manufacturing Instructions and Controls

BATCH MANUFACTURING INSTRUCTIONS
[Generic name] Tablets [USP] [000.0] mg.

Batch No: MNF Date:

Page 7 of 8.
MANUFACTURING INSTRUCTIONS Machine Sign Date
A+B
PART SIX - COATING SUBLOT 2
Coating Procedure: JB LJ
51. IDENTIFY and verify cleanliness of the coating equipment in use
Sublot Size ________ Kg. Equal to ___________ tablets.
SUB LOT No 2.
PREHEATING OF CORES: JB LJ
Coating machine (Type & No): Set parameters as follows:
Extraction Air Temperature: [00]º C - [00]º C
Incoming Air Temperature: [00]º C - [00]º C
Total Warming time: [0] Minutes Refer to Chapter 11.
Drum Speed: _________ rpm (minimum speed) Pre-warming core bed
Jogging cycle: One cycle every [0] minutes. rapidly JB
seals
LJ the
Limit of rpm: NLT [0] rpm: NMT [0] rpm. initial layer of film coat

SPRAYING PARAMETERS
Pump type: Peristaltic
JB LJ
Spray rate: [000] - [000] g/min
Nozzles: [0] - [0.0] mm
Angle of Guns to Bed: 90 degrees
Height above Bed: [00] cm
Incoming Air Temperature: [00]º C - [00]º C (Target: 00ºC)
JB LJ
Extraction Air Temperature: [00]º C - [00]º C (Target: 00ºC)

52. COAT tablet cores at a drum speed of [0] - [0] rpm and a spray rate JB LJ
of [000] - [000] g/min until the target COATED tablet weight of [000] mg
is obtained.
COATING COMPLETION PROCEDURE
53. REDUCE drum speed to minimum rpm and perform the following: JB LJ
- Reduce set point of incoming air temperature to 00ºC
- on reaching this temperature - close the inlet air.
- continue drum speed until the Extraction Air Temperature reaches [00ºC JB LJ
- 00]º C.
JB LJ
54. TRANSFER coated tablets into containers lined with two PE plastic
bags (clear inner, black outer) Seal bags with plastic ties and close
containers, and attach (bar coded) labels to the Bulk Containers for
transport to the holding area.
55. ATTACH the temperature graphs (Type & No) to the manufacturing JB LJ
instructions. Immediately add the batch / Sublot number to the
temperature graph(s) and date and sign graph.

56. WEIGH Coated tablets JB LJ

Actual production weight: [00.0] Kg. No of Containers

Edition Number: Effective Date APPROVED

01
Ed. Status: MM/DD/YY _____________ __________ _______________ _________/________
New Department R &D RA QC / QA

Handbook of Pharmaceutical Sect: 7 . 14 Generic Development

 ORAL TABLETS MANUFACTURE CHAPTER 7

Manufacturing Instructions and Controls

BATCH MANUFACTURING INSTRUCTIONS
[Generic name] Tablets [USP] [000.0] mg.

Batch No: MNF Date:

Page 8 of 8.
MANUFACTURING INSTRUCTIONS Machine Sign Date
A+B
PART SEVEN - COATING SUBLOT 3
Coating Procedure: JB LJ
57. IDENTIFY and verify cleanliness of the coating equipment in use
Sublot Size ________ Kg. Equal to ____________ tablets.
SUB LOT No 3.
PREHEATING OF CORES: JB LJ
Coating machine (Type & No) Set parameters as follows :
Extraction Air Temperature: [00]º C - [00]º C
Incoming Air Temperature: [00]º C - [00]º C
Total Warming time: [0] Minutes
Drum Speed: _________ rpm (minimum speed)
Jogging cycle: One cycle every [0] minutes. JB LJ
Limit of rpm: NLT _[0]_ rpm: NMT _[0]_ rpm. Refer to Chapter 11
for a detailed
SPRAYING PARAMETERS description of
Pump type: Peristaltic aqueous film coating
JB LJ
Spray rate: [000] - [000] g/min
Nozzles: [0] - [0.0] mm
Angle of Guns to Bed: 90 degrees
Height above Bed: [00] cm
Incoming Air Temperature: [00]º C - [00]º C (Target: 00ºC)
JB LJ
Extraction Air Temperature: [00]º C - [00]º C (Target: 00ºC) Refer to Chapter 11.
Each parameter needs
58. COAT tablet cores at a drum speed of [0] - [0] rpm and a spray rate JB LJ
to be fully specified
of [000] - [000] g/min until the target COATED tablet weight of [000] mg during scale-up of
is obtained. aqueous film coating
COATING COMPLETION PROCEDURE trials
59. REDUCE drum speed to minimum rpm and perform the following: JB LJ
- Reduce set point of incoming air temperature to 00ºC
- on reaching this temperature - close the inlet air
- continue drum speed until the Extraction Air Temperature reaches [00]º JB LJ
C - [00]º C
JB LJ
60. TRANSFER coated tablets into containers lined with two PE plastic
bags (clear inner, black outer) Seal bags with plastic ties and close
containers, and attach (bar coded) labels to the Bulk Containers for
transport to the holding area.
61. ATTACH the temperature graphs (Type & No) to the manufacturing JB LJ
instructions. Immediately add the batch / Sublot number to the
temperature graph(s) and date and sign graph.

62. WEIGH Coated tablets JB LJ

Actual production weight: [00.0] Kg. No of Containers
Edition Number: Effective Date APPROVED
01
Ed. Status: MM/DD/YY _____________ __________ _______________ _________/________
New Department R &D RA QC / QA

BATCH MANUFACTURING INSTRUCTIONS - Flow Chart Attached

Handbook of Pharmaceutical Sect: 7 . 15 Generic Development

 ORAL TABLETS MANUFACTURE CHAPTER 7

M a n u f a c t u r i n g
[Matrix excipient USP]
Flow Chart I
[Matrix excipient NF]
[Matrix excipient NF]
BATCH MANUFACTURING FLOW CHART
[Generic name] Tablets [USP] [000.0] mg.

Step 1
Matrix Premix Blend [[Active Material] High Speed Granulator
Tumble mixer Matrix Premix Blend PREMIX

Step 2 [Purified Water USP]

High Speed Granulator [Granulating Agent USP]
GRANULATION (Granulating Fluid)

Step 2b
High Speed Granulator [Purified Water USP}
Extra-granular GRANULATION if required
Glidant Excipient

Step 3 IPQC Testing

Fluid Bed Dryer % LOD analysis
Yield Analysis
DRYING
Milled Granulation Yield

Step 4
Communition stage
Lubricant MILLING

Step 5
Quick Sieve Stage 5 Extragranular Addition
Sieve # [0] pre-blending

IPQC testing
Step 6 Blend Uniformity
Final Blend Twin Shell / Flow Bin Sieve Analysis
Yield Analysis Blending

Tabletting Step 7 IPQC testing

Yield Analysis Compression stage Physical tests
Tabletting Assay
Dissolution

Step 8
Coating stage IPQC testing
[1/2/3] Sublots coated tablets- weight
Coating Yields
Overall Prod Yield

Finished Product
Chart One:

Handbook of Pharmaceutical Sect: 7 . 16 Generic Development

 ORAL TABLETS MANUFACTURE CHAPTER 7

M a n u f a c t u r i n g
Flow Chart II
Dry Granulation
Example of a Dry Granulation Manufacturing Process

PVP K-30 (POVIDONE USP) TRITURATION SIEVE 40 MESH

Y-CONE 5, 10 MINS.
ACTIVE MATERIAL USP
STARCH NF (REDRIED)
TRITURATION SIEVE 40 MESH

ANHYDROUS LACTOSE NF Y-CONE 5, 20 MINS.

STARCH NF (REDRIED) TRITURATION SIEVE 40 MESH

CONTAINER
ANHYDROUS LACTOSE NF #1
CONTAINER #2
3

SIEVE 30 MESH
1 2

Y-CONE 50, 15 MINS

ANHYDROUS LACTOSE NF

SIEVE 30 MESH

Y-CONE 50, 15 MINS

ANHYDROUS LACTOSE NF

SIEVE 30 MESH

Y-CONE 50, 15 MINS

MAGNESIUM STEARATE NF

SIEVE 50 MESH

Y-CONE 50, 5 MINS

TABLETTING SLUGS
KILIAN PHARMA

MILLING, FREWITT 2.5 mm

MILLING, FREWITT 0.8 mm

Y-CONE 50, 20 MINS

MAGNESIUM STEARATE NF

SIEVE 50 MESH

Y-CONE 50, 5 MINS

TABLETTING KILIAN T-300

Chart Two - Example of a Dry Granulation Manufacturing Process - Stages are Dry Mixing; Slugging;
Milling; Blending & Compression.

Handbook of Pharmaceutical Sect: 7 . 17 Generic Development

 ORAL TABLETS MANUFACTURE CHAPTER 7

Manufacturing
Flow Chart II

Wet Granulation - Low Dose

Chart Three

Lactose NF Hydrous 200 Mesh DIOSNA P-800

Starch NF
0.5 and 1.0 mg Active USP 30 sec Mixing: MIXER I
Color Yellow DC No. 10 Aluminum Lake 175 sec. Mixing: MIXER II
(for 0.5 and 1.0 mg tablets)
Color FDC Blue No. 1 Aluminum Lake 11-14

GRANULATION
DIOSNA P-800
PVP K-90 (Povidone USP)
Mixing:
Purified Water USP
MIXER II +
CHOPPER II
S/S Mixing vessel 140 seconds
Propeller Mixer

DIOSNA P-850
Purified Water USP Mixing:
MIXER II +
CHOPPER II

DRYING - FBD
Outlet temp. up to 45°C MILLING
Dry until
(target 42°C) 0.8 mm screen
Target LOD Inlet temp. up to 68°C
Reached (target 64°C)

Microcrystalline Cellulose NF MILLING

BLENDING
Y-CONE 200
(Avicel PH 102) 0.8 mm screen 15 min. Mixing

Y-CONE 200
Magnesium Stearate NF SCREENING 5 min. Mixing
50 mesh screen Discharging into drums

TABLETTING
Tabletting according to
specifications

Handbook of Pharmaceutical Sect: 7 . 18 Generic Development

 ORAL TABLETS MANUFACTURE CHAPTER 7

RANITIDINE HCl
300mg

COATED CAPLETS

MF
AND

MANUFACTURING PROCESS
INSTRUCTIONS

MANUFACTURING AND CONTROLS

Handbook of Pharmaceutical Sect: 7 . 19 Generic Development

 ORAL TABLETS MANUFACTURE CHAPTER 7

Master Manufacturing
Formula
and

Master Manufacturing
Instructions

Set of Instructions for each strength

A complete set of manufacturing instructions is herewith provided for each
strength of the solid oral dosage form. The dosage form has 2 strengths
namely:

150 mg Ranitidine HCl Tablets

Ü 300 mg Ranitidine HCl Caplets Û

Set of specifications for each strength

A complete set of specifications (in-process, tablet cores and film coated
tablets) are provided for each strength of dosage form.

Handbook of Pharmaceutical Sect: 7 . 20 Generic Development

 ORAL TABLETS MANUFACTURE CHAPTER 7

Manufacturing
Instructions
This section contains:
♦ Master Formula for 100 000 units (PIVOTAL)

♦ Master Formula for 200 000 units (MARKET)

♦ Description of Manufacturing Process

♦ Manufacturing Procedure Flow Chart

♦ Blank Master Production Batch Records for intended production lots

♦ Blank Packaging Records for intended production lots

♦ Formula comparison

♦ Equipment Comparison

♦ Description of Packaging Operation

Product application : Ranitidine HCl Tablets 300.0 mg.

Catalog Number : 8612-97 (Pivotal) / 8613-97 (Market)
Reference (RLD) : ZANTAC Tablets 300.0 mg.

Handbook of Pharmaceutical Sect: 7 . 21 Generic Development

 ORAL TABLETS MANUFACTURE CHAPTER 7

Manufacturing Instructions

OUTLINE OF STANDARD OPERATING PROCEDURES FOR :

MANUFACTURING AND PROCESSING OPERATIONS

1. Production Department - Prepares a production order or dossier for each

production batch according to the current posted production schedule.
2. Production Department - Assigns a batch number to the manufacturing lot,
according to the existing coding procedure, and enters these batch codes in
the batch numbers log. This operation may be performed by a computer
program.
3. Production Department - A clear photocopy of the Master Formula (MF)
and Master Manufacturing Instructions (MMI) is prepared with the allocated
manufacturing batch number.
4. Production Department - Prepares all forms and documents needed in the
manufacturing process which are placed in the product order file.
The file is then transferred to the Weighing Center or Dispensing Area.
5. Weighing/Dispensing Area - Weighs all raw material components
according to the master formula record. For each weighing, the raw material
receiving logbook number is entered on the master formula record. All
materials belonging to one manufacturing batch of the product is placed on a
separate pallet and covered with a pallet cover or clear shrink-wrap.
As per production schedule the pre-weighed raw material on pallets are
transferred to productions, by production personnel, under the responsibility
of the department head. Units are securely labeled with ID and designation.
6. Production Unit. - During manufacturing, the product test results are
recorded on the control forms which are attached to the master formula and
manufacturing instructions batch record.
7. Production Office - forwards a “Standard Packaging Sheet” with the
computerized order to the packaging department.
8. Packaging Department - forwards the “Standard Packaging Sheet” and the
computer order to the packaging materials warehouse.
9. Packaging Department - Authorizes packaging startup, in-process
compliance, on the “Packaging Work Sheet”.
10. After packaging, the packaged goods are transferred to the
warehouse/holding area under a quarantine status, pending QC release.
11. The product is tested by the QC analytical laboratory.
12. Production records and test results are analyzed by QA Department and on
release the product is moved to the warehouse ready for shipment.
13. The batch records are archived by the Quality Assurance Unit.
14. Shipping Department - maintains a complete traceability record (log) of the
shipping of each product's batch number and its final destination. A
comprehensive shipping disposition record of each batch produced is thus
on file.

Handbook of Pharmaceutical Sect: 7 . 22 Generic Development

 ORAL TABLETS MANUFACTURE CHAPTER 7

Manufacturing Instructions
MANUFACTURING INSTRUCTIONS FOR COMMERCIAL PRODUCTION

Identification of Batch Parameters.

Product name: Ranitidine HCl Tablets 300.0 mg

Catalog Number: 8613-97 Batch Size: 200 000 (Pivotal)
Department: Direct Compression Batch Size: 400 000 (Market)
Precautions: •‚ƒ Sub-lot No: þ1 þ2 ý3
Caution: †‰•6y> Manufacture Date:
Cat./Formula No: # 8613-97 Cores þ : Coated þ Caplets þ
Based on Validation: Batch # 86132 þ Validation Lot
þ Commercial Lot
Change Control for this document: Original - No Change þ : Change ý
Change made: - none

KEY:
Precautions: • Wear Mask and Gloves
‚ Wear disposable overalls
ƒ Use air stream face visor with AIR filter
„ Use Mask, Gloves and Safety glasses
Caution: …Avoid exposure to light / Protect form light
†Store in well closed containers
‡Potential danger to pregnant women
ˆPregnant women prohibited in this area
‰Do not store above 25øøC
• Tabletting Room humidity below 50%
6 Maximum time between granulation and compression
7 days.
y Pack blended granular material into a container with two
heavy duty plastic bags and seal 100% with a plastic tie.
> Place 2 x 500 g silica gel pack between plastic bags
ý 150 mg and 300 mg Ranitidine can not be geometrically
scaled.

Handbook of Pharmaceutical Sect: 7 . 23 Generic Development

 ORAL TABLETS MANUFACTURE CHAPTER 7

Manufacturing Instructions
COMMERCIAL BATCH MASTER FORMULA

Ranitidine HCl Caplets 300.0 mg. Cat: 8613-97

Batch No: Weighing Date:

PAGE 1 of 3.
Per % RM. Sign
UNIT Exc Lot weigh.
ess Raw Material Names per 400 000 cores
mg No Dept.

Kg g mg L mL A B
PART ONE
168.0 - Ranitidine Hydrochloride Granulated 67 200
129.6 - Microcrystalline Cellulose NF 51 840
Avicel pH 102
9.60 - Croscarmellose Sodium NF 3 840
AC-DI-SOL

- Theoretical End Weight. 122 880

PART TWO
168.0 - Ranitidine Hydrochloride Granulated 67 200
-

PART THREE
4.80 - Magnesium Stearate NF 1 920
- -
480.0 - Theoretical End Weight. 192 000
PART FOUR AQUEOUS FILM COAT SUSPENSION ¹
10 Aqueous Film Coating Suspension
8.2 Methocel E-5 Premium 3 620
Hydroxypropyl Methylcellulose USP
3.41 OPASPRAY-K-7000 [White] 3 000
- Methyl Chloride NF 70 300
- Isopropyl Alcohol USP 46 780

11.5 Theoretical End Weight. 123 700

366.0 mg of Granulated Ranitidine Hydrochloride is equivalent to 300.0 mg Ranitidine.

¹ Aqueous film coat suspension (Opaspray) contains ca. 49-51% solids
3
Coated tablet weight at end of drying stage is approximately 486 mg - 486.5 mg
Ed Number:01 Effective Date:
APPROVED
Ed. Status: DD/MM/YY P West E Hollmann C Frost C Latham R Ford
New Department R &D RA QC / QA

Handbook of Pharmaceutical Sect: 7 . 24 Generic Development

 ORAL TABLETS MANUFACTURE CHAPTER 7

Manufacturing Instructions
PIVOTAL BATCH MASTER FORMULA

Ranitidine HCl Caplets 300.0 mg. Cat: 8612-97

Batch No: Weighing Date:

PAGE 2 of 3.
Per % RM. Sign
UNIT Exc Lot weigh.
ess Raw Material Names per 200 000 units
mg No Dept.

Kg g mg L mL A B
PART ONE
168.0 - Ranitidine Hydrochloride Granulated 33 600
129.6 - Microcrystalline cellulose NF 25 920
Avicel pH 102
9.60 - Croscarmellose Sodium NF 1 920
AC-DI-SOL

213.70 - Theoretical End Weight. 61 440

PART TWO-
168.0 - Ranitidine Hydrochloride Granulated 33 600
-

PART THREE
4.80 - Magnesium Stearate NF 0 960
-
480.0 Theoretical End Weight. 96 000
- -

PART FOUR AQUEOUS FILM COAT SUSPENSION ¹

10% Aqueous Film Coating Suspension
8.2 Methocel E-5 Premium 1 810
Hydroxypropyl Methylcellulose USP
1
3.4 OPASPRAY-K-7000 [White] 1 500
- Methyl Chloride NF 35 150
- Isopropyl Alcohol USP 23 400

11.53 Theoretical End Weight. 61 860

168.0 mg of Granulated Ranitidine Hydrochloride is equivalent to 150.0 mg Ranitidine Hydrochloride.

¹ Aqueous film coat suspension (Opaspray) contains ca. 49-51% solids.
3
Coated tablet weight at end of drying stage is approximately 486mg (LCL) 486.5mg
(Target) - 487mg (UCL) representing an increase in tablet weight of 6.0 - 6.5 - 7.0 mg per
dosage unit during the organic spray coating process.
Ed Number: 01 Effective Date:
APPROVED
Ed. Status: DD/MM/YY P West E Hollmann C Frost C Latham R Ford
New Department R &D RA QC / QA

Handbook of Pharmaceutical Sect: 7 . 25 Generic Development

 ORAL TABLETS MANUFACTURE CHAPTER 7

Manufacturing Instructions
COMMERCIAL BATCH MASTER FORMULA
Ranitidine HCl Caplets 300.0 mg Cat : 8613-97

Batch No: Weighing Date:

PAGE 3 of 3.
Per % RM. Weigh
UNIT Exc Lot Center
ess Raw Material Names per 200 000 cores
mg No Sign.

Kg g mg L mL A B
PART FOUR - FILM COATING,
SUBLOT 1
300.0 Ranitidine 150 mg CORES 96 000 [200 000 Cores]
Ranitidine 150 mg core Aqueous 61 850
6.0² Film Coating Suspension (3.95%
solids in COATING SUSPENSION)
306.0 Theoretical End Weight. 98 000

PART FOUR - FILM COATING

SUBLOT 2
300.0 Ranitidine 150 mg CORES 96 000 [200 000 Cores]
Ranitidine 150 mg core Aqueous 61 850
6.0² Film Coating Suspension
306.0 Theoretical End Weight. 98 000

PART FOUR - FILM COATING

SUBLOT

PART FOUR - FILM COATING

SUBLOT

¹ Aqueous film coat suspension (Opaspray) contains ca. 50.% solids

² 3.95 - 4.15 % Solids remaining in tablet film coat. Tablet weight after drying 486 - 487 mg.

Ed Number: 02 Effective Date:

APPROVED
Ed. Status: 01 DD/MM/YY P West E Hollmann C Frost C Latham R Ford
Department R &D RA QC / QA

Handbook of Pharmaceutical Sect: 7 . 26 Generic Development

 ORAL TABLETS MANUFACTURE CHAPTER 7

Manufacturing Instructions
MANUFACTURING INSTRUCTIONS FOR COMMERCIAL PRODUCTION

PAGE 1 of 5.
Machine Sign Date
MANUFACTURING INSTRUCTIONS No: A B
Ranitidine HCl Caplets 300.0 mg Cat : 8613-97

1. IDENTIFY the equipment and verify the cleanliness prior to use.

PART ONE
Premix LAYER I
2. LOAD into the [Y-Cone blender] (Type 200) the ingredients in the
following order: PART I

RANITIDINE HYDROCHLORIDE GRANULATED

AVICEL pH-102 (MICROCRYSTALLINE CELLULOSE NF)
AC-DI-SOL (CROSCARMELLOSE SODIUM NF)

3. Mix for 1 minute.

Premix LAYER II
4. LOAD into the [Y-Cone blender] (Type 200) the ingredients in the
following order:
RANITIDINE HYDROCHLORIDE GRANULATED
5. Mix for 15 minutes.
Total Mixing Time is 15 minutes.
Start of Mixing Time - [ ] am /pm
Time of mixing - [ ] am /pm

4. PASS the MAGNESIUM STEARATE through SIEVE fitted with a 50

mesh screen into a 10 liter container / bin.

5. LOAD into the [Y-Cone blender] (Type 200) with the MAGNESIUM
STEARATE:
6. Mix for 5 minutes.
Total Mixing Time is 5 minutes.
Start of Mixing Time - [ ] am /pm
Time of mixing - [ ] am /pm
7. PASS the BLENDED MATERIAL through VIBRATING ELECTRIC
SIEVE fitted with a 2.5 mm screen into a sufficient 100 liter containers or
bins lined with 2 heavy duty plastic bags. Place 2 x 500g bags of silica
gel drying agent between the bags.
8. WEIGH the milled granulate. __________Kg. Immediately add the
batch number to the scale print-out, and attach to the manufacturing
instructions, date and sign the print-out.

Ed Number: 02 Effective Date:

APPROVED
Ed. Status DD/MM/YY P West E Hollmann C Frost C Latham R Ford
01 Department R &D RA QC / QA

Handbook of Pharmaceutical Sect: 7 . 27 Generic Development

 ORAL TABLETS MANUFACTURE CHAPTER 7

Manufacturing Instructions

MANUFACTURING INSTRUCTIONS FOR COMMERCIAL PRODUCTION

PAGE 2 of 5.
Machine Sign Date
MANUFACTURING INSTRUCTIONS A B
Ranitidine HCl Caplets 300.0 mg Cat : 8613-97

9. WEIGHT of the final blended material

Actual weight: [ ] Kg.

Theoretical Weight [ ] Kg.

No. of containers ___________ .

Calculate Yield:
Yield ___________ %
10. TRANSFER the milled granulate from stage 8 to the compression
Department. - Maximum storage period - 7 days in sealed bags.
Date: ______ Time _________
11. COLLECT 10 samples, each equivalent to the approximate weight of
three tablet (900 mg) in labeled sample containers. Collect samples from
upper, middle and lower part of each the container.
Send the samples to the QC laboratory for Blend Uniformity Testing.

Tablet core - Compression

12. IDENTIFY and verify the cleanliness of the tabletting equipment and
de-duster in use.
COMPRESS the final blend according to the written product
specifications
Tabletting machine: Type & No KILIAN TX
Machine Speed: 100 000 cores per hour
Limit of Speed : NLT 80 000 ; NMT 120 000 cores per hour.

13. WEIGH the tablet cores:

Actual production weight: [ ] Kg.
Weight of Samples taken: [ ] Kg.
Vacuum and rejects Weight: [ ] Kg.
Total weight [ ] Kg
No of Bulk Containers [ ]
Theoretical Weight [ ] Kg. Yield ________ %

(Yield Limits: NMT 2% unexplained loss compared to the final blend

weight from stage 9.
14. SEAL the double PE plastic bags (clear inner, black outer) with plastic
ties then close all containers, and attach (bar coded) labels to the Bulk
Containers for transport to the holding area.

Ed Number: 02 Effective Date:

APPROVED
Ed. Status: 01 DD/MM/YY P West E Hollmann C Frost C Latham R Ford
Department R &D RA QC / QA

Handbook of Pharmaceutical Sect: 7 . 28 Generic Development

 ORAL TABLETS MANUFACTURE CHAPTER 7

Manufacturing Instructions
MANUFACTURING INSTRUCTIONS FOR COMMERCIAL PRODUCTION

PAGE 3 of 5.
MANUFACTURING INSTRUCTIONS
Machine Sign Date
Ranitidine HCl Caplets 300.0 mg Cat : 8613-97 A B

PART SIX
ORGANIC FILM COATING SOLUTION
15. IDENTIFY and verify the cleanliness of the coating equipment.
Weigh:
[ ] Kg METHYL CHLORIDE NF
[ ] Kg ISOPROPYL ALCOHOL USP
into a stainless steel vessel fitted with a ROLLER MIXER. [# ]

16. ADD gradually while mixing the ingredient:

METHOCEL E-5 PREMIUM

(HYDROXYPROPYL METHYLCELLULOSE USP)
to STAGE 15 and mix to a uniform dispersion - for 30 minutes.

Total Mixing Time is 30 minutes.

Start of Mixing Time - [ ] am /pm
Time of mixing - [ ] am /pm

CHECK that the dispersion is homogeneous and smooth/uniform

17. ADD gradually while mixing the [OPASPRAY K-1-7000H-WHITE] to
STAGE 16 and mix to a uniform dispersion - about 15 minutes

Total Mixing Time is 15 minutes.

Start of Mixing Time - [ ] am /pm
Time of mixing - [ ] am /pm

18. PASS the AQUEOUS FILM COATING SUSPENSION through a 80

mesh screen [POLYMON] into a stainless steel container and close well.

19. SPLIT the AQUEOUS FILM COATING SUSPENSION into FOUR

equal sublots and label with (bar-coded) batch number and Sublot
number.

20. STIR the AQUEOUS FILM COATING SUSPENSION continuously

during the coating process.

Ed Number: 02 Effective Date:

APPROVED
Ed. Status: 01 DD/MM/YY P West E Hollmann C Frost C Latham R Ford
Department R &D RA QC / QA

Handbook of Pharmaceutical Sect: 7 . 29 Generic Development

 ORAL TABLETS MANUFACTURE CHAPTER 7

Manufacturing Instructions
MANUFACTURING INSTRUCTIONS FOR COMMERCIAL PRODUCTION
PAGE 4 of 5.
MANUFACTURING INSTRUCTIONS
Machine Sign Date
Ranitidine HCl Caplets 300.0 mg Cat : 8613-97 A B
COATING PROCEDURE - SUBLOT ONE
Wear Masks and Gloves.
Caution : Inflammable Solvents.
Coating Procedure:
21. IDENTIFY and verify the cleanliness of the coating equipment in use
Sublot Size[ 96 ] Kg. Equal to [200 000] ___________ Caplets.
SUB LOT No 1.
PREHEATING OF CORES:
Coating machine (Type & No: ACCELA-COTA) :
Incoming Air Temperature: [50]º C - [55]º C
Total Warming time: [10] Minutes
Drum Speed: MINIMUM rpm (minimum speed)
Jogging cycle: One cycle every [ 2 ] minutes.
Extraction Air Temperature: [35]º C - [42]º C
Limit of rpm: NLT MINIMUM rpm:NMT MINIMUM rpm.
SPRAYING PARAMETERS:
Pump type: REXON AIRLESS No: 107802
Spray rate: [000] - [000] g/min
Nozzles: [ 2 ] - [ ] mm (No: 1365)
Angle of Guns to Bed: 90 º degrees
Height above Bed: [ 25 ] cm
Incoming Air Temperature: [ 50 ]º C - [ 55 ]º C (Target: 53 º C)
Extraction Air Temperature: [ 35 ]º C - [ 42 ]º C (Target: 38 º C)
22. COAT tablet cores at a drum speed of [ 5 ] rpm and a pump pressure
1.5 for 10 minutes and then at a drum speed of [ 6] rpm at 1.5-2.0 Atms.
Target COATED tablet weight of [ 486.5 ] mg is obtained.
COATING COMPLETION PROCEDURE
23. REDUCE drum speed to minimum rpm and perform the following:
(1) - Increase SET POINT of incoming air to 90ºC for 30 mins.
(2) - Check Relative Humidity (via ROTRONIC Equipment)
(3) - if RH % is less than 10 % go to sub-step (5) RECORD [ca 7%] RH
(4) - if RH is more than 10 % dry for an extra 30 min. CHECK RH %
again
(5) - cool until the Extraction Air Temperature reaches 45ºC - 50ºC
24. TRANSFER coated tablets into containers lined with two PE plastic
bags (clear inner, black outer) Seal bags with plastic ties and close
containers, and attach (bar coded) labels to the Bulk Containers for
transport to the holding area.
25. ATTACH the temperature graphs (Type & No) to the manufacturing
instructions. Immediately add the batch / Sublot number to the
temperature graph(s) and date and sign graph.
26. WEIGH Coated tablets
Actual production weight: _______ [ ] Kg. No of Containers _____
Ed Number: 02 Effective Date:
APPROVED
Ed. Status: 01 DD/MM/YY P West E Hollmann C Frost C Latham R Ford
Department R &D RA QC / QA

Handbook of Pharmaceutical Sect: 7 . 30 Generic Development

 ORAL TABLETS MANUFACTURE CHAPTER 7

Manufacturing Instructions
MANUFACTURING INSTRUCTIONS FOR COMMERCIAL PRODUCTION
PAGE 5 of 5.
MANUFACTURING INSTRUCTIONS
Machine Sign Date
Ranitidine HCl Caplets 300.0 mg Cat : 8613-97 A B
COATING PROCEDURE - SUBLOT TWO
Wear Masks and Gloves.
Caution : Inflammable Solvents.
Coating Procedure:
21. IDENTIFY and verify the cleanliness of the coating equipment in use
Sublot Size[ 96 ] Kg. Equal to [200 000] ___________ Caplets.
SUB LOT No 1.
PREHEATING OF CORES:
Coating machine (Type & No: ACCELA-COTA) :
Incoming Air Temperature: [50]º C - [55]º C
Total Warming time: [10] Minutes
Drum Speed: MINIMUM rpm (minimum speed)
Jogging cycle: One cycle every [ 2 ] minutes.
Extraction Air Temperature: [35]º C - [42]º C
Limit of rpm: NLT MINIMUM rpm:NMT MINIMUM rpm.
SPRAYING PARAMETERS:
Pump type: REXON AIRLESS No: 107802
Spray rate: [000] - [000] g/min
Nozzles: [ 2 ] - [ ] mm (No: 1365)
Angle of Guns to Bed: 90 º degrees
Height above Bed: [ 25 ] cm
Incoming Air Temperature: [ 50 ]º C - [ 55 ]º C (Target: 53 º C)
Extraction Air Temperature: [ 35 ]º C - [ 42 ]º C (Target: 38 º C)
22. COAT tablet cores at a drum speed of [ 5 ] rpm and a pump pressure
1.5 for 10 minutes and then at a drum speed of [ 6] rpm at 1.5-2.0 Atms.
Target COATED tablet weight of [ 486.5 ] mg is obtained.
COATING COMPLETION PROCEDURE
23. REDUCE drum speed to minimum rpm and perform the following:
(1) - Increase SET POINT of incoming air to 90ºC for 30 mins.
(2) - Check Relative Humidity (via ROTRONIC Equipment)
(3) - if RH % is less than 10 % go to sub-step (5) RECORD [ca 7%] RH
(4) - if RH is more than 10 % dry for an extra 30 min. CHECK RH %
again
(5) - cool until the Extraction Air Temperature reaches 45ºC - 50ºC
24. TRANSFER coated tablets into containers lined with two PE plastic
bags (clear inner, black outer) Seal bags with plastic ties and close
containers, and attach (bar coded) labels to the Bulk Containers for
transport to the holding area.
25. ATTACH the temperature graphs (Type & No) to the manufacturing
instructions. Immediately add the batch / Sublot number to the
temperature graph(s) and date and sign graph.
26. WEIGH Coated tablets
Actual production weight: _______ [ ] Kg. No of Containers _____
Ed Number: 02 Effective Date:
APPROVED
Ed. Status: 01 DD/MM/YY P West E Hollmann C Frost C Latham R Ford
Department R &D RA QC / QA

Handbook of Pharmaceutical Sect: 7 . 31 Generic Development

 ORAL TABLETS MANUFACTURE CHAPTER 7

Manufacturing Instructions
COMMERCIAL BATCH MASTER FORMULA

Ranitidine HCl Caplets 300.0 mg Cat : 8613-97

OUTLINE OF
STANDARD OPERATING PROCEDURES FOR:
IN-PROCESS CONTROLS

STAGE 1.

D uring all stages of manufacture, processing, packaging and warehousing

appropriate control procedures are employed in conformity with current good
manufacturing practice (cGMP).
Strict precautions and documentary procedures are in place to ensure the
complete absence of previous product contamination or residual printed labeling
from the previous product.

STAGE 2.

A ppropriate in-process controls include material testing by the Quality Control

Unit and Quality Assurance personnel. These test are:

⇒ Content uniformity of final blend.

⇒ Physical specifications of the Tablets.

STAGE 3.

In-process material testing is performed by responsible on-line manufacturing

personnel and qualified Quality Assurance Unit Personnel.

STAGE 4.

T he Quality Assurance Unit reviews the batch test results and evaluates the
criteria of acceptance or rejection of each batch lot manufactured.

Handbook of Pharmaceutical Sect: 7 . 32 Generic Development

 ORAL TABLETS MANUFACTURE CHAPTER 7

Manufacturing Instructions
Ranitidine HCl Tablets 300.0 mg Cat: 8602-97

IN-PROCESS CONTROLS DURING TABLET COMPRESSION

Checks performed by production personnel

In-process testing (IPQC) is performed independently by both production and quality control
trained personnel. The IPQC tests specified in the tabulations are carried out in accordance
with written in-process specifications per product. Essential IPQC tests are conducted that
impact in the operation of the process parameters.
Trained production personnel test the physical specifications of samples taken at random
at each process stage according to the individual product specifications: A minimum
sampling frequency is tabulated for each eight hour work period.

Production In-process Testing Schedule:

PAGE 1 of 2
IPQC Test Sample Frequency per Acceptance & Rejection
PERFORMED Size 8 hr.(1) (min) Criteria (2)

AVERAGE WEIGHT 10 At 15 min. intervals. Within the specified range.

NMT two (2) tablets out of the

10 tested may deviate from
THICKNESS 10 3 times(1) product specifications.
No deviation is allowed from
the Double Limits(4)
specification.
NMT two (2) tablets out of the
10 tested may deviate from
HARDNESS 10 3 times(1) product specifications.
No deviation is allowed from
the Double Limits(3)
specification.
20 or 40 No deviation from the written
FRIABILITY According to each Twice product specifications is
product permitted.
DISINTEGRATION 6 Twice No deviation from the written
product specifications is
permitted.

KEY:
(1)
The testing frequency is performed twice when the overall compression running time is less
than four hours for the entire batch lot.
Deviations from the specifications and acceptance criteria, arising during the in-process
(2)
controls, shall determine the corrective/adjustment action performed on the tableting machinery
during the tablet compression stage.

The Double Limits for the Tablet Hardness Test are defined as C-±20% from the minimum
(3)

and maximum product specifications limits. When, there is a NLT 10 SCU Hardness
specification, the double limits may not exceed a minimum value of 8 SCU. (Not to go below 8
SCU).
Double Limits for Tablet Thickness Tests are defined as C ± 0.1mm from the minimum and
(4)

maximum values in the specifications, where C is the limit value.

Handbook of Pharmaceutical Sect: 7 . 33 Generic Development

 ORAL TABLETS MANUFACTURE CHAPTER 7

Manufacturing Instructions
COMMERCIAL BATCH MASTER FORMULA
Ranitidine HCl Caplets 300.0 mg Cat : 8613-97
Checks performed by Quality Control personnel
Quality Control personnel test the physical specifications of random samples
according to the individual product specifications sheets: A minimum sampling
frequency is tabulated for each eight hour (shift) period.
Quality Control - In-process Testing Schedule:
PAGE 2 of 2
Test Sample Frequency Acceptance
PERFORMED Size per shift (1) Criteria (2)
(Tablets) (min.)
INDIVIDUAL TABLET 20 (1) Twice NMT 2 tablets out of the 20 tested can
deviate from product spec. No deviation
WEIGHT
is allowed from Double Limits(3) spec.
THICKNESS 10 (1) Twice NMT 2 tablets out of the 10 tested can
deviate from product spec. No deviation
is allowed from Double Limits(4) spec.
HARDNESS 10 (1) Twice NMT 2 tablets out of the 10 tested can
deviate from product spec. No deviation
is allowed from Double Limits(5) spec.
DIAMETER Once No deviation from product specification
3 (1)
at start is allowed.
FRIABILITY 20 -40 (1) Twice
No deviation from product specification
According to
is allowed
product
DISINTEGRATION 6 (1) Twice No deviation from product specification
is allowed

KEY:
(1)Samples are taken, independently by QC personnel for batch release purposes, at least
once per hour throughout the tabletting run, producing a total representative sample quantity
of 300 -500 tablets. This representative sample lot is for QC batch release purposes .
(2)Deviations from specifications and acceptance criteria, arising during the in-process
controls, shall determine the corrective action to be performed on the tabletting machinery
during the compression stage.
(3) Double
Limits for the Individual Tablet Weight test are defined as the double value from the
minimum or maximum limit in relation to the nominal tablet value (i.e. target weight value).
Double Limits for Tablet Thickness Tests are defined as C - ± 0.1 mm from the minimum
(4)

and maximum specification limit values. Where C = limit value.

(5)Double Limits for Tablet Hardness Test are defined as C-±20% from the minimum and
maximum product specifications limits. When, there is a NLT 10 SCU Hardness
specification, the double limits may not exceed a minimum value of 8 SCU. (i.e. not permitted
to go below 8 SCU).

Handbook of Pharmaceutical Sect: 7 . 35 Generic Development

 ORAL TABLETS MANUFACTURE CHAPTER 7

Manufacturing Instructions
Ranitidine HCl Tablets 300.0 mg Cat: 8613-97

MANUFACTURING FLOW CHART

RANITIDINE GRANULES STEP ONE MIX FOR

AVICEL NF Y-CONE BLENDER 60 SECOND
AC-DI-SOL

STEP TWO MIX FOR

RANITIDINE GRANULES 15 minutes
(PART 2) Y-CONE BLENDER

Lubricant STEP THREE

Mg Stearate NF MIX FOR 5 minutes
PARTIAL COATING

Quick Sieve
Sieve MESH # [50]
IPQC testing
STEP FOUR Blend Uniformity
VIBRATING SIEVING
2.5 mm

Yield Analysis
BLENDING Yield
Tabletting
Yield Analysis STEP FIVE
Compression stage IPQC testing
Tabletting Physical tests
Assay

STEP SIX IPQC testing

Coating Yields
Overall Prod Yield COATING STAGE Coated tablets- weight
[1/2/3/4] Sublots

Finished Product

FP TESTING
PHYSICAL TESTS
ASSAY
IMPURITIES / RH
DISSOLUTION
OVI

Handbook of Pharmaceutical Sect: 7 . 36 Generic Development

 ORAL TABLETS MANUFACTURE CHAPTER 7

Manufacturing Instructions
MANUFACTURING INSTRUCTIONS FOR COMMERCIAL PRODUCTION

Ranitidine HCl Caplets 300.0 mg. Cat: 8613-97

ATTACHMENTS:

[THE FOLLOWING ATTACHMENTS ARE PLACED HERE:]

Drying
N/A

Milled granulate
N/A

Final Blend
Attachment # 1 Mixing time Print-Out of the Final Blend
Attachment # 2 Weight Print-Out of the Final Blend

Tablet Cores - Weight Control

Attachment # 3 Weight Print-Out of the total cores

Coated Tablets - Weight Control

Attachment # 4 Weight Print-Out of the coated tablets sub lot I - 2.

Coated Tablets - Temperature Control

Attachment # 5 Temperature profile Print-Out of the coated tablets sub lot I -2.

Handbook of Pharmaceutical Sect: 7 . 37 Generic Development

 ORAL TABLETS MANUFACTURE CHAPTER 7

Manufacturing Instructions
MANUFACTURING INSTRUCTIONS FOR COMMERCIAL PRODUCTION

IN-PROCESS CONTROL SPECIFICATION

GRANULATION AND TABLETTING SUMMARY

COMMERCIAL BATCH
PAGE 1 of 4

Product: Ranitidine HCl Tablets 300.0 mg Cat. No: 8613-97

Quantity 400 000 MNF Date:

Total Final Blend Yield Limit: NLT 98.0% (based on actual quantities
processed).

Yield = Wt of Final Blend = _______

Theoretical Weight

In-Process
Final Blend Uniformity Limit: 94.0 - 106.0% of labeled amount
RSD ≤ 6.0% (as per attached specifications)

Tabletting Yield NMT 2.0% unexplained loss from the

previous final blend step.

Overall Production Yield NLT 95.0%

Maximum Holding times for:

milled granulate (sealed) 14 days
tablet cores (sealed) 30 days
coated tablets (unpacked) 60 days

Environmental temperature 24ºC (Ñ 4ºC)

Environmental humidity 60% (Ñ 10%)

¹ Recorded on Statistical Data Work Sheets.

Handbook of Pharmaceutical Sect: 7 . 38 Generic Development

 ORAL TABLETS MANUFACTURE CHAPTER 7

Manufacturing Instructions
MANUFACTURING INSTRUCTIONS FOR COMMERCIAL PRODUCTION

IN-PROCESS CONTROL SPECIFICATION

CAPLET CORES
SUMMARY

COMMERCIAL BATCH
PAGE 2 of 4

Product: Ranitidine HCl Caplets 300.0 mg. CORES Cat: 8613-97

Labeled Amount: Each core contains Ranitidine 300.0 mg.

In-process Specifications for cores.

Punch Size (caplets - 300) 15.50 mm x 7.00 mm

Punch No [P24]
Die No. [D25]

Description White to pale fawn oblong core debossed

with the number [386] on one face of the
caplet core - [ plain ] on the opposite face.
Scoring Not scored

Core length Nominal 15.50 Limit: 15.400 - 15.65 mm

Core width Nominal 7.0 Limit: 6.9 - 7.3 mm

Individual core weight (±7.5%) Nominal 480.0 Limit: 444.0 - 516.0 mg:
Average core weight (±5.0%) Nominal 480.0 Limit: 456.0 -504.0 mg:

Thickness Nominal 4.6 Limit: 4.4 - 4.8 mm

Hardness (longitudinal) Target: 18 SCU NLT 14.0 - NMT 22 SCU.

Friability NMT 1.0 %

Disintegration Target: 5 Min NLT 2.0 - NMT 15 Min.

Handbook of Pharmaceutical Sect: 7 . 39 Generic Development

 ORAL TABLETS MANUFACTURE CHAPTER 7

Manufacturing Instructions
MANUFACTURING INSTRUCTIONS FOR COMMERCIAL PRODUCTION

IN-PROCESS CONTROL SPECIFICATION - COATING PROCESS

SUMMARY

COMMERCIAL BATCH
PAGE 3 of 4

Product: Generic name Ranitidine HCl Caplets 300.0 mg.. Cat: 8613-97

Quantity 200 000 MNF Date:

Grams Grams
Film Coating Controls Before Coating After Coating
¹TARGET Tablet weight (mg) [480.0] [486.0]

CHECK WEIGHTS
¹Target Coated weight (mg) - [30.250]

#1 - ¹Weight of 100 tablets (g) [48. ] [ ]

#2 - ¹Weight of 100 tablets (g) [48. ] [ ]
#3 - ¹Weight of 100 tablets (g) [48. ] [ ]
#4 - ¹Weight of 100 tablets (g) [48. ] [ ]
#5 - ¹Weight of 100 tablets (g) [48. ] [ ]

¹Average 100 tablet weight (g) [48.000] [48.600]

¹Average tablet weight (mg) 480.0 486.0

In-Process Yields

¹Yield after coating vs. Pre-coating _______ % [99.8]%

¹Yield after coating to theoretical _______ % [99.2]%

Film Coating Yield NMT 2.0% unexplained loss

from the previous step (tabletting)

¹ Recorded on Statistical Data Tablet Coating Work Sheets.

Handbook of Pharmaceutical Sect: 7 . 40 Generic Development

 ORAL TABLETS MANUFACTURE CHAPTER 7

Manufacturing Instructions
MANUFACTURING INSTRUCTIONS FOR COMMERCIAL PRODUCTION

RELEASE SPECIFICATION FOR COATED TABLETS / CAPLETS [USP]

SUMMARY
COMMERCIAL BATCH
PAGE 4 of 4

Product: Generic name Ranitidine HCl Caplets 300.0 mg. Cat: 8613-97

Labeled Amount: Each tablet/caplet contains: Ranitidine HCl 300.0 mg

Description White to off-white coated Caplet debossed

with the number letters [386] on one face of
the Caplet and [PLAIN] on the opposite
face.

Identification The Chromatogram of the sample solution

exhibits a major peak with the same
retention time as the standard solution.

Individual Tablet weight (±7.5%) Nominal [486.5] Limit: [450.0]-[523.5] mg

Average Tablet weight (±5.0%) Nominal [486.5] Limit: [462.5]-[510.8] mg

Core length Nominal 15.65 Limit: 15.4 - 15.9 mm

Core width Nominal 7.10 Limit: 6.9 - 7.3 mm
Thickness Nominal 4.7 Limit: 4.4 - 4.8 mm

Equivalent relative Humidity NMT 10%

Uniformity of Dosage Units Conforms to the current USP

Content Uniformity

Dissolution NMT 80 % (Q) IN 45 MINUTES

Min = Max =
Average = RSD =
Impurities /Degradation
Products determination
- Each Individual: NMT 0.5% of the labeled amount
- Any other Individual: NMT 0.3% of the labeled amount
- Total: NMT 1.0% of the Ranitidine HCl

Assay Limit: 95.0 - 105.0% of labeled amount

[285.0] - [315.0] mg / Tablet

OVI's and Residual Solvents.

Residual Solvent / OVI's, in the film coat release specification
Residual Solvents or OVI's.
Isopropanol + Dichloromethane NMT 0,2 % w/w (Class 3 Solvent)

Handbook of Pharmaceutical Sect: 7 . 41 Generic Development

 ORAL TABLETS MANUFACTURE CHAPTER 7

Manufacturing Instructions
MANUFACTURING INSTRUCTIONS FOR COMMERCIAL PRODUCTION

COMPARISON OF EXECUTED (PIVOTAL) AND PRODUCTION FORMULAE

Ranitidine HCl Caplets 300.0 mg. Cat: 8613-97

PAGE 1 of 1

Amount per Executed Batch Production

tablets 200,000 tablets Batch
Ingredients (mg) (kg) 400 000 tablets
(kg)

Ranitidine Hydrochloride Granulated 336.00 67.20 134.40

Microcrystalline cellulose NF 129.60 25.92 51.84

[Avicel pH 102]

Croscarmellose Sodium NF 9.60 1.92 3.84

[AC-DI-SOL[

Magnesium Stearate NF (200) 4.80 0.960 1.92

Organic Film Coat (After Drying) 6.50 1.30 2.60

OPASPRAY K-1-700 H (WHITE)

Total 486.500 97.30 194.60

Calculation for Ranitidine Hydrochloride Granulated on a Dry Basis if moisture content

is greater than 0.5 - 1.0% for the purpose of formulating to 100% of the labeled amount.

Weight Adjustment Calculation:

1. Note: 168.0 mg of Ranitidine HCl Granulated is equivalent to 150.0 mg of Ranitidine.

Quantity of Ranitidine HCl Granulated to be weighed = Batch Size x 168.0 x 100

100 - LOD
Where LOD = Loss on Drying of for Ranitidine HCl Granulated =

2. The actual quantity of a non active ingredient such as [Excipient NF] used in the formula will depend on
the WEIGHT for [Active Salt] used.

Handbook of Pharmaceutical Sect: 7 . 42 Generic Development

 ORAL TABLETS MANUFACTURE CHAPTER 7

Manufacturing Instructions
MANUFACTURING INSTRUCTIONS FOR COMMERCIAL PRODUCTION

COMPARISON OF EQUIPMENT AND MANUFACTURING CONDITIONS

BETWEEN EXECUTED AND PRODUCTION BATCHES

Caplets
PAGE 1 of 1
Equipment and Executed Batch Production
Manufacturing Conditions 100,000 units Batch
200,000 units
Premixing Ê Ê
Granulating - (High Shear Granulator) Ê Ê
FBD Drying Ê Ê
Sieve - Oscillating ü ü
Blending Y-cone 200 Y-cone 200

Tabletting Machines Kilian TX Kilian TX

Kilian T-300 Kilian T-300

Coating Suspension Stainless Steel Stainless Steel

Mixing Equipment Container Container
with Roller Mixer with Roller Mixer
80 mesh Screen 80 mesh Screen
Coating Unit AccelaCota AccelaCota AC
48/150 48/150

Equipment Variation NONE NONE

Manufacturing Area Production Production

Manufacturing Staff Production Production

QC and QC Personnel Production Production

SOPS Production Production

Handbook of Pharmaceutical Sect: 7 . 43 Generic Development

 ORAL TABLETS MANUFACTURE CHAPTER 7

Manufacturing Instructions
MANUFACTURING INSTRUCTIONS FOR COMMERCIAL PRODUCTION

PACKAGING OPERATION DESCRIPTION

Ranitidine HCl Caplets 300.0 mg. Cat: 8613-97

Stage One.
PACKAGING COMPONENTS:
1. Bulk Product
2. HDPE Containers
3. Package Insert or Outsert (Product Leaflets)
4. Desiccant (Silica Gel)
5. Container Label
6. Master Cartons
7. Carton Shipping Labels

Stage Two
PACKAGING PROCEDURE:

HDPE Container & Bulk Line Feed

⇓
HDPE Container Cleaning
Process
(Air and Vacuum)
⇓
Tablet Count & Fill
⇓
Cotton Coil
⇓
Insert / Leaflet
Capping (Screw or CRC) Minimum
⇓ &
Closure Torque Test Maximum
torque
⇓ Specs
Container Label
⇓
or Outsert Attaching
⇓

Packed in Master Shipping

Cartons

Handbook of Pharmaceutical Sect: 7 . 44 Generic Development

 ORAL TABLETS MANUFACTURE CHAPTER 7

Manufacturing Instructions

PACKAGING OPERATION - EQUIPMENT LISTING:

Ranitidine HCl Caplets 300.0 mg. Cat: 8613-97

PAGE 1 of 1

No Machine Manufacturer Serial # Type Operation Output

CONTAINERS
Supplier per min (2)

1 Schenck Schenck Process No: 1000-S HDPE Bottle or

Low 50
GMBH Darmstadt 543123 AccuRate Amber Glass High 100*
Feeding

2 King C.E. King Ltd, UK MK-2994 SuperKleen Air Cleaning Low 50

High 100*

3 Lakso Lakso MA US L-333 SLAT Counting & Filling Count

Low 40
L-334 FILLER(1) Tablets 50* 150*

4 RSP Coiler H.G. Kalish Inc., 2169-0003 5329 Dessicant Count

Low 60
Canada
Insertion High 100*

5 RSP Coiler H.G.Kalish Inc., 2234-9987 KOTNR-120- Cotton insertion Count

Low 60
Canada 8440 High 100*

6 Groninger Groninger & Co 2232-2234 DFVK Capping Count

50 60
Germany 6000 High 120*

7. Groninger Groninger & Co 5664 DFVK Outserter Count

Low
KarlsHeim, 3000 High
Germany

8. Prestek Prestek Ltd Science 53342 SmartDate Labelling & Count

Park Nottingham Intelligent Printing Low
High
Thermal
UK
Transfer
Printer

(1) Average figures for containers per minute output for Slow and High Speed.
(2) All indicated machine outputs are adjusted to the Tablet Slate Filler rate.

Handbook of Pharmaceutical Sect: 7 . 45 Generic Development

HANDBOOK of GENERIC DRUG DEVELOPMENT ANDA DEVELOPMENT

Pivotal Manufacturing Instructions

TABLE OF CONTENTS
(Overall ANDA Guideline Requirements for this Section).

This section contains:

◊ Description of Manufacturing Process

◊ Manufacturing Procedure Flow Chart

◊ Master Production Batch Records for intended production lots

◊ Packaging Records for intended production lots

◊ Formula comparison

◊ Equipment Comparison

◊ Description of Packaging Operation

◊ Reprocessing Statement

24 Volume
V Drug Development Series: Sect: 7.45 Oral DR TABLETS
HANDBOOK of GENERIC DRUG DEVELOPMENT ANDA DEVELOPMENT

Pivotal Manufacturing Instructions

OUTLINE OF STANDARD OPERATING PROCEDURES FOR :

MANUFACTURING AND PROCESSING

1. Production Planning - Prepares a production order file for each production

batch according to the production schedule.
2. Production Planning - Assigns batch numbers, according to the existing
code procedure, and enters these numbers in the batch numbers log.
3. Production Planning - A photocopy of the master formula record and
manufacturing instructions is prepared with the specific manufacturing batch
number.
4. Production Planning - Prepares all forms needed in the manufacturing
process which are placed in the product order file.
The file is then transferred to the Weighing Center/Dispensing Area.
5. Dispensing Area - Weighs all raw material components according to the
master formula record. For each weighing, the raw material receiving
logbook number is entered on the master formula record. All materials
belonging to one manufacturing batch of the product is placed on a separate
pallet and covered with a pallet cover or clear shrink-wrap.
As per production schedule the pre-weighed raw material on pallets are
transferred to productions, by production personnel, under the responsibility
of the department head.
6. Production Depts. - During manufacturing, the product test results are
recorded on the control forms which are attached to the master formula and
manufacturing instructions batch record.
7. Production Planning - forwards a “Standard Packaging Sheet” with the
computerized order to the packaging department.
8. Packaging Department - forwards the “Standard Packaging Sheet” and the
computer order to the packaging materials warehouse.
9. Packaging Department - Authorizes packaging startup, in-process
compliance, on the “Packaging Work Sheet”.
10. After packaging, the packaged goods are transferred to the
warehouse/holding area under a quarantine status, pending QC release.
11. The product is tested by the QC analytical laboratory.
12. Production records and test results are analyzed by QA Department and on
release the product is moved to the warehouse ready for shipment.
13. The batch records are archived by the Quality Assurance Department.
14. Shipping Department - maintains a complete and traceability record of the
dispatches of each product batch number and its final destination.

24 Volume
V Drug Development Series: Sect: 7.46 Oral DR TABLETS
HANDBOOK of GENERIC DRUG DEVELOPMENT ANDA DEVELOPMENT

Pivotal Manufacturing Instructions

ENTERIC COATED
TABLETS

DICLOFENAC Na EC TABLETS
50.0 & 75.0 mg.

ALCOHOLIC GRANULATION

24 Volume
V Drug Development Series: Sect: 7.47 Oral DR TABLETS
 HANDBOOK of GENERIC DRUG DEVELOPMENT ANDA DEVELOPMENT

Pivotal Manufacturing Instructions

MANUFACTURING INSTRUCTIONS FOR EXECUTED BATCH

Identification of Batch Parameters.

Product name: DICLOFENAC NA EC TABLETS 50.0 & 75.0 mg.

Batch Number: AIG0000-00
Department: ______________ Batch Size: 1 000 000 units
Precautions: •‚ƒ Sub-lot No: þ1 ý2 ý3
Caution: …† Manufacture Date: Month DD, YY
Cat./Formula No: # AIG034001-02 Cores ý : Coated þ : Tablets þ
Based on PQ: Batch # AIG-PQ01-05 þ PIVOTAL BATCH
þ Validation Lot ý Commercial Lot
Change Control for this document: Original - No Change þ : Change ý
Change made: - none
KEY:
Precautions: • Wear Mask and Gloves
‚ Wear disposable overalls
ƒ Use air stream face visor with AIR filter
„ Use Mask, Gloves and Safety glasses
Material causes extreme irritation to skin and eyes
Do not expose to skin or exposed areas.
Caution: … Avoid exposure to light / Protect form light
† Store in well closed containers and minimize or avoid
exposure to environmental air
‡ Raw material has to be stored at 5°°C - hold active
material at 25o C for one hour to reach room temperature
before weighing, sampling or processing
ˆ Potential danger to pregnant women, pregnant women
are prohibited in this area
‰ Do not heat above [00]ø øC
• Maintain Room humidity below 50%
SPECIAL NOTE
Manufacturing process for DICLOFENAC EC Tablets 50 & 75 mg provided as
geometric proportioned powder blend for all dosage strengths of 50 to 75 mg.
This specific set of manufacturing instructions is suitable for batch lots sizes of 950
000 - 1320 000 dosage units. The same granulate and manufacturing method is
used for both the TWO dosage strengths and is 100% geometrically proportional.
Each 'information or data field' is part of the essential record in order to meet current US
cGMP and FDA Pre-approval expectations.

24 Volume
V Drug Development Series: Sect: 7.48 Oral DR TABLETS
 HANDBOOK of GENERIC DRUG DEVELOPMENT ANDA DEVELOPMENT

Pivotal Manufacturing Instructions

EXECUTED BATCH MASTER FORMULA

DICLOFENAC Na EC TABLETS 50.0 mg. Lot: IA000-00

Batch No: Weighing Date :

Page 1 of 2 pages.
Per % Raw Material Names RM. Sign
UNIT Ex Lot weigh.
ce For [1000 000] kg
mg No Dept.
ss
Kg G mg
PART ONE
50.0 Diclofenac Sodium 50 000
90.0 Lactose Monohydrate NF (200 90 000
mesh)
7.6 Povidone USP (PVP K-30) 7 600
10.0 Sodium Starch Glycolate NF 10 000
12.4 Starch NF 12 400
PART TWO
GRANULATION SOLUTION
- Alcohol USP 25 000
- Alcohol USP q.s. (up to 4.2 kg) 000 000

PART THREE
18.5 Microcrystalline Cellulose NF 18 500
(Avicel PH-101
0.5 Aerosil 200 0 500
(Colloidal Silicon Dioxide NF)
PART FOUR
1.0 Magnesium Stearate NF 1 000
TOTAL 190 000
190.0 DICLOFENAC SODIUM E.C. 190 000
TABLETS 50 mg CORES
* 13.6 DICLOFENAC SODIUM TABLETS 50 109 500
mg FILM COATING DISPERSION
203.6 TOTAL (Theoretical) 203 600
Ed Number:
01
Effective Date:
APPROVED
Ed. Status DD/MM/YY _____________ __________ _______________ _________/________
New Department R &D RA QC / QA
* Average solids remaining on the tablet core

24 Volume
V Drug Development Series: Sect: 7.49 Oral DR TABLETS
 HANDBOOK of GENERIC DRUG DEVELOPMENT ANDA DEVELOPMENT

DICLOFENAC Na EC TABLETS 50.0 mg. Lot: IA000-00

Batch No: Weighing Date :

Page 2 of 2 pages.
Per % RM. Sign
Ex
Raw Materials
UNIT Lot For [1000 000] kg weigh.
mg ce No Dept.
ss
Kg G mg
20 ENTERIC COATING
SUSPENSION
PART ONE
0.88 20 Polyethylene glycol 6000 NF 1 050
- Purified water USP (60°C) 5 400

PART TWO
0.88 Talc USP 1 060
0.63 Titanium Dioxide USP 0 760
0.1 Color Ferric Oxide NF Red 0 120
0.05 Color Ferric Oxide NF Yellow 0 060
- Purified water USP 14 200

PART THREE
11.121 Methacrylic Acid Copolymer NF 44 480 (Ref)
(Eudragit L30D-55 SOLUTION
33%)
- Purified water USP 54 000

PART FOUR
13.66 TOTAL 163 900
190.0 DICLOFENAC SODIUM E.C. 190 000
TABLETS 50 mg CORES
* 13.6 DICLOFENAC SODIUM TABLETS 50 109 500
mg FILM COATING DISPERSION
203.6 TOTAL (Theoretical) 203 600

1
Solids (amount of solids = 30% of
the solution)
Ed Number:
01
Effective Date:
APPROVED
Ed. Status DD/MM/YY _____________ __________ _______________ _________/________
New Department R &D RA QC / QA

(Ref. calculation) 11.2 (solids) x 1.2 (20% excess) / 0.3 (solution concentration) = 44.480 Kg = (Weight of solution)

24 Volume
V Drug Development Series: Sect: 7.50 Oral DR TABLETS
 HANDBOOK of GENERIC DRUG DEVELOPMENT ANDA DEVELOPMENT

SECTION XII SECTION 12

Pivotal Manufacturing Instructions

EXECUTED BATCH MASTER FORMULA

DICLOFENAC Na EC TABLETS 75.0 mg. Lot: IA000-00

Batch No: Weighing Date :

Page 1 of 2 page.
Per % Raw Material Names RM. Sign
UNIT Ex Lot weigh.
ce For [1000 000] kg
mg No Dept.
ss
Kg G mg
PART ONE
75.0 Diclofenac Sodium 75 000
135.0 Lactose Monohydrate NF (200 135 000
mesh)
11.35 Povidone USP (PVP K-30) 11 350
15.0 Sodium Starch Glycolate NF 15 000
18.5 Starch NF 18 500
PART TWO
GRANULATION SOLUTION
- Alcohol USP 25 000
- Alcohol USP q.s. (up to 4.2 kg) 000 000

PART THREE
28.15 Microcrystalline Cellulose NF 28 150
(Avicel PH-101
0.5 Aerosil 200 0 500
(Colloidal Silicon Dioxide NF)
PART FOUR
1.5 Magnesium Stearate NF 1 500
TOTAL 285 000
285.0 DICLOFENAC SODIUM E.C. 285 000
TABLETS 75 mg CORES
21.6 DICLOFENAC SODIUM TABLETS 75 173 500
mg ENTERIC COATING DISPERSION
306.6 TOTAL (Theoretical) 306 600

Ed Number:
01
Effective Date:
APPROVED
Ed. Status DD/MM/YY _____________ __________ _______________ _________/________
New Department R &D RA QC / QA

24 Volume
V Drug Development Series: Sect: 7.51 Oral DR TABLETS
 HANDBOOK of GENERIC DRUG DEVELOPMENT ANDA DEVELOPMENT

DICLOFENAC Na EC TABLETS 75.0 mg. Lot: IA000-00

Batch No: Weighing Date :

Page 2 of 2 page.
Per % RM. Sign
Ex
Raw Materials
UNIT Lot For [1000 000] kg weigh.
mg ce No Dept.
ss

20 ENTERIC COATING Kg G mg
SUSPENSION
PART ONE
0.99 20 Polyethylene glycol 6000 NF 1 190
1.62 Purified water USP (60°C) 5 100
PART TWO
0.99 Talc USP 1 190
0.89 Titanium Dioxide USP 1 065
0.033 Color Ferric Oxide NF Red 0 040
0.017 Color Ferric Oxide NF Yellow 0 020
2.92 Purified water USP 14 100

PART THREE
12.431 Methacrylic Acid Copolymer NF 49 720 (Ref)
(Eudragit L30D-55 SOLUTION
33%)
0.82 Purified water USP 50 600
21.6 TOTAL 163 900

PART FOUR

285.0 DICLOFENAC SODIUM E.C. 285 000

TABLETS 75 mg CORES
21.6 DICLOFENAC SODIUM TABLETS 75 173 500
mg ENTERIC COATING DISPERSION
306.6 TOTAL (Theoretical) 306 600
1
Solids (amount of solids = 30% of
the solution)
Ed Number: 01 Effective Date:
APPROVED
Ed. Status DD/MM/YY _____________ __________ _______________ _________/________
New Department R &D RA QC / QA

2
Residual moisture after film drying of enteric coat.

24 Volume
V Drug Development Series: Sect: 7.52 Oral DR TABLETS
 HANDBOOK of GENERIC DRUG DEVELOPMENT ANDA DEVELOPMENT

SECTION XII SECTION 12

Pivotal Manufacturing Instructions

PIVOTAL BATCH MASTER FORMULA

DICLOFENAC Na EC TABLETS 50.0 mg. Lot: IA-000-00

Page: 1 of 5 pages
MANUFACTURING INSTRUCTIONS Machine Sign Date
for 50 mg tablet cores

PART ONE - PREPARATION OF GRANULES

Identify the equipment and room number. Verify the cleanliness
prior to use.
Sign verifying the cleanliness of the Blender / Y-CONE
Stage 1.
SIEVE the following materials through a electric QUICK SIEVE
fitted with a 1.5 mm mesh screen:
n DICLOFENAC SODIUM
n LACTOSE MONOHYDRATE NF (200 mesh)
n Povidone USP (PVP K-30)
n SODIUM STARCH GLYCOLATE NF
n STARCH NF
Stage 2. Place all sieved materials from step 1 in the -DIOSNA
P-800 and mix for 3 minutes. Settings: Mixer II + Chopper II
Total Mixing Time is 3 minutes.
Time of Start Mixing -[ ] am / pm
Time of END mixing -[ ] am / pm
Stage 3. Add the ALCOHOL USP and mix for 60 seconds.
Settings: Mixer II + Chopper II
Total Mixing Time is 60 seconds.
Time of Start Mixing -[ ] am / pm
Time of END mixing -[ ] am / pm
Stage 4. If necessary, add more ALCOHOL USP (Up to a
max. of 4 kg) [00] Kg and mix for another 5 seconds
Stage 5. Transfer the granulate of stage #4 to the Fluid Bed
Dryer (Glatt WSG 120) bowl by operating with speed setting
of Mixer 1.
Stage 6. Dry the granulate in the Fluid Bed Dryer (Glatt WSG
120)
Inlet air temperature 60°C (limits 55-65°C)
Outlet air temperature 35°C (limits up to 50°C)
Ed Number: 01 Effective Date:
APPROVED
Ed. Status DD/MM/YY _____________ __________ _______________ _________/________
New Department R &D RA QC / QA

24 Volume
V Drug Development Series: Sect: 7.53 Oral DR TABLETS
 HANDBOOK of GENERIC DRUG DEVELOPMENT ANDA DEVELOPMENT

DICLOFENAC Na EC TABLETS 50.0 mg. Lot: IA000-00

Page: 2 of 5 pages
MANUFACTURING INSTRUCTIONS Machine Sign Date
for 50 mg tablet cores

PART ONE - PREPARATION OF GRANULES

Stage 7. Grind by Frewitt oscillating granulator a small
quantity of the granulate of stage # 6 through 1.0 mm screen
Stage 8. Check Loss on Drying of the grounded granulate
(using Computrac-Max. 50, temperature 110°C
LOD required = 1.0 - 2.0%
LOD Result = ________%
If necessary, continue to dry the granulate until the required
LOD is obtained. Final LOD Result = ________%
Stage 9. Grind the dried granulate by Frewitt oscillating
granulator through 1.0 mm screen.
Stage 10. WEIGH the milled granulate.
Stage 11. SIEVE through a 30 mesh screen or quick sieve #
1.5 mm. ADD the,
MICROCRYSTALLINE CELLULOSE NF (AVICEL PH-101)
Stage 12. TRANSFER the granulate and the sieved powder
of stage 11 into Y-Cone 500 and mix for 15 minutes
Stage 13. SIEVE MAGNESIUM STEARATE NF through a 30
mesh screen.
Stage 14. ADD the screened MAGNESIUM STEARATE NF
from stage # 13 to the mixture of stage #12 and mix for an
additional 5 minutes [max.]
Stage 15. PASS the lubricated granulate from stage #14
through a Quick Sieve 3 mm screen into a [FLOW] BIN
Stage 16. COLLECT 10 samples from the lower, middle and
upper part of the 500 L CONTAINER/ [FLOW] BIN.
[1]. Weight of each sample is equivalent the fill weight of
NMT Three Tablets 50 mg.
[2]. Forward samples to the analytical laboratory for BLEND
UNIFORMITY testing.
Stage 17. Immediately add the batch number to the scale
print-out, attach to the manufacturing instructions after dating
and signing it.
Ed Number: 01 Effective Date:
APPROVED
Ed. Status DD/MM/YY _____________ __________ _______________ _________/________
New Department R &D RA QC / QA

24 Volume
V Drug Development Series: Sect: 7.54 Oral DR TABLETS
 HANDBOOK of GENERIC DRUG DEVELOPMENT ANDA DEVELOPMENT

DICLOFENAC Na EC TABLETS 50.0 mg. Lot: IA000-00

Page 3 of 5 pages
MANUFACTURING INSTRUCTIONS Machine Sign Date
for 50 mg tablets
Stage 18. Seal the blended material in extra heavy duty double
PE plastic bags (clear inner, 2 silica 500g bags, black outer) with
plastic ties then close all containers, and attach (bar coded) labels
to the Bulk Containers for transport to the holding area
Theoretical Weight [000.0] Kg. Yield [00.0] %

(Yield Limits: NLT 95% of Theoretical Weight.) No of Bins ____

Stage 19. Store the GRANULATE at NMT 25C until required for
use within 10 days.
Stage 20.
Compression
Verify cleanliness / Identification of tableting equip.
Identify and verify the cleanliness of the tablet equipment in use
COMPRESS according to the written product specifications
Stage 21.
Tablet machine: (Type & No [KILIAN TX / FETTA).
Machine Speed 90 000 Tablets per hour
Limit of rpm NLT 80 000 tph ; NMT 100 000 tph
Stage 22.
Weigh the Tablet CORE:
(Average weight of a Tablet core: - (190 mg)
Actual production weight: Ü [000.0] Kg.
Weight of Samples taken: less [00.0] Kg.
Vacuum and rejects Weight: less [00.0] Kg.
Total overall weight = [000.0] Kg
No of Bulk Containers filled = [0]
Theoretical Weight [190] Kg. Yield:- [00.0]%
(Yield Limits: NMT 2% unexplained loss compared to the final
blend weight from stage 15.
Stage 23.
Seal the double PE plastic bags (clear inner, 2 silica 500g bags,
black outer) with plastic ties then close all containers, and attach
(bar coded) labels to the Bulk Containers for transport to the
holding area PRIOR TO THE ENTERIC COATING PROCESS.

Ed. Number: Effective Date:

01
APPROVED
Ed. Status DD/MM/YY _____________ __________ _______________ _________/________
New Department R &D RA QC / QA

24 Volume
V Drug Development Series: Sect: 7.55 Oral DR TABLETS
 HANDBOOK of GENERIC DRUG DEVELOPMENT ANDA DEVELOPMENT

DICLOFENAC Na EC TABLETS 50.0 mg. Lot: IA000-00

Page 4 of 5 pages
Machine Sign Date
MANUFACTURING INSTRUCTIONS

for 50 mg tablet cores

ENTERIC COATING
PREPARATION OF COATING SUSPENSION
Identify the equipment and room number. Verify the cleanliness
prior to use.
Stage 24. Dissolve the POLYETHYLENE GLYCOL 6000 NF of
PART I in the PURIFIED WATER USP, 60°C (LIMIT 55-65°C)
using a roller mixer.
Stage 25.Place the PURIFIED WATER USP of PART II in a
colloidal mill and add while operating the colloidal mill the following
powders:
n TALC USP
n TITANIUM DIOXIDE USP
n COLOR FERRIC OXIDE NF RED
n COLOR FERRIC OXIDE NF YELLOW
Mill for 20 minutes.
Total Milling Time is 20 minutes.
Time of Start Milling - [00] am / pm
Time of END Milling - [00] am / pm
Stage 26.Transfer to a stainless steel container the solution of
stage 24 and the dispersion of stage 25 and the materials of
PART III namely
n METHACRYLIC ACID COPOLYMER NF (EUDRAGIT L3OD-55)
n PURIFIED WATER USP
Stage 27. Mix with a roller mixer for 5 MINUTES
Total Mixing Time is 5 minutes.
Time of Start Mixing - [00] am / pm
Time of END mixing - [00] am / pm
Stage 28. Filter the coating dispersion of stage 4 through a 80
mesh screen.
Stage 29. Divide the film coating dispersion into two equal
portions and identify each portion with the Batch number
Stage 30. STIR the EC FILM COATING SUSPENSION
continuously during the coating process.
Ed Number: 01 Effective Date:
APPROVED
Ed. Status DD/MM/YY _____________ __________ _______________ _________/________
New Department R &D RA QC / QA

24 Volume
V Drug Development Series: Sect: 7.56 Oral DR TABLETS
 HANDBOOK of GENERIC DRUG DEVELOPMENT ANDA DEVELOPMENT

Page 5 of 5 pages

MANUFACTURING INSTRUCTIONS Machine Sign Date

A B
for 50 mg tablet cores

Coating Procedure:
Stage 31. IDENTIFY and verify the cleanliness of the coating equipment
in use
Sublot Size [95.0] Kg. Equal to [500 000] tablets.
PREHEATING OF CORES:
Coating machine (Type & No) : [[ACCELA COTA AC150 / AC48 ]]
Extraction Air Temperature: [[29]º C - [[37]]º C
Incoming Air Temperature: [48]º C - [[56]] º C
Total Warming time: [2] Minutes
Drum Speed: [2] rpm (minimum speed)
Jogging cycle: One cycle every [2] minutes.
Limit of rpm: NLT [2] rpm: MT [3] rpm.
SPRAYING PARAMETERS
Pump type: Peristaltic
Spray rate: [200] - [700] g/min
Nozzles: [[3]] x [[1.5] mm
Angle of Guns to Bed: 90 degrees
Height above Bed: [25] cm
Incoming Air Temperature: [[48]]º C - [[56]]º C (Target: [50]ºC)
Extraction Air Temperature: [[29]]º C - [[37]]º C (Target: [32]ºC)

Stage 32. COAT tablet cores at a drum speed of [[3]] - [[9]] rpm and a
spray rate of [200] -[700] g/min until the target COATED tablet weight
of [203.6] for the 50 mg core and [306.6] mg for the 75 mg core is
obtained. Monitor the weight gain at 10-15 min intervals and record the
results obtained
COMPLETION OF COATING PROCEDURE
Stage 33. REDUCE drum speed to minimum rpm and perform the
following:
n Reduce set point of incoming air temperature to [40] ºC
n on reaching this temperature - close the inlet air
n continue drum speed until the Extraction Air Temperature reaches
[26] ºC - [30]ºC
Stage 34. TRANSFER coated tablets into containers lined with two PE
plastic bags (clear inner, black outer) Seal bags with plastic ties and close
containers, and attach (bar coded) labels to the Bulk Containers for
transport to the holding area.
Stage 35. ATTACH the temperature graphs (Type & No) to the
manufacturing instructions. Immediately add the batch / Sublot number to
the temperature graph(s) and date and sign graph.
Stage 36. WEIGH EC Coated tablets
Actual production weight: [000] Kg. No of Containers [0]

Ed Number: 01 Effective Date

APPROVED
Ed. Status: DD/MM/YY _____________ __________ _______________ _________/________
New Department R &D RA QC / QA

24 Volume
V Drug Development Series: Sect: 7.57 Oral DR TABLETS
 HANDBOOK of GENERIC DRUG DEVELOPMENT ANDA DEVELOPMENT

SECTION XII SECTION 12

Pivotal Manufacturing Instructions

PIVOTAL BATCH MASTER FORMULA

DICLOFENAC Na EC TABLETS 75.0 mg. Lot: IA000-00

Page 1 of 5 pages
MANUFACTURING INSTRUCTIONS Machine Sign Date
for 75 mg tablets
PART ONE - PREPARATION OF GRANULES
Identify the equipment and room number. Verify the cleanliness
prior to use.
Sign verifying the cleanliness of the Blender / Y-CONE
Stage 1.
SIEVE the following materials through a electric QUICK SIEVE
fitted with a 1.5 mm mesh screen:
n DICLOFENAC SODIUM
n LACTOSE MONOHYDRATE NF (200 mesh)
n Povidone USP (PVP K-30)
n SODIUM STARCH GLYCOLATE NF
n STARCH NF
Stage 2. Place all sieved materials from step 1 in the -DIOSNA
P-800 and mix for 3 minutes. Settings: Mixer II + Chopper II
Total Mixing Time is 3 minutes.
Time of Start Mixing -[ ] am / pm
Time of END mixing -[ ] am / pm
Stage 3. Add the ALCOHOL USP and mix for 60 seconds.
Settings: Mixer II + Chopper II
Total Mixing Time is 60 seconds.
Time of Start Mixing -[ ] am / pm
Time of END mixing -[ ] am / pm
Stage 4. If necessary, add more ALCOHOL USP (Up to a
max. of 4 kg) [00] Kg and mix for another 5 seconds
Stage 5. Transfer the granulate of stage #4 to the Fluid Bed
Dryer (Glatt WSG 120) bowl by operating with speed setting
of Mixer 1.
Stage 6. Dry the granulate in the Fluid Bed Dryer (Glatt WSG
120)
Inlet air temperature 60°C (limits 55-65°C)
Outlet air temperature 35°C (limits up to 50°C)
Ed Number: Effective Date:
01
APPROVED
Ed. Status DD/MM/YY _____________ __________ _______________ _________/________
New Department R &D RA QC / QA

24 Volume
V Drug Development Series: Sect: 7.58 Oral DR TABLETS
 HANDBOOK of GENERIC DRUG DEVELOPMENT ANDA DEVELOPMENT

Manufacturing Instructions
DICLOFENAC Na EC TABLETS 75.0 mg. Lot: IA000-00
Page 2 of 5 pages
MANUFACTURING INSTRUCTIONS Machine Sign Date
for 75 mg tablets
PART ONE - PREPARATION OF GRANULES
Stage 7. Grind by Frewitt oscillating granulator a small
quantity of the granulate of stage # 6 through 1.0 mm screen
Stage 8. Check Loss on Drying of the grounded granulate
(using Computrac-Max. 50, temperature 110°C
LOD required = 1.0 - 2.0%
LOD Result = ________%
If necessary, continue to dry the granulate until the required
LOD is obtained. Final LOD Result = ________%
Stage 9. Grind the dried granulate by Frewitt oscillating
granulator through 1.0 mm screen.
Stage 10. WEIGH the milled granulate.
Stage 11. SIEVE through a 30 mesh screen or quick sieve #
1.5 mm. ADD the,
MICROCRYSTALLINE CELLULOSE NF (AVICEL PH-101)
Stage 12. TRANSFER the granulate and the sieved powder
of stage 11 into Y-Cone 500 and mix for 15 minutes
Stage 13. SIEVE MAGNESIUM STEARATE NF through a 30
mesh screen.
Stage 14. ADD the screened MAGNESIUM STEARATE NF
from stage # 13 to the mixture of stage #12 and mix for an
additional 5 minutes [max.]
Stage 15. PASS the lubricated granulate from stage #14
through a Quick Sieve 3 mm screen into a [FLOW] BIN
Stage 16. COLLECT 10 samples from the lower, middle and
upper part of the 500 L CONTAINER/ [FLOW] BIN.
[1]. Weight of each sample is equivalent the fill weight of
NMT Three Tablets 75 mg.
[2]. Forward samples to the analytical laboratory for BLEND
UNIFORMITY testing.
Stage 17. Immediately add the batch number to the scale
print-out, attach to the manufacturing instructions after dating
and signing it.
Ed Number: Effective Date:
01
APPROVED
Ed. Status DD/MM/YY _____________ __________ _______________ _________/________
New Department R &D RA QC / QA

24 Volume
V Drug Development Series: Sect: 7.59 Oral DR TABLETS
 HANDBOOK of GENERIC DRUG DEVELOPMENT ANDA DEVELOPMENT

Manufacturing Instructions
DICLOFENAC Na EC TABLETS 75.0 mg. Lot: IA000-00
Page 3 of 5 pages
MANUFACTURING INSTRUCTIONS Machine Sign Date
for 75 mg tablets
Stage 18. Seal the blended material in extra heavy duty double
PE plastic bags (clear inner, 2 silica 500g bags, black outer) with
plastic ties then close all containers, and attach (bar coded) labels
to the Bulk Containers for transport to the holding area
Theoretical Weight [000.0] Kg. Yield [00.0] %

(Yield Limits: NLT 95% of Theoretical Weight.) No of Bins ____

Stage 19. Store the granulate at NMT 25C until required for use
within 10 days.
Stage 20.
Compression
Verify cleanliness / Identification of tableting equip.
Identify and verify the cleanliness of the tablet equipment in use
COMPRESS according to the written product specifications
Stage 21.
Tablet machine: (Type & No [KILIAN TX / MANESTY/ FETTA).
Machine Speed 90 000 Tablets per hour
Limit of rpm NLT 80 000 tph ; NMT 100 000 tph
Stage 22.
Weigh the tablet cores:
(Average weight of a tablet core:- (285 mg)
Actual production weight: Ü [000.0] Kg.
Weight of Samples taken: less [00.0] Kg.
Vacuum and rejects Weight: less [00.0] Kg.
Total overall weight = [000.0] Kg
No of Bulk Containers filled = [0]
Theoretical Weight [285] Kg. Yield:- [00.0]%
Equivalent to tablet cores [1 000 000.0]
(Yield Limits: NMT 2% unexplained loss compared to the final
blend weight from stage 15.
Stage 23.
Seal the double PE plastic bags (clear inner, 2 silica 500g bags,
black outer) with plastic ties then close all containers, and attach
(bar coded) labels to the Bulk Containers for transport to the
holding area.

Ed. Number: Effective Date:

01
APPROVED
Ed. Status DD/MM/YY _____________ __________ _______________ _________/________
New Department R &D RA QC / QA

24 Volume
V Drug Development Series: Sect: 7.60 Oral DR TABLETS
 HANDBOOK of GENERIC DRUG DEVELOPMENT ANDA DEVELOPMENT

DICLOFENAC Na EC TABLETS 75.0 mg. Lot: IA000-00

Page 4 of 5 pages
Machine Sign Date
MANUFACTURING INSTRUCTIONS

for 75 mg tablet cores

ENTERIC COATING
PREPARATION OF COATING SUSPENSION
Identify the equipment and room number. Verify the cleanliness
prior to use.
Stage 24. Dissolve the POLYETHYLENE GLYCOL 6000 NF of
PART I in the PURIFIED WATER USP, 60°C (LIMIT 55-65°C)
using a roller mixer.
Stage 25.Place the PURIFIED WATER USP of PART II in a
colloidal mill and add while operating the colloidal mill the following
powders:
n TALC USP
n TITANIUM DIOXIDE USP
n COLOR FERRIC OXIDE NF RED
n COLOR FERRIC OXIDE NF YELLOW
Mill for 20 minutes.
Total Milling Time is 20 minutes.
Time of Start Milling - [00] am / pm
Time of END Milling - [00] am / pm
Stage 26.Transfer to a stainless steel container the solution of
stage 24 and the dispersion of stage 25 and the materials of
PART III namely
n METHACRYLIC ACID COPOLYMER NF (EUDRAGIT L3OD-55)
n PURIFIED WATER USP
Stage 27. Mix with a roller mixer for 5 MINUTES
Total Mixing Time is 5 minutes.
Time of Start Mixing - [00] am / pm
Time of END mixing - [00] am / pm
Stage 28. Filter the coating dispersion of stage 4 through a 80
mesh screen.
Stage 29. Divide the film coating dispersion into two equal
portions and identify each portion with the Batch number
Stage 30. STIR the EC FILM COATING SUSPENSION
continuously during the coating process.

Ed Number: 01 Effective Date:

APPROVED
Ed. Status DD/MM/YY _____________ __________ _______________ _________/________
New Department R &D RA QC / QA

24 Volume
V Drug Development Series: Sect: 7.61 Oral DR TABLETS
 HANDBOOK of GENERIC DRUG DEVELOPMENT ANDA DEVELOPMENT

Page 5 of 5 pages

MANUFACTURING INSTRUCTIONS Machine Sign Date

A B
for 75 mg tablet cores

Coating Procedure:
Stage 31. IDENTIFY and verify the cleanliness of the coating equipment
in use
Sublot Size [142.5] Kg. Equal to [500 000] tablets.
PREHEATING OF CORES:
Coating machine (Type & No) : [[ACCELA COTA AC150 / AC48 ]]
Extraction Air Temperature: [[29]º C - [[37]]º C
Incoming Air Temperature: [48]º C - [[56]] º C
Total Warming time: [2] Minutes
Drum Speed: [2] rpm (minimum speed)
Jogging cycle: One cycle every [2] minutes.
Limit of rpm: NLT [2] rpm: MT [3] rpm.
SPRAYING PARAMETERS
Pump type: Peristaltic
Spray rate: [200] - [700] g/min
Nozzles: [[3]] x [[1.5] mm
Angle of Guns to Bed: 90 degrees
Height above Bed: [25] cm
Incoming Air Temperature: [[48]]º C - [[56]]º C (Target: [50]ºC)
Extraction Air Temperature: [[29]]º C - [[37]]º C (Target: [32]ºC)

Stage 32. COAT tablet cores at a drum speed of [[3]] - [[9]] rpm and a
spray rate of [200] -[700] g/min until the target COATED tablet weight
of [203.6] for the 50 mg core and [306.6] mg for the 75 mg core is
obtained. Monitor the weight gain at 10-15 min intervals and record the
results obtained
COMPLETION OF COATING PROCEDURE
Stage 33. REDUCE drum speed to minimum rpm and perform the
following:
n Reduce set point of incoming air temperature to [40] ºC
n on reaching this temperature - close the inlet air
n continue drum speed until the Extraction Air Temperature reaches
[26] ºC - [30]ºC
Stage 34. TRANSFER coated tablets into containers lined with two PE
plastic bags (clear inner, black outer) Seal bags with plastic ties and close
containers, and attach (bar coded) labels to the Bulk Containers for
transport to the holding area.
Stage 35. ATTACH the temperature graphs (Type & No) to the
manufacturing instructions. Immediately add the batch / Sublot number to
the temperature graph(s) and date and sign graph.
Stage 36. WEIGH EC Coated tablets
Actual production weight: [000] Kg. No of Containers [0]

Ed Number: 01 Effective Date

APPROVED
Ed. Status: DD/MM/YY _____________ __________ _______________ _________/________
New Department R &D RA QC / QA

24 Volume
V Drug Development Series: Sect: 7.62 Oral DR TABLETS
 HANDBOOK of GENERIC DRUG DEVELOPMENT ANDA DEVELOPMENT

Pivotal Manufacturing Instructions

PIVOTAL BATCH FLOWCHART

DICLOFENAC SODIUM TABLETS 50 mg and 75 mg

MANUFACTURING PROCEDURE

FLOW CHART

SUBLOT #1 SUBLOT #2

ÚÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄ¿ ÚÄÄÄÄÄÄÄÄÄÄÄÄ¿ ÉÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍ»

³ DICLOFENAC SODIUM ³ ³ PREMIX ³ º º
³ LACTOSE MONOHYDRATE NF (200 MESH)³ ÚÄÄÄÄÄÁÄÄÄÄÄÄÄÄÄÄÄÄÁÄÄÄÄÄ¿ º SAME AS SUBLOT #1 º
³ POVIDONE USP (PVP K-30) ³ ³ DIOSNA P-800 ³ º º
³ SODIUM STARCH GLYCOLATE NF ÃÄÄÄÄÄÄÄÄÄ> ³ MIXING TIME: 3 MIN ³ ÈÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍͼ
³ STARCH NF ³ ³ MIXER II CHOPPER II ³
ÀÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÙ ÀÄÄÄÄÄÄÄÄÄÄÄÂÄÄÄÄÄÄÄÄÄÄÄÄÙ
Ú
ÚÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄ¿ ÚÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄ¿
³ ALCOHOL USP ÃÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄ> ³ DIOSNA P-800 ³
ÀÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÙ ³ MIXING TIME: 1 MIN ³
³ MIXER II CHOPPER II ³
ÀÄÄÄÄÄÄÄÄÄÄÄÂÄÄÄÄÄÄÄÄÄÄÄÄÙ
Ú
ÚÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄ¿ ÚÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄ¿
³ ALCOHOL USP qs ÃÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄ> ³ DIOSNA P-800 ³
ÀÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÙ ³ MIXING TIME: ³
³ MIXER II CHOPPER II ³
ÀÄÄÄÄÄÄÄÄÄÄÄÂÄÄÄÄÄÄÄÄÄÄÄÄÙ
³
Ú
ÚÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄ¿
³ WSG 120 ³
³ INLET AIR TEMP 60°C (LIMITS 55-65°C) ³
³ OUTLET AIR TEMP 40°C (LIMITS up to 50°C)³
ÀÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÂÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÙ
³
³ <ÄÄÄÄÄÄÄÄÄÄÄÄÄÄ> IN-PROCESS TESTS
Ú
ÚÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄ¿
ÚÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄ¿ ³ OSCILLATING GRANULATOR ³ ÉÍÍÍÍÍÍÍÍÍÍÍ»
³ MICROCRYSTALLINE CELLULOSE NF ³ ³ FREWITT 1 mm SCREEN ³ º º
³ (AVICEL PH 101) ³ ÀÄÄÄÄÄÄÄÂÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÙ º SUBLOT #2 º
ÀÄÄÄÄÄÄÄÄÄÄÄÂÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÙ ³ º º
Ú ³ ÈÍÍÍÍÍÑÍÍÍÍͼ
ÚÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄ¿ ³ ÚÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄ¿ ³
³ #30 MESH SCREEN OR ³ ÀÄÄÄÄÄÄÄÄ> ³ Y-CONE 500 ³ <ÄÄÄÄÄÄÄÄÄÄÄÙ
³ QUICK SIEVE #1.5 MM ÃÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄ> ³ MIXING TIME: 15 MIN ³
ÀÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÙ ÀÄÄÄÄÄÄÄÄÄÄÄÂÄÄÄÄÄÄÄÄÄÄÄÙ
ÚÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄ¿ ³
³ MAGNESIUM STEARATE NF ³ ³
ÀÄÄÄÄÄÄÄÄÄÄÄÂÄÄÄÄÄÄÄÄÄÄÄÄÄÙ Ú
Ú
ÚÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄ¿ ÚÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄ¿
³ 30 MESH SCREEN ÃÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄ> ³ Y-CONE 500 ³
ÀÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÙ ³ MIXING TIME : 5 MIN ³
ÀÄÄÄÄÄÄÄÄÄÄÄÂÄÄÄÄÄÄÄÄÄÄÄÙ
Ú
ÚÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄ¿
³ QUICK SIEVE ³
³ #3 MM ³
ÀÄÄÄÄÄÄÄÄÄÄÄÄÂÄÄÄÄÄÄÄÄÄÄÙ
³
³
³ <ÄÄÄÄÄÄÄ> IN-PROCESS TESTS
Ú
ÚÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄ¿ ÚÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄ¿
³ TABLETTING MACHINE ³ <ÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄ´ TABLETTING ³ <ÄÄÄÄÄ> IN-PROCESS TESTS
³ KILIAN TX / P1200 ³ ÀÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÙ
ÀÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÙ

24 Volume
V Drug Development Series: Sect: 7.63 Oral DR TABLETS
 HANDBOOK of GENERIC DRUG DEVELOPMENT ANDA DEVELOPMENT

Pivotal Manufacturing Instructions

PIVOTAL BATCH FLOWCHART

DICLOFENAC SODIUM TABLETS 50 mg and 75 mg

COATING PROCEDURE

FLOW CHART

ENTERIC COATING PROCEDURE:-

SUBLOT #1 SUBLOT #2
FILM COATING SUSPENSION FILM COATING SUSPENSION

ÚÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄ¿ ÚÄÄÄÄÄÄÄÄÄÄÄÄÄÄ¿ ÉÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍ»

³ POLYETHYLENE GLYCOL 6000 NF ÃÄÄÄÄÄÄÄÄÄÄ> ³ ROLLER MIXER ³ º REPEAT as for º
³ PURIFIED WATER USP 60°C ³ ³ ³ º REPEAT AS SUBLOT #1
ÀÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÙ ÀÄÄÄÄÄÄÄÄÄÄÄÂÄÄÙ º SUBLOT #1 ºº
³ ÈÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍͼ
ÚÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄ¿ ³
³ TALC USP ³ ÚÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄ¿ ³ ³
³ TITANIUM DIOXIDE USP ³ ³ COLLOID MILL ³ ³ ³
³ COLOR FERRIC OXIDE NF RED ÃÄÄ> ³ MIXING TIME: ³ ³ ³
³ COLOR FERRIC OXIDE NF YELLOW³ ³ 20 MIN ³ ³ ³
³ PURIFIED WATER USP ³ ÀÄÄÄÄÄÄÄÄÄÄÄÂÄÄÄÄÙ ³ ³
ÀÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÙ ³ ³ ³
³ ³ ³
ÚÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄ¿ Ú Ú ³
³ EUDRAGIT L 30D-55 ÃÄÄÄÄÄÄ¿ ÚÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄ¿ ³
ÀÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÙ ÀÄÄÄÄÄÄÄÄÄÄÄÄ>³ ROLLER MIXER ³ ³
ÚÄÄÄÄÄÄÄÄÄÄÄÄ>³ MIXING TIME: 5 MIN ³ ³
ÚÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄ¿ ³ ÀÄÄÄÄÄÄÄÄÄÄÂÄÄÄÄÄÄÄÄÄÄÄÄÄÄÙ ³
³ PURIFIED WATER USP ÃÄÄÄÄÄÄÙ ÚÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÙ ³
ÀÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÙ Ú ³
ÚÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄ¿ ³
³ SCREENING ³ ÚÄÄÄÄÄÄÄÄÄÄÄÄÄÁÄÄÄÄÄÄÄÄÄÄÄÄÄ¿
³ 80 MESH SCREEN ³ ³ ³
ÀÄÄÄÄÄÄÂÄÄÄÄÄÄÄÄÄÄÄÙ ³ ³
ÚÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÁÄÄÄÄÄÄÄÄÄ¿ ³ ³
Ú Ú Ú Ú
SUBLOT #1 SUBLOT #2 SUBLOT #3 SUBLOT #4
(OF FILM COATING) (OF FILM COATING) (OF FILM COATING) (OF FILM COATING)

ÚÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄ¿ ÚÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄ¿ ÚÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄ¿ ÚÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄ¿

³ COATING PAN: ³ ³ COATING PAN: ³ ³ COATING PAN: ³ ³ COATING PAN: ³
³ ACCELACOTA AC-150 ³ ³ ACCELACOTA AC-150 ³ ³ ACCELACOTA AC-150 ³ ³ ACCELACOTA AC-150 ³
ÀÄÄÄÄÄÄÄÄÄÄÄÄÄÂÄÄÄÄÄÙ ÀÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÂÄÄÙ ÀÄÄÂÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÙ ÀÄÄÄÄÄÄÄÄÄÄÄÂÄÄÄÄÄÄÄÄÄÙ
³ ³ ³ ³
³ ÀÄÄÄÄÄÄÄÄÄÄÄÄÄ¿ ³ ÚÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÙ
ÀÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄ¿ ³ ³ ³
ÚÄÄÁÄÄÄÁÄÄÄÄÁÄÄÁÄ¿
³QC & IMPRINTING ³
ÚÄÄÄÄÄÁÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÁÄÄÄÄÄ¿
³ MARKEM 156A MARK III ³
ÀÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÄÙ

DELAYED RELEASE TABLET

Containers Final Packaging Blister

24 Volume
V Drug Development Series: Sect: 7.64 Oral DR TABLETS
 HANDBOOK of GENERIC DRUG DEVELOPMENT ANDA DEVELOPMENT

Pivotal Manufacturing Instructions

PIVOTAL BATCH MASTER FORMULA

MANUFACTURING INSTRUCTIONS FOR PIVOTAL PRODUCTION

EXECUTED BATCH

GRANULATION & COMPRESSION CONTROLS.

DICLOFENAC Na TABLETS 50.0 à 75 mg LOT: IA 000-00

ATTACHMENTS:
THE FOLLOWING ATTACHMENTS ARE PLACED HERE:

PROCESS PRINTED RECORD PROCESS STEP

Mixing Time
Attachment # 1 Mixing time Print-Out - Step 2
Attachment # 2 Mixing time Print-Out - Step 3
Attachment # 3 Mixing time Print-Out - Step 4

DRYING Temp
Attachment # 4 FDB Temperature/Time Graph - Step 6
Attachment # 5 Milled granulate LOD Print-Out - Step 8

Final Blend
Attachment # 6 Weight Print-Out of the milled granulate - Step
10
Attachment # 7 Mixing time Print-Out of the Intermediate Blend - Step 12
Attachment # 8 Mixing time Print-Out of the Final Blended material - Step 14
Attachment # 9 Weight Print-Out of the Final Lubricated material - Step 16/18

Compressed Tablets
Attachment # 10 Weight Print-Out of the bulk tablets - Step 22

Coated Tablets
Attachment # 11 FDB Temperature/Time Graph - Step 31
Attachment # 12 Weight Print-Out of the bulk tablets - Step 32

24 Volume
V Drug Development Series: Sect: 7.65 Oral DR TABLETS
 HANDBOOK of GENERIC DRUG DEVELOPMENT ANDA DEVELOPMENT

Pivotal Manufacturing Instructions

PIVOTAL BATCH CONTROLS

IN-PROCESS CONTROL SPECIFICATION

BLENDED MATERIAL SUMMARY OF YIELD AND LIMIT VALUES FOR

EXECUTED BATCH

Product: DICLOFENAC Na EC TABLETS 50.0 / 75 / 100 mg

Quantity 1000 000 LOT: 00 000-00

Quantity 1000 000 LOT: IAG-000-00

Yields
Final Blend Yield Limit: NLT 98.0%

Total Final Blend Yield Limit: NLT 98.0% (based on actual quantities
processed).
In-Process
Final Blend Uniformity Limit: 94.0 - 106.0% of labeled amount
RSD ≤ 6.0% (as per attached specifications)

Tabletting Yield NMT 2.0% unexplained loss from the

previous final blend step.

Overall Production Yield NLT 95.0%

¹ Recorded on Statistical Data Work Sheets.

¹ Recorded on Statistical Data Work Sheets.

Blend Uniformity
The requirements for Blend Uniformity are met if the amount of the active ingredient in each
of the 10 samples, as determined from the Blend Uniformity Analytical Method, lies within
the range of 90.0 - 110.0% of the labeled amount and the Relative Standard Deviation is
less than or equal to 6.0%.
If 1 sample is outside the range of 90.0 - 110.0% of labeled amount and no sample is
outside the range of 80.0 - 120.0% of labeled amount, or if the Relative Standard Deviation
is greater than 6.0%, or if both conditions prevail, test 20 additional samples.
The requirements are met if not more than 1 sample of the 30 is outside the range of 90.0 -
110.0% of labeled amount and no sample is outside the range of 80.0 - 120.0% of labeled
amount, the Relative Standard Deviation of the 30 samples does not exceed 7.8%.

24 Volume
V Drug Development Series: Sect: 7.66 Oral DR TABLETS
HANDBOOK of GENERIC DRUG DEVELOPMENT ANDA DEVELOPMENT

Pivotal Manufacturing Instructions

PIVOTAL BATCH CONTROLS

IN-PROCESS CONTROL SPECIFICATIONS

TABLET ý / CORES þ
EXECUTED BATCH

SUMMARY
Product: DICLOFENAC Na CORES 50 - 75 mg LOT: IA000-00
Labeled Amount: Each tablet contains DICLOFENAC Na [50.0]; [75.0 mg].
In-process tablet specifications
Punch Diameter 50.0mg 8.4 mm Punch No [P044] / Die No [D046]
Punch Diameter 75.0mg 9.5 mm Punch No [P058] / Die No [D058]
Description White round biconvex CORES debossed
with the number [50 or 75] on one face of the
core
Scoring [not scored]
Core Diameter 50mg Nominal 8.4 mm Limit: 8.2 - 8.8 mm
Core Diameter 75mg Nominal 9.5 mm Limit: 9.4 - 9.8 mm
Disintegration Time NMT 15 min
Method - USP Medium - Purified Water USP

50 mg TABLET
Individual core weight (±7.5%) Nominal 190.0 Limit: 176.0 - 204.0 mg
Average core weight (±5.0%) Nominal 190.0 Limit: 180.5 - 199.0 mg

75 mg TABLET
Individual weight (±7.5%) Nominal 285.0 Limit: 263.6 - 306.3 mg:
Average weight (±5.0%) Nominal 285.0 Limit: 270.8 - 299.0 mg:
Thickness 50.0mg Nominal 2.5 Limit: 3.0 - 4.00 mm
Thickness 75.0mg Nominal 4.2 Limit: 3.7 - 5.00 mm

Hardness 50.0mg Target: 7 SCU NLT 4.0 - NMT 10 SCU.

Hardness 75.0mg Target: 7 SCU NLT 4.0 - NMT 10 SCU.

Friability NMT 1.0 %

24 Volume
V Drug Development Series: Sect: 7.67 Oral DR TABLETS
 HANDBOOK of GENERIC DRUG DEVELOPMENT ANDA DEVELOPMENT

Pivotal Manufacturing Instructions

PIVOTAL BATCH CONTROLS

IN-PROCESS CONTROL SPECIFICATION

FILLING PROCESS SUMMARY

EXECUTED BATCH

Product: DICLOFENAC Na CORES 50.0 mg.

Quantity [0-000-000] Lot No: [00000] MNF Date: Month DD, YY
Labeled amount: Each Tablet contains: DICLOFENAC Na 50.0 mg.
LHS RHS
Weight Controls
¹Theoretical Tablet weight (mg) 190.0

¹Target Fill weight (mg) 190.0 190.0

¹Weight of 20 Tablet Cores #1 (g) 00.0 00.0
¹Weight of 20 Tablet Cores #2 (g) 00.0 00.0
¹Weight of 20 Tablet Cores #3 (g) 00.0 00.0
¹Weight of 20 Tablet Cores #4 (g) 00.0 00.0
¹Weight of 20 Tablet Cores #5 (g) 00.0 00.0

¹Average of 20 Tablet Cores (mg) 000.0 000.0

¹Average Tablet Core weight (mg) 000.0 000.0

In-Process Yields

¹Yield after filling vs. bulk material 00.0%

¹Yield after filling to theoretical 00.0%

Tablet Yield NMT 2.0% unexplained loss

from the previous step

¹ Recorded on Statistical Data Capsule Filling Work Sheets.

24 Volume
V Drug Development Series: Sect: 7.68 Oral DR TABLETS
 HANDBOOK of GENERIC DRUG DEVELOPMENT ANDA DEVELOPMENT

Pivotal Manufacturing Instructions

EXECUTED BATCH

RELEASE SPECIFICATION FOR TABLETS

Product: DICLOFENAC Na EC Tablets 50.0 & 75 mg LOT: IA000-00
Labeled Amount:Each tablet contains DICLOFENAC Na [50.0] ; [75.0 mg].

Description [Brown-50] [Pink-75] round enteric coated

tablet debossed with the number [50 or 75]
on one face of the tablet

Identification A The Infra Red Absorption Spectrum

conforms to the Reference Standard

Identification B The Chromatogram of the sample solution

exhibits a peak with the same retention time
as the standard solution.
50 mg TABLET
Average weight (±5.0%) Nominal 204.0 Limit: 189.0 - 219.0 mg
75 mg TABLET
Average weight (±5.0%) Nominal 307.0 Limit: 292.0 - 322.0 mg

Uniformity of Dosage Units Conforms to the current USP

Content Uniformity

Dissolution 900 mL, 37 C, RPM 50 USP App. 2 Paddle

[1] 10% of the labeled amount Acid stage (0.1N HCl)
is dissolved in 120 min
Sample 30, 60 & 120 min

[2] Phosphate Buffer stage Sodium Phosphate Buffer - pH : 6.8

Sample 5, 10, 20, 30, 45 & 60 min Tolerance: NLT [75]% (Q) of the labeled
is dissolved in [45] minutes.
Impurities /Degradation(1)
Products determination
- Any known NMT 1.5% of the labeled amount
- Diclofenac Related Compound A NMT 1.0% of the labeled amount
- Total: NMT 2.5% of the labeled amount

Assay Limit: 95.0 - 105.0% of labeled amount

50mg Equal to [47.5] - [52.5] mg / Tablet.

Assay Limit: 95.0 - 105.0% of labeled amount

75 mg Equal to [71.25] - [78.75] mg / Tablet.
(1)
Vendor or approved supplier dependent.

24 Volume
V Drug Development Series: Sect: 7.69 Oral DR TABLETS
HANDBOOK of GENERIC DRUG DEVELOPMENT ANDA DEVELOPMENT

Pivotal Manufacturing Instructions

COMPARISON OF EQUIPMENT AND MANUFACTURING CONDITIONS
BETWEEN EXECUTED AND PRODUCTION BATCHES
DICLOFENAC Na Tablets 50 & 75 mg

Equipment and Executed Batch Production

Manufacturing Conditions 1 000,000 units Batch
1 000,000 units

GRANULATION & BLENDING

GRANULATION DIOSNA P800 DIOSNA P800
FBD GLATT WSG120 GLATT WSG120
Electric Sieve QUICK SIEVE QUICK SIEVE
1.5 mm 1.5 mm
Blending Y-CONE 500 / Y- CONE 500 /
TUMBLER 500 TUMBLER 500

COMPRESSION
TABLET Machine KILIAN TX KILIAN TX
MANESTY MANESTY

PACKAGING
Packaging Units King / Lakso King / Lakso
Labeling Groninger Groninger
Prestek Prestek

FACILITIES
Equipment Variation NONE NONE
Manufacturing Area Production Production
Staff Production Production
SOP Production Production

24 Volume
V Drug Development Series: Sect: 7.70 Oral DR TABLETS
HANDBOOK of GENERIC DRUG DEVELOPMENT ANDA DEVELOPMENT

Pivotal Manufacturing Instructions

DICLOFENAC Na Tablets
50 & 75 mg

EQUIPMENT AND PIVOTAL BATCH PRODUCTION

MANUFACTURING BATCH
1 000,000
CONDITIONS TABLETS 1 000,000 TABLETS

1. Granulator DIOSNA P-800 DIOSNA P-800

2. Fluid Bed Drier WSG 120 WSG 120

3. Oscillating Granulator FREWITT FREWITT

4. Twin Shell Dry Blender Y-CONE 500 Y-CONE 500

5. Tabletting Machine KILIAN TX KILIAN TX

6. Roller Mixer JOSAN P-M JOSAN P-M

7. Colloidal Mill SUGAR MILL CO. SUGAR MILL CO.

8. Coating Pan ACCELA COTA ACCELA COTA

AC-150 AC-150

9. Imprinting Machine MARKEM 156A MARKEM 156A

MARK III MARK III

Equipment Variation NONE NONE

Manufacturing Section PRODUCTION PRODUCTION

Staff PRODUCTION PRODUCTION

S.O.Ps PRODUCTION PRODUCTION

24 Volume
V Drug Development Series: Sect: 7.71 Oral DR TABLETS
 HANDBOOK of GENERIC DRUG DEVELOPMENT ANDA DEVELOPMENT

Pivotal Manufacturing Instructions

COMPARISON OF EQUIPMENT AND MANUFACTURING CONDITIONS
BETWEEN EXECUTED AND PRODUCTION BATCHES
DICLOFENAC Na Tablets 50 mg

COMPARISON OF PIVOTAL II AND PRODUCTION FORMULAE II

Amount Pivotal Commercial

Active & non Active per unit Batch
Batch
INGREDIENTS Tablet

Diclofenac Sodium 50.0 mg 110.000 Kg 132.000 Kg

Lactose Monohydrate NF 200 90.0 mg 198.000 Kg 237.600 Kg
mesh
Povidone USP 7.6 mg 16.720 Kg 20.064 Kg
Sodium Starch Glycolate NF 10.0 mg 22.000 Kg 26.400 Kg
Starch NF 12.4 mg 27.280 Kg 32.736 Kg
Alcohol USP * Processing Solvent only
Microcrystalline Cellulose NF 19.0 mg 41.800 Kg 50.160 Kg
Magnesium Stearate NF 1.0 mg 2.200 Kg 2.640 Kg
3 3
Polyethylene Glycol NF 0.88 mg 2.323 Kg 2.788 Kg
1
Purified Water USP Processing Solvent only
3 3
Talc USP 0.88 mg 2.323 Kg 2.788 Kg
3 3
Titanium Dioxide USP 0.63 mg 1.662 Kg 1.996 Kg
3 3
Color Ferric Oxide NF [Red] 0.10 mg 0.264 Kg 0.317 Kg
3 3
Color Ferric Oxide NF [Yellow] 0.05 mg 0.132 Kg 0.158 Kg
2 3 3
Methacrylic Acid Copolymer NF 11.12 mg 97.856 Kg 117.427 Kg
[solution form]
Number of theoretical units 1 units 2,200,000 units 2,650,000 units

1
Processing Solvent only.
2
Solids (amount of solids = 30% of the solution)
3
Including 20% excess

24 Volume
V Drug Development Series: Sect: 7.72 Oral DR TABLETS
 HANDBOOK of GENERIC DRUG DEVELOPMENT ANDA DEVELOPMENT

Pivotal Manufacturing Instructions

COMPARISON OF EQUIPMENT AND MANUFACTURING CONDITIONS
BETWEEN EXECUTED AND PRODUCTION BATCHES
DICLOFENAC Na Tablets 50 mg

COMPARISON OF PIVOTAL III AND PRODUCTION FORMULAE III

Amount Pivotal Commercial

Active & non Active per unit Batch Batch
INGREDIENTS Tablet

Diclofenac Sodium 75.0 mg 117.000 Kg 140.400 Kg

Lactose Monohydrate NF 200 135.0 mg 210.600 Kg 252.720 Kg
mesh
Povidone USP 11.4 mg 17.784 Kg 21.340 Kg
Sodium Starch Glycolate NF 15.0 mg 23.400 Kg 28.080 Kg
Starch NF 18.6 mg 29.016 Kg 34.819 Kg
1
Alcohol USP Processing Solvent only

Microcrystalline Cellulose NF 28.5 mg 44.460 Kg 53.352 Kg

Magnesium Stearate NF 1.5 mg 2.340 Kg 2.808 Kg
3 3
Polyethylene Glycol NF 1.4 mg 2.620 Kg 3.145 Kg
1
Purified Water USP Processing Solvent only
3 3
Talc USP 1.4 mg 2.620 Kg 3.145 Kg
3 3
Titanium Dioxide USP 1.25 mg 2.340 Kg 2.808 Kg
3 3
Color Ferric Oxide NF [Red] 0.047 mg 0.088 Kg 0.106 Kg
3 3
Color Ferric Oxide NF [Yellow] 0.024 mg 0.045 Kg 0.054 Kg
2 3 3
Methacrylic Acid Copolymer NF 17.53 mg 109.388 Kg 131.266 Kg
(solution form)
Number of theoretical units 1 units 1,560,000 units 1,872,000 units

1
Processing Solvent only.
2
Solids (amount of solids = 30% of the solution)
3
Including 20% excess

24 Volume
V Drug Development Series: Sect: 7.73 Oral DR TABLETS
HANDBOOK of GENERIC DRUG DEVELOPMENT ANDA DEVELOPMENT

Pivotal Manufacturing Instructions

GENERAL PACKAGING OPERATION DESCRIPTION

TABLETS DR [USP] - SCHEMATIC PRESENTATION

Stage One.
PACKAGING COMPONENTS:
1. Bulk Product
2. HDPE Containers
3. Package Insert / Outsert (Product Leaflets)
4. Desiccant (Silica Gel)
5. Container Label
6. Master Cartons
7. Carton Shipping Labels

Stage Two
PACKAGING PROCEDURE:
HDPE Container & Bulk Line Feed

HDPE Container Cleaning

Process (Air and Vacuum)

Tablet Count & Fill

Cotton Coil

Closure Torque Test

Insert / Leaflet Container Label

Capping (Screw or CRC) Lot # Expiry Date

Packed in Master Shipping

Cartons or Outsert Attaching

24 Volume
V Drug Development Series: Sect: 7.74 Oral DR TABLETS
 HANDBOOK of GENERIC DRUG DEVELOPMENT ANDA DEVELOPMENT

Pivotal Manufacturing Instructions

SCHEMATIC PACKAGING OPERATION - EQUIPMENT LISTING:

[Generic name] Tablets [USP] [000.0] mg. Lot: [00-0000]

No. Machine Operation Manufacturer Type Serial # Output

CONTAINERS
Supplier per min (2)

1 Schenck HDPE Bottle Schenck Process 1000-S No: 50 Low

or Amber GMBH Darmstadt AccuRate 543123 100 High
Glass
Feeding

2 King Air Cleaning C.E. King Ltd, UK SuperKleen MK- 50 Low

2994 100 High
3 Lakso Counting & Lakso MA US SLAT L-333 Count
50 100
Filling Tablets FILLER(1) L-334 50* 100*

4 RSP Coiler Dessicant H.G. Kalish Inc., 5329 2169- 50 Low

Canada 0003 100 High
Insertion

5 RSP Coiler Cotton H.G.Kalish Inc., KOTNR-120- 2234- 50 Low

insertion Canada 8440 9987 100 High
6 Groninger Capping Groninger & Co DFVK 2232- 50 Low
2234 100 High
Germany 6000

7. Groninger Outserter Groninger & Co DFVK 5664 50 Low

KarlsHeim, 3000 100 High

Germany

8. Prestek Labelling & Prestek Ltd Science SmartDate 53342 50 Low

Printing Park Nottingham Intelligent
100 High
Thermal
UK
Transfer
Printer

(1) Average figures for containers per minute output for Slow and High Speed.
All indicated machine outputs are adjusted to the Tablet Slate Filler rate.
(2)

24 Volume
V Drug Development Series: Sect: 7.75 Oral DR TABLETS
 ORAL TABLETS IN-PROCESS CONTROLS CHAPTER 8

I n- P rocess Q uality C ontrols

…‘A critical stage of the development validation
choosing process and product in-process controls…’

Manufacturing In-process Controls Product in-process ontrols

In-process control specifications of the
M anufacturing parameters and in-
process controls are set in order
to produce consistent batch-to-
bulk material is generally set at
marginally tighter control limits than
batch product lots. the finished product release
During the development stages of the specifications.
manufacturing process the principal This procedure prevents the finished
parameters that need to be evaluated product from being released at the
are: extremes of the release specifications.
◊ Sieving of dry powders (sieve #). This permits a safety margin for
◊ dissolving times for granulation product aging (shelf life).
solution (Aqueous or alcoholic
solvent).
Standards governing in-process
controls to:-
◊ the order of addition of the
◊ ensure the bulk product will
ingredients.
adequately pass the finished product
◊ grouping of large/small weight
release specifications
excipients into a single
◊ ensure the product remains in
manufacturing step.
specification for the entire shelf life.
◊ specifying the rate of addition for
◊ Minimum parameters are;
critical ingredients (in high shear
mixers). ♦ Description + markings
◊ Identifying mixing speeds and ♦ Color
settings. ♦ Thickness range
◊ Identifying length of mixing. ♦ Friability
◊ Identifying drying parameters (inlet ♦ Weight / tablet (limits)
and outlet temperatures, drying ♦ Hardness (range)
times and target moisture values).
◊ Specifying grinding parameters.
♦ Disintegration time
◊ Identifying blending parameters. ♦ Content Uniformity and Assay
Identify the critical stages and the Dissolution
critical temperatures, times and
optimal mixing speeds and settings of
Dissolution profile, if not a compendial
requirement, may be omitted if it has
the manufacturing process.
been appropriately validated during
Qualify ranges and limits product development and
If a critical range is indicated, demonstrated in the pivotal and three
manufacture the batch at the lower and validation batches as well as in every
upper limits and test for compliance in tenth consecutive production batch. A
meeting the Finished Product current tendency exists today to
Specifications e.g. Tablet Hardness evaluate dissolution with each
Qualification
.

production batch.

Handbook of Pharmaceutical Sect: 8 . 1 Generic Development

 ORAL TABLETS IN-PROCESS CONTROLS CHAPTER 8

ØC H E C K L I S T ×
CL # P-HGD-03-01Y2K

In-process controls during the

manufacturing process

‘ well developed manufacturing procedures with good in-process

controls…
…will ensure a failure-free end product...’

1. All dry powders are screened (state mesh size) prior to processing? qYes qNo

2. Mixing of small weight excipients in plastic bags is not permitted ? qYes qNo

3. The granulating agent is dissolved in the granulating solvent (at a qYes qNo
specific temperature) with a clearly defined mixing time?

4. The order of addition of excipients is clearly identified? qYes qNo

5. The rate of addition for critical ingredients (e.g. spraying of granulating qYes qNo
solution) is clearly identified and documented in the manufacturing
procedure
6. Compatible excipients are grouped into a single manufacturing step qYes qNo
where suitable?

7. Granulating mixing times are identified and recorded by ‘start and qYes qNo
stop’ entries?
8. Granulating mixing speeds (rpm) and blade settings are identified ? qYes qNo

9. FBD inlet, outlet and bed temperatures and tray dryers operating qYes qNo
temperatures (±20 C) are identified as well as overall drying times.

10. Granulate moisture is controlled during drying stage as a critical qYes qNo
processing parameter (moisture frequently affects hardness and
dissolution during product aging).
11. The granulate is dried to a specific granulate moisture content by qYes qNo
milling a sample portion and evaluating the LOD using IR equipment ?

12. Drying is continued until the desired moisture content is obtained? qYes qNo

13. Milling speeds (rpm) sieve size (rpm) and knife settings are qYes qNo
identified ?

Footnote : The procedure for selecting approved suppliers for non active ingredients will minimize
inter-batch excipient variation significantly. This variation, if present, may impact upon the in-process
controls. The absence of adequate GMP (cleaning procedures) may adversely affect the microbial
bioburden of the bulk material during the manufacture and the filling process.

Handbook of Pharmaceutical Sect: 8 . 2 Generic Development

 ORAL TABLETS IN-PROCESS CONTROLS CHAPTER 8

ØC H E C K L I S T ×
CL # P-HGD-03-01Y2K

In-process controls during the

manufacturing process

‘the test result is only as good as the sampling procedure...’

Routine in-process quality controls on the final product consists of testing the bulk granulate
and the in-process tablets or cores during the compression stage: The following parameters
should be evaluated in the granulate, compressed tablets, or tablet cores and coated tablets:

14. Maximum processing times are stipulated for key stages and the qYes qNo
overall manufacturing time is controlled and documented ?

15. Routine IPQC. testing on the granulate material is controlled by: qYes qNo

⇒ moisture control (IR-LOD) on milled sample (at the drying stage) qYes qNo

⇒ Content uniformity (after blending stage) qYes qNo

16. Infra-red moisture testing unit for granulates is calibrated against qYes qNo
oven LOD moisture values.
17. LOD moisture values for granulates qualified by manufacturing qYes qNo
(drying) the product at the lower and upper limits of the Intermediate
Product Release Specification during the product development stage.

18. Infra-red moisture testing unit temperature setting determined. qYes qNo

19. Infra-red moisture testing unit type and model number qYes qNo
documented.

20. NB. A standard granulate quantity and uniform spreading on IR qYes qNo
trays is documented and emphasized in the IR - LOD method ?
21. Hardness Range Qualification - Range limits (e.g. hardness) have qYes qNo
been suitably qualified by manufacturing the product at the lower and
upper limits of the Finished Product Release Specification during the
product development stage (thickness, disintegration and dissolution
were evaluated) ?

22. In-process limits of tablet weight and hardness are set marginally qYes qNo
tighter than the product release specifications?

23. Target fill weight and rpm range limits for the tabletting procedure qYes qNo
were established during the product development stage and then
validated as a critical process parameter ?

Handbook of Pharmaceutical Sect: 8 . 3 Generic Development

 ORAL TABLETS IN-PROCESS CONTROLS CHAPTER 8

ØC H E C K L I S T ×
CL # P-HGD-03-01Y2K

In-process controls during the

manufacturing process

‘…the test result is only as good as the sampling procedure...’

24. Routine In-Process Quality Control testing performed on tablet qYes qNo
cores or uncoated tablets are:

⇒ Scoring and Embossing & Color (3 units) qYes qNo

⇒ Capping, chipping or pitting (10 units) qYes qNo

⇒ Individual Tablet Weight (10 units) qYes qNo

⇒ Average Tablet Weight (20 units) Limits NMT 5% qYes qNo

⇒ Diameter Limits NMT 2.5% qYes qNo

⇒ Dimensions (for caplets - length x width) Limits NMT 1% qYes qNo

⇒ Thickness Limits NMT 5% -10% qYes qNo

⇒ Hardness (10 units-(in-process) Limits ~7-11 SCU qYes qNo

⇒ Hardness (10 units -(check) Limits ~6-14 SCU qYes qNo

⇒ Friability (NMT 1.0%) qYes qNo

⇒ Disintegration (NMT 15 min) qYes qNo

25. Routine In-Process Quality Control testing on coated tablets are: qYes qNo

• Final Coated Weight (10 units) approximately 15 mg film coating qYes qNo
for a 18 x 8 mm caplet

• Final Coated Thickness (increase tablet thickness range from core to qYes qNo
coated - upper specification only, by ~0.5 - 1.0 mm)

Setting the limits for tablet thickness may be achieved by compressing the tablet at the extreme ends of the
hardness range (lowest and highest values) and measuring the resulting thickness.
The range may be skewed to the right, if necessary. As an example a 4.0 mm tablet - is set a range of 90 to
115% if there is a possibility of a significant variation in raw material bulk density (i.e. 3.6 to 4.6 mm).
The range specification may be reviewed in the forthcoming annual report after several batches have been
produced commercially.

Handbook of Pharmaceutical Sect: 8 . 4 Generic Development

 ORAL TABLETS IN-PROCESS CONTROLS CHAPTER 8

Ø IN-PROCESS CONTROLS ×
CL # P-HGD-03-01Y2K

In-process controls during the

manufacturing process

GENERAL IN-PROCESS CONTROLS

OVERVIEW
STAGE 1.
During all stages of manufacture, processing, packaging and warehousing
appropriate control procedures are employed in conformity with current good
manufacturing practice (cGMP).
Strict precautions and documentary procedures are in place to ensure the complete
absence of previous product contamination or residual printed labeling from the
previous product.

STAGE 2.
Appropriate in-process controls include material testing by the Quality Control Unit
and Quality Assurance personnel.
These test are:
⇒ Content uniformity of final blend.
⇒ Physical specifications of the Tablets.

STAGE 3.
In-process material testing is performed by responsible on-line manufacturing
personnel and qualified Quality Assurance Unit Personnel.

STAGE 4.
The Quality Assurance Unit reviews the batch test results and evaluates the criteria
of acceptance or rejection of each batch lot manufactured.

IN-PROCESS CONTROLS DURING TABLET COMPRESSION

In-process testing (IPQC) is performed independently by both production and quality
control trained personnel. The IPQC tests specified in the tabulations are carried out
in accordance with written in-process specifications per product. Essential IPQC
tests are conducted that impact in the operation of the process parameters.

Handbook of Pharmaceutical Sect: 8 . 5 Generic Development

 ORAL TABLETS IN-PROCESS CONTROLS CHAPTER 8

Ø IN-PROCESS CONTROLS ×
CL # HPGD-03-069Y

In-process controls during the

manufacturing process

Trained production personnel test the physical specifications of samples taken

at random at each process stage according to the individual product specifications:
A minimum sampling frequency is tabulated for each eight hour work period.

Production In-process Testing Schedule:

PAGE 1 of 2
IPQC Test Sample Frequency per Acceptance & Rejection
PERFORMED Size 8 hr.(1) (min) Criteria (2)

AVERAGE WEIGHT 10 At 15 min. Within the specified range.

intervals.
NMT two (2) tablets out of the 10 tested
may deviate from product specifications.
THICKNESS
No deviation is allowed from the Double
10 3 times(1) Limits(4) specification.
NMT two (2) tablets out of the 10 tested
may deviate from product specifications.
HARDNESS
No deviation is allowed from the Double
10 3 times(1) Limits(3) specification.

FRIABILITY 20 or 40 No deviation from the written product

specifications is permitted.
According to Twice
each product
KEY:
(1)
The testing frequency is performed twice when the overall compression running time is less
than four hours for the entire batch lot.
Deviations from the specifications and acceptance criteria, arising during the in-process
(2)
controls, shall determine the corrective/adjustment action performed on the tableting machinery
during the tablet compression stage.
(3)Double Limits for the Individual Tablet Weight test are defined as the double value taken from
the minimum or maximum limit in relation to the nominal tablet value (i.e. the magnitude
between the target value and the lower or upper specification -see diagram below).
(4) Double Limits for Tablet Thickness Tests are defined as c-± 0.1 mm from the minimum and
maximum specification limit values. Where C = limit value.
(5) Double Limits for Tablet Hardness Test are defined as c-±20% from the minimum and
maximum product specifications limits. When, there is a NLT 10 SCU Hardness specification,
the double limits may not exceed a minimum value of 8 SCU. (Not go below 8 SCU) .
DOUBLE VALUES

Double this value Double this value

Lower Limit Target Value Upper limit

Handbook of Pharmaceutical Sect: 8 . 6 Generic Development

 ORAL TABLETS IN-PROCESS CONTROLS CHAPTER 8

Ø IN-PROCESS CONTROLS ×
CL # HPGD-03-01Y2K

In-process controls during the

manufacturing process

Checks performed by Quality Control personnel

Quality Control personnel test the physical specifications of random samples
according to the individual product specifications sheets: A minimum sampling
frequency is tabulated for each eight hour (shift) period.
Quality Control In-process Testing Schedule:
PAGE 2 of 2
Test Sample Frequency Acceptance
PERFORMED Size per shift (1) Criteria (2)
(Tablets) (min.)

INDIVIDUAL 20 (1) Twice NMT 2 tablets out of the 20 tested can

deviate from product spec. No deviation
TABLET WEIGHT
is allowed from Double Limits(3) spec.

THICKNESS 10 (1) Twice NMT 2 tablets out of the 10 tested can

deviate from product spec. No deviation
is allowed from Double Limits(4) spec.

HARDNESS 10 (1) Twice NMT 2 tablets out of the 10 tested can

deviate from product spec. No deviation
is allowed from Double Limits(5) spec.
DIAMETER 3 (1)
Once No deviation from product specification
at start is allowed.
FRIABILITY 20 -40 (1) Twice
No deviation from product specification
According
is allowed
to product
KEY:
(1)Samples are taken, independently by QC personnel for batch release purposes, at least once per
hour throughout the compression run, producing a total representative sample quantity of 300 -500
tablets. This representative sample lot is for QC batch release purposes .

Deviations from specifications and acceptance criteria, arising during the in-process controls, shall
(2)

determine the corrective action to be performed on the tabletting machinery during the compression
stage.

Double Limits for the Individual Tablet Weight test are defined as the double value from the
(3)

minimum or maximum limit in relation to the nominal tablet value (i.e. target weight value).
(4)
Double Limits for Tablet Thickness Tests are defined as C - ± 0.1 mm from the minimum and
maximum specification limit values. Where C = limit value.

Double Limits for Tablet Hardness Test are defined as C-±20% from the minimum and maximum
(5)
product specifications limits. When, there is a NLT 10 SCU Hardness
specification, the double limits may not exceed a minimum value of 8 SCU. (i.e. not permitted to go
below 8 SCU).

Handbook of Pharmaceutical Sect: 8 . 7 Generic Development

 ORAL TABLETS IN-PROCESS CONTROLS CHAPTER 8

Ø IN-PROCESS CONTROLS ×
IN-PROCESS CONTROL SPECIFICATION
GRANULATION MATERIAL
YIELD VALUES
Page 1 of 2.

Product: Tablets [USP] [000.0] mg. Lot No:

Quantity MNF Date: Month DD, Y2K

Dried Granulation Limit: 1.0 - 1.5 %

Moisture Content

Milled Granulation Yield Limit: NLT 98.0%

Total Final Blend Yield Limit: NLT 98.0% (based on actual quantities
processed).

In-Process
Final Blend Uniformity Limit: 94.0 - 106.0% of labeled amount
RSD ≤ 6.0% (as per attached specifications)

Tabletting Yield
NMT 2.0% unexplained loss from the
previous final blend step.

Overall Production Yield NLT 95.0%

Maximum Holding times for:
milled granulate (sealed) 2 days
tablet cores (sealed) 14 days
coated tablets (unpacked) 60 days

Environmental temperature 24ºC (Ñ 4ºC)

Environmental humidity 60% (Ñ 10%)

¹ Recorded on Statistical Data Work Sheets.

Handbook of Pharmaceutical Sect: 8 . 8 Generic Development

 ORAL TABLETS IN-PROCESS CONTROLS CHAPTER 8

Ø IN-PROCESS CONTROLS×

IN-PROCESS CONTROL SPECIFICATION

TABLET / CAPLET CORES
Page 2 of 2.

CORE CONTROLS
IN-PROCESS SPECIFICATIONS
Product: Tablets [USP] [000.0] mg.
Labeled Amount: Each tablet contains [000.0] mg [Active Material]

IN-PROCESS CORE SPECIFICATIONS

Punch Number [#00]

Die Number [#00]

Caplet Debossing
Face ABC 72

Obverse XYZ

Description [Color] (white to off-white) tablet / caplet core

debossed with the number/letters [ABC-72] on
one face of the tablet / caplet core and [XYZ]
on the opposite face.

Scoring [Scored on face side of caplet]

Individual core weight: (±7.5%) Nominal [650.0] Limit: [601.0] - [699.0]mg

Average core weight: (±5.0%) Nominal [650.0] Limit: [618.0] - [682.0]mg

Thickness: Nominal [6] Limit: [5.5] - [6.5] mm

Hardness (longitudinal): Target: [9] NLT [7] - NMT [12] SCU.

Hardness (longitudinal): Release specifications ± 20-25% wider than IPQC
Friability: % NMT [1.0]

Dimensions for CR Caplets

Core length Nominal 16.0 Limit: 15.7 - 16.3 mm
Core width Nominal 8.0 Limit: 8.0 - 8.2 mm

NOTE: Tablet may read as Tablet or Caplet

Handbook of Pharmaceutical Sect: 8 . 9 Generic Development

 ORAL TABLETS IN-PROCESS CONTROLS CHAPTER 8

Ø IN-PROCESS CONTROLS×
IN-PROCESS CONTROL SPECIFICATION
ON COATED TABLET / CAPLET

FILM COATING CONTROLS

IN-PROCESS SPECIFICATIONS
Product: Tablets [USP] [000.0] mg.
Labeled Amount: Each tablet contains [000.0] mg [Active Material]

¹Theoretical Tablet weight (mg Before Coating After Coating

NOTE:
Tablet may read as Tablet or Caplet where [650.0] [662.0]
appropriate.

¹Target Coated weight [662.0]

¹Weight of 100 tablets #1 (1st check) [000.0]

¹Weight of 100 tablets #2 (2nd check) [000.0]

CORE CONTROL
¹Weight of 100 tablets #3 (3rd check) [000.0]
In-process weight
controls on tablet
¹Weight of 100 tablets #4 (4th check) during the coating [000.0]
cores sub-lot
¹Weight of 100 tablets #1 (5th check) process to [000.0]
determine the
target weight
¹Weight of 100 tablets #1 (6th check) [000.0]
representing end
of coating process
¹Weight of 100 tablets #1 (7th check) [000.0]

¹Weight of 100 tablets #1 (8th check) [000.0]

¹Average weight 100 tablets (g) [000.0]

¹Average tablet weight (mg) [000.0]

PRODUCTION YIELDS

¹Yield Post-coating vs. Pre-coating [98.0]%

¹Post-coating Overall Yield to [95.0]%

theoretical quantities

¹ Recorded weight results on 'Statistical Data - Tablet Coating Work Sheets.'

Handbook of Pharmaceutical Sect: 8 . 10 Generic Development

 ORAL TABLETS IN-PROCESS CONTROLS CHAPTER 8

STANDARD OPERATING
PROCEDURES
CL # HPGD-03-01Y2K

In-process Quality Controls

The following Standard Operating Procedures are recommended for a generic

development unit :

In-process Quality Control

Development phase
P-005-03-01Y2K Choosing In-process Quality Control Limits.

P-010-03-01Y2K Qualification of Manufacturing In-process Controls.

P-015-03-01Y2K Qualification of Product In-process Controls.

P-020-03-01Y2K Establishing & Qualifying the Critical In-process Controls.

P-025-03-01Y2K Establishing & Qualifying the Critical Product Parameters.

P-030-03-01Y2K Qualification of Bulk In-process LOD Controls.

P-035-03-01Y2K Qualification of Bulk In-process U of C Controls.

P-040-03-01Y2K Qualification of Product Compression Controls.

P-045-03-01Y2K Qualification of Product film coating Controls.

P-050-03-01Y2K Time Limitations on Manufacturing Processing Stages.

4
[End of Document]

ED. N0: 02 Effective Date APPROVED:

Replaces Ed 01. :
Ed. Status: MM/DD/2000
Operational Department R&D QC QA

Handbook of Pharmaceutical Sect: 8 . 11 Generic Development

 ORAL TABLETS FP SPECIFICATIONS CHAPTER 9

Finished Product Specifications

…‘these are the product specifications
indicating the product quality throughout the shelf life…’

Finished Product Specifications Reduced Testing Programs

consist of a group of three sets of A well structured drug development
specifications of the drug product. The program can reduce the number of
difference in these specification values specifications tests required for release,
depends on the time the actual check, and finished product.
measurement is made. Content Uniformity of Tablets:
These end-product specifications are:- • end of granulation stage - in-process
• the release specifications • As a tablet release specification
• the stability (check) specifications Dissolution is established with the
• the Finished Product Specifications development and qualification lots, then
Finished Product Specifications (FPS) demonstrated with pivotal and validation
are the specifications the product must batches. If a consistent dissolution profile is
maintain for the full length of the allocated exhibited during all development stages -it
shelf life. falls into a product release specification.
Stability (Check) Specifications are a Friability and disintegration are In-process
sub-set of the FPS and are the monitored Specifications (post compression stage) and
specifications of the Finished Product that not routine product stability or finished
tend to change with aging and may or do product quality control tests.
impact on the overall product quality. Uncoated tablets may exhibit hardness
Since only a few specifications have a aging changes with aging (granulate moisture
significance there are always less check content) and hardness monitoring may be
specifications. Check specifications ranges present in the in-process, release, and
may not be greater that the Finished stability specifications.
Product Specifications.
The choice and rationale of correctly
The Release Specifications are the values placing the product specification in either:
required for batch release purposes only.
⇒ in-process [bulk]
The Assay of a drug product, for example,
is usually set at: ⇒ release [ T0 ]
⇒ Release - 95.0 - 105.0% ⇒ finished product [overall]
⇒ Check - 90.0 - 110.0% ⇒ stability [shelf life]
⇒ Finished - 90.0 - 110.0% categories with appropriate limit values
depends on when the test is performed and
of labeled amount.
whether it is of a stability indicating value.
Check & Finished Product Specifications
are usually the same values & ranges. A well developed and validated
Not all finished product specifications are product formula and manufacturing process
stability indicating, with the result that will significantly reduce the amount of
there are less specifications in the stability release testing that would otherwise be
testing protocol than in the overall finished necessary. Note: Compendial requirements
drug product specifications. are Finished Product Specifications.

Handbook of Pharmaceutical Sect: 9 . 1 Generic Development

 ORAL TABLETS FINISHED PRODUCT SPECIFICATIONS CHAPTER 9

RELEASE SPECIFICATION
TABLET / CAPLET - COATED
Page 1 of 2.

FINISHED PRODUCT CONTROLS

RELEASE SPECIFICATIONS
Product: Tablets [USP] [000.0] mg.
Labeled Amount: Each tablet contains [000.0] mg [Active Material]
TEST SPECIFICATION
Description1 [Color] (white to off-white) caplet core debossed with
the number / letters[ABC - 72] on one face of the
Tablet and [XYZ] on the opposite face
Identification A1 The Infra Red Absorption Spectrum conforms to the
Reference Standard
Identification B1 The Chromatogram of the assay preparation exhibits a
major peak with the same retention time as the
standard solution (Where a drug is chiral (single or
racemate) add a stereochemical ID as well.
Individual Caplet weight Nominal [662.0] Limit: [612.0] - [711.0]mg
(±7.5%) - Example 622mg
Average Caplet weight Nominal [662.0] Limit: [629.0] - [695.0]mg
(±5.0%)
Uniformity of Dosage Units Conforms to the current USP Content Uniformity
Dissolution1 Equipment: USP App. No 2 (Paddle)
NLT 80% (Q) of the labeled Media: 900 mL, 37Ð C. [Ñ0.5ÐC] 0.1N HCl]
amount within 45 min. pH 1.2 (Ñ0.05)
RPM - 100
UV detector at 275 nm
Assay %1 Limit: 95 - 105% of labeled amount
Assay mg [000.0] - [000.0] mg / Tablet or Caplet
Impurities / Degradation Products determination
Each Individual: 1 NMT 0.5% of the labeled amount

Any other Individual: 1 NMT 0.5% of the labeled amount

Total : 1 NMT 2.0% of the labeled amount
Residual Solvents Class 3 - Acetone NMT 500 ppm
or OVI's Class 3 - Ethanol NMT 1000 ppm
Class 3 - Isopropanol NMT 5 000 ppm

Note: Residual Solvent / OVIs, if present in the film coat require a release specification.
1 Stability Check Specifications Tests performed during stability evaluation.

Handbook of Pharmaceutical Sect: 9 . 2 Generic Development

 ORAL TABLETS FINISHED PRODUCT SPECIFICATIONS CHAPTER 9

STABILITY SPECIFICATION
TABLET / CAPLET
Page 2 of 2.

FINISHED PRODUCT CONTROLS

CHECK SPECIFICATIONS
Product: Tablets [USP] [000.0] mg.
Labeled Amount: Each tablet contains [000.0] mg [Active Material]
TEST SPECIFICATION
Description1 [Color] (white to off-white) caplet core debossed with
the number / letters [ABC - 72] on one face of the
Tablet and [XYZ] on the opposite face
Identification A1 The Infra Red Absorption Spectrum conforms to the
Reference Standard
Identification B1 The Chromatogram of the assay preparation exhibits a
major peak with the same retention time as the
standard solution (Where a drug is chiral (single or
racemate) add a stereochemical ID as well.

PHYSICAL TESTS

Friability 1 NMT 1.0%

Moisture: 1 NMT 0.0%

Dissolution1 Equipment: USP App. No 2 (Paddle)
NLT 80% (Q) of the labeled Media: 900 mL, 37Ð C. [Ñ0.5ÐC] 0.1N HCl]
amount within 45 min. pH 1.2 (Ñ0.05)
RPM - 75
UV detector at 275 nm

ASSAY Percentage and Quantity of labeled amount

Assay % Limit: 90.0 - 110.0%

Assay mg [000.0] - [00.0] mg / Tablet or Caplet
Impurities / Degradation Products determination

Each Individual: NMT 0.5% of the labeled amount

Any other Individual: NMT 0.5% of the labeled amount

Total: NMT 2.0% of the labeled amount

NOTE:
Difference between release assay 95 - 105% and stability check assay 90.0 - 110.0
1Stability Check Specifications Tests recommended - if deemed to be necessary during product
development - (JUNE 1998 DRAFT STABILITY GUIDANCE TO INDUSTRY).

Handbook of Pharmaceutical Sect: 9 . 3 Generic Development

 ORAL TABLETS FINISHED PRODUCT SPECIFICATIONS CHAPTER 9

ØC H E C K L I S T ×
SOP # P-HGD-03-0Y2K

FINISHED PRODUCT SPECIFICATIONS

‘…release, check and finished product specifications all have minor

c h a n g e s - the difference is in the size of the ranges…‘

1. The Finished Product Specifications have both release and a stability qYes qNo
check specifications that allows for appropriate product aging throughout
the allocated shelf life ?

2. All the stability specifications are shown to be - stability indicating ? qYes qNo

3. Release specifications have narrower limits than the stability check qYes qNo
specifications, allowing an appropriate margin of safety as the product
ages ?

4. Development and qualification lots show content uniformity is similar qYes qNo
for the granulation material and the compressed tablets or uncoated
tablet cores ?

5. The firm performs specified critical in-process controls to insure that qYes qNo
the finished product testing is always in specification (e.g. content
uniformity) ?

6. Content Uniformity is evaluated at the end of granulate blending, to qYes qNo

insure a successful tablet compression ?

7. The assay release specifications are set at 95.0 - 105.0% ? qYes qNo

8. The assay check specifications are set at 90.0 - 110.0% ? qYes qNo

9. Batches released at <97.0% are investigated and monitored for qYes qNo
stability, if development studies show active loss is >7% for claimed
shelf-life) ?

Handbook of Pharmaceutical Sect: 9 . 4 Generic Development

 ORAL TABLETS FINISHED PRODUCT SPECIFICATIONS CHAPTER 9

ØC H E C K L I S T ×
SOP # P-HGD-03-01Y2K

FINISHED PRODUCT SPECIFICATIONS

‘…release, check and finished product specifications all have minor

c h a n g e s - the difference is when you measure the ranges…‘

10. Tablet Hardness, Friability and Disintegration tests are not qYes qNo
performed as a finished product release test as these tests are
routinely addressed during in-process controls?

11. Tablet Hardness is not evaluated as a check specification, if qYes qNo

development studies shows no increase in hardness with tablet age
(see granulate moisture controls)?

12. Tablet Hardness Range Qualification was performed to verify qYes qNo
that all the Check Finished Product Specification remained in
specification when processed at the lower and upper hardness
limit?

13. The Dissolution Test USP was evaluated in the development qYes qNo
and qualification batches and consistently demonstrated in the
pivotal and three full size commercial validation lots?

14. If yes to # 13, then dissolution assay monitoring is qYes qNo

unnecessary for routine commercial lots, if it is not a USP
compendial monograph requirement?

15. The Description allows for possible minor changes in color qYes qNo
from product release to end of shelf life (i.e. white to off-white
tablet)?

Footnote : Where the product batch history shows test failures due to environmental or raw material
variations is a clear indication that both these parameters should be further investigated and
addressed

Handbook of Pharmaceutical Sect: 9 . 5 Generic Development

 ORAL TABLETS FINISHED PRODUCT SPECIFICATIONS CHAPTER 9

STANDARD OPERATING
PROCEDURES
SOP # P-HGD-03-01Y2K Page 1 of 1

FINISHED PRODUCT SPECIFICATIONS

The following Standard Operating Procedures are recommended for a generic

development unit :

Finished Product Specifications

P-HGD-02-12YY Choosing Finished Product Specification limits.

P-HGD-02-12YY Qualifying Finished Product Specification limits.

P-HGD-02-12YY Choosing release Specification limits.

P-HGD-02-12YY Choosing Check Specification limits.

P-HGD-02-12YY Reducing stability specifications by developing rugged

generic product formulations.

4
[End of Document]

ED. N0: 02 Effective Date: APPROVED:

Replaces Ed 01.
Ed. Status: MM/DD/2000
Operational Department R&D QC QA

Handbook of Pharmaceutical Sect: 9 . 6 Generic Development

 TABLETS ORAL P R O C E S S - O P T I M I Z A T I O N CHAPTER 10

Process
Optimization
‘…choosing the right formula and process specifications
prior to qualification…'

Qualification of LOD Limits containers and placed on stability at

Process Optimization is applied when 40°C/75% RH for 3 months. The
required to establish processing target formula and physical properties of the
values and limits in formulation fine- granulates obtained are presented in
tuning, LOD studies (aqueous) or Table No. 08-09. and stability results
lubrication type and quantity decisions. outlined in Table No. 10-12.
The target LOD for granules with The stability results highlight the
corresponding narrow target LOD limits acceptable qualification of the granulate
e.g. 1 - 2% may not impact on tablet LOD limits.
hardness or dissolution during ageing
(i.e. its shelf life period) Qualification of Lubricant Limits
LODs for granules with corresponding Process Optimization (PO) - fine tuning
WIDE limits that cannot be avoided e.g. lubrication percentages or combinations
1.8 - 3.8% may indeed impact on tablet takes place after the LOD Studies. The
hardness and its dissolution profile order of critical qualification studies are:
during the drug's shelf life and thus
♦ Formula Antioxidant (PO)
Qualification of LOD Limits should be
undertaken. ♦ LOD (PO)
Procedure:-
Manufacture a medium sized batch - ♦ Lubrication (PO)
dry the granules to the higher LOD limit ♦ Granule Content Uniformity (PQ)
(e.g. 3.5%) -then remove half the load
from the FBD and process as a ♦ Hardness (PQ)
separate sub-lot I. Process Optimization & Process
Continue to dry the remaining half to Qualification (PQ) - Differences.
the LOD limit (e.g. 1.8%) -then remove
the half-load from the FBD and process Formula, LOD and Lubrication Studies
as sub-lot II. are Optimization Studies as the choice
The proposed limits for granulates are of the formula, ingredients or
LOD: 2.0 - 3.5% (tested on a IR manufacturing controls are not
Computrac™ MAX 50, with testing established and are in the process of
temperature set at 92°C). being chosen.
Optimization batches P-06 (LOD = Granule Content Uniformity and Tablet
3.8%) and P-07 (LOD = 1.8%) were Hardness Qualification are Process
granulated in Diosna P-10™ (high Qualification, as both the formula and
speed mixer) and dried in the Fluid Bed process are final and the PQ studies
Granulator Drier (Glatt WSG-10™), are in fact challenging and verifying
tabletting in the Fetta P1200 tabletting Content Uniformity and Tablet
machine. The tablets were coated in a Hardness limits with a final formula and
AccelaCota15™, packed in HDPE manufacturing process.

Handbook of Pharmaceutical Sect: 10.1

10.1 Generic Development
TABLETS ORAL P R O C E S S - O P T I M I Z A T I O N CHAPTER 10

Qualification of Antioxidant & Lubricant

Oral Tablets 250 mg Active Material
Optimization Batch Stage
Table No. 08
Formulae Ingredients Amount per tablet core (mg)
ò
P-06 P-07 P-08 P-08 P-10
Batch No. è
Part I - Pre-mix (dry) LOD STUDY LUBRICATION STUDY
Active Material USP 250.0 250.0 250.0 250.0 250.0
Microcrystalline Cellulose NF 30.0 30.0 30.0 30.0 30.0
(Avicel PH101™)
Povidone USP 8.0 8.0 8.0 8.0 8.0
PVP K-30™
Starch NF 40.0 40.0 40.0 40.0 40.0
Part II - Granulation solution Granulating Stage
Butylated Hydroxyanisole NF 0.40 0.40 0.40 0.40 0.40
(BHA).
Alcohol USP (95%) Qs Qs Qs Qs Qs
Purified Water USP Qs Qs Qs Qs Qs
PART III - Extra-granule Dry Mixing
Microcrystalline Cellulose NF 50.0 50.0 50.0 50.0 50.0
(Avicel PH102™)
PART IV - Lubrication Rapid Dry Blending
Stearic Acid NF 8.0 8.0 8.0 7.0 6.0
Magnesium Stearate NF 1.0 1.0 1.0 2.0 3.0
Total Core Weight 390.0 390.0 390.0 390.0 390.0

AQUEOUS FILM COATING SUSPENSION

Opadry OY-S-345™ - Orange 10.0 10.0 10.0 10.0 10.0
Purified Water USP Qs Qs Qs Qs Qs
Total 400.0 400.0 400.0 400.0 400.0
Note: Qs = Processing aqueous and non-aqueous solvents only.

FORMULA FORMULA
FOR FOR
OPTIMISING OPTIMISING
LOD RANGE LUBRICANTS

Handbook of Pharmaceutical Sect: 10.2

10.2 Generic Development
TABLETS ORAL P R O C E S S - O P T I M I Z A T I O N CHAPTER 10

Qualification of Antioxidant & Lubricant

Physical Characterization of Granulates
For Oral Tablets 250 mg Active Material
Optimization Batch Stage

Table No. 09

Ø Optimization Batch Stage - Granulate Physical Characterization

Oral Tablets containing 250 mg of Active Material
BATCH NO. è P-06 P-07 P-08 P-09 P-10
Granulation Tests Results:
Bulk Density (BD) 0.59 0.57 0.55 0.57 0.58
(g/mL)
Tapped Bulk Density (TD) 0.70 0.71 0.70 0.68 0.69
(g/mL)
Carr’s Index - Compressibility (%) 21 21 19 19 18

Sieve Analysis Method Jet Sifter

Percentage remaining or Sonic Sifter
Sieve 20 Mesh 4 6 4 6 3
Sieve 40 Mesh 8 10 8 7 11
Sieve 60 Mesh 20 17 20 17 18
Sieve 80 Mesh 18 16 18 15 15
Sieve 100 mesh 10 12 10 16 16
Sieve 130 mesh 19 17 19 17 17
Amount in PAN 22 22 21 22 20
LOD (%) 3.8 1.8 2.9 3.3 2.2

Tablet
Physical Parameters

Capping Absent Absent Absent Absent Present

Chipping Absent Absent Absent Absent MILD

Pitting Absent Absent Absent Absent MILD

Placed on
Stability &
tested for:- Physical
Assay Parameters
Impurities evaluated
Dissolution

Handbook of Pharmaceutical Sect: 10.3

10.3 Generic Development
 TABLETS ORAL P R O C E S S - O P T I M I Z A T I O N CHAPTER 10

Qualification of LOD Limits

Oral Tablets 250 mg Active Material
Optimization Batch Stage

Optimization Batch Stage - Stability studies

Container / closure system : HDPE container 110cc
Fill size : 150 tablets
Storage conditions : 40°C / 75% Relative Humidity
Table No. 10

Assay and Impurities (%)

Batch P-06 Containing BHA 0.1% w/w

Parameters Thin Layer (TLC) HPLC

Storage Appearance BHA Assay Impurity Impurity Impurity ANY TOTAL Impurity ANY TOTAL
(months) % I II III Impurity
I II Impurity Impurity
TLC TLC TLC I HPLC II II
NMT
Specs. White to Off 50- 90.0 - NMT NMT NMT NMT NMT NMT NMT NMT
White
110 110.0 1.0 0.5 0.5 0.1 3.0 0.5 0.1 1.0
0 Conforms 90 102.0 <0.1 <0.1 <0.1 <0.1 <0.3 <0.02 <0.02 <0.07
1 Conforms 60 99.8 <0.1 <0.1 <0.1 <0.1 <0.3 <0.02 <0.02 <0.07
2 Conforms 65 101.2 <0.1 <0.1 <0.1 <0.1 <0.3 <0.02 <0.05 0.07
3 Conforms 55 100.8 0.1 0.1 0.1 0.1 0.3 <0.02 <0.05 <0.07

Table No. 11
Assay and Impurities (%)
Batch P-07 - Containing BHA 0.10% w/w
Parameters Thin Layer (TLC) HPLC
Storage Appear BHAAssay Impurity Impurity Impurity ANY TOTAL Impurity ANY TOTAL
(months) ance % I II III Impurity I II Impurity Impurity
TLC TLC TLC I HPLC II II
Specs White to NMT 90.0 - NMT NMT NMT NMT NMT NMT NMT NMT
Off 50- 110.0 1.0 0.5 0.5 0.1 3.0 0.5 0.1 1.0
White 110
0 Conforms 90 102.2 <0.1 <0.1 <0.1 <0.1 <0.3 <0.02 <0.02 <0.04
1 Conforms 70 100.4 <0.1 <0.1 <0.1 <0.1 <0.3 <0.02 <0.02 <0.04
2 Conforms 70 102.0 <0.1 <0.1 <0.1 <0.1 <0.3 0.02 0.03 0.05
3 Conforms 60 101.8 <0.1 0.1 0.1 0.1 0.3 0.02 0.05 <0.07
Key:
Assay % of Label Claim of Active BHA Butylated Hydroxyanisole NF Dissolution % of Label Claim of Active
ANY I = Any other impurities (by TLC) TOTAL I = Total impurities (by TLC) ANY II = Any other impurities (HPLC)
TOTAL II = Total impurities (by HPLC)

Handbook of Pharmaceutical Sect: 10.4

10.4 Generic Development
TABLETS ORAL P R O C E S S - O P T I M I Z A T I O N CHAPTER 10

Qualification of LOD Limits

Oral Tablets 250 mg Active Material
Optimization Batch Stage

Optimization Batch Stage - Dissolution Studies

Container / closure system : HDPE container 110cc Fill size: 150 Tablets
Storage conditions : 40°C / 75% Relative Humidity Mfg. Date:
Packaging Date : Expiration: Date Stability Start Date:
Table No. 12.
Storage Appearance
Assay & Dissolution
(%)
in Batchð
P-06 P-07
months Assayò 10’ 20’ 30’ 10’ 20’ 30’

Specs. White to Off White 90.0-110.0 NLT 75% (Q) NLT 75% (Q)
dissolved in 30’ dissolved in 30’

0 Conforms 101.5 94.6

(5.1)
98.6
(3.0)
96.8
(4.5)
96.6
(5.1)
98.1
(3.0)
97.8
(2.5)

1 Conforms 100.7 98.0 98.0

(2.1) (2.1)

2 Conforms 100.2 99.8 99.8

(2.2) (2.2)

3
Conforms 100.5 96.1 97.2 98.7 97.1 97.2 96.7
(3.1) (2.6) (2.4) (2.0) (2.4) (2.4)

OPTIMUM
LOD & Lower &
LUBRICANT Upper LOD
COMBINATION. Range fully
qualified
DISSOLUTION
is in Specification

Handbook of Pharmaceutical Sect: 10.5

10.5 Generic Development
 TABLETS ORAL S C A L E - U P CHAPTER 11

S C A L E - UP
P r ocedures
‘…Scale-up is a development procedure -
pivotal and validation lots are demonstration procedures…’

SCALE-UP OF DEVELOPMENT LOTS

♦ mixing / granulating speeds (e.g.
T he scale-up of the manufacturing
procedure remains a development
procedure and should be applied
Mixer speed II and Chopper speed II)
or to a maximum torque value.
initially to:
♦ drying requirements of time /
• the process qualification batch temperatures
• the pivotal batch
♦ Granulate LOD
• the full size validation lots.
♦ Milling sieve sizes
The Process Qualification batch should
♦ Dry blending disintegrant /glidants.
mimic the pivotal batch in all its
aspects. Ideally it is the same size or ♦ Optimization of the mixing time of
about 70% of the market batch and is unlubricated granulate by sampling at
seen a prototype test run for the pivotal three different mixing times: (e.g. 5
procedures, QC controls and full min., 10 min. and 15 min).
processing documentation package.
♦ Y-cone blending times of lubricated
Batch size considerations:- granulate (lubricated granulate mixing
The pivotal batch must be 10 % or time: 5 min - i.e. shortest possible time.)
greater than the size the corresponding
validated commercial batch lot (OGD’s ♦ Tabletting target speeds and rpm
Regulation). limits sampling procedures & protocol
The pivotal size may in fact be equal in ♦ Processing times;
size to the validated commercial lots
and since every commercial lot size ◊ in-process
must be separately and individually ◊ prior to compression
validated - scale up procedures need to
consider both the pivotal batch and the ◊ total manufacturing time
commercial lots. Scale-up procedures
Major principal areas for scale-up of
Granulating loading procedures
tabletting procedures are:-
The addition of bulk solids to large
♦ Granulation process (e.g. addition of mixer / granulator may require careful
Purified Water USP during mixing time mechanical transfer to reduce
period, for (say) 45 seconds exactly. ingredient dust cross-contamination.

Handbook of Pharmaceutical Sect: 11.1

11.1 Generic Development
 TABLETS ORAL S C A L E - U P CHAPTER 11

Load the active drug substance Quantity of PURIFIED WATER USP

initially, then follow with the largest added ____kg. Mixing time from ____
excipient and continue in decreasing to ____ .”
order of ingredient weight in the The mixing speed (rpm) for the
addition order chosen. granulating step is a critical processing
Split the granulating agent (e.g. PVP stage and requires complete
solution or dry PVP) into two separate documentation of blade speeds and
granulating steps to achieve longer settings or end-torque values (where
mixing times (producing less fines when equipped) to insure complete uniform
dried as granule is more cohesively mixing and subsequent content
bound). uniformity.
Granulating mixing procedures Since mixing speeds and mixing times
Mix and blend the dry mix for fixed impact significantly on the content
period (2-5 minutes) using mixer and uniformity of the bulk batch, mixing
chopper at the maximum mixing operations are considered to be critical
settings. process parameters.
Granulating solutions Note: Manufacturing equipment for
Prepare the granulating solution or pivotal and commercial batch sizes
granulating paste in an specified must have the same operating
container recording:- principles and differs only in scale of
• the mixer or stirrer used and rpm the operation.
setting.
• solvent temperature (±30 C) and the
Bulk transfer to dryers
Discharging of wet granulate mix by
overall mixing time to produce a clear
direct transferred into the processing
solution or a smooth homogeneous
FBD bowels. Record discharge and
paste.
transfer steps in batch manufacturing
Granulation end-point is reached either instructions with appropriate signatures.
when a set torque value is obtained, or
in the absence of a torque meter, to a FBD Drying
set granulating time operating at set Dry the granulate in the FBD (specify
blade speeds (i.e. mixer 1 - chopper I type) until the required LOD of a milled
or II). Wet mixing times are 30-45 sec. sample is between 1.2% - 2.5%.
The rate of addition of the granulating Example of air temperatures and
fluid is controlled either by spraying or ranges:
controlled pumping. The total O O

dispersion time is recorded. Inlet air :- 53 C (± 3 C)

O O

Mixing efficacy will differ from pilot Outlet air:- 33 C (± 4 C)

mixers and small scale granulators to Total Drying time ________ minutes.
large processing units and large scale
granulator-mixers such as the Diosna Grinding / Milling Scale-up
P850™. Pass a small quantity about 0.5 kg of
To ensure that a suitably formed the dried granulate through an
granulate is obtained - add the follow oscillating granulator (stating machine
manufacturing step: type) equipped with a 0.8 -1.0 mm
“ Add further PURIFIED WATER USP screen and check LOD (specify the IR
q.s. if required. Speed: mixer I, chopper LOD equipment to be used and the IR
II. Mix for up to 30 seconds. testing equipment temperature setting).

Handbook of Pharmaceutical Sect: 11.2

11.2 Generic Development
 TABLETS ORAL S C A L E - U P CHAPTER 11

'Report LOD _____ % reading. Typical lubrication blend times to

Where necessary, continue drying achieve optimum granule surface
until the target LOD is obtained. coating is about 3 to 5 minutes using
Report target LOD _____ % reading." 0.25% to 1.0% of 50 mesh screened
Note: Avoid this type of scale-up Magnesium Stearate NF. Avoid over-
process instruction “Dry the granulate coating of granules by minimizing the
until the required LOD is less than 2.0 granule lubrication blending time.
%” - as over-drying of the granulate is Avoid changes of lubricant vendors
possible while the manufacturing as Magnesium Stearate differs in
process remains in specification. overall surface area and lubricity.
Blending Scale-up Note:
Transfer the milled granulate to a Lubricant Qualification Study
twin shell blender / Y-cone of stated During the product development
capacity. A portion of the stages, unlubricated granules, with
disintegrating agent (e.g. ~33%) may 0.5, 0.75, and 1.0% of lubricant
be added during transfer of the should be evaluated using the
milled granulate and blended to a proposed commercial tabletting
uniform mixture. press fitted with the commercial
The intra-granular disintegrant would punches and dies intended for the
facilitate rapid tablet disintegration marketed product.
and enhance initial dissolution
values. Blend unlubricated granules Blending summary
for usually 5 to 15 minutes and ⇒ Blend sublots with glidant and
perform a blend analysis to insure extra-granular disintegrant.
uniformity of content.
⇒ Sieve lubricant by:-
Granule lubrication
The granulate-mix should be ◊ Passing lubricant through 50
lubricated with the minimum quantity mesh.
of lubricant (Magnesium Stearate ⇒ Lubricate granulate using:-
◊

NF) and coating time strictly ◊ Minimum lubrication time

controlled - rarely over 5 minutes in a
Y-cone or Bin tumbler. ◊ Combination Lubricants
Granules required to be partially ◊ Lubricants + Dry Starch NF
coated to allow for a lubricated ◊ Lubricants + Disintegrant
compression without degrading the ⇒ Discharge granulate into :-
compressed tablets dissolution ◊ Double polyethylene lined
profile. Dry Starch NF (Ref. Chap 6) drums with Silica Gel Bags in
acting as a glidant may protect from between linings.
over lubrication and improve ⇒ Seal pre-compression granulate
dissolution. ◊ Tie inner liners and seal drum
Combinations of Magnesium
Stearate (0.25%) and Stearic Acid Compression specifications
(2.0%) in a I:8 ratio often provide Compress lubricated granules
excellent lubrication with the addition according to the tablet specifications.
of Dry Starch NF. Record the following:-

Handbook of Pharmaceutical Sect: 11.3

11.3 Generic Development
 TABLETS ORAL S C A L E - U P CHAPTER 11

Tabletting machine type: may be possible with certain

Punch and Die # equipment or modifications.
Machine Speed: Formulations may contain pigments
♦ Target ____ tph as well as surfactants and
plasticizers. While the polymer grade
♦ Lower Speed ____ tph
and concentration is the prime factor
♦ Upper Speed ____ tph affecting solution viscosity, additional
coating excipients can effect
COATING STAGE - Overview (increase) the viscosity of the
Preparation of Film Coat Dispersion:- spraying solution.
Optimization of the tablet coating Five well established methods for
process is undertaken during scale- preparing coating solutions during
up. Disperse in Purified Water USP scale-up procedures are described.
the commercial brand of film coat 1. Dilution of commercial coating
dispersion (e.g. Colorcon™ solutions (e.g. Colorcon OPADRY™
OPADRY™ YS series) by passing YS series) with purified water NF
through a roller mixer until a uniform according to set instructions.
dispersion is achieved. Keep stirring. 2. Dispersion in Hot Water
Roller mixer: Speed II. Since HMP Cellulose's are not
Mixing time: 30 minutes. soluble in hot water, it is an ideal
Filter the color dispersion through a aqueous suspending agent to
80 mesh screen and divide if produce lump-free dispersions. Such
necessary into the appropriate dispersions act as colloidal
number of coating sub-lots required. suspensions and can easily be
Label with batch and sub-lot number. accomplished by dispersion in Hot
Preparing the coating solution Purified Water. Temperatures of 80-
Proper preparation of the coating 85oC are commonly used. Lower
solution is necessary to achieve a temperatures between 60-80oC will
good coating in a reasonable amount only slightly aid in polymer
of time. Many coating polymers dispersion. In order to get the
(HPMC) are supplied as a fine polymer hydrated, the suspension is
powder and will rapidly hydrate in cooled under continuous stirring,
cold water. The hydration is so rapid causing the HPMC polymer to
that without continuous agitation hydrate. Cooling is generally via
lumps or clumps of gel with un- natural heat loss, however cold water
dissolved dry powder inside are jacketed vessels or part of the water
formed. may be reserved (40-50%) as cold
Once formed additional agitation, water and added to the hot polymer
time and labor are required to fully dispersion.
hydrate the polymer coat. 3.Dry Blending Coating Excipients
Regardless of the delivery system Blending coating excipients initially in
coating solutions must be formulated the dry phase generally dilutes the
to have a sprayable solution coating polymer. Dry pigments, dry
viscosity. Generally this means a plasticizer and dry polymer may be
viscosity of the coating solution in the blended and then added to the
range of 180-400 mPas. processing purified water (lower
Higher viscosities (450-600 mPas) temperatures may be used.)

Handbook of Pharmaceutical Sect: 11.4

11.4 Generic Development
 TABLETS ORAL S C A L E - U P CHAPTER 11

3. Dispersion in Hydroalcoholic The coating solution should be

Solvents. continually stirred during the entire
Hydroalcoholic solvent systems are spray coating process.
used where the water content of the Minimize foaming by reducing
solvent mixture may range from 25- agitation and allowing sufficient time
75% by weight. The higher the for complete polymer hydration.
alcohol content the faster the drying Foaming occurs due to entrapped air
at relatively low temperatures and by excessive agitation. Polymers are
incoming air volumes. surface active and once the tendency
HPMC (Hydroxypropyl methyl to foam has occurred settling over
cellulose) is not soluble in 95% time is required or the formula may
alcohol or alcohol USP. HPMC call for the addition of a defoamer
solubility is effective when 20-25% (Dow Corning AF™).
purified water NF is added to the Filter the coating solution via a 60-80
alcohol. The use of alcohol/water mesh screen to remove very small
solvents allow for a relatively fast lumps or incompletely hydrated
coating, but slower that the older polymers.
organic methyl chloride/alcohol Tablet film coating
systems. Note: Prepare separate coating
4. Dispersion in Ambient Water. instructions for each sub-lot required.
Cold water dispersion is the most Warm the tablet cores until the inlet,
difficult, however is often used in outlet air and bed temperatures are
large scale commercial coating reached. The pan loading and tablet
operations due to equipment and dimension will also affect coating
heat transfer limitations. efficiency. Most coating pans must
Very slow controlled addition of the be filled to an operative volume for
HPMC polymer to the ambient successful tablet/caplet coating.
purified water, in conjunction with Too few or too many tablets lead to
good agitation. Foaming occurs with inconsistent coating quality. Even the
higher speeds or excessive mixing. shape of the tablets/caplets will
Proper agitation should adequately effect the optimal loading and drying
move the dispersion surface in the efficiency of the coating operation.
vessel and pull a small vortex (10- Core friability should be kept below
20% of vessel height). Adjust blade 0.5-1.0%
height (between 1\3 and 2/3 of Common operating parameters are
vessel) given below (example).
After complete mixing do not use the Inlet air : 53 C
O
(± 2 C)
O

solution immediately - a quiescent Outlet air :

O
35 C
O
(± 1 C)
period of 30-45 minutes is usually O O
Bed Temperature 41 C (± 4 C)
recommended after mixing to allow
Spray settings _____
most of the entrapped air to move to
Drum rpm. _____
the surface. Preparation of the Drying time _____ minutes.
coating dispersion an hour or two The volume, incoming temperature and
before use and kept under continual humidity of the drying air are critical in
slow stirring in the most common optimization of the coating process.
practice.

Handbook of Pharmaceutical Sect: 11.5

11.5 Generic Development
 TABLETS ORAL S C A L E - U P CHAPTER 11

Generally it is desirable to deliver the displacement pump or less

greatest possible amount of air at the frequently a pressurized air pot
desired temperature [70-90oC] without delivery system.
causing over-fluidization of the core When using positive displacement
bed. Normally inlet air is controlled in pumps viscosity of the coating
the range of 70 to 90oC. solution is not a critical factor in the
Higher and lower temperatures may be
flow rate. Viscosity is important in
desired for specific temperature
pressurized air pot delivery systems.
products or for fast coating
applications. Relative humidity of the Increasing the temperature (kept
inlet air affects the drying capacity. The below thermal gelation temperature)
higher the RH of the incoming air the of the coating solution will decrease
less effective the drying process. the viscosity.
Uncontrolled RH of the inlet air will Spray the coating solution / dispersion
impact on the drying and coating and coat the tablet cores until the
process according to the current or dispersion is complete. Dry the coated
daily atmospheric conditions. tablets with forced warm air (~ 42 C ±
O

APPLICATION RATE O
2 C) for ~8 minutes and then with
The rate of coating solution delivery ambient air for an additional ~5
is an important process control minutes.
variable. Pre-warming the cores Discharge the coated tablets into a
allows for an initial fast coat of the double polyethylene lined drums, seal
primary layer. While fast application liners and drum and weigh. Record net
of the coating solution is important to weight and calculate yield.
minimize batch times, it must be Scale-up coating problems
remembered that there are Tablet Coats may slow down the
limitations to each type of equipment dissolution during the initial 10-15
and coating solutions being utilized. minute sampling. PVP K#30 tablet
Practical limitations can be binder in granulating solutions (at 2-
determined by utilizing the basic 4%) and certain commercial HPMC
thermodynamic relationships and coating solutions may slow down the
monitoring exhaust air temperature. initial curve of the dissolution profile,
It is important to make the smallest especially accelerated stability
o
possible droplet size to insure rapid samples (40 C/75%RH).
drying. Pigmented coating problems
The amount of air being applied and Tablet Coats are frequently opaque
the amount of pressure being utilized pigmented coatings. Clear
to atomize the liquid droplets can transparent coats are occasionally
determine the efficiency and used. Pigmented coating can provide
effectiveness of the coating system. additional light stability to dosage
Air atomization is generally preferred forms and help to differentiate tablets
with aqueous systems as it enhances by color coding. Pigments used in
the initial liquid droplet evaporation. tablet coating are generally
Small droplets are necessary to aluminum lakes or iron oxides with
achieve a fine smooth surface on titanium dioxide or talc used in white
coating tablets. coats or for color dilution in pastel
The flow rate of the coating solution colors.
is generally controlled by a positive

Handbook of Pharmaceutical Sect: 11.6

11.6 Generic Development
 TABLETS ORAL S C A L E - U P CHAPTER 11

Most pigments are supplied as color blending step and re-sample exactly as
dispersions in alcohol, propylene before. (Note: sampling procedures and
glycol or water. sampling positions must be recorded).
Pigments reduce film strength. The content uniformity should not differ
Tablet coating pigments have a in both sampling sets of the two
significant effect on the film procedures.
properties. As pigments are added, a
reduction in flexibility and film
Revalidation
strength is experienced. Pigmented Infrequent re-blending should only
films exhibit a distinct loss of film occur in incidences of mechanical
strength from unpigmented films. breakdown.
Generally 20-30% additional Where the re-blending process
plasticizer (polyethylene glycol - becomes more frequent review and
PEG 600) is added when formulating revalidate the manufacturing process to
pigmented films. re-qualify the blending steps.
General Scale-up concepts COATING SUMMARY
The processing time for each
manufacturing step requires a ‘start and ¯ Hot water (80oC) dispersion is best
stop’ document entry. Where possible ¯ Allow to de-aerate before use
automatic recording control charts ¯ Continual stirring of coat maintained
should be in place for monitoring ¯ Filter (80 mesh) before use
processing times and critical process
temperatures. ¯ Quiescent period of 30-45 min.
Recording temperatures ¯Agitate coating solution continually
Temperature end-points for drying are during spraying
documented in the format of a range, ¯ Tablet friability - <0.5 - 1.0%
O O
i.e. ‘Inlet air 55 C (± 3 C) or heat bed ¯ Control core-bed load/weight
O O
to 42 C (± 2 C).’ It is not necessary to
¯ Avoid overloading or underloading
qualify both ends of such narrow
operating temperature limits (as there is ¯ Pre-warm core bed
no significant impact on the product or ¯ Jog bed until even temperature
process). distribution is obtained.
Re-mixing a step ¯ Set bed jogging cycle and jogging
Repeating a mixing or blending step is time to achieve correct bed temperature
acceptable, if the procedure has been ¯ Control inlet air temperature and RH
correctly qualified during the product ¯ Control inlet air volume
development phase.
¯ Control spraying rate (g/min)
To qualify a re-mixing or re-blending
¯ Control number of spray nozzles,
step manufacture the batch with the
height and angle.
initial mixing step. Sample the bulk at
the different sampling levels and ¯ Control nozzle distance form core
positions. bed.
Do not composite any samples for ¯ Insure smallest possible droplet size
content uniformity tests. ¯ Control outlet air temperature
With the same evaluation batch ¯ Insure a thermodynamic balance
immediately repeat the exact mixing or between heat in and water evaporation.

Handbook of Pharmaceutical Sect: 11.7

11.7 Generic Development
 TABLETS ORAL S C A L E - U P CHAPTER 11

ØC H E C K L I S T ×
CL # P-HGD-03-01Y2K

SC AL E UP P ROCEDURES
‘ the order is clear:- develop - scale-up - process qualification
- pivotal and validation lots ’

1. The process qualification batch is a ‘carbon copy’ of the pivotal lot? qYes qNo

2. The process qualification batch is manufactured under normal production qYes qNo
facilities ?

3. The process qualification batch documentation is similar or identical to the qYes qNo
pivotal lot documentation, which is identical to the commercial lots?.
4. Where two commercial batch sizes are manufactured, the equipment used qYes qNo
differs only in capacity or size?

5. Each batch size has a dedicated set of processing documentation? qYes qNo
6. All mixing/granulating times have a ‘start and stop’ entry? qYes qNo

7. All end-temperatures are documented with the recorded entries? qYes qNo

8. Speed, temperature and time control charts attached to manufacturing qYes qNo
instructions clearly identify batch, vessel, and processing step #?
9. Documentation records overall manufacturing and filling times ? qYes qNo

10. Special instructions exist to prevent product contamination during normal qYes qNo
processing breaks and temporary work stoppages?

11. Filling instructions document equipment cleaning and filling times? qYes qNo

12. Adequate controls exist to prevent over week-end/holiday manufacture? qYes qNo

13. Containers are air blown to reduce particulate matter and bioburden? qYes qNo

14. Line screen covers protect open containers from aerial particle settling? qYes qNo

15. Control procedures in place to minimize environmental contamination qYes qNo

during tablet filling (bioburden reduction)?

Footnote : The Process Qualification Batch Documentation is the basis for the Pivotal manufacturing
documentation. Pivotal and commercial batch manufacturing instructions and procedures are in fact
identical in all respects with exceptions in equipment size changes. Both the process and the
manufacturing documentation under goes appropriate scale-up procedures.

Handbook of Pharmaceutical Sect: 11.8

11.8 Generic Development
 TABLETS ORAL S C A L E - U P CHAPTER 11

ØC H E C K L I S T ×
CL # P-HGD-03-01Y2K

S CA LE U P P ROCEDURES

The following selected model Standard Operating Procedures are RECOMMENDED

in the SOP appendix :

Scale-up procedures
SOP
P-00-01-01Y2K Preparing a scale-up report for pivotal and validation batches.
P-00-01-01Y2K Time limitations between equipment cleaning and batch processing.
P-00-01-01Y2K Time limitations for completing overall granulation procedures.
P-00-01-01Y2K Maximum time between end of granulation and start of tabletting
operation.

Processing times:
The following pre-processing and processing controls have SOP documentation:
◊ maximum time period between equipment cleaning and batch processing

◊ maximum time period to complete a critical manufacturing step (e.g. granulation)

◊ the maximum period allowed between end of granulation and start of tabletting
operation.

◊ the maximum period allowed between end of tabletting and start of coating
operation.

◊ the overall manufacturing time and the overall packaging time

4
[End of Document]

ED. N0: 02 Effective Date APPROVED:

Replaces Ed 01. :
Ed. Status: MM/DD/2000
Operational Department R&D QC QA

Handbook of Pharmaceutical Sect: 11.9

11.9 Generic Development
 ORAL TABLETS CLEANING LIMITS CHAPTER 12

CLEANING
LIMITS
…‘Check the baby not the bath rinse water
Check the pot not the dish water…’

C
leaning validation is a focal contaminants from process equipment,
point of inspection for piping and hoses used.
regulatory agencies ∗ active material residues (limit)
throughout the world. For pre-
approval inspections conducted by ∗ excipient residues (non-soluble)
the FDA for any product ultimately ∗ Detergent and solvent residues
directed to the US market, many ∗ microorganisms (bioburden
companies have been denied reduction)
approval because of deficiencies in
their cleaning program or a lack of ∗ machinery lubricants
cleaning validation for their products. Solubility factors
This chapter reviews and highlights Non soluble active and insoluble
key regulatory expectations for a excipient residues require specific
satisfactory pre-approval inspection cleaning mechanisms to prevent cross
program. contamination or adulteration of the
next batch product. Maximum Residual
Validation Protocol limits are required to be established for
A cleaning validation program is an each active.
essential part of the generic product
Adulteration
development program. Zero adulteration for penicillin's has
Product approval has been denied been regulated. Steroids (e.g.
during pre-approval inspections hydrocortisone and estrogen) as well
(PAIs) conducted by the FDA due to as sulfa drugs require extremely low
the absence of appropriate scientific levels of active residues remaining in
rationale and documented the equipment after cleaning.
acceptance criteria for cleaning
program.
Written procedures
Written cleaning procedures (SOPs)
Residue types
are required detailing the cleaning
A well structured cleaning validation process for each piece of equipment
plan requires the removal after used in the manufacturing and filling
manufacture of the following principle process.

Handbook of Pharmaceutical Sect: 12.1

12.1 Generic Development
 ORAL TABLETS CLEANING LIMITS CHAPTER 12

Parameters evaluated Clean to remove

Written procedures detail the cleaning extraneous peaks
procedures are required:
to below their LQ
♦ between different batches of the in the next batch, if
same product (minor cleaning)
they affect your assay
♦ between different product changes
Extraneous HPLC peaks may result in
♦ for water soluble product residues the analytical testing laboratory if active
materials from the previous
♦ for non-water soluble product
manufacturing lot are carried-over in
residues
the next non-serial batch (i.e. when a
♦ for dedicated equipment and hoses different active product is manufactured
as the following batch).
Each cleaning validation protocol Where extraneous peaks do occur, the
needs to address the following: HPLC procedure needs to establish the
exact peak position and its possible
♦ Responsible person for approving origins from the previous manufactured
the cleaning protocol batch product.
♦ Responsible person for performing Peak purity needs to be established to
the actual cleaning procedures ensure that the main peak of the next
active has no underlying minor
♦ The specific written cleaning extraneous peaks of the previous
procedure product, thus augmenting the assay
results erroneously.
♦ Sampling procedures
Limits and Acceptance Criteria
♦ Analytical methodology (and Establishing the criteria for acceptance
sensitivity) of a cleaning procedure requires that
♦ Acceptance criteria and the procedure consistently cleans to a
establishment of residual limits after chosen target value residue or limit.
cleaning Choosing the residual target value
limits vary between individual firms
♦ Protection after cleaning and time manufacturing the same products.
limits This standard method highlights an
exceptionally elegant and simple
♦ A re-validation period
procedure for choosing the appropriate
♦ The final validation cleaning report clean limit using a scientifically derived
‘clean formula’.
Routine cleaning procedures in a Chosen residue values need to be
development / production department based on good scientific rationale and
need to assure that the residual levels appropriate medical opinion that
of the active drug substance, after the evaluates and takes into account the
cleaning process does not introduce total daily dose that may be prescribed
extraneous HPLC peaks in the next to the patient.
development / production batch (for This dose should be 'free' to a limit of
non-serial product lots). the previous material manufactured.

Handbook of Pharmaceutical Sect: 12.2

12.2 Generic Development
 ORAL TABLETS CLEANING LIMITS CHAPTER 12

Contaminating materials in a The TR for the lower dose tablets are

pharmaceutical Master Cleaning Plan 1:4 as well as for the 100mg
fall into two to three main types for presentation (MDD for cancer
evaluation and limit testing. These are: indications = 400mg). The TR is
therefore defined for its intended
• the active material medical indication profile.
• the cleaning detergent
• colored and/or insoluble excipients
Clean to leave
Strongly colored or insoluble 1 in 1000
excipients should be removed by
cleaning to a pre-set limit value for
active residuals in
active materials and cleaning the next dosage unit
detergents.
If excipients are not remove to a ‘zero Cleaning levels per next unit dose may
visible level’ a further residue limit readily be achieved down to 0.5-1
should be set for the problematic microgram contamination limits or
ingredient. Generally water soluble and better. Firms cleaning to a maximum
easy-to-clean excipients do not require residual limits of 1/2000 would be well
analytical limit testing to a pre-set limit within the pharmaceutical industry
value. standard while residual limits of
1/10000 could be considered a
Establish acceptance possible cleaning over-kill and a costly
criteria sanitation procedure for standard
routine drug manufacturing processes.
and residual limits
The purpose of a cleaning validation is
for the cleaning to obtain documented evidence that the
process cleaning procedure of the firm will
provide a high degree of assurance
Maximum cleaning limits that the overall cleaning process will
The maximum residual limits of active effectively remove, to a predefined
limit, active product and cleaning agent
material A is acceptable when it is
residues from all the processing
present at a 1 in 1000 part in product B
equipment used, for the purpose of
and when expressed as a function of
establishing the absence of product-to-
the therapeutic ratio (TR) of product B.
product cross-contamination.
What is the TR of a product ?
The therapeutic ratio is the lowest Set detergent
marketing dose (LMD) divided by the
maximum daily dose for the intended residual limits to
1 in 1000 of its
purpose (i.e. LMD / MDD). The LMD is
in fact for all purposes the lowest
therapeutic dose of the active drug
substance, for the intended clinical
lowest toxic dose
indications.
This implies that the cleaning methods
Occasionally vitamins or steroid used are effective in removing all
hormones such as methoxy- product and cleaning residues that are
progesterone are available for widely in direct contact with the equipment
varying clinical indications. In the surface areas during the manufacturing
steriod example both 2.5 mg / 5 mg / process.
10mg and 100mg tablets are available.

Handbook of Pharmaceutical Sect: 12.3

12.3 Generic Development
 ORAL TABLETS CLEANING LIMITS CHAPTER 12

For cleaning detergent limits, a similar ratio employs current medical opinion
end point marker is used by along with appropriate safety factors
substituting toxic dose for therapeutic and allows a firm to defend its overall
dose. The cleaning detergent limit may cleaning program during regulatory
be defined or written as: review. Furthermore it allows the R&D
“the maximum contamination of detergent to development and coordinate and
residuals in the maximum daily dose for the standardize the scientific rationale for a
next product will not be more than 1/1000 cleaning validation program in all future
of its lowest toxic dose (LTD). ” product development.

The LTD is the recorded LD50 of the Residual limits

detergent’s active material obtainable
from the published literature.
are always based
Using the above wording as a standard on the lowest
written format, the acceptance criteria
for the residual limits of any active raw therapeutic dose
material after the cleaning process has It is essential that cleaning limits are
been completed may be defined as:
independent of the dosage strength of
“ the maximum contamination limit of the contaminating material - thus a 30,
the residual active drug from the 60, and 120 mg Diltiazem granulate, all
previous product (A) expressed in terms have the same cleaning limits. This is a
of the maximum daily dose for the next further safety factor as the clean
product (B) will not be more than 0.1% formula uses the lowest marketing dose
of Product A’s lowest labeled strength (i.e. 30 mg Diltiazen is used in each
(LLS) ” calculation and is known as the lowest
labeled strength (LLS)).
In the case where the next batch lot is
not known (in R&D / development units)
The amount of residual Diltiazen
or production cleaning is performed contaminating the next batch will be the
independently of the production same for granulates of 30 mg to 120
scheduling, the QA department should mg strength.
apply a worst case product scenario. To simplify the cleaning validation
The calculation variables for the firm’s program the firms products may be
granulation-tabletting line would be: grouped according to common
• the Lowest Label Strength of parameters (the active’s solubility and
previous product A specific dosage form - i.e. tablets with
• the largest therapeutic ratio [TR] water soluble actives) and an
• calculated at 1/1000 parts. appropriate limit for a worst case
cleaning model evaluated using the
above safety ratios for developing limits
Cleaning Limit = LLSA x TR
based on the medical risk assessment
(in mcg) 1000
of the firms current products.
TR = The Lowest Marketed Dose From these worst case variables a
(LMD) divided by the Total Daily Dose target cleaning limit may be calculated
(TDD). Obtained from the medical with ease and presented in a simplified
literature for the products intended form as shown.
indication profile. Calculations- The calculation to
The state-of-the-art scientific rationale determine the limit of residuals in the
using the concept of the therapeutic next known product for oral dosage
forms is given below:

Handbook of Pharmaceutical Sect: 12.4

12.4 Generic Development
 ORAL TABLETS CLEANING LIMITS CHAPTER 12

CLEAN Equation. No II. depressive tablet in which the products

package insert (product leaflet) allows
Clean Limits = LLSA x LSB
for a maximum administration of 2
(in mcg / dose) 1000 x MDD
tablets every 6 hours - i.e. a total of 8
mg in 24 hours. Thus the MDD is 8mg.
Where:
CL = Residuals of A in mcg per
dosage unit of Product B Worst case calculation:
LLSA = Lowest Label Strength of The therapeutic ratio for the firms
product A expressed in mg. ‘worst case’ scenario is thus 1:8 which
LSB = Label strength of product B is a fixed value.
(mg) Therefore the equation II simplifies to:
1000 = Reduction factor of 1/1000
MDD = Maximum Daily Dose of B (mg) CLEAN Equation. No IV.

A = Last manufactured product Clean Limits = LLS(A)

B = Next manufactured product (in mcg/dose) 8000

Calculations for a ‘worst case’ The equation may be expressed in

scenario. words as:
The calculation to determine the limit of The limit of residuals (expressed as
residuals in the next unknown product mcg per dose) in a ‘worst case’
(N) for oral dosage forms is given as scenario for the next manufactured
follows: product is 1/8000th of the last
CLEAN Equation. No III. manufactured product’s lowest labeled
strength expressed in mgs.
Clean Limits = LLSA x
LSN The equation may be further expressed
(in mcg/dose) 1000 x MDD for daily use in the cleaning and QA
departments as a much simplified
Where: arithmetic formula - the limit of
CL = Residuals of A in mcg per allowable residuals after cleaning,
dosage unit of Product N. stated in micrograms is 1/8 of the last
LLSA = label strength of product A manufactured product’s mg labeled
(mg) strength.
LSN = label strength of product N (mg) Establishing the largest therapeutic
1000 = Reduction factor 1/1000
range (LMD / MDD) and expressing as
MDD = Maximum Daily Dose of N
a ratio may seldom exceed the value of
A = Last Manufactured Product.
N = Product with largest therapeutic 1: 8.
ratio (LMD / MDD). This procedure permits the QA
LMD = Lowest Marketing Dose department to evaluate the cleaning
procedure to a routine standard limit
Firms can rapidly establish from their (mcg / dose) of 1/8000th of the last
product lists the largest therapeutic batch’s lowest labeled strength. 3
ratio (LMD / MDD) of products
processed in the plant. References:
1. USP/NF XXIII USPC Rockville Maryland USA
Lets show how simple this formula 1994.
2. Scale up and Post approval Changes
works in practice. The Company Manufacturing and Controls In vitro Dissolution and
examines its product profile and finds In Vivo Bioequivalence Documentation CDER 1995
that it markets a potent 1.0 mg anti- (SUPAC)

Handbook of Pharmaceutical Sect: 12.5

12.5 Generic Development
 ORAL TABLETS CLEANING LIMITS CHAPTER 12

ØC H E C K L I S T ×
SOP #P-HGD-03-01Y2K

Cleaning Limits & Procedures

ACTIVE AND EXCIPIENTS
‘...Set active and detergent residual limits
and clean to this target level...’

1. Is there is a written cleaning procedure for every processing unit? qYes qNo

2. Is there a written cleaning procedure for all auxiliary equipment? qYes qNo

3. Cleaning procedures require rapid equipment flushing, immediately qYes qNo

after manufacture to prevent products from drying and becoming more
difficult to clean?
4. After each manual cleaning procedure a quantitative rapid test qYes qNo
procedure is used to evaluate the cleaning process ?
5. When ever there is a detergent; formulation; cleaning equipment or qYes qNo
procedures change, the cleaning process requires to be re-validated ?
6. Operators are initially qualified and periodically thereafter re- qYes qNo
qualified to ensure satisfactory cleaning procedure performances ?
7. Cleaning procedures are performed after maintenance / calibration qYes qNo
periods?
8. Cleaning procedures are performed after shut-down periods? qYes qNo

9. Cleaning re-validation is performed after persistent microbial levels qYes qNo

are obtained, in excess of ‘alert’ or ‘warning’ limits ?
10. Visual examination, surface swabs and final rinse water analysis qYes qNo
are collectively used to test for permissible residual limits?
11. Final rinse water analysis is only used for soluble active materials qYes qNo
as a routine QC monitoring procedure?
12. Aqueous (Purified Water USP) and non-aqueous (alcohol) solvents qYes qNo
are used to wet the swabs - dependent on the nature and solubility of the
active and excipients?
13. Standard swabs (e.g. Whatmans # 4™, 9.0 cm filter paper) are qYes qNo
used?
14. A standardized surface area (approx. 0.1 - 0.2 m2 ) is wiped in a qYes qNo
unidirectional manner with the swab?
15. Cleaning procedure manuals or SOPs highlight ‘hard to clean’ qYes qNo
areas such as valves, threads, seals, shafts and mixer blades - where
product may accumulate and remain static after cleaning? These ‘hard to
clean’ areas are evaluated during the cleaning validation procedure ?

Handbook of Pharmaceutical Sect: 12.6

12.6 Generic Development
 ORAL TABLETS CLEANING LIMITS CHAPTER 12

ØC H E C K L I S T ×
SOP #P-HGD-03-01Y2K

Cleaning Limits & Procedures

ACTIVE AND EXCIPIENTS
‘Detailed visual checking by cleaning operator and
supervisor is a cGMP requirement ’

16.The 1/1000 of the lowest marketing dose (LMD) are the acceptable qYes qNo
active material residue limits ?
17.The 1/1000 of the LD50 are the acceptable detergent residue limits? qYes qNo

18. Wiping-solvents for cleaning swabs are specifically pre-determined qYes qNo
for each active material - subject to whether it's water soluble or insoluble?
19. Purified Water USP is the wiping solvent for most detergents? qYes qNo

20. Rapid assessment of equipment cleanliness after manual qYes qNo

procedures is achieved by simple analytical test methods ?
21. High pressure hot water jets and steam jets are available in the qYes qNo
cleaning area?
22. The final rinse water is Purified Water USP ? qYes qNo

23. Maximum time limits prior to cleaning have been established ? qYes qNo

24. Maximum time limits between equipment cleaning and sampling qYes qNo
have been established to avoid post-cleaning sampling errors ?
25. Maximum time limits between equipment cleaning and next batch qYes qNo
production have been established?
Use a combination of swabs and rinse waters tests
26. Equipment covers are used to protect exposed cleaned surfaces qYes qNo
during storage between batches (portable mixers etc.)?
27. Detergent concentration is standardized for soluble and non- qYes qNo
soluble active materials ?
28. Where applicable detergents and chlorine bleach are used qYes qNo
together?
29. Where applicable detergents and hydrogen peroxide are used qYes qNo
together?
30. Disposable clean cloths or filtered hot air is used for drying qYes qNo
equipment ?
31. Residual rinse waters are completely removed, after cleaning ? qYes qNo

Handbook of Pharmaceutical Sect: 12.7

12.7 Generic Development
 ORAL TABLETS CLEANING LIMITS CHAPTER 12

STANDARD OPERATING
PROCEDURES
SOP #P-HGD-03-01Y2K Page 1 of 1.

CLEANING VALIDATION
…‘Time limits before and after cleaning must be laid down
in writing…’

Cleaning Validation Requirements

The following Standard Operating Procedures are recommended for a generic
development unit :

Cleaning Validation SOPs

P- HB -01-01Y2K Cleaning validation requirements for non-sterile manufacturing.
P- HB -01-01Y2K Aspects of tablet cleaning validation.
P- HB -01-01Y2K Equipment cleaning verification.
P- HB -01-01Y2K Serial (minor) and non-serial (major) equipment cleaning.
P- HB -01-01Y2K Reserved.

4
[End of Document

ED. N0: 02 Effective Date:

Replaces Ed 01.
APPROVED:
Ed. Status: MM/DD/2000
Operational
Department R&D QC QA

Handbook of Pharmaceutical Sect: 12.8

12.8 Generic Development
 ORAL TABLETS CLEANING LIMITS CHAPTER 12

CLEANING DEVELOPMENT

Cleaning Procedures
as the FDA See It
‘…These guidelines are intended for Bulk Pharmaceutical
Chemicals but almost every word applies to Drug Products…

BPC CLEANING (& Drug Products) This guide is intended to cover

equipment cleaning for chemical
GUIDE TO INSPECTIONS residues only.
VALIDATION OF CLEANING II. BACKGROUND
PROCESSES For FDA to require that equipment be
clean prior to use is nothing new, the
I. INTRODUCTION 1963 GMP Regulations (Part 133.4)

V
alidation of cleaning procedures stated as follows "Equipment… shall
has generated considerable be maintained in a clean and orderly
discussion since agency manner…." A very similar section on
documents, including the Inspection equipment cleaning (211.67) was
Guide for Bulk Pharmaceutical included in the 1978 cGMP
Chemicals and the Biotechnology regulations.
Inspection Guide, have briefly Of course, the main rationale for
addressed this issue.
requiring clean equipment is to
CLEANING prevent contamination or adulteration
of drug products.
PROCEDURES Historically, FDA investigators have
must be validated looked for gross non-sanitation due to
inadequate cleaning and maintenance
These Agency documents clearly of equipment and/or poor dust control
establish the expectation that cleaning systems.
procedures (processes) be validated.
This guide is designed to establish
CLEANING
inspection consistency and uniformity PROCEDURES
must consistently
by discussing practices that have
been found acceptable (or
unacceptable). Simultaneously, one
must recognize that for cleaning meet the limits set
validation, as with validation of other Also, historically speaking, FDA was
processes, there may be more than more concerned about the
one way to validate a process. contamination of non-penicillin drug
In the end, the test of any validation products with penicillins or the cross-
process is whether scientific data contamination of drug products with
shows that the system consistently potent steroids or hormones.
does as expected and produces a A number of products have been
result that consistently meets recalled over the past decade due to
predetermined specifications.

Handbook of Pharmaceutical Sect: 12.9

12.9 Generic Development
 ORAL TABLETS CLEANING LIMITS CHAPTER 12

actual or potential penicillin cross- FDA instituted an import alert in 1992

contamination. on a foreign bulk pharmaceutical
PAST HISTORY - 'The Resin Story' manufacturer which manufactured
One event which increased FDA potent steroid products as well as
awareness of the potential for cross non-steroidal products using common
contamination due to inadequate equipment.
procedures was the 1988 recall of a This firm was a multi-use bulk
finished drug product, Cholestyramine pharmaceutical facility. FDA
Resin USP. considered the potential for cross-
The bulk pharmaceutical chemical contamination to be significant and to
used to produce the product had pose a serious health risk to the
become contaminated with low levels public.
of intermediates and degradants from The firm had only recently started a
the production of agricultural cleaning validation program at the
pesticides. time of the inspection and it was
The cross-contamination in that case considered inadequate by FDA.
is believed to have been due to the
reuse of recovered solvents. The
One of the reasons it was considered
inadequate was that the firm was only
recovered solvents had been
looking for evidence of the absence of
contaminated because of a lack of
the previous compound. The firm had
control over the reuse of solvent
evidence, from TLC tests on the rinse
drums.
water, of the presence of residues of
Solvent Recovery reaction byproducts and degradants
Storage Drums from the previous process.

were used twice III. GENERAL REQUIREMENTS

without cleaning limits FDA expects firms to have written
Drums that had been used to store procedures (SOPs) detailing the
cleaning processes used for various
recovered solvents from a pesticide
pieces of equipment.
production process were later used to
If firms have one cleaning process for
store recovered solvents used for the
cleaning between different batches of
resin manufacturing process.
the same product and use a different
The firm did not have adequate process for cleaning between product
controls over these solvent drums, did changes, we expect the written
not do adequate testing of drummed procedures to address these different
solvents, and did not have validated scenario.
cleaning procedures for the drums.
Some shipments of this pesticide Minor Cleaning
contaminated bulk pharmaceutical Same Product
were supplied to a second facility at a
different location for finishing. This
resulted in the contamination of the
Major Cleaning
bags used in that facility's fluid bed Different Product
dryers with pesticide contamination. Similarly, if firms have one process
This in turn led to cross contamination for removing water soluble residues
of lots produced at that site, a site and another process for non-water
where no pesticides were normally soluble
produced. residues, the written procedure should

Handbook of Pharmaceutical Sect: 12.10

12.10 Generic Development
 ORAL TABLETS CLEANING LIMITS CHAPTER 12

address both scenarios and make it - FDA expects firms to conduct the
clear when a given procedure is to be validation studies in accordance with
followed. written cleaning protocols and to
Cleaning SOP document the results of studies.
- FDA expects a final validation
Water Soluble Residues report which is approved by
Cleaning SOP management and which states
whether or not the cleaning process is
Non-Soluble Residues valid.
Bulk pharmaceutical firms may decide The data should support a conclusion
to dedicate certain equipment for that residues have been reduced to an
certain chemical manufacturing "acceptable level."
process steps that produce tarry or IV. EVALUATION OF CLEANING
gummy residues that are difficult to VALIDATION
remove from the equipment. The first step is to focus on the
Fluid bed dryer bags are another objective of the validation process,
example of equipment that is difficult and we have seen that some
to clean and is often dedicated to a companies have failed to develop
specific product. Any residues from such objectives.
the cleaning process itself It is not unusual to see manufacturers
(detergents, solvents, etc.) also have use extensive sampling and testing
to be removed from the equipment. programs following the cleaning
Cleaning Limits process without ever really evaluating
the effectiveness of the steps used to
For 'Active Residues' clean the equipment.
Several questions need to be
& Limits addressed when evaluating the
For 'Cleaning Agents' cleaning process. For example:
Q. At what point does a piece of
What Do The FDA Expect equipment or system become clean?
- FDA expects firms to have written Q. Does it have to be scrubbed by
general procedures on how cleaning hand?
processes will be validated. Q. What is accomplished by hand
- FDA expects the general validation scrubbing rather than just a solvent
procedures to address who is wash?
responsible for performing and Q. How variable are manual cleaning
approving the validation study, the processes from batch to batch and
acceptance criteria, and when product to product?
revalidation will be required. The answers to these questions are
- FDA expects firms to prepare obviously important to the inspection
specific written validation protocols in and evaluation of the cleaning process
advance for the studies to be since one must determine the overall
performed on each manufacturing effectiveness of the process.
system or piece of equipment which Answers to these questions may also
should address such issues as identify steps that can be eliminated
sampling procedures, and analytical for more effective measures and result
methods to be used including the in resource savings for the company.
sensitivity of those methods.

Handbook of Pharmaceutical Sect: 12.11

12.11 Generic Development
 ORAL TABLETS CLEANING LIMITS CHAPTER 12

Determine the number of cleaning Also check the written and validated
processes for each piece of cleaning process to determine if these
equipment. systems have been properly identified
Ideally, a piece of equipment or and validated.
system will have one process for
cleaning, however this will depend on LIST ALL
the products being produced and
whether the cleanup occurs between Complex Cleaning
batches of the same product (as in a processes and
large campaign) or between batches
of different products. Validate
Minor Cleaning In larger systems, such as those
employing long transfer lines or
of Same Product piping, check the flow charts and
Does not Require piping diagrams for the identification
of valves and written cleaning
Validation or Limits procedures.
W hen the cleaning process is used Piping and valves should be tagged
only between batches of the same and easily identifiable by the operator
product (or different lots of the same performing the cleaning function.
intermediate in a bulk process) the Sometimes, inadequately identified
firm need only meet a criteria of, valves, both on prints and physically,
"visibly clean" for the equipment. have led to incorrect cleaning
Such between batch cleaning practices.
processes do not require validation
('Minor Clean'). LIST Maximum
1. Equipment Design
Examine the design of equipment, Time Limits Allowable
particularly in those large systems that Between Process End
may employ semi-automatic or fully
automatic clean-in-place (CIP) and Start of Cleaning
systems since they represent
significant concern. Always check for the presence of an
For example, sanitary type piping often critical element in the
without ball valves should be used. documentation of the cleaning
processes; identifying and controlling
When such non-sanitary ball valves
the length of time between the end of
are used, as is common in the bulk
processing and each cleaning step.
drug industry, the cleaning process is
more difficult. This is especially important for
W hen such systems are identified, it topicals, suspensions, and bulk
is important that operators performing drug operations.
cleaning operations be aware of In such operations, the drying of
problems and have special training in residues will directly affect the
cleaning these systems and valves. efficiency of a cleaning process.
Determine whether the cleaning W hether or not CIP systems are used
operators have knowledge of these for cleaning of processing equipment,
systems and the level of training and microbiological aspects of equipment
experience in cleaning these systems. cleaning should be considered.

Handbook of Pharmaceutical Sect: 12.12

12.12 Generic Development
 ORAL TABLETS CLEANING LIMITS CHAPTER 12

This consists largely of preventive system that requires some type of

measures rather than removal of specific documentation for performing
contamination once it has occurred. each step.
Depending upon the complexity of the
There should be some evidence that system and cleaning process and the
routine cleaning and storage of ability and training of operators, the
equipment does not allow microbial amount of documentation necessary
proliferation. for executing various cleaning steps or
For example, equipment should be procedures will vary.
dried before storage, and under no
circumstances should stagnant water W hen more complex cleaning
be allowed to remain in equipment procedures are required, it is
subsequent to cleaning operations. important to document the critical
cleaning steps (for example certain
Protect bulk drug synthesis processes).
'Cleaned Equipment' In this regard, specific documentation
on the equipment itself which includes
from subsequent information about who cleaned it and
microbial contamination when is valuable.
However, for relatively simple cleaning
Subsequent to the cleaning process, operations, the mere documentation
equipment may be subjected to that the overall cleaning process was
sterilization or sanitization procedures performed might be sufficient.
where such equipment is used for Other factors such as history of
sterile processing, or for non-sterile cleaning, residue levels found after
processing where the products may cleaning, and variability of test results
support microbial growth. may also dictate the amount of
W hile such sterilization or sanitization documentation required.
procedures are beyond the scope of
this guide, it is important to note that 'Clean Equipment'
control of the bioburden through to a specific
adequate cleaning and storage of
equipment is important to ensure that residue limit
subsequent sterilization or sanitization For example, when variable residue
procedures achieve the necessary levels are detected following cleaning,
assurance of sterility. particularly for a process that is
This is also particularly important from believed to be acceptable, one must
the standpoint of the control of establish the effectiveness of the
pyrogens in sterile processing since process and operator performance.
equipment sterilization processes may
not be adequate to achieve significant
Appropriate evaluations must be
made and when operator performance
inactivation or removal of pyrogens.
is deemed a problem, more extensive
2. Cleaning Process Written documentation (guidance) and training
Procedure and Documentation may be required.
Examine the detail and specificity of
3. Analytical Methods
the procedure for the (cleaning)
Determine the specificity and
process being validated, and the
sensitivity of the analytical method
amount of documentation required.
used to detect residuals or
W e have seen general SOPs, while contaminants. Current advances in
others use a batch record or log sheet analytical technology, can detect

Handbook of Pharmaceutical Sect: 12.13

12.13 Generic Development
 ORAL TABLETS CLEANING LIMITS CHAPTER 12

residues from the manufacturing and are satisfactory and can be readily
cleaning processes at very low levels. used.
If levels of contamination or residual Advantages of direct sampling are
are not detected, it does not mean that that areas hardest to clean and which
there is no residual contaminant are reasonably accessible can be
present after cleaning. It only means evaluated, leading to establishing a
that levels of contaminant greater than level of contamination or residue per
the sensitivity or detection limit of the given surface area.
analytical method are not present in Additionally, residues that are "dried
the sample. out" or are insoluble can be sampled
Firms should challenge the analytical by physical removal.
method in combination with the [b]. RINSE SAMPLES
sampling method(s) used to show that Two advantages of using rinse
contaminants can be recovered from
samples are that a larger surface area
the equipment surface and at what
may be sampled, and inaccessible
level, i.e. 50% recovery, 90%, etc.
systems or ones that cannot be
This is necessary before any routinely disassembled can be
conclusions can be made based on sampled and evaluated.
the sample results. A negative test A disadvantage of rinse samples is
may also be the result of poor that the residue or contaminant may
sampling technique (see below). not be soluble or may be physically
4. Sampling occluded in the equipment.
There are two general types of An analogy that can be used is the
sampling that have been found "dirty pot." In the evaluation of
acceptable. The most desirable is the cleaning of a dirty pot, particularly with
direct method of sampling the surface dried out residue, one does not look at
of the equipment. Another method is the rinse water to see that it is clean;
the use of rinse solutions. one looks at the pot.
Surface Cleaning Check the Baby
can be checked by not the
Surface Swabs Bath Water
or Check to see that a direct

Rinse Samples measurement of the residue or

contaminant has been made for the
[a]. Direct Surface Sampling - rinse water when it is used to validate
Determine the type of sampling the cleaning process.
material used and its impact on the For example, it is not acceptable to
test data since the sampling material simply test rinse water for water
may interfere with the test. For quality (does it meet the compendia
example, the adhesive used in swabs tests) rather than test it for potential
has been found to interfere with the contaminates.
analysis of samples. c. Routine In-Process Control
Therefore, early in the validation Monitoring - Indirect testing, such as
program, it is important to assure that conductivity testing, may be of some
the sampling medium and solvent value for routine monitoring once a
(used for extraction from the medium) cleaning process has been validated.

Handbook of Pharmaceutical Sect: 12.14

12.14 Generic Development
 ORAL TABLETS CLEANING LIMITS CHAPTER 12

This would be particularly true for the In establishing residual limits, it may
bulk drug substance manufacturer not be adequate to focus only on the
where reactors and centrifuges and principal reactant since other chemical
piping between such large equipment variations may be more difficult to
can be sampled only using rinse remove.
solution samples. There are circumstances where TLC
Any indirect test method must have screening, in addition to chemical
been shown to correlate with the analyses, may be needed. In a bulk
condition of the equipment. process, particularly for very potent
During validation, the firm should chemicals such as some steroids, the
document that testing the uncleaned issue of by-products needs to be
equipment gives a not acceptable considered if equipment is not
result for the indirect test. dedicated.
V. ESTABLISHMENT OF LIMITS The objective of the inspection is to
FDA does not intend to set ensure that the basis for any limits is
acceptance specifications or methods scientifically justifiable.
for determining whether a cleaning VI. OTHER ISSUES
process is validated. It is impractical a. Placebo Product
for FDA to do so due to the wide In order to evaluate and validate
variation in equipment and products cleaning processes some
used throughout the bulk and finished manufacturers have processed a
dosage form industries. placebo batch in the equipment under
The firm's rationale for the residue essentially the same operating
limits established should be logical parameters used for processing
based on the manufacturer's product.
knowledge of the materials involved A sample of the placebo batch is then
and be practical, achievable, and tested for residual contamination.
verifiable.
It is important to define the sensitivity
Testing a
of the analytical methods in order to Placebo Batch
set reasonable limits.
Some limits that have been may only be
mentioned by industry representatives
in the literature or in presentations
Supportive Data
include analytical detection levels However, we have documented
such as 10 PPM, biological activity several significant issues that need to
levels such as 1/1000 of the normal be addressed when using placebo
therapeutic dose, and organoleptic product to validate cleaning
levels such as no visible residue. processes.
One cannot assure that the
Check the manner in which limits are contaminate will be uniformly
established. Unlike finished distributed throughout the system.
pharmaceuticals where the chemical
identity of residuals are known (i.e., For example, if the discharge valve or
from actives, inactives, detergents) chute of a blender are contaminated,
bulk processes may have partial the contaminant would probably not
reactants and unwanted by-products be uniformly dispersed in the placebo;
which may never have been it would most likely be concentrated in
chemically identified. the initial discharge portion of the
batch.

Handbook of Pharmaceutical Sect: 12.15

12.15 Generic Development
 ORAL TABLETS CLEANING LIMITS CHAPTER 12

Additionally, if the contaminant or They test, resample, and retest

residue is of a larger particle size, it equipment or systems until an
may not be uniformly dispersed in the "acceptable" residue level is attained.
placebo. For the system or equipment with a
Some firms have made the validated cleaning process, this
assumption that a residual practice of resampling should not be
contaminant would be worn off the utilized and is acceptable only in rare
equipment surface uniformly; this is cases.
also an invalid conclusion. Constant retesting and resampling
Finally, the analytical power may be can show that the cleaning process is
greatly reduced by dilution of the not validated since these retests
contaminate. Because of such actually document the presence of
problems, rinse and/or swab samples unacceptable residue and
should be used in conjunction with the contaminants from an ineffective
placebo method. cleaning process.
b. Detergent
If a detergent or soap is used for
Repeat Testing to
cleaning, determine and consider the
difficulty that may arise when
'Clean Compliance'
attempting to test for residues. is NOT the
A common problem associated with
detergent use is its composition. Many
detergent suppliers will not provide
Route to Go
specific composition, which makes it
difficult for the user to evaluate REFERENCES
residues. 1) J. Rodehamel, "Cleaning and Maintenance,"
Pgs 82-87, University of Wisconsin's Control
As with product residues, it is Procedures in Drug Production Seminar, July 17-
important and it is expected that the 22, 1966, William Blockstein, Editor, Published by
manufacturer evaluate the efficiency the University of Wisconsin, L.O.C.#66-64234.
of the cleaning process for the 2) J.A. Constance, "Why Some Dust Control
removal of residues. Exhaust Systems Don't Work," Pharm. Eng.,
January-February, 24-26 (1983).
However, unlike product residues, it is 3) S.W. Harder, "The Validation of Cleaning
expected that no (or for ultra sensitive Procedures," Pharm. Technol. 8 (5), 29-34 (1984)
analytical test methods - very low) 4) W.J. Mead, "Maintenance: Its Interrelationship
detergent levels remain after cleaning. with Drug Quality," Pharm. Eng. 7(3), 29-33
(1987).
Detergents are not part of the
5) J.A. Smith, "A Modified Swabbing Technique for
manufacturing process and are only Validation of Detergent Residues in Clean-in-Place
added to facilitate cleaning during the Systems," Pharm. Technol. 16(1), 60-66 (1992).
cleaning process. 6) Fourman, G.L. and Mullen, M.V., "Determining
c. Test Until Clean Cleaning Validation Acceptance Limits for
Pharmaceutical Manufacturing Operations,"
Examine and evaluate the level of Pharm. Technol. 17(4), 54-60 (1993).
testing and the retest results since
7) McCormick, P.Y. and Cullen, L.F., in
testing until clean is a concept utilized Pharmaceutical Process Validation, 2nd Ed.,
by some manufacturers. edited by I.R. Berry and R.A. Nash, 319-349
(1993)
Note: How the Agency view this cleaning document:
This document is reference material for investigators and other FDA personnel. The document does not bind
FDA, and does no confer any rights, privileges, benefits, or immunities for or on any person(s).

Handbook of Pharmaceutical Sect: 12.16

12.16 Generic Development
 ORAL TABLETS ANALYTICAL CHAPTER 13

Analytical
However validation of new generic
products in the pipeline may not have
an official assay method.

Validation
A totally new assay method possibly
based on a Pharmacopeial Forum
methodology is adapted in-house for
Analytical Validation - a working assay as well as for stability indicating
validation protocol for HPLC system. testing methodology.

A nalytical assay validation of the

generic drug active material
requires to be evaluated
New HPLC methods require complete
validation whether the method
reasonable early in the drug originates from an outside
development process. In many cases manufacturer, whether developed in-
the Official USP assay (if available at house or adapted from the literature.
the time) is not really a stability
indicating testing procedure.
What to validate?
⇒ Assays
This article provides an example (for
tablets) of a typical hand-on analytical ⇒ Stability Assays
⇒ Impurity Package
validation for in-house HPLC methods
that may or…

Official USP ⇒ Dissolution

Analytical method for when in-house.
well known actives These procedures ensure that the
are not generally Product Development Process of the
stability- indicating generic drug up to the Process
Qualification Batch testing is based on
test methods as well a foundation of Good Laboratory
Practice, using validated test method
may not be based on official USP
procedures.
methodology, as well as showing that
these methods are stability-indicating. Analytical Product Development.
Validation terms used frequently by Ruggedness testing validates the
technical transfer of the methodology to
different pharmaceutical and analytical
the Quality Control laboratory at the
researchers may have different
commercial manufacturing site.
meanings in different research
departments. Terms used here are In-house analytical validation applies to
defined in a real-life HPLC context. each non-compendial analytical assay
When a methods is based on the USP method intended for ANDA (or OTC-
official method but is modified in-house ANDA) manufactured products.
for stability indicating test purposes, it Validation also applies to Stability-
requires a full in-house validation Indicating Assays and limit testing of
procedure. This is often the preferred impurities based on compendia
route most generic labs follow. methods.

ED. N0: 02 Effective Date:

Replaces Ed 01.
APPROVED:
Ed. Status: MM/DD/2000
Operational
Department R&D QC QA
Handbook of Pharmaceutical Sect: 13.1
13.1 Generic Development
 ORAL TABLETS ANALYTICAL CHAPTER 13

and the assay value the analyst should

Analytical obtain. It simply implies freedom of

error. In a development laboratory
validation protocol, accuracy may often
A spects be expressed simply as the percent
recovery (with a zero bias) by the assay
E ach Product strength will follow a
full method validation procedure.
One general all purpose analytical
of known added amounts of the active
analyte.
validation is not sufficient for multiple Bias needs to be understood in
dosage strengths (e.g. 200, 400 800mg analytical accuracy. Drawing an
tablets) as sample aliquots, ranges and example from the game of throwing
linearity data may change as a function darts, accuracy is an all important
of the dosage strength. factor, this means getting all the darts
tightly clustered around the bulls-eye -
Method Validation right in the center 50-point ring!
Non-compendial method validation
usually follows the USP direction for Placing all the darts in a neat tight
parameters needed for the validation of circle at three-0-clock is precise
test methods. throwing but not accurate. There is a
Typical parameters for validating positive bias in the true mean of the
dart's results and the real true value
assays and other non-compendial
actually required - i.e. the bulls-eye!
analytical methods designed for
providing quantitative reproducible Thus bias is simple the error between
results include: the mean of the analytical HPLC assay
results obtained and their true value.
♦ Accuracy
Bias may be positive or negative
♦ Recovery (assays with a mean of 102.4% show a
positive bias while an assay reading
♦ Precision 97.9% yields a negative bias).
(Repeatability, Reproducibility and Bias is important for release and
Intermediate precision (ruggedness) stability check specifications assays as
♦ Specificity the product may indeed fail, not due to
a sub-potent assay, but simply a biased
♦ Linearity analysis.
♦ Range Frequent revalidation
♦ 1
Ruggedness & Robustness of analytical assay
methods is an
1
(Two analysts on different days using
different equipment models / columns).
essential procedure
Terms used in analytical validation
should be defined as the reviewer may for detecting bias
need a clear definition from the author Precision - may be of a method - or
for all values submitted. Typical the precision of the HPLC system i.e.
definitions are:
system precision.
Accuracy - This is the degree of
The precision of the system removes
correlation of the HPLC assay result to
the true value (also called trueness) the potential sampling error.

ED. N0: 02 Effective Date:

Replaces Ed 01.
APPROVED:
Ed. Status: MM/DD/2000
Operational
Department R&D QC QA
Handbook of Pharmaceutical Sect: 13.2
13.2 Generic Development
 ORAL TABLETS ANALYTICAL CHAPTER 13

Analytical been demonstrated in the method

validation. In most cases the
A spects injected volume will display a linear
response - however the need to
The Precision of the System demonstrate the full range in the
Is defined as the degree of method linearity is essential.
agreement among the individual
assay results when the assay step is Linearity of an HPLC test method is
applied to replicates of the standard its ability of the HPLC detector to
(volumetric) preparation (i.e. the elicit a response that is directly
variation due to sampling is proportional to the concentration of
eliminated) - this sampling variation the analyte in the sample in the
may be significant in tablet chosen range e.g. 50-150%.
granulation material or semi-solid Linearity may require a trans-
dosage forms. formation equation to show
proportionality.
Method precision
The range of a test method is
includes sampling demonstrated as the interval
error between the upper (150%) and lower
levels (50%) of the analyte to be
The ‘precision of a method’ is
injected into the HPLC that shows
challenged by including the sampling
linearity as well as accuracy and
error in an homogeneous sample or
precision. A fixed volume loop must
composite of samples. No granulate
be within the chosen range.
material is perfectly homogeneous
thus the ‘precision of the method’ is Peaks must be
detecting both the minor variations in
homogeneous.
the homogeneity of the sample and
the precision of the HPLC system, Not a mixture of
due to minor detector, pump, co-eluting peaks
mechanical and electronic
fluctuations. Peak Homogeneity is a
Precision of a method is defined as chromatographic term. A peak is
the degree of agreement between homogeneous if it corresponds to a
individual HPLC test assay results single chemical entity i.e. it is not a
when the analytical method mixture of co-eluting peaks possibly
procedure is applied repeatedly to derived from impurities or the
multiple samplings of a homo- placebo excipients.
geneous sample of composite. Placebo Analysis.
A frequent error cited by the agency A mixture of non-actives (placebo) is
inspectors deals with linearity and prepared and subjected to HPLC
range. Laboratory HPLC analysts analysis.
inject amounts that are outside the Normally no interfering peaks are
range for which the linearity of the observed in the graph of the placebo
test method has chromatogram.

ED. N0: 02 Effective Date:

Replaces Ed 01.
APPROVED:
Ed. Status: MM/DD/2000
Operational
Department R&D QC QA
Handbook of Pharmaceutical Sect: 13.3
13.3 Generic Development
 ORAL TABLETS ANALYTICAL CHAPTER 13

Where interfering peaks are During the production process in the

observed, their position should be manufacture of the drug product,
noted as well as checked that no abnormal heat stress may be present
reinforcement of the active peak is due to heat produced by fluidized
present - resulting in biased or bed dryers, tray ovens, or heat
skewed assay results. generated by high shear mixers, at
Standard Solution - Stability. - Take maximum settings.
care to evaluate the stability of the
Standard solution. It is assessed by Take care that the
re-injection of the standard solution product and the placebo
again after the said period of days are stressed to realistic
the standard will be used and
comparing with the original values.
abnormal production
Standard Solutions must be stored at heat or hydrolysis
controlled temperatures and light stresses to detect
conditions and so labeled on the flask. extraneous HPLC peaks
Stability Indicating Procedures. Processing Heat Stress
For the Stability Indicating Method,
the product sample shall include The Manufacturing process can
forced degradation by stressed cause ingredient breakdown, giving
analysis. Conditions such as the new extraneous peaks.
concentration and reaction times Care needs to be taken that the
may vary depending on the stability manufacturing process does not
of active drug substance as to introduce high heat stress factors
whether it is thermo or chemolabile. into the in-process bulk product. High
------------------------------------------ speed mixer may create hot spots for
Routine stressed conditions tested a brief time period, while FBD / Tray
are generally the following drying procedures, or maintaining hot
categories: oils, waxes or purified water for a
lengthy period, during topical semi-
♦ Oxidation Stress solid processing, may cause the
[H2O2] plus length of standing time. appearance of new HPLC peaks.
♦ Base Hydrolysis
[NaOH] plus length of standing time.
It may be important in a heat stress
evaluation to run a test to mimic the
♦ Acid Hydrolysis
highest manufacturing operating
[HCl] plus length of standing time.
temperature (plus an extra 20-30%
♦ Sun light Stress degrees C margin) for the duration
6 to 24 hours standing time.
equal to the maximum time period
♦ Heat Stress I required for the largest batch size,
@ T1 oC - abnormal production. processing step (plus 20 - 30%
♦ Heat Stress II added process stress time).
@ T2 oC - active breakdown.

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13.4 Generic Development
 ORAL TABLETS ANALYTICAL CHAPTER 13

Analytical Identify known

degradants, and label
A spects and tag unknown
Specificity and Suitability
degradants and
Resolution and Tailing Factors. impurities
The peak purity of the main peak is
W hen a satisfactory separations of normally given for each stressed
all the degradation peaks have been analysis (determined by peak-slicing
achieved through the forced using diode-array UV detection and
degradation reactions, a Resolution comparing with stressed and
Factor (according to the USP standard references).
requirements) between the main
active peak and the nearest
Validation of limit testing for
degradant peak is calculated using impurity methods shall include :
the USP formula. Specificity and Selectivity
Limit of Detection (LOD / DL)
Stressing Limit of Quantitation (LOQ / QL)
the placebo is often The Detection Limit (DL) is the lowest
ignored when searching concentration of analyte in a sample
for extraneous HPLC that can be reliably detected, but not
necessary accurately quantified with
peaks in stability the method used. DL and QL are
indicating methods specific to the actual method used.
A Tailing Factor (according to the The Limit of Quantitation or
USP formula) is also calculated for Quantitation Limit (LOQ or QL) is a
the main active substance peak. more valuable tool and represents the
Both the resolution and tailing factors lowest concentration of analyte in a
are standard procedures and should sample that can be determined at a
be presented in a standard format in defined precision and accuracy for the
every method validation protocol and test method employed.
report. The LOD and LOQ limit values have
Relative Retention Time of Main and become important parameters in
Additional peaks: analytical aspects of cleaning
In each stressed analysis routinely validation protocols and reports.
indicate the percentage by which the Frequently firms presenting a master
Main peak Is decreased as well as validation cleaning plan or specific
the relative retention time (RRT) for major or minor cleaning protocols for
any other Additional peaks. the various soluble and non-soluble
If the RRT of an Additional Peak classes of active material processed
by the firm - ignore the analytical
corresponds to a known degradant /
aspects of the trace amounts they are
impurity etc. it is stated in the
trying to detect or quantify. 3
analytical validation report.

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13.5 Generic Development
 ORAL TABLETS ANALYTICAL CHAPTER 13

Analytical Aspects I
Validation of analytical methodology
for an HPLC system.
1. PURPOSE
The purpose of this Standard Analytical Procedure is to demonstrate the procedure
required to validate in-house HPLC analytical methods and to show that the methods
are stability-indicating. Methods based on the USP but modified for stability
indicating test purposes require full in-house validation.
This procedure ensures that the Product Development Process and Process
Qualification Batch analysis is based on a foundation of Good Laboratory Practice
using validated test procedures.

2. RESPONSIBILITY
The Head of Analytical Development in coordination with the managers of QC and
Regulatory Affairs at the proposed manufacturing site.

3. FREQUENCY
For each non-compendial analytical method intended for ANDA (or OTC ANDA)
manufactured products.

For Stability-Indicating Assays and limit testing of impurities that may be based on
compendial methods. Each Product strength will follow the full method validation
procedure.

4. PROCEDURE
[a]. Method Validation
Non-compendial methods validation will follow the USP direction for parameters
needed for the validation of test methods.
Typical parameters for validating assays and other non-compendial analytical
methods designed for providing quantitative results shall include :
• Accuracy
• Recovery
• Precision ( System reproducibility, Method reproducibility )
• Specificity
• Linearity
• Range
• Ruggedness (different analysts / days /different equipment models / columns)

[b]. Placebo Analysis.

A mixture of non-actives (placebo) shall be prepared and subjected to analysis.
No interfering peaks shall be observed in the graph of the placebo chromatogram.
[c]. The stability of the Standard solution is assessed by re-injection of the
standard solution after 24 x n hours (where n = number of days the Standard will be
used).

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 ORAL TABLETS ANALYTICAL CHAPTER 13

Standard Preparation for Assay

Comparison of standard solutions for Assay of Active material, injected after say 3
days / one week and freshly prepared solutions demonstrate that the standard
solutions are stable and do not lose its potency after the above period of
refrigeration.
Standard Preparation for Impurity
Comparison of standard solutions of (Guanine) an impurity, injected after one month
and freshly prepared demonstrate that the standard solutions are stable and do not
lose their quality after 1 month if refrigerated.

Name of standards Storage conditions Difference. relative

to freshly prepared
standard
[Active] 100% 4°C <2%
[Impurity] 100% 4°C <2%

Standard Solutions are stored at controlled temperatures and light conditions as per
labeling.

[d]. Stability Indicating Procedures.

For the Stability Indicating Method, the product sample usually includes forced
degradation by stressed analysis. Conditions of concentration and reaction time
may vary depending on the active drug substance and drug product - e.g:
• Oxidation - [H2O2] plus a fixed exposure time
• Base Hydrolysis - [NaOH] x N a fixed plus exposure time
• Acid Hydrolysis - [HCl] conc. a fixed plus exposure time.
• Sun light - (24 hours exposure time).
• Heat - (T oC a fixed plus exposure time).

Summary of Stability Indicating Results

Stressed Conditions Temp. Time Raw Material; Tablets
o
( C) (hr) Remaining Peak Purity, Remaining Peak
Substance. (Figure) Substance Purity,
(%) (%) (Figure)
Solution heating 90 12 100.2 pure 98 pure
Solid heating 160 2 101.3 pure 92 pure
Sunlight 765 w/m2 40 14 101.1 pure 84.8 pure
3,3N Sodium Hydroxide 70 10 99.8 pure 100.2 pure
10%Hydrogen Peroxide 37 3 77.5 pure 90.5 pure
5% Hydrochloric Acid Room 20 79.7 pure 78.6 pure

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13.7 Generic Development
 ORAL TABLETS ANALYTICAL CHAPTER 13

[e]Specificity and Suitability. (Resolution and Tailing Factors).

When a satisfactory separations of all the degradation peaks have been achieved
through the forced degradation reactions, a Resolution Factor (according to the USP
requirements) between the main active peak and the nearest degradant peak is
calculated using the USP formula.
A Tailing Factor (according to the USP formula) is calculated for the main active
peak.
[f] System Suitability Test
A mixture of [Active] AS. standard at the concentration about [0.1]mg/mL and of
[Impurity] AS. standard at the concentration about [0.01]mg/mL according to Method
SI-1000 was prepared and injected into the HPLC system.
For chromatogram obtained the following values were calculated (according to
USP):

1. Relative Retention Time for [Impurity] peak

RRT = RT [Impurity] = 2.65 = 0.31
RT [Active] 8.45

2. Tailing factor for [Active] peak

W0.05 9
Tf = = = 1.1
2f 4.2

The values depict the specificity of the method for resolution between the main peak
and impurity peak. (values shown for demonstrations purposes).

Peak Purity
The photo diode-array is used for the evaluation of the stability indicating nature of
the assay method number SI-1000 for [000]mg and [000]mg tablets using a Waters
996™ Unit, controlled by the chromatography manager Millennium 2010™.
Peak purity and match results are reported as:

Purity Angle is a measure of spectral non-homogeneity across a peak - i.e. the

weighed average of all Spectral Contrast Angles calculated by comparing all spectra
in the integrated peak against the peak apex spectrum.

Purity Threshold is the sum of Noise Angle and Solvent Angle. It is the limit of
detection of shape differences between two spectra.

Match Angle is a comparison of the spectrum at the peak apex against a library
spectrum.

Match Threshold is the sum of the Match Noise Angle and Match Solvent Angle.

Noise Angle is a measure of spectral non-homogeneity caused by system noise.

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 ORAL TABLETS ANALYTICAL CHAPTER 13

Solvent Angle is a measure of spectral non-homogeneity caused by solvent

composition.
It the purity angle is smaller than the purity threshold and the match angle is smaller
than the match threshold, this indicates that no significant differences between
spectra are detected. There is no spectroscopic evidence for co-elution and the
peak is considered pure.

[f] Relative Retention Time of Main and Additional peaks.

Each stressed analysis shall indicate the percentage by which the Main peak is
decreased as well as the RRT for any other Additional peaks.

If the RRT of an Additional peak corresponds to a known degradant/impurity etc. it

shall be stated.
The peak purity of the main peak shall be given for each stressed analysis (where
possible).

[g]. Validation of limit testing for impurity methods shall include :

♦ Specificity
♦ Detection Limit (DL)
♦ Quantitation Limit (QL)

Detection Limit (DL)

The detection limit of an individual analytical procedure is the lowest amount of
analyte in a sample which can be detested but not necessary quantitated as an
exact value.

Quantitation Limit (QL)

The Quantitation limit of an individual analytical procedure is the lowest
amount of analyte in a sample which can be quantitatively determined with
suitable precision and accuracy. Used in the determination of impurities and or
degradation products.

[h]. Contents of a typical HPLC Analytical Validation Protocol

Part II of this article deals with the typical validation attributes that need to be
addressed in the development of a new drug's. overall analytical validation
package. Three separate development protocols are impacted. These are;
• The active bulk substance analytical validation package
• The finished product stability indicating assay and impurity profile
◊ The finished product impurity profile (quantitative or limit tests)
◊ The finished product dissolution assay
• Clinical sample assay for active and metabolites during the biostudy (this
assay development and validation is performed by the CRO undertaking the
study).

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13.9 Generic Development
 ORAL TABLETS ANALYTICAL CHAPTER 13

Analytical Aspects II
Validation of analytical methodology
for an HPLC system.

1. Introduction 2. System Repeatability

A brief description pertaining into the Precision
following test method specifications: Ten replicate (single) injections of the
standard solution at the nominal
♦ Method and Edition # used. concentration described in the method
Batch # of samples tested (test is performed by the same analyst and
the lowest and the highest label the RSD calculated. The Results
strength. (sample number and peak areas) are
♦ Type of detector used to analyze tabulated. The Average Peak Area,
stressed samples. S.D., and R.S.D are shown in the
table. Target values for RSD lie
♦ Stress testing of Standard solution between 0.5 to 1.0
to determine origin of Additional (Keep this standard solution for the
peaks stability of Standard Solutions - Point
nine [9]).

Precision - Table 1.
System Repeatability
[Also called intra-assay precision]

SYSTEM REPEATABILITY
SAMPLE No. PEAK AREAS

1
2 Repeatability shows
3 precision
4 under the same operating
5 conditions over a short
6 interval of time - same day
7 same morning
8
9
10
Average Peak Area
Standard Deviation =
Relative Standard Dev. =
= 0.5 - 1.0

W here possible standard expected statistical values have been entered as an

numerical guide. Depending on the active material and equipment used, these
values may differ slightly in specific case studies.

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 ORAL TABLETS ANALYTICAL CHAPTER 13

[3] Method Reproducibility - Precision

The full analytical method # is carried out and repeated Ten

times on the finished
product (batch #) and the RSD is calculated. Two HPLC injections are performed
per method assay and the peak areas are averaged.

♦ The Results (assay %) are tabulated.

♦ The Average Assay %, SD and RSD are calculated and shown in the tabulations.
♦ Target values for RSD = 1.5 to 3.0.

METHOD REPRODUCIBILITY

SAMPLE No ASSAY %

Batch No:

1
Method Reproducibility
2 monitors the sample-to-
3 sampling variation of the
4 same drug product by
5 evaluating the full
6 analytical method over
7 and over again.
8 (same operator - same
9 equipment)
10
Average Assay % =
Standard Deviation =
Relative Standard = 1.5 - 3.0
Deviation.

[4] Accuracy
The Accuracy of an analytical procedure expresses the closeness of agreement
between the true value and the value found.

Ten replicate (single) injections of the standard solution at the nominal concentration
of x mg/100 mL as described in the Analytical Method / Ed is made and the percent
deviation from the true values as determined from the linear regression line is
calculated.
♦ The Results (Peak areas and % accuracy) are tabulated.
♦ The Mean, SD and C.of.V are shown in the tabulations

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 ORAL TABLETS ANALYTICAL CHAPTER 13

[4] Accuracy (continued)

Accuracy may be termed trueness as well

ACCURACY

INJECTION PEAK CALCULATED %

No AREA CONC. ACCURACY

1
2
3
4
5
6
7
8
9
10

Mean (% Accuracy) =
Standard Deviation =
% Coef. of Variation =

[5] Recovery (Extraction time)

The extraction efficiency is Not less than three different extraction

demonstrated by varying the extraction times are used namely:
time of prepared sample solutions as ♦ T (half)
described in the analytical method ♦T
Two HPLC injections are performed per
method assay and the peak areas are
♦ T (one & half)
(where T is the extraction time of the
averaged.
method).
Peak values from Peak values from
the SAME DIFFERENT
sample solution may sample solution
be averaged
may not be
The extraction time suitable to ensure
complete extraction is highlighted. averaged

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 ORAL TABLETS ANALYTICAL CHAPTER 13

[5] Recovery (Extraction time - tabulations continued).

The Results (Extraction time and Assay %) are tabulated as shown.

RECOVERY - EXTRACTION

TIME IN
MINUTES % ASSAY
Batch No:

0.5 T Run at between

3 and 5
0.75 T extraction times
to
T
demonstrate
1.25 T recovery

1.5 T

[6] Recovery VALIDATE THE ANALYTICAL

(of spiked placebo samples) METHODS FOR THE
ACTIVE SUBSTANCE
Five spiked admixtures of the active
AND
substance and the non-active vehicle
(placebo) at concentrations of about
FINISHED DOSAGE FORM
50% to 150% of the stated SIDE-BY-SIDE.
concentration required by the assay
procedure is prepared and analyzed to
show the percentage active recovery.
Two HPLC injections are performed per
method assay and the peak areas are
averaged.
RECOVERY The Results (Theoretical conc. Actual
TESTING conc. and % recovery ) are tabulated.
ALSO
DEMONSTRATES ♦ The Average Recovery
DETECTOR ♦ SD and the
LINEARITY ♦ % Coefficient of Variation
are tabulated.

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 ORAL TABLETS ANALYTICAL CHAPTER 13

[6] Recovery (spiked placebo samples tables - continued).

The recovery results are shown graphically (peak area Vs conc. (mg/100 mL).
These results also show extraction method and detector linearity.

R E C O V E R Y
Standard solution mg/100mL Peak Area =

CONC. PEAK AREA CONC. PERCENTAGE

Theoretical FOUND FOUND RECOVERY
(mg/100ml) (mg/100ml)

50
75
100
125
150

Mean (% Recovery) =
Standard Deviation =
% Coef. of Variation =

Display values
The Linear Regression value, Slope and Y-Intercept are shown in the GRAPH. The
placebo chromatogram (vehicle only) is shown to highlight the absence of Additional
Peaks

[7] Linearity and Range.

The linearity on an analytical procedure is its ability (within a given range) to obtain
test results which are directly proportional to the concentration (amount) of the
analyte in the test sample.

Five Standard solutions in a concentration range of (about) 50 % to 150 % of the

stated concentration required by the assay procedure are prepared and analyzed by
the stated method.
Two HPLC injections are performed per method assay and the peak areas are
averaged.

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 ORAL TABLETS ANALYTICAL CHAPTER 13

[7] Linearity and range - (continued).

The Area count and concentration range is plotted. Linear regression analysis will
demonstrate the acceptability of the method for quantitative analysis over the full
spectrum of the concentration range. Detector linearity is also demonstrated
between the upper and lower analyte concentrations.

The Results (Range conc. and peak areas ) are tabulated.

LINEARITY AND RANGE

CONC.
Batch No: PEAK AREAS
50 %
75 %
100 %
125 %
150 %

Linear Regression =
Y-Intercept =
Slope =

The results are shown graphically (peak area Vs range conc. (mg/100 mL).

GRAPH OF LINEARITY
120000
P
e 100000
a
80000
k
60000
A
40000
r
e 20000
a
0
0 25 50 75 100 125 150
Conc. mg/100mL

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 ORAL TABLETS ANALYTICAL CHAPTER 13

[8] Robustness. validation packages erroneously, under

the heading of one or the other. Internal
Ruggedness and Robustness. and external analytical parameters
The USP defines ruggedness as "the should be separated and appraised
degree of reproducibility of test results individually.
obtained by the analysis of the same
samples under a variety of normal test
Ruggedness
conditions such as:- is a USP
♦ Different laboratories Requirement
♦ Different analysts Robustness
♦ Different instruments is not.
♦ Different reagent lots
The Robustness of an analytical
♦ Different analysis days procedure is a measure of its capacity
♦ Different elapsed assay times to remain unaffected by small but
♦ Different assay temperatures …" deliberate variations in method
parameters thus providing an indication
These factors are all external to the
of its reliability under normal usage.
written analytical method and each
parameter should show a lack or indeed The method may be evaluated for
absence of influence on the test results specificity using two different columns.
obtained. No differences in specificity, selectivity
or column performance should be
Ruggedness observed.
Measures External Robustness determinations are
Robustness essential when transferring analytical
methods from the development
Internal Variations. laboratory to the commercial quality
control laboratory. There may usually
Ruggedness measures the lack of be a difference in columns or HPLC
external influence on the test results machine models used.
whereas robustness measures the
lack of internal influences on the test
results.
Internal and external variations are
often mixed together in analytical

Robustness is defined by both the USP and the ICH Tripartite guidelines as "a
measure of its capacity to remain unaffected by small but deliberate variations in
method parameters and provides an indication of its reliability during normal use "
Robustness is defined both in the USP and ICH, but is not required.
Robustness variations.
Deliberate variations according to the following table were made to the critical
parameters of the method such as column, flow rate and concentration of [organic
acid] in the mobile phase. Using the System Suitability solution and LOQ (also QL)
solution as the Test Solutions the performance of the method was evaluated.
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 ORAL TABLETS ANALYTICAL CHAPTER 13

Robustness variations (Tabulated ).

Column 1: Phenomenex Bondclone 10µ, C-18, 300 x 3.9mm (OOH-2117-CD)
Column 2: Waters µ-Bondapak 10µ, C-18, 300 x 3.9mm (27324)
CONDITION RESULTS
Condition Column Flow Rate Buffer RRT Tf RSD RSD
No. mL/min Conc. (%) bet. LOQ of bet. LOQ of
[Active] [Impurity]
1 1 2.5 0.1 0.3 1.1 <10 <10
2 1 2.2 0.1 0.3 1.1 <10 <10
3 1 2.8 0.1 0.3 1.1 <10 <10
4 1 2.5 0.15 0.3 1.1 <10 <10
5 2 2.5 0.1 0.3 1.1 <10 <10

[8] Ruggedness - (Tabulations).

The Results (Average assay % for Analyst 1 and 2 ) are tabulated.

RUGGEDNESS
ANALYST % ANALYST %
No 1 ASSAY No 2 ASSAY
Column I Column 2
1
2
3
4
5
6
7
8
9
10
Mean (% Accuracy) =
Standard Deviation =
% Coef of Variation =

Notes on different terms frequently used:

The analytical variation expressed between laboratories on different days; with
different equipment; or different analysts is known as - intermediate precision.

This intra-laboratory precision or the precision between laboratories is known as

reproducibility or more specifically - intra-laboratory reproducibility. Both the above
are ruggedness - and a USP requirement.

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 ORAL TABLETS ANALYTICAL CHAPTER 13

Ruggedness & Robustness Evaluation.

The evaluation of ruggedness and robustness (where necessary) should
be finalized at the end of the development phase - around the time of the
process qualification lot manufacture.

The robustness evaluation should be developed with the commercial

laboratory equipment in mind. It should show the reliability of an analysis
with respect to deliberate variations in the method parameters.

A consequence of robustness evaluation is that a series of system

suitability parameters are established to ensure that the validity of the
analytical procedure is maintained whenever used.

[9] Stability of Standard solutions

Re-chromatography of ten replicate single injections of the same standard
solution (which have been allowed to stand for x hours ) against freshly
prepared Standards showed no significant differences from the original
results.

STABILITY OF
THE STANDARD SOLUTION

mg/100mL mg/100mL
Initial Analysis Repeat Analysis
(Date) 2nd (Date)
1 injection 1 injection
2 injection 2 injection
3 injection 3 injection
4 injection 4 injection
5 injection 5 injection
6 injection 6 injection
7 injection 7 injection
8 injection 8 injection
9 injection 9 injection
10 injection 10 injection
Mean =
Standard Deviation =
Relative Standard Dev. = NMT 2.0 %

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 ORAL TABLETS ANALYTICAL CHAPTER 13

[10] Typical Chromatograms.

Representative chromatograms of the following traces are routinely provided:-
♦ System Suitability
♦ Standard Solution
♦ Drug Product
♦ placebo
When Representative Chromatograms are displayed - all peaks are LABELED with
the peak name and RRT.

Representative chromatogram
Drug Product

Label the peak

clearly
Name and Retention
time (8.78 min)

[11]Conclusion. It is important to emphasize that

(Closing Statement) analytical validation applies to a drug
An appropriate conclusion should be formula and a set manufacturing
given stating clearly that: procedure. Extraneous peaks and
“The method # 005 Ed. No 00 is shown processing stresses are specific to a
to be accurate and precise for carrying manufacturing procedure, equipment
out assay analysis as part of the Assay used and the nature of the excipients.
and Stability Studies for the Drug
Product conforming to the formula as
Where there is a formulation or
excipient change as well or a new
shown in Appendix 1” .
processing principle of the
[12] References & Appendixes. manufacturing procedure, the analytical
Acknowledgment to references as well validation package should be amended
as attachments such as the drug to account for appropriate changes.
product formula are attached at the end Frequently this involves a full
of the validation protocol. revalidation of the overall methodology.

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 ORAL TABLETS ANALYTICAL CHAPTER 13

Revalidation
An entire validation procedure should Validation Checklist
be repeated again for new approved 1. Are all in-house methods validated?
sources of the active material as the 2. Is the dissolution method for
new active may well display a different development, release and stability
impurity profile and an altered validated.
degradation pattern under stressed 3. Are the different validation editions
conditions. comparable with the previous
edition?
All of the above validation parameters 4. Was the stability assay and
are mentioned in the SUPAC (3) guide dissolution method validated at the
for analytical methods, developed for time of process optimization
bioequivalence blood sample testing: 5. Was the stability assay and
i.e. dissolution method validated at the
♦ Accuracy time of process qualification
6. Is the validated stability assay,
♦ Specificity
impurity profile and dissolution
♦ Recovery method used in the pivotal essential
♦ Precision (interday & intraday) similar to the commercial validation
♦ Linearity (of standard curves) lots so that data is comparable.
♦ Sensitivity 7. When a new edition is not
♦ Stability (Storage & handling) comparable to the previous edition -
is a new method number allocated?
8. Has the lab an historical track record
Bioequivalence studies of all assay dissolution etc. methods
Linearity and range at the extreme
used from early development to
lower ends of the active analyte or
commercial validation?
metabolite(s) in sera are important
parameters in assaying blood serum References:
concentrations.
1. "Validation of compendial methods" USP 23
Range studies MUST be linear at the <1225> USPC Rockville Maryland USA
lower and upper limits as found in the 1994.
serum samples or those used for 2. USP/NF XXIII USPC Rockville Maryland
USA 1994.
calibration curves, a point sometimes 3. Scale up and Post approval Changes
frequently overlooked by analytical Manufacturing and Controls In vitro
method developers in clinical Dissolution and In Vivo Bioequivalence
environments when dealing with very, Documentation CEDER 1995 (SUPAC)
4. International Conference on Harmonization
very dilute concentrations. "Guidelines on validation of Analytical
Procedures: Definitions and Terminology;
All analytical validation attributes Federal Register (March 1, 1995.)
require to be taken into account, 5. ASTM Standard Guide For Conducting
including ruggedness. No robustness Ruggedness Tests E1169 American Society
tests are officially required for USP and for testing Materials Philadelphia 1989.
6. G. Kateman and L. Buydens, The
ICH, however prudent analytical Ruggedness Test Quality Control in the
method developers should build in a Analytical chemistry John Wiley and Sons
robust test, whether official or not. NY 2nd Edition 1993, pp118 125.

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 ORAL TABLETS ANALYTICAL DEVELOPMENT CHAPTER 13

OUT-OF-SPECIFICATION
TEST RESULTS
‘…Investigate all Out-of-Specification Results routinely and immediately,
the findings may well be in the firms commercial interests...’

Out Of Specification
P
racticing the correct do’s and don’t
procedures in out-of-specification
decisions making is a central
(OOS) Retesting and
requirement for an analytical laboratory Product failures based
personnel. The FDA 1998 draft OOS on the 1993 Judgment
guidelines applies to all drug product Drug developers and manufacturers
manufacturers and may be a useful tool should be thoroughly conversant with the
for the day-to-day administration and FDA's September 1998 draft 'Out-of-
decision making in a research or routine Specification' guidelines and current
quality control analytical laboratory (see thinking which may provide an appropriate
OOS checklist). base for decisions in routine QC and
Judge Alfred M Wolin’s original 1993 production OOS investigations.
interpretation of Good Manufacturing An Out of Specification
Practice (GMP) issues embedded in the
landmark US court ruling five and half (OOS) Result
years ago is the underlying basis of the may or may not
FDA's September 1998 DRAFT Out-of-
Specification guidelines for the generic be a product failure
and innovative pharmaceutical industry. Out-of-Specification results are not
Notwithstanding that the court ruled in necessary product failures, a term FDA
April 1993 on important OOS laboratory investigators commonly use in PAI and
practices, FDA EIRs and 483 Inspection GMP inspections. Handling out-of-
observations, still cite non-compliance specification lab data has become a
practice with respect to product retesting primary GMP inspection focal point.
and Out-of-Specification (OOS) test The failure for some firms to conduct an
results in both Generic and Innovative adequate data investigation has become a
drug firms. frequent citation in PAIs and routine GMP
The interpretation and application of the Agency Inspections.
Good Manufacturing Practices (GMP) Act Where is my data
have set practical ‘hands-on’ guidelines invalidating
that support the industry rules for handling
out-of-specification test results, retesting
an Out-of-Specification
procedures and product failure (OOS) Result?
investigations. Out-of-Specification results
These rules are now incorporated in the must not become ‘un-investigated
draft 'guidance for industry investigating failures’. The maxim “we investigated but
out-of-specification test results for didn’t write it down” is often heard and
pharmaceutical industry'. carries little weight with an agency official.

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What the PAI investigator really hears is, and has no scientific merit or statistical
“we didn’t bother to investigate and don’t value).
have any SOP requiring us to do so”. For practical purposes this invalid result
Such an attitude is in violation of the new was technically never done and should
draft guidelines and the firm needs to not be used for any calculation or
address its investigation procedures statistical evaluation. However the
impacting on product retesting and analyst error must be thoroughly
evaluating drug product approvals. documented and properly invalidated -
Out-of-Specification Test Results (OOS) may with written reasons, supervisor and
be:- Reversible due to a:- analyst signatures and date of
invalidation process.
Ü genuine laboratory error
Ü sampling error
Investigate according
Or non- reversible due to a :- to a set procedure
Ü manufacturing processing error and then retest if the
Ü manufacturing operator error error is conclusive?
Genuine Laboratory Error. Inconclusive errors
Laboratory errors can occur when Where an error is investigated and the
analysts make analytical mistakes. All result of the investigation is inconclusive
laboratory technicians and analysts may the following rules apply to the retest
mistakes at times in their career. There is procedure.
no such concept as an error-free Inconclusive errors retest
laboratory analyst or that all standard
solutions are always correct and that data An inconclusive error is an OOS where
is never miscalculated. Samples may be the 'supervisor-analyst investigation' did
incorrectly prepared, diluted, injected or not draw a firm conclusion and the reason
stored at inappropriate environmental for the error was not clearly identified.
temperatures or quite simply that What to do: Answer - Retest with new
containers where not properly closed or aliquot (replicates, if required) from the
even placed in the correct designated same sample, if the sampling procedure
sampling container. was proven OK by investigation. If the
A suspected laboratory error must be sampling procedure was found to be in
investigated and if found genuine can error, then re-sample the target material
immediately be invalidated and the result and perform a new duplicate analysis.
simply filed and disregarded completely.
The investigation or ‘failure investigation’ For process failures
should where ever possible identify the confirmed by laboratory
cause of the OOS and its impact. testing - means the
Retest procedures product has failed?
must follow DECISION TREE
pre-written rules An overview of Out-of-Specification
Once the nature of the OOS has been Results procedures is provided by the
decision tree.
identified - as an laboratory error - a
Re-sampling the material for a new
repeat test must be performed and the representative sample should take place only
initial test totally ignored. (Remember this when the original procedure was found to be
initial test result is invalid - it was an error clearly non-representative of the whole.

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Do’s
& Don’ts
The ‘Retesting Rules’: Retest procedures
Do insure that the firm has a written
must follow
Retest SOP. pre-written rules.
Do insure the retest SOP indicates when The Don’ts
testing stops and the product is evaluated. Don’t - use the outlier test for a
Do retest only after; dissolution test or profile.
Don’t - use the outlier test for an
⇒ reporting,
Assay or a Content Uniformity test.
⇒ classifying and Don’t - use the outlier test frequently
⇒ investigating jointly. to reject non-chemical test results.
Don’t - use the outlier test outside
Do retest on the same sample
the USP specifications prescribed.
collected.
Don’t - retest before an investigation
Do feel free to prepare a second aliquot is completed and closed.
from the same sample as the first.
Don’t - retest before reporting to
Do use a larger portion of the first your supervisor and conducting an
sample, if required. informal investigation - together.

Do know when you can and can’t use Don’t - ignore ever the rules for
governing a single or multiple OOS result.
the outlier test.
Don’t - re-sample unless the sample
Do re-sample if the original sampling procedure was proved to be faulty.
procedure is proven by investigation, as
not representative. Don’t - re-sample without your
supervisor permission obtained only after
Do re-sample if the original sample was an informal investigation.
improperly prepared (clearly shown after
the required investigation). Averaging passing and
OOS results together
Do investigate and then close the
investigation within 30 days after the
is not GMP
OOS. Don’t - Average good and bad
results - as they simply hide the true test
Do keep a ‘Failure Report” or an values. 3
‘Investigation Report’ log.

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 ORAL TABLETS ANALYTICAL DEVELOPMENT CHAPTER 13

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OUT-of-SPECIFICATION RESULTS
‘…Averaging passing and OOS Test Results together
is not permitted as it conceals the full analytical picture…’

IDENTIFYING OOS TEST RESULTS

1. Does the firms have a clear SOP spelling out the procedure and qYes qNo
investigations required when ever an OOS result is obtained?
2. Are all firm's 'rejected batch' OOS results investigated as well? qYes qNo
3. Are the previous (or related) batches associated with the failed batch qYes qNo
specification reviewed and the overall impact (on quality) evaluated?
4. Are written investigations undertaken and then follow-up procedures qYes qNo
recommended in writing?
5. Are the investigations performed in a timely manner and follow a qYes qNo
defensible scientific logic (see attached Decision Tree)?
6. Does the companies 'Investigation SOP' include the three key tenants qYes qNo
i.e. TO INVESTIGATE - TO CONCLUDE - TO FOLLOW-UP?
7. Have the laboratory analysts been instructed to keep the original qYes qNo
'suspect test solutions' for possible reanalysis (Ref. Decision Tree)?
8. When an OOS has been detected does the initial review, before the qYes qNo
investigation, check for instrument or system suitability malfunction,
faulty reagents, calculation, documentation or transcribing errors?
9. If no clear analytical errors are detected in a 'suspect result' does a qYes qNo
comprehensive 'failure investigation' ALWAYS follow?
10. Where malfunctions are identified and detected are all prior 'suspect qYes qNo
data' evaluated and reviewed for a possible related (or similar) errors?
11. Are analytical failures tracked back to their original point of failure? qYes qNo
12. When a faulty lab procedure is detected, is the analytical test qYes qNo
procedure immediately terminated (as a matter of routine)?
13. Have the analysts been trained to immediately report to their qYes qNo
supervisors an obvious error or an analytical fault?
14. Are obvious errors (spilling, incorrect dilution, injection volume etc.) qYes qNo
documented in the lab book and a brand new test restarted?

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OUT-of-SPECIFICATION RESULTS
‘…failure investigations are conducted to determine
what caused the unexpected OOS result…’

INVESTIGATING OOS TEST RESULTS

1. Does the supervisor's 'initial assessment' follow the abbreviation qYes qNo
' DECIDED procedure ' (See box)?
2. Are the retained 'suspect' sample preparations examined during the qYes qNo
'initial assessment' and then retested promptly on initiating the
'failure investigation'?
3. Where a clear error is identified, is the result immediately invalidated? qYes qNo
4. Where clear error is NOT identified, is a failure investigation qYes qNo
conducted immediately?
5. Is the firm's full scale failure investigation fully predefined in writing? qYes qNo
6. Does the firm's own QC Unit perform the 'full scale failure qYes qNo
investigation'?
7. Does the general review include a list of related batches - impacted? qYes qNo
8. Does the full scale failure investigation include the production side qYes qNo
and the laboratory side?
9. Does the laboratory protocol include the two key steps - retesting the qYes qNo
original sample and testing a new sample from the batch lot?
10.Retesting the original sample with a new analyst, is generally the first qYes qNo
step after the 'initial assessment' is completed?
11.Are the number of retests (usually duplicates) specified and not qYes qNo
exceeded? Averaging 'original suspect' and retest results is
forbidden.
12. When improperly prepared samples are proved, then the original qYes qNo
results may be immediately invalidated?
13. The firm may re-sample when the investigation highlights that the qYes qNo
original sample was unrepresentative?
14. Where the investigation concludes that the sampling method is in qYes qNo
error a new sampling method must be developed and qualified ?
15. To prove the original aliquot is faulty, the analyst prepare two qYes qNo
additional aliquots and compares the three sets of results?

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OUT-of-SPECIFICATION RESULTS

‘…Batches must be formulated with the intent to provide 100%

of the labeled amount…'

AVERAGING IN OOS RESULTS

16.Averaging results from a standard solution or a test aliquot is qYes qNo
acceptable (i.e. averaging replicate results).
17.Averaging results from microbial count plates are quite acceptable. qYes qNo
18.Averaging a set of results, where some are OOS is not acceptable. qYes qNo
19.Hiding an OOS result in any average is not acceptable. qYes qNo
20.When the intent is to highlight variability within the product then qYes qNo
averaging is not acceptable, but RSD (CV) values are generally
reported to show statistical significance.
21.Replicate peak responses whether test or standard should be qYes qNo
averages as one result.
22.Are analysts trained, not to average passing and OOS results qYes qNo
together in order to hide the failing results?
23.Composite assays, require only one assay result and are in fact qYes qNo
average assay values, as opposed to individual content uniformity
values.

OUTLIER USE IN OOS RESULTS

24.Where 'control' and 'specification' lower and upper limits are used in qYes qNo
QC criteria an OUTLIER may be outside the control limits but inside
the specifications limits? [i.e. an example of OUTLIER use.]
25.Analyst are trained not to assume OUTLIERS as testing errors but qYes qNo
inherent variability in the sample.
26.The firm has an OUTLIERS SOP detailing the use of OUTLIER qYes qNo
TESTS.
27.OUTLIERS are not permissible in Content Uniformity and Dissolution qYes qNo
tests.
28.Where the intent is to measure the variability, OUTLIERS should not qYes qNo
be used.

Handbook of Pharmaceutical Sect: 13.26

13.26 Generic Development
 ORAL TABLETS ANALYTICAL DEVELOPMENT CHAPTER 13

OUT-OF-SPECIFICATION
TEST RESULTS
‘…An Out-of-Specification Test Result is not necessary
a product failure - and needs to be qualified …

FDA's NEW OOS GUIDANCE This guidance applies to laboratory

testing during the manufacture of active
GUIDANCE FOR INDUSTRY pharmaceutical ingredients, excipients,
Investigating Out-of-Specification and other components and the testing
of finished products to the extent that
(OOS) Test Results for current good manufacturing practices
Pharmaceutical Production (CGMP) regulations apply (21 CFR
I. INTRODUCTION parts 210 and 211). Specifically, the
guidance discusses how to investigate
T his guidance has been prepared by
the Office of Compliance / Division
of Manufacturing and Product 1 Quality,
suspect, or OOS test results, including
the responsibilities of laboratory
Center for Drug Evaluation and personnel, the laboratory phase of the
Research (CDER) at the Food and investigation, additional testing that
Drug Administration. This guidance may be necessary, when to expand the
document represents the Agency’s investigation outside the laboratory,
current thinking on evaluating OOS test and the final evaluation of all test
results. It does not create or confer any results.
rights for or on any person and does 4
not operate to bind FDA or the public.
An alternative approach may be used if
TABLE OF CONTENTS
I. INTRODUCTION
such approach satisfies the
II. BACKGROUND
requirements of the applicable statute,
III. IDENTIFYING AND ASSESSING OOS TEST
regulations, or both.
RESULTS
This guidance for industry provides the A. Responsibility of the Analyst
Agency’s current thinking on how to B. Responsibilities of the Supervisor
evaluate suspect, or out of specification IV. INVESTIGATING OOS TEST RESULTS
(OOS), test results. A. General Investigational Principles
For purposes of this document, the B. Laboratory Phase of an Investigation
term OOS results includes all suspect V. CONCLUDING THE INVESTIGATION
results that fall outside the A. Interpretation of Investigation Results
specifications or acceptance criteria B. Reporting
established in new drug applications,
official compendia, or by the 4
manufacturer.

Handbook of Pharmaceutical Sect: 13.27

13.27 Generic Development
 ORAL TABLETS ANALYTICAL DEVELOPMENT CHAPTER 13

II. BACKGROUND of the investigation be made including

FDA considers the integrity of the conclusions of the investigation and
laboratory testing and documentation follow-up (211.192).
records to be important during drug To be meaningful, the investigation
manufacturing. Laboratory testing, should be thorough, timely, unbiased,
which is required by the cGMP well-documented, and scientifically
regulations (§ 211.165), is necessary to defensible.
confirm that components, containers-
closures, in-process materials; finished
The first phase of the investigation
includes an initial assessment of the
products, conform to specifications,
accuracy of the laboratory's data,
including stability.
before test solutions are discarded,
Testing also supports analytical and whenever possible.
process validation efforts. General
CGMP regulations covering laboratory
Investigate, Conclude
operations can be found in part 211, and Follow-up Every
subparts I (Laboratory Controls) and J
(Records and Reports).
Specification Failure
These regulations provide for the This way, hypotheses regarding
establishment of scientifically sound laboratory error or instrument
and appropriate specifications, malfunctions may be tested using the
standards, and test procedures that are same test solutions. If this initial
designed to ensure that components assessment indicates that no errors
and containers of drug products were made in the analytical process
conform to the established standards. used to arrive at the data, a complete
Section 211.165(f) of the CGMP failure investigation should follow.
regulations specifies that products that A. Responsibility of the Analyst
fail to meet established standards and The first responsibility for achieving
other relevant quality control criteria accurate laboratory testing results lies
will be rejected. 4 with the analyst who is performing the
III. IDENTIFYING AND ASSESSING test. The analyst should be aware of
OOS TEST RESULTS potential problems that could occur
during the testing process and should
FDA regulations require that an
watch for problems that could create
investigation be conducted whenever
OOS results.
an OOS test result is obtained. The
purpose of the investigation is to In accordance with the CGMP
determine the cause of the OOS. Even regulations1 the analyst should ensure
if a batch is rejected based on an OOS that only those instruments meeting
result, the investigation is necessary to established specifications are used and
determine if the result is associated that all instruments are properly
with other batches of the same drug calibrated. 1(§ 211.160 (b)(4)),
product or other products. Certain analytical methods have
Every Failure (OOS) system suitability requirements, and
MUST be investigated systems not meeting such requirements
should not be used. For example, in
and its impacts on chromatographic systems, reference
related batches evaluated standard solutions may be injected at
Batch rejection does not negate the intervals throughout chromatographic
need to perform the investigation. The runs to measure drift, noise, and
regulations require that a written record repeatability.

Handbook of Pharmaceutical Sect: 13.28

13.28 Generic Development
 ORAL TABLETS ANALYTICAL DEVELOPMENT CHAPTER 13

If reference standard responses assumptions as to the cause of the

indicate that the system is not OOS result.
functioning properly, all of the data Data should be assessed promptly to
collected during the suspect time ascertain if the results may be
period should be properly identified attributed to laboratory error, or
and should not be used. whether the results could indicate
The cause of the malfunction should problems in the manufacturing process.
be identified and corrected before a Is the OOS a Laboratory or
decision is made whether to use any
data prior to the suspect period.
Production Error?
An immediate assessment could
Track Analytical include re-examination of the actual
Failures Back to solutions, test units, and glassware
used in the original measurements and
Their Origin Point preparations, which would allow more
Before discarding test preparations or credibility to be given to laboratory
standard preparations, analysts should error theories.
check the data for compliance with Steps should be taken as part of the
specifications. When unexpected supervisor's assessment:
results are obtained and no obvious Key:- [D E C I D E D]
explanation exists, test preparations [1]. Discuss the test method with the
should be retained and the analyst analyst; confirm analyst knowledge of and
should inform the supervisor. performance of the correct procedure.
An assessment of the accuracy of the [2]. Examine the raw data obtained in the
results should be started immediately. analysis, including chromatograms and
If errors are obvious, such as the spectra, and identify anomalous or suspect
information.
spilling of a sample solution or the
[3]. Confirm the performance of the
incomplete transfer of a sample instruments.
composite, the analyst should [4]. Determine that the appropriate
immediately document what reference standards, solvents, reagents,
happened. and other solutions were used and that
Analysis Developing they meet quality control specifications.
[5]. Evaluate the performance of the
a Fault MUST be testing method to ensure that it is
Stopped Immediately performing according to the standard
expected based on method validation
Analysts should not knowingly data.
continue an analysis they expect to [6]. Document and preserve evidence of
invalidate at a later time for an this assessment.
assignable cause (i.e., analyses should The assignment of a cause for OOS
not be completed for the sole purpose results will be greatly facilitated if the
of seeing what results can be obtained retained sample preparations are
when obvious errors are known). These examined promptly.
same responsibilities extend to
analysts at contract testing labs. Hypotheses regarding what might have
B. Responsibilities of the Supervisor happened (e.g. dilution error,
instrument malfunction) can be tested.
Once an OOS result has been Examination of the retained solutions
identified, the supervisor's assessment can be performed as part of the
should be objective and timely. There laboratory investigation.
should be no preconceived

Handbook of Pharmaceutical Sect: 13.29

13.29 Generic Development
 ORAL TABLETS ANALYTICAL DEVELOPMENT CHAPTER 13

Examples: that error and take corrective action to

n Solutions can be re-injected as part ensure that it does not occur again.
of an investigation where a transient To ensure full compliance with the
equipment malfunction is suspected. CGMP regulations, the manufacturer
This could occur, if bubbles were also should maintain adequate
introduced during an injection on a documentation of the corrective action.
chromatographic system, which other OOS Rules:
tests indicated was performing
properly. Such theories are difficult to Clear Error- Invalidate
prove. Unclear Failure - Investigate
However, a re-injection can provide
strong evidence that the problem Do not assume anything!
should be attributed to the instrument, In summary, when clear evidence of
rather than the sample or its
laboratory error exists, laboratory
preparation.
testing results should be invalidated.
n For release rate testing of certain When evidence of laboratory error
specialized dosage forms, where remains unclear, a failure investigation
possible, examination of the dosage should be conducted to determine what
unit tested might determine whether it caused the unexpected results.
was damaged in a way that affected its
performance. Such damage would It should not be assumed that failing
provide evidence to invalidate the OOS test results are attributable to analytical
test result, and a retest would be error without performing and
indicated. documenting an investigation. Both the
n Further extraction of a dosage unit initial laboratory assessment and the
can be performed to determine whether following failure investigation should be
it was fully extracted during the original documented fully.
analysis. Incomplete extraction could 4
invalidate the test results and should IV. INVESTIGATING OOS TEST RESULTS
lead to questions regarding validation Full scale investigations
of the test method (i.e. the extraction
When the initial assessment does not
procedure).
determine that laboratory error caused
It is important that each step in the the OOS result and testing results
investigation be fully documented. The appear to be accurate, a full-scale
supervisor should ascertain not only failure investigation using a predefined
the reliability of the individual value procedure should be conducted.
obtained, but also the significance
these OOS results represent in the
The objective of such an investigation
should be to identify the source of the
overall quality assurance program.
OOS result. Varying test results could
Supervisors should be especially alert
indicate problems in the manufacturing
to developing trends.
process, or result from sampling
Laboratory error should be relatively problems.
rare. Frequent errors suggest a
problem that might be due to
Such investigations present a
challenge both to employees and to
inadequate training of analysts, poorly
management and should be given the
maintained or improperly calibrated
highest priority.
equipment, or careless work.
Whenever laboratory error is identified, The investigation should be conducted
the firm should determine the source of by the quality control unit

Handbook of Pharmaceutical Sect: 13.30

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 ORAL TABLETS ANALYTICAL DEVELOPMENT CHAPTER 13

and should involve all other [2]. Testing a specimen from the
departments that could be implicated, collection of a new sample from the
including manufacturing, process batch
development, maintenance, and [3]. Re-sampling testing data
engineering. Other potential problems [4]. Using outlier testing.
should be identified and investigated.
1. RETESTING
QC Unit Investigates:
Part of the investigation may involve
Production and Laboratory retesting of a portion of the original
sample. The sample used for the
Systems & Documentation retesting should be taken from the
same homogeneous material that was
The records and documentation of the originally collected from the lot, tested,
manufacturing process should be fully
and yielded the OOS results.
investigated to determine the possible
cause of the OOS results. For a liquid, it may be from the original
[A]. General Investigational Principles unit liquid product or composite of the
liquid product; for a solid it may be an
A failure investigation should consist of additional weighing from the same
a timely, thorough, and well- sample composite that had been
documented review. prepared by the analyst.
The written record should reflect that
the following general steps have been Situations where retesting is indicated
taken. [ I - T R A C ] include investigating testing instrument
[1]. The reason for the Investigation has malfunctions or to identify a possible
been clearly identified. sample handling integrity problem, for
[2]. The overall manufacturing process example, a suspected dilution error.
sequences that may have caused the Generally, retesting is neither specified
problem should be summarized. nor prohibited by approved applications
[3]. Results of the documentation review or by the compendia.
should be provided with the assignment of
actual or probable cause.
Investigation Retesting:
[4]. A review should be made to determine First Performed on
if the problem has occurred previously.
[5]. Corrective actions taken should be the original sample
described. by a Second Analyst
The general review should include a Decisions to retest should be based on
list of other batches and products the objectives of the testing and sound
possibly affected and any required scientific judgement. Retesting should
corrective actions taken including any be performed by an analyst other than
comments and signatures of the one who performed the original
appropriate production and quality test.
control personnel regarding any
material that may have been
The CGMP regulations require the
establishment of specifications,
reprocessed after additional testing.
standards, sampling plans, test
[B]. Laboratory Phase of an Investigation
procedures, and other laboratory
A number of practices are used during
control mechanisms (§ 211.160).
the laboratory phase of an
investigation. These include: The establishment of such control
[1]. Retesting a portion of the original mechanisms for examination of
sample additional specimens for commercial or
regulatory compliance testing must be

Handbook of Pharmaceutical Sect: 13.31

13.31 Generic Development
 ORAL TABLETS ANALYTICAL DEVELOPMENT CHAPTER 13

in accordance with "predetermined Consider OOS + Retest

guidelines or sampling strategies"
(USP 23, General Notices and Requirements, p.9).
Result - if the
Some firms have used a strategy of Investigated OOS
repeated testing until a passing result can not be Invalidated
is obtained (testing into compliance),
2. RE-SAMPLING
then disregarding the OOS results
without scientific justification. Testing While retesting refers to analysis of
into compliance is objectionable under the original sample, re-sampling
the CGMPs. involves analyzing a specimen from the
Multiple Retesting: collection of a new sample from the
batch. The establishment of control
Into Compliance mechanisms for examination of
Is a GMP Violation additional specimens for commercial or
regulatory compliance testing should
The number of retests to be performed be in accordance with predetermined
on a sample should be specified in procedures and sampling strategies (§
advance by the firm in the SOP. 211.165(c)).
The number may vary depending upon In some cases, when all data have
the variability of the particular test
been examined, it may be concluded
method employed, but should be based
that the original sample was prepared
on scientifically sound, supportable
improperly and was therefore not
principles. The number should not be
representative of the batch (§
adjusted depending on the results
211.160(b)(3)).
obtained.
The firm's predetermined testing Re-sample Only if
procedures should contain a point at Original Sample
which the testing ends and the product
is evaluated. If, at this point, the results
is Proved
are unsatisfactory, the batch is suspect as Unrepresentative
and must be rejected or held pending A re-sampling of the batch should be
further investigation (§ 211.165(f)). conducted if the investigation shows
In the case of a clearly identified that the original sample was not
laboratory error, the retest results representative of the batch.
would substitute for the original test This would be indicated, for example,
results. The original results should be by widely varied results obtained from
retained, however, and an explanation several aliquots of the original
recorded. composite (after determining there was
This record should be initialed and no error in the performance of the
dated by the involved persons and analysis).
include a discussion of the error and Re-sampling should be performed by
supervisory comments. the same qualified, validated methods
If no laboratory or statistical errors are that were used for the initial sample.
identified in the first test, there is no
scientific basis for invalidating initial However, if the investigation
OOS results in favor of passing retest determines that the initial sampling
results. All test results, both passing method was in error, a new accurate
and suspect, should be reported and sampling method must be developed,
considered in batch release decisions. qualified, and documented.
(§§ 211.160 and 165(c)).

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13.32 Generic Development
 ORAL TABLETS ANALYTICAL DEVELOPMENT CHAPTER 13

3. AVERAGING The assay result would be calculated

using the peak response average. This
Averaging test data can be a valid
determination is considered one test
approach, but its use depends upon the and one result. This is a distinct
sample and its purpose. For example, difference from the analysis of different
in an optical rotation test, several portions from a lot, intended to
discrete measurements are averaged determine variability within the lot.
to determine the optical rotation for a
sample, and this average is reported as The use of replicates should be
the test result. If the sample can be included in the written, approved, test
assumed to be homogeneous (i.e., an methodology. Unexpected variation in
individual sample preparation designed replicate determinations should trigger
to be homogeneous), using averages investigation and documentation
can provide a more accurate result. requirements (21 CFR 211.192).
In the case of microbiological assays, In some cases, a series of assay
the USP prefers the use of averages results may be a part of the test
because of the innate variability of the procedure. If some of the results are
biological test system. OOS and some are within specification
Reliance on averages has the and all are within the documented
disadvantage of hiding variability variation of the method, the passing
among individual test results. results should be given no more
For this reason, unless averaging is credence than the failing results, in the
specified by the test method or absence of documented evidence that
adequate written investigation analytical error had occurred.
procedures, all individual test results Relying on test data averaging in such
should be reported. a case can be particularly misleading.
In some cases, a statistical treatment For example, in an assay with a given
of the variability of results should be range of 90 to 110 percent, test results
reported. For example, in a test for of 89 percent, 89 percent, and 92
dosage form content uniformity, the percent would produce an average of
standard deviation (or relative standard 90 percent even though two of the
deviation) is also reported. assay values represent failing results.
Averaging also can conceal variations To use averaged results for assay
in the different portions of the sample. reporting, all test results should
For example, the use of averages is conform to specifications. Although the
inappropriate when performing powder above average of 90 percent may be
blend/mixture uniformity or dosage form useful in terms of an overall
content uniformity determinations. assessment of process capabilities, the
individual assay results indicate non-
In these cases, the testing is intended
conformance because two of the three
to measure variability within the
product, and the individual results results are outside of the range. A low
should be reported. assay value should also trigger
It should be noted that a test might concerns that the batch was not
formulated properly because the batch
consist of replicates to arrive at a
must be formulated with the intent to
result. For instance, an HPLC assay
provide not less than 100 percent of the
result may be determined by averaging
labeled or established amount of active
the peak responses from a number of
consecutive, replicate injections from ingredient (21 CFR 211.101(a)). The
the same preparation (usually 2 or 3). above example does not necessarily

Handbook of Pharmaceutical Sect: 13.33

13.33 Generic Development
 ORAL TABLETS ANALYTICAL DEVELOPMENT CHAPTER 13

require the manufacturer to fail the response can be a serious source of

batch, but indicates that an immediate bias. . .the rejection of observations
investigation should be conducted for solely on the basis of their relative
batch disposition decisions. magnitudes is a procedure to be used
sparingly" (USP 23, p. 1705).
4. OUTLIER TESTS
For validated chemical tests with
The CGMP regulations require that
relatively small variance, and if the
statistically valid quality control criteria sample being tested can be considered
include appropriate acceptance and/or homogeneous (for example, an assay
rejection levels (§ 211.165(d)). On rare of composited dosage form to
occasions, a value may be obtained determine strength), an outlier test is
that is markedly different from the only a statistical analysis of the data
others in a series obtained using a obtained from testing and retesting.
validated method. Such a value may
qualify as a statistical outlier. An outlier It will not identify the cause of an
may result from a deviation from extreme observation and, thus should
prescribed test methods, or it may be not be used to invalidate the data.
the result of variability in the sample. An outlier test may be useful as part of
It should never be assumed that the the evaluation of the significance of
reason for an outlier is error in the that result for batch evaluation, along
testing procedure, rather than inherent with other data.
variability in the sample being tested. Don't Use
Outlier testing is a statistical procedure Outlier Testing in
for identifying from an array those data Dissolution Content Uniformity
that are extreme. The possible use of (i.e. where variability exists)
outlier tests should be determined in
advance. This should be written into
Outlier tests have no applicability in
SOPs for data interpretation and be cases where the variability in the
well documented. product is what is being assessed,
such as for content uniformity,
The SOPs should include the specific dissolution, or release rate
outlier test to be applied with relevant determinations.
parameters specified in advance.
In these applications, a value
The SOPs should specify the minimum
perceived to be an outlier may in fact
number of results required to obtain a
be an accurate result of a non-uniform
statistically significant assessment from
product.
the specified outlier test.
4
For biological assays having a high V. CONCLUDING THE INVESTIGATION
variability, an outlier test may be an To conclude the investigation, the
appropriate statistical analysis to results should be evaluated, the batch
identify those results that are quality should be determined, and a
statistically extreme observations. release decision should be made.
The USP describes outlier tests in the The SOPs should be followed in
section on 'Design and Analysis of arriving at this point. Once a batch has
Biological Assays' (USP 23, p. 1705). In been rejected, there is no limit to
these cases, the outlier observation is further testing to determine the cause
omitted from calculations. The USP of the failure so that a corrective action
also states that "arbitrary rejection or can be taken.
retention of an apparently aberrant

Handbook of Pharmaceutical Sect: 13.34

13.34 Generic Development
 ORAL TABLETS ANALYTICAL DEVELOPMENT CHAPTER 13

[A]. Interpretation of Investigation Results [2] does not confirm the OOS result —
An OOS result does not necessarily the OOS result should be retained in
mean the subject batch fails and must the record and given full consideration
be rejected. in the batch or lot disposition decision.

OOS Results OOS Results

Do Not Use the results
Automatically of inconclusive
Fail the Batch investigations
(investigate & interpret fully) (Consider with other data)
The OOS result should be Statistical treatments of data should
not be used to invalidate a discrete
investigated, and the findings of the
chemical test result.
investigation, including retest results,
In very rare occasions and only after a
should be interpreted to evaluate the
full investigation has failed to reveal the
batch and reach a decision regarding
cause of the OOS result, a statistical
release or rejection (§ 211.165).
analysis may be valuable as one
In those instances where an assessment of the probability of the
investigation has revealed a cause, OOS result as discordant, and for
and the suspect result is invalidated, providing perspective on the result in
the result should not used to evaluate the overall evaluation of the quality of
the quality of the batch or lot. the batch.
Invalidation of a discrete test result Records must be kept of complete data
may be done only upon the observation derived from all tests performed to
and documentation of a test event that ensure compliance with established
can reasonably be determined to have specifications/standards (21 CFR 211.194).
caused the OOS result. [B]. Reporting
In those cases where the investigation For those products that are the subject
indicates an OOS result is caused by a of applications, regulations require
factor affecting the batch quality (i.e., submitting within three working days a
an OOS result is confirmed), the result Field Alert Report (FAR) of information
should be used in evaluating the quality concerning any failure of a distributed
of the batch or lot. batch to meet any of the specifications
A confirmed OOS result indicates that established in an application (21 CFR
314.81(b)(1)(ii).
the batch does not meet established
standards or specifications and should
OOS test results not invalidated on
distributed batches/lots for this class of
result in the batch's rejection, in
products are considered to be one kind
accordance with § 211.165(f), and
of “information concerning any failure”
proper disposal.
described in this regulation.

For inconclusive investigations — in This includes OOS results that are

considered to be discordant and of low
cases where an investigation:-
value in batch quality evaluation. In
[1] does not reveal a cause for the
these cases, a FAR should be
OOS test result and
submitted.

Handbook of Pharmaceutical Sect: 13.35

13.35 Generic Development
 ORAL TABLETS ANALYTICAL DEVELOPMENT CHAPTER 13

THE INS and OUTS of OUTLIERS

OUTLIERS
MAYBE:
OUTLIERS OUTLIERS
CAN BE:

TEST SAMPLE
DEVIATIONS VARIABILITY

Your BEST assumption

when you get an outlier is
a variation in the sample

Don’t - use the outlier The statistical outlier test

test outside the USP cannot be used when you are
specifications prescribed testing for variation in the
sample

Don't assume an
way out result must be
a testing error UNIFORMITY
DISSOLUTION
OF
TESTING
CONTENT

(COURTESY: IJGD
Vol. 02 #07 (1998)
international Journal of Generic Drugs

The Development The Development

unit must have a unit must train
clear and well defined personnel to use
outlier SOP outliers correctly

Handbook of Pharmaceutical Sect: 13.36

13.36 Generic Development
 ORAL TABLETS ANALYTICAL DEVELOPMENT CHAPTER 13

DECISION OOS DETECTED

TREE. (Follow Route 'A' and Route 'B')
(COURTESY: IJGD Vol. 02 #07 1998)

YES

B A
PRODUCTION Investigate LABORATORY

OOS NO NO
Clear laboratory
Retest
error
YES
YES
SPECIFICATION
FAILURE Same Sample
Different Analyst Invalidate
(Evaluate Batch result & retest
for Rejection) (DO NOT RETAIN RESULT)

IF

OOS NO

YES

Retain & Suspect Product

Report result result PASSES

The

RE-SAMPLE
New representative
specimen

IF

YES OOS NO
Don't Apply Outliers To:
Content Uniformity
Dissolution test
Composite Assays

Out-of-Specification Decision Tree

Handbook of Pharmaceutical Sect: 13.37

13.37 Generic Development
 ORAL TABLETS ANALYTICAL DEVELOPMENT CHAPTER 13

ASSAY VALIDATION

Ruggedness
and

Robustness

♦ Different elapsed assay times

R
uggedness and robustness testing is
applicable to pharmaceutical R&D
and QC Laboratories, especially ♦ Different assay temperatures …"
when methods are transferred and These factors are all external to the written
distinguishes the similarities and differences analytical method and each parameter should
between the two analytical concepts and show a lack or indeed absence of influence
how they are applied in the laboratory. on the test results obtained.
Analytical methods are usually developed in But what about the internal factors of the
an R&D laboratory and eventually written test method such as a change in the
transferred to the production quality control flow rate (mL/min) or the concentration of
laboratory for routine product analysis. This the organic acid in mobile phase (HPLC
process of technical data transfer from one systems) or better still, a change from a
lab to the other requires a clear Phenomenex Bondclone™ 10µ C-18
demonstration that the methodology can be column to a Waters µ-Bondapak™ 10µ C-
successfully transferred. How is it done? 18 column? These small but deliberate
There is an easy-to-use procedure to meet internal variations in method parameters of
this regulatory and compendial requirement. the written analytical procedure should be
evaluated to access whether the analytical
Ruggedness procedure remains unaffected by these slight
is a USP changes.

Requirement Robustness is defined by both the USP and

the ICH Tripartite guidelines as "a measure
Robustness of its capacity to remain unaffected by small
but deliberate variations in method
is not. parameters and provides an indication of its
reliability during normal use " Robustness
Ruggedness and Robustness.
is defined both in the USP and ICH, but is
The USP defines ruggedness as "the degree
not required.
of reproducibility of test results obtained by
the analysis of the same samples under a Furthermore, ruggedness measures the lack
variety of normal test conditions such as: of external influence on the test results
♦ Different laboratories whereas robustness measures the lack of
internal influences on the test results.
♦ Different analysts Internal and external variations are often
♦ Different instruments mixed together in analytical validation
♦ Different reagent lots packages erroneously, under the heading of
one or the other. Internal and external
♦ Different analysis days analytical parameters should be separated

Handbook of Pharmaceutical Sect: 13.38

13.38 Generic Development
 ORAL TABLETS ANALYTICAL DEVELOPMENT CHAPTER 13

and appraised individually. A simple Even more dramatic, for eleven variables
experimental design can evaluate both (11 x 12) a minimum of 132 one-factor-at-a-
ruggedness and robustness, as separate time data points would be required, but via
distinguishable entities - together. matrix testing using an twelve-run design,
only 12 HPLC assays are needed to produce
Table 1 Comparison Table. the equivalent of 132 individual one-factor-
Attribute. Ruggedness. Robustness. at-time assays.
USP Validation þ ý
Few, if any HPLC assay analytical methods
Requirement could have more than 12-15 significant
ICH Validation environmental or method variations.
ý ý
Requirement Table 1.
Internal change ý þ An Eight Run Design Template
External / Internal ASSAY
External change þ - Test Changes / Variations TEST
Method - þ No A B C D E F G RESULT
Variations
Environmental þ - 1 + + + − + − − 99.3
Variations 2 − + + + − + − 101.5
3 − − + + + − + 100.4
Designing Analytical Experiments
4 + − − + + + − 97.9
Such a designed experiment can
demonstrate that methodology and 5 − + − − + + + 98.5
environmental factors may or may not 6 + + − − + + 99.0
influence the test results. It is hoped that the 7 + + + − − + 97.9
analytical method is both rugged and robust,
however a well designed experiment may 8 − − − − − − − 100.9
identify test conditions or specification limits The (+) or (-) signs are used as variables in the 8 run
design. Assign (-) to Analyst I ; Day I; Column I and
that need to be closely controlled and (+) to Analyst II; Day II; Column II and so on
tightened or even test parameters that need A to G are chosen as the external variations
further investigation and optimization. (ruggedness) anticipated to arise during use in the
Development Lab.
Advantages - Designing the Experiment Table 2. 8 RUN DESIGN
A designed experiment is a simple matrix
design. The Plackett-Burman designs are Template for Ranked Effect and Means
most applicable to technical transfer of a External & Internal Ranked M
validated analytical methods from changes/variations Effects values
development to quality control centres. For
A - Analyst I & II 1.8 -1.35
the most cost-effective design, the attributes
of both R&D and QC laboratories should be F - Analyst III & IV -0.76
incorporated into development validation G - Reagents I & II -0.35
protocol of the assay method. E - Week I & II 0
The advantages of these designs are quite B - Week III & IV +0.35
simple - the number of tests required is
C - Column I & II +0.76
simply dramatically reduced. 56 assays (i.e.
7 x 8) are needed to evaluate seven internal D - HPLC No I & No II 0 +1.35
and/or external variables, these can be The M values are obtained from statistical design
reduced to eight quick assays using an eight- tables. The ranked Effects are calculated by simple
addition of assay test results and then dividing by
run Plackett-Burman design.
half the number of runs (i.e. 4 in a 8 run design).

Handbook of Pharmaceutical Sect: 13.39

13.39 Generic Development
 ORAL TABLETS ANALYTICAL DEVELOPMENT CHAPTER 13

Calculating the Ranked Effects ruggedness and robustness when transferring

For A Figure 1. a method to another laboratory.
99.3 + Table 3.
101.5 − An Twelve Run Design Template
100.4 − External / Internal ASSAY
97.9 + Sum the Assay Changes / Variations (11) TEST
98.5 − values by
No A B C D E F G H I J K
assigning RESULT
99.0 + a positive or
97.9 + negative value 1 + + − + + + − − − + − 99.3
100.9 − obtained from 2 − + + − + + + − − − + 101.5
the 8 run
-7.2 ∑ 3 + − + + − + + + − − − 100.4
design
-1.8 /4 4 − + − + + − + + + − − 97.9
5 − − + − + + − + + + − 98.5
For D Figure 2. 6 − − − + − + + − + + + 99.0
99.3 − 7 + − − − + − + + − + + 98.8
101.5 + 8 + + − − − + − + + − + 99.9
100.4 + 9 + + + − − − + − + + − 100.6
97.9 + Perform this 10 − + + + − − − + − + + 98.9
98.5 − addition for 11 + − + + + − − − + − + 97.9
each of the eight
99.0 − variables and 12 − − − − − − − − − − − 100.9
97.9 + divide the The (+) or (-) signs are used as variables in the 12 run
100.9 − sum by 4 design. Assign (-) to Analyst I ; Day I; Column I and (+) to
(half the number Analyst II; Day II; Column II and so on…
0 ∑ of runs) A to K are chosen as the external (ruggedness) / internal
0 /4 (robustness) variations anticipated during the transfer from
the R&D to QC laboratory.
The assay results are entered into the table on completion of
Results. the12 HPLC assay analyses.
A linear-linear scale is used. Plotting the Table 4.
Ranked Effect on the X-axis vs. the M Template for Ranked Effect and Means
values on the Y-axis produce a normal External & Internal Ranked M
probability plot of effects. If a value lies changes/variations Effects values
outside this straight line one can conclude A- R&D & QC Lab -1.59
that the method is not rugged / or robust, as F- Day I & II -1.06
classified, for that particular variable (e.g. G- Analyst I & II -0.73
[say] flow rate). E- Analyst III & IV -0.46
B- Reagents I & II -0.22
12 Run Designs.
H- [Solvent] I & II +0.00
A template for 12 run design is used (Tables
C- Heating Rate I & II +0.22
3 & 4), when more than seven factors are
J - Column I & II +0.46
present. This design will give 11 factors for
K- Temperature I & II +0.73
analysis. The M values are constant for any
I - Flow rate I & II +1.06
given design and are actually the means of
D- Elapsed time I & II +1.59
the order statistics (3) for a sample size of
The M values are obtained from statistical design tables.
eleven. As they always remain the same, the The Ranked Effects are calculated by simple addition of
template can be used for any ruggedness / (-) (+) assay test results and then dividing by half the
Robustness validation method protocol. Use number of runs (i.e. divide by 6 in a 12 run design).
a Eight Run for evaluating say, ruggedness The effects form A - K were selected as the most
significant variables between the two labs. Templates are
only, and a Twelve Run design for both available for up to 100 run variables (100 x 99).

Handbook of Pharmaceutical Sect: 13.40

13.40 Generic Development
 ORAL TABLETS ANALYTICAL DEVELOPMENT CHAPTER 13

Method Procedure.
1. Choose the number of variables required Process Qualification Stage.
and select a run design template. The evaluation of ruggedness and
robustness should be finalised at the end
2. Assigning the minus (-) or plus (+) values: of the development phase - around the
These are arbitrary designations. As a time of the process qualification lot
standard rule assign a 'minus' (-) to I or a
manufacture. The
lower limit and a 'plus' (+) to II or a upper
ruggedness/robustness evaluation should
limit. Evaluate a range limit by assign (-)
value for lower and (+) value for higher (i.e. be developed with the commercial
Flow rate 1.2 mL/min assign (-) and 1.8 laboratory equipment in mind. It should
mL/min assign (+)). Likewise Day I assign (- show the reliability of an analysis with
) and Day II assign (+) and so on… respect to deliberate variations in the
method parameters.
3. Perform the HPLC assays in a random
order. Ruggedness/robustness determinations
are essential when transferring analytical
4. Tabulate the assay results in the template.
methods from the development
5. Calculate the Effects (Figures 1 and 2). laboratory to the commercial plant
6. Rank the Effects from smallest to largest. quality control laboratory. There may
usually be a difference in columns or
7. Plot the Effects against the M values.
HPLC machine models used.
8. Evaluate the plot. A consequence of ruggedness /
Conclusion. robustness evaluation is that a series of
The results from the plot form a near system suitability parameters are
straight line. It can be concluded that the established to ensure that the validity of
analytical method is (a) rugged for the the analytical procedure is maintained
external factors over the tested range and whenever used.
(b) robust for the internal factors over the
tested range in the 12 run design.
References:
Figure 3.
1. "Validation of compendial methods" USP 23
A Normal Probability Plot of Effects <1225> USPC Rockville Maryland USA 1994.
2. International Conference on Harmonization
+1.5 "Guidelines on validation of Analytical
* Procedures: Definitions and Terminology…;
M Federal Register (March 1, 1995.)
* 3. "Validation of compendial methods" USP 23
V <1225> USPC Rockville Maryland USA 1994.
A * 4. USP/NF XXIII USPC Rockville Maryland USA
L 1994.
U * 5. Scale up and Post approval Changes
E Manufacturing and Controls In vitro Dissolution
S * and In Vivo Bioequivalence Documentation
CEDER 1995 (SUPAC)
* 6. ASTM Standard Guide For Conducting
Ruggedness Tests E1169 American Society for
* testing Materials Philadelphia 1989.
-1.5 7. Kateman and L. Buydens, The Ruggedness Test
Quality Control in the Analytical chemistry John
-8 Ranked Effects +7
Wiley and Sons NY 2nd Edition 1993, pp118
125.

Handbook of Pharmaceutical Sect: 13.41

13.41 Generic Development
 ORAL DOSAGE FORMS ANALYTICAL DEVELOPMENT CHAPTER 13

ANDAs Impurities in
Drug Substances.
IAGIM Scientific Committee GUIDANCE FOR INDUSTRY
Block JD; Holmann E ; West P

INTRODUCTION
TABLE OF CONTENTS - 11/1999
Evaluate & Compare
I. INTRODUCTION
Innovator Drug
II. CLASSIFICATION OF IMPURITIES
III. RATIONALE FOR THE REPORTING AND
CONTROL OF IMPURITIES
Impurities
A. Organic Impurities
B. Inorganic Impurities
CHEMISTRY ASPECTS
C. Residual Solvents including classification and
IV. ANALYTICAL PROCEDURES identification of impurities, generating
V. REPORTING IMPURITY CONTENT OF reports, setting specifications, and a
BATCHES brief discussion of analytical
VI. ACCEPTANCE CRITERIA FOR IMPURITIES procedures; and
VII. QUALIFICATION OF IMPURITIES SAFETY ASPECTS,
VIII. NEW IMPURITIES including comparative studies and
ATTACHMENT I — Impurities Decision Tree (Generic genotoxicity testing. Specific guidance is
Drug Substance)
provided for:
ATTACHMENT II — ICH Decision Tree for Safety
Studies l Qualifying impurities found in a drug
ATTACHMENT III — Glossary substance used in an ANDA by a
comparison with impurities found in the
ANDAs: Impurities in Drug related U.S. Pharmacopeia (USP)
Substances. [Nov 1999] monograph, scientific literature, or
INTRODUCTION innovator material;

T his FINAL guidance of Nov. 1999

provides recommendations for
including information in abbreviated new
l Qualifying impurities found at higher
levels in a drug substance used in an
ANDA than found in the related USP
drug applications (ANDAs) and monograph, scientific literature, or
supporting drug master files (DMFs) on innovator material;
the identification and qualification of
impurities in drug substances produced
Ø Qualifying impurities in a drug
substance used in an ANDA that are
by chemical syntheses for both
not found in the related USP
monograph and non-monograph drug
monograph, scientific literature, or
substances. Impurities in drug
innovator material; and Threshold levels
substances are addressed from two
below which qualification is not needed.
perspectives:

Handbook of Pharmaceutical Sect: 13.42

13.42 Generic Development
 ORAL DOSAGE FORMS ANALYTICAL DEVELOPMENT CHAPTER 13

This guidance is NOT applicable to; establishes the biological safety of

individual impurities or a given impurity
Ø Biological/biotechnological profile at the levels specified).
Ø Peptide Generic drugs are not covered by ICH
Ø Oligonucleotide Q3A; however, many of the
Ø Radiopharmaceutical recommendations in ICH Q3A are
Ø Fermentation applicable to drug substances used in
generic drug products.
Øsemi-synthetic products derived
therefrom, herbal products, or crude To provide, to the extent possible,
products of animal or plant origin. comparable processes for new and
generic drug review, this guidance was
The recommendations in this guidance developed using the ICH Q3A
are effective on publication and should
framework.
be followed in preparing new
applications and supplements for An FDA meeting2 recommended that
changes in drug substance synthesis or there should be a 0.1 percent threshold
process. above which isolation and
However, if the information in a drug characterization of individual impurities
should apply to chemically synthesized
substance DMF cited in such an ANDA
drug substances including drug
or ANDA supplement has been
substances used in generic drug
reviewed prior to the publication of this
products.
final guidance, this guidance does not
apply. For compendial materials, the USP 23
in General Notices and Requirements
Evaluate this (p. 7) states that it is manifestly
impossible to include in each
Draft Guidance monograph a test for every impurity that
side-by-side may arise from a change in the source
of material or a change in processing.
with Q3A & Q3A(R) Consequently, few USP monographs
have acceptance criteria for individually
This guidance is intended to be a
identified impurities.
companion document to the
International Conference on However, USP has adopted a 0.1
Harmonization (ICH) guidance Q3A percent threshold for impurity
Impurities in New Drug Substances. identification via the publication of Other
Impurities in General Notices and
The ICH Q3A guidance1 was published Requirements (Sixth Supplement, p. 3636),
on January 4, 1996 and issued as a
became official on November 15, 1996.
Center for Drug Evaluation and
II. CLASSIFICATION OF IMPURITIES
Research (CDER) guidance. ICH Q3A
provides recommendations for inclusion Impurities can be classified into the
of information regarding specified following categories:
impurities in certain new drug Organic Impurities (Process and
applications (NDAs) (identified and
Drug Related)
unidentified impurities in new drug
substance specifications) and Inorganic Impurities
qualification of impurities (the process of
acquiring and evaluating data that
Residual Solvents
2
1 June 22, 1993 - Ad Hoc Advisory Committee
Federal Register (61 FR 371)

Handbook of Pharmaceutical Sect: 13.43

13.43 Generic Development
 ORAL DOSAGE FORMS ANALYTICAL DEVELOPMENT CHAPTER 13

n Organic impurities III. RATIONALE FOR THE REPORTING

May arise during the manufacturing AND CONTROL OF IMPURITIES
process and/or storage of the drug n (A) Organic impurities
substance. They may be identified or The DMF holder or the ANDA applicant
unidentified, volatile or non-volatile, and should summarize those actual and
include: potential impurities most likely to arise
Ø Starting materials during the synthesis, purification, and
Ø By-products storage of the drug substance.
Ø Intermediates Obtain a
Ø Degradation products
Ø Reagents, ligands, and catalysts Drug Substance
Organic Impurities Impurities Report
that are degradants from DMF Holders
This
are the most DMF
summary should be based on
sound scientific appraisal of the
Significant chemical reactions involved in the
synthesis, impurities associated with
n INORGANIC IMPURITIES raw materials that could contribute to
May derive from the manufacturing the impurity profile of the drug
process. They are normally known and substance, and possible degradation
identified and include: products.
Ø Reagents, ligands, and catalysts This discussion may include only those
impurities that may reasonably be
Ø Heavy metals expected based on knowledge of the
Ø Inorganic salts chemical reactions and conditions
Ø Other materials (e.g., filter aids, involved.
charcoal) In addition, the DMF holder or the
n RESIDUAL SOLVENTS ANDA applicant should summarize the
Are organic or inorganic liquids used laboratory studies conducted to detect
during the manufacturing process. impurities in the drug substance.
Because these are generally of known
toxicity, the selection of appropriate A Comparative
controls is easily accomplished.
Stress Study on the
Excluded from this document are drug substance
(1) Extraneous contaminants, which & ANDA formula
should not occur in drug substances
and are more appropriately addressed is essential
as good manufacturing practice issues
(2) Polymorphic form, a solid state
This summary should include test
results of materials manufactured during
property of the drug substance; and
the development process and batches
(3) Enantiomeric impurities. from the proposed commercial process,
as well as results of intentional

Handbook of Pharmaceutical Sect: 13.44

13.44 Generic Development
 ORAL DOSAGE FORMS ANALYTICAL DEVELOPMENT CHAPTER 13

degradation studies used to identify Identification of impurities below

potential impurities that arise during apparent levels of 0.1 percent is
storage. generally not considered necessary.
Assessment of the proposed
commercial process may be deferred Do not ID stability
until the first batch is produced for
marketing.
impurity/degradants
The impurity profile of the drug BELOW 0.1%
substance lots intended for marketing However, identification should be
should be compared with those used in attempted for those potential impurities
development and any differences that are expected to be unusually
discussed. potent, producing toxic or
The studies (e.g., NMR, IR, and MS) pharmacologic effects at a level lower
conducted to characterize the structure than 0.1 percent. In all cases, impurities
of actual impurities present in the drug should be qualified as described later in
substance at or above an apparent level this guidance.
of 0.1 percent (e.g., calculated using the Although it is common practice to round
response factor of the drug substance) analytical results of between 0.05 and
should be described. 0.09 percent to the nearest number (i.e.,
All recurring impurities at or above an 0.1 percent), for the purpose of this
apparent level of 0.1 percent (see guidance, such values should not be
section IV) in batches manufactured by rounded to 0.1 percent in determining
the proposed commercial process whether to identify the impurities.
should be identified.
Do not round
Degradation products observed in
stability studies at recommended impurity assays
storage conditions should be similarly
identified. {above 0.1%} up to 0.1%
When identification of an impurity is not n (B) INORGANIC IMPURITIES
feasible, a summary of the laboratory Inorganic impurities are normally
studies demonstrating the unsuccessful detected and quantitated using
effort should be included in the DMF or pharmacopoeial or other appropriate
application. procedures. Carryover of catalysts to
Where attempts have been made to the drug substance should be evaluated
identify impurities below the 0.1 percent during development.
level, it is useful also to report the The necessity for inclusion or exclusion
results of these studies. of inorganic impurities in the drug
Summaries of substance specifications should be
discussed. Acceptance criteria should
unidentifiable be based on pharmacopoeial standards
or known safety data.
Drug Substance n (C) RESIDUAL SOLVENTS
Impurities are The control of residues of solvents used
in the manufacturing process for the
required from drug substance should be discussed.
Any solvents that may appear in the
DMF Holders drug substance should be quantified

Handbook of Pharmaceutical Sect: 13.45

13.45 Generic Development
 ORAL DOSAGE FORMS ANALYTICAL DEVELOPMENT CHAPTER 13

using analytical procedures with an standard or to the response of the drug

appropriate level of sensitivity. substance itself.
Inorganic impurities Reference standards used in the
analytical procedures for control of
are seldom impurities should be evaluated and
characterized according to their
a problem intended uses.
Pharmacopeial or other appropriate It is considered acceptable to use the
procedures should be used. Acceptance drug substance to estimate the levels of
criteria should be based on impurities when the response factors of
pharmacopeial standards or known the drug substance and impurities are
safety data, taking into consideration close. In cases where the response
dose, duration of treatment, and route of factors are not close, this practice may
administration. still be acceptable, provided a correction
Particular attention should be given to factor is applied or the impurities are, in
fact, being overestimated.
quantitation of toxic solvents used in the
manufacturing process as described in Analytical procedures used to estimate
the ICH guidance Q3C Impurities: identified or unidentified impurities are
Residual Solvents often based on analytical assumptions

Residual solvents
(e.g., equivalent detector response).
These assumptions should be
have their own discussed in the DMF submission or
abbreviated application.
guidelines V. REPORTING IMPURITY CONTENT
IV. ANALYTICAL PROCEDURES OF BATCHES
The DMF or abbreviated application Analytical results should be provided
(ANDA) should include documented for all batches of the drug substance
evidence that the analytical procedures used for stability testing, as well as for
are validated and suitable for the batches representative of the proposed
detection and quantitation of impurities. commercial process.

New Draft LoDs are

Analytical Validation about 2 - 4 times
Guidelines above baseline noise
LoQs are at least
(To replace the Old 1987 Guide - Sept 2000)
Differences in the analytical procedures
used during development and proposed double LoDs
for the commercial product should be (DL = Detection limit = LoDs)
discussed in the DMF or abbreviated (QL= Quantitation limit = LoQs)
application (ANDA). The content of individual impurities,
Organic impurity levels can be both identified and unidentified, and
measured by a variety of techniques, total impurities observed in these
including those that compare an batches of the drug substance should
analytical response for an impurity to be reported with the analytical
that of an appropriate reference procedures indicated.

Handbook of Pharmaceutical Sect: 13.46

13.46 Generic Development
 ORAL DOSAGE FORMS ANALYTICAL DEVELOPMENT CHAPTER 13

A tabulation (e.g., spreadsheet) of the impurities likely to occur in the

data is recommended. Impurities should commercial product.
be designated by code number or by an The selection of impurities to include in
appropriate descriptor, for example, the drug substance specification should
name or retention time. be based on the impurities found in the
Levels of impurities that are present but batches manufactured by the proposed
are below the validated limit of commercial process.
quantitation (LOQ) are not reported. Those impurities selected for inclusion
If analytical procedures change during in the specification for the drug
development, reported results should be substance are referred to as specified
linked with the procedure used, and impurities in this guidance. Specified
appropriate validation information impurities may be identified or
should be provided. unidentified and should be individually
listed in the drug substance
Representative chromatograms should specification (see below).
be provided. Chromatograms of such
representative batches, from methods
A rationale for the inclusion or
validation studies showing separation exclusion of impurities in the
and detectability of impurities (e.g., on specification should be presented. This
spiked samples), along with any other rationale should include a discussion of
impurity tests routinely performed, can the impurity profiles observed in batches
serve as the representative impurity under consideration, together with a
profiles. consideration of the impurity profile of
material manufactured by the proposed
The ANDA applicant or DMF holder commercial process.
should ensure that complete impurity
profiles (i.e., chromatograms) of stability A specified impurity
is synthesis
batches are available if requested.
A tabulation should be provided
comparing impurity levels between dependant
stability and other batches. For each
batch of the drug substance, the report Specific identified impurities should be
should include: included along with recurring
unidentified impurities estimated to be at
Ø Batch identity and size or above 0.1 percent.
Ø Date of manufacture For impurities known to be unusually potent
Ø Site of manufacture or to produce toxic or unexpected
Ø Manufacturing process pharmacological effects, the quantitation
and/or detection limit of the analytical
Ø Impurity content, individual and total methods should be commensurate with the
Ø Use of batches level at which the impurities need to be
controlled. For unidentified impurities, the
Ø Reference to analytical tests used procedure used and assumptions made in
VI. ACCEPTANCE CRITERIA establishing the level of the impurity should
FOR IMPURITIES be clearly stated.
The specification for a drug substance Different suppliers
should include acceptance criteria for
impurities. Stability studies, chemical
may have different
development studies, and routine batch 'specified impurities'
analyses can be used to predict those (different routes of synthesis)

Handbook of Pharmaceutical Sect: 13.47

13.47 Generic Development
 ORAL DOSAGE FORMS ANALYTICAL DEVELOPMENT CHAPTER 13

Unidentified impurities included in the Organic Impurities:

specification should be referred to by Ø Each specified identified impurity
some appropriate qualitative analytical
descriptive label (e.g., "unidentified A,"
Ø Each specified unidentified impurity
at or above 0.1 percent
"unidentified with relative retention of
0.9"). Ø Any unspecified impurity, with a limit
Finally, a general acceptance criteria of of not more than 0.1 percent
not more than 0.1 percent for any Ø Total impurities
unspecified impurity should be included. Residual Solvents
Acceptance criteria should be set no Inorganic Impurities
higher than the level that can be justified A summation of assay value and
(see the Impurities impurity levels generally may be used to
Decision Tree for generic drug obtain mass balance for the test sample.
substances, Attachment I) either by The mass balance need not add to
comparative studies or genotoxicity exactly 100 percent because of the
studies, and unless such data indicate analytical error associated with each
otherwise, no lower than the level analytical procedure.
achievable by the manufacturing
process and the analytical capability.
The summation of impurity levels plus
the assay value may be misleading, for
In other words, where there is no safety example, when the assay procedure is
concern, impurity acceptance criteria nonspecific (e.g., potentiometric
should be based on data generated on titrimetry) and the impurity level is
actual batches of the drug substance, relatively high.
allowing sufficient latitude to deal with VII. QUALIFICATION OF IMPURITIES
normal manufacturing and analytical
variation, and the stability
Qualification is the process of acquiring
characteristics of the drug substance. and evaluating data that establishes the
biological safety of an individual impurity
A specified or a given impurity profile at the levels

impurity is a impurity
specified.
Erratic
specified in the batch-to-batch
drug monograph impurity levels
(identified or unidentified) may indicated
Although normal manufacturing incomplete validation
variations are expected, significant
variation in batch-to-batch impurity The DMF holder or the ANDA applicant
levels could indicate that the should provide a rationale for selecting
manufacturing process of the drug impurity acceptance criteria based on
substance is not adequately controlled safety considerations.
and validated. The level of any impurity present in a
In summary, the drug substance drug substance that is in compliance
acceptance criteria should include, with a USP specification or has been
where applicable, acceptance criteria adequately evaluated in comparative or
for: in vitro genotoxicity studies or has been

Handbook of Pharmaceutical Sect: 13.48

13.48 Generic Development
 ORAL DOSAGE FORMS ANALYTICAL DEVELOPMENT CHAPTER 13

evaluated via an acceptable Proposals from applicants for

Quantitative Structure Activity alternative threshold levels will be
Relationships (QSAR) database considered by the FDA on a case-by-
program is considered qualified for case basis.
ANDAs.
The Impurities Decision Tree for
Impurities that are also significant generic drug substances (Attachment I)
metabolites do not need further describes considerations for the
qualification. qualification of impurities when
If data are unavailable to qualify the thresholds are exceeded.
proposed acceptance criteria of an In some cases, decreasing the level of
impurity, studies to obtain such data impurity below the threshold, rather than
may be needed when the usual providing additional data, may be the
qualification threshold levels given simplest course of action. Alternatively,
below are exceeded: adequate data may be available in the
scientific literature to qualify an impurity.
Maximum Daily Dose Qualification The studies that should be performed to
Threshold qualify an impurity will depend on a
Maximum Daily Dose Qualification Threshold number of factors, including the patient
≤2g/day 0.1% or 1 mg per population, daily dose, and route and
day (lowest value) duration of drug administration.
>2g/day 0.05% Such studies are normally conducted
on the drug substance containing the
impurities to be controlled, although
Higher or lower threshold levels for
studies using isolated impurities are
qualification of impurities may be acceptable.
appropriate for some individual drugs
based on scientific rationale and level of Five of the Six
concern, including drug class effects.
For example, qualification may be impurity levels
especially important when there is
evidence that such impurities in certain
impact on ANDAs
drugs or therapeutic classes have Levels L1 through L4 are
previously been associated with recommendations for the type of
adverse reactions in patients. information that would be considered to
In these instances, a lower qualification provide assurance that the impurity in
threshold level may be appropriate. question is "innocuous by virtue of
having no significant, undesirable
BPC Manufacturers biological activity in the amounts
present" (see USP <1086> Impurities in
should decrease Official Articles).

the impurity below Only in Level L5, where concern

regarding possible toxicity is indicated,
the maximum level is additional testing recommended (e.g.,
by a battery of in vitro genotoxicity
Technical factors (manufacturing
tests).
capability and control methodology) may
be considered as part of the justification Level L6 would be for those rare
for selection of alternative threshold instances where an impurity has not
levels. been qualified. In such cases, the ANDA

Handbook of Pharmaceutical Sect: 13.49

13.49 Generic Development
 ORAL DOSAGE FORMS ANALYTICAL DEVELOPMENT CHAPTER 13

would then fall outside the purview of The impurity is qualified if it is found at
section 505(j) of the Federal Food, similar levels (no more than twofold
Drug, and Cosmetic Act (the Act). higher, but not to exceed 1.0% for most
Additional clarification regarding the drug substances). Twofold higher
levels in the Impurities Decision Tree for criteria are justified for several reasons.
Unidentified
generic drug substances is provided
below:
The Levels impurities present
Ø First level (L1): Is the impurity in
question "above threshold"? (See the in both innovator &
generic are deemed
threshold table in section VII.)
This level is identical to the
corresponding level in the ICH Decision acceptable
Tree for Safety Studies (Attachment II).
Ø Second Level (L2): For example, the innovators' impurity
acceptance criteria are set higher than
Is the "structure elucidated"? levels observed in drug substances, and
This refers to structural identification or the safety studies that qualified the
characterization exactly as in the ICH innovators' drug substances are carried
Decision Tree for Safety Studies. out at significantly higher levels than the
However, in those rare cases where it is specifications agreed to under FDA's
not possible to identify the impurity by pharmacology and toxicology
structure, the efforts made should be evaluations.
satisfactorily documented. In certain dosage forms where
Once the impurity has been structurally sensitivity or toxicity concerns arise, the
identified, one could go to level L3. impurity levels should be no higher than
Ø Third Level (L3a): Compliance with a the innovator's level for toxic impurities.
USP acceptance criterion for a known In generic drugs, an unidentified
individual impurity (e.g., see impurity impurity may still be considered
listed in the Clidinium Bromide USP qualified in cases where the impurity is
monograph). observed at similar levels in the
innovator's product via a comparative
Evaluate 3 or more study.
innovators lots to Unidentified
establish ANDA's impurities present in
impurity baseline
the innovator drug
Third Level (L3b): A comparison of the
impurity profile of the generic drug are qualified
substance with the process impurities Third Level (L3c): This level looks at an
profile on an average of three or more
impurity at a "higher level, or a different
different lots of the innovator's drug
new impurity."
product is recommended.
New means one that was not previously
This comparative study should be seen in the bulk drug substance.
performed using appropriate The level of the new impurity may be
discriminating analytical tests such as
qualified from the scientific literature if it
HPLC or Capillary Electrophoresis.
is substantiated that this impurity is an

Handbook of Pharmaceutical Sect: 13.50

13.50 Generic Development
 ORAL DOSAGE FORMS ANALYTICAL DEVELOPMENT CHAPTER 13

ordinary impurity (see USP <1086>) at the

levels used. The scientific literature would Wherever possible
include recognized scientific publications.
the onus is on BPC
Alternatively, the new impurity may be
qualified by lowering it to below the ICH manufacturer to
lower or remove
threshold level, or by following the next
level in the Impurities Decision Tree for
generic drug substances.
the offending impurity
Ø Fourth Level (L4):
Is the impurity "related to others with Ø Fifth Level (L5): This level describes
known toxicity"? As one approach, the evaluation of the toxicity of an impurity
use of a Quantitative Structure Activity via a battery of in vitro genotoxicity tests
Relationships (QSAR) database (see the ICH Decision Tree for Safety
program may be helpful in identifying Studies regarding genotoxicity studies).
whether an impurity is related to others If the result of genotoxicity testing raises
of known toxicity. a concern, the need for additional
The use of such a program is toxicity testing will be evaluated on a
acceptable to the Office of Generic case-by-case basis.
Drugs (OGD). Modules currently Factors to be considered include the
recommended are: Rodent therapeutic use of the drug product, its
Carcinogenicity, Developmental Toxicity intended duration of use, and results of
Potential, Ames Mutagenicity (five the QSAR analysis.
strains), and for topicals, Skin However, even in those cases where no
Sensitization. potential for concern is indicated by the
If no potential for concern is indicated genotoxicity testing, the necessity for
by QSAR evaluation, the impurity is further toxicity testing should be
considered qualified, but it should not evaluated if the impurity level exceeds
exceed a level of 0.5 percent or 500 either 1 percent of the drug substance
micrograms per day, whichever is less or 1 mg/day, whichever is lower, at the
(equivalent to 0.5 percent of 100 mg of a human therapeutic dose of the drug
drug substance), without other product.
supporting data (such as genotoxicity If toxicity issues are confirmed by these
test data). in vitro tests, the DMF holder or ANDA
A determination to accept the QSAR applicant may either purify the drug
data will be made on a case-by-case substance to reduce the impurity to a
basis, taking into consideration the level below the ICH threshold or go to
therapeutic use of the drug product, it the next level (L6) in the Impurities
intended duration of administration, and Decision Tree for generic drug
the results of the QSAR analysis. substances.
However, if the QSAR evaluation does Level Six
not provide sufficient information
because the program cannot perform Impurity Testing
the evaluation due to the lack of
relevant information in the database, the violates the ANDA
manufacturer should lower the impurity
level to below the ICH threshold or submission status
qualify the new impurity at the L5 level.

Handbook of Pharmaceutical Sect: 13.51

13.51 Generic Development
 ORAL DOSAGE FORMS ANALYTICAL DEVELOPMENT CHAPTER 13

Ø Sixth Level (L6): Studies should compare the drug

This level involves qualification of the substances containing a representative
impurity "by general toxicity testing" level of the new impurity with previously
(see Attachment II, items 2 and 3). qualified material, although studies
using the isolated impurity are also
If this pathway is used, the ANDA would acceptable.
fall under section 505(b) of the Act.
General toxicity testing involves animal
testing, thus an application would not be 10 'RULES TO REMEMBER'
deemed acceptable by OGD under
section 505(j) of the Act. Rule No.1 - Evaluate the RLD
The drug substance manufacturer as impurity profile (i.e. get a through
well as the ANDA applicant should be baseline profile).
cognizant of this issue before the ANDA
applicant commits to extensive studies Rule No.2. Treat with CAUTION
with the bulk drug substance.
or REJECT a vendor impurity
VIII. NEW IMPURITIES profile HIGHER than the innovator
During the course of a drug material.
development program, the qualitative
impurity profile of the drug substance
may change or a new impurity may Rule No.3. LOOK at impurity
appear, for example, as a result of profiles in the major
synthetic route changes, process pharmacopoeia (USP / BP / JP)
optimization, or scale-up. and compare with vendor's
The impurity dedicated synthesis (comparing
profiles is important)
package depends on
the synthesis route
Rule No.4. 'Approved vendors'
may have unique impurities due to
New impurities may be identified or the purifying process.
unidentified. Such changes call for LOOK for these 'specified
consideration of the need for impurities' in the actives
qualification of the level of the impurity chromatograms (i.e. "Stress the
unless it is below the threshold values Active material").
as noted above.
When a new impurity exceeds the Rule No.5. Unknown impurities
threshold, the Impurities
(after stability testing) must not
Unidentified exceed 0.1% (if they do, go back to
below the level active vendor to clean up the
material).
Identified
above the level Rule No.6. Organic impurities are
Decision Tree for generic drug the main focus in impuritiy profiles
substances (Attachment I) should be
consulted.
(Note: residual solvents

Handbook of Pharmaceutical Sect: 13.52

13.52 Generic Development
 ORAL DOSAGE FORMS ANALYTICAL DEVELOPMENT CHAPTER 13

have there own guideline and Extraneous Substance: An impurity

limits). arising from any source extraneous to
the manufacturing process
Rule No.7. Do get the DMF Genotoxicity Tests: Genotoxicity tests
can be defined as in vitro tests designed
holder to state the 'specific to detect compounds that induce genetic
impurities' and the potential damage directly or indirectly by various
impurities (i.e. those impurities mechanisms.
which do arise and those which Compounds that are positive in tests
that detect such kinds of genetic
can arise). damage have potential to be human
carcinogens and/or mutagens (i.e., may
Rule No.8. Always stress the induce cancer and/or heritable
active material in-house to see damage).
which impurities do occur. Herbal Products: Medicinal products
containing, exclusively, plant material
Rule No.9. In drug development, and/or vegetable drug preparations as
if the active has an unknown active ingredients. In some traditions,
materials of inorganic or animal origin
>0.1% - and it can not be reduced
may also be present.
- Look for an alternative supply Identified Impurity: An impurity for
with a better profile. which a structural characterization has
been achieved
Rule No.10. REMEMBER an Impurity: Any component of the drug
unknown impurity close to 0.1% substance that is not the chemical entity
may grow to >0.1% on stability defined as the drug substance
(ageing). There's no such concept Impurity Profile: A description of the
identified and unidentified impurities
as a safe unknown >0.1%
present in a drug substance
Intermediate: A material produced
Glossary of Terms during steps of the synthesis of a drug
Acceptance Criteria: Numerical limits, substance that must undergo further
ranges, or other suitable measures for molecular change before it becomes the
acceptance of the results of analytical drug substance
procedures Ligand: An agent with a strong affinity
Chemical Development Studies: to a metal ion
Studies conducted to scale-up, optimize, Mass Balance: The process of adding
and validate the manufacturing process together the assay value and levels of
for a drug substance degradation products to see how closely
Drug Substance: The designated these add up to 100 percent of the initial
therapeutic moiety. See also the value, with due consideration of the
definition in 21 CFR 314.3. margin of analytical precision.
Enantiomers: Compounds with the New Drug Substance: The designated
same molecular formula as the drug therapeutic moiety that has not been
substance, which differ in the spatial previously registered in a region or
arrangement of atoms within the member state (also referred to as a new
molecule and are nonsuperimposable molecular entity or new chemical entity).
mirror images It can be a complex, simple ester, or salt
of a previously approved drug
substance.

Handbook of Pharmaceutical Sect: 13.53

13.53 Generic Development
 ORAL DOSAGE FORMS ANALYTICAL DEVELOPMENT CHAPTER 13

Polymorphism: The occurrence of unidentified impurity that is selected for

different crystalline forms of the same inclusion in the drug substance
drug substance specifications and is individually listed
Potential Impurity: An impurity that, and limited to ensure the safety and
from theoretical considerations, arising quality of the drug substance
from or during manufacture. It may or Starting Material: A material used in
may not appear in the drug substance. the synthesis of a drug substance that is
Qualification: The process of acquiring incorporated as an element into the
and evaluating data that establishes the structure of an intermediate and/or of
biological safety of an individual impurity the drug substance. Starting materials
or a given impurity profile at the levels normally are commercially available and
specified of defined chemical and physical
Quantitative Structure Activity properties and structure.
Relationship (QSAR): Used for Toxic Impurity: Impurities having
rationalization and prediction of in vivo significant undesirable biological activity
mammalian toxicity of chemicals on the Unidentified Impurity: An impurity that
basis of their overall and/or local is defined solely by qualitative analytical
properties, as defined by their chemical properties (e.g., chromatographic retention time)
structure and evaluated by using an Validated Limit of Quantitation: For
appropriate database and modules impurities at a level of 0.1 percent, the
Reagent: A substance, other than a validated limit of quantitation should be
starting material or solvent, used in the less than or equal to 0.05 percent.
manufacture of a drug substance Impurities limited at higher levels may
Safety Information: The body of have higher limits of quantitation.
information that establishes the
biological safety of an individual impurity
or a given impurity profile at the levels
Do's & Don'ts
specified Do establish all the potential impurities
Solvent: An inorganic or an organic that can arise from the approved
liquid used as a vehicle for the manufacturers (suppliers) synthesis
preparation of solutions or suspensions pathway.
in the synthesis of a drug substance Do collaborate with the approved
Specification: A list of tests, references supplier on which residual impurities
to analytical procedures, and actually remaining in the active drug
appropriate acceptance criteria that are substance.
numerical limits, ranges, or other criteria Don't qualify an impurity if it can be
for the tests described. It establishes the removed from the active material.
set of criteria to which a drug substance Don't exceed the RLD's impurity levels.
or drug product should conform to be Don't test for other synthesis pathway
considered acceptable for its intended impurities
use. ----------------------------------------------
Conformance to specifications means WHO PREPARED THIS GUIDANCE
that the drug substance and/or drug This guidance has been prepared under the direction of the
Chemistry, Manufacturing, and Controls 1 Coordinating
product, when tested according to the Committee (CMC CC) in the Center for Drug Evaluation and
listed analytical procedures, will meet Research (CDER) at the Food and Drug Administration. This
guidance document represents the Agency's current thinking
the listed acceptance criteria. on the review of impurities in drug substances used in generic
Specifications are binding quality drug products. It does not create or confer any rights for or on
any person and does not operate to bind FDA or the public. An
standards that are agreed to between alternative approach may be used if such approach satisfies the
the appropriate governmental regulatory requirements of the applicable statutes, regulations, or both.
agency and the applicant. ----------------------------------------------
Specified Impurity: An identified or

Handbook of Pharmaceutical Sect: 13.54

13.54 Generic Development
 ORAL DOSAGE FORMS ANALYTICAL DEVELOPMENT CHAPTER 13

DISPARITY of IMPURITIES From Table 1 Felodipine ER 10mg

Table 1 showing amount of unknown unknown impurities at 0.094% may not
impurity intake versus maximum daily exceed 9 µg before identification and
dose . A 10mg drug product taken three possible qualification of the unknown
times daily (as the maximum dosage) impurity. While Tranexamic acid with a
would have an unknown impurity intake daily dose of 4.5g may have unknown
of 30 µg at a 0.1% level. Yet a drug impurities peaks at 0.094% of the
such as 5-aminosalicylic acid with a labeled amount which exceed 2000 µg
maximum daily dose of 3g (Table 2) before identification and possible
would allow an unknown impurity intake qualification is necessary. Based on the
of 1500 µg at a 0.05% level - a fifty Maximum Daily Dose Qualification
times (50) greater impurity intake. Threshold Table (below) a significant
IAGIM Scientific Committee e-mail: [email protected] difference in impurity intake exists in
ANDAs
Maximum Daily Dose Qualification Threshold
Maximum Daily Dose Qualification Threshold
≤2g/day 0.1% or 1 mg per
day (lowest value)
>2g/day 0.05%
TABLE 1.

Maximum Daily Dose Individual Impurity Swing

Category (mg) Daily Intake (µg) from base
DOSE % Unknown Imp. Unknown impurity in µg % Factor
30 0.1% 30 µg 0 0
60 0.1% 60 µg 100 2
90 0.1% 90 µg 300 3
120 0.1% 120 µg 400 4
300 0.1% 300 µg 1000 10
500 0.1% 500 µg 1650 16.5
750 0.1% 750 µg 2500 25
1000 0.1% 1000 µg 3300 33
1500 1mg 1000 µg 3300 33
2000 0.05% 1000 µg 3300 33
2500 1.25mg (0.5%) 1250 µg 4160 41
3000 1.5mg (0.5%) 1500 µg 5000 50
4000 2mg (0.5%) 2000 µg 6 600 66
ANDA s- Table showing amount of unknown impurity intake versus maximum daily dose
TABLE 2.
Common existing Maximum Daily Assay Limit for
Drug Examples Dose - MDD (mg) unknown impurities
Published MDD % Parts
Sodium Valproate 1750 0.06 1 :1660
Fosfomycin 3000 0.05 1 :2000
5-aminosalicylic acid 2000 - 3000 0.05 1 :2000
Tranexamic acid 4500 0.05 1 :2000
Sucralfate 4000 0.05 1 :2000

Handbook of Pharmaceutical Sect: 13.55

13.55 Generic Development
 ATTACHMENT I

Impurities Decision Tree

(Generic Drug Substance)

Decrease impurity level Yes No

L1 Above Threshold Qualified
below threshold

Yes
Is the impurity
No No observed in the No
Decrease below
L2 Structure elucidated? innovator’s drug
threshold
product and at a
similar level?
Yes

* Toxicity documented and Yes

sufficient?

• Compliance with a USP drug

No Yes
L3a substance specification for
an identified impurity?
No
• Is the impurity observed in
Decrease below No the innovator’s drug product Yes
L3b Qualified
threshold and at a similar level?
No

No • If at a higher level, or a new Yes

L3c impurity is detected…
is it qualified from the
scientific literature?

No Yes

No Related to others with Yes Acceptable

L4
known toxicity? Justification**

No

No Qualified by a simple Yes

Decrease below
L5 battery of Qualified
threshold
genotoxicity tests?

No

No Qualified by additional Yes Qualified

L6 toxicity testing? but not 505(j)

* Generic Drug Pathway

** e.g., qualified by QSAR
 Attachment II

ICH Decision Tree for Safety Studies

Decrease impurity level Yes No
Above Threshold Qualified
below threshold

Yes

No
Structure elucidated?

Yes

Yes Toxicity documented and

sufficient?

No

Related to others with Yes Acceptable

known toxicity? justification?

No No Yes

Consider patient population

Qualified
and duration of use

Consider need for:

1. Genotoxicity studies (point mutation, chromosomal aberration) a
2. General toxicity studies (one species, min. 14 days, max. 90 days) b
3. Other specific toxicity endpoint, as appropriate

Adverse Effects

Yes No

Consider additional testing

Qualified
or removal of impurity

a If considered desirable, a minimum screen for genotoxic potential should be conducted. A study to detect point

mutations and one to detect chromosomal aberrations, both in vitro, are seen as an acceptable minimum screen.

b For NDAs, if general toxicity studies are desirable, study(ies) should be designed to allow comparison of

unqualified to qualified material. The study duration should be based on available relevant information and
performed in the species most likely to maximize the potential to detect the toxicity of an impurity. In general, a
minimum duration of 14 days and a maximum duration of 90 days will be acceptable.
 ORAL TABLETS ANALYTICAL DEVELOPMENT CHAPTER 13

Post-approval Changes in
Analytical Testing Laboratory Sites
'PAC-ALTS'

Post-approval Changes in Changes in an approved application to

Analytical Testing Laboratory allow for the use of a different facility or
establishment, including a different
Sites - PAC-ATLS GUIDELINE: contract laboratory, normally require
FDA approval before the change is
INTRODUCTION made (21 CFR 314.70(b)).
FDA regulations at 21 CFR 314.70(a)
T his approved guidance (April 1998)
provides recommendations
pharmaceutical sponsors of new
to provide that applicants may make
changes to an approved application in
drug applications (NDAs) and accordance with a guidance, notice, or
abbreviated new drug applications regulation published in the Federal
(ANDAs) who intend to change an Register that provides for a less
analytical testing laboratory site for:- burdensome notification of the change
(e.g., by notification at the time a
Ø drug product containers, closures, supplement is submitted or in the next
Ø packaging materials annual report).

Ø in-process material testing This document provides guidance on a

less burdensome approach to providing
Ø drug product testing during the
notice (i.e., Changes Being Effected
postapproval period.
(CBE) supplement) of certain post-
Analytical testing laboratories include approval changes within the meaning of
those performing physical, chemical, 314.70(a).
biological, and microbiological testing
to monitor, accept, or reject materials
This guidance does not comment on or
otherwise affect compliance/inspection
as well as those performing stability
documentation that has been defined
testing.
by CDER's Office of Compliance or
FDA's Office of Regulatory Affairs.
When Changing
Testing Laboratories This guidance does not affect any post-
approval changes other than the ones
FOUR key conditions specified.
for a CBE Supplement For changes filed in a Changes Being
need to be met Effected (CBE) supplement (21 CFR
314.70(c)), the FDA may, after a review

Handbook of Pharmaceutical Sect: 13.56

13.56 Generic Development
 ORAL TABLETS ANALYTICAL DEVELOPMENT CHAPTER 13

of the supplemental information, decide approved analytical testing laboratory

that the changes are not approvable. site and the new testing facility should
be included in the supplement with the
FOUR KEY CONDITIONS exception that this information need not
Ø Meets 21CFR 314.70(d) be submitted for the pyrogen and
Ø Meets PA Commitments bacterial endotoxin tests (LAL Test).

Ø Adequate Facilities Information about the cGMP status of a

firm may be obtained by requesting a
Ø TWO Years cGMP copy of the Quality Assurance Profile
(QAP) from the FDA's Freedom of
DISCUSSION Information (FOI) Office. The QAP
An analytical testing laboratory site
reports information on the cGMP
change can be submitted as a Changes compliance status of firms which
Being Effected (CBE) supplement if :- manufacture, package, assemble,
(1) the test method(s) approved in the repack, relabel or test human drugs,
application or methods that have been devices, biologics and veterinary drugs.
implemented under 21 CFR 314.70(d)
are used, FOI HANDBOOK
(2) all postapproval commitments made All FOI requests must be in writing and
by the applicant relating to the test should follow the instructions found in
method(s) have been fulfilled (e.g., the reference entitled:
providing methods validation, samples), A Handbook for Requesting Information
(3) the new testing facility has the and Records from FDA.
capability to perform the intended An electronic version of this reference
testing, and, handbook is available on the Internet at
http://www.fda.gov/opacom/background
(4) the new testing facility has had a
ers/foiahand.html
satisfactory current good manufacturing
practice (cGMP) inspection within the When submitting a supplement for a
past 2 years. change in an analytical testing
Prior to submitting analytical testing laboratory site, the applicant should
laboratory site change supplements, an confirm in a written statement why a
applicant should determine that the PAC-ATLS CBE supplement is
laboratory has the capability to perform appropriate (i.e., the four circumstances
the intended testing. Information to listed above exist).
support the capability of a laboratory to
perform the intended testing (e.g., The supplement should also contain
comparative data, CGMP history of the name and address of the new
performing the test, appropriate analytical testing laboratory site and a
standard operating principles (SOPs), full description of the testing to be
equipment and personnel in place) performed by the new facility.
should be available for FDA The supplement should be clearly
investigator review.
identified in the heading and text as
Data demonstrating that the new being filed under PAC-ATLS. If the
testing facility can perform the proposed change in the analytical
analytical test(s) being transferred need testing laboratory site does not fall
not be included in the supplement, within the scope of PAC-ATLS, it is
except for biological tests. In the case recommended that the change be filed
of biological tests, comparative data in a prior approval supplement.
from an

Handbook of Pharmaceutical Sect: 13.57

13.57 Generic Development
 ORAL TABLETS ANALYTICAL DEVELOPMENT CHAPTER 13

in, the preparation of the drug product

GLOSSARY OF TERMS (21 CFR 210.3(b)(9)).
The following terms are being provided
to assist the reader in using this Satisfactory Current Good
guidance document. Manufacturing Practice (cGMP)
Active Ingredient: Inspection:
A satisfactory cGMP inspection is one
This term is used interchangeably with
during which:-
active pharmaceutical ingredient (API)
and drug substance. (1) no objectionable conditions or
Any component that is intended to practices were found during an
furnish pharmacological activity or other inspection (No Action Indicated (NAI))
direct effect in the diagnosis, cure, or,
mitigation, treatment, or prevention of a (2) objectionable conditions were found,
disease, or to affect the structure of any but corrective action is left to the firm to
function of the human body, but does take voluntarily and the objectionable
not include intermediates used in the conditions do not justify further
synthesis of such ingredient. administrative or regulatory actions
The term includes those components (Voluntary Action Indicated (VAI)).
that may undergo chemical change in
the manufacture of the drug product
and are present in the drug product in a
modified form intended to furnish the ALT-SUMMARY
specified activity or effect (21 CFR Ø Applies to all analytical tests at any
210.3(b)(7) and 314.3(b)). stage of drug product's life-cycle.
Biological Tests:
Biological tests include animal, cell
Ø Lab must prove test can be fully
culture or biochemical based testing performed with accuracy and precision.
that measures a biological, biochemical Ø Lab must prove its testing capability
or physiological response.
Ø Lab must have a history of
Component: performing the specific test (i.e. written
Any ingredient intended for use in the
data.)
manufacture of a drug product,
including those that may not appear in Ø Lab must have appropriate SOPs for
such drug product (21 CFR the test(s) concerned.
210.3(b)(3)).
Ø Lab must have suitable calibrated
Drug Product: equipment for the test(s).
A finished dosage form, for example,
tablet, capsule or solution, that contains Ø Lab must have trained personnel for
an active ingredient, generally, but not the test(s) (written training records).
necessarily, in association with inactive
Ø Lab's overall capabilities must be
ingredients (21 CFR 210.3(b)(4)).
available for agency inspection.
Inactive Ingredients:
Any component other than an active Ø Lab's GAP must be satisfactory
ingredient (21 CFR 210.3(b)(8)). (Request Firm's GAP Report from FDA's
Freedom of Information (FOI) Office.)
In-process Material:
Any material fabricated, compounded, Ø Update FDA-OGD via the Annual
blended, or derived by chemical Report or a future Supplement (which-
reaction that is produced for, and used ever is sooner.)

Handbook of Pharmaceutical Sect: 13.58

13.58 Generic Development
 ORAL TABLETS ANALYTICAL DEVELOPMENT CHAPTER 13

ØC H E C K L I S T ×
CL # P-HGD-01-01Y2K Page 1 of 1

PAC-ATLS GUIDELINE - POSTAPPROVAL CHANGES

Analytical Testing Laboratory Sites
‘…the laboratory must not only say that the tests can be performed
but prove that they can be done…’

1. This change procedure applies to approved drug products only. qYes qNo
2. Applies to all analytical tests at any stage of drug product's life-cycle qYes qNo
- from raw material analysis to post approval stability.
3. A copy of the laboratory's Quality Assurance Profile (QAP) from the qYes qNo
FDA's Freedom of Information (FOI) Office.
4. The chosen laboratory passed a satisfactory cGMP inspection within qYes qNo
the last two years (See attached SOP for IQOQ qualification).
5. No objectionable conditions or practices were found during the last qYes qNo
inspection.
6. Where objectionable conditions were found, adequate corrective qYes qNo
action has been taken to satisfy the FDA's initial objections.
7. Analytical testing Laboratory (ATL) must prove test can be fully qYes qNo
performed with accuracy and precision.
8. ATL must prove its testing capability for each and every test. qYes qNo
9. ATL must have a recorded history of performing the specific test(s) qYes qNo
(i.e. a written track record.)
10. ATL must have appropriate SOPs for the specific test(s) and qYes qNo
procedures.
11. ATL must have suitable calibrated equipment for the test procedures qYes qNo
12. ATL must have suitable information to support its capability to qYes qNo
perform the intended analytical testing procedures.
13. ATL must have trained personnel to perform the test procedures qYes qNo
(availability of updated training records, specific to the required
analysis)
14. ATL overall capabilities must be available for agency inspection. qYes qNo
15. FDA will be informed of the change being effected, via the Annual qYes qNo
Report or a future Supplement (whichever is submitted sooner.)
16. Where a supplement is filed, it is clearly identified in the heading and qYes qNo
text as being filed under PAC-ATLS rules - and,
17. A written statement is included why a PAC-ATLS CBE supplement qYes qNo
is appropriate (i.e., the four circumstances listed above, all exist.)

Handbook of Pharmaceutical Sect: 13.59

13.59 Generic Development
 ORAL TABLETS ANALYTICAL DEVELOPMENT CHAPTER 13

SOP # HB-500-04-1Y2K STANDARD OPERATING Total Pages: 14.

PROCEDURES
Installation & Operational Qualification
REQUIREMENTS for
LABORATORY EQUIPMENT
Page 1 of 13.
This SOP is intended for the metrology unit or individual or groups responsible for the
management and operation of the installation and operational qualification of laboratory and
pilot equipment in generic and innovative drug development units. The SOP documentation
may be applied to scale-up and production units as well.
1. PURPOSE
The purpose of this Standard Operational Procedure is to provide a standard
INSTALLATION AND OPERATION Qualification (IQOQ) PROTOCOL for laboratory
equipment whether analytical or pharmaceutical in order that operation and routine
use the equipment is in accordance with the relevant operating Instructions.
2. Frequency
All laboratory mechanical and electrical equipment units shall have the required
INSTALLATION AND OPERATION Qualification documentation prior to its initial
use. In cases where exiting laboratory equipment has not been initially Installation
and Operationally Qualified the procedure and documentation (as shown in
attachment 1) shall be fully completed.
3. Procedure
n Attach a permanent equipment identification number to each unit of laboratory
equipment.
n Prepare a copy of the INSTALLATION AND OPERATION Qualification Protocol as
per attached standard protocol document.
n Complete the INSTALLATION AND OPERATION Qualification document.
n Calibrate the equipment units on completion of initial check operation.
4. Limits
Each INSTALLATION AND OPERATION Qualification document shall apply to a
single unit of laboratory equipment. Identical model units shall be qualified for
INSTALLATION AND OPERATION however only one identical unit where necessary
shall be qualified for Performance Operation (PQ). PQ is not required for additional
pieces of the same type/model of equipment when used in the same
process/operation
5. Retesting
The INSTALLATION AND OPERATION Qualification document shall be re-qualified
when a significant change or modification has been made to the equipment or the
equipment has been re-housed to a different campus
6. Documentation
INSTALLATION AND OPERATION Qualification document as attached

ED. N0: 02 Effective Date :

APPROVED:
Replaces Ed 01.
Ed. Status: January 200Y
Operational
Laboratory Maintenance Metrology QA
Handbook of Pharmaceutical Sect: 13.60
13. Generic Development
 ORAL TABLETS ANALYTICAL DEVELOPMENT CHAPTER 13

SOP # HB-500-04-1Y2K STANDARD OPERATING Total Pages: 14.

PROCEDURES
Installation & Operational Qualification
REQUIREMENTS for
LABORATORY EQUIPMENT
Page 2 of 13.

ATTACHMENT ONE
(This attachment consists of 12 pages)

EQUIPMENT IDENTIFICATION
Description

Manufacturer

Model No: List all attachments to the

equipment and record all
identification numbers
Serial No:

Equipment ID No:

[Same model Installed - Principle and operation is the same]

Location 1

[Same model Installed] Identical models and

Location 2 makes (e.g. Lab HPLC,
balances) may be
[Same model Installed] installed in several
Location 3
locations.
ONLY IQ AND OQ
[Same model Installed]
Location 4 REQUIRED

ED. N0: 02 Effective Date :

APPROVED:
Replaces Ed 01.
Ed. Status: January 200Y
Operational
Laboratory Maintenance Metrology QA
Handbook of Pharmaceutical Sect: 13.61
13. Generic Development
 ORAL TABLETS ANALYTICAL DEVELOPMENT CHAPTER 13

SOP # HB-500-04-1Y2K STANDARD OPERATING Total Pages: 14.

PROCEDURES
Installation & Operational Qualification
REQUIREMENTS for
LABORATORY EQUIPMENT
Page 3 of 13.

CONTENTS
PROCEDURE COMPLETED
n Approval Document Completed q

n Installation Document Completed q

n Annual Review Record Completed q

n Operational Qualification tests Completed q

¯ Operational Tests Completed q

¯ Summary of test results Completed q

¯ Conclusion Completed q

n Standard Operating Procedure for this Completed q

equipment

n Responsible Personnel for Undertaking Test Completed q

Work

n List of appendices Completed q

ED. N0: 02 Effective Date :

APPROVED:
Replaces Ed 01.
Ed. Status: January 200Y
Operational
Laboratory Maintenance Metrology QA
Handbook of Pharmaceutical Sect: 13.62
13. Generic Development
 ORAL TABLETS ANALYTICAL DEVELOPMENT CHAPTER 13

SOP # HB-500-04-1Y2K STANDARD OPERATING Total Pages: 14.

PROCEDURES
Installation & Operational Qualification
REQUIREMENTS for
LABORATORY EQUIPMENT
Page 4 of 13.

Approval Document
According to the data collected as a result of the protocol, this equipment as defined
under equipment identification has been properly installed and operationally
qualified in accordance with the attached Standard Operational procedures in
practice.

Option 1
n Installation Qualification has been carried out prior to the use Yes q NO q
of the equipment.

Option 2
n Installation Qualification has been carried AFTER to the use of Yes q NO q
the equipment.

Option 3
n The equipment has been fully qualified and calibrated Yes q NO q

Option 4
n The equipment is now fully qualified and is suitable for use Yes q NO q

AUTHORIZATION
On completion of Option 3 the equipment is dually authorized by signing the
authorization and approval footer at the end of each page.

ED. N0: 02 Effective Date :

APPROVED:
Replaces Ed 01.
Ed. Status: January 200Y
Operational
Laboratory Maintenance Metrology QA
Handbook of Pharmaceutical Sect: 13.63
13. Generic Development
 ORAL TABLETS ANALYTICAL DEVELOPMENT CHAPTER 13

SOP # HB-500-04-1Y2K STANDARD OPERATING Total Pages: 14.

PROCEDURES
Installation & Operational Qualification
REQUIREMENTS for
LABORATORY EQUIPMENT
Page 5 of 13.

Installation Document
According to the manufacturer's specification this equipment has been properly
installed and is in compliance with the attached Standard Operational procedure.

INSTALLATION
UNIT SPECIFICATION APPROVAL STATUS

Installation Qualification of the equipment has been Approved q NA q

carried out by suitably qualified personnel.
Equipment Installation has been according to Approved q NA q
manufacturers instructions
Site Position is suitable Approved q NA q
Power requirement are correctly installed Approved q NA q
Water requirement are correctly installed Approved q NA q
Vacuum requirement are correctly installed Approved q NA q
Compressed Air requirement are correctly installed Approved q NA q
Compressed Gas requirement are correctly installed Approved q NA q
Heating requirement are correctly installed Approved q NA q
Cooling requirement are correctly installed Approved q NA q
Wiring requirement are correctly installed Approved q NA q
Piping requirement are correctly installed Approved q NA q
Fire Prevention system is correctly installed Approved q NA q
Operator safety guards are correctly installed Approved q NA q
Other Specifications - Approved q NA q
Other Specifications - Approved q NA q
Other Specifications - Approved q NA q
Other Specifications - Approved q NA q

ED. N0: 02 Effective Date :

APPROVED:
Replaces Ed 01.
Ed. Status: January 200Y
Operational
Laboratory Maintenance Metrology QA
Handbook of Pharmaceutical Sect: 13.64
13. Generic Development
 ORAL TABLETS ANALYTICAL DEVELOPMENT CHAPTER 13

SOP # HB-500-04-1Y2K STANDARD OPERATING Total Pages: 14.

PROCEDURES
Installation & Operational Qualification
REQUIREMENTS for
LABORATORY EQUIPMENT
Page 6 of 13.

Annual Review Record

Each year after this IQOQ Protocol and Report is completed, all changes to the
operation of this equipment shall be listed,
W here no changes have taken place this must be documented. The listing
procedure is performed annually until a new IQOQ Protocol and Report is prepared
and completed.

EQUIPMENT CHANGES
CHANGES TO THE DOCUMENT Reviewer's Year
LABORATORY EQUIPMENT REFERENCE Signature

1999
Major or fundamental
changes may require a
complete re-qualification
(if equipment has a 2000
different operating
principle)

2001
After 5 years have elapsed
examine the documents and
equipment in order to evaluated
if a full re-qualification is 2002
necessary

2003

ED. N0: 02 Effective Date :

APPROVED:
Replaces Ed 01.
Ed. Status: January 200Y
Operational
Laboratory Maintenance Metrology QA
Handbook of Pharmaceutical Sect: 13.65
13. Generic Development
 ORAL TABLETS ANALYTICAL DEVELOPMENT CHAPTER 13

SOP # HB-500-04-1Y2K STANDARD OPERATING Total Pages: 14.

PROCEDURES
Installation & Operational Qualification
REQUIREMENTS for
LABORATORY EQUIPMENT
Page 7 of 13.

Operational Test
OPERATIONAL TEST
OBJECTIVE
To test the operation of the equipment under normal operating conditions.

Written SOPs require to qualify

procedure after a major internal
ACCEPTANCE CRITERIA or external repair or complete
overall

Parameters are defined as a pre-

written protocol PRIOR to any
METHOD work being performed on the
equipment

Prepare the full testing

procedure - allow for
modifications and changes
during the real-time testing

LIMITATION & RESTRICTIONS

Similar model equipment may have a Reduced Testing Procedure - if rationale is
logically qualified in the pre-written protocol.

ED. N0: 02 Effective Date :

APPROVED:
Replaces Ed 01.
Ed. Status: January 200Y
Operational
Laboratory Maintenance Metrology QA
Handbook of Pharmaceutical Sect: 13.66
13. Generic Development
 ORAL TABLETS ANALYTICAL DEVELOPMENT CHAPTER 13

SOP # HB-500-04-1Y2K STANDARD OPERATING Total Pages: 14.

PROCEDURES
Installation & Operational Qualification
REQUIREMENTS for
LABORATORY EQUIPMENT
Page 8 of 13.

TEST RESULTS

Test results for operational function are tabulated here:

Approved q Failed q

Approved q Failed q

Approved q Failed q

Approved q Failed q

Attach all printouts Approved q Failed q

fully dated and signed.
Photocopy heat-sensitive printout Approved q Failed q
paper and resign
with lab supervisor
Approved q Failed q

Approved q Failed q

Approved q Failed q

Approved q Failed q

Approved q Failed q

Approved q Failed q

Approved q Failed q

COMPLETED BY DATE:

ED. N0: 02 Effective Date :

APPROVED:
Replaces Ed 01.
Ed. Status: January 200Y
Operational
Laboratory Maintenance Metrology QA
Handbook of Pharmaceutical Sect: 13.67
13. Generic Development
 ORAL TABLETS ANALYTICAL DEVELOPMENT CHAPTER 13

SOP # HB-500-04-1Y2K STANDARD OPERATING Total Pages: 14.

PROCEDURES
Installation & Operational Qualification
REQUIREMENTS for
LABORATORY EQUIPMENT
Page 9 of 13.

SUMMARY TEST RESULTS

n Display summary of test results certifying that for each laboratory model or pilot
plant unit - indicating that equipment has been:-
- Qualified or re-qualified (IQOQ)
- Cleaning program results are within specification
- Routine equipment maintenance program functional
- Calibration program operational and effective
- SOP review has been undertaken and signed-off according at the time of review.

CONCLUSIONS
n This Installation & Qualification Program applies to: Laboratory / pilot plant
instrumentation and equipment.

The equipment has been Installation & each model type operationally qualified. The
following real time systems have been put in place.
[1] An Audit and Check Program has been installed to ensure that appropriate
IQOQ (or re-qualification) program has been executed according to the current
IQOQ SOP.
[2] An Audit and Check Program has been installed to ensure that an appropriate
MAINTENANCE PROGRAM has been put in place for relevant equipment.
[3] An Audit and Check Program has been installed to ensure that an appropriate
CALIBRATION program has been put in place for relevant equipment.
[4] An Audit and Check Program has been installed to ensure that appropriate
PERFORMANCE VERIFICATION program has been put in place for relevant
equipment.

COMPLETED BY DATE:

ED. N0: 02 Effective Date :

APPROVED:
Replaces Ed 01.
Ed. Status: January 200Y
Operational
Laboratory Maintenance Metrology QA
Handbook of Pharmaceutical Sect: 13.68
13. Generic Development
 ORAL TABLETS ANALYTICAL DEVELOPMENT CHAPTER 13

SOP # HB-500-04-1Y2K STANDARD OPERATING Total Pages: 14.

PROCEDURES
Installation & Operational Qualification
REQUIREMENTS for
LABORATORY EQUIPMENT
Page 10 of 13.

STANDARD OPERATING PROCEDURES

FOR THIS EQUIPMENT

EQUIPMENT OPERATING PROCEDURES STATUS

(List SOPs)

TITLE Checked q SOP # q

Critical Data:-
Edition [0-]
The SOP number and the
TITLE current edition number must Checked q SOP # q
be clearly identified Edition [0-]
TITLE Checked q SOP # q
Edition [0-]

CLEANING SANITATION PROCEDURES (List SOPs)

TITLE All equipment require an; Check q SOP # q
Operating SOP Edition [0-]
Minor +Major Cleaning SOP
TITLE Check q SOP # q
Calibration SOP
Edition [0-]
Maintenance SOP
TITLE Check q SOP # q
Edition [0-]

CALIBRATION & PREVENTIVE MAINTENANCE PROGRAM: (List SOPs)

TITLE Calibration SOP Check q SOP # q
Calibration Procedures are Edition [0-]
TITLE both internal (in-house) and Check q SOP # q
External (3rd Party) Edition [0-]
(annually or biannually)
TITLE Check q SOP # q
Edition [0-]
TITLE Check q SOP # q
Edition [0-]

CHECKED BY DATE:

ED. N0: 02 Effective Date :

APPROVED:
Replaces Ed 01.
Ed. Status: January 200Y
Operational
Laboratory Maintenance Metrology QA
Handbook of Pharmaceutical Sect: 13.69
13. Generic Development
 ORAL TABLETS ANALYTICAL DEVELOPMENT CHAPTER 13

SOP # HB-500-04-1Y2K STANDARD OPERATING Total Pages: 14.

PROCEDURES
Installation & Operational Qualification
REQUIREMENTS for
LABORATORY EQUIPMENT
Page 11 of 13.

RESPONSIBLE PERSONNEL FOR UNDERTAKING TEST WORK

IN-HOUSE DEPARTMENT AND PERSONNEL

QUALIFICATION TEST DEPARTMENT RESPONSIBLE

PERSON

Installation

Describe the installation

level relevant to each
responsible person
(What did each in-house
installer actually do)

Operational Test

Tests Performed
In-house test methods
performed according to protocol
Kept on file in metrology /
engineering department as
prescribed in the SOP.

COMPLETED BY DATE:

ED. N0: 02 Effective Date :

APPROVED:
Replaces Ed 01.
Ed. Status: January 200Y
Operational
Laboratory Maintenance Metrology QA
Handbook of Pharmaceutical Sect: 13.70
13. Generic Development
 ORAL TABLETS ANALYTICAL DEVELOPMENT CHAPTER 13

SOP # HB-500-04-1Y2K STANDARD OPERATING Total Pages: 14.

PROCEDURES
Installation & Operational Qualification
REQUIREMENTS for
LABORATORY EQUIPMENT
Page 12 of 13.

IDENTIFICATION OF PERSONNEL UNDERTAKING TEST WORK

CONTRACTED EXTERNAL THIRD PARTY PERSONNEL

QUALIFICATION TEST DEPARTMENT RESPONSIBLE

PERSON

Installation
Describe the installation
level relevant to each
responsible person
(What did each contracting
installer actually do)

Operational Test

Tests Performed
Third party test methods
to be kept on file in
metrology / engineering
department / or signed
summaries.

An appendix to this report stating that all non-employees as listed above are
competent to perform the installation or operational qualification work pertaining to
this equipment.

COMPLETED BY DATE:

ED. N0: 02 Effective Date :

APPROVED:
Replaces Ed 01.
Ed. Status: January 200Y
Operational
Laboratory Maintenance Metrology QA
Handbook of Pharmaceutical Sect: 13.71
13. Generic Development
 ORAL TABLETS ANALYTICAL DEVELOPMENT CHAPTER 13

SOP # HB-500-04-1Y2K STANDARD OPERATING Total Pages: 14.

PROCEDURES
Installation & Operational Qualification
REQUIREMENTS for
LABORATORY EQUIPMENT
Page 13 of 13.

APPENDICES
LIST OF APPENDICES TO THIS REPORT ATTACHED HERE

1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
List the number of
11.
appendices and attachments
12. affixed to this report at each
13. time period.
14.
15.

THERE ARE [ ] LISTED APPENDICES TO THIS REPORT AS OF MM/DD/YY

THERE ARE [ ] LISTED APPENDICES TO THIS REPORT AS OF / /
THERE ARE [ ] LISTED APPENDICES TO THIS REPORT AS OF / /
THERE ARE [ ] LISTED APPENDICES TO THIS REPORT AS OF / /
THERE ARE [ ] LISTED APPENDICES TO THIS REPORT AS OF / /
THERE ARE [ ] LISTED APPENDICES TO THIS REPORT AS OF MM/DD/YY

This is a full list of appendices to this report .

All appendices listed are attached

COMPLETED BY: DATE:

3
[End of Document]

ED. N0: 02 Effective Date :

APPROVED:
Replaces Ed 01.
Ed. Status: January 200Y
Operational
Laboratory Maintenance Metrology QA
Handbook of Pharmaceutical Sect: 13.72
13. Generic Development
 ORAL TABLETS PROCESS QUALIFICATION CHAPTER 14

Process
QUALIFICATION
‘…The process qualification batch is a simulation of the forthcoming pivotal
l o t proving in-house, that the process really works…‘

Process qualification lots and the cleaning procedures and

Getting to the end point in the generic operation routine production SOPs.
development program is the These are the conditions under which
manufacture of the process the regulatory pivotal lot will be
qualification batch. All generic manufactured, as an exhibition
development, product and control submission to the FDA in the ANDA
specifications are challenged in this An Exhibition Batch
batch. The Plant Production Director needs to
Simulation of Pivotal fully comprehend the importance of the
It is a full simulation of the pivotal firm’s in-house Process Qualification
process with completed process batch and the FDA Pivotal production
documentation and fully validated batch. Although not for commercial
analytical methods, including stability sale both exhibition batches are
indicating assay analysis. manufactured under standard
Development of the formula and commercial conditions.
manufacturing process terminates at Simulating the Pivotal Batch
this point, as all specifications and The Process Qualification is a full in-
parameters have now been qualified house simulation of the Pivotal batch
and optimized. (which has a legal status with the
Complete Documentation FDA). Final minor optimization and
Full manufacturing instructions and documentation editing is performed
specific SOPs and all supporting after the manufacturing and packaging
analytical documentation is complete of the Process Qualification Batch.
and audited and signed off. Documentation fine-tuning
Qualification of Process The final PQ documentation and
The intention is to challenge every specifications are the data basis from
aspect of the formula, process which the Pivotal Batch manufacturing
instructions and all product instructions and specifications evolve.
specifications, which include full Technical Transfer Documentation
accelerated stability tests. The Process Qualification Batch
Commercial conditions manufacturing documentation, in-process
The PQ batch is manufactured in the and complete finished product
plant’s commercial facilities where the specifications are the principal documents
marketing lots will be produced, using in the Technical Transfer Documentation
Dossier (TTD) that is transferred from the
standard production raw materials and
Generic Development Unit to the
personnel, as well as routine QA commercial plant production unit after the
procedures. execution of the Pivotal Batch. New
Production Equipment information gleaned from the pivotal
The equipment used are the same experience is added to the TTD as the
models as planned for the marketing final Pivotal Batch Report.

Handbook of Pharmaceutical Sect: 14.

14 1 Generic Development
 ORAL TABLETS PROCESS QUALIFICATION CHAPTER 14

ØC H E C K L I S T ×
CL # P-HGD-03-01Y2K

PROCESS QUALIFICATION
‘…well developed process qualification batch with good in-process
controls
and excellent documentation will ensure a failure-free pivotal lot…’

1. The Process Qualification batch is equal to the 70% or more of the pivotal qYes qNo
batch or the smallest commercial batch size that will be validated?

2. The active material source has been verified as an ‘Approved Supplier’ ? qYes qNo

3. All non actives are routine production excipients or have been approved qYes qNo

4. The container closure-system is the final marketing pack? qYes qNo

5. The Master Product Formula Record has all authorization signatures ? qYes qNo

6. The Master Manufacturing Batch Instructions has all authorization qYes qNo
signatures?

7. The manufacturing flow chart (identifying all equipment and process qYes qNo
parameters) is final with all authorization signatures?

8. In-process QC specifications and processing parameters are complete? qYes qNo

9. Standard packaging instruction (including sampling protocol) complete? qYes qNo

10. Release Specifications (with narrower lower and upper limits) complete? qYes qNo

11. Check Specifications (with maximum lower and upper limits) complete? qYes qNo

12. Overall Finished Product Specifications complete? qYes qNo

13. Accelerated stability protocol complete and signed-off ? qYes qNo

14. The analytical methods and stability indicating assay are complete? qYes qNo

15. The PQ is not a regulatory requirement but a in-house dry run! qYes qNo

16. The Granulate Content Uniformity Protocol is prepared for qYes qNo
evaluation during PQ batch manufacture.

17. The Tablet Hardness Qualification protocol will be evaluated during the PQ qYes qNo
batch manufacture.

Handbook of Pharmaceutical Sect: 14.

14 2 Generic Development
 ORAL TABLETS PROCESS QUALIFICATION CHAPTER 14

STANDARD OPERATING
PROCEDURES
CL # P-000-03-01Y2K Page 1 of 1

PROCESS QUALIFICATION

The following Standard Operating Procedures are recommended for a generic

development unit:

Process Qualification SOPs

P-01-02-01Y2K Granule Content Uniformity Qualification.

P-02-02-01Y2K Tablet Hardness Qualification.

P-03-01-01Y2K Documentation requirements for the Process Qualification batch.

P-04-01-01Y2K Side-by-side comparison of Process Qualification and Pivotal

batch parameters

4
[End of Document]

ED. N0: 02 Effective Date: APPROVED:

Replaces Ed 01.
Ed. Status: MM/DD/2000
Operational Department R&D QC QA

Footnote: It is important to understand that no development or even minor specification changes

may take place after the pivotal production. Therefore all development is complete at the start of
the pivotal batch production. The pivotal batch is solely a legal demonstration or exhibition batch
for regulatory submission. Firms with appropriate pilot facilities may execute the process
qualification batch under pilot conditions and repeat the process, if deemed necessary, at the
commercial production site.

Handbook of Pharmaceutical Sect: 14.

14 3 Generic Development
 ORAL TABLETS PROCESS QUALIFICATION CHAPTER 14

Process
Qualification
‘these are the product specifications
indicating the product quality throughout the shelf life’

technology using modern

Blend Analysis sampling devises provides a
means to consistently collect
minute, representative unit dose
BLEND UNIFORMITY SAMPLING samples from a much larger (10 6 )
vs. WOLIN RECOMMENDATIONS static powder blend without a
sampling bias does not always

J udge Wolin's decision in the

US vs. Barr Laboratories
prompted the FDA to re-
hold true. A comprehensive
review and evaluation of the
scientific literature highlights that
examine and modify its policies current sampling technology is
and understanding on blend beset by a predominance of
uniformity and sampling varying sampling techniques with
techniques. The FDA proposes to resulting sampling bias.
amend the cGMP regulations to
rule that the commercial batch
Different Sampling
final blended granulate (for solid thieves or dies give
dosage forms) be routinely tested different results with the
for active ingredient homogeneity
(Content Uniformity USP). same final blend
W olin's ruling stated simply that S ampling error can be introduced
the sample size of the final blend by three key factors namely:
should be set at no more than
three times (3X) the dosage unit ♦ Sample thief design
weight of the tablet or capsule. ♦ Sampling technique
Sampling could be either from the
♦ Final blend formulation properties
drum or preferable the mixing
unit.
The physical design of the sample thief
1X to 3X Sampling and even the most recently developed
side-sampling1 or end-sampling2,3 "slug
of the final blend thief" can produce unacceptable large
may well give a poor sampling errors. 1Globe-Pharma NJ; 2Du-
Pont-Merck; 3Rutgers University - "best unit".
uniformity result S ampling technique should
always be the same from
Both Judge Wolin's and the FDA's
development to commercial batch
assumption that the current
lots.

Handbook of Pharmaceutical Sect: 14.

14 5 Generic Development
 ORAL TABLETS PROCESS QUALIFICATION CHAPTER 14

ØBlend Analysis The GMP rules require that the process

is validated and consistently produces
the desired end product.

D
ifferent sampling Testing final blend content uniformity
techniques with the same
as a suitable in-process control may
thief can profoundly impact
well evaluate and highlight the
on sampling error, producing non
incoming ingredient batch-to-batch
re-presentative results, with
differences as well as the physical
respect to the true blend uniformity
variations in different lots of active
value.
material thus producing granule
♦ Sampling motion variation.

Bulk
♦ Sampling Angle
density and particle size of the
active material may be received within
♦ Sampling Orientation
the range specification, but at either
extremes of the specification limit.
♦ Bed depth However routine testing should not be a
GMP requirement as blending is not the
can bias results final unit process. Tablet compression
or capsule filling are the end
F actors that can bias the sample
processes!
in four different ways are:-
♦ Sampling motion (smooth, twisting Thus the necessity to establish both
jerking, or oscillating actions etc.) lower (LCL) and upper control limits
(UCL) for the content uniformity of the
♦ Sampling angle (vertical, acute, blend is self evident. The final blended
downwards). granulate assay should conform to
within the mean Ñ3 SD representing the
♦ Sampling thief orientation in the bed
(Side-sampling probe rotation of lower & upper control limits (See SOP).
chamber is up (3600á), down
0 0
(180 â), or on the side (either 45 ä
; 900 à or 1350 æ). References

♦ Depth of powder bed (top, middle or 1. Current Good manufacturing Practice of Certain
Requirements for the Finished Pharmaceuticals;
bottom sampling). Proposed Rules May 3 1996 (61 FR 20103).
In general, if development studies show 2. United States of America vs. Barr Laboratories
Inc., civil action for the district of N.J., Feb 1993.
the need for 3X sampling as a 3. J.T. Carstensen and M.V. Dali "Blending
prerequisite, then do so and amend Validation and Content Uniformity of low content
your SOPs (see model) as sampling …powder blends " Drug development and Industrial
Pharmacy Vol. 22 Issue 4 pp. 285-290 (1996).
error increases as the sample size 4.J Berman, A Schoeneman and JT Shelton, Unit
and/or formulation potency decreases. Dose Sampling - a tale of two thieves" Drug
development and Industrial Pharmacy Vol. 22 Issue
Final blending process, like Tablet 11 pp.1211-1132 (1996).
5. J Berman, and J.A. Planchard "Blend Uniformity
Hardness Qualification, is one of the and Unit Dose Sampling" Drug development and
series of unit processes that require Industrial Pharmacy Vol. 21 Issue 11 pp.1257-1283
(1995).
validation. This validation should be 6.J.T. Carstensen and C.T. Rhodes " Sampling in
performed at the Process Qualification Blending Validations" Drug development and
and / or Pivotal batch manufacturing Industrial Pharmacy Vol. 19 Issue 20 pp.2699-2708
(1993).
stage.

Handbook of Pharmaceutical Sect: 14.

14 6 Generic Development
 ORAL TABLETS PROCESS QUALIFICATION CHAPTER 14

Sampling Record for Final Granulate

PRODUCT STRENGTH q- LAB RECEIPT No
Batch No: Date of Sampling: Sampling Unit No: Die No:
q PIVOTAL & q BIOEQUIVALENCE LOT q PROCESS QUALIFICATION LOT
q VALIDATION LOT q RE-VALIDATION LOT
Milled No of Weight of TOP MIDDLE BOTTOM Time Signature
Granulate Samples Sample - g

Final
Granulate

Sampling Record for Compression or Filling

q Tablets q- MACHINE TYPE:
q Capsule Filling q- LAB RECEIPT No
Machine LOW HIGH No of Units LEFT RIGHT Time Signature
No: Hardness Hardness SAMPLED
TARGET SPEED - RPM
q q
q q
q q
q q
LOW SPEED - RPM
q q
q q
q q
q q
HIGHSPEED - RPM
q q
q q
q q
q q

Sampling Record for Coating

q Tablet Coating q Granule Coating
q Caplet Coating q- LAB RECEIPT No:
Sublot No: Machine Quantity Sampled Time: Signature:
No: in Grams ~ 100 tabs.
Sublot 1
Sublot 2
Sublot 3
Sublot 4
Sublot 5

ED. N0: 02 Effective Date: APPROVED:

Replaces Ed 01.
Ed. Status: MM/DD/2000
Operational Department R&D QC QA
Handbook of Pharmaceutical Sect: 14.
14 7 Generic Development
 ORAL TABLETS PROCESS QUALIFICATION CHAPTER 14

ØBlend Analysis In-process controls

Do remember that the variation in the
final blend is generally greater, than in
Do's and Don'ts the finished drug product.
Development Do compare the mean of the final
blend with the mean of the compressed
Do keep particle size distribution of cores/tablets or filled capsules.
granulate material as narrow as
Do sample 30 unit dose samples,10 for
possible - fines percolating through
analysis and 20 for reserve testing, if
coarser material may well result in non-
needed later.
representative final blend assay values.
Do use the same sampling thief type Sampling
for all development, scale-up, and Do Remember that the Wolin's
validation sampling operations. decision does not take into account all
Do formulate with appropriate glidants inherent problems in current sampling
to keep the flow attribute of all the technology and equipment.
ingredients similar, thus preventing Do use the same sampling style, thief
differential flow properties, resulting in orientation, and hand operations when
non-representative samples & assays. sampling - retrain operators biannually.
Do take into account that bed
SOPs pressures at the bottom of powder beds
Do prepare a sampling and testing give different samples (and thus
SOP for Pivotal batches - (as shown). assays) to those results from the top
Do use this SOP for sampling and and middle container positions.
testing all key development, pivotal, Do sample at the same level and at the
and commercial validation batches. same entrance angle - every time.
Do Develop a Standardised Sampling Do keep the side-chambered sample
SOP to replicate routine sampling thief orifice pointing in the same
procedures with Sampling Record direction every time you sample, i.e.
Forms. (either at 360o; 45o; 90 o; 135 o or 180o).
Samplers Don't use different sample thief types
Do take into account that all samplers - choose the 'best' available and use it
sample dissimilarly, due to different consistently, in a standardized manner.
construction geometry. Don't rely solely on the final blend
Do remember that the latest "end- assay as an in-process test; above a
sampling slug thieves" also produce well specified, process controlled and
significant sampling errors. validated manufacturing procedure (due
Do sample 1X to 3X unit dose size, to inherent sampling error of the final
depending on the detailed development blended material). Uniformity changes
report recommendations. can occur during compression or filling
Do Remember that development data Don't forget that the assay of the final
supporting 3X sampling is acceptable granulate blend is as good as the
especially where unit dose weights or sampling technique - and no final blend
tablet potencies are low. sampling procedure is free of error.
,

ED. N0: 02 Effective Date: APPROVED:

Replaces Ed 01.
Ed. Status: MM/DD/2000
Operational Department R&D QC QA
Handbook of Pharmaceutical Sect: 14.
14 8 Generic Development
 ORAL TABLETS PROCESS QUALIFICATION CHAPTER 14

QUALIFYING
Tablet Hardness…
T ablet Hardness is an important
Qualification for a development
batch lot that has reached the
hardness range has been fully qualified
at the lower and upper hardness limits
on production machinery operating at
process qualification stage just prior to optimum target speeds - all performed
the pivotal manufacture. in a production environment.
During the commercial manufacture of Hardness Range Qualification means
a compressed tablet, the tabletting that, not only is tablet weight and
machines are set at an optimum thickness within specifications, but the
machine speed and compress at a set important dissolution profile remains
target hardness value. within the set parameters. More
This hardness value is developed from precisely the dissolution profile
experimental batch lots during the supports the specified Q value and
tablet development. Its value may be does not fluctuate beyond the lower or
close to the mean or average hardness the upper control limits (See Attached
range expressed between a lower and SOP of the hardness values (i.e. LCL
an upper hardness value. Such a range and UCL).
as NLT 8 - NMT16 Strong Cobb Units Normally only 10% of the batch is
(SCU) may be a common example, compressed at the lower and the upper
however ranges may be significantly hardness limits while the remaining
wider and still be acceptable such as 80% of the batch size is compressed at
NLT 6 - NMT 24 SCU, (Kg or SCU) the target hardness specifications.
may be used as the unit of Standard Pivotal batches produced for
measurement for hardness). regulatory submission are required to
deliver not less than 100 000 tablets
Hardness net (packed).
Its is expedient to produce a Pivotal
Qualification means batch on around 110 000 units - thus
that the dissolution the number of tablets run at the two
ends of the hardness limits would be
profile remains in approximately ten to eleven thousand
each.
specification Representative sampling during the
What makes these seemingly wide hardness qualification trials is
hardness range values reasonable and essential. Sufficient samples need to
appropriate for commercial be taken that fully represent the mini
manufacture is the fact that the tablet sub-lot for the standard routine quality
control,

Handbook of Pharmaceutical Sect: 14.

14 9 Generic Development
 ORAL TABLETS PROCESS QUALIFICATION CHAPTER 14

TABLET
HARDNESS QUALIFYING TABLET HARDNESS
QUALIFICATION
retention samples and hardness
evaluation qualification tests. THE TABLET HARDNESS MAY BE
QUALIFIED DURING THE PIVOTAL
Prudent development labs will reserve RUN OR BEFORE DURING THE
a portion of the compressed tablets at Process Qualification Run
the hardness limit ends and place them
on real time stability.
It is well documented that tablet
Choose Upper & Lower Hardness
hardness may change with ageing, - values based on results from the
thus impacting on the dissolution Development PQ Batch
profile. This is especially the case
when the tablet moisture content may
be marginally higher (i.e. tablets
exceeding 2.0 to 2.5% LOD, or PREPARE THE WRITTEN PROTOCOL
greater). TITLED:
'TABLET HARDNESS QUALIFICATION'
Qualifying tablet hardness ranges
within the expected shelf life is at times
overlooked by the drug development COMPRESS BATCH
firm - an omission which may cause an IN THREE DISTINCT STAGES:-
out-of-specification product, while in 10% - LOW HARDNESS
80% - TARGET HARDNESS
the market place.
10% - HIGH HARDNESS
(Do not exceed a 15%-70%-15% ratio)
Qualify dissolution
profile on CAUTION

aged tablets as well

If running a Pivotal Lot the TARGET
HARDNESS (~80% Portion)
must be at least 100 000 units (NET)
The process qualification batch is an thus the batch size is ~ 125 000
ideal time to evaluate the ageing of the
tablet hardness limits and gives a
margin of safety during tablet SAMPLING OF EACH STAGE.
Sample according to a written
development prior to the pivotal batch sampling protocol or specific SOP
lot manufacture. NOTE:
No pivotal batch should be processed Order
of Testing PHYSICAL TESTS PERFORMED:
if the developer has not carefully the Ø WEIGHT ×
evaluated the dissolution profile on sampled Ø THICKNESS ×
tablets compressed at both ends of the units. Ø HARDNESS ×
commercial hardness
EVALUATE TESTspecification
RESULTS …
Show that physical and dissolution parameters
are in specification with
Low, Target, and High DISSOLUTION TESTING
Hardness Samples. OF LOW, TARGET, & HIGH
Show Upper & Lower Control Limits HARDNESS SAMPLES.
Show Upper & Lower Specification Limits.

Handbook of Pharmaceutical Sect: 14.

14 10 Generic Development
 ORAL TABLETS PROCESS QUALIFICATION CHAPTER 14

STANDARD OPERATING
SOP # D-000-02-089Y PROCEDURES

PROTOCOL FOR TABLET HARDNESS QUALIFICATION

(PROSPECTIVE HARDNESS QUALIFICATION PROTOCOL)

Page 1 of 2.

1. PURPOSE
The purpose of this Standard Operating Procedure is to provide a protocol (• ‚) to
qualify the recommended hardness range of [Immediate Release] [00] mg Tablets/
caplets, in order to achieve the dissolution profile which corresponds to the finished
product specifications

2. RESPONSIBILITY
Responsibility of actions is represented in the text by symbol:-.
• indicates Protocol is prepared by R&D Project and Process Development
Managers. Protocols are approved by the R&D and QA.
‚ indicates performed by validation team.
ƒ indicates performed by plant QA Technicians.
… indicates in-process testing performed by the plant QC Analytical Laboratory.
† indicates testing performed by the R&D Analytical Laboratory.
‡ indicates analysis and evaluation of the test data generated, performed by the
R&D Validation Team and approved by the R&D Quality Assurance.

3. FREQUENCY
Performed with the Process Qualification and the Pivotal Lot

4. PROCEDURE
PROSPECTIVE HARDNESS RANGE QUALIFICATION
4.1 Sampling Plan:
Samples are collected as they are compressed at target machine speed. The tablets/
caplets are compressed at the upper and lower limits of the hardness tablet
specification range. 10% of the batch is compressed at the upper and lower
hardness limits and 80% at the target limits.

4.2 Testing Plan:

Tablets or caplets are compressed at each hardness limit (namely the upper and
lower hardness limits).
The tablets / caplets are tested ƒ † as follows:
20 units for weight determination ƒ †
20 units for thickness (mm) ƒ †
20 units for hardness testing (SCU) ƒ †
12 units for dissolution profile (sampling time: 10, 20, 30, 45 etc. min as specified) †

Edition Number:
02
Effective Date
APPROVED
Ed. Status: DD/MM/YY ______________ __________ _______________ ______/__________
Supercedes: 01 Department R &D RA QC / QA
Handbook of Pharmaceutical Sect: 14.
14 11 Generic Development
 ORAL TABLETS PROCESS QUALIFICATION CHAPTER 14

STANDARD OPERATING
SOP # D-000-02-089Y PROCEDURES

PROTOCOL FOR TABLET HARDNESS QUALIFICATION

(PROSPECTIVE HARDNESS QUALIFICATION PROTOCOL)

Page 2 of 2.

5.0 ACCEPTANCE CRITERIA ‡

5.1 All parameters tested will be within the upper and lower control limits of the
control chart.
5.2 These limits for the in-process and finished product test shall be within the
defined specification limits for the in-process and finished product.
5.3 The overall process shall be evaluated for capability and shall be within the
process capability index for the finished product.

For In-process Product Testing:

5.4 The Upper control limit (UCL) is defined as the mean + 3 x Standard Deviation
5.5 The Lower control limit (LCL) is defined as the mean - 3 x Standard Deviation

For Finished Product Testing:

5.6 The Upper control limit (UCL) is defined as the mean + 3 x Standard Deviation
5.7 The Lower control limit (LCL) is defined as the mean - 3 x Standard Deviation
5.8 Cp ≤ 1.0 (Note: Cp = UCL - LCL / 6SD)
6.0 LIMITS and LIMITATIONS
6.1 Final blend granulate - critical step.
The content uniformity of the Final blend granulate prior to compression shall be
tested … for < content uniformity USP>. The Final blend granulate shall fall within
the control limits calculated from the ten individual sampling assay results.
Special Note:
In-process specifications for the Final Blend Granule Content Assay.
For In-process Granule Content Testing (Content Uniformity):
6.2 The Upper control limit (UCL) is defined as the mean + 3 x Standard Deviation
6.3 The Lower control limit (LCL) is defined as the mean - 3 x Standard Deviation

7.0 DOCUMENTATION
7.1 A Hardness Range Qualification Report (HRQR-‡) including tabulation of
results, statistical evaluation, process capability evaluation, report conclusions and
recommendations will be submitted to QA Unit, Production and Development Unit
Managers.
3
[End of Document]

Edition Number:
02
Effective Date
APPROVED
Ed. Status: DD/MM/YY ______________ __________ _______________ ______/__________
Supercedes: 01 Department R &D RA QC / QA
Handbook of Pharmaceutical Sect: 14.
14 12 Generic Development
TABLETS ORAL P I V O T A L CHAPTER 15

PIVOTAL
BATCH
‘the generic product has been developed and qualified
this is a key demonstration batch for regulatory submission.’

THE PIVOTAL BATCH batch may be for clinical use it is in fact a

small scale full GMP commercial batch.
T he Pivotal batch is
demonstration batch containing the
manufacturing documentation, product
that
Validated pivotal batches may in fact be
marketed after approval is obtained, if the
specifications and accelerated stability data product displays sufficient marketable shelf
normally submitted to the FDA as part of life.
the regulatory data necessary for the Analytical methods
ANDA filing. All analytical development methodology,
stability indicating assays and impurity
The data is generated from the Pivotal profiles are complete at this stage.
Batch manufacture and testing process. The pivotal batch is tested by the fully
Bioequivalency testing against a reference validated analytical assay method and the
drug is performed with samples from this accelerated stability tests performed on the
batch. generic drug product will be evaluated by
FDA exhibition/pivotal batch the stability indicating test analysis.
The pivotal is a key exhibition batch for
legal and regulatory purposes and serves as
SUMMARY
The Pivotal Batch is:
a model system or exhibition batch for the
FDA as to the exact wording of the ♦ the ANDA submission batch
♦ the regulatory reference batch
manufacturing processing instructions, drug
♦ the process exhibition batch
product specifications and test results ♦ the bioequivalence batch
obtained. It is used as a reference point. ♦ a process qualified batch
ANDA Submission ♦ the validation-basis batch
♦ a production processed batch
The OGD expects that the commercial ♦ a full GMP batch
lots will have the identical specifications ♦ a stability tested batch
and parameters as specified in the ANDA The Pivotal Batch contains the :
which has been based on the pivotal lot. ◊ ingredients from ‘approved suppliers
Production Facilities ◊ final product formulation.
The FDA expect that the pivotal batch will ◊ final processing instructions.
be manufactured, filled and packaged under ◊ final in-process specifications.
full GMP conditions using the commercial ◊ final release specifications.
production equipment and staff under ◊ final stability specifications.
which the proposed future commercial ◊ final F P specifications.
batch lots will be manufactured. ◊ final filling specifications.
The Bioequivalent evaluation against the ◊ final packaging specifications.
Reference Listed Drug is carried out using ◊ full analytical S.I. methodology.
the pivotal batch product. As the pivotal ◊ full microbiological methodology.

Handbook of Pharmaceutical Sect: 15.

15 1 Generic Development
 TABLETS ORAL P I V O T A L CHAPTER 15

ØC H E C K L I S T ×
CL # P-HGD-03-01Y2K

THE PIVOTAL BATCH

‘…Development stops here!
After the pivotal, there are no significant specification changes…’

1. The product formula for the pivotal is the final marketing formula? qYes qNo
2. The Manufacturing Instructions are suitable for routine production? qYes qNo
3. The pivotal batch manufacturing equipment is standard production qYes qNo
equipment operated by production staff with routine QA personnel?
4. A side-by-side comparison of the pivotal equipment and the validation qYes qNo
batch equipment are similar, and differ in a change in scale only?
5. The pivotal batch production will follow all production SOPs? qYes qNo
6. The pivotal batch size is 10 % or greater of the largest proposed qYes qNo
commercial lot?
7. The complete pivotal batch must be 100 % filled and packaged in the qYes qNo
marketing container-closures (no part-packaging permitted)?
8. All production equipment has been physically checked for appropriate qYes qNo
recorders and control units as written in the pivotal documentation ?
9. The validation protocol for the first three full scale lots is drawn up? qYes qNo
10. The validation protocol addresses all key processing parameters, qYes qNo
that if changed, will significantly impact on product quality ?
11. All microbiological methodology has been audited and signed-off ? qYes qNo
12. Assays and test methods based on the USP, with in-house qYes qNo
modifications has been validated?
13. The active’s assay has been validated and is a stability indicating qYes qNo
test?
14. The stability protocol addresses the key stability indicating qYes qNo
specifications ?
15. The overall pivotal manufacturing file is audited and signed-off ? qYes qNo

Footnote : The Pivotal Batch is sometimes referred to as the; the

Bioequivalent Batch, the Exhibition Batch, the Demonstration Batch, the
Clinical Batch (strictly NDA), the Regulatory Batch, or the ANDA Batch.
The names have all the same meaning.

Handbook of Pharmaceutical Sect: 15.

15 2 Generic Development
 TABLETS ORAL P I V O T A L CHAPTER 15

STANDARD OPERATING
PROCEDURES
CL # P-HGD-03-01Y2K Page 1 of 1

THE PIVOTAL BATCH

The following Standard Operating Procedures are recommended for a generic

development unit:

The Pivotal Batch

P-000-01-02YY Documentation requirements for the Pivotal Batch.
P-000-01-02YY Side-by-side comparison of Pivotal and Validation Batch
parameters.
P-000-01-02YY Pivotal Batch OGD Requirements - Oral Single Dose Tablets.
P-000-01-02YY Do’s and Don’ts when preparing for Pivotal Batches.
P-000-01-02YY Auditing the pivotal batch CMC documentation.

Note: Revised FDA COMPLIANCE POLICY GUIDE NUMBER 7157.02 (1996).

The FDA has been sensitive to the need for industry to protect information
generated by internal in-house GMP auditing programs. It is the agencies intention
not to review the internal audit results, except under circumstances of litigation or a
judicial search warrant.
A firm requires to have a written quality assurance program in place at the regulated
site in order for the FDA not to review or copy the firm’s records and reports that
resulted from audits of a written quality assurance in-house program.
A written ‘Certificate of Audit’ notifying management that such audits and inspections
have been implemented, performed and documented and that all corrective action
necessary has been taken is required.
The intent of the FDA policy is to encourage firms to conduct in-house quality
assurance program audits and self-inspections that are both candid and meaningful.

4
[End of Document]

ED. N0: 02 Effective Date: APPROVED:

Replaces Ed 01.
Ed. Status: MM/DD/2000
Operational Department R&D QC QA

Handbook of Pharmaceutical Sect: 15.

15 3 Generic Development
 TABLETS ORAL P I V O T A L B A T C H CHAPTER 15

STANDARD OPERATING
SOP # P-000-05-01Y2K
PROCEDURES
Total Pages: 5

IN-PROCESS SAMPLING & TESTING PROCEDURES FOR PILOT

SCALE & PIVOTAL BATCH LOTS

Page 1 of 5.

1. PURPOSE
The purpose of this Standard Operating Procedure is to describe the production in-
process sampling procedure and the testing to be performed on each pivotal lot or
pilot plant scale batch lot. This sampling plan is structured upon the FDA's
"Guidance on the Packaging of Test Batches", of February 8, 1995 Number 41-95" &
PDA Technical Report, April 30 1997. It meets the draft FDA June 1998 Guidance
For Industry, titled "Stability Testing of Drug Substances and Drug Products".

2. RESPONSIBILITY
Responsibility of actions is represented by the relevant symbol in the text.
• Symbol indicates Protocol is prepared by Development Project Unit and Process
Development Managers. Protocols are approved by the Development and QA Unit.
‚ Symbol indicates performed by process validation team.
ƒ Symbol indicates sampling performed by the Plant QA Technicians.
„ Symbol indicates In-process testing performed by the Plant QA Technicians.
… Symbol indicates Batch Release Testing performed by the Plant QC Analytical
Laboratory.
† Symbol indicates testing performed by the Development Analytical Laboratory.
‡ Symbol indicates analysis and evaluation of the test data generated, performed by
the Development Unit Validation Team and approved by the Development Quality
Assurance Unit.
3. FREQUENCY
The procedure is performed with each pivotal or pilot-plant batch lot.
4. PROCEDURE
4.1 In-Process Control - Sampling and Testing
Final Blended Material - (Immediately prior to compression or capsule filling).
Physical Testing - Sampling Protocol
A total of Six samples (about 100g per sample) is collected from the storage
containers, representing the top, middle and the end of the final blended material.
Three 100g samples are used for testing and the balance of the samples reserved
for further testing, if so required.

Chemical Testing - Sampling Protocol

Ten (10) samples, each sample equivalent to the approximate weight of one (to
three)³ dose units are collected from the left, right arm, and base Y-Cone / Twin
shell blender. Sampling techniques are outlined in the written product protocol and
the Batch Manufacturing Instructions (BMI).

ED. N0: 02 Effective Date: APPROVED:

Replaces Ed 01.
Ed. Status: MM/DD/2000
Operational Department R&D QC QA
Handbook of Pharmaceutical Sect: 15.
15 5 Generic Development
 TABLETS ORAL P I V O T A L B A T C H CHAPTER 15

STANDARD OPERATING
SOP # P-000-05-01Y2K
PROCEDURES
Total Pages: 5

IN-PROCESS SAMPLING & TESTING PROCEDURES FOR PILOT

SCALE & PIVOTAL BATCH LOTS

Page 2 of 5.
Chemical Testing - Sampling Protocol - (continued)
Where sampling procedures from the Y-Cone Twin shell blender are not possible,
the reasons are described in the written product protocol.
In the case of a flow-bin being used is as a blender, then the samples are collected
from the top, middle and bottom of the blending unit.
Sample collection ‚ƒ ƒ
40 samples are collected
10 samples, each equivalent to the approximate weight of one (to three)³ unit dose(s)
‚ƒ, are collected from the storage containers, according to SOP, "Sampling of
Granulate for Blend Uniformity". (³ See limits and Limitations)
30 samples will be collected ‚ƒ ƒ as above and stored as retention samples for
additional testing, if required. When a flow-bin is used both as a blending unit and
as a storage container, no additional samples are taken.
Sampling collection:
The samples are collected via an appropriate “Sampling Thief” equipped with the
necessary die - unless otherwise instructed in the written protocol.
4.2 Physical Testing Protocol
Each sample is tested for:
• Sieve analysis (wet granulation process only)
• Bulk and tapped density
4.3 Chemical Testing Protocol
• The samples will be assayed according to the full monograph.
4.4 Finished Processed Material - Tablets and Capsules
Applies to compressed Tablets, Caplets and Filled Capsules and Hardness Range
Qualification Testing for tablets and tablet cores only.
Sampling Protocol
Samples are collected at the target compression speed at the upper and lower limits
of hardness specification.
Testing Protocol
Tablets compressed at the upper and lower limit will be tested as follows [¹ Tests are
performed on the same tablets in the following order.]
• 20 tablets for thickness ¹
• 20 tablets for weight ¹
• 20 tablets for hardness ¹

ED. N0: 02 Effective Date: APPROVED:

Replaces Ed 01.
Ed. Status: MM/DD/2000
Operational Department R&D QC QA
Handbook of Pharmaceutical Sect: 15.
15 6 Generic Development
 TABLETS ORAL P I V O T A L B A T C H CHAPTER 15

STANDARD OPERATING
SOP # P-000-05-01Y2K
PROCEDURES
Total Pages: 5

IN-PROCESS SAMPLING & TESTING PROCEDURES FOR PILOT

SCALE & PIVOTAL BATCH LOTS

Page 3 of 5.

Testing Plan… (continued)

For Friability Test - (10 or 20 units tested):-
• Tablets less than 650 mg, test 6.0-6.5 g of tablets, but NLT 20 tablets.
• Tablets more than 650 mg, test 10 tablets.
Tablet / Capsule Dissolution Profile:-
• 12 tablets / Capsules.

4.5 Batch Testing during the actual compression or filling Process.

Sampling Protocol
Samples at target hardness should be collected directly as they exit the press/filling
machine, at a minimum of three time intervals, representing the beginning, middle
and end of the tabletting / capsules filling process.

Testing Protocol †
Each sample will be tested † as follows - ¹ Tests performed on the same tablets:
• 20 tablets for thickness ¹
• 20 tablets/capsules for weight ¹
• 20 tablets for hardness ¹
For Friability:-
• For tablets less than 650 mg, test 6.0-6.5 g of tablets, but not less than 20
tablets.
• For tablets more than 650 mg, test 10 tablets.
For Tablet / Capsule Dissolution Profile:-
• Tablets / capsules ²
• Assay on each sample as per product monograph.
² Where tablets are film-coated, a dissolution profile is performed on tablets collected at each of the
three exit time interval, making a total of 18 tablets.

4.6 Coated Tablets

When more than one load is processed in the coating machine, the dissolution test
as per finished product specifications is performed on 6 coated tablets from each
load. When only one load is processed in the coating machine, dissolution will be
performed as described in paragraph. 4.7.

ED. N0: 02 Effective Date: APPROVED:

Replaces Ed 01.
Ed. Status: MM/DD/2000
Operational Department R&D QC QA
Handbook of Pharmaceutical Sect: 15.
15 7 Generic Development
 TABLETS ORAL P I V O T A L B A T C H CHAPTER 15

STANDARD OPERATING
SOP # P-000-05-01Y2K
PROCEDURES
Total Pages: 5

IN-PROCESS SAMPLING & TESTING PROCEDURES FOR PILOT

SCALE & PIVOTAL BATCH LOTS

Page 4 of 5.

4.7 QC Release/Stability Testing (Time Zero) of Finished Packed Product

A representative sample taken from the production packaging run is tested … as
per product release specifications, except that a 12 tablet dissolution profile is
performed instead of the normal 6 tablet dissolution test.
Each package type (smallest and largest pack) is tested† for the initial time zero
stability assay requirements - as per product stability protocol.
Samples are submitted to the laboratory with the specific testing protocol • and
appropriate sampling record forms (refer: sampling attachment forms).
Laboratory acceptance† of the test samples is verified by signing the sampling
record forms.

4.8 Evaluation of Tested Parameters † ‡

The physical and chemical parameters tested are evaluated to confirm the uniformity
of the batch and where applicable to comply with the required specifications ‡.
4.8.1 The limits for the in-process and finished product testing shall be within the
defined specification limits for the in-process and finished product.
4.8.2 All Tablet Hardness Qualification parameters tested will be within the upper
and lower control limits of the control chart.
4.8.3 The overall process shall be evaluated for process capability and shall be
within the process capability index (CpK) for the finished product.
Special Note:
For In-process specifications for the Final Blend Granule Content Assay.
In-process Granule Content Testing (Content Uniformity)4:
5.0 The Upper control limit (UCL) is defined as the mean + 3 x Standard Deviation
5.1.1 The Lower control limit (LCL) is defined as the mean - 3 x Standard Deviation

For In-process Product Testing:

5.2 The Upper control limit (UCL) is defined as the mean + 3 x Standard Deviation
5.3.1 The Lower control limit (LCL) is defined as the mean - 3 x Standard Deviation

For Finished Product Testing:

5.4 The Upper control limit (UCL) is defined as the mean + 3 x Standard Deviation
5.5 The Lower control limit (LCL) is defined as the mean - 3 x Standard Deviation
5.6 CpK ≤ 1.0 (Note: CpK = UCL - LCL / 6SD)

ED. N0: 02 Effective Date: APPROVED:

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Ed. Status: MM/DD/2000
Operational Department R&D QC QA
Handbook of Pharmaceutical Sect: 15.
15 8 Generic Development
 TABLETS ORAL P I V O T A L B A T C H CHAPTER 15

STANDARD OPERATING
SOP # P-000-05-01Y2K
PROCEDURES
Total Pages: 5

IN-PROCESS SAMPLING & TESTING PROCEDURES FOR PILOT

SCALE & PIVOTAL BATCH LOTS

Page 5 of 5.

6.0 LIMITS and LIMITATIONS

6.1 Final blend granulate - critical step.
The content uniformity of the Final blend granulate prior to compression shall be
tested … for < Content Uniformity USP>. The Final blend granulate shall fall within
the control limits calculated from the ten individual sampling assay results.

This SOP is restricted to the sampling and testing of in-process controls during
pivotal or pilot-scale batch manufacture for chemical and physical testing, and
includes Tablet Hardness Qualification Testing. This SOP does not specify the
actual number of packed units to be representatively sampled for: QC Retention,
Stability Profile, Stability Reserve or Bioequivalence Testing and Bioequivalence
Reserve.

³ Sample size may be increased to three dosage units where appropriately qualified
in the process development report.
4 In-process
Granule Content Testing (Content Uniformity):
Where appropriately qualified by suitable batch analysis (or clearly established
during process development), the in-process lower and upper limits for Granule
Content Testing (Content Uniformity) may be narrowed to:
The Upper control limit (UCL) is defined as the mean + 2 x Standard Deviation
The Lower control limit (LCL) is defined as the mean - 2 x Standard Deviation

7. CORRECTIVE ACTION
Out-of-specification test results (OOS) are handled according to the firms current
Out-of-Specification SOP.

8. DOCUMENTATION
Each protocol will be accompanied • by a manufacturing process flowchart.
The sampling record ‚ forms are filed with the manufacturing batch records.
Sampling Record Forms for data completion at the time of sampling are as follows:
Attachment 1 - " Sampling Record for Final Blended Granulate "
Attachment 2 - " Sampling Record for compressed Tablet / Caplet & Capsule Filling"
Attachment 3 - " Sampling Record for Coated Tablets / Caplets "
Attachment 4 - " Sampling Record for Finished Product Release & Stability T0 Test "
3
[End of Document]

ED. N0: 02 Effective Date: APPROVED:

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Ed. Status: MM/DD/2000
Operational Department R&D QC QA
Handbook of Pharmaceutical Sect: 15.
15 9 Generic Development
 TABLETS ORAL P I V O T A L P R O C E D U R E S CHAPTER 15

Auditing the
Inspecting and comparing the pivotal
batch documentation line-for-line and
page-by-page is a prudent, worthwhile
Pivotal Batch and judicious auditing operation.
Retrieving and reviewing the plant
production and cleaning logs or
T he Pivotal (Regulatory or Exhibition)
Batch is the demonstration batch lot
that is submitted to the regulators
ingredient inventory cards are a
necessary part of the job. Checking
as the example and legal basis on batch numbers, dates and signatures,
which the future commercial lots will be possible transposed numbers or
marketed and sold. It represents a omitted data, require careful vigilance
baseline of procedures and product by the auditor or audit team. Auditing
specifications that are the regulatory with a formal procedure, simplifies the
basis for government agency approval. task and allows the audit checklist to
grow when new and unusual errors or
This is generally the first production omissions are detected.
batch in which all the production and
control parameters and specifications Update audit checklists
have been fully set. Little practical
experience has been gained so far, after each pivotal lot
from the manufacture of a minimum 100 An audit checklist that remain static
000 units (net / packed quantity). over the years, may well reflect an
Production familiarity, experience and ineffective inspection, analysis and
process fine tuning, by the firm will be detection procedure.
gauged, only after the product has been The Pivotal Batch Audit Checklist.
approved, during the many commercial Checklist Do's:-
production manufacturing lots.
♦ Divide audit checklist into
Error-Free Pivotal representative sections portraying each
documentation saves operation, manufacturing and control
procedure.
time and money ♦ Add new check points to the list,
when a new error or omission arises.
Thus the need to get it right, at the very ♦ Test the checklist, by evaluating
first attempt at the production level routine production batches, to get a
(pivotal lot) is paramount. Careless sense of possible omission categories.
omissions in the batch documentation ♦ Break multiple check points into
will eventually result in an agency individual audit items on the checklist.
deficiency letter and thereby delaying
approval for an additional few months -
♦ Carefully cross-reference hand-
written dates and times on the
costing both time and valuable
production forms against machine print-
development and lost sales dollars.
outs that have immediately follow the
Experienced Pharmaceutical Firms operational step.
know the high costs of undetected ♦ Remember - weighing, LOD, HPLC
documentation omissions or data fields, and temperature print-outs and charts
and have set up efficient development normally give the date and the exact
quality assurance units that closely time of the operation or test procedure.
examine, inspect, audit and review Evaluate production yields and
every aspect of the batch adherence to time-limitation against
documentation for submission actual weighing & recording print-outs. 2

Handbook of Pharmaceutical Sect: 15.

15 11 Generic Development
 TABLETS ORAL P I V O T A L B A T C H CHAPTER 15

STANDARD OPERATING
SOP # P-000-02-01Y2K
PROCEDURES

CHECKLIST FOR AUDITING THE PIVOTAL BATCH

Product Name: Dosage Strength; mg

Batch No. Date of Audit: / /Y2K
Page 1 of 3.
Yes No
1. PRODUCT MASTER DOCUMENTS
ü Master documents approved and signed by appropriate personnel. q q
ü Master documents available during the audit for comparison. q q
2. ACTUAL BATCH DOCUMENTS (Executed Batch)
ü Are the batch documents equivalent to the Master documents and available for the q q
audit?
ü Is the batch size equal or greater than 110,000 units? q q
ü Are the batch document pages numbered correctly? q q
ü Evaluate whether some of the pages could be replaced or rewritten? q q
ü Is there any evidence of erasures or white-outs? q q
ü Are cross-outs legible and correctly signed and dated ? q q
3. PRODUCT MASTER FORMULA - Check MF
ü Batch number q q
ü Lot No of ingredients q q
ü Two Signatures and date(s) for each weighing q q
ü Check ingredients weigh-out sheets q q
ü Computer weighing print-outs show gross, tare and net weights. q q
ü Are print-outs available and accurate? q q
4. BATCH MANUFACTURING INSTRUCTIONS - Check BMI for
ü Batch numbers recorded in correct data fields q q
ü ID numbers for Processing Machine present q q
ü Signatures and date(s) for each separate processing step q q
ü LOD figures correct and are in the specification limit q q
ü Weight of processed material and yield calculation performed q q
ü % yield conform to written specifications limits on BMI q q

5. PRINT-OUTS & ATTACHMENTS - Check for full identification:

ü 'Equipment Cleaned' labels attached to batch record q q
ü In-process LOD print-outs recording target moisture achieved q q
ü In-process weight sheets/print-outs recording in-process yields q q
ü Recording charts for drying temperature (FBD /Ovens /Dryers etc.) q q
ü Recording charts for time of mixing (FBD / mixers/blenders/coaters). q q

ED. N0: 02 Effective Date: APPROVED:

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Ed. Status: MM/DD/2000
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Handbook of Pharmaceutical Sect: 15.
15 13 Generic Development
 TABLETS ORAL P I V O T A L B A T C H CHAPTER 15

STANDARD OPERATING
SOP # P-000-02-01Y2K
PROCEDURES

CHECKLIST FOR AUDITING THE PIVOTAL BATCH

Product Name: Dosage Strength; mg

Batch No. Date of Audit: / /Y2K
Page 2 of 3.
Yes No
6. ROOM PREPARATION - Check for:
ü Machine Card details corresponds to batch record q q
ü Room Preparation Card details and dates correct q q
ü Check that card dates coincide with batch record dates. q q
ü If equipment was used in 2 sublots, were both entries recorded? q q

7. BATCH RUN SHEETS - Check Production sheets for:

ü All Product details are complete as per product Specifications. q q
ü Work station approved as clean and initialed before opening. q q
ü Opening of Production Work station initialed. q q
ü Operator and QC in-process control charts separate & identified. q q
ü Transferred of numbers are correct to BATCH SHEETS. q q
ü Operator and QC in-process on-line check results within the specifications limits q q
set. q q
ü Number of in-process checks according to current SOP. q q
ü In-process sampling during manufacturing as per protocol. q q
q q
8. INSTRUCTIONS FOR CAPSULE FILLING Check for:
ü All Product details are accurate, including Lot No. of empty capsules.
q q
ü Minimum, maximum and average empty capsule weight
ü Minimum, maximum and average theoretical fill weight q q
ü Minimum, maximum and average of filled capsule weight q q
ü Signatures of Production and Quality Control personnel q q
q q
9. COATING MANUFACTURING INSTRUCTIONS
ü Check continual stirring of coating suspension :
ü All Product entries are complete - including sub lot number. q q
ü Preheating of cores parameters. q q
ü Spraying parameters set-up (settings, nozzle type, distance, angle) q q
ü Coating spraying procedure including equipment graph. q q
ü Percentage yield conforms to specifications and within limits. q q
ü Summary of manufactured sub lots. q q
q q
q q

ED. N0: 02 Effective Date: APPROVED:

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Ed. Status: MM/DD/2000
Operational Department R&D QC QA
Handbook of Pharmaceutical Sect: 15.
15 14 Generic Development
 TABLETS ORAL P I V O T A L B A T C H CHAPTER 15

STANDARD OPERATING
SOP # P-000-02-01Y2K
PROCEDURES

CHECKLIST FOR AUDITING THE PIVOTAL BATCH

Product Name: Dosage Strength; mg

Batch No. Date of Audit: / /Y2K
Page 3 of 3.
Yes No
10. STANDARD PACKAGING SHEET - Check for:
q q
ü Product details required for packaging operation complete.
q q
ü Lot numbers present of packaging components.

11. PACKAGING CONTROL SHEET - Check:

ü All Product details required & entered are accurate q q
ü Cleanliness check of work station is approved q q
ü Product and packaging material identification is approved q q
ü Approval for start-up of the line q q
ü In-process control checks complete q q
ü Packaging 100% completion check q q
ü Quantity of the packaged product compared to the estimates q q
ü Sample of labels used with Lot No and Expiration Date q q
ü In-process QC checks of product packs q q
ü Representative sampling of each pack type and pack size. q q
12. PACKAGING MATERIALS BALANCE - Check for:
ü All Product details are accurate on reconciliation form q q
ü Labels are reconciled and printed material balance correct q q
ü Production and QA Signatures complete and dated. q q

13. PRODUCTION & PACKAGING SHEET - Check for:

ü All Product details required & entered are accurate q q
ü Yield reconciliation of each stage of manufacture q q
ü Time limitation at each stage of production in specification q q
ü Authorization signature of Quality Control Manager q q

14. MANUFACTURING DEVIATION REPORT - Check MDR for:

ü All Product descriptive details are entered accurately q q
ü Full description of the deviation q q
ü Source of process deviation q q
ü Proposed solution stated precisely q q
ü Decision on batch disposition confirmed q q
ü Authorization of Quality Assurance Unit q q
q q

ED. N0: 02 Effective Date: APPROVED:

Replaces Ed 01.
Ed. Status: MM/DD/2000
Operational Department R&D QC QA
Handbook of Pharmaceutical Sect: 15.
15 15 Generic Development
 ORAL DOSAGE FORMS DISSOLUTION & B I O S T U D Y CHAPTER 16

Generic Bioequivalence
and the Reference Listed Drug

AVERAGE IR & CR BIOEQUIVALENT and therapeutic equivalent parameters.

ASSESSMENT OF GENERIC DRUGS There is a need to define
Immediate and controlled release bioequivalence and therapeutic
products can be separated into two equivalence.
distinct categories when evaluating BIOEQUIVALENCE
average bioequivalence, namely: A generic drug product that is either a
n Pharmaceutical equivalent products pharmaceutical equivalent or a
n Pharmaceutical alternative products pharmaceutical alternative drug product
that shows equivalent or comparable
PHARMACEUTICAL EQUIVALENCE bioavailability against the Reference
requires the test and reference drug Listed Drug (RLD). Bioequivalence for
(RLD) to meet the following parameters: IR/CR dosage forms is an invivo
Ü Same Active Ingredient measurement of the active moiety
(moeities) in biological fluid.
Ü Same strength (concentration)
THERAPEUTIC EQUIVALENCE has six
Ü Same Dosage Form (Drug Type) additional key considerations, namely
Ü Same Route of Administration the drug product must be:-
Ü Complies with identity, strength, Ø a pharmaceutical equivalent drug
quality and purity Compendial / Ø a bioequivalent drug
Pharmacopoeial Standards.
Ø an interchangeable drug
Ü Comparable labeling.
Ø shown to have same clinical effect
and safety profile
PHARMACEUTICAL ALTERNATIVES
require that the test and reference drug Ø a cGMP manufactured product
meet the following parameters:- Ø adequately labelled product
Ü Identical Therapeutic Moiety
REFERENCE LISTED DRUGS (RLDs)
Ü May not be 'Same strength' These are approved drug products
Ü May not be 'Same Dosage Form' appearing in the FDA publication
Ü May not be 'Same Salt or Ester' "Approved Drug Products with
Therapeutic Equivalent Evaluation
Ü May meet its own Standards of
Edition 20 (2000) " an annual
purity, identity strength and Quality.
publication commonly known as the
Thus an equivalent generic drug has 'Orange Book'.
either the same active ingredient or an This reference lists the following:-
identical therapeutic chemical moiety n Drug products approved for safely
and requires to meet both bioequivalent and efficacy (NDAs & ANDAs)

Handbook of Pharmaceutical Sect: 16.

16 1 Generic Development 24 Volume Series
 TABLETS ORAL DISSOLUTION & B I O S T U D Y CHAPTER 16

n Interchangeable Drug Products ('AB') BIOAVAILABILITY & BIOEQUIVALENT

(BA/BE) REQUIREMENTS.
n RLDs (are identified with + sign) A generic drug (Abbreviated Drug
A drug product coded AB+ would be a Product) needs to meet six
Therapeutic Equivalent Reference requirements for a successful BA/BE
Listed Drug where: application:
AB = Therapeutic Equivalent Ü meet the requirements for which a
abbreviated application may be
submitted (21 CFR 314.92)
+ = Reference Listed Drug
Ü content presented in the format of an
AB+ = Reference Listed Drug and Abbreviated Application (21 CFR 314.94)
Therapeutic Equivalent Ü meet the Guidelines for Industry1 on
Design, Type and conduct of
NOTE: bioavailability and bioequivalent studies
The principle purpose of an RLD is to
assure that all generic products remain Ü meet requirements to show BA/BE
equivalent to a common standard. The (i.e. pass the study/studies) (21 CFR 320)
Orange Book may list more than one Ü meet the waiver requirements for
RLD for the active material. multiple dose applications.

HOW IS AN RLD SELECTED HOW BIOEQUIVALENCE IS

ASSESSED
Selection of RLDs depend on the
The assessment of bioequivalence
source(s) of the drug product(s) i.e.
generally follows three distinct
Single source - A single source approaches and methodologies via
product is generally the innovator either an:
marketing as the only product under its ð INVIVO STUDY
Brand Name. The product is the only ð INVITRO STUDY
NDA on the market - thus the single ð OTHER STUDY TYPES
source classification.
INVIVO INVITRO OTHER
Multiple source
[A] There may be TWO or more NDAs
launched from different companies. In Study Endpoints are:
this case the RLD is generally the
market leader.
Pharmacokinetic Physico- Waiver of
[B] There may be TWO or more ANDAs Chemical Invivo study
launched from different companies (no Pharmacodynamic (Resins)
longer an NDA on the market). In this
In Vitro-
case the RLD is generally the ANDA Clinical Testing
market leader.
1Guidelines for Industry, describe the agency's
[C] There may be TWO or more ANDAs
policy, current thinking and regulatory approach to
launched from different companies an issue and are not legally binding requirements on
(both are BA/BE to each other). In this the public or agency, alternative methods are
case there are TWO or more RLDs. acceptable generally with prior discussion with the
agency.

Handbook of Pharmaceutical Sect: 16.

16 2 Generic Development
 TABLETS ORAL DISSOLUTION & B I O S T U D Y CHAPTER 16

INVIVO BIOEQUIVALENCE STUDIES TEST & REFERENCE

The requirements for a controlled Important Specifications for the uTest
release invivo bioequivalent study fall Drug and vReference Drug (RLD) are:
under the following headings, namely:- u A Production-size cGMP Batch v
è Type of Study u Strength and Potency determined v
è Food-Effect considerations1 u Complies with Content Uniformity v
è Drug Products evaluated u Batch or Lot Number referenced v
è Study Subjects u Inferred Expiration Date from
è Study Design stability evaluation.
è Sample Collection u Comparative Dissolution Profile
(CDP) Evaluated against RLD v.
è Sample Analysis
u Complies in full with content and
è Analysis of Study Data format of an ANDA Dossier.
è Bioequivalent evaluation
1Draft 10/97 'Food-Effect Guidance to Industry' STUDY DESIGN
Ÿ Cross-Over (Most IR/CR/DR Drugs)
TYPES OF STUDIES
- Treatment/Periods/Sequences
l Pharmacokinetic - Solid Oral Dosage
Forms - IR, CR, MR, (ER + DR) - Wash out period
l Pharmacodynamic (Selected MDIs & - Randomization
Topical Dosage Forms) Ÿ Parallel Design (Most long half-life drugs)
l Clinical (Topical & Vaginal Anti-
- Treatments
fungals and Non-Absorbed Drug
Products) - Randomization

EVALUATING CR PRODUCTS STUDY SUBJECTS

[A] Extended Release (Controlled Ÿ Normal subjects / Patients
Release) Drug Products - (ER & MR) Ÿ Inclusion and exclusion Criteria
[B] Delayed Release (Enteric Coated) Ÿ Medical History
Drug Products - (DR) Ÿ Physical & Clinical Evaluation
Ÿ Demographic Profile
[A] INVIVO STUDY TYPES (CR)
Ÿ Restrictions
ER & MR - Single Dose (Fasting) Ÿ Numbers enrolled & Completed
(Drop outs / Add-ons / Replacement)
ER & MR - Single Dose (Food)
SAMPLE COLLECTION
ER & MR - Multiple Dose (Fasting) Ÿ Appropriate biological matrix
screened
[B] INVIVO STUDY TYPES (DR) Ÿ Ascending phase
Ÿ Maximum concentration phase
DR - Single Dose (Fasting) Ÿ Elimination phase
DR - Single Dose (Food) SAMPLING FREQUENCY
Ÿ Adequate during ascending phase

Handbook of Pharmaceutical Sect: 16.

16 3 Generic Development
 TABLETS ORAL DISSOLUTION & B I O S T U D Y CHAPTER 16

Ÿ Intensive sampling around expected STATISTICAL BIOEQUIVALENCE

time of maximum concentration (Cmax) Statistical bioequivalence is concluded
Ÿ Sufficient sampling during elimination between Test and Reference when 90%
phase. Confidence Interval for the ratio of the
Ÿ Extend the sampling period to at least means (population geometric means
three longest half-lives of analyte based on log transformed data) fall
(metabolite.) within between 80 -125% for AUC

SAMPLE STORAGE & PROCESSING SINGLE DOSE - FASTING STUDY

Ÿ Appropriate temperature storage (time Ÿ AUC0 -LQC (Point Estimate +20%)
limits.)
Ÿ AUC0 - inf (Point Estimate +20%)
Ÿ No analyte (metabolite) loss or
degradation over full concentration Ÿ Cmax (Point Estimate
range. +20%)
SAMPLE ANALYSIS (REPRESENTATIVE) Ÿ Tmax
Ÿ Parent Drug Ÿ Kel
Ÿ Metabolites
Ÿ T1/2
VALIDATION OF BIOASSAY
Ÿ Accuracy Ÿ Tlag (Delayed Release Enteric Coated)
Ÿ Precision
Ÿ Linearity MULTIPLE DOSE - FASTING STUDY
Ÿ Specificity & Sensitivity Ÿ AUC0 - TAU (90% Conf. Interval)
Ÿ Recovery from matrix Ÿ Cmax - ss (90% Conf. Interval)
Ÿ Stability of analytes
Ÿ Cmin - ss
ANALYSIS OF STUDY DATA
Ÿ Logarithm transformed Data Ÿ Cave. - ss
Ÿ Analysis of Variance (ANOVA) Ÿ Tmax
- Subject, Sequence, period, Treatment
Effects Ÿ Percentage Swing
- Test & RLD Means Difference Ÿ Percentage Fluctuation
- Intra Subject variability LQC = Lowest Quantifiable Concentration
Ÿ Statistical Bioequivalence Criteria
- Two one-side test procedures IN VITRO DISSOLUTION TESTING
- 90% Confidence Interval (80-125%) Dissolution is a key requirement during
drug development, batch-to-batch
BIOAVAILABILITY METRICS
quality control, product registration and
SINGLE DOSE - FASTING STUDY evaluating the comparative dissolution
Ÿ AUC0 -LQC (90% Conf. Interval) profile information required for the
Ÿ AUC0 - inf (90% Conf. Interval) bioequivalence section (VI) of the
ANDA submission, thus an integral part
Ÿ Cmax (90% Conf. Interval) of the bioequivalence assessment.
Ÿ Tmax Evaluating whether your firm's generic
Ÿ Kel drug will pass the biostudy first time is a
key requirement. The primary goal is to
Ÿ T1/2
ensure that the generic drug is
Ÿ Tlag (Delayed Release Enteric Coated) essentially similar to the reference
drug.

Handbook of Pharmaceutical Sect: 16.

16 4 Generic Development
 TABLETS ORAL DISSOLUTION & B I O S T U D Y CHAPTER 16

Knowing the reference drugs overall ♦ Validated Dissolution Method

dissolution profile and dissolution A fully validated dissolution assay
ageing parameters (ex stability tests) method is essential to obtain
are critical input data requirements. meaningful results from the comparative
In in-vitro dissolution testing, a dissolution profile (CDP) between the
dissolution profile of the Test Drug Generic and RLD. Prudent
versus the Reference Listed Drug is development laboratories will evaluate
generated. Both Test and Reference several CDPs using multipoint and
must pass all compendial media profiles with several (3) batches,
specifications, if available at time of hopefully with different manufacturing
data submission. dates and thus assessing
miscellaneous product ages.
Modified release (controlled release) Validated dissolution method
preparations, where non-compendial, requirements are highlighted in Table 2.
need to develop dissolution method
settings and specification ranges, (i.e. ♦ Multipoint Dissolution Profiles
sampling points and recovery ranges), A least three different batch lots of the
for each CR preparation. RLD using multipoint dissolution
profiles should be performed. (use
For testing dissolution and accessing
validated assay procedures.)
similarity between generic drug and
reference listed drug (RLD) assess Where possible age or stress one of
the:- the RLD lots and evaluate with and
without a surfactant, where appropriate.
♦ Drug Classification Evaluate profiles at low and high rpm
Classify the drug product according to rotational speeds. Comparative
its solubility, dissolution, permeability dissolution program are time consuming
and pharmacokinetics parameters. The but may well constitute the difference
Biopharmaceutics Classification System between a 'biostudy' pass or failure.
(BSC1) is designed for immediate ♦ Dissolution Profile 'Similarity Test'
release (IR) dosage forms, however the calculate the unbiased 'Similarity
identification of high and low solubility
actives impacts directly on the Factor' for each CDP. The result ƒ²
formulation choices made as to the should be between 50 to 100 to
release controlling excipients for the demonstrate 'similarity' between the two
controlled release formulation. formulations.
Furthermore distinguish narrow (~25 ♦ IVIV / Bioequivalence Pilot Study
drugs) and non-narrow therapeutic In the case of high-cost biostudies a
range drugs as well as long half-life small IVIVC pilot study of the drug may
drugs. give meaningful results and enable
formula or process adjustments
1. The type of dissolution studies necessary in intricate drug
considered necessary to fully evaluate comparisons. Adequate IVIVC data may
the formulated drug against the RLD be estimated from the pilot study data
that has been selected. of 6 or more subjects.
2. Whether it is possible to establish an
IVIVC (In-vitro, In-vivo Correlation)
♦ Bioequivalence Study.
Based on appropriate dissolution
between your drug and the intended
testing, similarity testing and IVIVC
bioequivalence study necessary for
filing with the FDA..

Handbook of Pharmaceutical Sect: 16.

16 5 Generic Development
 TABLETS ORAL DISSOLUTION & B I O S T U D Y CHAPTER 16

estimates, the development unit should comparable values.

be able to perform a full-size biostudy, Statistical analysis for pharmacokinetic
supported with adequate CDP data and parameters (metrics), e.g. area under
statistical assessments to pass the the curve (AUC) and peak concen-
mandatory bioequivalency evaluation tration (Cmax ), was based on a test
against the Reference Listed Drug. procedure termed "the two one-sided
1Current-in-progress are two draft guidelines to tests procedure," which determined
industry - (1) Draft FDA Guideline on "Waiver of whether the average values for
Invivo Bioavailability and Bioequivalence Studies on
Immediate Release Solid Oral Dosage Forms pharmacokinetic parameters measured
containing certain active moieties/active ingredients after administration of the test &
based on a Biopharmaceutics Classification System reference products were comparable
(BSC)"
(2) Draft FDA Guideline on Bioassays methods (i.e. average bioequivalence).
validation for Human studies based on drug or
metabolite assay in a biological matrix
This recommended procedure involved
the calculation of a 90% confidence
POPULATION & INDIVIDUAL interval for the ratio of the averages of
BIOEQUIVALENCE the test and reference product. To
establish bioequivalence, the calculated
NEW DEVELOPMENTS confidence interval was to fall within a
Bioavailability and bioequivalence are bioequivalence limit, usually 80-125%
usually measured by an in-vivo study, for the ratio of the product averages.
that assesses metrics of plasma or
blood concentration-time curves to
In addition to this general approach for
determining bioequivalence, the 1992
establish the rate and extent of
guidance provided specific
absorption of an appropriate active
recommendations for:-
drug / metabolite (bioavailability), or to
[1] - logarithmic transformation of
compare the rate and extent of
pharmacokinetic data
absorption of a test and reference
[2] - methods to evaluate sequence effects
formulation (bioequivalence). [3] - methods to evaluate outlier data.
PAST FDA GUIDANCE PROPOSED FDA GUIDANCE
In the 1992 guidance, FDA (CDER) CDER's (Oct 1997) Draft Guidance for
recommended that a standard in vivo Industry recommends that the average
bioequivalence study design be based bioequivalence method for determining
on administration of the test and bioequivalence recommended in the
reference products on separate initial 1992 guidance be replaced by
occasions to healthy subjects, either in two new approaches, termed
single or multiple doses, with random population and individual bioequiv-
assignment to the two possible alence. (Aug 1998 guideline still in draft status.)
sequences of drug product
administration. The Differences are
The guidance stated that samples of Subject-by-Formulation
plasma or blood should be analysed for
drug and/or metabolite(s) interactions and Test &
concentrations, and pharmacokinetic References Variances
parameters be obtained from the Statistically, the average bio-
resulting concentration-time curves. equivalence approach focuses only on
The guidance suggested that the the comparison of population averages
pharmacokinetic parameters be of a bioavailability metric of interest and
analysed statistically to determine if the not on the variances of the metric for
test and reference products yielded the test and reference products.

Handbook of Pharmaceutical Sect: 16.

16 6 Generic Development
 TABLETS ORAL DISSOLUTION & B I O S T U D Y CHAPTER 16

In addition, average bioequivalence PRESCRIBABILITY.

ignores the subject-by-formulation (s-b- Refers to the clinical setting where a
f) interaction, that is, the variation that practitioner prescribes a drug product
may be present among individuals in to a patient for the first time. In this
average test and reference difference. setting, the prescriber relies on an
understanding that the average
In contrast, population and individual performance of the drug product has
bioequivalence approaches include
been well characterised and relates in
comparisons of both averages and
some definable way to the clinical trial
variances of the study metric.
material on which safety and efficacy
Draft Guidance for Industry (Oct 1997) is based on
work performed by the Individual Bioequivalence Working data were originally generated.
Group operating under the Biopharmaceutics Co-ordinating
Committee in CDER; scientific studies performed under FDA USES: - For line extensions to an approved
contract; recommendations from the Generic Drugs Advisory NDA (e.g., for changes from immediate release
Committee and the Advisory Committee for Pharmaceutical to controlled release, additional strengths, or
Science, and numerous scientific publications and
presentations. new dosage regimens) the population
bioequivalence approach should be used.
POPULATION BIOEQUIVALENCE
SWITCHABILITY
The population bioequivalence Refers to the setting where a
approach assesses the total variability practitioner transfers a patient from one
of the metric (AUC etc.) in the population. drug product to another. This setting
INDIVIDUAL BIOEQUIVALENCE arises with generic substitution, as well
The individual bioequivalence approach as with certain post-approval changes
additionally assesses the within-subject by an innovator or generic firm in the
variability as well as the subject-by- formulation and/or manufacturing of a
formulation interaction. drug product. Under these
The population and individual circumstances, the prescriber and
bioequivalence approaches reflect patient require assurance that the
differences in the objectives of newly administered drug product will
bioequivalence testing at various yield comparable safety and efficacy to
stages of drug development. These that of the previously administered
differences are embodied in the product for which it is being substituted.
concepts of 'prescribability' and Note: In certain specific situations for a line
'switchability'. extension (e.g., where a strength twice that of a
currently available strength is under
Population BE Individual BE investigation and the primary question is one of
switchability, i.e., what happens when a patient
For NDA pre-approval For POST-approval switches from two units (2x200mg) of the
major changes Brand currently available strength to one unit
and Generic (1x400mg) of the new strength), the individual
For Brand Products For Pre-approval of bioequivalence approach may be more
Generic and RLD appropriate.
2-period biostudy Replicated biostudy
designs required i.e. designs required i.e. WHICH APPROACH TO USE
TR / RT RTTR / TRRT
Biostudy Cost Factor Biostudy Cost Factor
Whether the population or individual
=1 = 2 - ~2.5 (more bioequivalence approach should be
costly) used to assess in-vivo bioequivalence
Assumes variability of Does not assume depends on whether the bioequivalence
Test & Reference drug variability of Test & testing is being conducted prior or
is the same Ref. drug is the same
subsequent to approval of an
Penalises better Rewards manufacturer
generic products of a better generic innovator drug product.
(less variable) product

Handbook of Pharmaceutical Sect: 16.

16 7 Generic Development
 TABLETS ORAL DISSOLUTION & B I O S T U D Y CHAPTER 16

The guidance recommends that the Switchability. Means that a patient

population bioequivalence approach be can swop from one brand to another
used by NDA sponsors who wish to without any significant or noticeable
assess bioequivalence during the changes between the drug brands.
investigation phase of drug Normally a patient will switch from a
development. more expensive brand to a cheaper
generic product.
NDAs
For example, use of the population The concept of Switchability is based
bioequivalence approach may be on the theory that the absorption of one
appropriate in the context of an NDA to brand may be different than another
assess bioequivalence between a 'to- brand, in some patients, even though
be-marketed' and 'clinical trial drug' the products are bioequivalent using
product when significant changes have the current average bioequivalent
been made prior to approval in the methods, by which all generics to date
formulation and / or manufacturing of have been evaluated.
the clinical trial product. Switchability is based on the concept
GENERIC & RLD that subject-by-formulation interactions
appear to exist in some replicate design
The guidance recommends that the
studies. The subject-by-formulation (s-
individual bioequivalence approach be
b-f) interactions theoretically assesses
used by sponsors of ANDAs and
the differences between the responses
AADAs to assess bioequivalence
due to the test and reference drug
between the generic and reference
formulations. However, in actual fact,
listed drug. The draft guidance also
this is not strictly true, as the subject-
recommends that the individual
by-formulation interactions measures a
bioequivalence approach be used by all
'bundle of responses' namely the
sponsors of NDAs, ANDAs, and AADAs
similarity (or no similarity) of the
who, during the post-approval period, pharmacokinetic (Pk) responses
wish to reassess in vivo bioequivalence (including dissolution and absorption)
when a change of sufficient magnitude observed in the test subjects when they
occurs in the formulation and/or are switched from one product to
manufacturing of the drug product. another, irrespective of whether or not
there are any formulation differences. It
Switchability is quite incorrect to assume that serum
No Subject by Subject by concentration or the response of a
Formulation Formulation branded product (or elected RLD) will
interaction interaction necessary be the same, in the same
(lines almost //) patient set, on different occasions.
1.25
Since s-b-f interactions are a function
of the summed PK responses, then
Ln AUC day-to-day variability in subjects may in
fact be a part or a sub-set of the s-b-f
term. Additionally intra-batch RSD
Test Ref.` Test Ref.
dissolution value variations may play a
Average and Average but part of this sub-set term. Currently the
individual no individual significance of the sub-set parts of the
Bioequivalence Bioequivalence s-b-f interaction term is not at all clear
or well understood due to limited data.

Handbook of Pharmaceutical Sect: 16.

16 8 Generic Development
 TABLETS ORAL DISSOLUTION & B I O S T U D Y CHAPTER 16

Same & Different Batches Prescribability Switchability.

S-b-f should measure inter-formulation New patients are Patient is already
prescribed the drug taking the drug
(TR) differences, i.e. differences product for the very product and there is a
between the Test and Reference and first time (usually the substitution of one
not same formulation differences (TT or innovator's product as formula with another,
RR). Same formulation differences may no generics are due to generic product
occur between the test-and-test (TT) or currently available) availability.
reference-and-reference (RR) due to
The existence of subject-by-formulation interactions
standard batch-to-batch differences in are currently based on relatively few data sets (21) /
the manufactured batch lots and/or study observations (9). The detection of subject-by-
significantly different RSD values formulation interactions in some replicate design
studies submitted to the FDA is, in part, justification
apparent in the TT or RR dissolution in support of the theory. Further more the scientific
profiles. validity or need of IBE studies based on appropriate
scientific rationale have not been clearly established
On balance, a drug must show that, on in the light of two or more available RLDs in the
the average, the product performs Orange Guide and / or the period-to-period inter-
batch (i.e. batch-to-batch) variation of two or more
appropriately, but not identically, in Reference Listed Drugs or innovator drug lots.
the same subjects, on different days. Convincing statistical evidence needs to be
No individual dosage form accumulated on the significance and possible
clinical impact of s-b-f variations.
(tablet/capsule) is identical to another
whether its source is from an intra Comparative Dissolution
(same) or inter batch lot. (different lot).
Equally, the same patient set, has non-
Profiles - Laboratory Work:
identical responses on different days. Evaluate the RLD's inter-batch
The switchability between different comparative dissolution profile (CDP)
batch lots of the same drug product differences using up to 3 or 4 differently
may well be impacted under these dated RLD batch lots with a 6-12
conditions and thus would need to be months spread.
evaluated and clarified in certain active Stressed Profiles:
substances. Comparative Dissolution Profiles (CDP)
using 3 to 4 different dated Reference
What is the evidence that s-b- Listed Drug batch lots placed on
f interaction exist? accelerated stability at 40° C / 75% RH
for 3 - 6 months. (Evaluate Assay and
Published data demonstrates that Impurity profiles). It is significant to
brand products fail to respond, on
evaluate the variability in the RLD
different days, in an identical manner to
product under normal and, after
the same batch lot. Repeated studies of
stressed conditions. Purchasing the
Nifedipine SR, Isoptin SR, Oxfloxacin,
RLD at various manufacturing dates
Propafenone and others in normal
(different lot numbers manufactured at
volunteer subjects, reveal a high level
different periods) allows for the
of day-to-day variability of serum
product's process and formulation
concentration within individuals
variability to be determined. Successful
receiving, the same dose, of the same
bioequivalence studies depend greatly
brand, under strictly controlled
on the scope and detail of this RLD
conditions.
data. (Multiple lots at different manufacturing
date, normal, and aged studies). Intra-batch
Thus subject-by-same formulation (s-b- and inter-batch variability of the RLD should be
fs) or alternatively day-to-day subject evaluated with care with appropriate validation
variability exists in controlled studies. of the dissolution method.

Handbook of Pharmaceutical Sect: 16.

16 9 Generic Development
 TABLETS ORAL DISSOLUTION & B I O S T U D Y CHAPTER 16

Bioavailability Bioequivalence
COMPARATIVE DISSOLUTION PROFILE FOR DRUG PRODUCT
LOTS USED IN BIOEQUIVALENCE STUDIES:
[Generic Name] Tablets USP [000.0] mg. Lot No:1234
12 TABLETS

Real Time Study

3 months Stability at 28° C / 60% RH
Figure No. 1. Comparative Dissolution Profile

Generic Tablets vs RLD 00mg

120

100

80

60 P-01234
RLD AA0000
% DISSOLVED 40

20

10 20 30 40 50

TIME (minutes)

DISSOLUTION CONDITIONS (CR Tablets):

Volume: 000 mL
Media: 0.0 N [Media Type / Buffer]
Surfactant (if necessary) [0.0%] [Surface Active Agent] Use for Low
pH of Media1, 2, 3 [0.0] pH1 [0.0] / pH2 / [0.0] pH3 Solubility
Drugs
Apparatus: 1 USP (basket) / (Paddle),
Speed: 000 rpm (calibrated)
Intermediate sampling point [0.0], [0.0], [0.0], [0.0] [0.0]
Intermediate assay values [0.0], [0.0], [0.0], [0.0] [0.0]
Tolerance: NLT 00% (Q) in 00 Minutes
Intermediate
Specifications Final Tolerance
Specification

Handbook of Pharmaceutical Sect: 16.

16 10 Generic Development
 TABLETS ORAL DISSOLUTION & B I O S T U D Y CHAPTER 16

Bioavailability / Bioequivalence
COMPARATIVE DISSOLUTION PROFILE FOR DRUG PRODUCT
LOTS USED IN BIOEQUIVALENCE STUDIES:
12 Tablets per test on multiple RLD batch lots under normal and stressed conditions

Stress Study
3 months Stability at 40° C / 75% RH
Figure No. 2. Comparative Dissolution Profile

Generic Tablets vs RLD 00mg - Stressed

120

100

80
P-01234
60 RLD-AA000
% DISSOLVED
40
Time Scale changes
20 for different active
ingredients i.e.
0 generally from
10 20 30 40 50 60 30 - 60 minutes

TIME (minutes)

CERTIFICATES OF ANALYSIS REPRESENTING THE DRUG PRODUCTS USED IN

BIOEQUIVALENCY STUDY

♦ [Generic name] Tablets [USP] [000.0] mg. Lot: 1234 CoA No:
0000
♦ [RLD] Tablets [USP] [000.0] mg. Lot: AA000 CoA No: 0000

The analytical results of the Certificates of Analysis for [Generic Company Name Inc. / Ltd.] and
[RLD Company Name Inc. / Ltd.] Drug Product lots were tested the Analytical Research Laboratories
of [Generic Company Name Inc. / Ltd. & Address].

Handbook of Pharmaceutical Sect: 16.

16 11 Generic Development
 TABLETS ORAL DISSOLUTION & B I O S T U D Y CHAPTER 16

OVERVIEW OF TEST DESIGNS

Invivo Bioequivalence Studies
Types of Studies for Immediate and Modified Release

TEST DRUG & REFERENCE DRUG

MODIFIED RELEASE

IMMEDIATE RELEASE EXTENDED RELEASE DELAYED RELEASE

(Controlled Release) (Enteric Coated Forms)

Single Dose Study (fasting) Single Dose Study (fasting)

or special conditions Single Dose Study (food) Single Dose Study (fasting)
Single Dose Study (food) Multiple Dose Study (fasting) Single Dose Study (food)

DESIGN OF STUDY
CROSS OVER [Most Drugs]
PARALLEL [Long ½ life Drugs]

Single Dose Single Dose Multiple Dose

FASTING FED FASTING
AUC 0-LQC (PE) AUC 0-Tau (CI)
AUC 0-LQC (CI)
AUC 0-INF (PE) Cmax ss (CI)
AUC 0-INF (CI)
Cmax (PE) Cmin ss
Cmax
Tmax Cave ss
Tmax
KEL Tmax
KEL
T½
T½ % SWING
% Fluctuation

LQC : Lowest Quantifiable Concentration

CI : 90% Confidence Interval (80 - 125%)
PE : Point Estimate (± 20%)

Handbook of Pharmaceutical Sect: 16.

16 12 Generic Development
 TABLETS ORAL DISSOLUTION & B I O S T U D Y CHAPTER 16

EVALUATING TEST DATA

Statistical Bioequivalence
90% Confidence Interval

Logarithm transformed Data

Biostudy
results in
these ranges
favor
IBE data

BOTH
BIOSTUDIES
0.80 1.0 1.25 PASS IBE
but
TEST / REFERENCE RATIO FAIL ABE

Bioequivalence Failure

Bioequivalence Pass

ANALYSIS OF VARIANCE STATISTICAL

Subject : Sequence : Period :Treatment BIOEQUIVALENCE CRITERIA
Test & Reference Means Differences Two One-sided Tests Procedure (α=0.05)
Intra-subject Variability 90% Confidence Interval (80-125%)

With acknowledgments:
Fast marketing Authorization for Generics London Kensington Posthouse Conference December 3&4th 1997;
Understanding Bioequivalence and Therapeutic Equivalence Conference June 25/26 1998 Rockville MD USA.
Professor Laszlo Endrinyi - University of Toronto; Walter W Hauck PhD., Thomas Jefferson University. Andrew
Grieve-Biometrics Department Pfizer Central Research; Anderson and Hauck J. Pharmacokin. & Biopharm.
1990. Shein-Chung Chow & Jen-Pei Liu (1992) Design and Analysis of Bioavailability and Bioequivalent
Studies, Marcel Dekker; Drug Information Journal 03, July-Sept 1995, Dedicated to Bioavailability and
Bioequivalence.

Handbook of Pharmaceutical Sect: 16.

16 13 Generic Development
 TABLETS ORAL DISSOLUTION & B I O S T U D Y CHAPTER 16

EXPLAINING 'THE EQUATION'

THE IBE EQUATION
PROPOSED METRICS FOR INDIVIDUAL BIOEQUIVALENCE

Individual bioequivalence's (IBE) basic tenet assumes that the currently employed
methods and criteria for the assessment of bioequivalence are inadequate to
provide assurance that the brand product can be switched to a generic product and
vice versa - however…
…the demands for an equivalent of the generic should not exceed those required to
show equivalence of the brand itself. New requirements should be based on a
demonstrated need for change or a bona fide risk and not on conjecture or
theoretical supposition.
Switchability Term DIFFERENCE
DIFFERENCE OF VARIANCES
OF MEANS

Subject by
formulation
interaction
(s-b-f)

µT - µR)2 +
(µ σD2 + σ2WT _ σ2WR) ≤ θP
(σ
σ2W0
POSITIVE ASPECTS REGULATORY
Addresses switchability CONSTANT SCALED CRITERIA
but at a study cost of (UN-SCALED) Ln 1.25
more than double
average bioequivalence
POSITIVE ASPECTS
Does not assume that the
variability of the Test and MAY BE SCALED
Reference formulations are the FOR HVDS
same - therefore rewards a better
manufactured product σ2WR

Disadvantages of the proposed approach

• How often is switchability a problem (σD2) - relatively little evidence due to relatively few replicate
studies - a possible case of "if it ain't broke don't fix it."
• Switchability will be assessed in a very small group of healthy subjects and may not reflect the
extent of the problem in various groups of patients.
• Scaling with a variance term (σWR2) may differ from one study to the next - aggregate/scaled
criterion means that the differences in means and a significant subject by formulation interaction
could be off-set by differences in the variability of the test and reference formulations - "what you
lose on the swings you could gain on the roundabouts" - or vice versa.

Handbook of Pharmaceutical Sect: 16.

16 14 Generic Development
 TABLETS ORAL DISSOLUTION & B I O S T U D Y CHAPTER 16

EXPLAINING THE EQUATION

THE BIG IBE PICTURE
FDAs PROPOSED METRIC FOR INDIVIDUAL BIOEQUIVALENCE

Individual bioequivalence (IBE) basic tenet assumes that if one were to ask a man
or woman in the street what they believe is meant by approval of a generic drug as
equivalent to a name-brand product…
… the answer will come back something like this, " it doesn't really matter which
product I take"
Switchability Term WITHIN SUBJECT
DIFFERENCE (Not always significant) VARIANCES
OF MEANS
(AUC; Tmax)
Subject by
formulation
interaction
(s-b-f)

µT - µR)2 +
(µ σD2 + σ2WT _ σ2WR) ≤ θP
(σ
σ2WR
REGULATORY
NEGATIVE ASPECTS
CRITERIA SET
Switchability (s-b-f SCALED
variation) not significant Ln 1.25
Highly Variable Drugs
in many studies with
healthy subjects
NEGATIVE ASPECTS Scaling helps highly
More variability of σ2WR will variable drugs (HVD) to
make it easier to pass pass the individual
bioequivalence criteria

Summary of proposed approach

• Difference in variability between test and reference formulation have a major impact (+ or -) on the
results for individual bioequivalence (µT - µT)2
• SIGNIFICANT DIFFERENCES in means may be off-set in differences in variability between test
and reference formulations (>30%)
• These SIGNIFICANT DIFFERENCES could lead to different conclusions for average versus
individual bioequivalence, thus - "what you lose on the swings you could gain on the roundabouts"
- could have positive and negative implications.
• When the switchability and variance terms are very small, the IBE equation reverts to the ABE
formula. Biostudy expenditure estimated to cost twice as much to establish the significance and
impact of these two terms.

Handbook of Pharmaceutical Sect: 16.

16 15 Generic Development
 TABLETS ORAL DISSOLUTION & B I O S T U D Y CHAPTER 16

COMPARING ABE AND IBE

COMPARING THE DATA
'WHAT YOU LOOSE ON THE SWINGS YOU GAIN ON THE ROUNDABOUTS'
Three examples below of full size studies performed1 comparing results for individual and average
bioequivalence in order to assess the importance of the different terms in the aggregate measure of
individual equivalence on replicated designs. S-b-f interaction were not significant but differences in
variability (+ &-) between test and reference formulations have a major impact on the results for IBE.
Significant differences in means may be off-set by differences in variability between drug
formulations.
STUDY 1 µT µR σD σWT σWR
33 healthy male subjects AUC 1.23 0.93 0.067 0.37 0.40
Replicated study - randomized crossover Cmax 1.13 0.88 0.073 0.41 0.44
Two sequences; 4 Periods (RTTR ; TRRT) µT / µR σWT /σWR
Single oral dose AUC 1.33 0.93
Two week wash out between periods Cmax 1.30 0.93
16 blood samples taken after each dose A B E. I B E.
LC/MS validated Assay 90% CI P / F 95% UL P / F
FDA Proposed Data Analysis AUC 1.21-1.47 Fail 1.20 Pass
Standard PK analysis (non-compartmental) Cmax 1.15-1.46 Fail 1.14 Pass
STUDY 2 µT µR σD σWT σWR
32 healthy male subjects AUC 1673 1628 0.031 0.20 0.19
Replicated study - randomized crossover Cmax 219 221 0.099 0.46 0.30
Two sequences; 4 Periods (RTTR ; TRRT) µT / µR σWT /σWR
Single oral dose AUC 1.03 1.05
Two week wash out between periods Cmax 0.99 1.53
15 blood samples taken after each dose A B E. I B E.
HPLC/Fluorescence validated Assay 90% CI P / F 95% UL P / F
FDA Proposed Data Analysis AUC 0.98-1.08 Pass 1.05 Pass
Standard PK analysis (non-compartmental) Cmax 0.88-1.11 Pass 2.90 Fail
STUDY 3 µT µR σD σWT σWR
40 healthy female subjects AUC 550 468 0.021 0.25 0.30
Replicated study - randomized crossover Cmax 67.2 53.1 0.02 0.27 0.37
Two sequences; 4 Periods (RTTR ; TRRT) µT / µR σWT /σWR
Single oral dose AUC 1.18 0.83
Two week wash out between periods Cmax 1.26 0.73
15 blood samples taken after each dose A B E. I B E.
GC/NPD validated Assay 90% CI P / F 95% UL P / F
FDA Proposed Data Analysis AUC 1.10-1.26 Fail 0.85 Pass
Standard PK analysis (non-compartmental) Cmax 1.16-1.37 Fail 0.70 Pass
Data Analysis:- Log transformed AUC and Cmax
Average bioequivalence limit: 0.8-1.25 Individual bioequivalence: [Ln(1.25)/0.2]2 = 1.24
SAS PROC GLM, 90%CI using s-b-f as error SAS PROC MIXED
Form,Period, Sequence, Period*sequence (form)
1
With acknowledgments Phoenix International CSH var-cov matrix for random effects
Fast marketing Authorization for Generics REM estimates; CI: 2000 Bootstrap samples.
London Conference December 1997;
Understanding Bioequivalence and Therapeutic Equivalence Conference June 25/26 1998 Rockville MD USA.. Draft Guidance to
Industry Invivo Bioequivalence studies based on Population & Individual Bioequivalent Approaches FDA CDER BP X Oct 1997.

Handbook of Pharmaceutical Sect: 16.

16 16 Generic Development
 TABLETS ORAL DISSOLUTION & B I O S T U D Y CHAPTER 16

OUTLINE IN VIVO BIOSTUDY for should be able to capture the Cmax and Tmax
during the absorption period. Sampling
AVERAGE BIOEQUIVALENCE should be carried out for at least three
FASTED STUDY - OVERALL PICTURE
terminal elimination half-lives for both parent
The Purpose of this general model outline of drug and active metabolite(s). Whole blood,
an in vivo bioequivalence study is intended plasma or serum, whichever is appropriate
as a BASIC guide. for the analytes, should be harvested
The design of the actual study may vary promptly and samples should be frozen at -
depending on the drug and dosage form. 20oC or -70oC to maintain sample stability.
Objective - To compare the rate and extent
of absorption of the Test Drug Product for Analytical Method - The assay
which bioequivalence is sought to the methodology selected should ensure
Reference Listed Drug (RLD). specificity, accuracy, interday and intraday
Design - The study design should be a precision, linearity of standard curves, and
single dose, two-treatment, two-period adequate sensitivity, recovery, and stability
crossover with adequate washout period of the samples under the storage and
between the two phases of the study. Equal handling conditions associated with the
numbers of subjects should be randomly analytical method.
assigned to each of the two dosing Pharmacokinetic Analysis - From the
sequences. plasma drug concentration-time data, AUC0-t,
Selection of Subjects: - The number of AUC0-inf, Cmax, Tmax, Kel and t1/2 should be
subjects enrolled in the bioequivalence study estimated.
should be determined statistically to account
for the intra-subject variability and to meet Statistical Analysis - Analysis of variance
the current bioequivalence interval. appropriate for a crossover design on the
pharmacokinetic parameters using the
Procedure: - Each subject should receive general linear models procedures of SAS or
the following two treatments: an equivalent program should be performed,
Treatment 1: Generic Product or Test Drug. with examination of period, sequence and
Treatment 2: Reference Listed Drug (RLD). treatment effects. The 90% confidence
Following an overnight fast of at least 10 intervals for the estimates of the difference
hours, subjects should receive either between the test and reference least
Treatments 1 or 2 above with 240 mL water. squares means for the pharmacokinetic
Food should not be allowed until 4 hours parameters (AUC0-t, AUC0-inf, Cmax) should
after dosing. Water may be allowed after be calculated, using the two one-sided t-test
the first hour. Subjects should be served procedure.
standardized meals beginning at 4 hours
during the study.
REFERENCES
Restrictions - Prior to and during each study 1. Code of Federal Regulations 210.3(b)(2) and (10), 310.3(b)
phase, water may be allowed ad libitum and (g), and 320.1(a) and (e).
except for 1 hour before and after drug 2. Federal Register. Vol. 59, No. 183, September 22, 1994, pp
48754-59.
administration. The subject should be 3. “Guideline for Industry: Stability Testing of New Drug
served standardized meals and beverages at Substances and Products,” U.S. Department of Health and
specified times. No alcohol or xanthine- or Human Services, FDA, September 1994.
caffeine-containing foods and beverages 4. Guideline for Submitting Documentation for the Manufacture
and Controls for Drug Products,” U.S. Depart-ment of Health and
should be consumed for 48 hours prior to Human Services, FDA, February 1987.
each study period and until after the last 5. Policy and Procedure Guide #22-90: “Interim Policy on
blood sample is collected. Exceptions to the Batch-Size and Production Condition
Requirements for Non-Antibiotic, Solid, Oral-Dosage Form Drug
Blood Sampling: - Blood samples should be Products Supporting Proposed ANDA’s”, U.S. Department of
Health and Human Services, Center for Drug Evaluation and
collected in sufficient volume for analysis of Research, Office of Generic Drugs, September 13, 1990.
parent drug and active metabolite(s), if any.
The sampling times should be such that it

Handbook of Pharmaceutical Sect: 16.

16 17 Generic Development
 TABLETS ORAL DISSOLUTION & B I O S T U D Y CHAPTER 16

Generic Drug Dissolution

and
Reference Listed Drug

D issolution is a key requirement

during drug development, batch-
to-batch quality control, product
[1]. The type of dissolution studies
considered necessary to fully the RLD
that has been selected (Ref. evaluate
registration and evaluating the
your formulated drug against Graph 1
comparative dissolution profile
& Graph 2, page 215/216) demonstrate
information required for IVIV
Real time and accelerated stability
Correlations and the Bioequivalence
study profiles.
section (VI) of the ANDA submission.
[2] Whether it is possible to establish
Evaluating whether your firms generic
an IVIVC in-vitro, in-vivo correlation
drug will pass the Biostudy first time is (see flowchart below) between your
a key requirement. The primary goal is drug and the intended bioequivalence
to ensure that the generic drug is study necessary for filing with the FDA.
similar to the reference drug.
Knowing the reference drugs overall ♦ Validated Dissolution Method
dissolution profile and ageing Assay Methods:
parameters are critical input data A fully validated Dissolution assay
requirements. method is essential to obtain
meaningful results from a comparative
This section combines the recent
dissolution profile (CDP) between the
developments in dissolution Testing Generic and RLD.
and data correlation of SUPAC, IVIVC
Prudent development laboratories will
and BCS to produce a working model
evaluate several CDPs using multi-
on accessing similarity between your
point and media profiles with multiple
drug and the reference listed drug
(3) batches, hopefully with different
(RLD)
manufacturing dates and thus
Five essential steps your development
assessing miscellaneous product ages.
unit can do to achieve this goal?
Validated dissolution method
♦ Drug Classification requirements are highlighted in table 2.
Classify the drug product according to
♦ Multipoint Dissolution Profiles
its solubility and permeability.
Distinguish narrow (25 drugs) and non- A least three different batch lots of the
narrow therapeutic range drugs as RLD using a multipoint dissolution
well. This classification will furnish two profiles should be performed. (See
useful aspects; References Attached).

Handbook of Pharmaceutical Sect: 16.

16 18 Generic Development
 TABLETS ORAL DISSOLUTION & B I O S T U D Y CHAPTER 16

Where possible age or stress one of Reference Listed Drug batch Lots
the RLD lots and evaluate with and placed on accelerated stability at 40° C
without a surfactant. / 75% RH for 3 - 6 months. (Evaluate
Assay and Impurity profiles).
Evaluate profiles at low and high rpm
rotational speeds. The higher cost of a
It is significant to evaluate the
full comparative dissolution program variability in the RLD product under
may well be the difference between a normal and, after stressed conditions
'biostudy' pass or failure. as well as at different RLD
manufacturing dates (where the RLD is
Dissolution Profile 'Similarity Test'
purchased with different Lot Numbers
calculate the unbiased 'Similarity
i.e. made at different times).
Factor' for each CDP. The result ƒ² Success of a costly Bioequivalence
should be between 50 to 100 to study may hinge or depend on the
demonstrate 'similarity' between the detail of the RLD's data (i.e. Multiple
two formulations. Where similarity is lots at different manufacturing date,
obtained cross check values using normal, and aged studies).
alternative functions (e,g Chow, Intra-batch and inter-batch variability of
ANCOVA etc.) the RLD should be evaluated with care.
♦ Bioequivalence Study - Pilot
In the case of high cost biostudies a
pilot study may give meaningful results
DISSOLUTION STUDIES
What is Important?
and enable necessary formula or
process adjustments in intricate drug
comparisons. Should the pilot study fail Fully Functioning Equipment
Routine Calibration & Performance Verification.
or 'just' fail' - it is important to note the No minor mechanical damage or misalignments.
full participant study would have failed
and at a significantly higher cost. In
'just fail' situations, reformulate drug Fully Validated
product and in parallel improve the Dissolution Assay Procedures available
before Formula & Process Optimization,
discrimination power of the dissolution PQ, and Pivotal Lots.
testing procedure.
♦ Bioequivalence Study - Full Discriminating Test Procedures
Agitation, pH, Surfactant, Media, Deaeration
Your R&D unit should be ready to
perform a full-scale biostudy supported
with adequate CDP data and statistical Operator Excellence & Training
assessments to pass the pending Routine Standard Operating
biostudy against the Reference Drug. Procedures

LABORATORY WORK: DISSOLUTION TESTING

Overview of Lab. Work Done is used in development for:-
Evaluate Comparative Dissolution Ø Evaluating the RLD ×
Profiles (CDP) using 3 to 4 different Ø Formula Optimization ×
Ø Process Qualification ×
dated RLD batch Lots obtained at 3 to Ø Comparative Dissolution Profiles ×
6 month intervals apart from the time of Ø FP Quality Control ×
manufacture Ø Evaluating IVIVC ×
Ø Bioequivalency ×
Stressed Profiles: Ø Food-Effect Studies ×
Comparative Dissolution Profiles Ø Obtaining Bio Waivers ×
Ø SUPAC TESTING ×
(CDP) using 3 to 4 different dated

Handbook of Pharmaceutical Sect: 16.

16 19 Generic Development
 TABLETS ORAL DISSOLUTION & B I O S T U D Y CHAPTER 16

Formula Development. Modified Release Tablets.

The USP has introduced three levels
The dissolution test should be used as of correlation. Level A - Multipoint in-
early as possible to aid formulation, the
vitro dissolution curve and
choice of excipients and process
corresponding in-vivo input curve
development parameters. The value of
(produced by deconvolution of the
different media, varying pH levels and
plasma level data) is the most useful
test conditions in the dissolution test
absorption profile to use. Level B and
will be determined by its preference to
C have less value.
discriminate between the test and
characteristics of the reference
For delayed or extended release
formula. tablets and capsules it is possible to
establish a USP Level A correlation.
Table 2: Dissolution Validation
Comparative
Validation Aspect Dissolution Profiles
Accuracy / Recovery: Recovery
drug should not be affected by the
of
are as good as the
presence of a placebo. De-aerated media
should always be used.
Dissolution method
Linearity: Detection method should be Where a point-to-point correlation is
linear over the concentration range (10- achieved then the in-vitro correlation of
110% of the label amount). the dosage form can serve as a
surrogate for its in-vivo performance.
Filter Bias: Recovery of drug should not
be affected by on-line filters, manual filters Definitions 3:
or the automated tubing. Solubility - calculated on the minimum
concentration of the drug (mg/mL) with reference to
Specificity: Detection method must be the largest dosage strength determined in
free from excipient interference physiological pH ranges at 370 C. - i.e. [1mg/mL] of
a 400 mg tab ≡ 400 mL Dose Solubility volume.
Sampling: Recovery should be assessed Drug Solubility Reference:-
to ensure that the drug does not adsorb High - Dose solubility volume = > 250 mL
onto the tubing and that the dissolution Low - Dose solubility volume = ≤ 250 mL
profiles obtained by automatic and manual
sampling are similar and contain no bias Permeability - is the effective human
due to the automation. jejunum wall permeability of a drug (Pe' cm per
second) and includes intestinal membrane
Ruggedness: The degree of resistance to mass transport.
reproducibility of the dissolution test High - Absorption greater than 90 %.
results obtained by analysis of the same
References:
sample under a variety of normal test 1. 'Validation of Compendial Methods' USP 23
conditions, i.e. different days, analysts, Section<1225> pp. 1982-1984
apparatus, laboratories. Ruggedness is an 2. International Conference on Harmonisation "Guideline
on Validation of Analytical Procedures: Definitions and
official USP requirement. Changes are Terminology (Federal Register March 1, 1995)
external to the written method. 3. Scale-up and Post Approval Changes Guidance for
Immediate Release Products (SUPAC-IR) US D.O.H and
Note: Human Services FDA Rockville Maryland USA 1996
Robustness is defined by the USP and 4. Biopharmaceutical Drug Classification and International
Drug Regulation - Seminar and Open Forum 14, May
ICH but not officially required and is 1996 Geneva Switzerland
defined as a measure of the dissolution 5.AAPS/CRS/FDA Workshop on Scientific Foundation
method's capability to remain unaffected and Application for the Biopharmaceutical Classification
System and IVIVC April 1997 Arlington Virginia USA
by small but deliberate variations in 6.G. L. Amidon et. al A Theoretical Basis for a
method parameters. Changes are internal Biopharmaceutical Drug Classification A correlation of In-
to the written method. vitro Drug Product Dissolution and In-Vivo bioavailability"
Pharm Res. 12 413-420 (1995).

Handbook of Pharmaceutical Sect: 16.

16 20 Generic Development
 TABLETS ORAL DISSOLUTION & B I O S T U D Y CHAPTER 16

USING A TYPICAL IVIV MODEL

Development Formula Development Formula
(dissolution dependent) (dissolution independent)

prepare
SLOW
MEDIUM
FAST profiles Optimum Formula

Fine tune 12 point comparative dissolution

FORMULA profile (USP Apparatus I or II)
discrimination
via different
dissolution Pilot study An pilot
media and (Formula Development) 1-3 subject
settings. (1-3-6 subjects) mini-study
may reduce
development
time
(Level C guide)
Adjust pilot formula
Release controlling excipients
Deconvolution calculations
If necessary
alter dissolution
Adjust formula or media, pH
process 12 point comparative dissolution rpm speed
parameters to profile (USP Apparatus I or II) paddle or
mimic reference [ADJUSTED FORMULA] basket for a
drug 1:1
dissolution values correlation

Full IVIVC study

(Final Formula)
(6 or more subjects)
Deconvolution calculations
(Wagner-Nelson)

CHECK FINAL FORMULA Level

Comparative Dissolution Profile A?
(make minor formula or process
adjustments to reference drug)

TO COMPARATIVE BIOEQUIVALENT STUDY

Handbook of Pharmaceutical Sect: 16.

16 21 Generic Development
 TABLETS ORAL DISSOLUTION & B I O S T U D Y CHAPTER 16

CHOOSING & USING

THE LEVELS
LEVEL A - ['Concentration Profile']

A MULTI point-to A mathematical model that predicts the Normally a linear

-point evaluation relationship between invitro and invivo curves. relationship is
between an invitro The dissolution profile and the plasma drug developed. Scaling
dissolution profile concentration profile evaluated mathematically factors
and an invivo permissible
dissolution profile The most useful and
informative level

LEVEL B - ['Time Profile'] Uses

Statistical
moment
NOT a point- A mathematical model that predicts relationships analysis.
to-point between invitro and invivo time courses. CANNOT
correlation Compares the mean invitro dissolution time and discriminate
mean invitro dissolution time (or rate constant) between
different invivo
The least useful curves with the
informative level same mean
residence time

LEVEL C - ['Single Point']

DOES not show
A SINGLE point- the shape of the
to point evaluation Establishes a single point relationship between a single plasma
between an invitro dissolution parameter (say a 4 hr assay ) and a single concentration
dissolution value invivo parameter (i.e. AUC , or Tmax, or Cmax) time curve
and an invivo (CRITICAL!)
dissolution value The most useful
SINGLE point level
Use for pilot and development or
optimization formula/process studies

MULTIPLE LEVEL C - ['Some Points']

DOES not show
A One or Two the whole shape
point evaluation Establishes a partial relationship between dissolution of the plasma
between invitro parameter (2 & 4 hr assay ) and some invivo concentration
dissolution values parameters (AUC , Tmax , Cmax) time curve
and invivo (Try Level A)
dissolution values Useful to extend to a
Level A correlation

Handbook of Pharmaceutical Sect: 16.

16 22 Generic Development
 TABLETS ORAL DISSOLUTION & B I O S T U D Y CHAPTER 16

Dissolution Testing of IR
Solid Oral Dosage Forms
FDA's DISSOLUTION TESTING PROCEDURES
SOLID ORAL DOSAGE FORMS
I. INTRODUCTION II. BACKGROUND

T his chapter is based on the FDA

guidance for industry in the
development of immediate release (IR)
Drug absorption from a solid dosage
form after oral administration depends
on the release of the drug substance
dosage forms and is intended to from the drug product, the dissolution or
provide:- solubilization of the drug under
physiological conditions, and the
(1) general recommendations for
permeability across the gastrointestinal
dissolution testing
tract.
(2) approaches for setting dissolution Because of the critical nature of the first
specifications related to the bio- two of these steps, invitro dissolution
pharmaceutics characteristics of the may be relevant to the prediction of
drug substance invivo performance.
(3) statistical methods for comparing When 85% of
dissolution profiles.
Highly Soluble Drugs
(4) a process to help determine when
dissolution testing is sufficient to grant a
dissolve in 15 minutes
waiver for an in vivo bioequivalence in 0.1N HCl they are
study. equivalent to a solution
This document also provides
recommendations for dissolution tests Based on this general consideration,
to help ensure continuous drug product invitro dissolution tests for immediate
quality and performance after certain release solid oral dosage forms, such
post-approval manufacturing changes. as tablets and capsules, are used to:-
This guidance is intended to (1) assess the lot-to-lot quality of a drug
complement the SUPAC - IR guidance product
for industry: Immediate Release Solid
(2) guide development of new
Oral Dosage Forms: Scale-up and Post-
formulations
Approval Changes: Chemistry,
Manufacturing and Controls, In Vitro (3) ensure continuing product quality
Dissolution Testing, and In Vivo and performance after certain changes,
Bioequivalence Documentation, with such as changes in the formulation, the
specific reference to the generation of manufacturing process, the site of
dissolution profiles for comparative manufacture, and the scale-up of the
purposes. manufacturing process.

Handbook of Pharmaceutical Sect: 16.

16 23 Generic Development
 TABLETS ORAL DISSOLUTION & B I O S T U D Y CHAPTER 16

Current knowledge about the solubility, The Biopharmaceutics Classification

permeability, dissolution, and System (BCS) designed primary for IR
pharmacokinetics of a drug product drugs identifies possible invitro-invivo
should be considered in defining correlations between the drug
dissolution test specifications for the classification (Solubility / Permeability)
drug approval process. and dissolution parameters of the
This knowledge should also be used to Generic and Reference Drug.
ensure continued equivalence of the Where appropriate, invitro dissolution
product, as well as to ensure the tests involving single / multipoint
product's sameness under certain dissolution profiles in varying media
scale-up and post-approval changes. may be used to demonstrate similarity
Invitro dissolution data are generally between reference and generic product.
obtained from batches that have been The BCS applies primarily to immediate
used in pivotal, clinical and / or release drug preparations but impacts
bioavailability studies and other studies on HS / LP for CR preparations
conducted during product development. Case 1: High Solubility - High
Acceptable bioequivalence data and Permeability Drugs
comparable invitro dissolution and CMC Case 2: Low Solubility - High
data are required for approval of Permeability Drugs
abbreviated new drug applications Case 3: High Solubility - Low
(ANDAs) (21 CFR 314.94). Permeability Drugs
The invitro specifications for generic Case 4: Low Solubility - Low
products should be established based Permeability Drugs
on a dissolution profile. For new drug
applications, as well as generic drug
This classification can be used as a
applications, the dissolution basis for setting in vitro dissolution
specifications should be based on specifications and can also provide a
acceptable clinical, bioavailability, and / basis for predicting the likelihood of
or bioequivalence batches. achieving a successful in vivo-in vitro
correlation (IVIVC).
Once the specifications are established
in an NDA, the dissolution
Highly Soluble Drugs
specifications for batch-to-batch quality are defined as:-
assurance are published in the United Highest Strength dissolving
States Pharmacopoeia (USP) as in < 250 mL buffer
compendial standards, which become
the official specifications for all
The solubility of a drug is determined
subsequent IR products with the same by dissolving the highest unit dose of
actives. Generally these compendial the drug in 250 mL of buffer adjusted
dissolution standards are single-point between pH 1.0 and 8.0.
dissolution tests, not profiles. A drug substance is considered highly
soluble when the dose/solubility volume of
solution are ≤ 250 mL.
BIOPHARMACEUTICS High-permeability drugs are generally
CLASSIFICATION SYSTEM those with an extent of absorption that is
greater than 90% in the absence of
Based on drug solubility and documented instability in the
permeability, the Biopharmaceutics gastrointestinal tract or those whose
Classification System (BCS) is recom- permeability has been determined
mended in the literature (Amidon 1995) experimentally.

Handbook of Pharmaceutical Sect: 16.

16 24 Generic Development
 TABLETS ORAL DISSOLUTION & B I O S T U D Y CHAPTER 16

The BCS suggests that for high consistency and to signal potential
solubility, high permeability (case 1) problems with in vivo bioavailability. For
drugs and in some instances for high NDAs, the dissolution specifications
solubility, low permeability (case 3) should be based on acceptable clinical,
drugs, 85% dissolution in 0.1N HCl in pivotal bioavailability, and/or
15 minutes can ensure that the bioequivalence batches.
bioavailability of the drug is not limited For ANDAs/AADAs, the dissolution
by dissolution. In these cases, the rate specifications should be based on the
limiting step for drug absorption is performance of acceptable
gastric emptying. bioequivalence batches of the drug
The mean T50% gastric residence product.
(emptying) time is 15-20 minutes under The NDA dissolution specifications
fasting conditions. Based on this should be based on experience gained
information, a conservative conclusion during the drug development process
is that a drug product undergoing 85% and the in vitro performance of
dissolution in 15 minutes under mild appropriate test batches. In the case of
dissolution test conditions in 0.1N HCl a generic drug product, the dissolution
behaves like a solution and generally specifications are generally the same as
should not have any bioavailability the reference listed drug (RLD).
problems. The specifications are confirmed by
If the dissolution is slower than gastric testing the dissolution performance of
emptying, a dissolution profile with the generic drug product from an
multiple time points in multimedia is acceptable bioequivalence study.
recommended.
If the dissolution of the generic product
In the case of low solubility / high is substantially different compared to
permeability drugs (case 2), drug that of the reference listed drug and the
dissolution may be the rate limiting step in vivo data remain acceptable, a
for drug absorption and an IVIVC may different dissolution specification for the
be expected. generic product may be set.
A dissolution profile in multiple media is Once a dissolution specification is set,
recommended for drug products in this the drug product should comply with
category. In the case of high solubility / that specification throughout its shelf
low permeability drugs (case 3), life.
permeability is the rate controlling step
and a limited IVIVC may be possible,
The International Conference on
harmonization (ICH) Q1A guideline
depending on the relative rates of
(Stability Testing of New Drug
dissolution and intestinal transit.
Substances and Drug Products) has
Drugs in case 4 LS/LP (i.e., low recommended that for an NDA, three
solubility / low permeability drugs) batches (two pilot and one smaller
present significant problems for oral scale) be placed into stability testing.
drug delivery.
These batches also may be used to set
Ø SETTING DISSOLUTION dissolution specifications when a
suitable bioequivalence relationship
SPECIFICATIONS × exists between these batches and both
Invitro dissolution specifications are the pivotal clinical trial batch and the
established to ensure batch-to-batch drug product intended for the market.

Handbook of Pharmaceutical Sect: 16.

16 25 Generic Development
 TABLETS ORAL DISSOLUTION & B I O S T U D Y CHAPTER 16

Three key categories of dissolution test pharmaceutics and CMC review staff in
specifications for immediate release the Office of Pharmaceutical Science
drug products are the following. (OPS).
Ü SINGLE-POINT SPECIFICATIONS For NDAs, the specifications should be
As a routine quality control test. (For based on the dissolution characteristics
highly soluble and rapidly dissolving of batches used in pivotal clinical trials
drug products.) and/or in confirmatory bioavailability
studies.
Ü TWO-POINT SPECIFICATIONS If the formulation intended for marketing
1. For characterizing the quality of the
differs significantly from the drug
drug product.
product used in pivotal clinical trials,
2. As a routine quality control test for
dissolution and bioequivalence testing
certain types of drug products (e.g.,
between the two formulations are
slow dissolving or poorly water soluble
recommended.
drug product like carbamazepine).
Ü DISSOLUTION PROFILE COMPARISON Dissolution testing should be carried
1. For accepting product sameness out under mild test conditions, basket
under SUPAC-related changes. method at 50/100 rpm or paddle method
2. To waive bioequivalence at 50/75 rpm, at 15-minute intervals, to
requirements for lower strengths of a generate a dissolution profile. For
dosage form. rapidly dissolving products, generation
3. To support waivers for other of an adequate profile sampling at 5- or
bioequivalence requirements. 10-minute intervals may be necessary.
In the future, a two-time point approach For highly soluble and rapidly
may be useful, both to characterize a dissolving drug products (BCS classes
drug product and to serve as quality 1 and 3), a single-point dissolution
control specification. test specification of NLT 85% (Q=80%)
in 60 minutes or less is sufficient as a
Approaches for Setting routine quality control test for batch-to-
Dissolution Specifications for batch uniformity.
a New Chemical Entity For slowly dissolving or poorly water
Dissolution methodology and soluble drugs (BCS class 2), a two-
specifications developed by a sponsor point dissolution specification, one at
are presented in the bio-pharmaceutics 15 minutes to include a dissolution
section (21 CFR 320.24(b)(5)), and the range (a dissolution window) and the
chemistry, manufacturing, and controls other at a later point (30, 45, or 60
section (21 CFR 314.50(d)(1)(ii)(a)) of an minutes) to ensure 85% dissolution, is
NDA. recommended to characterize the
quality of the product.
The dissolution characteristics of the
drug product should be developed The product is expected to comply with
based on consideration of the pH dissolution specifications throughout its
solubility profile and pKa of the drug shelf life. If the dissolution
substance. characteristics of the drug product
change with time, whether or not the
The drug permeability or octanol / water specifications should be altered will
partition coefficient measurement may depend on demonstrating
be useful in selecting the dissolution bioequivalence of the changed product
methodology and specifications. The to the original biobatch or pivotal batch.
dissolution specifications are
established in consultation with bio-

Handbook of Pharmaceutical Sect: 16.

16 26 Generic Development
 TABLETS ORAL DISSOLUTION & B I O S T U D Y CHAPTER 16

To ensure continuous batch-to-batch [2] USP Drug Product Dissolution

equivalence of the product after scale- Test Not Available; Dissolution Test
up and post-approval changes in the for Reference Listed NDA Drug
marketplace, dissolution profiles should Product Publicly Available
remain comparable to those of the In this instance, a dissolution profile at
approved biobatch or pivotal clinical 15-minute intervals of test and
trial batch(es). reference products (12 units each)
using the method approved for the
Once the Bioequivalent
reference listed product is
batch is accepted recommended. The Division of
All future scale-up, validation Bioequivalence may also request
etc. batches must show submission of additional dissolution
testing data as a condition of approval,
similarity when scientifically justified.
Three Approaches for Setting [3] USP Drug Product Dissolution
Dissolution Specifications for Test Not Available; Dissolution Test
Generic Products for Reference Listed NDA Drug
Product Not Publicly Available
The approaches for setting dissolution
specifications for generic products fall
In this instance, comparative dissolution
into three categories, depending on testing using test and reference
whether an official compendial test for products under a variety of test
the drug product exists and on the conditions is recommended. The test
nature of the dissolution test employed conditions may include different
for the reference listed drug. dissolution media (pH 1 to 6.8), addition
of surfactant, and use of apparatus 1
All approved new drug products should and 2 with varying agitation. In all
meet current USP dissolution test cases, profiles should be generated as
requirements, if they exist. The three previously recommended. The
categories are: dissolution specifications are set based
[1]. USP Drug Product Dissolution on the available bioequivalence and
Test Available other data.
In this instance, the quality control SPECIAL CASES
dissolution test is the test described in 1. Two-Point Dissolution Test
the USP. The Division of For poorly water soluble drug products
Bioequivalence, Office of Generic (e.g., carbamazepine), dissolution
Drugs, also recommends taking a testing at more than one time point for
dissolution profile at 15-minute intervals routine quality control is recommended
or less using the USP method for test to ensure in vivo product performance.
and reference products (12 units each). Alternatively, a dissolution profile may
The Division of Bioequivalence may be used for purposes of quality control.
also recommend submitting additional 2. Two-Tiered Dissolution Test
dissolution data when scientifically To more accurately reflect the
justified. Examples of this include (1) physiologic conditions of the
cases in which USP does not specify a gastrointestinal tract, two-tiered
dissolution test for all active drug dissolution testing in Simulated Gastric
substances of a combination product Fluid (SGF) with and without pepsin or
and (2) cases in which USP specifies Simulated Intestinal Fluid (SIF) with and
use of disintegration apparatus. without pancreatin may be employed to

Handbook of Pharmaceutical Sect: 16.

16 27 Generic Development
 TABLETS ORAL DISSOLUTION & B I O S T U D Y CHAPTER 16

assess batch-to-batch product quality If the products with the extreme range
provided the bioequivalence is of dissolution characteristics are found
maintained. to be bioequivalent to the standard or
Recent examples involving soft and hard gelatin
capsules show a decrease in the dissolution
the to be marketed dosage form, future
profile over time either in SGF or in SIF without batches with dissolution characteristics
enzymes. This has been attributed to pellicle between these ranges should be
formation. When the dissolution of aged or equivalent to one another.
slower releasing capsules was carried out in the
presence of an enzyme (pepsin in SGF or This approach can be viewed as
pancreatin in SIF), a significant increase in the verifying the limits of the dissolution
dissolution was observed. In this setting, specifications. Product dissolution
multiple dissolution media may be necessary to
adequately assess product quality.
specifications established using a
mapping approach will provide
Mapping or Response Surface maximum likelihood of ensuring stable
Methodology quality and product performance.
Mapping is defined as a process for Depending on the number of products
determining the relationship between evaluated, the mapping study can
Critical Manufacturing Variables (CMV) provide information on invitro-invivo
and a response surface derived from an correlations and/or a rank order
in vitro dissolution profile and an in vivo relationship between invivo and invitro
bioavailability data set. The CMV data.
include changes in the formulation,
process, equipment, materials, and
Invivo-Invitro Correlations
methods for the drug product that can For highly water soluble (BCS Class 1
significantly affect in vitro dissolution and 3) immediate release products
The goal is to develop product using currently available excipients and
specifications that will ensure manufacturing technology, an IVIVC
bioequivalence of future batches may not be possible.
prepared within the limits of acceptable For poorly water soluble products, BCS
dissolution specifications. Several class 2, an IVIVC may be possible.
experimental designs are available to The value of dissolution as a quality
study the influence of CMV on product control tool for predicting invivo
performance. performance of a drug product is
One approach to study and evaluate significantly enhanced if an invitro-in
the mapping process includes:- vivo relationship (correlation) is
established. The in vitro test serves as
(1) prepare two or more dosage a tool to distinguish between acceptable
formulations using CMV to study their in and unacceptable drug products.
vitro dissolution characteristics
Acceptable products are bioequivalent,
(2) test the products with fastest and in terms of invivo performance, whereas
slowest dissolution characteristics along unacceptable products are not. To
with the standard or the to be marketed achieve an invitro-invivo correlation, at
dosage form in small groups (e.g., least three batches that differ in the in
n>12) of human subjects vivo as well as the in vitro performance
(3) determine the bioavailability of the should be available.
products and in vitro-in vivo If the batches show differences in invivo
relationship.
performance, then invitro test conditions
The products with extreme dissolution can be modified to correspond with the
characteristics are also referred to as in vivo data to achieve an invitro-invivo
side batches (Siewert 1995). correlation.

Handbook of Pharmaceutical Sect: 16.

16 28 Generic Development
 TABLETS ORAL DISSOLUTION & B I O S T U D Y CHAPTER 16

If no difference is found in the invivo (1) scale-up

performance of the batches and if the
(2) manufacturing site changes
invitro performance is different, it may
be possible to modify test conditions to (3)component and composition changes
achieve the same dissolution
(4) equipment and process changes.
performance of the batches studied in
vivo. A changed product may also be a lower
Very often, the invitro dissolution test is strength of a previously approved drug
found to be more sensitive and product. In the presence of certain
discriminating than the invivo test. minor changes, the single-point
From a quality assurance point of view, dissolution test may be adequate to
a more discriminative dissolution ensure unchanged product quality and
method is preferred, because the test performance.
will indicate possible changes in the For more major changes, a dissolution
quality of the product before invivo
profile comparison performed under
performance is affected.
identical conditions for the product
Validation and verification before and after the change(s) is
recommended (see SUPAC-IR).
of specifications Dissolution profiles may be considered
Confirmation by invivo studies may be similar by virtue of;-
needed for validation of an invitro
system. Here, the same formulation [1] overall profile similarity and
should be used but non-formulation [2] similarity at every dissolution sample
CMV should be varied. Two batches time point.
with different invitro profiles should be The dissolution profile comparison may
prepared (mapping approach). be carried out using model independent
These products should then be tested or model dependent methods.
in vivo. If the two products show
different in vivo characteristics, then the
Three ways to
system is validated. compare dissolution profiles
In contrast, if there is no difference in to show similarity
the invivo performance, the results can (test-to-reference or biobatch-to-
be interpreted as verifying the
dissolution specification limits as commercial batches)
discussed under mapping. [A]. Model Independent Approach
Thus, either validation or verification of Using a Similarity Factor
dissolution specifications should be A simple model independent approach
confirmed. uses a difference factor (f1) and a
similarity factor (f2) to compare
Using Dissolution Profile dissolution profiles (Moore 1996).
Comparisons The difference factor (f1) calculates the
Until recently, single-point dissolution percent (%) difference between the two
tests and specifications have been curves at each time point and is a
employed in evaluating scale-up and measurement of the relative error
post-approval changes, such as: between the two curves:

Handbook of Pharmaceutical Sect: 16.

16 29 Generic Development
 TABLETS ORAL DISSOLUTION & B I O S T U D Y CHAPTER 16

Difference Factor (f1) similarity factor (f2) using the above

f1 = {[Σ t-1n | Rt - Tt | ] • 100 equations.
[ Σ t-1 R t ]} [3]. For curves to be considered similar,
where:- f1 values should be close to 0, and f2
n = is the number of time points values should be close to 100.
R1 = is the dissolution value of the Generally, f1 values up to 15 (0-15) and
reference t (pre-change) batch at time t, f2 values greater than 50 (50-100)
Tt = is the dissolution value of the test ensure sameness or equivalence of the
(post-change) batch at time t two curves and, thus, of the
The similarity factor (f2) is a logarithmic performance of the test (post-change)
reciprocal square root transformation of and reference (pre-change) products.
the sum of squared error and is a In Four Points Comparative
measurement of the similarity in the
percent (%) dissolution between the two
Dissolution Profiles -
curves. Show similarity with a
Dissolution profiles are 'similar' when model independent method
the result, which is unbiased gives a
value between 50 to 100. i.e.
This model independent method is
most suitable for dissolution profile
ƒ² = 50 to 100. comparison when three to four or more
Formula: dissolution time points are available. As
further suggestions for the general
ƒ²=50 log{[1+1/n∑nt=1(Rt -Tt)2 ]-0.5 x 100 approach, the following
recommendations should also be
considered:
where:- Ø The dissolution measurements of the
ƒ² = Formula Similarity Factor. test and reference batches should be
R = RLD (Reference Listed Drug). made under exactly the same
T = Test Drug. conditions. The dissolution time points
Rt = % dissolved at each time point. for both the profiles should be the same
Tt = % dissolved at each time point. (e.g., 15, 30, 45, 60 minutes). The
reference batch used should be the
Dissolution profiles using most recently manufactured prechange
SIMILARITY FACTOR product.
may be compared between Ø Only one measurement should be
Pre & Post Change considered after 85% dissolution of both
Key Batches the products.
A specific procedure to determine
Ø To allow use of mean data, the
percent coefficient of variation at the
difference and similarity factors is as
earlier time points (e.g., 15 minutes)
follows:
should not be more than 20%, and at
[1]. Determine the dissolution profile of other time points should not be more
two products (12 units each) of the test than 10%.
(post-change) and reference (pre- Ø The mean dissolution values for Rt
change) products.
can be derived either from (1) last
[2]. Using the mean dissolution values prechange (reference) batch or (2) last
from both curves at each time interval, two or more consecutively
calculate the difference factor (f1) and manufactured prechange batches.

Handbook of Pharmaceutical Sect: 16.

16 30 Generic Development
 TABLETS ORAL DISSOLUTION & B I O S T U D Y CHAPTER 16

for each unit, fit the data to the most

[B] Model Independent Multivariate
appropriate model.
Confidence Region Procedure
[3]. A similarity region is set based on
In instances where within batch
variation of parameters of the fitted
variation is more than 15% CV, a
model for test units (e.g., capsules or
multivariate model independent
tablets) from the standard approved
procedure is more suitable for
batches.
dissolution profile comparison.
[4]. Calculate the MSD in model
If within batch CVs parameters between test and reference
exceeds 15% batches.
Show Similarity via [5]. Estimate the 90% confidence region
of the true difference between the two
Model Independent
batches.
Multivariate CR Procedure [6]. Compare the limits of the
The following steps are suggested: confidence region with the similarity
region. If the confidence region is within
[1]. Determine the similarity limits in
the limits of the similarity region, the test
terms of multivariate statistical distance
batch is considered to have a similar
(MSD) based on interbatch differences
dissolution profile to the reference
in dissolution from reference (standard
batch.
approved) batches.
[2]. Estimate the MSD between the test DISSOLUTION & SUPAC-IR
and reference mean dissolutions. The SUPAC-IR guidance defines the
[3]. Estimate 90% confidence interval of levels of changes, recommended tests,
true MSD between test and reference and filing documentation to ensure
batches. product quality and performance of
reference (prechange product) with
[4]. Compare the upper limit of the postapproval changes in:-
confidence interval with the similarity
limit. Ø components and composition,
The test batch is considered similar to Ø site of manufacturing,
the reference batch if the upper limit of Ø the scale of manufacturing, and
the confidence interval is less than or
equal to the similarity limit. Ø process and equipment changes in
the manufacturing of immediate release
[C] Model Dependent Approaches
products.
Several mathematical models have
been described in the literature to fit Depending on the level of change and
dissolution profiles. To allow application the biopharmaceutics classification
of these models to comparison of system of the active drug substance,
dissolution profiles, the following the SUPAC-IR guidance recommends
procedures are suggested: different levels of in vitro dissolution test
[1]. Select the most appropriate model and/or in vivo bioequivalence studies.
for the dissolution profiles from the Tests vary depending on therapeutic
standard, prechange, approved range and solubility and permeability
batches. A model with no more than factors of the drug substance. For
three parameters (such as linear, formulation changes beyond those
quadratic, logistic, probit, and Weibull listed in the guidance, additional
models) is recommended. dissolution profile determinations in
[2]. Using data for the profile generated several media are recommended.

Handbook of Pharmaceutical Sect: 16.

16 31 Generic Development
 TABLETS ORAL DISSOLUTION & B I O S T U D Y CHAPTER 16

For manufacturing site changes, scale- "Components and Composition,"

up equipment changes, and minor discussed in the SUPAC-IR guidance.
process changes, only dissolution In all cases, the approval of additional
testing should be sufficient to ensure strengths is based on dissolution profile
unchanged product quality and comparisons between these additional
performance. strengths and the strength of the batch
used in the pivotal BE study.
The SUPAC-IR guidance recommends Dissolution Testing Conditions
dissolution profile comparisons for
approving different levels of changes Apparatus
and documenting product sameness The most commonly employed
between the test (postchange) and dissolution test methods are (1) the
reference (prechange) product. It basket method (Apparatus 1) and (2)
recommends dissolution profile com- the paddle method (Apparatus 2) (Shah
parisons using a model independent 1989). The basket and the paddle
methods are simple, robust, well
approach and the similarity factor (ƒ² )
standardized, and used worldwide.
B I O W A I V E R S These methods are flexible enough to
allow dissolution testing for a variety of
In addition to routine quality control drug products. For this reason, the
tests, comparative dissolution tests official in vitro dissolution methods
have been used to waive described in U.S. Pharmacopoeia
bioequivalence requirements biowaivers (USP), Apparatus 1 and Apparatus 2
for lower dosage form strengths. should be used unless shown to be
For biowaivers, a dissolution profile is unsatisfactory. The in vitro dissolution
generated and evaluated using a procedures, such as the reciprocating
method described under dissolution cylinder (Apparatus 3) and a flow-
profile comparisons in this guidance, through cell system (Apparatus 4)
"Dissolution Profile Comparisons." described in the USP, may be
Bioequivalent on considered if needed.
Highest Dosage Strength These methodologies or other
alternatives/modifications should be
Biowaivers on considered on the basis of their proven
Lowest Strengths superiority for a particular product.
Biowaivers are generally provided for Because of the diversity of biological
multiple strengths after approval of a and formulation variables and the
bioequivalence study performed on one evolving nature of understanding in this
strength, using the following criteria:- area, different experimental
For multiple strengths of IR products modifications may need to be carried
with linear kinetics, the bioequivalence out to obtain a suitable in vivo
study may be performed at the highest correlation with in vitro release data.
strength and waivers of in vivo studies Dissolution methodologies and
may be granted on lower strengths, apparatus described in the USP can
based on an adequate dissolution test, generally be used either with manual
provided the lower strengths are sampling or with automated procedures.
proportionately similar in composition Dissolution Medium
(21 CFR 320.22(d)(2)). Dissolution testing should be carried out
Similar may also be interpreted to mean under physiological conditions, if
that the different strengths of the possible. This allows interpretation of
products are within the scope of dissolution data with regard to invivo
changes permitted under the category performance of the product.

Handbook of Pharmaceutical Sect: 16.

16 32 Generic Development
 TABLETS ORAL DISSOLUTION & B I O S T U D Y CHAPTER 16

However, strict adherence to the is recommended (Shah 1989, 1995).

gastrointestinal environment need not be The need for and the amount of the
used in routine dissolution testing. The surfactant should be justified. NOTE:
testing conditions should be based on The use of a hydro-alcoholic medium is
physicochemical characteristics of the drug discouraged.
substance and the environmental
conditions the dosage form might be Dissolution Parameters
exposed to after oral administration. All dissolution tests for IR dosage forms
Dissolution Volume should be conducted at 37±0.5°C.
The volume of the dissolution medium is The basket and paddle method can be
generally 500, 900, or 1000 mL. Sink used for performing dissolution tests
conditions are desirable but not under multimedia conditions (e.g., the
mandatory. initial dissolution test can be carried out
Dissolution pH at pH 1.2, and, after a suitable time
n An aqueous medium with pH range interval, a small amount of buffer can be
1.2 to 6.8 (ionic strength of buffers the added to raise pH to 6.8). Alternatively,
same as in USP) should be used. if addition of an enzyme is desired, it
can be added after initial studies
n To simulate intestinal fluid (SIF), a
dissolution medium of pH 6.8 should be
(without enzymes).
employed. A higher pH should be justified Use of Apparatus 3 allows easy change
on a case-by-case basis and, in general, of the medium. Apparatus 4 can also be
should not exceed pH 8.0. adopted for a change in dissolution
n To simulate gastric fluid (SGF), a medium during the dissolution run.
dissolution medium of pH 1.2 should be Certain drug products and formulations
employed without enzymes. are sensitive to dissolved air in the
Dissolution enzymes dissolution medium and will need
The need for enzymes in SGF and SIF deaeration.
should be evaluated on a case-by-case In general, capsule dosage forms tend to float
basis and should be justified. during dissolution testing with the paddle
method. In such cases, it is recommended that
Recent experience with gelatin capsule products
a few turns of a wire helix (USP) around the
indicates the possible need for enzymes (pepsin
capsule be used.
with SGF and pancreatin with SIF) to dissolve
pellicles, if formed, to permit the dissolution of
the drug. The apparatus suitability tests should
be carried out with a performance
Purified Water standard (i.e., calibrators) at least twice
due to variation is not a year and after any significant
a good dissolution media equipment change or movement.
De-aerate the dissolution
Use of water as a dissolution medium media as a Standard
also is discouraged because test
conditions such as pH and surface
Operating Procedure
tension can vary depending on the However, a change from basket to
source of water and may change during paddle or vice versa may need re-
the dissolution test itself, due to the calibration. The equipment and
influence of the active and inactive dissolution methodology should include
ingredients. the product related operating
For water insoluble or sparingly water instructions such as deaeration of the
soluble drug products, use of a dissolution medium and use of a wire
surfactant such as sodium lauryl sulfate helix for capsules.

Handbook of Pharmaceutical Sect: 16.

16 33 Generic Development
 TABLETS ORAL DISSOLUTION & B I O S T U D Y CHAPTER 16

Validation of automated procedures and dissolution parameters of the

compared to the manual procedures Generic and Reference Drug.
should be well documented.
Validation of determinative steps in the Where appropriate, in-vitro dissolution
dissolution testing process should tests involving single / multipoint
comply with the set standards for dissolution profiles in varying media
analytical methodology. may be used to demonstrate similarity
Agitation between reference and generic product.
In general, mild agitation conditions The BCS applies primarily to immediate
should be maintained during dissolution release drug preparations but impacts
testing to allow maximum discriminating on HS / LP for CR preparations
power and to detect products with poor
in vivo performance.
REFERENCES
Dissolution Speeds Amidon, G. L., H. Lennernas, V. P. Shah, and J. R.
Crison, 1995, "A Theoretical Basis For a

òPaddle - Slower Biopharmaceutic Drug Classification: The Correlation

of In Vitro Drug Product Dissolution and In Vivo

ñBasket - Faster Bioavailability,"Pharmaceutical

420.
Research,12:413-

FDA, 1995, Center for Drug Evaluation and

Using the basket method, the common Research, Guidance for Industry: Immediate Release
Solid Oral Dosage Forms. Scale-up and Post-
agitation (or stirring speed) is 50-100 Approval Changes: Chemistry, Manufacturing and
rpm; with the paddle method, it is 50-75 Controls, In Vitro Dissolution Testing, and In Vivo
rpm (Shah et al., 1992). Bioequivalence Documentation [SUPAC-IR],
November 1995.
Apparatus 3 and 4 are seldom used to Meyer, M. C., A. B. Straughn, E. J. Jarvi, G. C.
Wood, F. R. Pelsor, and V. P. Shah, 1992, "The
assess the dissolution of immediate Bioequivalence of Carbamazepine Tablets with a
release drug products. History of Clinical Failures," Pharmaceutical
Research, 9:1612-1616.
Validation Moore, J. W. and H. H. Flanner, 1996, "Mathematical
Comparison of Dissolution Profiles," Pharmaceutical
Validation of the dissolution Technology, 20 (6):64-74.
apparatus/methodology should include;- Shah, V. P., et al., 1989, "In Vitro Dissolution Profile
of Water Insoluble Drug Dosage Forms in the
(1) the system suitability test using Presence of Surfactants," Pharmaceutical Research,
calibrators 6:612-618.
Shah, V. P., et al., 1992, "Influence of Higher Rate of
Agitation on Release Patterns of Immediate Release
(2) deaeration, if necessary Drug Products," Journal of Pharmaceutical Science,
81:500-503.
(3) validation between manual and Shah, V. P., J. P. Skelly, W. H. Barr, H. Malinowski,
automated procedures and G. L. Amidon, 1992, "Scale-up of Controlled
Release Products - Preliminary Considerations,"
(4) validation of a determinative step Pharmaceutical Technology, 16(5):35-40.
Shah, V. P., et al., 1995, "In Vivo Dissolution of
(i.e., analytical methods employed in Sparingly Water Soluble Drug Dosage Forms,"
quantitative analysis of dissolution International Journal of Pharmaceutics, 125:99-106.
samples). This should include all Siewert, M., 1995, "FIP Guidelines for Dissolution
Testing of Solid Oral Products," Pharm. Ind. 57:362-
appropriate steps and procedures of 369.
analytical methods validation. International Journal of Generic Drugs, Vol 02-No02.
Skelly, J. P., G. L. Amidon, W. H. Barr, L. Z. Benet,
The Biopharmaceutics Classification J. E. Carter, J. R. Robinson, V. P. Shah, and A.
System (BCS) designed primary for Yacobi, 1990, "In Vitro and In Vivo Testing and
Correlation for Oral Controlled/Modified-Release
IRdrugs projects possible invitro-invivo Dosage Forms," Pharmaceutical Research, 7:975-
correlations between the drug 982.
United States Pharmacopeia (USP), U.S.
classification (Solubility / Permeability) Pharmacopeial Convention, Inc. Rockville, MD.

Handbook of Pharmaceutical Sect: 16.

16 34 Generic Development
 TABLETS ORAL DISSOLUTION & B I O S T U D Y CHAPTER 16

The Overall Dissolution Picture

USE Deaerate
Calibrate a VALIDATED the
the System Dissolution dissolution
FULLY Assay medium

ØSee SOPs Compare Manual & Automatic Procedures

Attached×

Dissolution Validation
Use mild rpm
Mimic the pH
conditions
Paddle 50-75 rpm of the GIT
Basket 50-100 rpm Target Site

Dissolution Performance
Sample every Use a Surfactant
15 minutes for for water insoluble or
IR Dosages sparing soluble drugs
(i.e. Na lauryl sulfate)

Dissolution Comparisons

Perform a
Comparative Evaluate the Choose the
Dissolution SIMILARITY right statistical
Profile Statistical Approach
(4 or more points) Factors
Dependent Independent
Approach Approach

⇒ Compare Test vs. Reference Drug Product

⇒ Compare Bioequivalent Batch-to-Commercial Validation Lots
⇒ Compare Pre-change to Post-Change (when a key change is made)

Handbook of Pharmaceutical Sect: 16.

16 35 Generic Development
 TABLETS ORAL DISSOLUTION & B I O S T U D Y CHAPTER 16

DRUG DEVELOPMENT

Dissolution Testing of IR Biopharmaceutics

Classification System

Solid Oral Dosage Forms

FDA's DISSOLUTION TESTING and New Draft BC System

SOLID ORAL DOSAGE FORMS

I. INTRODUCTION a waiver for an in vivo bioequivalence
study.
T his subchapter is based on the three
interrelated and interwoven FDA
guidance documents for industry. For
This guide also provides
recommendations for dissolution tests to
complete integration certain key help ensure continuous drug product
dissolution aspects are repeated quality and performance after certain
post-approval manufacturing changes.
Firstly; the draft guidance relating to
the 'waiver of in-vivo bioavailability and Thirdly the guidance is intended to
bioequivalence studies for immediate complement the SUPAC - IR guidance
release solid oral dosage forms for industry entitled:
containing certain active moieties/active "Immediate Release Solid Oral
ingredients based on a Dosage Forms: Scale-up and Post-
Biopharmaceutics Classification System Approval Changes: Chemistry,
(BCS)… ' Manufacturing and Controls, In Vitro
It should be read in conjunction with the Dissolution Testing, and In Vivo
agencies guide in the development of Bioequivalence Documentation", with
dissolution for immediate release (IR) specific reference to the generation of
dosage forms4 which in itself is intended dissolution profiles for comparative
to provide the reader the following:- purposes.
(1) General recommendations for Thus the three guidance documents
dissolution testing dovetail and interface with each other.
Some agency repetition occurs in each
(2) Approaches for setting dissolution of the published document.
specifications related to the bio-
pharmaceutics characteristics of the II. BACKGROUND
drug substance Drug absorption from a solid dosage form
after oral administration depends on the
(3) Statistical methods for comparing release of the drug substance from the
dissolution profiles. drug product, the dissolution or
solubilization of the drug under
(4) A process to help determine when physiological conditions and the
dissolution testing is sufficient to grant permeability across the gastrointestinal
tract.

Handbook of Pharmaceutical Sect: 16.

16 36 Generic Development
 TABLETS ORAL DISSOLUTION & B I O S T U D Y CHAPTER 16

Because of the critical nature of the first Acceptable bioequivalence data and
two of these steps, invitro dissolution comparable invitro dissolution and CMC
may be relevant to the prediction of data are required for approval of
invivo performance. abbreviated new drug applications
(ANDAs) (21 CFR 314.94).
When 85% of The invitro specifications for generic
Highly Soluble Drugs products should be established based
dissolve in 15 minutes on a dissolution profile.

in 0.1N HCl they are For new drug applications, as well as

generic drug applications, the
equivalent to a solution dissolution specifications are based on
acceptable clinical, bioavailability, and /
Based on this general consideration, or bioequivalence batches.
invitro dissolution tests for immediate
release solid oral dosage forms, such as
Once the specifications are established
in an NDA, the dissolution specifications
tablets and capsules, are used to:-
for batch-to-batch quality assurance are
(1) Assess the lot-to-lot quality of a drug published in the United States
product Pharmacopoeia (USP) as compendial
standards, which become the official
(2) Guide development of new
specifications for all subsequent IR
formulations products with the same actives.
(3) Ensure continuing product quality Generally these compendial dissolution
and performance after certain changes, standards are single-point dissolution
such as changes in the formulation, the tests, not profiles.
manufacturing process, the site of
manufacture, and the scale-up of the BIOPHARMACEUTICS
manufacturing process.
CLASSIFICATION
Current knowledge about the solubility,
permeability, dissolution, and
SYSTEM
pharmacokinetics of a drug product Based on drug solubility and
should be considered in defining permeability, the Biopharmaceutics
dissolution test specifications for the Classification System (BCS) is recom-
drug approval process. mended in the literature (Amidon 1995)

This knowledge should also be used to The Biopharmaceutics Classification

ensure continued equivalence of the System (BCS) designed primary for IR
product, as well as to ensure the drugs identifies possible invitro-invivo
product's sameness under certain scale- correlations between the drug
up and post-approval changes. classification (Solubility / Permeability)
and dissolution parameters of the
Invitro dissolution data are generally Generic and Reference Drug.
obtained from batches that have been Where appropriate, invitro dissolution
used in pivotal, clinical and / or tests involving single / multipoint
bioavailability studies and other studies dissolution profiles in varying media is
conducted during product development. used to demonstrate similarity between
reference and generic product.

Handbook of Pharmaceutical Sect: 16.

16 37 Generic Development
 TABLETS ORAL DISSOLUTION & B I O S T U D Y CHAPTER 16

The BCS applies primarily to immediate bioavailability of the drug is not limited
by dissolution.
release drug preparations but impacts
on HS / LP for Controlled Release Oral Bioequivalent studies are
preparations. generally performed on
PERMEABILITY & SOLUBILITY TABLE Highest Dosage Strength
Case 1: High Solubility - High In these cases, the rate limiting step for
Permeability Drugs drug absorption is gastric emptying.
Case 2: Low Solubility - High The mean T50% gastric residence
Permeability Drugs (emptying) time is 15-20 minutes under
Case 3: High Solubility - Low fasting conditions.
Based on this information, a
Permeability Drugs
conservative conclusion is that a drug
Case 4: Low Solubility - Low product undergoing 85% dissolution in
Permeability Drugs 15 minutes under mild dissolution test
conditions in 0.1N HCl behaves like a
This classification can be used as a solution and generally should not have
basis for setting in vitro dissolution any bioavailability problems.
specifications and can also provide a
basis for predicting the likelihood of Soluble Drugs dissolving
achieving a successful in vivo-in vitro over 85% in less than 15 min
correlation (IVIVC). in acid media
Highly Soluble Drugs can be considered as a liquid
are defined as:- preparation
Highest Strength dissolving If the dissolution is slower than gastric
in <250 mL buffer emptying, a dissolution profile with
multiple time points in multimedia is
The solubility of a drug is determined by recommended.
dissolving the highest unit dose of the In the case of low solubility / high
drug in 250 mL of buffer adjusted permeability drugs (case 2), drug
between pH 1.0 and 8.0. dissolution may be the rate limiting step
A drug substance is considered highly for drug absorption and an IVIVC may
soluble when the dose/solubility volume be expected.
of solution are ≤250 mL. A dissolution profile in multiple media is
High-permeability drugs are generally recommended for drug products in this
those with an extent of absorption that is category. In the case of high solubility /
greater than 90% in the absence of low permeability drugs (case 3),
documented instability in the permeability is the rate controlling step
gastrointestinal tract or those whose and a limited IVIVC may be possible,
permeability has been determined depending on the relative rates of
experimentally. dissolution and intestinal transit.
The BCS suggests that for high Drugs in case 4 LS/LP (i.e., low
solubility, high permeability (case 1) solubility / low permeability drugs)
drugs and in some instances for high present significant problems for oral
solubility, low permeability (case 3) drug delivery.
drugs, 85% dissolution in 0.1N HCl in 15
minutes can ensure that the

Handbook of Pharmaceutical Sect: 16.

16 38 Generic Development
 TABLETS ORAL DISSOLUTION & B I O S T U D Y CHAPTER 16

BIOPHARMACEUTICS
CLASSIFICATION SYSTEM (BCS)
The Biopharmaceutics Classification System (BCS) designed primary for IR drugs,
projects possible Invitro-Invivo Correlations between the drug classification (Solubility /
Permeability) and dissolution parameters of the Generic and Reference Drug. Where
appropriate, in-vitro dissolution tests involving single/multipoint dissolution profiles in
varying media may be used to demonstrate similarity between reference and generic
product. The BCS applies primarily to immediate release drug preparations but impacts
on HS / LP for CR preparations
Table 1:
GROUP Drug Dissolution IVIVC
Solubility EXPECTATION
Parameters Studies needed
Permeability

HS / HP CORRELATION - HIGH Single point: HIGH

CASE 1 If drug dissolution rate is slower than the 0.1N HCl
gastric emptying rate (15-20 min).
High Q NLT 85%
Solubility CORRELATION - LOW
in 15 min
High If drug dissolution rate is faster than the
Permeability gastric emptying rate. (i.e. rapid dissolving 900mL LOW
drugs) Rpm 50 [1] / 100 [2]

LS / HP CORRELATION - HIGH Multipoint [5]: HIGH

CASE 2 These drugs the solubility is rate-limiting H20; 0.1N HCl
If dissolution rate of drug invitro = USP Buffer Media pH
dissolution rate of drug invivo. 4.5; 6.5; 7.5
Low
Solubility NOTE : 90% Dissolved
For CR Dosage Sample at 15, 30, 45,
High
Forms 60,120 min
Permeability
[+Surfactant]

HS / LP CORRELATION - LOW (IR.) Multipoint [5]: LOW

These drugs the Permeability is rate- H20; 0.1N HCl
CASE 3 limiting
USP Buffer Media pH
Immediate release formulations IVIVC low 4.5; 6.5; 7.5
90% Dissolved HIGH
High
Solubility CORRELATION - HIGH (DR./ER) Sample at 15, 30, 45,
Low Extended Release formulations IVIVC is 60,120 min
Permeability high where dissolution rate is rate-limiting. [+Surfactant]

LS / LP CORRELATION - LOW Multipoint

CASE 4 These drugs the Permeability and Surfactant LOW

solubility are rate-limiting.
Low Enzymes
Limited applications for oral solid drugs as
Solubility dissolution is not predictive of
Low bioavailability
Permeability

Handbook of Pharmaceutical Sect: 16.

16 39 Generic Development
 TABLETS ORAL DISSOLUTION & B I O S T U D Y CHAPTER 16

Biopharmaceutics Guidance to Industry

Classification System
Draft Guidance to Industry

‘ … waiver of in-vivo bioavailability and bioequivalence studies for immediate release

solid oral dosage forms containing certain active moieties/active ingredients based on a
Biopharmaceutics Classification System (BCS)…

GUIDANCE TO INDUSTRY I. INTRODUCTION

T he January 1999 draft document

provides guidance to sponsors and
applicants of new drug applications
TABLE OF CONTENTS (NDAs) and abbreviated new drug
I. Introduction applications (ANDAs), and supplements
to these applications, who wish to
II. Background.
request a waiver of in vivo bioavailability
III. THE BIOPHARMACEUTICS (BA) and/or bioequivalence (BE) studies
CLASSIFICATION SYSTEM (biowaivers) for certain immediate
release solid oral dosage forms.
[a]. - Solubility
Currently, regulations at 21 CFR 320
[b]. - Permeability
("Bioavailability and Bioequivalence
[c]. - Dissolution Requirements") address the
requirements for BA/BE data for the
IV. Methodology for Classifying a Drug
approval of drug applications and
[a]. - Determining Solubility Class
supplemental applications submitted to
[b]. - Determining Permeability Class
the Center for Drug Evaluation and
V. Requesting a waiver of in vivo BA/BE Research (CDER). Section 320.22
studies provides for waivers of in vivo BA/BE
VI. Additional considerations when studies under some conditions.
planning a request for a waiver This DRAFT guidance for industry
[a]. - Instability in the Gastrointestinal clarifies the BA/BE regulations and
Tract explains when waivers for in vivo BA/BE
[b]. - Evaluation of Excipients studies (biowaivers) can be requested
[c]. - Exceptions for certain immediate release solid oral
dosage forms based on a
VII. Regulatory Application of the BCS Biopharmaceutics Classification System.
[a]. INDs/NDAs - Documenting
II. BACKGROUND
Bioavailability and Bioequivalence
In 1974, the Office of Technology
[b]. - ANDAs
Assessment's Drug Bioequivalence
[c]. - Postapproval Changes
Study Panel made eleven
Attachment A: Suggested model drugs recommendations, one of which stated:

Handbook of Pharmaceutical Sect: 16.

16 40 Generic Development
 TABLETS ORAL DISSOLUTION & B I O S T U D Y CHAPTER 16

"It is neither feasible nor desirable that active moieties / active ingredients that
studies of bioavailability be conducted are highly soluble and highly permeable
for all drugs or drug products. Certain from other drug products.
classes of drugs for which evidence of For such products, in vivo
bioequivalence is critical should be demonstration of bioequivalence may
identified. Selection of these classes of not be necessary because the BA/BE of
drugs should be based on clinical a drug product so characterized
importance, ratios of therapeutic to toxic approaches that of a solution and is thus
concentrations in blood, and certain self-evident (21 CFR 320.22(b) (3)).
pharmaceutical characteristics"
Furthermore, a suitable invitro / Invivo
Based on this and other
correlation can be assumed for a rapidly
recommendations of the panel, FDA dissolving drug product of a highly
proposed and finalized regulations in soluble and highly permeable drug
1977 entitled: substance, as long as its inactive
Bioequivalence Requirements and In ingredients do not significantly affect
Vivo Bioavailability Procedures absorption of the active ingredients.
(42 FR 1624; January 7, 1977). Conversely, drugs that are poorly
These regulations, which evolved over permeable, poorly soluble, and/or
time and are now codified at [21 CFR Part formulated in slowly dissolving dosage
320.33,] provide criteria for assessing forms may be considered to be drugs
actual or potential bioequivalence with actual or potential BE problems.
problems.
III. THE BIOPHARMACEUTICS

DRAFT
For drug products that were considered
to pose bioequivalence problems, the
regulations required that BA/BE be
demonstrated through in vivo studies.
CLASSIFICATION SYSTEM
The Biopharmaceutics Classification
System (BCS) is a general approach

GUIDELINE
For drug products that were not
considered to pose bioequivalence
problems, BA/BE could be demonstrated
that can be used by sponsors and
applicants to justify a biowaiver for
immediate release (IR) solid oral dosage
forms.
through in vitro studies.
The approach is based on the fact that
At the time of the passage of the Drug
invivo dissolution differences in the
Price Competition and Patent Term gastrointestinal tract are a primary
Restoration Act of 1984 (Waxman- reason for observed differences in
Hatch), FDA’s policy was to require bioavailabilities of two IR products
invivo demonstration of bio-equivalence
containing the same drug substance.
for all post-1962 (post-DESI2) non-
solution drug products. With occasional In the BCS, a drug is classified as
exceptions, this approach has continued belonging to either:-
to the present. ¯ 1) high or low solubility class,
PURPOSE ¯ 2) a high or low permeability class,
The purpose of this guidance is to ¯ 3) a IR dosage form is categorized
describe alternative ways, not based on as belonging to a rapid or slow
invivo methods, acceptable to FDA for dissolving class.
demonstrating bioequivalence for certain These classes and methods for
post-1962 immediate release solid oral classifying a drug are discussed in the
drug products based on a classification following sections. The term class
system that distinguishes rapidly boundary is used to indicate how the
dissolving drug products containing class should defined.

Handbook of Pharmaceutical Sect: 16.

16 41 Generic Development
 TABLETS ORAL DISSOLUTION & B I O S T U D Y CHAPTER 16

A. Solubility dosage form under specified test

The solubility class boundary is based conditions and is intended to indicate
on the highest dose strength of an IR rapid in vivo dissolution in relation to the
product that is the subject of a biowaiver average rate of gastric emptying in
request. humans under fasting conditions.

Bioequivalent performed on Rapidly Dissolving Drugs

Highest Dosage Strength Defined in two media
An IR drug product is considered rapidly
Biowaivers requested on dissolving when not less than 85% of the
Lowest Strengths label amount of the drug substance
A drug substance is considered highly dissolves within 30 minutes using the
USP Apparatus I at 100 rpm (or
soluble when the highest dose strength
Apparatus II at 50 rpm) in a volume of
is soluble in 250 ml or less of water over
900 ml, or less, in each of the following
the pH range of 1-8.
media:
The volume estimate of 250 ml is ¯ (1) acidic media, such as 0.1 N HCl
derived from typical bioequivalence or Simulated Gastric Fluid USP - without
study protocols that prescribe enzymes;
administration of a drug product to
fasting human volunteers with a glass ¯ (2) a pH 4.5 buffer; and (3) a pH 6.8
(about 8 ounces) of water — the buffer or Simulated Intestinal Fluid USP
- without enzymes.

administration
protocols.
DRAFT
minimum volume anticipated in the
stomach at the time of drug
during the study
IV. METHODOLOGY
CLASSIFYING A DRUG
FOR

The following experimental approaches

B. Permeability
The GUIDELINE
permeability class boundary is
based on the extent of absorption of a
are recommended for classifying a drug
according to the BCS.
A. Determining Solubility Class
drug substance in humans, or other An objective of the BCS approach is to
appropriate measurements of the rate of
determine the equilibrium solubility of a
mass transfer across intestinal
drug under approximate physiological
membranes, or well-characterized
conditions.
models of human intestinal membranes.
A drug substance is considered highly For this purpose, determination of pH-
permeable when the extent of solubility profiles over a pH range of 1-8
absorption in humans is determined to is suggested. Preferably eight or more
be >90% of an administered dose based pH conditions should be evaluated.
on a mass balance determination, or in Buffers that react with the drug should
comparison to an intravenous reference not be used.
dose in the absence of evidence An acid or base titration method can
suggesting instability in the also be used for determining drug
gastrointestinal tract. Other methods to solubility.
assess permeability are discussed in The solubility class is determined by
Section IV.
calculating what volume of an aqueous
C. Dissolution
media is sufficient to dissolve the
The dissolution class boundary is based highest anticipated dose strength.
on the in vitro dissolution rate of an IR

Handbook of Pharmaceutical Sect: 16.

16 42 Generic Development
 TABLETS ORAL DISSOLUTION & B I O S T U D Y CHAPTER 16

monitored to determine if significant loss

Solubility is defined on of radioactivity occurs via this route.
highest dosage strength The dose-normalized ratios of
A drug substance is considered highly cumulative urinary recovery of
soluble when the highest dose strength radioactivity after oral and intravenous
is soluble in 250 ml or less of aqueous drug administration can be used to
media over the pH range of 1-8 . estimate the extent of absorption when
the excretion pattern (for example: ratios
Solution stability of a test drug in of radioactivity found in urine and feces)
selected buffers (or pH conditions) does not vary with the dose and the
should be documented using a validated route of administration.
stability-indicating assay. Data collected In situations when intravenous
on both pH-solubility and pH-stability administration is not feasible, the
should be submitted in the biowaiver cumulative urinary recovery of the oral
application along with information on the dose can be considered the minimum
ionization characteristics, such as amount of dose absorbed.
pKa(s), of a drug.
2. Intestinal Permeability Methods
B. Determining Permeability Class
Studies of the extent of absorption in
The following methods can be used to
determine the permeability of a drug
humans, or intestinal permeability
from the gastro-intestinal tract:
methods, can be used to determine the
permeability class membership of a ¯ (1) in vivo intestinal perfusion studies
drug.
DRAFT
To be classified as highly permeable, a
test drug should have an extent of
in humans;
¯ (2) in vivo or in situ intestinal
perfusion studies in animals;
¯ (3) in vitro permeation experiments
information
GUIDELINE
absorption >90% in humans. Supportive
on permeability
characteristics of the drug substance
should also be derived from its physical-
using excised human or animal intestinal
tissues; and
¯ (4) in vitro permeation experiments
chemical properties (e.g., octanol : water across a monolayer of cultured human
partition coefficient). intestinal cells.
1. Studies of the Extent of Absorption in W hen using these methods, the
Humans
experimental permeability data should
Pharmacokinetic mass-balance and correlate with the known extent-of-
absolute bioavailability studies using absorption data in humans.
unlabeled, stable isotopes, or a A correlation can be established using
radiolabeled drug substance can be
20 or more selected model drugs for
used to document the extent of
which reliable estimates of extent-of-
absorption of a drug.
drug absorption and information on
Sufficient numbers of subjects (e.g., six
absorption mechanisms (including
or more) should be enrolled in a study to
potential for intestinal efflux via p-
provide a reliable estimate of the extent
glycoprotein or other efflux systems) are
of absorption.
available.
For mass-balance studies using a When a method enables the selected
radiolabeled drug, serial blood, urine,
model drugs to be categorized into the
and fecal samples should be collected
correct permeability class, that method
for about 10 elimination half lives. Serial
can be considered useful for the BCS
samples of exhaled air should be
and can be used to determine the

Handbook of Pharmaceutical Sect: 16.

16 43 Generic Development
 TABLETS ORAL DISSOLUTION & B I O S T U D Y CHAPTER 16

permeability class membership of test (1) drug absorption is shown to be via a

drugs. passive transport mechanism, or
Once a suitable method has been (2) a linear relationship between doses
chosen and assuming experimental (including the highest dose strength) of
conditions are held constant, it is not a drug and its rate and extent of
necessary to reestablish the suitability of absorption can be documented. Passive
the method using 20 or more model transport mechanisms can be supported
drugs . by documenting a lack of dependence of
For subsequent experiments, one or two measured permeability value on:
well-characterized model drugs can be (1) initial drug concentrations (e.g., 0.1,
used as internal standards and tested 1, and 10 times the highest dose
simultaneously along with the test drug strength dissolved in 250 ml), in the
being classified. donor chamber or perfusion fluid, and
(2) transport direction (e.g., a similar
Judicious selection of a high rate of transport between apical-to-
permeability internal standard may basolateral and basolateral-to-apical
simplify classification of a test drug (e.g., directions for the selected drug
when the ratio of the permeability of the concentrations).
test drug to that of a highly permeable V. REQUESTING A WAIVER OF
internal standard is ≥one, the test drug
may also be considered highly
IN VIVO BA/BE STUDIES
permeable). Submissions requesting biowaivers

to DRAFT
A low permeability internal standard is
suggested ensure intestinal
membrane integrity. The permeability
based on the BCS should contain
documentation on the following:
¯ 1. The drug substance for which a

GUIDELINE
values of the two internal standards can
be used to verify reproducibility of the
experimental method.
waiver is being requested should be
highly soluble and highly permeable, as
defined above.
¯ 2. An IR drug product should be
The internal standards should be
compatible with the drug being rapidly dissolving, as defined above.
evaluated (i.e., they should exhibit no ¯ 3. For waiver of an in vivo BA study,
physical or chemical interactions). dissolution should be greater than 85%
A list of potential model drugs and in 30 minutes in the three recommended
chemicals along with their permeability dissolution media.
class membership is provided in Tablet For waiver of bioequivalence, test and
A. reference products should exhibit similar
In vitro methods, such as those using a dissolution profiles under the dissolution
cultured monolayer of human intestinal test conditions defined for rapidly
cells, should be further examined to dissolving products.
identify any expressions of specialized Two dissolution profiles may be
transport/efflux systems for the selected considered similar when compared using
experimental conditions (e.g., the f2 metric (f2 ≥50) as described in the
bidirectional transport studies using guidance for industry on dissolution
model compounds, such as verapamil, testing4.
of the p-glycoprotein efflux system). When both the test and the reference
Permeability class membership products dissolve 85% or more of the
determined using such in vitro methods label amount in ≤15 minutes, in all three
can be considered reliable when:- dissolution media recommended above,
a profile comparison is unnecessary.

Handbook of Pharmaceutical Sect: 16.

16 44 Generic Development
 TABLETS ORAL DISSOLUTION & B I O S T U D Y CHAPTER 16

4. The drug should not be a narrow establish permeability class

therapeutic index drug. (criteria currently membership.
being developed by the FDA) Stability in gastrointestinal fluids can be
This limitation is expected to be applied documented by
primarily to NDA and ANDA [1] pH-stability profiles in the pH range
bioequivalence studies after approval, of 1-8 and
as well as bioequivalence studies [2] stability in gastric and intestinal fluids
submitted in an ANDA, recognizing that obtained from human subjects or
during the IND period an investigational animals. Drug solutions in these fluids
drug may not be clearly identified as an can be incubated at 37 C for about three
narrow therapeutic index drug . hours and analyzed using a validated
5. Excipients used in the dosage form stability indicating assay. Significant
should have been used previously in degradation or loss (>5%) of a drug in
FDA approved IR solid dosage forms. about three hours could suggest
The quantity of excipients in the IR potential instability.
product should be consistent with their B. Evaluation of Excipients
intended function. Large quantities of Excipients can sometimes affect the
certain excipients, such as surfactants
rate and extent of drug absorption.
like sodium lauryl sulfate, may be
Using excipients that are currently in
problematic.
FDA-approved IR solid oral dosage
6. All other application commitments
forms should generally not affect the
should be met.
rate or the extent of absorption of a

DRAFT
VI. ADDITIONAL CONSIDERATIONS
WHEN PLANNING A REQUEST FOR A
WAIVER
highly permeable drug that is formulated
in a rapidly dissolving IR product.
When new excipients, or atypically
When
GUIDELINE
requesting a waiver for in vivo
BA/BE studies for IR solid oral dosage
forms, applicants also should consider
the following issues, which could affect
large amounts of commonly used
excipients, are used in an IR dosage
form, additional information documenting
the absence of an impact on
their request or the documentation of bioavailability could be requested by the
their request. Agency.
A. Instability in the Gastrointestinal Include a list of
Tract
Determining the extent of absorption in
formula excipients
humans based on mass balance using when requesting the
total radioactivity in urine does not Biowaver
consider the extent of degradation of a
drug in the gastrointestinal fluids prior to Such information can be supplied via a
intestinal membrane permeation. relative bioavailability study using a
Also, some methods for determining simple aqueous solution as the
reference product.
permeability could be based on loss, or
clearance, of a drug from fluids perfused A request for biowaiver based on the
into the human and/or animal BCS should include a list of all
gastrointestinal tract either in vivo or ex excipients used in the products, the
vivo. Documenting that drug loss from amount used in the test product,
the gastrointestinal tract arose from intended functions, a brief summary
intestinal membrane permeation, rather describing the manufacturing process,
than a degradation process, will help and a list of equipment used.

Handbook of Pharmaceutical Sect: 16.

16 45 Generic Development
 TABLETS ORAL DISSOLUTION & B I O S T U D Y CHAPTER 16

C. Exceptions also rapidly dissolving, as defined in

Section III, this information can be used
A request for a waiver of in vivo BA/BE to support the waiver of subsequent in
studies based on the BCS, as described
vivo BA/BE studies during the IND
in this guidance, would not be
period, including an in vivo BA study on
considered appropriate for dosage forms
the pivotal clinical trial material.
intended for retention in the oral cavity
(e.g., sublingual or buccal tablets), or for The in vivo BA/BE studies considered
those intended for dissolution in the oral for waiver in this guidance are designed
cavity and/or designed for administration to demonstrate release of the drug
without the aid of water. substance from the drug product, as
measured by rate and extent of
Permeability class membership of pro- absorption, and do not include food-
drugs may depend on whether
effect or clinical pharmacology studies.
conversion to the active moiety occurs in
the gastrointestinal tract or following Two specific examples of BA/BE studies
intestinal membrane permeation. that could be waived are discussed in
the following paragraphs.
The sponsor should consult with the 1. Initial Clinical Trial Formulation for a
appropriate review division before
Phase 1 Study
applying the BCS for requesting
biowaivers to IR products containing For a highly soluble, highly permeable
pro-drugs. drug substance manufactured in a
VII. REGULATORY rapidly dissolving IR solid dosage form,
as defined in Section III, with in vivo BA
APPLICATION OF THE BCS
documented, additional in vivo BA/BE
A. INDs/NDAs — Documenting
studies could be waived for subsequent
Bioavailability and Bioequivalence
clinical trial formulations, up to and
In establishing a drug’s BA in including the to-be-marketed
accordance with 21 CFR 320.20, a formulation, providing dissolution
regulatory objective is to fix the remains rapid and the products exhibit
performance of the formulation used in similar dissolution profiles, as defined in
pivotal clinical studies for demonstrating Section V.
substantial evidence of safety and The choice of dissolution test apparatus
effectiveness (320.38(b)(1)). (USP I or II) should be based on a
The BA of a solid dosage form intended comparison of in vitro dissolution and
for oral administration can be available in vivo pharmacokinetic data
established relative to a solution or on the product. For certain products in
suspension of the drug substance given vitro (but not in vivo) dissolution may be
by the same route of administration (21 slow due to the manner in which a
CFR 320.25 (d)(2) and (3)) or, if problems disintegrated IR product settles at the
with absorption exist, to an intravenously bottom of a dissolution vessel.
administered drug formulation Comparison of in vitro dissolution and in
(320.25(d)(3)).
vivo pharmacokinetic data (e.g., BA
A formulation should be optimized for study using a simple solution dosage
performance (BA) during the clinical form as the reference product) may be
investigational period. If a highly useful to justify deviations from
soluble, highly permeable drug dissolution test conditions outlined in
substance is formulated so that it is Section V.

Handbook of Pharmaceutical Sect: 16.

16 46 Generic Development
 TABLETS ORAL DISSOLUTION & B I O S T U D Y CHAPTER 16

2. Pivotal Clinical Trial Formulation

Irrespective of whether early clinical trial C. Postapproval Changes
The SUPAC-IR guidance recommends
formulations of a highly soluble, highly dissolution profile comparisons for approving
permeable drug substance meet the different levels of changes and documenting
specifications for rapid dissolution as product sameness between the test (postchange)
defined in Section III, optimization of the and reference (prechange) product. It
recommends dissolution profile comparisons
performance of the clinical trial using a model independent approach and the
formulation could be achieved so that its similarity factor (ƒ² )
dissolution becomes rapid.
In this circumstance, an in vivo BA study is For significant postapproval changes to
recommended, but re-documentation of in a rapidly dissolving IR product
vivo BA/BE of subsequent clinical trial containing a highly soluble, highly
formulations, up to, and including, the to- permeable drug substance, such as
be-marketed formulation, could be waived, Level 3 changes in components and
provided dissolution remains rapid, as composition, the need for in vivo
defined, and the products exhibit similar bioequivalence re-documentation for
dissolution profiles based on the f2 metric postapproval changes may be waived
criteria defined in Section V. provided dissolution remains rapid, as
B. ANDAs defined, and the products exhibit similar
dissolution profiles, [Section V]
For a highly soluble, highly permeable
drug substance formulated so that its
For a pioneer product, dissolution
dissolution is rapid as defined in Section profiles of the postchange product
III, - an in vivo BE study can be waived, should be compared with that of the
provided the reference listed drug prechange product and found similar, as
product is also rapidly dissolving and the defined.
test product exhibits similar dissolution
profiles to the reference listed drug
The Generic Postchange Drug
product, as defined in Section V. is compared with the RLD

For a generic drug product, dissolution

For Class I Drugs profiles of the postchange product
[HS/HP] should be compared with the reference
compare RLD listed drug products and found similar,
as defined.
for essential similarity
FDA
encourages
Where feasible, the choice of
dissolution apparatus (USP I or II) contact when
should be limited to that established for problems may arise
the innovator product. Many complex situations may arise in
the regulatory application of the BCS.
For Class I Drugs When questions arise, FDA encourages
sponsors and applicants to contact the
[HS/HP] appropriate review staff in CDER’s
Significant SUPAC Office of Clinical Pharmacology and
changes may be waived Biopharmaceutics and Office of Generic
Drugs.

Handbook of Pharmaceutical Sect: 16.

16 47 Generic Development
 TABLETS ORAL DISSOLUTION & B I O S T U D Y CHAPTER 16

ATTACHMENT A: References:
SUGGESTED MODEL DRUGS 1 DESI2 drugs were identified as part of the Drug
Efficacy Study Implementation Program, which was a
Suggested model drugs for use in retrospective evaluation of the effectiveness of drugs
cleared through the new drug procedures only on the
establishing method suitability as basis of safety between 1938 and 1962.
described in section IV.
The DESI program was undertaken to implement the
The permeability class memberships of requirement set forth in the 1962 Drug Amendments
these compounds were determined to the Federal Food, Drug, and Cosmetic Act that
based on data available to the FDA. drug products be approved for marketing based on a
demonstration of effectiveness as well as safety.
Potential Internal Standards (IS) are
2 Amidon, G. L., H. Lennernas, V. P. Shah, and J. R.
also identified. Crison, “A Theoretical Basis For a Biopharmaceutic
Tablet-A
Drug Classification: The Correlation of In Vitro Drug
Drug Product Permeability Product Dissolution and In Vivo Bioavailability,”
Class Pharmaceutical Research, 12: 413-420 (1995).
3 The United States Pharmacopeia, 23, January
Ketoprofen High 1995. United States Pharmacopeial Convention, Inc.
Rockville, Maryland.
DRAFT GUIDELINE
Naproxen High 4. Guidance for Industry, Dissolution Testing of
Immediate Release Solid Oral Dosage Forms, FDA,
Verapamil High CDER, August 1997.
5. Criteria for identifying a narrow therapeutic index
Carbamazepine (Narrow High drug are currently being developed by FDA.
Therapeutic Range Drug) 6 Guidance for industry, Immediate Release Solid
Oral Dosage Forms: Scale-Up and Post-Approval 7
Propranolol High Changes, November 1995.
7. International Journal of Generic Drugs, Vol. 02-No
02. 1998
Metoprolol High 8. Skelly, J. P., G. L. Amidon, W. H. Barr, L. Z.
[Potential IS Candidate] Benet, J. E. Carter, J. R. Robinson, V. P. Shah, and
A. Yacobi, 1990, "In Vitro and In Vivo Testing and
Theophyllin - Narrow High Correlation for Oral Controlled/Modified-Release
Therapeutic Range Drug Dosage Forms," Pharmaceutical Research, 7:975-
982.
9 FDA Narrow Therapeutic Range Drug List
Caffeine High

Antipyrine High SOURCE OF THIS GUIDANCE

[Potential IS Candidate]
PREPARATION
Furosemide LOW This guidance has been prepared by the
Biopharmaceutic Classification System Working
Hydrochlorthiazide LOW Group of the Biopharmaceutics Coordinating
Committee in the Center for Drug Evaluation
and Research (CDER) at the Food and Drug
Alpha Methadopa LOW Administration.

Atenolol LOW CURRENT AGENCY THINKING

This guidance represents the Agency’s current

Ranitidine LOW thinking on the topic. It does not create or confer
any rights for or on any person and does not
Polyethylene Glycol LOW operate to bind FDA or the public.
[Potential IS Candidate] OTHER APPROACHES

An alternative approach may be used if such

Mannitol LOW approach satisfies the requirements of the
[Potential IS Candidate]
applicable statute, regulations, or both.

Handbook of Pharmaceutical Sect: 16.

16 48 Generic Development
 TABLETS ORAL DISSOLUTION & B I O S T U D Y CHAPTER 16

Narrow Therapeutic Range Drugs

Tablet-B
FDA List.
DRUG Dosage Modified Oral
Form Release Capsules

Tablets & Capsules IR & ER

Aminophylline Tablets ER Tablets
Carbamazepine Tablets
Clindamycin Hydrochloride Capsules
Clonidine Hydrochloride Tablets
Dyphylline Tablets
Disopyramide Phosphate ER Capsules Capsules
Ethinyl Estradiol/Progestin Tablets [Oral Contraceptive]
Guanethidine Sulfate Tablets
Isoproterenol Sulfate Tablets
Lithium Carbonate Tablets ER Tablets Capsules
Metaproterenol Sulfate Tablets
Minoxidil Tablets
Oxtriphylline Tablets ER Tablets
Phenytoin, Sodium Extended Capsules
Prazosin Hydrochloride Capsules
Primidone Tablets
Procainamide Hydrochloride Tablets ER Tablets Capsules
Quinidine Sulfate Tablets ER Tablets Capsules
Quinidine Gluconate ER Tablets
Theophylline Tablets ER Tablets Capsules
ER Capsules
Valproic Acid, Syrup Capsules
Divalproex, Sodium DR Tablets
DR Capsules
Warfarin, Sodium Tablets

Inhalation Aerosol
Isoetharine Mesylate Inhalation Aerosol

Transdermal Patches
Clonidine Patch

Syrups & Suspensions

Valproic Acid Syrup
Carbamazepine, Oral Suspension
Primidone Suspension
Phenytoin, Sodium Oral Suspension
ER - Extended Release (9)
DR - Delayed Release (2)

Handbook of Pharmaceutical Sect: 16.

16 49 Generic Development
 TABLETS ORAL DISSOLUTION & B I O S T U D Y CHAPTER
16

HIGHLY SOLUBLE
ACTIVES - KETOROLAC
EVALUATING POTENTIAL DISSOLUTION
DIFFERENCES BETWEEN THE
Drug substance, Powder Blend & Compressed Tablets

T he Intrinsic Dissolution Rate and

aqueous solubility of highly soluble
drugs are related to the bioavailability
Drug Ketorolac tromethamine Solubility at
25oC in water (pH 6.8) = 0.55g/mL
Intrinsic Dissolution Rate at 25oC in HCl (pH
2.0) = 16-18mg/min/mL
in the solid oral dosage form1
Drug absorption is also unlikely to be SCHEMATIC PROTOCOL
dissolution rate limiting when the
Intrinsic Dissolution Rate at 25oC in
HCl (pH 2.0) is greater than DRUG
Different Particle
1mg/min/mL.2 size do not readily
Evaluating the dissolution rate Dissolution Profile
effect dissolution
Drug Substance
differences between the dissolution profile
profiles of the active dug substance
and the compressed tablets
Active's dissolution profile
authenticates the optimisation of the gives optimum reference High drug solubility
formulation and blending process. for DC tablet dissolution >0.55g/mL

Dissolution differences in the profiles

between the drug substance, the pre-
compression powder blend and the BLEND
directly compressed oral tablets Particle size
Dissolution Profile did not effect
highlight the level of optimization Powder Blend dissolution
achieved during overall development. or content
Assays show that at each time interval uniformity
(10, 20, 30, and 45 minutes) little
differences exist between the fine, Drug Dissolution Profile
shows compression
medium and course particle sizes of impact on DC Tablets
three similar crystal polymorphs.
Furthermore the dissolution profile for
the highly soluble active drug TABLET
substance and the DC tablets were Particle size
similar at each sampling interval. Dissolution Profile did not effect
of DC Tablet dissolution
Dissolution Conditions set: Paddle, RPM 50, 600mL or content
Purified Water; UV Detector 322 nm). uniformity
Table 1 shows the dissolution rate of active drug
substance of three polymorphs Phase I, II, III,
(Median Particle size:- 13µm, 23µm & 55µm)
Table 2 shows the dissolution rate of the active drug Dissolution Profile
substance formulated in the pre-compression
similar to active
powder blend.
Table 3 shows the dissolution rate of the active drug
drug substance
substance formulated in the direct compression
tablets

Handbook of Pharmaceutical Sect: 16.

16 50 Generic Development
TABLETS ORAL DISSOLUTION & B I O S T U D Y CHAPTER
16

DISSOLUTION PARAMETERS IN
VERY SOLUBLE ACTIVES
ESTABLISHING A CORRELATION BETWEEN
Drug substance, Powder Blend & Compressed Tablets
Table 1
DRUG SUBSTANCE - DISSOLUTION PROFILE
Percentage assay ketorolac tromethamine dissolved in:-
Method SI-00-00 Edition #00-00 RPM 50 Paddle 600mL Water
Median
10 min 20 min 30 min 45 min
Particle
size
13 85.0 ± 7.1 92.0 ± 3.8 96.0 ± 2.1 98.5 ± 1.1
23 84.0 ± 5.5 88.0 ± 4.2 91.0 ± 3.1 93.0 ± 2.1
55 87.0 ± 7.2 93.0 ± 3.4 96.0± 2.5 98.0 ± 0.9
Solubility at 25oC in water (pH6.8) = 0.55g/mL
Intrinsic Dissolution Rate at 25oC in HCl (pH2.0)= 16-18mg/min/mL
Ketorolac tromethamine has five polymorphic forms [XRD/DSC]; crystal forms I - IV and one
amorphous form. Crystal forms I, II and III have very similar crystal lattice energies, melting
points (162oC), solubilities and intrinsic dissolution rates.

DISSOLUTION OF FINAL POWDER BLEND (uncompressed)

Table 2
POWDER BLEND - DISSOLUTION PROFILE
Method SI-00-00 Edition #00-00 RPM 50 Paddle 600mL Water
Percentage active dissolved in:-
Median
10 min 20 min 30 min 45 min
Particle
size
13 83.9 ± 6.2 90.5 ± 2.9 94.8 ± 1.9 97.8 ± 1.1
23 85.1 ± 4.1 89.0 ± 3.3 90.2 ± 2.4 95.0 ± 1.6
55 86.0 ± 6.2 91.9 ± 3.7 95.6± 2.1 99.1 ± 1.1

DC TABLET DISSOLUTION PROFILE (compressed)

Table 3
DRUG PRODUCT - DISSOLUTION PROFILE
Percentage active dissolved in:-
Method SI-00-00 Edition #00-00 RPM 50 Paddle 600mL Water

10 min 20 min 30 min 45 min

UNIT 1 94.0 99.0 99.0 99.8
UNIT 2 73.0 83.0 99.0 100.20
UNIT 3 95.0 97.0 99.0 99.9
UNIT 4 69.0 75.0 85.0 91.0
UNIT 5 67.0 92.0 63.0 98.0
UNIT 6 93.0 99.0 99.0 99.0
X¡-Mean 82.0 91.0 95.0 98.0
RSD¡ 15 10 6 4

References - 1. Berge, SM., Bighly, L.D., & Monkhouse, D.S., J. Pharm Sci. 66 (1977) p1-192.
Current Conceps in Pharmaceutical Sciences Dosage form Design and Bioavailability, Swarbrick
Lea & Febiger (1973, 18)

Handbook of Pharmaceutical Sect: 16.

16 51 Generic Development
 TABLETS ORAL DISSOLUTION & B I O S T U D Y CHAPTER
16

Food-Effects
IN BA-BE Studies
FOOD and FED STUDIES
IMPACT OF 'FOOD EFFECTS" IN BA-BE STUDIES

I n October 1997, the FDA issued for

comment, an eight page draft Preapproval Food Effect
guidance titled 'Food-Effect Studies need to show
Bioavailability and Bioequivalent
Studies',
ANDA formulations
The guidance highlights the type and same as RLD
potential number of biostudies that are Food-Effect Bioavailability
required for both NDAs and ANDAs.
Almost twelve months later, the and Bioequivalence Studies
essence of the guidelines are as
follows: INTRODUCTION
This document provides guidance to
FDA's Oct.1997 sponsors of new drug applications
Draft Guidance (NDAs), abbreviated new drug
Highlights Study Types applications (ANDAs), and abbreviated
antibiotic drug applications (AADAs)
The Draft Guidance to industry is who intend to conduct food-effect
intended not only to recommend when a bioavailability (BA) and bioequivalence
food study is advisable but when both (BE) studies for oral immediate release
FOOD and FASTING studies should be (IR) or modified release (MR) dosage
undertaken. forms.
The guidance includes recommen- BA and BE studies are generally
dations on BA and BE Food Effects, conducted to meet regulatory
including study design, statistical data requirements delineated in 21 CFR 320
analysis, waivers, dissolution and the (see also 314.94(a)(7)).
potential impact on immediate and They are performed during the
modified release oral dosage forms. preapproval phase for NDAs and
This chapter reviews the proposed ANDAs and also postapproval under
guidance as it exists some twelve certain circumstances.
months after initial issue and correlates The BA/BE guidance provides
the impact on other guidance issued recommendations for study design,
before and after this guideline. The data analysis, and labeling, and
guidance to industry covers all drug indicates situations in which food-effect
types namely, INDs, NDAs and ANDAs. BA/BE studies may not be important.

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performed during the IND (Notice of

DISCUSSION Claimed Investigational Exemption for a
A. Potential Causes of Food-Effects New Drug) stage to determine whether
coadministration of food affects the BA
Food induces changes in the
of the drug substance and/or the
physiology of the gastrointestinal tract. release of the drug substance from the
Physiological changes induced by food drug product.
can result in delayed gastric emptying,
stimulation of bile flow, changes in pH, If a food effect (e.g., a change in
and increase in splanchnic blood flow. pharmacokinetic parameters or a
change in safety and efficacy) is
Food can also alter lumenal observed, the effect should be
metabolism and physically or considered when designing clinical
chemically interact with a drug studies.
substance.
The impact of any observed food
The effects of food on BA and BE effects and dosing instructions relative
depend on:- to meals should be specified in the
Ø the physico-chemical (solubility) labeling.

Ø pharmacokinetic (site, rate, and C. Food-Effect BE Studies

extent of absorption, first pass Preapproval
metabolism)
For ANDAs/AADAs during the
Ø properties of the drug preapproval period, food-effect BE
studies could be important to ensure
Ø the dissolution of the drug that the effects of food on the
substance from the drug product. ANDA/AADA formulation are the same
as that on the formulation of the
Different Procedures for reference listed drug (RLD).

Bioavailability and D. Food-Effect BE Studies

Bioequivalence Studies Postapproval
The effects of coadministration of For both NDAs and ANDAs/AADAs, the
meals with drugs is maximal when the performance of food-effect BE studies
drug product is administered should be considered during the
immediately after completion of a meal. postapproval period when scale-up and
The nutrient content, fluid volume, postapproval changes (SUPAC) are of
temperature, and caloric content of such magnitude that redocumentation
meals influence the magnitude of of BE is considered important under
physiological changes that could affect both fed and fasted conditions.
drug absorption. Generally, postapproval food-effect
Meals that are high in calories, fat, and studies will be important only for
density are likely to provide the greatest changes in components and/or
effects on BA. composition and for major changes in
the manufacturing process (referred to
B. Food-Effect BA Studies — subsequently in this guidance as
Preapproval formulation and processing factors).
Food-effect BA studies can be

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E. When Food-Effect BA/BE Sponsors must motivate

Studies May Not Be Important why a Food Effect Study
Once a primary food-effect BA study is not warranted
has been conducted, subsequent food-
effect studies during the IND phase, For a drug product, the diagnostic
food-effect BE studies for ANDAs / factors include:-
AADAs and postapproval food-effect
BE studies for NDAs, ANDAs/AADAs (1) rapidly dissolving drug product (e.g.,
may not always be important. Case A specifications in SUPAC IR)
(2) in-vitro dissolution characteristics
Perform Food Effect similar in different pH media and
studies when rotation speeds for basket or paddle in
formula and processing USP 23 Apparatus 1 or 2.

factors are implicated These characteristics should be

present to obviate redocumentation of
Specifically, if the effect of food is food-effect BA or BE.
primarily on absorption of the drug If all these characteristics are not
substance, subsequent food effect present, sponsors should provide
BA/BE studies should be performed justification for why a food-effect BA or
only when the effect of food is likely to BE study is not important.
arise from formulation and / or
processing factors. III. STUDY CONSIDERATIONS
Also, for ANDAs / AADAs, food-effect Primary studies to assess the effect of
studies should not be performed food on the BA/BE of the drug
routinely based solely on a labeling substance and the release of the drug
statement for the RLD describing a food substance from the drug product should
effect or specifying administration in be conducted according to the design
relation to meals. proposed in this guidance.
Certain drug substance and IR drug Additional studies using different meals
product characteristics, referred to and different times of drug intake in
subsequently in this guidance as relation to meals may be important to
diagnostic factors, can be used to amplify the information from these initial
determine whether additional food- studies and to provide optimal labeling
effect studies are important. statements for dosage and
For a drug substance, these administration. Alternate approaches
diagnostic factors include: can be used with appropriate
n (1) high drug solubility across the justification.
intended dose range; [A] GENERAL DESIGN
n (2) high drug permeability across the A randomized, balanced, single-dose,
intended dose range (e.g., oral two-treatment, two-period, two-
absorption greater than 90%); and sequence crossover is recommended
n (3) minimal or no effect of inactive for food-effect BA studies designed to
ingredients on absorption of the drug assess the effects of food on either the
substance in the fasted state (i.e., BE drug substance/and or the release of
shown between the test formulation and the drug substance from the drug
a simple solution or suspension). product.

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Fasted and Food BA However, early studies often use a

Studies are done on the formulation that is different from that to-
same subject set be-marketed.
In such cases, using the above-
The formulation to be tested should be described diagnostic factors, the NDA
administered under fasted conditions in sponsor should assess whether an
one treatment and immediately identified food effect suggests that
following a test meal (fed condition) for further studies should be performed
the other treatment. with subsequent changes in formulation
The recommended study design should and / or processing.
be adjusted if the primary purpose of
the study is to ascertain the effects of Carefully evaluate
food on the absorption of the drug if Food-Effect is solely
substance. In this case, the drug
substance can be administered in a
due to the Active
simple solution or suspension
formulation. If it is reasonable to conclude that the
food effect is due to the drug substance
A similar design is recommended for a and not the formulation and/or
food-effect BE study except that the
processing factors, additional food-
treatments consist of the test
effect studies may not be important,
formulation and the RLD formulation
even with major formulation and/or
administered under fed conditions.
process changes for IR dosage forms.
An adequate washout period should
separate the two treatments.
ANDAs for IR Products:
Food BE Studies are for When a food effect is believed to be
Test & Reference related to the drug substance and not
comparisons the formulation and/or processing
[B]. SUBJECT SELECTION factors, ANDA food-effect studies on IR
formulations may not be important.
Food-effect BA and BE studies are
usually carried out in healthy human When such information is unavailable,
volunteers. An adequate number of the test and RLD products should be
subjects should complete the study so compared under fed conditions in
as to achieve sufficient power for addition to the comparison under fasted
appropriate statistical assessment (see condition.
section on Data & Statistical Analysis),
but should not be fewer than 12. Once drug-specific guidances are
[C]. DOSAGE FORM SELECTION developed, they will provide
suggestions for the need of food-effect
NDAs for IR Products: BE studies.
Food-effect information should be
provided on the to-be-marketed As noted, scientific information should
formulation. A food-effect study lead to a need for a food-effect BE
conducted early in drug development study, not the presence or absence of a
could be useful to optimise dosing in food-effect statement in labeling of the
clinical trials. RLD.

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NDAs for MR Products: For ANDAs, the lot and strength tested
in the pivotal BE fasted study should be
Information on food effects should be
tested in the food-effect BE study.
obtained for the to-be-marketed When multiple strengths of MR drug
formulations of all NDAs for MR products are intended for marketing
products. and the food-effect BA or BE study is
Additional studies during MR performed on one of these strengths,
formulation development can be invitro dissolution testing should be
undertaken by sponsors who wish to conducted for all other strengths in
distinguish between food effects due to three different pH media.
drug substance versus effects due to Similarity of dissolution should be
formulation and/or processing factors. established in accordance with the f2
Major postapproval changes in test specified in SUPAC guidance
formulation and/or processing leading documents. Lack of similarity of
to a recommendation for a fasted BE dissolution could indicate that
study (see SUPAC-MR) should be additional food-effect studies should be
accompanied by a food-effect BE study. performed using other strengths.
Sponsors should provide justification ANDAs CR/DR/MR need
for not conducting this postapproval
study. 12 point Dissolution
MR/CR/DR ANDAs Similarity Testing
Require Fasted [D]. TEST MEAL
and Fed Studies The primary food-effect BA and BE
study should be conducted under
ANDAs for MR Products: conditions expected to provide maximal
All ANDAs for MR formulations should perturbation due to presence of food in
establish, in addition to BE under fasted the GI tract.
conditions, BE to the RLD formulation A high fat (approximately 50% of total
under fed conditions. caloric content of the meal), high calorie
Major postapproval changes in (approximately 1000 calories) breakfast is
formulation and/or processing involving therefore recommended as a test meal for
a fasted BE study should be food-effect BA and BE studies.
accompanied by a food-effect BE study. A representative example is 2 eggs fried in
Sponsors should provide justification for butter, 2 strips of bacon, 2 slices of toast
not conducting this postapproval study. with butter, 4 ounces of hash brown
Strength: potatoes, 8 ounces of whole milk (i.e.,
approximately 150 protein calories, 250
Generally, the highest strength of a carbohydrate calories, 500-600 fat
product should be tested in food-effect calories).
BA and BE studies. In some cases,
clinical safety concerns could warrant
use of lower strengths of the dosage Alternative meals with equivalent
form. nutritional content can be used. Details
of the meal should be recorded prior to
Highest Dosage Strength the study and provided in the study
is normally chosen report. The sponsor should provide a
scientific rationale, if the selected meal
For The Food-Effect BE is not high in calories and fat.

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In BA Food Effect Studies In such instances, sampling times

should be adjusted to obtain the
the Fasted Study complete plasma concentration-time
serves as the Reference profile.
[E]. ADMINISTRATION [G]. DATA AND STATISTICAL
ANALYSIS
Fasted treatments: Following an
overnight fast of at least 10 hours, The following measurements should be
subjects should take the drug product obtained from the resulting
with 180 ml (6 fl oz) of water. concentration-time profiles:
No food should be allowed for at least Ü Area under the concentration-time
4 hours post-dose. Water can be curve (AUC0-∞ , AUC0-t )
allowed ad libitum after 2 hours. Ü Peak concentration (C ) max
Scheduled standardized meals should
be served throughout the remaining Ü Time to peak concentration (t ) max

study period. Ü Lag-time (t ) for delayed release

lag

products
Fed treatments:
Following an overnight fast of at least Individual subject parameters, as well
10 hours, subjects should be served the as summary statistics (e.g., group
test meal and ingest this meal within 30 averages, standard deviations,
minutes. The drug product should be coefficients of variation, 90%
administered with 180 ml (6 fl oz) of confidence intervals [CI]) should be
water immediately (within 5 minutes) reported.
after completion of the meal.
In food-effect BA studies, the fasted
No food should be allowed for at least treatment serves as the reference. In
4 hours post-dose. Water can be
food-effect BE studies, the RLD product
allowed ad libitum after 2 hours.
Subjects should be served scheduled administered under fed conditions
standardized meals throughout the serves as the reference.
remaining study period.
The results for food-effect BA studies
[F]. SAMPLE COLLECTION will be evaluated according to the
For both treatment periods, timed following options:
biological fluid samples should be In BE Food Effect
collected from the subjects to permit
characterization of the complete plasma
the RLD Fed Study
concentration-time profile for drug is the reference
and/or metabolites. Food Effect Absent: Absence of a
food effect will be concluded when the
For Delayed Release 90% CI for the ratio of means
(Enteric Coated) Adjust (population geometric means based on
log-transformed data) of fed and fasted
blood sampling times treatments fall within 80%-125% for
Caution should be used when studying AUC and 70%-143% for Cmax
MR dosage forms (e.g., enteric coated Food Effect Documented: A food
products) where coadministration with effect will be concluded when the 90%
food can delay in vivo drug release. CI for the ratio of means (population

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geometric means based on log- (a). Food Effect Absent

transformed data) of fed and fasted When absence of a food effect is
treatments fall outside 80%-125% for documented, product labeling should
AUC and 70%-143% for Cmax. state that a food effect was not present.
Clinical relevance of the observed
magnitude of effect is indicated by the
If co-administration with food is
otherwise clinically beneficial, the
sponsor.
DOSAGE AND ADMINISTRATION
Food Effect Indeterminant: section of the labeling should provide
When a food effect is neither absent appropriate instructions.
nor documented according to the above
criteria, a food effect should be (b). Food Effect Documented
concluded to be indeterminant. When a food effect is documented, the
Clinical relevance of the observed dosage and administration section of
magnitude of effect should be indicated the labeling should indicate the
by the sponsor. magnitude of food-effect on AUC and
Cmax & discuss the clinical relevance.
For NDAs, clinical relevance of a
possible (indeterminant) or documented (c). Food Effect Indeterminant
food effect should be addressed by When a food effect is indeterminant,
sponsors in the product labeling (see the DOSAGE AND ADMINISTRATION
section on NDA labeling, below). section of the labeling should indicate
For ANDAs, an equivalent food effect the magnitude of the food effect on
will be concluded when the 90% CI for AUC and Cmax (unless population mean
the ratio of means (population differences are < 10%) and the clinical
geometric means based on log- relevance should be discussed.
transformed data) of the test and RLD In general, the DOSAGE AND
fall within 80-125% for AUC and 70- ADMINISTRATION section of the
143% for Cmax . labeling should provide the optimal
ANDAs are instructions for drug administration in
Equivalent for relation to food.

80% - 125% AUC (d).Other Labeling Considerations

Study Design:
& Study design can be described in the
appropriate labeling sections, when
70% - 143% Cmax relevant.
If these CI criteria are not satisfied, the Formulation:
If the formulation tested in a food-effect
test formulation might not be study differs from the formulation to be
considered equivalent to and marketed, but the two drug products can
interchangeable with the RLD. be expected to perform similarly under fed
For both NDAs and ANDAs, clinical conditions (see Discussion section), the
relevance of any change in tmax and t lag lack of food effect should be noted in the
should be considered. labeling.
The label, however, should state the
IV. NDA LABELING specific formulation tested in the food-
effect study. If there is insufficient
Regulations pertaining to labeling information to assume that the food effect
requirements can be found in 21 CFR is due to the drug substance and not
201. Some general recommendations formulation factors, labeling should state
on how to address food effects in the that information on food effects unavailable
labeling in NDAs are discussed below. for the to-be-marketed formulation 4

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SIDE-BY-SIDE COMPARISON
BA & BE FOOD EFFECT STUDIES

BA FOOD EFFECT BE FOOD EFFECT

STUDIES STUDIES

Fasted
& Food
NDA ANDA
conducted
STUDIES STUDIES
on SAME
B/E Batch

REFERENCE STUDY REFERENCE STUDY

is the FASTED STUDY is the RLD FED STUDY

FOOD EFFECT PRESENT

for NDAs with metrics of:- EQUIVALENT METRICS
80 - 125% AUC for ANDAs are
& 70 - 143% Cmax 80 - 125% AUC
are OUTSIDE the LIMITS & 70 - 143% Cmax
90%CI
FOOD EFFECT ABSENT
for NDAs with metrics of:-
80 - 125% AUC Immediate Release ANDAs
& 70 - 143% Cmax Note: Dissolution Studies:
are INSIDE the LIMITS n Dissolution Similarity Testing
n Normally Fasted Studies
n One Single Dose Study only
n On Highest Dosage Form
NDA Labeling n Waivers on lower strengths
REQUIREMENTS

Address effect of Food

Absent
Present
Food effects related to Drug
Indeterminant Substance & NOT formulation or
(Effect on AUC and Cmax) processing may not be significant

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ANALYTICAL VALIDATION
GUIDANCE FOR INDUSTRY

Bioanalytical Method
Validation for Biostudies
‘…designed for all biostudies and applies specifically to
generic comparative bioequivalency studies…

clinical pharmacology, bioavailability

IMPACTS ON GENERIC BIOSTUDIES
(BA), and bioequivalence (BE)
Bioanalytical Methods Validation for studies.
Human Studies
This guidance does not address
DRAFT GUIDANCE analytical methods used for non-human
U.S. Department of Health and Human Services Food and pharmacology/toxicology studies, CMC
Drug Administration Center for Drug Evaluation and Research information, or in vitro dissolution
(CDER) December 1998 BP #
studies. Date of Guidance Dec. 1998
TABLE OF CONTENTS Instrumentation
I. INTRODUCTION The information in this draft guidance
II. BACKGROUND is generally applicable to gas
III. REFERENCE STANDARD chromatography or high-pressure liquid
IV. PRE-STUDY VALIDATION chromatography analytical methods
[a]. Specificity performed on drugs and metabolites
[b]. Calibration Curve obtained from biological matrices such
[c]. Precision, Accuracy, and as blood, serum, plasma, or urine.
Recovery
[d]. Quality Control Samples
Methodology
[e]. Stability This guidance should also apply to
[f]. Acceptance criteria other analytical techniques such as
V. IN-STUDY VALIDATION immunological and microbiological
VI. DOCUMENTATION methods or other biological matrices,
REFERENCES such as tissue samples including skin
samples, although in these cases a
I. INTRODUCTION higher degree of variability may be
This guidance provides assistance to observed.
sponsors and applicants of II. BACKGROUND
investigational new drug applications
(INDs), new drug applications (NDAs), Selective and sensitive analytical
abbreviated new drug applications methods for the quantitative
(ANDAs), and supplements, in determination of drugs and their
developing validation information for metabolites (analytes) are critical for
bioanalytical methods used in human successful performance of clinical
pharmacology, BA, and BE studies.

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Analytical method validation includes Minor Changes:

all of the procedures recommended to For minor modifications, such as a
demonstrate that a particular method change in the ratio of solvents for
for the quantitative measurement of an elution, a change in buffer system, the
analyte in a given biological matrix, number of extractions of the biological
such as blood, plasma, serum, or urine, matrix, or a small change in column
is reliable and reproducible. temperature to obtain better separation,
The parameters essential to this only limited validation may be
validation include: recommended.
[1] ×AccuracyØ Major Changes:
[2] ×PrecisionØ For major modifications, such as
[3] ×SensitivityØ change of an instrument, solvent
[4] ×SpecificityØ system, detector, or temperature, full
[5] ×LinearityØ and validation of the modified method
[6] ×ReproducibilityØ. should be performed.
The analytical laboratory conducting
In addition, the stability of the analyte
BA and BE studies should closely
in the matrix under study storage
adhere to FDA’s Good Laboratory
conditions should be determined.
Practices (GLPs) (21 CFR Part 58) and
[7 ×Analyte StabilityØ. to sound principles of quality assurance
Validation involves documenting throughout the testing process. In
through the use of specific laboratory addition, the analytical methods for in
investigations that the performance vivo bioavailability studies must meet
characteristics of the method are the criteria in 21 CFR 320.29.
suitable and reliable for the intended The analytical laboratory should have
analytical applications (Shah 1992, Taylor a written set of standard operating
1983).
procedures (SOPs) to ensure a
The acceptability of analytical data complete system of quality assurance.
corresponds directly to the criteria used The SOPs should cover all aspects of
to validate the method.
analysis from the time the sample is
Published methods of analyte analysis collected and reaches the laboratory
are often modified to suit the until the results of analysis are
requirements of the laboratory reported.
performing the assay.
Written SOPs
Minor Changes for methodology
Ø = Limited validation Security &
Major Changes Chain of Custody
Ø= Full validation
They also should include record
These modifications should be keeping, security and chain of sample
validated to ensure suitable custody (accountability systems that
performance of the analytical method. ensure integrity of test articles), sample
W hen changes are made to a preparation, and analytical tools, such
previously validated method, the as methods, reagents, equipment,
analyst should exercise judgement as instrumentation, and procedures for
to how much additional validation is quality control and verification of
needed. results.

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The process by which a specific (3) Other materials of documented

analytical method is validated may be purity custom-synthesized by an
divided into:- analytical laboratory or other non-
(1) reference standard preparation commercial establishment.
(2) pre-study validation for analytical The source and lot number, certificates
method development and method of analyses when available, and/or
establishment, and internally or externally generated
(3) in-study validation to include study evidence of identity and purity should
performance, drug analysis, and be furnished for each reference
acceptance criteria (Shah 1992, Brooks standard.
1985).
A master standard (a synthetic batch
SAMPLE INTEGRITY for which identity and purity are clearly
established and acceptable) should be
from fluid withdrawal maintained for each reference
to reporting results standard. All subsequently synthesized
is CRITICAL batches are to be compared
chromatographically with that master
These three processes are described standard.
in the following sections of the
guidance:- REFERENCE MATERIALS
III. REFERENCE STANDARD Must Be Free
Analysis of drugs and their metabolites of
in a biological matrix is invariably INTERFERING
carried out using samples spiked with
calibration standards and quality PEAKS
control (QC) samples. All reference materials should be
The quality of the reference standard checked prior to use to determine if
used to prepare spiked samples can there are significant interfering
affect study data. chromatographic peaks at the retention
For this reason, an authenticated time of the analyte and / or the internal
analytical reference standard should be standard, using the analytical
used to prepare solutions of known procedure to be used in the study.
concentrations. IV. PRE-STUDY VALIDATION
If possible, the reference standard Pre-study validation should include
should be identical to the analyte.
analytical method development and
W hen this is not possible, an documentation.
established chemical form (free base or
acid, salt or ester) of known purity can Bioassays
be used as a surrogate. to be
Reference standards VALIDATED
Three types of reference standards are prior to the
usually used:-
(1) Certified reference standards (e.g.,
BIOSTUDY
USP compendial standards); Validation should be performed for
(2) Commercially supplied reference each biological matrix and for each
standards obtained from a reputable chemical species to be measured in the
commercial source; and / or biological matrix (Shah 1992, Buick 1990).

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Pre-study Validation those obtained with an aqueous

In addition, the stability of quality solution of the analyte at a
control samples and the analyte in concentration near the limit of
spiked samples should be determined. quantitation (LOQ).
Typical performance parameters that Any blank sample with significant
should be assessed during pre-study interference at the retention time of the
validation include: drug, metabolites, or internal standard
should be rejected.
(1) Specificity,
(2) Calibration curve and its linearity, BLANK SAMPLES
(3) Precision, accuracy, recovery, are compared with
(4) Quality control samples,
(5) Stability of analyte in spiked
ANALYTE / METABOLITE
samples, at the
(6) Acceptance criteria. Quantitation Level [QL]
A. Specificity If more than 10% of the blank samples
Specificity is the ability of an analytical exhibit significant interference at these
method to differentiate and quantitate retention times, additional matrix blank
the analyte in the presence of other samples should be tested.
constituents in the sample and refers If more than 10% of this subsequent
directly to the ability of the method to group of blank samples still shows
produce a response for a single analyte interference, the method should be
(Karnes 1991). changed to eliminate the interference.
Bioassays Potential interfering substances in a
biological matrix include endogenous
must be matrix components, metabolites,
SPECIFIC decomposition products, and, in the
actual study, concomitant medication.
for ACTIVE Potential interference from nicotine
and METABOLITE and common OTC drugs and
metabolites, such as caffeine, aspirin,
For specificity, analyses of blank
acetaminophen, and ibuprofen should
samples of the appropriate biological
be routinely tested.
matrix (plasma, urine, or other matrix)
should be obtained from six Potential Interfering
individuals under controlled PEAKS
conditions, with reference to time of
day, food ingestion, and other factors from common OTCs
considered important in the intended are routinely evaluated
study.
Each blank sample should be tested If the method is intended to quantitate
for interference using the proposed more than one analyte, each analyte
extraction procedure and should be injected separately to
chromatographic or spectroscopic determine its retention time and to
conditions. ensure that impurities from one analyte
do not have the same retention time as
The results should be compared to another analyte.

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B. Calibration Curve - No interference present in blanks at

Calibration is the relationship between the retention time of the analyte at this
instrument response and known concentration, or typical response at
concentrations of the analyte. this concentration at least five times
A calibration (standard) curve should greater than any interference in blanks
be generated for each analyte in the at the retention time of the analyte
sample. - Analyte peak (response) identifiable,
A sufficient number of standards discrete, and reproducible with a
should be employed to adequately precision of 20% and accuracy of 80 -
define the relationship between 120% - (Shah 1992).
concentration and response. 2. Linearity
A calibration curve should be prepared The simplest workable regression
in the same biological matrix as the equation should be used with minimal
samples in the intended study by or no weighting. Selection of weighting
spiking with known concentrations of and use of a complex regression
the analyte. equation should be justified.
Precautions should be taken to avoid CALIBRATION CURVES
precipitation while spiking the biological Four factors should be met in
matrix.
developing a calibration curve:-
The number of standards used in - ≤20% deviation of the LOQ from
constructing a calibration curve will be nominal concentration (Shah 1992)
a function of the anticipated range of - ≤15% deviation of standards other
analytical values and the nature of the than LOQ from nominal concentration
analyte / response relationship. (Shah 1992)
Concentrations of standards should be - At least four out of six non-zero
chosen on the basis of the standards meeting the above criteria,
concentration range expected in a including the LOQ and the calibration
particular study. standard at the highest concentration
A calibration curve should consist of a - 0.95 or greater correlation
blank sample (matrix sample coefficient (r)
processed without internal standard), a C. Precision, Accuracy, and
zero sample (matrix sample processed
with internal standard), and five to eight Recovery
non-zero samples covering the The precision of an analytical
expected range, including lower LOQ. method describes the closeness of
Blank and standard zero samples individual measures of an analyte when
should not be used in the calibration the procedure is applied repeatedly to
function, but should only serve to multiple aliquots of a single
evaluate interference. homogeneous volume of biological
matrix.
Additional factors in developing a Precision should be measured using a
calibration curve relate to LOQ and
minimum of five [5] determinations per
linearity.
concentration.
1. Limit of Quantitation (LOQ)
A minimum of three [3] concentrations
The lowest standard on the calibration in the range of expected concentrations
curve should be accepted as the limit of is recommended.
quantitation if the following conditions The precision determined at each
are met: concentration level should not exceed

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15% coefficient of variation (CV) except Recovery experiments should be

for the LOQ where it should not exceed performed by comparing the analytical
20% CV. results for extracted samples at three
Precision is further subdivided into concentrations (low, medium, and high)
within-day, intra-batch precision or with unextracted standards that
reproducibility, which assesses represent 100% recovery.
precision during a single analytical run,
and between-day, inter-batch D. Quality Control Samples
precision or reproducibility, Pre-study validation of an analytical
[ruggedness] which measures method should be carried out using at
precision with time & involves different least three batches of biological matrix,
analysts, equipment, reagents, & where each batch is collected from a
laboratories (Shah 1992, USP XXII '90, Brooks 1985) different source. Each batch should
Accuracy contain:
The accuracy of an analytical
[1] A calibration curve constructed
using a blank sample, zero sample, and
method describes the closeness of test
five to eight non-zero standards,
results obtained by the method to the
true value of the analyte. [2] LOQ quality control samples,
Accuracy is determined by replicate [3] Low QC samples,
analysis of samples containing known [4] Medium QC samples,
amounts of the analyte. [5] High QC samples,
A minimum of five [5] determinations [6] A matrix blank sample,
per concentration should be conducted [7] A reference standard.
for a minimum of three [3]
concentrations in the range of expected Quality control samples at
concentrations. concentrations noted below should be
The mean value should be within 15% made from a stock solution separate
of the actual value except at LOQ, from that used to prepare the
where it should not deviate by more standards.
than 20%. The deviation from the true LOQ QC sample: Same concentration
value serves as the measure of as the lowest non-zero standard
accuracy (USP XXII 1990, Brooks 1985). Low QC sample: #3 x LOQ
Recovery Medium QC sample: Approximately
The recovery of an analyte in an midway between the high and low QC
assay is the detector response concentrations
obtained from an amount of the analyte High QC sample: 75 to 90% of highest
added to and recovered from the calibration standard
biological matrix, compared to the The accuracy of preparation of
detector response obtained for the pure calibration and QC samples should be
authentic standard (Brooks 1985,Mehta 1989) checked with the first batch.
Recovery pertains to the extraction The data from replicate analyses of QC
efficiency of an analytical method within samples and duplicate analyses of
the limits of variability. reference standards should be used to
Although recoveries close to 100% are obtain the intra-day (within batch)
desirable, the extent of recovery of an precision, inter-day (between batch)
analyte and/or the internal standard may precision, accuracy, and recovery.
be as low as 50 to 60% if the recovery is To obtain within-batch data, the mean,
precise, accurate, and reproducible.
standard deviation, and CV of each QC

Handbook of Pharmaceutical Sect: 16.

16 65 Generic Development
TABLETS ORAL DISSOLUTION & B I O S T U D Y CHAPTER 16

concentration in each batch should be the analyte in the appropriate analyte-

calculated. free, interference-free biological matrix.
The global (overall) mean, standard Stock solutions of the analyte for
deviation, and CV for each QC stability evaluation should be prepared
concentration from the three batches in an appropriate solvent at
should be calculated to obtain concentrations defined in the method
between-batch data. SOP. Further information about
Precision is indicated by the %CVs. validation for these factors appears in
Percent accuracy is determined by the following five sections of the
dividing the mean concentration of a guidance.
QC by its nominal concentration, and 1. Freeze and Thaw Stability
multiplying by 100. Testing for freeze and thaw analyte
E. Stability stability should be determined during
three freeze and thaw cycles.
Drug stability in a biological fluid is a
function of the storage conditions, the
At least three aliquots at each of the
chemical properties of the drug, the low and high concentrations should be
matrix, and the container system. stored at -20oC, or the intended storage
temperature, for 24 hours and thawed
The stability of an analyte in a
unassisted at room temperature.
particular matrix and container system
is relevant only to that matrix and W hen completely thawed, the samples
container system and should not be should be transferred back to the
extrapolated to other matrices and original freezer and kept refrozen for 12
container systems. to 24 hours. The cycle of thawing and
freezing should be repeated two more
ANALYTE STABILITY times, then analyzed on the third cycle.
is evaluated at Three
u Frozen u u Freeze Thaw u
u Freeze Thaw u are proposed
and If an analyte is unstable at -20o C, the
u Ambient Conditions u stability sample should be frozen at -70
o
C during the three freeze and thaw
Stability procedures should evaluate cycles (Shah 1992, Buick 1990).
the stability of the analytes in biological 2. Short-Term Room Temperature
fluids after long-term (frozen at the Stability
intended storage temperature and
conditions) and short- term (bench top, Three aliquots of each of the low and
room temperature and conditions) high concentrations should be thawed
storage, and after going through freeze at room temperature and kept at this
and thaw cycles and the analytical temperature from 4 to 24 hours (based
process. on the expected duration that samples
will be maintained at room temperature
The procedure should also include an in the intended study) and analyzed
evaluation of analyte stability in stock (Buick 1990).
solution (Buick 1985, Pachla 1989).
3. Long-Term Stability
All stability determinations should use
a set of standard samples prepared The storage time in long-term stability
from a freshly made stock solution of evaluation should exceed the time
between the date of first sample

Handbook of Pharmaceutical Sect: 16.

16 66 Generic Development
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collection and the date of last sample The stability of both the drug and the
analysis. internal standard should be evaluated
Long-term stability should be in validation samples under these
determined by storing at least three conditions by determining
aliquots of each of the low and high concentrations on the basis of original
concentrations under the same calibration standards.
conditions as the study samples. Although the traditional approach of
A suggested storage temperature for comparing analytical results for stored
the majority of drugs and metabolites in samples with those for freshly prepared
a biological matrix is -20 C, but lower samples has been referred to in this
temperatures (e.g., -70 C) may be guidance, other statistical approaches
recommended to prevent degradation based on confidence limits are also
problems observed at higher available for the development of SOPs
temperatures. for evaluation of an analyte’s stability in
The volume of samples should be a biological matrix - (Timm 1985).
sufficient for analysis on three
occasions. SOPs to describe
The concentrations of all the stability Statistical methodology
samples should be compared to the
mean of back calculated values for the and rules used
standards at the appropriate
concentrations from the first day of
W hatever approach is used, the SOPs
should clearly describe the statistical
long-term stability testing (Buick 1990).
method and rules employed. Additional
4. Stock Solution Stability validation may include investigation of
The stability of stock solutions of drug samples from dosed subjects.
and the internal standard should be F. Acceptance Criteria
evaluated at room temperature for at
An analytical method is considered fully
least 6 hours. validated when it meets the following
The stability samples should then be criteria:
refrigerated or frozen for 7 to 14 days Precision: The between-batch CVs for
or other relevant period. low, medium, and high concentrations
After completion of the desired storage should be ≤15%, and ≤20% for the
time, the stability should be tested by LOQ QC, using a minimum of three
comparing the instrument response batches.
with that of freshly prepared solutions Accuracy: The between-batch mean
(Buick 1990). value should be within ±15% of the
nominal value at low, medium, and high
5. Autosampler Stability
QC concentrations and should not
The stability of processed samples in deviate by more than ±20% at the LOQ.
the auto-sampler should be determined
at the auto-sampler temperature that Sensitivity: The lowest standard
will be used during analysis, which is should be accepted as the limit of
usually room temperature, but may quantitation of the method if the
sometimes be a lower temperature between-batch CV at the LOQ QC is
(e.g., when a refrigerated auto-sampler ≤20%.
Specificity: The responses of
is used). Stability should be assessed
interfering peaks at the retention time
over the anticipated run time for the of the analyte should be less than 20%
batch size to be used in studies.
of the response of an LOQ standard.

Handbook of Pharmaceutical Sect: 16.

16 67 Generic Development
TABLETS ORAL DISSOLUTION & B I O S T U D Y CHAPTER 16

Responses of interfering peaks at the Extrapolation

retention time of the internal standard
should be ≤5% of the response of the
below LD
concentration of the internal standard should be avoided
to be used in studies. Estimation of concentration in
Stability: Long-term, short-term, freeze unknown samples by extrapolation of
and thaw, stock solution, and auto- standard curves below LOQ or above
sampler stability data should meet the the highest standard is not
criteria specified in the SOP. recommended.

V. IN-STUDY VALIDATION Instead, the standard curve should be

redefined or samples with higher
Assays of all samples of an analyte in concentration should be diluted and
a biological matrix should be completed assayed (Shah 1992).
within the time period for which stability
data are available. All Subject Samples
In general, analysis of biological should be analysed
samples can be done with a single
determination without duplicate or
in a single sitting
replicate analysis if the assay method All study samples from a subject
has acceptable variability as defined by should be analyzed in a single run.
validation data. ONCE the analytical method has been
This is true for procedures where validated for routine use, its accuracy
precision and accuracy variabilities and precision should be monitored
routinely fall within acceptable regularly to ensure that the method
tolerance limits. continues to work satisfactorily.
For a difficult procedure with a labile To achieve this objective, a number of
analyte, where high precision and separately prepared QC samples
accuracy specifications may be difficult should be analyzed with processed test
to achieve, duplicate or even triplicate samples at intervals based on the total
analyses may be recommended for number of samples.
better estimate of analyte. The QC samples in duplicate at three
A calibration curve should be concentrations;
generated for each analyte to assay - one near the LOQ (i.e., #3 x LOQ),
samples in each analytical run and it one in midrange, and one close to the
should be used to calculate the high end of the range) should be
concentration of the analyte in the incorporated in each assay run.
unknown samples in the run. The results of the QC samples provide
The spiked samples may contain more the basis of accepting or rejecting the
than one analyte. An analytical run run.
could consist of either all the processed 2/3 of QC Samples
samples to be analyzed as one batch
or a batch composed of processed should be within
unknown samples of one or more 20% of nominal value
volunteers in a study, QC samples, and At least four of the six QC samples
calibration standards. should be within ±20% of their
The calibration (standard) curve should respective nominal value.
cover the expected unknown sample Two of the six QC samples may be
concentration range in addition to a outside the ±20% of their respective
calibrator sample at LOQ.

Handbook of Pharmaceutical Sect: 16.

16 68 Generic Development
TABLETS ORAL DISSOLUTION & B I O S T U D Y CHAPTER 16

nominal value, but not both at the same

concentration. Documentation for pre-study
validation should include:
1/3 at Different Strengths
- A description of the analytical method
maybe outside
(Shah 1992, Brooks 1985, Buick 1990, Mehta 1989, Ayers 1981). - A description of stability studies and
supporting data
VI. DOCUMENTATION - A description of experiments
The validity of an analytical method conducted to determine accuracy,
should be established and verified by precision, recovery, specificity, linearity,
laboratory studies. limit of quantitation, and relevant data
obtained from these studies
Documentation of successful
completion of such studies should be - Tables of intra- and inter-day
provided in the assay validation report. precision and accuracy
Protocols that define a set of specific - Evidence of purity of drug standards,
metabolites, and internal standards used in
directions that must be followed are
validation experiments
important if the analytical results are
useful for a given purpose. - Deviations from SOP, if any, and
justification for deviation.
General and specific SOPs and good
record keeping are essential parts of a ALL Study Documentation
validated analytical method.
The analytical protocols and SOPs is subject to a
should be signed and dated by the Comprehensive Audit
laboratory director and updated
regularly. as is the rest of
the ANDA
RE-ASSAY SOPs
specifying exact Documentation for in-study
validation should include:
RETEST conditions
to be fully in place ² Calibration curves used in
analyzing samples and intra-day
The SOP should state situations under accuracy and precision data
which re-assay of samples is permitted.
² Information on inter-day values of C
Re-assays samples and data on inter-day accuracy
should be done and precision from calibration curves and
QC samples used for accepting the
in triplicate. analytical run

The pre-study validation experiments, ² A protocol for re-assay of samples that

the data generated from them, and the describes the reasons for re-assay and
assay quality control data should be acceptance criteria for re-assayed samples
recorded in a bound laboratory ² Reasons for missing samples
notebook.
The entries should be signed by the ² Acceptance criteria for reported
chemist and witnessed by the values when all unknown samples are
laboratory supervisor. assayed in duplicate.
All records should be available for data
audit and inspection.

Handbook of Pharmaceutical Sect: 16.

16 69 Generic Development
TABLETS ORAL DISSOLUTION & B I O S T U D Y CHAPTER 16

Taylor, J.K., “Validation of Analytical Methods,”

² Deviations from the protocol or Analytical Chemistry 1983; 55:60OA-608A.
SOP, with reasons and justifications for Timm, U., M.Wall, and D. Dell, “A New
Approach for Dealing with the Stability of Drugs
the deviations
in Biological Fluids,” J Pharm Sci 1985; 74:972-
977.
Documentation for submission The United States Pharmacopeia XXII:
Validation of Compendial Methods, USP
to the Agency should include: Convention Inc. 1990; 1710.

± Pre-study validation data SOURCE OF DRAFT GUIDANCE

± Calibration curves, equations, and This guidance is based primarily on a

weighting factors used, if any conference on Analytical Methods Validation:
Bioavailability, Bioequivalence and
Pharmacokinetic Studies, which was held on
± In-study validation data December 3 - 5, 1990.
Sponsored by the American Association of
± Complete serial chromatograms of Pharmaceutical Scientists, U.S. Food and Drug
20% of subjects, with standards and Administration, Federation Internationale
Pharmaceutique, the Canadian Health
QC samples Protection Branch, and the Association of
Official Analytical Chemists (Shah 1992).
± All SOPs, raw data, calculations of
concentration, and re-assay sample
sets. ABOUT THIS DRAFT GUIDANCE

PREPARATION
REFERENCES This guidance has been prepared by the
Biopharmaceutics Coordinating Committee and
Ayers, G., D. Burnett, A. Griffiths, and A.
the Clinical 1 Pharmacology Section of the
Richens, “Quality Control of Drug Assay,” Clin
Medical Policy Coordinating Committee in the
Pharmacokinetics 1981; 6:106-117.
Center for Drug Evaluation and Research
Brooks, M.A. and R.E. Weifeld, “A Validation
(CDER) at the Food and Drug Administration.
Process for Data from the Analysis of Drugs in
Biological Fluids,” Drug Development and
Industrial Pharmacy 1985; 11: 1703-1728. CURRENT AGENCY THINKING
Buick, A.R., M.V. Doig, S.C. Jeal, G.S. Land, This guidance document represents the
and R.D. McDowall, “Method Validation in the Agency’s current thinking on validation of
Bioanalytical Laboratory,” Journal of analytical methods for human studies based on
Pharmaceutical and Biomedical Analysis 1990; drug or metabolite assay in a biological matrix.
8:629-637. ALTERNATIVE APPROACHES
Karnes, S.T., G. Shiu, and V.P. Shah, It does not create or confer any rights for or on
“Validation of Bioanalytical Methods,” any person and does not operate to bind FDA
Pharmaceutical Research 1991; 8:421-426. or the public.
Mehta, A.C., “The Validation Criteria for An alternative approach may be used if such
Analytical Methods used in Pharmacy Practice approach satisfies the requirements of the
Research,” J Clin Pharm Ther 1989; 14:465- applicable statute, regulations, or both.
473.
Pachla, L.A., D.S. Wright, and D.L. Reynolds,
“Bioanalytical Considerations for DRAFT RELEASE DATE
Pharmacokinetic and Biopharmaceutic RELEASE DATE OF THIS DRAFT GUIDANCE
Studies,” J Clin Pharmacol 1986; 26:332-335. December 1998
Shah, V.P., K.K.Midha, S.V.Dighe, et al.,
Analytical Methods Validation: Bioavailability, U.S. Department of Health and Human Services
Bioequivalence and Pharmacokinetic Studies Food and Drug Administration Center for Drug
(Conference report). Pharmaceutical Research Evaluation and Research (CDER) Dec. 1998 BP # [ ]
1992; 9:588-592. DOCUMENT CODE j:\!guidance\2578dft.wpd 12/14/98

Handbook of Pharmaceutical Sect: 16.

16 70 Generic Development
TABLETS ORAL DISSOLUTION & B I O S T U D Y CHAPTER 16

ØC H E C K L I S T ×
CL # P-HB01-03-1Y2K

Bioanalytical HPLC/GC Method Validation

for Biostudies
‘…When the analytical method is not properly validated, the new
drug is adulterated…

1. Has theGC / HPLC analytical method been fully validated in the oYes qNo
appropriate biological matrix (blood, serum, plasma, or urine) prior to the
Start of the Study
2. Does the pre-study written validation protocol include all the listed six oYes qNo
[6] parameters as well as stability of the relevant matrix?
3. Has the firm a complete set of SOPs exist covering record keeping, oYes qNo
security and chain of sample custody (accountability systems) to ensure
the integrity of test articles from pre-sampling procedures to final report?
4. Can the analyte in the test samples be evaluated in an interference- oYes qNo
free biological matrix for each sample (i.e. for each individual subject.)?
5. Has the validated analytical method met the control percentages allow o Yes qNo
for Accuracy Precision Sensitivity Specificity and Stability criteria?
6. Has a standard calibration curve covering the expected unknown oYes qNo
sample concentration range in addition to a calibrator sample at LOQ
been established?
7. Have all subject samples been analysed in a single continuous test oYes qNo
run? (one sitting?)
8. Are QC samples analyzed concomitantly with the test samples at oYes qNo
intervals to test accuracy and precision of the VALIDATED method?
9. Do the test samples meet the criteria spread of 'Near the LOQ' (i.e., oYes qNo
#3 x LOQ), 'midrange', and 'High end range?
10. Are Re-assay SOPS specifying exact retest conditions fully in place? oYes qNo
11. Is there a set of written SOPs controlling The Protocol - The Test oYes qNo
Method, - The method Validation and the final Assay Validation Report?
12. Is a written protocol available for the analytical method PRIOR to oYes qNo
validation
13. Has the analytical method been fully validated, documented with the oYes qNo
presentation of a final Assay Validation Report?
14. Have the Lab books been corrected signed and audited? oYes qNo
15. Has all Study Documentation is subject to a Comprehensive Audit? oYes qNo

Handbook of Pharmaceutical Sect: 16.

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SOP # A-528-01-069Y STANDARD OPERATING

PROCEDURES
Total Pages: 8.

PERFORMANCE VERIFICATION OF DISSOLUTION APPARATUS

Page: 1 of 8.
PURPOSE:
The purpose of this Standard Operating Procedure is to perform the following
performance verification & calibration test procedures on the dissolution apparatus
In order to ensure the functioning of apparatus at parameters prescribed by USP/BP
Pharmacopoeias and by the September 1997 Approved Guidance to Industry:-
Performance Verification is carried out by:-
n Routine calibration & checking
n Eccentricity of shafts
n Apparatus suitability
n Calibration & checking of apparatus
RESPONSIBILITY:
1. Routine Checking & Calibration Procedure
Each analyst shall verify the apparatus suitability prior to use.
2. Eccentricity of Shafts
The analyst in charge of the apparatus shall check the eccentricity of the shafts.
3. Apparatus Suitability
The analyst in charge of the apparatus shall verify that the apparatus is suitable for
performing dissolution tests.
4. Calibration & Checking of Apparatus
The appointed laboratory technician shall check the correct functioning of the
apparatus.

FREQUENCY:
1. Routine Calibration
Immediately prior to each dissolution testing procedure.
2. Eccentricity of Shafts
Once a month or when shafts are changed.
3. Apparatus Suitability
Every six months and after any maintenance procedure.
4. Calibration & Checking of Apparatus
Annually and after any maintenance procedure.

ED. N0: 01 Effective Date :

APPROVED:
Replaces NEW
Ed. Status : 01 January 200Y
Department R&D RA QC / QA
Handbook of Pharmaceutical Sect: 16.
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 TABLETS ORAL DISSOLUTION & B I O S T U D Y CHAPTER 16

SOP # A-528-01-069Y STANDARD OPERATING

PROCEDURES
Total Pages: 8.

PERFORMANCE VERIFICATION OF DISSOLUTION APPARATUS

Page: 2 of 8.

PROCEDURE:
Routine Calibration (See Form 01/9Y).
1. Vessels:-
Inspect each vessel for any defects (cracks, etc.), and ensure that the numbered
vessels are in the correct positions.
After the test has been performed, make sure that each vessel is thoroughly cleaned
and safely stored.

2. Centering:-
Place vessels through their holes in the bath cover. Center each vessel using a
suitable centering unit with respect to the vertical axis of its shaft.

3. Revolutions Per Minute:-

Select the required RPM. The requirements are met if the RPM is kept within the
limits ±4% (check using a suitable calibrated Microprocessor Tachometer).

4. Medium:-
Dissolution Media should be vacuum filtered if necessary.
Using a graduated cylinder, place the specified amount of media pre-warmed to
approximately 37°C, or media at room temperature, into each vessel. Allow the
medium to assume the temperature of the water bath (37° ±0.5°C ). Observe the
stirrer and the walls of the vessel: No air bubbles should be noted.

5. Temperature:-
Prior to starting the test, check the temperature of the Dissolution Medium in each
vessel (37 ±0.5°C). Use a calibrated thermometer.

6. Paddle or Basket Depth:-

Using a spacing tool or another equipment device, adjust each shaft and basket
assembly or paddle so that the distance from the bottom of each basket/blade to the
bottom of each flask is 25 ± 2 mm.

7. Paddle or Basket Condition:-

Inspect paddles and baskets for defects. Replace where necessary.
Make sure that the numbered paddles and baskets are in their correct position.

ED. N0: 01 Effective Date :

APPROVED:
Replaces NEW
Ed. Status : 01 January 200Y
Department R&D RA QC / QA
Handbook of Pharmaceutical Sect: 16.
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SOP # A-528-01-069Y STANDARD OPERATING

PROCEDURES
Total Pages: 8.

PERFORMANCE VERIFICATION OF DISSOLUTION APPARATUS

Page: 3 of 8.
8. Covers:-
Place the appropriate cover over each vessel.

9. Visual Observation:-
Observe the remaining contents of the baskets/vessels after dissolution. Record
remarks on attachment Form "Routine checking and calibration" (See Form 01/9Y).

Eccentricity of Shafts (See Form 02/9Y)

n Check the eccentricity of shafts with a calibrated Mitutoyo™ instrument, [Cat. No.
204608-9] or similar model equipment.
n Place the magnetic base of the instrument on the surface of the dissolution
apparatus.
n Switch on the drive motor.
n Adjust the instrument so that the prong just touches the paddle shaft at a distance
25 mm above the blade, and at the bottom of the basket.
n While the paddle or basket is rotating, observe the needle on the dial.
Apparatus Suitability
Calibration for dissolution is provided for the Apparatus Suitability Test and refers to
such with six or more spindles. The USP suitability test for any apparatus (I or II) is a
four point test.

USP Non-Disintegrating Type - Salicylic Acid Tablets, 300 mg

Type of Apparatus:
Apparatus I (Basket) (See Form 03/9Y).
Apparatus II (Paddle) (See Form 04/9Y).

Medium: Dissolution medium: 0.05M Phosphate buffer pH 7.4 ±0.05.

Dissolve 170.125g Potassium Dihydrogen Phosphate (KH2PO4) and 39g of Sodium

Hydroxide into 25L of distilled water.

Volume: 900 mL.

Temperature: 37.0±0.5°C
Stirring Rate: 50 and 100 rpm.
Time: 30 minutes.

ED. N0: 01 Effective Date :

APPROVED:
Replaces NEW
Ed. Status : 01 January 200Y
Department R&D RA QC / QA
Handbook of Pharmaceutical Sect: 16.
16 74 Generic Development
 TABLETS ORAL DISSOLUTION & B I O S T U D Y CHAPTER 16

SOP # A-528-01-069Y STANDARD OPERATING

PROCEDURES
Total Pages: 8.

PERFORMANCE VERIFICATION OF DISSOLUTION APPARATUS

Page: 4 of 8.
Procedure
Place the stated volume of Dissolution Medium in the vessels of the apparatus,
assemble the apparatus, equilibrate the Dissolution Medium to 37.0 ± 0.5°C and
remove the thermometer.

Use 6 tablets individually weighed for Dissolution Test.

Place 1 tablet in each vessel, or in each dry basket, taking care to exclude air
bubbles from the surface of the tablets, and immediately operate the apparatus at
the stated rate.

After the stated time passes, withdraw a specimen of solution from a zone midway
between the surface of the Dissolution Medium and the top of the rotating paddle or
basket, not less than 1 cm from the vessel wall.
Filter, using a 0.45µ membrane filter HAWP (or similar), discarding the first few mL
of the filtrate.

Transfer 5 mL of the clear filtrate to a 25 mL volumetric flask, dilute with Dissolution

Medium to volume and mix (or dilute 1000 µL of the clear filtrate with a 4000 µL
Dissolution Medium by the aid of a dilutor - Sample solution).

Standard Solution
Transfer about 20 mg of Salicylic Acid USP Reference Standard, accurately
weighed, to a 200-mL volumetric flask. Add about 2 mL of Ethanol and sonicate for
about 2 minutes until dissolved, allow the solution to cool to room temperature.
Dilute with Dissolution Medium to volume and mix. Filter using a 0.45µ membrane
filter HAWP (or similar) discarding the first few mL of the filtrate.

Pipette 5 mL of filtered Standard solution into a 25-mL volumetric flask, dilute with
Dissolution Medium to volume and mix, (or dilute 1000µL of the filtered Standard
solution with 4000µL Dissolution Medium by the aid of a dilutor [Hamilton] ).

Determine the amount of salicylic acid dissolved from ultraviolet absorbances at the
wavelength of maximum absorbance at about 296 nm of Sample solution in
comparison with the Standard solution, using the Dissolution Medium as the blank.

ED. N0: 01 Effective Date :

APPROVED:
Replaces NEW
Ed. Status : 01 January 200Y
Department R&D RA QC / QA
Handbook of Pharmaceutical Sect: 16.
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SOP # A-528-01-069Y STANDARD OPERATING

PROCEDURES
Total Pages: 8.

PERFORMANCE VERIFICATION OF DISSOLUTION APPARATUS

Page: 5 of 8.

CALCULATIONS AS FOLLOWS FOR:

Au x Wst x 5 x 900 x 25 =
As 200 25 300 5

Au
x Wst x 1.5 = % of the labeled amount of SALICYLIC ACID dissolved per tablet
As

Au = absorbance of Sample solution

As = absorbance of Standard solution
Wst = weight of Salicylic Acid USP Reference Standard in mg

4.3.2 USP Disintegrating Type - Prednisone Tablets, 50 mg.

4.3.2.1 Apparatus:
Apparatus I (Basket) (See Form 05/9Y).
Apparatus II (Paddle) (See Form 06/9Y).

Medium: Dissolution medium: De-aerated Purified Water USP.

Volume: 900 mL.

Temperature: 37.0±0.5°C
Stirring Rate: 50 and 100 rpm.
Time: 30 minutes.
Procedure
Place the stated volume of Dissolution Medium in the vessels of the apparatus,
assemble the apparatus, equilibrate the Dissolution Medium to 37.0 ± 0.5°C and
remove the thermometer.
Use 6 individually weighed tablets for the Dissolution Test.
Place 1 tablet in each vessel, or in each dry basket, taking care to exclude air
bubbles from the surface of the tablets, and immediately operate the apparatus at
the stated rate.

ED. N0: 01 Effective Date :

APPROVED:
Replaces NEW
Ed. Status : 01 January 200Y
Department R&D RA QC / QA
Handbook of Pharmaceutical Sect: 16.
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SOP # A-528-01-069Y STANDARD OPERATING

PROCEDURES
Total Pages: 8.

PERFORMANCE VERIFICATION OF DISSOLUTION APPARATUS

Page: 6 of 8.

After the stated time passes, withdraw a specimen of solution from the zone midway
between the surface of the Dissolution Medium and the top of the rotating paddle or
basket, not less than 1 cm from the vessel wall.
Filter, using a 0.45µ membrane filter HAWP (or similar), discarding the first few mL
of the filtrate.
Ü Apparatus I, 50 rpm
Use the filtered solution with no further dilution.
Ü Apparatus I, 100 rpm;
Ü Apparatus II, 50 and 100 rpm
Pipet 4 mL of the filtered solution into a 10 mL volumetric flask, dilute to volume with
purified water and mix (or dilute 2000 µL of the filtered solution with 3000 µL purified
water by dilutor).
Standard Solution
Transfer about 10 mg of Prednisone USP Reference Standard, accurately weighed,
to a 50 mL volumetric flask. Add about 5 mL of Ethanol and sonicate for about 2
minutes until dissolved, allow the solution to cool to room temperature.
Dilute with purified water to volume and mix. Filter using a 0.45µ membrane filter
HAWP (or similar) discarding the first few mL of the filtrate.
Pipette 5 mL of Standard solution into a 100 mL volumetric flask, dilute with purified
water to volume and mix (or dilute 250 ml of the filtered standard solution with a
4750 ml Dissolution Medium using a dilutor).
Determine the amount of prednisone dissolved from ultraviolet absorbances at the
wavelength of maximum absorbance at approximately 242 nm of Sample Solution in
comparison with the Standard Solution, using Purified Water USP as the blank.

CALCULATIONS AS FOLLOWS FOR:

Ü APPARATUS I: 50 rpm;

Au x Wst x 5 x 900 x 100 =

As 50 100 50

Au x Wst x 1.8 = % of the labeled amount of prednisone dissolved/tablet

As

ED. N0: 01 Effective Date :

APPROVED:
Replaces NEW
Ed. Status : 01 January 200Y
Department R&D RA QC / QA
Handbook of Pharmaceutical Sect: 16.
16 77 Generic Development
 TABLETS ORAL DISSOLUTION & B I O S T U D Y CHAPTER 16

SOP # A-528-01-069Y STANDARD OPERATING

PROCEDURES
Total Pages: 8.

PERFORMANCE VERIFICATION OF DISSOLUTION APPARATUS

Page 7 of 8.

CALCULATIONS AS FOLLOWS FOR:

Ü APPARATUS I: 100 rpm;
Ü APPARATUS II: 50 and 100 rpm

Au x Wst x 5 x 900 x 10 x 100 =

As 50 100 50 4
Au x W x 4.5 = % of the labeled amount of Prednisone dissolved per tablet
st
As

Au = absorbance of Sample preparation

As = absorbance of Standard preparation
Wst = weight of Prednisone USP Reference Standard in mg

LIMITS/LIMITATIONS
Routine Calibration Specification Limits
[1] Revolutions per minute → Specified rpm ±4%
[2] Temperature - Celsius → 37° ±0.5°C
[3] Paddle or basket depth → 25 ± 2 mm
[4] Eccentricity of shafts: → 2.0 mm [basket]
→ 1.0 mm [paddle].
[5] Apparatus Suitability
The test limits are stated in the certificate for the USP dissolution calibrator (non-
disintegrating type and disintegrating type).

CORRECTIVE ACTION:
[1] Routine Calibration
If, during verification, the rpm is not within the specified range, immediately contact
the technician.
[2] Eccentricity of Shafts
If during verification the eccentricity of the shafts is not within the specified range,
repeat the verification with a new paddle or basket shafts.
r successful verification - discarded old shaft.
r unsuccessful verification - do not use and contact the technician immediately.

ED. N0: 01 Effective Date :

APPROVED:
Replaces NEW
Ed. Status : 01 January 200Y
Department R&D RA QC / QA
Handbook of Pharmaceutical Sect: 16.
16 78 Generic Development
 TABLETS ORAL DISSOLUTION & B I O S T U D Y CHAPTER 16

SOP # A-528-01-069Y STANDARD OPERATING

PROCEDURES
Total Pages: 8.

PERFORMANCE VERIFICATION OF DISSOLUTION APPARATUS

Page 8 of 8.
[3] Apparatus Suitability
If the individual calculated values at each indicated speed are not within the
specified ranges as shown in table I or II in the certificate for the USP dissolution
calibrator, the following system should be verified:
þ Routine calibration
þ Eccentricity of shafts
þ Performance verification of analytical balance (Monthly check according to SOP)
þ Dissolution medium
[4] Calibrator Suitability
n If all of the above are found to be in correct working order, open another USP
dissolution calibrator (Salicylic Acid Tablets, 300 mg., or Prednisone Tablets, 50
mg.) and repeat the test.
n If the test is within the specified range, discard the old calibrator.
n If not, shut down the apparatus and immediately contact the lab technician. Place
a "Temporarily Out of Order" sign on the apparatus.

DOCUMENTATION:
Form 01 - "Routine Checking and Calibration".
Form 02 - "Eccentricity of Shafts".
Form 03 - "Apparatus Suitability - Salicylic Acid" (Basket Method)
Form 04 - "Apparatus Suitability - Salicylic Acid" (Paddle Method)
Form 05 - "Apparatus Suitability - Prednisone Tablets" (Basket Method)
Form 06 - "Apparatus Suitability - Prednisone Tablets" (Paddle Method)

White label (stuck on the apparatus after apparatus SUITABILITY test).

Green label (stuck on the apparatus after CALIBRATION of apparatus).

WHITE LABEL GREEN LABEL

SUITABILITY TEST CALIBRATION
ANALYST: Metrology Dept:
Date: Date:
Next Date: _________ Next Date: _________

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Ed. Status : 01 January 200Y
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Handbook of Pharmaceutical Sect: 16.
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SOP # D-528-01-01Y2K STANDARD OPERATING

PROCEDURES
Total Pages for D-528: 5

PERFORMANCE VERIFICATION OF
DISSOLUTION APPARATUS

ECCENTRICITY OF SHAFTS
Dissolution Apparatus ______________________ No ______________
Shaft Paddle Limit Basket Limit
Number
1
2
3 1.0 mm 2.0 mm
4
5
6
Form: 02/ 9Y

Results performed on ________[DD] _______[MM] ______[YY] were found to be:-

r within specifications.
r outside specifications.
r Monthly verification r Change of shaft.

REMARKS________________________________________________________________
__________________________________________________________________________
__________________________________________________________________________

OPERATOR: ______________ SUPERVISOR: __________________ Date: __________

q R&D LAB q QC LAB q QA LAB

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01
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Handbook of Pharmaceutical Sect: 16.
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SOP # D-528-01-01Y2K STANDARD OPERATING

PROCEDURES
Total Pages for D-528: 5

PERFORMANCE VERIFICATION OF
DISSOLUTION APPARATUS

APPARATUS SUITABILITY
SALICYLIC ACID STANDARD
[Basket Method]

USP Salicylic Acid Reference Standard Lot No.: ____________

Dissolution Apparatus: ______________________Unit No: ____________

USP Non-disintegrating Type-SALICYLIC ACID Tablets, 300 mg. Lot No. ____________
USP SALICYLIC ACID Reference Standard Lot No.: ____________

BASKET METHOD
q RPM: 50 q RPM: 100
Limits: ___________ Limits: ____________

q Approved: ___________________
q Rejected: ___________________
REMARKS:
__________________________________________________________________________
__________________________________________________________________________

OPERATOR: ______________ SUPERVISOR: __________________ Date: __________

q R&D LAB q QC LAB q QA LAB
Form: 03/9Y

ED. N0: 01 Effective Date : APPROVED:

Replaces NEW
Ed. Status : January 200Y
01
Department R&D RA QC / QA
Handbook of Pharmaceutical Sect: 16.
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 TABLETS ORAL DISSOLUTION & B I O S T U D Y CHAPTER 16

SOP # D-528-01-01Y2K STANDARD OPERATING

PROCEDURES
Total Pages for D-528: 5

PERFORMANCE VERIFICATION OF
DISSOLUTION APPARATUS

APPARATUS SUITABILITY
SALICYLIC ACID STANDARD
(Paddle Method)
USP Salicylic Acid Reference Standard Lot No.: _________

Dissolution Apparatus: ______________________Unit No: ____________

USP Non-disintegrating Type-SALICYLIC ACID Tablets, 300 mg. Lot No. ___________
USP SALICYLIC ACID Reference Standard Lot No.: ___________

PADDLE METHOD
q RPM: 50 q RPM: 100
Limits: ___________ Limits: ____________

q Approved: ___________________
q Rejected: ___________________
Remarks:
________________________________________________________________________

OPERATOR: ______________ SUPERVISOR: ________________ Date: __________

q R&D LAB q QC LAB q QA LAB
Form: 04/9Y

ED. N0: 01 Effective Date : APPROVED:

Replaces NEW
Ed. Status : January 200Y
01
Department R&D RA QC / QA
Handbook of Pharmaceutical Sect: 16.
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SOP # D-528-01-01Y2K STANDARD OPERATING

PROCEDURES
Total Pages for D-528: 5

PERFORMANCE VERIFICATION OF
DISSOLUTION APPARATUS

APPARATUS SUITABILITY
PREDNISONE STANDARD TABLETS
[Basket Method]

Dissolution Apparatus: ____________________Unit No: _______

USP Disintegrating Type - Prednisone Tablets, 50 mg. Lot No. ____________

USP Prednisone Reference Standard Lot No.: ____________

BASKET METHOD
q RPM: 50 q RPM: 100
Limits: ___________ Limits: ____________

q Approved: ___________________
q Rejected: ___________________
REMARKS:
___________________________________________________________________________
___________________________________________________________________________
OPERATOR: ______________ SUPERVISOR: __________________ Date: __________

q R&D LAB q QC LAB q QA LAB

Form: 05/9Y

ED. N0: 01 Effective Date : APPROVED:

Replaces NEW
Ed. Status : January 200Y
01
Department R&D RA QC / QA
Handbook of Pharmaceutical Sect: 16.
16 83 Generic Development
 TABLETS ORAL DISSOLUTION & B I O S T U D Y CHAPTER 16

SOP # D-528-01-01Y2K STANDARD OPERATING

PROCEDURES
Total Pages for D-528: 5

PERFORMANCE VERIFICATION OF
DISSOLUTION APPARATUS

APPARATUS SUITABILITY
PREDNISONE STANDARD TABLETS
(Paddle Method)

Dissolution Apparatus: ______________________Unit No: ____________

USP Disintegrating Type - Prednisone Tablets, 50 mg. Lot No.; ______________

USP Prednisone Reference Standard Lot No.: _______________

PADDLE METHOD
q RPM: 50 q RPM: 100
Limits: ___________ Limits: ____________

q Approved: ___________________
q Rejected: ___________________
Remarks:
___________________________________________________________________________
___________________________________________________________________

OPERATOR: ______________ SUPERVISOR: __________________ Date: __________

q R&D LAB q QC LAB q QA LAB
Form 06/9Y

ED. N0: 01 Effective Date : APPROVED:

Replaces NEW
Ed. Status : January 200Y
01
Department R&D RA QC / QA
Handbook of Pharmaceutical Sect: 16.
16 84 Generic Development
 TABLETS ORAL DISSOLUTION & B I O S T U D Y CHAPTER 16

False Positives
EXAMINED

Chow, Pitt
Similarity Testing and
Others

Similarity (f2)
Pitfalls
'Points to Consider'
A REVIEW DISSOLUTION SIMILARITY EVALUATION
IMPACT OF 'SIMILARITY TESTING" IN DISSOLUTION PROFILES

I n August 1997, the FDA issued an

approved Guidance for Industry titled
'Dissolution Testing of Immediate Release
Dissolution Profile 'Similarity Test'
Dissolution profile of the test formulation
is concluded 'similar' to that of the
Solid Oral Dosage Forms' where the
reference if the similarity factor, which is
dissolution profiles between Test and
unbiased gives a numerical value
Reference products could be evaluated
between 50 to 100. i.e. ƒ² = 50 to 100.
for similarity between dissolution profiles.
In many cases this comparison may yield Mathematically, the similarity factor is
appropriate results, however there are defined as the 'logarithmic reciprocal
certain pitfalls with the procedure. square root transformation of one plus the
mean squared (the average sum of
FDA's DISSOLUTION squares) difference in observed average
SIMILARITY EQUATION cumulative percent dissolved between the
HAS POTENTIAL PITFALLS test and reference formulations over all
sampling time points,' and is given as:
Evaluating your firm's generic drug
against the RLD requires an accurate and Formula:
precise dissolution 'snapshot' of the Test
(T) and Reference (R) Drug at a variety of
product development stages.
ƒ²=50 log{[1+l/n∑nt=1(Rt -Tt)2 ]-0.5 x 100
The continuation of the development
project to the next stage frequently
where:-
depends on getting the dissolution profile
right. This reliance on comparative ƒ² = Formula Similarity Factor.
dissolution profiling from formula R = RLD (Reference Listed Drug).
development through process qualification
to a possible IVIVC and finally BE T = Test Drug.
evaluation leaves little to error in Rt = % dissolved at each time point.
dissolution testing and assessment.
Tt = % dissolved at each time point.

Handbook of Pharmaceutical Sect: 16.

16 86 Generic Development
 TABLETS ORAL DISSOLUTION & B I O S T U D Y CHAPTER 16

Logarithm function The large-sample distribution of f2 by the

ƒ² can be expressed in terms of a linear usual delta method fails to provide an
function of logarithm of 1 + Q/n as18:- adequate approximation to the empirical
ƒ² = 100 - 25Log (1 + Q/n). distribution obtained by simulation. In
addition, simulation results also indicate
where Q/n is the mean squared differences in that the similarity factor is too liberal in
population averages over all sampling time points concluding similarity between dissolution
plus the mean variance computed over sampling profiles
and time points. Q is the sum of the squares of
average differences in cumulative percent DOUBLE CHECK the
dissolved. In the case, where average cumulative
percent dissolved of both formulations shift by the SIMILARITY RESULT
same amount, Q and f2 remain unchanged, as f2 is
a continuous function of Q.
with alternative methods
Several statistical issues relating to the This review investigates the sensibility of
similarity factor f2 as a criterion for commonly used methods for analysing
assessment of similarity between two and evaluating the similarity of the
invitro dissolution profiles in simulated dissolution profiles of two drug products
models arise from this simulation:- (namely the Test and Reference Product -
These include:- i.e. the RLD).
n the invariant property of f2 with respect Note:- A useful analysis only results from
to the location change a well designed protocol. A valid
n the consequence of failure to take into experimental design is thus absolutely
account the shape of the dissolution curve essential in comparative dissolution
and unequal spacing between sampling profile testing (CDP.)
time points. Prior to the experiment being conducted,
n The similarity factor f2 is simply a a carefully planned written dissolution
sample statistic (which cannot be used to protocol is required highlighting the
formulate a statistical hypothesis for procedure such as the suitability of the
assessment of dissolution similarity.) apparatus (e.g., rotating basket for
capsules, paddle for tablets), the choice
It is, therefore, impossible to evaluate of media, pH, responses measured,
false positive and false negative rates of location of dissolution basket i.e. (2 x (3,3)
decisions for approval of drug products or (6, 0) (0, 6) for Reference and Test (R,
based on f2. T), and so on.
It is quite possible that the criterion based IN VITRO DISSOLUTION has been
on the similarity factor may have a quite recognised as an important element in
high false positive rate. generic and innovative drug development.
Implementation of f2 to assess dissolution Reference to FDA's similarity formula
similarity is, in fact, a one-sided problem appears in five major guidelines (See box)
rather than an interval criterion suggested and can be used to determine the rate
by the guidance. and extent of IR drug release, but may be
used with carefully considered sample
Complexity of the form in the distribution interval spacing in MR/DR dosage forms.
of f2 even under a very strict assumption
In addition, it is referred in the IVIVC and
prevents one from finding its expected
Food-Effect BA/BE guidelines and as a
variance and hence, confidence interval
useful comparative surrogate tool for the
for the mean.

Handbook of Pharmaceutical Sect: 16.

16 87 Generic Development
 TABLETS ORAL DISSOLUTION & B I O S T U D Y CHAPTER 16

assessment of bioequivalence under process) is fully covered.

certain prescribed conditions.
Two Similarity
Guidance Documents Referred:
Approaches exist:-
1. SUPAC IR (Nov 1995)
CURVE FITTING or
2. SUPAC MR (Sept 1997)
STATISTICAL ANALYSIS
3. Dissolution Testing (Aug 1997)
To compare dissolution profiles between
4. ER & IVIVC Applications (9/97) two drug products, several methods have
5. Food Effect BA-BE Studies (10/97) been proposed. These methods, by the
nature of the procedures, could be
For dissolution testing, as stated in the classified as model dependent (curve
USP/NF, the rotating basket and paddle fitting) and model independent (statistical
are two of the most commonly adapted analysis).
apparatus for the testing. In the USP XXIII The commonly used models in the curve
a three-stage sampling plan is specified to fitting procedures include exponential5,
determine whether the test results meet probit, Gompertz6, logistic7, Weibull8, and
the acceptance criteria4. the three control factor models9. For the
In the scale-up and postapproval changes curve fitting procedure, it is assumed that
(SUPAC) guidance to Industry issued by the dissolution profiles can be expressed
the FDA, the dissolution testing is by the selected curve.
classified into cases A, B, and C1. The procedure is first to fit the curve of
Case A is the dissolution of Q = 85% in the response of the experiment (eg, Time
15 minutes in 900 (mL) of 0.1 HCl, using a to d percentage dissolved (T%d),
rotating basket at 100 rpm or a paddle at percentage dissolved to time t (%Dt), and
50 rpm. area under the curve (AUCdiss.), and the
Case B is the multipoint dissolution relative efficiency) and compute the
profiles in the application/compendia associated parameters of the model for
medium at 15, 30, 45, 60, and 120 both reference and test, respectively.
minutes or until an asymptote is reached It is then followed by comparing the
for the proposed and currently accepted corresponding parameters from the two
formulation. curves.
Case C is the multipoint dissolution For the curve fitting procedure, selecting
profiles performed in water, 0.1 N HCl, an appropriate curve is critical. Where
and USP buffer media at pH = 4.5, 6.5, selected curves are inappropriate, it will
and 7.5 for five separate profiles for the be misleading to compare the dissolution
proposed and currently accepted profiles by testing the parameters from the
formulations. two models.
Sampling time is specified as Case B or In other words, the error of making an
until either 90% of the drug from the drug incorrect conclusion could actually occur
product is dissolved or an asymptote is in two ways:- Firstly, by selecting the
reached. wrong model and secondly by, making the
wrong judgement when comparing the
The requirement for the dissolution testing corresponding parameters.
for different level changes in components
and composition, site, batch size, and Therefore, the lack-of-fit test is essential
manufacturing (including equipment and before comparing the associated
parameters.

Handbook of Pharmaceutical Sect: 16.

16 88 Generic Development
 TABLETS ORAL DISSOLUTION & B I O S T U D Y CHAPTER 16

ANCOVA is the the properties and show the implications

of the most commonly used methods (eg,
most widely used ANCOVA, two-way ANOVA, and Gill's
STATISTICAL ANALYSIS Split-plot analysis) in comparing
dissolution profiles.
The most commonly used statistical
The performance of these methods may be
methods include moment based compared with the similarity factor of FDA
comparison, individual time point test, and Chow’s methods via a model simulation
two-way ANOVA, ANCOVA10, analysis of study under the assumption that the
first difference11, repeated measurement dissolution profile can be approximated by a
split-plot12, multivariate analysis13, and so linear or quadratic relationship over time.
forth. Methods of Similarity Factor, Split-plot, and
These methods do not require the pre-set Chow all have limits and restrictions in their
curve of the profiles. approach and use
Some analyses, however, have an FDA & Chow models
underlying assumption that requires the are not sensitive in
responses to be independent. This
assumption can not be applied to QUADRATIC
dissolution testing since the amount Dissolution Profiles
dissolved over time within the same drug DISCUSSION
product is in fact correlated. Although the In cases where the dissolution profiles are
multivariate analysis takes into account linear or could be approximated linearly, if
the correlation problem, the procedure is the two profiles are in fact identical, FDA’s
fairly complicated. similarity factor is not as sensitive as
Moreover, if the time point selected is Chow’s is for variation changes in the
large (e.g., larger than three), it is difficult amount of dissolution. Other methods
to interpret the results. In the SUPAC have the probability to declare
guideline1, FDA indicates that dissolution dissimilarity of 10%.
profiles could be compared based on a If two drugs are different in the initial
similarity factor. Although this method is amount of dissolution but the same in the
easy to apply, it lacks scientific dissolution rate, then both FDA and Chow
justification. have a lower probability of detecting the
difference than other methods.
Recently, Chow2 used the concept of
bioequivalence and developed a In particular, FDA’s method cannot detect
procedure by utilising a time series any difference until the initial amount
approach14. This method takes into dissolved between two drug products is
account the correlation structure of the 20% apart. Other methods are very
amount dissolved over time and evaluates sensitive to the differences. The
the equivalence in the dissolution profiles. probability is 100% in the simulation even
Chow also derives a formula to examine for a slight difference (e.g., 2.5%
the local similarity at each time point2. difference), and the probability is a
decreasing function of σ.
ANCOVA, ANOVA If two drug products have the same initial
Split-plot & Chow are dissolution but differ in the dissolution
rate, neither the FDA nor the Chow
Alternative methods to method are as sensitive as others for
FDA's Similarity Factor small variation. In general, FDA’s method
The objective of this review is to highlight has a smaller probability than Chow’s
method regardless of the variation.

Handbook of Pharmaceutical Sect: 16.

16 89 Generic Development
 TABLETS ORAL DISSOLUTION & B I O S T U D Y CHAPTER 16

If the variance is large, then the The sensitivity of split-plot and two-way
probability of declaring a difference with ANOVA are decreasing functions of
Chow’s method is even larger than other variation.
methods no matter what change exists in Fda' and Chow's
the initial amount or rate of dissolution. methods are more
Generally the FDA's relaxed than others
SIMILARITY Equation is less In general, the FDA and Chow methods
discriminatory are more relaxed than the others.
than Chow Although FDA’s similarity factor is easy to
manipulate and results do not change if
In cases where dissolution profiles are the role of test and reference interchange,
quadratic or can be approximated by a it, however, lacks scientific justification
quadratic model, if the amount dissolved and has the following disadvantages:
is the same for two drug products at two [1]. It is not based on an hypothesis
boundaries but different in the dissolving testing procedure, therefore, there is no
rate, neither the FDA method nor the measurement of the associated error
Chow method are sensitive to the (Type I or II errors)
differences and have zero probability of [2]. It is a function of the pair difference
declaring a difference of less than 15% between two drug products. If the time
(FDA) or 20% (Chow). points selected for two drug products are
When the variation is large, Chow has a different, the method could not be
large probability of declaring a difference applied
even when two profiles are identical (eg., [3]. The measurement is an average of
probability = 50% for s =6) but FDA stays differences observed. After the asymptote
the same. is achieved, the differences could be fairly
The other methods detect the difference small.
right away (100% for even a slight In the guideline, no time point selection is
difference). If two profiles are the same specified. If the analyst selects a large
before 45 minutes and both have Q0.75 = number of time points after the asymptote
75% but differ afterwards, the same is achieved, then the average difference
pattern as the earlier case is observed could be small.
with FDA and Chow and they are even In consequence, f2 will tend to have a
less sensitive to the difference. value between 50 and 100 which results
If two profiles are different except for the in similarity although two profiles could be
origin in the study range where the very different.
difference between R and T are within 5% Too many sampling
at Q0.75 and Q2, FDA and Chow both have
zero probability of detecting the difference points after asymptote
when the variation is small. The same can distort the
pattern is observed for Chow for its SIMILARITY result
sensitivity to the variation (eg., 50% for s
=6 and 75% for s =8 even when two Chow’s method has an advantage in that
profiles are identical). it defines the equivalence limits for
For the second order model, ANCOVA similarity based on Q value when
specified in the appropriate USP
has a small probability of declaring the
monograph method.
difference, which may due to its linear
relationship assumption. It also takes into account that the
dissolution series observed are in fact

Handbook of Pharmaceutical Sect: 16.

16 90 Generic Development
 TABLETS ORAL DISSOLUTION & B I O S T U D Y CHAPTER 16

dependent and the dependency is a For example, the interval derived from the
decreasing function of time, as opposed auto correlation2 model for the data in
to Gill’s method where the relationship is Tsong and Hammerstrom5 is within two
assumed to be constant over time. tenth points of the auto correlation model1
It however, has the following (i.e. 86.7% and 112.9%)
disadvantages and weaknesses:
Gill's method uses
Chow' s Method Time as the Variable -
Depends on (Q)
a Limiting Disadvantage
excludes T0 and requires
identical procedures For Gill’s method, the advantage is that it
reflects the fact that correlation between
CHOWS DISADVANTAGES
the amount dissolved for the same
[1] When time T0 is included, Chow’s
product exists.
method will declare dissimilarity for almost
100% regardless of the variation. It can be This assumption, however, seems
explained that Chow’s test statistic is, in oversimplified since it is assumed to be
fact, a ratio of two random deviates. If the constant. In addition, due to the algorithm
denominator is close to 0, then R is large. used in hypothesis testing, a Type I error
Therefore, the probability of concluding obtained is twice as high as
dissimilarity is also large. it should be since dissimilarity could be
[2]. If Q is not specified, the method is concluded in two cases, that is, if the
difficult to implement in actual practice, treatment by time interaction exists or if
[3] The method is based on relative the difference between treatments is
dissolution that requires the same number found in the reduced model.
of time points and the same number of Moreover, using time as a class variable
locations (e.g., baskets) for the Test & in the analysis dramatically reduces the
RLD in the evaluation. degrees of freedom available and thus a
If either one is different, the method could disadvantage of the method.
not be applied,
[4]. The response is based on the ratio of ANCOVA Estimates
test over reference. - If the role of two
drug products is interchanged in the Rate & Similarity
computation, the resulting confidence
interval will vary. In consequence, it might
but
lead to a different conclusion, needs Special Conditions
[5]. It is very sensitive to the variation. Ithas been observed that ANCOVA and
If the variation is large, the probability of two-way ANOVA are often used in
declaring similarity is large even when the comparing dissolution profiles.
underlying distribution of two profiles is
identical. ANCOVA especially is preferred by most
since it can estimate the dissolution rate
Chow’s method may be extended into the of drug products other than testing the
auto correlation2 model, which takes into similarity of the profiles.
account the correlation of more than one
time point. ANCOVA
The results achieved are very similar to
the auto correlation model1 with a slightly
needs at least 5-6
wider confidence interval. time points

Handbook of Pharmaceutical Sect: 16.

16 91 Generic Development
 TABLETS ORAL DISSOLUTION & B I O S T U D Y CHAPTER 16

It should be noted that the method is not 7. Pena Romero A, et. al. Water uptake and force
appropriate if the dissolution profiles are development in an optimized prolonged release
not linear or if only a few time points are formulation. Int J Pharm. 1991;73:239–248.
8. Langenbucher F. Linearization of dissolution
tested. rate curves by the Weilbull distribution. J Pharm
Choose the Test Pharmacol. 1972;24:979–981.
9. Kervinen L, Yliruusi J. Modelling S-Shaped
Procedure for the dissolution curves. Int. J. Pharm. 1993 ;92:115 –
122.

Specific Parameter 10. Montgomery D. Design and Analysis of

Experiments. 3rd ed. New York: John Wiley and

Required
Sons; 1991.
11. Mauger JW, et al. On the analysis of
dissolution data. Drug Dev Ind Pharm. 1986:12(7)
Moreover, the correlation nature of the :969–992.
12. Gill JL. Repeated measurement: split-plot
dissolution series within the same product trend analysis versus analysis of first differences.
violates the underlying independent Biometrics. 1988; 44:289–297.
assumptions required for applying either 13. Tsong Y. Statistical assessment of mean
of the methods. differences between two dissolution data sets.
Presented at the DIA Dissolution Workshop,
The validity of the results is, therefore, Rockville, Maryland, 1995.
questionable. 14. Box GEP, et al. Time Series Analysis,
Forecasting and Control. 3rd ed. Englewood Cliffs,
NJ: Prentice Hall; 1994.
15. Shah VP, Lesko LJ. Current challenges and
future regulatory directions in in vitro dissolution.
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16. Leeson LJ. In vitro/in vivo correlations. Drug
1. FDA. Guidance for industry: immediate release Info J. 1995; 903–915.
solid oral dosage forms scale-up and post- 17. Chow SC, Ki FYC. Statistical comparison
approval changes: chemistry, manufacturing and between dissolution profiles of drug products. J
controls, in vitro dissolution testing, and in vivo Biopharma Stat. 1997;7:241–258
bioequivalence documentation. Rockville, MD: 18. Chow SC, Liu JP. Current issues in
Food and Drug Administration; November 15, bioequivalence trials. Drug Inf J. 1995;29:795–
1995. 804.
2. Chow SC. Statistical comparison between Chow SC, Liu JP, Ma MC Statistical evaluation of
dissolution profiles of drug products. Presented at similarity factor f2 for assessment of similarity
Department of Health, Executive Yuan, Taipei, between dissolution profiles Drug Inf J.
Taiwan, 1995. 1997;31:1255–1271
3. Chow SC, Liu JP. Statistical Design and 19.Metzler CM. Bioavailability: A problem in
Analysis in Pharmaceutical Science. New York: equivalence. Biometrics. 1974;30:309–317.
Marcel Dekker; 1995. 20. Chow SC, Liu JP. Design and Analysis of
4. USP/NF. The United States Pharmacopoeia Bioavailability and Bioequivalence Studies. New
XXIII and the National Formulary. Rockville, York:
Maryland:The United States Pharmacopeial 21. Leeson LJ. In vitro/vivo correlation. Drug Inf. J.
Convention; 1990. 1995;29:903–915.
5. Tsong Y, Hammerstrom T. Statistical issues in 22. FDA. Guidance on Statistical Procedures for
drug quality control based on dissolution testing. Bioequivalence Studies Using a Standard Two-
Proceedings of Biopharmaceutical section of Treatment Crossover Design. Rockville, Maryland:
American Statistical Association, 1994;295–300. Division of Bioequivalence Office of Generic
Tsong Y. Statistical assessment of mean Drugs, Food and Drug Administration.
differences,. between two dissolution data sets. 23. Moore JW, Flanner HH. Mathematical
Presented at the 1995 Drug Information comparison of curves with an emphasis on
Association Dissolution Workshop, Rockville, dissolution profiles. 1992 Pharma Technol.
Maryland. 6. Dawoodbhai S, et. al. Optimization of 1996;20:64–74
tablet formulation containing talc. Drug Dev Ind 24. Serfling RJ. Approximation Theorems of
Pharm. 1991;17: 1343–1371. Mathematical Marcel Dekker, Inc.; 1992.

Handbook of Pharmaceutical Sect: 16.

16 92 Generic Development
 ORAL TABLETS Technical Transfer CHAPTER 17

TTD
Technical Transfer
Documentation-Pharmaceutical

T he successful development and full-

scale manufacture of a newly
developed generic drug represents
reports and results that are in the
domain of the
development department.
Pharmaceutical

a difficult and complex process of The Pharmaceutical TTD file contains

integrating the new technology into the all necessary process methods,
existing production and control process qualification, product
infrastructure. Many steps must be specifications, technical data, reports,
completed before the company can tabulations and summaries based on
successfully manufacture the product in the Pharmaceutical development work
compliance with the specifications listed regarding the generic drug
in the application and GMP regulations. development from the pre-formulation to
Organizing a well structured TTD is one process qualification stage.
of these steps.
This data is required for manufacturing
TTDs should be and control of the pivotal submission
batch and the initial three full size
comprehensive validation batches produced at the
commercial manufacturing site facility.
and well Really g o o d
structured TTDs will
get your product
Moving the Technical Transfer to the market
Documentation from the development
or researched-based unit to
sooner
manufacture will enable production and TTD programs of excellence are more
quality control personnel to get to know than just transferring data. They include
the ins and outs of the newly developed an evaluation of the product
drug product. Such dossiers are development documentation
referred to as the ‘TTDs’ and consist of (Development Report’), the proposed
manufacturing process, the in-process
ü Material and product specifications specifications, and the quality systems
ü pharmaceutical manufacturing data used to control the product.
A guideline SOP is given.
ü analytical development methods W ell managed TTD programs are
ü microbiological procedures and essential to firms engaged in the
results development of new products which
require regulatory approval. A
ü stability profile, results and full
structured on-time program will improve
stability reports
efficiency and effectiveness in moving
This section deals with the the product from development to
Pharmaceutical TTD content. Data product launch. 3

Handbook of Pharmaceutical Sect: 17.

17 1 Generic Development
 ORAL TABLETS TECHNICAL TRANSFER CHAPTER 17

TTD
Technical Transfer
Documentation
‘the time has come the researcher said to speak of many things
- of pivotal and protocols and to validated cleanings...’

Technical Transfer Documentation Structure

T he purpose of the TTD is to
transfer all technical data from the
R&D or generic development
The technical information should be
structured in a well developed and
organized dossier containing all the
sections to the production,
product and process specific
engineering, laboratory quality control,
documentation and final specifications.
quality assurance and administration
The documentation should be written
personnel involved with producing the
in an easily understood manner and
newly developed generic drug.
similarly to SOPs contain a ‘read and
Which Data? understood’ paragraph or certification
The data is obtained from two pre- section.
existing sources:- the audited ANDA
Chemistry, Manufacturing and Control Production and
control personnel
section (CMC) and the Product
Development Report.
The efficient transfer of technology
from the development environment to
need to know
the full scale commercial
manufacturing plant is a complex
the new process
process. Technical Personnel
The TTD documents support this Production and control personnel at
overall manufacturing and control the selected manufacturing site will
process. The entire spectrum initiating ensure that the technical data has
from the purchasing of raw materials been clearly absorbed and understood
from approved suppliers to the final full prior to commencement of full scale
size validation protocol should be commercial or validation lot
covered by the transfer manufacture.
documentation. From the inspection point of view, the
Rationale TTD file is the basic documentation
Product development reports and that will be needed to support the
technology transfer documentation pending PAI agency program. Since
provide final CMC technology and the the FDA requires that the firm be
rationale of the component and prepared for the PAI program
process choices made during the (inspection-audit) at the time of file
product development. submission to agency headquarters,

Handbook of Pharmaceutical Sect: 17.

17 2 Generic Development
 ORAL TABLETS TECHNICAL TRANSFER CHAPTER 17

it is essential to transfer the TTD to Production Know-how

production well before the pending on- The pivotal batch ends with the Pivotal
site agency inspection. Batch Report and this report finalizes
The Pre-filing Audit. the Technical Transfer Documentation
Furthermore the firms should fully process. There should be no further
audit all raw data and control scale-up processing after the pivotal
documentation before filing the ANDA lot has been manufacture other than
to allow for corrections and possible possible fine-tuning adjustments to the
errors that may be present in the scaled-up process. No new process or
pharmaceutical, microbiological and product specification may be
analytical raw data. This essential introduced into the documentation
pre-filing audit will be an effective after the demonstration of the pivotal
measure of the sites ability and batch. In generic drug development
readiness to manufacture the newly the pivotal batch is usually the batch
developed drug product as well as the on which the bioequivalence study
firms readiness to deal with the FDA against a selected reference drug
during the forthcoming product-specific (RLD) is performed.
and GMP PA Inspection. It is this batch that is filed in the ANDA
submission. When a biostudy has
Firms may continue the review and been performed, the pivotal batch may
audit process after filing the ANDA to also be referred to as ‘the Biobatch’.
evaluate and address the current GMP
The Development Report
profile specific to the filed process.
The Development Report is a separate
Improvements or upgrading of the report containing all development
firms general GMP profile should not work, supporting information and
impact on or alter the filed data. collated data on the newly developed
The TTD process will allow the product. The preparation of a
manufacturing and control personnel development report is simply good
at the commercial site to be fully development practice and not an
updated and familiar with the CMC agency CFR or FDA requirement.
section portions of the TTD package. The Development Report and the
Since the TTD has been dove-tailed CMC together generally contain all
and integrated with the submitted necessary documentation for a
ANDA application containing product complete technical transfer of
and process specifications - site information to the commercial
personnel will be able to manufacture manufacturing and control sectors.
and control the initial three validation
lots and subsequent routine Development
commercial production lots without
disparity to the filed data. This is a Pharmaceutical
critical point pertaining to current FDA and
thinking and logic.
Analytical
The Development
Data
Report is is Transferred
part of the to the factory
Transfer Process floor

Handbook of Pharmaceutical Sect: 17.

17 3 Generic Development
 ORAL TABLETS TECHNICAL TRANSFER CHAPTER 17

[Master Formula; Process

TTD Contents Instructions; IPQC, Finished
Product Specifications]

T echnical Transfer Documentation

consists of five principle sections
targeting 10 key departments:
♦ Engineering Units
[cleaning validation ; Process
validation; Metrology (calibration-
◊ specifications for purchasing standards) HVAC System, Air
depart-ment (Active material System; Nitrogen System; Purified
‘Approved Suppliers’ detailed Water System, Water For Injection
specifications). System; Washing Tunnels;
◊ Manufacturing,
Autoclave Systems; Oven System;
engineering and Freeze Drier Systems; Sanitation
quality control procedures and Systems. (Where appropriate).
specifications of the generic drug
product and process. ♦ Quality Control Laboratory
◊ All analytical methodology and
[validated analytical methods;
impurity profiles; stability indicating
results including stability protocol and
test methods for assays, dissolution
results.
and impurities; in-process, release
◊ All microbiological methodology and and check specifications]
results. ♦ Microbiology Laboratory
◊ The Development Report and ANDA [validated microbial methods;
File and development notes and microbiological specifications.]
graphs.
♦ Stability Unit
Operational Departments [stability protocols; stability results
All Technical Transfer Documentation and reports; filed ANDA
is essentially contained in the ANDA commitments]
file and the Development Report.
However the data is rearranged into ♦ Quality Assurance
specific modules and targeted to the
[SOPs and checklists; In house and
following departments:
vendor audits programs and results]
♦ Purchasing and Procurement ♦ Regulatory Affairs
[active material; excipients; [Letters of Authorization; Approved
container-closures purchasing Suppliers update commitments etc.]
specifications to the 'Approved Raw
Material Suppliers' ]. ♦ Archives
[ANDA copy; Development Report;
♦ Artwork and Graphics
Process Optimization Report ;
[label; package insert or Outsert; Process Qualification Report; TTD
carton; blister strip, printing Reports; Development Notebooks,
requirements, as specified in the Pharmaceutical, Analytical, and
ANDA submission file] microbiological Notebooks and
Logs; Analytical HPLC IR UV etc.
♦ Manufacturing Process and graphs and charts].
Controls

Handbook of Pharmaceutical Sect: 17.

17 4 Generic Development
 ORAL TABLETS TECHNICAL TRANSFER CHAPTER 17

ØC H E C K L I S T ×
CL # P-HGD-03-01Y2K

TECHNICAL TRANSFER DOCUMENTATION

‘ …give the production unit all your experiences…

… also tell them what NOT to do… ‘

1. The buying department has purchasing specifications for the qYes qNo
procurement of approved actives, excipients and container-closure
systems ?
2. Printing specification and QA approved artwork for product labels, qYes qNo
cartons, package inserts and advertising claims are approved ?
3. The manufacturing formula and master processing instructions for each qYes qNo
commercial batch sizes are approved ?
4. Cleaning validation protocol specific to the active material is complete ? qYes qNo
5. The validation protocol for the first three consecutive batches is qYes qNo
approved?
6. All new manufacturing equipment has been fully qualified (IQOQ)? qYes qNo

7. The metrology department has calibrated all equipment recording qYes qNo
units?
8. Plant QC laboratory has evaluated the transferred analytical methods qYes qNo
for system suitability and robustness (ruggedness) ?
9. Microbiological laboratory has all methods and specifications? qYes qNo
10. Physical QC lab has all container-closure methods and qYes qNo
specifications?
11. All product specific SOPs have been distributed and signed as ‘read qYes qNo
and understood’ by the production operators and supervisors?
12. Stability unit has the ANDA commitment stability protocol (real-time qYes qNo
study) and the validation stability protocol for first three consecutive
batches?
13. All vendor DMF deficiencies (and GMP concerns) have been qYes qNo
corrected?
14. The CMC file is compiled in full and signed-off ? qYes qNo

15. The Product ‘Development Report’ is complete and signed-off ? qYes qNo

Handbook of Pharmaceutical Sect: 17.

17 5 Generic Development
 ORAL TABLETS TECHNICAL TRANSFER CHAPTER 17

STANDARD OPERATING
PROCEDURES
CL # P-HGD-03-01Y2K Page 1 of 1.

TECHNICAL TRANSFER DOCUMENTATION

The following Standard Operating Procedures are recommended for a generic

development unit :

Technical Transfer Documentation

P-T01-01-01Y2K The Pivotal Batch Report

P- T02-01-01Y2K Preparing The Technical Transfer Documentation

P- T03-01-01Y2K Checklist for a TTD File.

P- T04-01-01Y2K Defining the contents of a TTD File - in detail.

Footnote : In-house training must be given to all QC oratory staff, production

and QA sections on specific manufacturing and control aspects of the newly
developed drug as well as SOP training pertaining to the commercial aspects of
the generic drug manufacture

4
[End of Document]

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Handbook of Pharmaceutical Sect: 17.

17 6 Generic Development
 ORAL TABLETS TECHNICAL TRANSFER CHAPTER 17

STANDARD OPERATING
PROCEDURES
SOP # TTD-01-06Y2K

TECHNICAL TRANSFER DOCUMENTATION FOR ORAL TABLETS

Ø PHARMACEUTICAL PART ×
Page: 1 of 3
1. PURPOSE
The purpose of this Standard Operating Procedure is to establish the overall table of
contents for the preparation of the pharmaceutical part or section of the technical
transfer file for product information transfer to the selected commercial manufacturing
site facility. This SOP is specific for ANDA preparations covering oral tablets.

2. RESPONSIBILITY
The Head of Pharmaceutical Development together with the Responsible Researcher
for the Generic Drug Development Project.

3. FREQUENCY
Each ANDA product formula developed for the US market.

4. PROCEDURE or SCOPE
[4.1]. The responsible personnel for the product development will prepare the
pharmaceutical section of the technical transfer file (TTD) for process and data
information transfer to the commercial manufacturing site facility.
[4.2]. The Pharmaceutical TTD file will contain all necessary pharmaceutical master
formula, manufacturing methods, validation criteria, product specifications, technical
data, reports, tabulations and summaries based on the pharmaceutical development
work pertaining to all strengths of the generic drug development from the pre-
formulation to process qualification stage.
This data is required for the manufacture and control the pivotal submission batch
and the three initial full size validation batches produced at the commercial
manufacturing site facility.
[4.3]. Each section of the TTD File is presented in a modular form for ease of
updating. Sections are numbered [A] to [K]. The outline of the TTD requirements is
presented in a standard operating procedure format.
[4.4]. The requirements of the Pharmaceutical Technical Transfer documentation will
be part of the Product Development SOP for the specific dosage form. This
documents is based on formulation development for oral tablet dosage forms.
[4.5]. An pharmaceutical TTD SOP will be prepared for each separate generic dosage
form under product development. 3

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Handbook of Pharmaceutical Sect: 17.
17 7 Generic Development
 ORAL TABLETS TECHNICAL TRANSFER CHAPTER 17

STANDARD OPERATING
PROCEDURES
SOP # TTD-01-06Y2K

TECHNICAL TRANSFER DOCUMENTATION FOR ORAL TABLETS

Ø PHARMACEUTICAL PART ×
Page: 2 of 3

GUIDELINE TO PHARMACEUTICAL TTD REQUIREMENTS

Section [A]. - General ANDA Data (Prior to starting pharmaceutical work)
1.0 Basis for ANDA Submission approved.
1.1 Patent Certification statement.
1.2 No Process Patent infringement.
1.3 Exclusivity Statement has no infringements.
1.4 Comparison - Generic Drug and Reference Listed Drug composition performed.
1.5 Environmental Impact Analysis Statement.

Section [B]. - Active Ingredient

1.0 Letter of Access from US Applicant authorizing Approved Supplier # 1 and # 2
1.1 Letter of Access from Active Supplier(s) authorizing referencing of DMF to FDA
1.2 LOA notification of "Specification change statement" from Active Supplier/s #1 and #2
1.3 Active Ingredient Release Specifications (include particle size, bulk density).
1.4 Particle Size Specifications (and range).
1.5 Bulk Density Specifications (and range).
1.6 Certificates of Analysis of Drug Substance batches over past 12 months (6 copies).

Section [C]. - Non active Ingredients

1.0 LOA. from Approved Suppliers to US Applicant (ANDA Holder).
1.1 Raw Material Release Specifications per Ingredient.
1.2 Raw Material - Full Certificates of Analysis - per Ingredient - US Approved Suppliers.
1.3 Raw Material - Full Certificates of Analysis - per Ingredient - Non-US Suppliers.
1.4 Confirmation from US on Local Raw Material Availability in US (with C. of A.).
1.5 Raw Material Data Safety Sheet per Ingredient.
1.6 Qualification of each non-active vendor (approval statement)
1.7 GMP Certification of each non-active vendor.

Section [D]. - Container Closure System

1.0 LOA. from Approved Suppliers to US Applicant (ANDA Holder).

1.1 Statement from Container Manufacturers(s) indicating GMP status of MNF plant
1.2 Market Packaging (Container-Liner-Closure) Specifications.
1.3 Component Drawing and Specifications of container-liner-closure.
1.4 CFR / USP Certifications (as per Container-Closure SOP).

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Handbook of Pharmaceutical Sect: 17.
17 8 Generic Development
 ORAL TABLETS TECHNICAL TRANSFER CHAPTER 17

STANDARD OPERATING
PROCEDURES
SOP # TTD-01-06Y2K

TECHNICAL TRANSFER DOCUMENTATION FOR ORAL TABLETS

Ø PHARMACEUTICAL PART ×
Page: 3 of 3.

Section [E]. - Master Formula.

1.0 Master Formula and quantities (per unit dose and per 100 000 units)
1.1 Master Formula and quantities for each tablet strength.

Section [F]. - Manufacturing Procedure.

1.0 Detailed Manufacturing Procedures / method
1.1 Master Blank Batch Records for each batch size and strength
1.2 Safety Procedures and special precautions / remarks
1.3 Proposed Cleaning Validation Protocol
1.4 Proposed Process Validation Protocol
1.5 Manufacturing Standard Operating Procedures specific to new product
1.6 Reprocessing Statement.

Section [G]. - In-process Controls.

1.0 In-process Manufacturing Specifications
1.1 Frequency of In-process Test Procedures for plant QC
1.2 In-process Test Procedures for plant QC
1.3 Sampling protocol for in-process and finished product.

Section [H].- Finished Product Controls.

1.0 Finished Product Release Specifications.
Section [I]. - Stability.
1.0 Stability Check Specifications for the proposed shelf-life.
1.1 Stability Protocol.
1.3 Stability Reports and Tabulations on Development Batches.
1.4 Statement on proposed expiration date for production labeling
1.5 Stability Post Approval Commitments (given in Annual Reports).

Section [J]. - Audit and Review.

1.0 SOP Index and Checklists (read and understood - signed and dated)
1.1 Manufacturing and Control Audit Checklists (signed and dated)
1.2 Pharmaceutical Development Completion Form. (signed and dated).

Section [K] - Development Report.

1.0 Pharmaceutical Development Report. 3

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Handbook of Pharmaceutical Sect: 17.
17 9 Generic Development
 TABLETS ORAL TECHNICAL TRANSFER CHAPTER 17

STANDARD OPERATING
SOP # A-00-01-Y2K
PROCEDURES

CONTENTS OF THE TECHNICAL TRANSFER DOCUMENTATION

ANALYTICAL PART

Page: 1 of 3

1. PURPOSE
The purpose of this Standard Operating Procedure is to establish the overall table
of contents for the preparation of the analytical part or section of the technical
transfer file for product information transfer to the selected commercial
manufacturing site facility. This SOP is specific for ANDA preparations of solid oral
dosage forms.

2. RESPONSIBILITY
The Head of Analytical Development together with the Responsible Researcher for
the Generic Drug Development Project.

3. FREQUENCY
Each ANDA product formula under development intended for the US market.

4. PROCEDURE or SCOPE
[4.1]. The responsible personnel for the product development will prepare the
analytical section of the technical transfer file (TTD) for method and data information
transfer to the commercial manufacturing site facility.
[4.2]. The Analytical TTD file will contain all necessary analytical methods, method
validations, product specifications, technical data, reports, tabulations and
summaries based on the analytical development work pertaining to the generic drug
development from the pre-formulation to process qualification stage.
This data is required for testing and analyzing the pivotal submission batch and the
three initial full size validation batches produced at the commercial manufacturing
site facility.
[4.3]. Each section of the TTD File is presented in a modular form for ease of
updating. Sections are numbered [A] to [G]. The outline of the TTD requirements is
presented in the standard operating procedure format.
[4.4]. The requirements of the Analytical Technical Transfer documentation will be
part of the Product Development SOP for the specific dosage form. This documents
is based on a Q&Q formulation development for solid oral dosage forms.
[4.5]. An analytical TTD SOP will be prepared for each separate generic dosage form
under product development.

4
[End of Page]

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Handbook of Pharmaceutical Sect: 17.
17 10 Generic Development
 TABLETS ORAL TECHNICAL TRANSFER CHAPTER 17

STANDARD OPERATING
SOP # A-00-01-Y2K
PROCEDURES

CONTENTS OF THE TECHNICAL TRANSFER DOCUMENTATION

ANALYTICAL PART
Page: 2 of 3

GUIDELINE TO ANALYTICAL TTD REQUIREMENTS

Section [A]-General ANDA Data (prior to starting analytical work)

1.0 Basis for ANDA Submission approved.
1.1 Patent Certification clear.
1.2 Exclusivity Statement clear .
1.3 Comparison - Generic Drug and Reference Listed Drug composition.
1.4 Innovator's Insert obtained via FDA FOI (latest edition).

Section [B]. - Active Ingredient

1.0 Letter of Authorization from US Applicant authorizing Approved Supplier # 1 and # 2
1.1 Letter of Authorization from Active Supplier(s) authorizing referencing of DMF to FDA
1.2 LOA notification of "Specification change statement" from Active Supplier(s) #1 & #2.
1.3 Active Ingredient Release Specifications (include particle size, bulk density).
1.4 Pharmacopoeia Assay method (if, USP).
1.5 Validated Assay Method and S-I Study Results - (if assay is not USP).
1.6 Limit Tests on Impurities and Method Validation (when required).
1.7 Summary Report in Impurity Profile of active substance.
1.8 Certificates of Analysis of Drug Substance batches over past 12 months (6
copies).

Section [C]. - Non active Ingredients

1.0 LOA. from US Applicant authorizing selected US Approved Suppliers.
1.1 Raw Material Release Specifications per Ingredient.
1.2 Raw Material - Full Certificates of Analysis - per Ingredient - US Approved Suppliers.
1.3 Raw Material - Full Certificates of Analysis - per Ingredient - Non-US Approved
Suppliers.
1.4 Confirmation from US on Local Raw Material Availability in US (with C. of A.).
1.5 Raw Material Test Methods (Compendial and Non-compendial) per Ingredient.
1.6 Statement that Inactive Ingredients (at max. conc. per route) in FDA Inactive
Ingredient Guide.

Section [D]. - Container Closure System

1.0 Letter of Authorization (LOA) from US Applicant authorizing Approved Supplier
1.1 LOA. from Container Manufacturers(s) authorizing referencing of DMF to FDA
1.2 Market Packaging (Container-Liner-Closure) Specifications.
1.3 Side-by Side Comparison of Applicant and RLD Component Specifications.
1.4 Component Drawing and Specifications of container-liner-closure.
1.5 CFR / USP Certifications (as per Container-Closure SOP)

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Handbook of Pharmaceutical Sect: 17.
17 11 Generic Development
 TABLETS ORAL TECHNICAL TRANSFER CHAPTER 17

STANDARD OPERATING
SOP # A-00-01-Y2K
PROCEDURES

CONTENTS OF THE TECHNICAL TRANSFER DOCUMENTATION

ANALYTICAL PART
Page: 3 of 3.

Section [E]. - In-process Controls.

1.0 In-process Control Specifications (Bulk)
1.1 In-process Test Procedures
1.2 Results of In-process Control tests (including print-outs)
1.3 Assay method statement - i.e. same as Release Assay.

Section [F]. - Finished Product Controls.

1.0 Finished Product Release Specifications
1.1 Finished Product Test Methods
1.2 Pharmacopeial Assay method (if USP)
1.3 Validated Assay (if not USP) - same as Stability Assay.
1.4 Limit Tests on Impurities and Method Validation (where required).
1.5 Certificate of Analysis of Applicant's Product.
1.6 Certificate of Analysis of Innovator's / RLD Drug.

Section [G]. - Stability.

1.0 Stability Check Specifications for the proposed shelf-life.
1.1 Stability Protocol.
1.2 Stability Summary of Applicant's Generic Product.
1.3 Stability Summary of Innovator's / RLD Drug. (2 or 3 lot #’s)
1.4 Stability Reports and Tabulations on Drug Substance from Approved Supplier.
1.5 Stability Reports and Tabulations of Applicant's Product.
1.6 Stability Reports and Tabulations of Innovator's/RLD Drug.
1.7 Statement on proposed expiration date
1.8 Method for Drug Substance Assay.
1.9 Method for Drug Product Assay.
2.0 Assay method validation
2.1 Stability-Indicating Test Results

Section [H]. - Audit and Review.

1.0 Vendor Compliance Audit - Approved Active Supplier/s (On-site, Mail or Fax Audit).
1.1 SOP Index and Checklists (read and understood - signed and dated)
1.2 Audit Checklists (signed and dated)
1.3 Project Completion Form. (signed and dated) 3

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Handbook of Pharmaceutical Sect: 17.
17 12 Generic Development
 ORAL TABLETS PROCESS VALIDATION CHAPTER 18

Process Validation
‘…process validation needs to show that the data from the first three
commercial lots of each batch size are essentially similar and compare
well with product data of the biobatch…’

VALIDATION three consecutive commercial batches

to be validated.
Validation is a quality system
to ensure that quality is designed into a Consistency
product and process. The FDA define The validation process must
the term as: demonstrate that the overall
…Establishing documented evidence manufacturing process performs
which provides a high degree of consistently, as expected, and that the
assurance that a specific process will generic drug product consistently meets
consistently produce a product meeting its predetermined filed specifications
its predetermined specifications and (i.e. in-process & finished product
quality attributes… specifications).
The use of validation to establish Validation Timing
acceptability of a product formula and The generic drug process must be
manufacturing process has been an validated before the product is
ongoing process in the pharmaceutical distributed and shipped, i.e. usually the
industry and the cornerstone to the time between FDA approval and first
development of a critical quality system. marketing.
A strict requirement for the validation is Experienced companies may well
the preparation of a validation protocol, validate the process prior to approval, if
which as defined by the FDA is; the risk is considered minimal and it is
"…A written plan stating how validation thought the FDA review letter will not
will be conducted, including test challenge the process or product
parameters, product characteristics, specifications.
production equipment and decision
Cleaning Validation
points on what constitutes acceptable
Approved cleaning validation must be
test results …"
performed immediately after the pivotal
Note the ' decision points ' include a and after each of the first three
sampling protocol as to where, when commercial batches.
and how much sample will be taken at a
specific time point. Samples during a
Cleaning validation specifications are
essentially part of the generic product
validation run exceed by some tenfold
development program and are in place
normal production batch runs - since
before the validation process.
the actual work in validation involves
collecting large numbers of samples for Validation Parameters
QC evaluation as per the written The parameters shown in the table
validation sampling protocol generally impact on the consistency of
When performing process validation or the bulk and finished product and are
re-validation on of the most critical part of the overall development
elements to be determined are then validation plan from initial development
acceptance criteria to be utilized to to process optimization and process
measure success. qualification, then finally concluding
The requirements of an FDA approved with the process commercial validation
generic drug product requires the first of the first three consecutive production
lots.

Handbook of Pharmaceutical Sect: 18.

18 1 Generic Development
 ORAL TABLETS PROCESS VALIDATION CHAPTER 18

ØC H E C K L I S T ×
CL # PV-05-03-01Y2K

PROCESS VALIDATION BATCH

‘…to demonstrate that the process really works... ’

1 The manufacturing product and processing controls of the commercial lots are qYes qNo
substantially the same (equivalent) as those listed in the ANDA filing?
2. Before the validation process and validation batches are run, the firm has qYes qNo
conducted a thorough and comprehensive on-site review and audit of all
development and analytical raw data?
3. The firm has performed a side-by-side evaluation of the validation protocol and qYes qNo
the submitted ANDA file to ensure that the product and process specification and
control points are common in both documents?
4. QC conducts routine particle size and bulk density analysis on the active qYes qNo
material(s) present in the drug product (a particle size range is given)?
5. Particle size and bulk density QC specifications have been established for the qYes qNo
active material(s) present in the final product formula?
6. During the product development the finished product has been evaluated at qYes qNo
both ends of the particle size and bulk density ranges and suitable meet the
finished product specification?
7. Process controls on granulator-mixers (time, rpm and settings) are qYes qNo
documented in the full scale commercial process instructions?
8. Uniformity of Content is a critical processing parameter for the bulk qYes qNo
granulation material after the blending process and prior to compression?
9. Granulation samples taken during sampling operations - for the assay qYes qNo
determination - are equivalent to one dosage unit?
10. In the event that it is not possible to obtain the equivalent of one dosage qYes qNo
unit in granulation samples, the closest approximation should be sampled (a
function of sampling thief used)?
11. A tapered sampling thief may during sampling operations be unsatisfactory qYes qNo
for sampling the equivalent of one dosage unit uniformly (use uniform diameter
thieves)?
12. Uniformity of Content is evaluated after the blending process with and qYes qNo
without lubricants added ?
13. Manufacturing instructions clearly indicate corrective action taken where qYes qNo
older mixers or blenders (pony / ribbon) display ‘dead spots’ where no direct
mixing action can occur (around shaft / bearing area or discharge valves) ?

Handbook of Pharmaceutical Sect: 18.

18 2 Generic Development
 ORAL TABLETS PROCESS VALIDATION CHAPTER 18

ØC H E C K L I S T ×
CL # PV-05-03-01Y2K

PROCESS VALIDATION BATCH

‘…and to show equivalency with the pivotal / biobatch... ’

14. Dedicated FBD bags are used for drug products containing colored qYes qNo
or insoluble active drug substances?
15. All critical process parameter temperature and time controls qYes qNo
incorporate automatic recording equipment?.
16. The product batch number and date is routinely entered on the qYes qNo
automatically recording temperature and time control graphs?
17. Dissolution profiles are performed on 12 dosage units for each of qYes qNo
the three validation lots. Note: Six units are appropriate when
generating the Q release data.
18. Where validation batches are used for sale then routine Finished qYes qNo
Product Testing must be performed on composite sample representative
of the overall production run.
19 This sampling procedure is a routine procedure and independent qYes qNo
and separate to the validation sampling requirements?
20. Assay, Content Uniformity, and Dissolution testing are critical qYes qNo
parameters and results are compared side-by-side to the bioequivalent /
pivotal batch for equivalency?
21. Equivalency of the bioequivalent / pivotal batch with the validation qYes qNo
batch lots implies a variation < 5% from the filed Biobatch?
22. All results, including failing results (if any) have been fully qYes qNo
discussed and explained in the validation report?
23. The basis for concluding that the validation process is satisfactory, qYes qNo
particularly those batch lots with failing results has been fully evaluated
in the validation report?
24. Any out-of-specification product or process result during validation qYes qNo
will be fully investigated and an Investigation Report will be completed
and signed-off within 30 days ?
25. A separate ‘Validation Concluding Statement’ is included in the qYes qNo
validation report? (Place on the approval page).
26. The ‘validation concluding statement’ indicates that the three qYes qNo
production lots are equivalent in all aspects to the filed ANDA batch?

Handbook of Pharmaceutical Sect: 18.

18 3 Generic Development
 ORAL TABLETS PROCESS VALIDATION CHAPTER 18

STANDARD OPERATING
PROCEDURES
CL # PV-05-03-01Y2K Page 1 of 1.

PROCESS VALIDATION BATCH

The following Standard Operating Procedures are recommended for a generic

development unit :

The Process Validation Batches

P-HBPD - 05-01Y2K Performing Validation with ‘old type‘ equipment.

P- HBPD - 10-01Y2K Do’s and Don’ts when preparing for Validation Batches.

P- HBPD - 15-01Y2K Documentation requirements for the Validation Batches.

P- HBPD - 20-01Y2K Validation Batch Guidelines for Solids Dosage Forms.

P- HBPD - 25-01Y2K Bioequivalency and Validation Batch comparisons.

P- HBPD - 30-01Y2K Dissolution requirements for the validation batches.

P- HBPD -35-01Y2K Handling Failed Validation Batches.

P- HBPD -40-01Y2K Preparing the Validation Concluding Statement.

Footnote : During the pre-approval inspection the proposed commercial

manufacturing documentation (each batch size) is subject to inspection.
These processing instructions will be compared to the pivotal batch
(ANDA) documentation and examined for substantial similarity
(comparability). The FDA require that the plant be ready for a PAI
inspection when the firm files the application.

4
[End of Document]

ED. N0: 02 Effective Date: APPROVED:

Replaces Ed 01.
Ed. Status: MM/DD/2000
Operational Department R&D QC QA

Handbook of Pharmaceutical Sect: 18.

18 4 Generic Development
 ORAL TABLETS PROCESS VALIDATION CHAPTER 18

Validation Batch
GUIDELINES
‘…The validation batch is proof positive that the commercial process really works…‘

PROCESS VALIDATION What does the PROCESS

Solid Dosage Forms VALIDATION do?
The intention of the validation is to

T
hese Guidelines are suitable for
challenge every aspect of the
post pivotal commercial
manufacturing filling and packaging
validation of solid dosage forms.
process and written instructions and
The guidelines are supplemented by
then test that all written product
various guideline SOPs, flowcharts
specifications are within limits.
and process validation checklists.
NOTE:-The minimum number of
batches is three lots per strength.
The Guidelines are suitable for a:-
What documentation must I
1. Oral IR Tablet Dosage Form have?
2. Oral IR Capsule Dosage Form Documentation must be
3. Solid Oral MR/CR Dosage Complete i.e.
Form PRODUCTION
Full master formula and manufacturing
Prior to starting the Process instructions for each batch size and a
Validation, each validation procedure master validation SOP plus validation
requires the following FIVE key protocol with all supporting analytical
documentation packages. test documentation.
ANALYTICAL
a. General Validation Guideline The assay and dissolution test must be
b. Validation Master SOP fully validated at this stage and be
c. Validation Protocol (Specific) 'essentially similar' the pivotal or
d. Validation Checklist (Specific) demonstration batch.
e. Validation Flowchart (Specific) Where are the 3 validation lots
made?
At the end of the Process Validation a Full Commercial conditions
Process Validation Report is prepared. The three Validation batches are
manufactured in the plant’s
This Process Validation Report commercial facilities where the
contains the test results and marketing lots will be produced, using
conclusions of the Validation Protocol standard production raw materials
specific to the dosage form evaluated from the warehouse and production
personnel, as well as routine QA
f. Product Validation Report. procedures.

Handbook of Pharmaceutical Sect: 18.

18 5 Generic Development
 ORAL TABLETS PROCESS VALIDATION CHAPTER 18

What equipment must I use? Final minor specification and

documentation editing is performed
Production Equipment after the manufacturing and packaging
The manufacturing equipment used of the three validation Batch lots.
are the same operating principles
(same model) as planned for the
Is filling and packaging part of
marketing lots utilizing routine the validation procedure?
operation production SOPs YES, - there are FOUR stages to
What validated cleaning commercial process validation
procedure must I use? Manufacturing
Standard Production cleaning Filling Process
The cleaning procedures must be Packaging Process
validated and similar to the conditions Product Testing (in-process +
under which the routine commercial
final)
lots will be manufactured.
What is the importance of the
What does the validation
report look like?
three validation lots?
The validation report contains all the
Full Commercial Simulation statistical analysis of the test sample
The three Validation LOTS are a full results that have been performed on
simulation of the commercial process the variety of samples taken during the
with complete process documentation validation of the three batch lots.
and fully validated analytical methods,
for testing the drug product
What does the Technical
During pivotal and validation testing Transfer Documentation look
the analytical assays must be fully like?
validated and at the level of a stability Technical Transfer Documentation.
indicating assay analysis. The PQ and three validation lot
Modified release an controlled release
manufacturing dossiers, plus in-
products require THREE pivotal Batch
process and end product test results
Lots as compared to one lot for
and statistical graphs are the principal
immediate release.
documents in the Technical Transfer
NOTE: For MR dosage forms each Documentation Dossier (TTD).
strength and lot size is defined. There
are Three (3) pivotal batch lots per lot This dossier is transferred from the
size and three validation lots of each Validation Unit to the commercial plant
commercial batch size. production unit after the statistical
Are minor process or analysis has been performed on all the
tests carried out on the samples of the
specification changes allowed three validation batch lots.
as a result of the validation All new information resulting from the
batch analysis of three lots? validation runs are added to the
YES, - Minor specification changes standard production procedures (batch
are allowed if shown to be significant documents) and are included in the
in the product validation report Validation Report.
analysis.

Handbook of Pharmaceutical Sect: 18.

18 6 Generic Development
 ORAL TABLETS PROCESS VALIDATION CHAPTER 18

OVERALL VALIDATION PLAN

SOLID ORAL DOSAGE FORMS
PARAMETER EVALUATED [a] [b] [c] [d] [e]
Development Develop & Process Process Process
QC Testing Optimization Qualification Validation

Particle size controls on actives [a] [c]

Pivotal Lot
Bulk Density controls on actives [a] [c]
to include
Purified Water USP bioburden [a] in ANDA
Addition rates to granulator [a] fits in [c] [d]
between
Critical Process Parameters [CPP] - [a] [D] & [E] [c] [d]
Controls on mixing speeds, chopper I/II
Re-mixing step - max. time allowed? [a] [c] [d]
Drying temperatures time [a] [c] [d]
Milling parameters - mesh size, milling [a] [c] [d] End
Formula & Process Development Validation
speed, knife position
Critical process parameters - control on [a] [c] [d]
LOD / FBD / Tray Drier Temp.
LOD Range Qualification [d]
Content Uniformity [a] [b] [c] [e]
Blender LHS. + RHS. [a] [d] [e]
Weight vs. rpm testing [a] [c] [d] [e]
Hardness range qualification [d]
Content Uniformity Qualification [a] [d] [e]
Written Sample plan / protocol [d] [e]
Dead-spot position sampling [d] [e]
Assay results cf. pivotal lot [e]
Dissolution profile cf. pivotal lot [e]
Thickness / Hardness / Friability / [a] [b] [c] [d] [e]
Disintegration / Dissolution controls
Individual weight control. [b] [c] [d] [e]
10 unit weight control (average). [b] [c] [d] [e]
Processing time limitations. [b] [e]
Recording devices and charts. [d] [e]
KEY
[a] - During product development
[b] - During product development and QC tested in commercial validation
[c] - During formula / Process Optimization
[d] - During Process Qualification
[e] - During post pivotal THREE Process Validation Lots
NOTE: The above parameters impact on the consistency of the in-process and finished product and comprise of the
overall development validation plan from formulation through process optimization and process qualification to the
final tree lot commercial validation. The Pivotal batch is placed between Process Qualification and Process Validation

Handbook of Pharmaceutical Sect: 18.

18 7 Generic Development
 ORAL TABLETS PROCESS VALIDATION CHAPTER 18

ØG u i d e l i n e s ×
CL # CVG-S04-Y2K

PROCESS VALIDATION
‘…well developed process validation batch lots with good in-process controls
and excellent documentation will ensure failure-free COMMERCIAL production…’

1. The Process validation batch is equal to 100% of the smallest, middle or qYes qNo
largest commercial batch size? Each size must be validate separately.
2. The active material source has been qualified as an ‘Approved Supplier’ ? qYes qNo
3. All non actives are routine production excipients and have been approved? qYes qNo
4. The container closure-system is the final chosen marketing pack? qYes qNo
5. The Master Product Formula Record has all authorization signatures ? qYes qNo
6. The Master Manufacturing Batch Instructions has all authorization qYes qNo
signatures?
7. The manufacturing flow chart (identifying all manufacturing equipment and qYes qNo
process parameters) is final with all authorization signatures?
8. In-process QC specifications and processing parameters are complete? qYes qNo
9. Standard packaging instruction (including sampling protocol) are complete? qYes qNo
10. Release Specifications (with narrower lower and upper limits) are complete? qYes qNo
11. Check Specifications (with maximum lower and upper limits) are complete? qYes qNo
12. Overall Finished Product Specifications are complete? qYes qNo
13. The process validation PROTOCOL is written and signed-off ? qYes qNo
14. The analytical assay methods and stability indicating assay are complete? qYes qNo
15. The process validation is a full commercial batch performed after the qYes qNo
PIVOTAL batch
16. The Content Uniformity PROTOCOL is prepared for evaluation during qYes qNo
process validation batch manufacture.
17. The Uniformity of Content PROTOCOL will be evaluated during the qYes qNo
process validation batch manufacture?
18. Hardness Vs Dissolution testing (target value and range extremes) have qYes qNo
been performed, so as to produce an acceptable dissolution profile at all harness
values

Handbook of Pharmaceutical Sect: 18.

18 8 Generic Development
 ORAL TABLETS PROCESS VALIDATION CHAPTER 18

ØG u i d e l i n e s ×
CL # PVG-S04-Y2K

PROCESS VALIDATION
‘…process validation needs to show that the data from the first
three commercial lots of each batch size are essentially similar
and compare well with product data of the biobatch…’

19. All critical process parameter temperature and time controls qYes qNo
incorporate automatic recording equipment?.

20. The product batch number and date is routinely entered on the qYes qNo
automatically recording temperature and time control graphs?

21. Dissolution profiles are performed on 12 dosage units for each of qYes qNo
the three validation lots.

Note: Six units are appropriate when generating the QC release data.

22. Where validation batches are used for sale then routine Finished qYes qNo
Product Testing must be performed on composite sample representative
of the overall production run.
23. This sampling procedure is a routine procedure and independent qYes qNo
and separate to the validation sampling requirements?
24. Assay, Content Uniformity, and Dissolution testing are critical qYes qNo
parameters and results are compared side-by-side to the bioequivalent/
pivotal batch for equivalency?

25. Equivalency of the bioequivalent / pivotal batch with the validation qYes qNo
batch lots implies a variation < 5% from the filed Biobatch?

26. All results, including failing results (if any) have been fully qYes qNo
discussed and explained in the validation report?
27. The basis for concluding that the validation process is satisfactory, qYes qNo
particularly those batch lots with failing results has been fully evaluated
in the validation report?

28. Any out-of-specification product or process result during validation qYes qNo
will be fully investigated and an Investigation Report will be completed
and signed-off within 30 days ?

29. A separate ‘Validation Concluding Statement’ is included in the qYes qNo

validation report? (Place on the approval page).

30. The ‘validation concluding statement’ indicates that the three qYes qNo
production lots are equivalent in all aspects to the filed ANDA batch?

Handbook of Pharmaceutical Sect: 18.

18 9 Generic Development
 ORAL TABLETS PROCESS VALIDATION CHAPTER 18

ØG u i d e l i n e s ×
CL # PVG-S03-Y2K

PROCESS VALIDATION
Commercial LOT Requirements
SOPs & Protocols - (Master Documentation Preparation)
1. Master Validation SOP is prepared and approved qYes qNo
2. VALIDATION PROTOCOL prepared and approved qYes qNo
3. CONTENT UNIFORMITY PROTOCOL prepared and approved qYes qNo
4. HARDNESS Vs DISSOLUTION PROTOCOL prepared and approved qYes qNo

OPERATIONAL PARAMETERS
1. FULL PRODUCTION FACILITIES qYes qNo
2. VALIDATION LOTS SIZE = COMMERCIAL SIZE qYes qNo
3. STANDARD PRODUCTION DOCUMENTATION PACKAGE qYes qNo
4. ROUTINE SOPS ; ROUTINE STAFF ; ROUTINE QC ; ROUTINE QA qYes qNo

SIMILARITY TESTING
1. Includes minimum of FIRST THREE commercial batch lots PER size qYes qNo
2. Minimum of FIRST THREE commercial batch lots PER dosage strength qYes qNo
3. Similarity Testing Performed on FIRST THREE commercial batches qYes qNo
4. Similarity Testing evaluated COMPARING commercial batch lots qYes qNo
(between themselves - intrabatch) and between the Pivotal Biostudy batch
lot as well (inter-batch comparison).

VALIDATION REPORTS
5. TEST RESULTS OF VALIDATION SAMPLING PLAN qYes qNo
6. TABULATION OF TEST RESULTS AND SUPPORTING GRAPHS qYes qNo
7. PRODUCT VALIDATION REPORT qYes qNo
ED. N0: 03 Effective Date: APPROVED:
Replaces 02
Ed. Status : DD / MM / Y2K
Current
Department R&D RA QC / QA
The validation requirements of an FDA approved generic drug product requires that the first three
consecutive commercial batches to be validated. The validation process must demonstrate that the
overall manufacturing process performs consistently, as expected, and that the generic drug product
consistently meets its predetermined filed specifications (i.e. in-process & finished product
specifications).

Handbook of Pharmaceutical Sect: 18.

18 10 Generic Development
 ORAL TABLETS PROCESS VALIDATION CHAPTER 18

ØG u i d e l i n e s ×
CL # PVG-D03-Y2K

VALIDATION PROTOCOL
The Contents of a Validation Protocol
VALIDATION PROTOCOL - (Tablet & Capsule Forms)
n PURPOSE of DISSOLUTION STUDY ¨Yes ¨No
n RESPONSIBILITIES of LAB PERSONNEL ¨Yes ¨No
n FREQUENCY of Testing ¨Yes ¨No
n ANALYSIS - CRITICAL STEPS - DEFINED ¨Yes ¨No
n CRITICAL PARAMETERS - LIMITS & TARGET VALUES SPECIFIED ¨Yes ¨No
n SAMPLING PLAN - Written ¨Yes ¨No
n TESTING PLAN - Physical & Chemical ¨Yes ¨No
n ACCEPTANCE CRITERIA ¨Yes ¨No

SAMPLING PLAN - (Solid Dosage Forms)

n Tablet / Capsules - Physical Tests Only qYes qNo
n UNIT WEIGHT - (3-4 Intervals during filling run) ¨Yes ¨No
n LOWER LIMIT HARDNESS - HARDNESS VS DISSOLUTION Testing (Tabs) ¨Yes ¨No
n UPPER LIMIT HARDNESS - HARDNESS VS DISSOLUTION Testing (Tabs) ¨Yes ¨No

PHYSICAL TESTING PLAN - (Solid Dosage Forms)

All Tablets (% of lot size)1 ALL Capsules ¨Yes ¨No

LOWER LIMIT HARDNESS 1(>15%) TARGET WEIGHT ~70% ¨Yes ¨No

UPPER LIMIT HARDNESS 1(>15%) DISSOLUTION TESTING - ALL ¨Yes ¨No

All Tablets LOWER LIMIT DISSOLUTION ¨Yes ¨No

TARGET WEIGHT 1(>75%) UPPER LIMIT DISSOLUTION ¨Yes ¨No

LOWER/UPPER LIMIT WEIGHT TARGET LIMIT DISSOLUTION ¨Yes ¨No
All Tablets Content Uniformity - All Dosages ¨Yes ¨No
Thickness; Friability; Wt Uniformity STABILITY TESTING ¨Yes ¨No
Stability Profile (Normal + stressed) ¨Yes ¨No

VALIDATION LOT DISSOLUTION REPORT

• Aim and Purpose of Study • Acceptance Criteria Evaluation
• List of Materials used • Analysis of Results (+ statistical)
• List of Testing Equipment (Pre-Qualified) • Similarity Statement
• Critical Test Steps Studied • Additional Test Recommendations
• Results of Data Collected • Attachments (Assay Results & CoAs)

ED. N0: 03 Effective Date: APPROVED:

Replaces 02
Ed. Status : DD / MM / 2000
Current
Department R&D RA QC / QA

Handbook of Pharmaceutical Sect: 18.

18 11 Generic Development
 ORAL TABLETS PROCESS VALIDATION CHAPTER 18

ØG u i d e l i n e s ×
Sampling Record for Final Granulate
PRODUCT STRENGTH q- LAB RECEIPT No
Batch No: Date of Sampling: Sampling Unit No: Die No:
q PIVOTAL & q BIOEQUIVALENCE LOT q PROCESS QUALIFICATION LOT
q VALIDATION LOT q RE-VALIDATION LOT
Milled No of Weight of TOP MIDDLE BOTTOM Time Signature
Granulate Samples Sample - g

Final
Granulate

Sampling Record for Compression or Filling

q Tablets q- MACHINE TYPE:
q Capsule Filling q- LAB RECEIPT No
Machine LOW HIGH No of Units LEFT RIGHT Time Signature
No: Hardness Hardness SAMPLED
TARGET SPEED - RPM
q q
q q
q q
q q
LOW SPEED - RPM
q q
q q
q q
q q
HIGHSPEED - RPM
q q
q q
q q
q q

Sampling Record for Coating

q Tablet Coating q Granule Coating
q Caplet Coating q- LAB RECEIPT No:
Sublot No: Machine Quantity Sampled Time: Signature
No: in Grams ~ 100 tabs. :
Sublot 1
Sublot 2
Sublot 3
Sublot 4
Sublot 5

Handbook of Pharmaceutical Sect: 18.

18 12 Generic Development
 ORAL DOSAGE FORM PROCESS VALIDATION CHAPTER 18

PROCESS OPTIMIZATION VALIDATION M A S T E R PLAN.

Choice of
FORMULA
PROCESS 1. LOD QUALIFICATION
OPTIMIZATION
2. LUBRICANT QUALIFICATION
FORMULATION
Drug Development Phase (VIA WRITTEN PROTOCOLS)

SCALE-UP

Choice of
PROCESS PROCESS QUALIFICATION
The Documentation
PROCESS OPTIMIZATION

PIVOTAL BATCH
VALIDATION - PROTOCOL
SAMPLING PLAN
TESTING PLAN
VALIDATION
3 Full Size Batches VALIDATION REPORT

MARKETED PRODUCT

RE-VALIDATION
of Commercial Product after;
MAJOR
CHANGE
[1] New Process Equipment Introduced
[2] Major Process Change.

Handbook of Pharmaceutical Sect: 18.

18 13 Generic Development
 ORAL TABLETS PROCESS VALIDATION CHAPTER 18

PROCESS VALIDATION M A S T E R PLAN.

FORMULATION
Drug Development Phase

INTRA-BATCH VARIABILITY
(Reproducibility of the
O P T I M I Z A T I O N
Three Validation Lots)
via:
• Dissolution Profile
• Content Uniformity
• Parameters within LCL-UCL Range SCALE-UP

INTER-BATCH EQUIVALENCY PROCESS QUALIFICATION

(Equivalency of the three Validation Lots
and the Biostudy Batch) The Documentation
• Dissolution Profile
PIVOTAL BATCH
VALIDATION - PROTOCOL
CRITICAL STAGES SAMPLING PLAN
1. Milled granulate VALIDATION
2. Final Blend TESTING PLAN
3 Full Size Batches
3. Tablet Compression
VALIDATION REPORT
4. Tablet Coating
5. Capsule Filling

MARKETED PRODUCT
CONTROL LIMITS
UCL
LCL
RE-VALIDATION
MAJOR of Commercial Product after;
PROCESS CAPABILITY CHANGE [1] New Process Equipment Introduced
CP ≤ 1 [2] Major Process Change.

Handbook of Pharmaceutical Sect: 18.

18 14 Generic Development
 ORAL TABLETS PROCESS VALIDATION CHAPTER 18

PROCESS VALIDATION M A S T E R PLAN THE DOCUMENTATION

VALIDATION PROTOCOL
• PURPOSE of STUDY
STEP
• RESPONSIBILITIES of PERSONNEL
• FREQUENCY
• PROCESS - CRITICAL STEPS - DEFINED
ONE
• CRITICAL PARAMETERS - SPECIFIED
• SAMPLING PLAN
• TESTING PLAN SAMPLING PLAN - Solid Dosage Forms
• ACCEPTANCE CRITERIA
MILLED GRANULATE - Physical Tests Only
FINAL BLEND - Content Uniformity - Unit Dose Sampling
TABLET COMPRESSION - Monograph Testing (3-4 Intervals) TWO
TABLET COATING - Monograph Testing

TESTING PLAN
CORES COATED
Tablet Weight Tablet Weight
Thickness Thickness
Hardness & Hardness Qualification Profile -
Friability / Disintegration - (if necessary) -
Assay (composite 10 cores) Assay THREE
Content Uniformity Content Uniformity
Dissolution Dissolution
Dissolution Profile (Hardness Qualification) Dissolution Profile

VALIDATION REPORT
• Aim and Purpose of Study • Acceptance Criteria Evaluation
• List of Raw Material used in MNF • Analysis of Results (+ statistical) FOUR
• List of MNF Equipment (Pre-Qualified) • Validation Statement of Process
• Critical Process Steps Studied • Validation Recommendations
• Results of Data Collected • Attachments (Batch Records & CoAs)

Handbook of Pharmaceutical Sect: 18.

18 15 Generic Development
 ORAL TABLETS PROCESS VALIDATION CHAPTER 18

PROCESS VALIDATION ORAL DOSAGE

MASTER P RFORMS
OTOCOL
Commercial Validation
SIMILARITY TESTING
is performed here

INTRA-BATCH VARIABILITY
(Reproducibility of the
Three Validation Lots) VALIDATION BATCH
via:
• Dissolution Profile
• Content Uniformity
• Parameters within LCL-UCL Range
VALIDATION LOTS
Minimum 3 Full Size Batches
per strength and size

INTER-BATCH EQUIVALENCY
The Validation Documentation
Show Statistical Similarity
(Equivalency of the three Validation Lots
and the Biostudy Batch) VALIDATION - PROTOCOL
• Dissolution Profile

CRITICAL STAGES SAMPLING PLAN

1. Milled granulate (LOD Flow etc.) TESTING PLAN

CONTROL LIMITS
UCL 2. Final Dry Blend (UoC + granule flow)
3. Product Wt (fill or compression weight) VALIDATION REPORT
LCL
4. Dissolution Profile

PROCESS CAPABILITY
MARKETED PRODUCT
CP ≤ 1
RE-VALIDATION
MAJOR of Commercial Product after;
CHANGE [1] New Process Equipment Introduced
[2] Major Process Change.

Handbook of Pharmaceutical Sect: 18.

18 16 Generic Development
 TABLETS ORAL P R E - A P P R O V A L S CHAPTER 19

Pre-Approval
Inspections
'…Did you do what you wrote? - Can you do what you said?…'

P AIs (Pre-approval inspections) may

be feared with some trepidation or
looked forward to with a knowing
and key Regulatory concerns.
Prior to the PAI inspection team’s
arrival, the PAI members are expected
assurance that the Generic or to carefully review the data pertaining
Research-based Company will pass the to the product specific ANDAs / NDAs
agency inspection, probably with a few and to select those issues that may
minor agency orientated requests in need careful attention during the
order to bring the company into line coming on-site inspection.
with current FDA and cGMP thinking. As a minimum requirement, every
This chapter deals with the nuts-and- inspection undertaken focuses on an in-
bolts issues of PAIs pertaining to the depth evaluation of process and
Development, Regulatory, cGMP laboratory tests failures, and product
requirements of a newly developed process changes.
drug and then very briefly to the
production environment, both essential Failures
to maintain a successful Research or Process and lab failures are road signs
Development program from pre- to the agency inspection team, who in
formulation to the first validated general have a limited window-of-
commercial batches. observation into the firm's year round
Its purpose is to get newly developed activities, especially during foreign
drug products to the market place on visits.
time, while significantly reducing Obviously, process failures are the
development and research costs. most important points to cover during
the inspection and these failures and
The issues concerning foreign process changes have a significant
inspections are covered notably the impact on the adequacy of the final
areas of where they differ from local US manufacturing process validation.
Pre-Approval Inspections and the
reasons why. The inspection findings do recommend
to withhold approval of an ANDA / NDA
Agency inspectors need to review all subject to proper implementation of
aspects of drug development from pre-
corrective action.
formulation to the proposed first
For foreign firms a follow up visit for on-
marketing batches, as well as obtaining site evaluation a year or more later may
a general overview of the firms be conducted prior to the approval of
development Standard Operating the product applications.
Procedures (SOPs) in the R&D
departments of Pharmaceutical,
This is the main difference between
Analytical development, Microbiological foreign reviews and US domestic
parameters, Drug Stability Programs plants.

Handbook of Pharmaceutical Sect: 19.

19 1 Generic Development
 TABLETS ORAL P R E - A P P R O V A L S CHAPTER 19

Follow-up visits do not follow within 12 Build an Effective

months and the firms needs to wait for a
period that may be as long as 12-18 Interdisciplinary
months before a re-visit can be
scheduled. Team for PAI
Although the inspection findings and Success
judgments made are consistent with Management responsible for the
those judgment formed when similar operation needs to involve all
issues are found in US domestic firms, departments associated directly and
the follow-up inspection may well be a indirectly (technical services and
year or so later. maintenance) with the generic or
No foreign drug firm can place its' innovative drug development - from the
ANDA approval program on hold for pre-formulation scientists to the night
twelve months or longer - thus the need shift cleaning squads. The cardinal
for vital care and detailed organization need to build an effective
in PAI preparation cannot be over interdisciplinary team is a vital factor to
emphasized. PAI success.
Firms with a good history of GMP You can never be
credibility and effective correction
action plans may not be subject to a “too prepared”.
follow-up PAI inspection, when based R&D or Development Units alone can
on impressive past cGMP and audit not assure a successful Pre-Approval
tract records Inspection. The FDA will definitely
interact with other departments to
Last Development Milestone
assure that a facility is consistently
The PAI is the last milestone in the drug
capable of routine commercial
product approval cycle prior to ANDA
manufacturing.
approval. It is a review of every aspect
of the drug development and Exhaustive PAI preparation is equally
manufacturing process up to and valid for Generic developers as well as
including the regulatory batch(es). NDA Researched-based units.
A pro-active approach is necessary to The rules are the same - only the
documentation changes.
succeed and pass your PAI.
Preparation for the newly developed Failed PAIs can
drug or reformulated drug product
applies to all personnel employed in the effect your
existing or
pharmaceutical firm. Above all it
requires a major team effort.
Selecting the best team members and pending products
building a near-perfect PAI action group
requires effective harmonization All pharmaceutical companies
between departments with individual conducting drug research and
departmental responsibilities. development must eventually face a
PAI review. The consequences of a
No single individual is not impacted or failed PAI may well impact on existing
affected during the PAI preparations. It
products, especially if the deficiency is
is simply the concern of all the
a major GMP concern.
personnel.

Handbook of Pharmaceutical Sect: 19.

19 2 Generic Development
 TABLETS ORAL P R E - A P P R O V A L S CHAPTER 19

A crash corrective action plan may be What does the

necessary to minimize the impact of a
failed inspection on the Company’s FDA expect
approved and pending drug products, in
the agency review queue. during a PAI?
Essentially generic development can
be distilled into a Master Checklist of
All data must be rapidly retrievable
Drug Development Procedures during the PAI audit and review. The
representing the best and most widely Biobatch (NDA) or Pivotal Batch
used methods available. (ANDA) records will be asked for - as
well as the development rationale from
In drug product development program - early pre-formulation to process
both the advances and the failures of validation protocols.
the experimental batch lots need to be
documented and addressed.
A firm should have a well structured
and assembled Product Development
Non-US sites - Generic Development.
Report - although not a FDA/21 CFR
The Procedures that govern Non-US regulatory requirement, it will certainly
sites, in development of the drug go a long way to convince the agency
dosage form must be carefully reviewers of a fully justified overall
structured to insure that the process that consistently produces the
development/scale-up and pivotal desired end-product.
procedures are fully understood and
interfaced with the proposed
The Development Report is the basis
on which the validation protocol is
manufacturing facility in the US.
designed and structured - without it,
Complete integration of product validation may well be incomplete or
manufacturing, Quality Assurance, inconclusive.
Quality Control and technical Services
(engineering, maintenance &
Review records need to show:
metrology) is essential, to assure that a Authentic, clear and accurate data.
facility is consistently capable of An organized process change
commercial manufacture of the program.
proposed product batches (sizes).
any reprocessing must be justified.
Process validation should be
An essential similarity, within SUPAC
performed after the PAI (in the US) and rules, between Pivotal (ANDA) used for
before the PAI in Non-US the bioequivalent study and the
manufacturing plant - reason; to proposed full scale commercial
prevent an extra year’s delay until re- production lots.
inspected.
Cleaning validation & report, and (in the
During the PAI, the FDA expect to find US) process validation protocol.
that the firm complies fully with cGMPs.
No deviation from raw material
No firm will pass a Pre-approval specifications and suppliers listed in the
Inspection if GMP is sorely deficient or application unless justified by scientific
documentation is absent. data.
Confirmation that the firm has used In NDAs, a substantial connection
appropriate scientific data to justify between Biobatch and the proposed
process and actions must be clearly full scale NDA commercial production.
demonstrated.

Handbook of Pharmaceutical Sect: 19.

19 3 Generic Development
 TABLETS ORAL P R E - A P P R O V A L S CHAPTER 19

A checklist of FDA expectations during The testing procedures used in the

a PAI review is provided to aid your drug development unit must be
firms Pre-Approval preparation. designed and dovetailed for rapid
transfer to the commercial testing QC
The Agency needs the assurance that a
laboratory.
facility is capable of commercially Equipment and facilities (HPLCs etc.)
manufacturing the drug product as should be pre-evaluated to insure test
detailed in the file submission. Further method and analytical validation
more the Agency expects that all transferability.
problems arising from audit inspections
are correctly promptly. Where possible, Comprehensive and easily understood
firms should correct the omission or documentation is an essential
fault during the actual inspection or if ingredient to a successful Pre-approval
not possible very shortly afterwards. Inspection. R&D, RA, QA and
Manufacturing must work together to
Audit corrections given the highest create a comprehensive development
and production documentation package
work priority, during PAIs promote
that covers all the issues and enhances
cooperation.
the FDA Investigator’s review.
Remember some of the observations
may impact on other drug products The Documentation serves as a guide
already being manufactured and may to the inspection as well as a means to
bring them technically out-of- enhance the investigators
compliance. understanding of the submission. It the
If all corrections are done before the investigator is completely satisfied it
generally means that all the correct
Center of Drug Evaluation and
documentation is in place and all
Research (CDER) asks for PAI
essential aspects of the product
inspection concurrence. The PAI
development, scale-up and cleaning
inspectors will then concur with the
and process validation have been
drug product approval.
thoroughly executed.
Using Technology
Transfer (TTD) for Effective Development
Process Improvements & Production
and PAI success
Documentation
Manufacturing equipment and scale-up
procedures require dove-tailing with speeds up the PAI
both facilities. Analytical and microbial
laboratory test methods are needed to
immensely
be rugged and operational in both
facilities. Great care needs to be taken Thorough documentation methods will
to insure and demonstrate the accelerate your firm’s inspection.
ruggedness of these laboratory tests.
Provide the investigator with a
Testing procedure methods should be complete set of documentation that
chosen in close cooperation with the ‘feels and looks right’ in addition to
production laboratory facilities to insure being complete. Physical logs and
a smooth transfer of technical notebooks need to be seen and
documentation (TTD operational reviewed by the investigator.
requirements).

Handbook of Pharmaceutical Sect: 19.

19 4 Generic Development
 TABLETS ORAL P R E - A P P R O V A L S CHAPTER 19

Stock cards or inventory control cards The ultimate Pivotal lot

for the active material, and finished is a validated batch
goods are generally called for, to check
and review the deduction quantities at
ready for shipping on
the relevant batch manufacturing or use approval
dates. (equal to the commercial lot with at
least 2 years shelf life remaining
The Finished Product Inventory Cards after ANDA approval .)
detail the overall drug product trail or
disposition of the dosage units. Packing the pivotal batch.
Reserve samples, biostudy samples The Pivotal batch needs to be fully
and quantities, QC and stability packed in the proposed marketing
amounts required for testing and packs (OGD rules). Frequently the
evaluation are carefully deducted from pivotal batch is packed into 2 to 4
the total units packed in each different pack types and several
container-closure system. different pack sizes and closure
combinations. (Glass, HDPE, Clic-loc,
Finished Product Blister pack etc.)

Inventory Cards The tablet/capsule trail identifies the

quantity packed into each container-
(PICs) closure system. The overall packaging
are essential for totals to 100% of the net pivotal batch.
At least 10-20 % of the exhibition
complete product trails. (pivotal) batch should be packed into
In the manufacture of the Pivotal each container closure category.
batch, a minimum of 100 000 (net)
dosage units is required. Many firms
Self Inspection
prepare documentation for 100 000 Audits
dosage units gross, ignoring the fact
that there may well be 2% to 5% are an Essential
production losses. The net batch yield
turns out to be 98 000 or 95 000 Pre-approval
Requirement
dosage units well below the 100
thousand net required by FDA’s OGD.
Capsules may have a greater
manufacturing loss than tablets - thus it Auditing your firm
is prudent to scale the pivotal batch for before the PAI.
at least 110 000 dosage units.
Development and production
remember the pivotal batch may range
documentation for the newly developed
from 10% to 100% net of the proposed
dosage form should describe the
commercial batch.
purpose and the principles generally
Experienced Generic firms who do not needed to meet the scientific,
anticipate any problems with the pivotal regulatory and GMP objectives of a well
documentation often target the pivotal run development and production unit.
quantity to 70% of the proposed During the PAI inspection the ANDA
commercial lot thus achieving product is tracked from pre-formulation
appropriate scale-up and pivotal in a to Pivotal batch.
single batch.

Handbook of Pharmaceutical Sect: 19.

19 5 Generic Development
 TABLETS ORAL P R E - A P P R O V A L S CHAPTER 19

The development and production

documentation is the tracking agent Do You Have
used by the agency reviewers - thus the Cleaning Validation
presence of ‘holes’ or deficiencies are
the concern of the firms PAI audit team. firmly in place ?
Finding these deficiencies and Remote Development
correcting them on time before the Generic Development of
arrival of the agency investigators is the pharmaceutical drugs may take place in
prime objective. No document or a Non-US development laboratory
inventory card should be left unturned. facility i.e. an oversees facility. Where
Identify deficiencies product development occurs in a
remote development unit (i.e. not
well before attached to the proposed manufacturing
the actual investigation site - special SOPs dovetailing the
Carefully conducted departmental in- procedures at the remote and
house pre-PAI audits may save manufacturing site are necessary for
research based firms and generic such a situation.
developers significant review time and Preparing Foreign
thousands of much needed
development dollars.
drug firm sites for
The pre-PAI audit team should start Pre-approval
reviewing the generic drug Inspection
development departments, namely
pharmaceutical, analytical, Emphasis is often placed on external
microbiological and stability units and development (outside the US) while
end with the manufacturing, packaging / commercial manufacturing is targeted
disposition of the pivotal lot. for a US commercial site. In the majority
of these cases the regulatory ‘Pivotal’
Is your Cleaning Program batch for regulatory inclusion into the
and residual limits ANDA submission file, is best targeted
- ready for the for manufacture at the US-based
commercial manufacturing site.
Pre-approval Inspection ?
Oversees developers who have FDA
Cleaning Validation: inspected / approved commercial
The Cleaning validation protocol and manufacturing facilities may produce
Report pertaining to the ANDAs under the pivotal batch at a non-US small or
question must be available for PAI large scale manufacturing facility. The
review. manufacturing and testing facility must
Many firms fall short of a fully be in full GMP compliance, as if it were
documented cleaning validation a US based operation.
protocol and validation report. Non-GMP R&D or drug development
Frequently the firms omit to establish facilities are not suitable for clinical or
the limits of contamination of the pivotal drug manufacturing. Full cGMP
previously manufactured batch to which pilot plants or to use the more
they are required to clean. An excellent appropriate terminology ‘small scale
mathematically derived rule of thumb manufacturing’ facilities are the correct
for establishing the maximum allowable venue for manufacturing clinical
residual limits (mcg/dose) is simply batches.
1/8000 of the last batch’s lowest mg
labeled strength.

Handbook of Pharmaceutical Sect: 19.

19 6 Generic Development
 TABLETS ORAL P R E - A P P R O V A L S CHAPTER 19

Where the object is to routinely Firms who have open and strong
manufacture at an approved GMP US audit programs in place inevitably do
commercial production site then the well in PAIs. Multiple mock trail-runs
pivotal batches, for regulatory prior the anticipated inspection will
submission to the authorities, should iron-out the hidden deficiencies and
always be manufactured at the US give valuable training and confidence
commercial site as the intended market to all personnel concerned.
is the USA. What are Common
Conducting Mock Inspections. PAI
Preparing your department and firm’s Issues and Concerns ?
personnel for what is to come seems a
daunting challenge. It does not have to Staff learn to answer questions directly
be so. An intensive pre-approval in- - and not to talk any more than
house mock inspection with QA or RA necessary or advance gratuitous
role playing as the agency inspection information. Where foreign languages
team pays excellent dividends. are involved, a good practice is to
appoint a QA/RA spokesperson to
Conduct an Intensive handle all communication and remain
close to the inspectorate at all times.
mock In-house Create an SOP to define Agency-
Inspection Company Interactions and
communications. Key personnel speak
Challenge and dissect the through the designated QA and RA
manufacturing and controls necessary Director to the inspectorate. As an
to support approval of a new or inspection has generally two or
reformulated drug whether it be a new sometimes three agency personnel -
active or a generic. the need to appoint at least three
Asking awkward questions, before the Spokespersons e.g. QA, RA and
inspector does, may save months of Production usually cover all situations.
work and your companies reputation -
such as; Ensure the investigation
♦ Formula development runs smoothly
♦ Method development on-site
♦ Actual Process Development The firms representatives should each
♦ Master Specifications have a set of ‘runners’ - key aids, who
do not speak but rapidly retrieve
⇒ active documentation requested for by the
⇒ Raw Materials inspectors.
⇒ In-process
⇒ Finished Process Review rapidly the requested
⇒ Cleaning documentation with the Head of the
⇒ Check /Stability relevant department as to the
correctness of the data requested.
♦ Stability File Submission Batch
Then present the information to the
♦ Scale-up inspector by opening the desired
♦ Validation Lots page(s) - use book markers -
♦ Data Archiving (& Rapid Retrieval) highlighting the raw data only. Don’t
allow reviewers to wander through lab-
books.

Handbook of Pharmaceutical Sect: 19.

19 7 Generic Development
 TABLETS ORAL P R E - A P P R O V A L S CHAPTER 19

PAI SUMMARY:
Set aside the board • Pharmaceutical Development
room or other venue Notebooks containing All the
experimental data
for the Inspectors ◊
exclusive use • Analytical Development Notebooks
containing all the analytical / micro
As lab books are confidential data from early active material
documents, inspectors do not and investigation to validation of stability
should not page randomly through an indicating assays and impurities
analytical raw data lab book. The ◊
opened lab book is placed in front of • A full Development Report based on
the reviewer with ‘begin and end’ a series of development lots in a
bookmarks designating the raw data for progressive, logical manner with
the relevant batch(es) requested. scientifically valid
Daily Work Venue decisions
Reserve the firms board room or a large being made
meeting room as a routine workplace
for the company and PAI Officials. ◊
Display all ANDAs, NDAs, Development • Full Plant Documentation of the
Reports, Protocols, cleaning and Pivotal Lot Manufacture
process validation reports. Copies of & Packing
the USP, BP and other Official ◊
Reference works used should be on • Full stability data and an operational
hand. & functional stability unit
Select what to file ◊
• The submitted ANDA is able to be
after the PAI - via SUPAC verified against the departmental
(post approval) raw data
◊
Display on a separate table all the • The plant is capable of
product documentation under review. producing the drug as specified in
Label and group documentation and the ANDA
reports together (e.g. ANDA +
Development Report + Cleaning and ◊
process validation protocols and • Full cGMP in place
Reports represent a product throughout the plant and labs.
documentation group). Lastly provide ◊
light refreshments. 3 • An operational and functional
SOP system
◊
• IQOQ Equipment (calibrated)
The Agency needs the
assurance ◊
• Process Validation Protocol
that product development prepared
yields the following:- è ◊

Handbook of Pharmaceutical Sect: 19.

19 8 Generic Development
 TABLETS ORAL P R E - A P P R O V A L S CHAPTER 19

ØC H E C K L I S T ×
CL # HPGD-03-01Y2K

Pre-approval Inspection Team’s Set-up and

Responsibilities

‘Pre-approval inspection preparation is part of the overall drug

development process and not a post-submission regulatory crisis'

1. The firm has selected a multifaceted pre-approval inspection team? qYes qNo

2. The PAI Team has outlined its charter and team responsibilities ? qYes qNo
3. The Quality Assurance Head has approved and signed the charter ? qYes qNo

4. The PAI team has issued a SOP detailing regulatory procedures and qYes qNo
protocols to be followed during inspection procedures ?
5. The PAI team leader is the Head of Quality Assurance or his designate? qYes qNo
6. The PAI team is fully updated on the FDA Pre-approval Program ? qYes qNo

7. A suitably equipped room has been dedicated for use during the PAI? qYes qNo
8. A working list of documents, ANDA files, Pharmacopoeia, raw data lab qYes qNo
books etc. is available on-site in the PAI audit room, during the course
of the inspection ?
9. The PAI team has reviewed all product-specific files and appropriate qYes qNo
documentation for accuracy, clarity, and consistency - noting logical
dates, and signatures ?
10.The PAI team has focused on the pivotal batch dossier and the qYes qNo
proposed commercial manufacturing documentation with on-site
evaluations of actual filed manufacturing facilities?
11.The PAI team has, examined the product development report, together qYes qNo
with the project leader, and evaluated the explanations and scientific
rationale for changes that occurred during the process development right
up to the pivotal lot manufacture?
12.The PAI team has evaluated the product(s) cleaning validation, residual qYes qNo
limits, acceptance criteria and actual cleaning validation results?
13.The PAI team has evaluated the product(s) process validation protocol? qYes qNo

14.The PAI team is geared to provide assistance in the preparation of qYes qNo
written responses to the investigators concerning adverse finding -
during the actual PAI review?
15.The PAI team has established and coached a core of key personnel able qYes qNo
to properly respond to questions asked by FDA investigators during the
PAI review?

333

Handbook of Pharmaceutical Sect: 19.

19 9 Generic Development
 TABLETS ORAL P R E - A P P R O V A L S CHAPTER 19

ØC H E C K L I S T ×
CL # HPGD-03-01Y2K

Pre-approval Inspection Team’s Audit

Activities
‘Pre-approval inspection preparation impacts on R&D, Manufacture
Quality Control / Assurance and Regulatory Affairs from day one of the new
product development '

1. Review submitted ANDA and FDA correspondence, manufacturing qYes qNo

and controls sections (MF and MI), active and excipients (lot #s,
CoAs) as used in the pivotal formula?

2. Development

3. Review the development report in detail and assure adequate qYes qNo
supporting documentation for process and optimization changes
made?

4. Has the active’s particle size, bulk density and polymorphism been qYes qNo
fully addressed?

5. Does the development report support a scientific basis for the qYes qNo
process validation protocol?

6. Do individual development validation studies support formula and qYes qNo

process changes made?

7. Process Qualification

8. Examine Process Qualification scientific rationale in establishing qYes qNo

product specifications?

9. Review cleaning validation, residual limits, and acceptance criteria qYes qNo
for the cleaning process?

10.Review that similar water quality was used from process qYes qNo
qualification to commercial lots?

11.Review that any reprocessing/rework stage has been fully qualified qYes qNo
and evaluated?

Handbook of Pharmaceutical Sect: 19.

19 10 Generic Development
 TABLETS ORAL P R E - A P P R O V A L S CHAPTER 19

Ø CHECKLIST×
CL # HPGD-03-01Y2K

Pre-approval Inspection Team’s Audit

Activities
‘…Pre-approval inspection preparation is the last step in
the long chain of product development…
…A weak link can sink the whole project… '

PIVOTAL BATCH
1. Review list of manufacturing and packaging equipment used in qYes qNo
pivotal lot.
2. Examine machine cards and cleaning verification cards or tags. qYes qNo
3. Examine room cleaning cards. qYes qNo
4. Examine all pivotal manufacturing, packaging and labeling records qYes qNo
(review date order, signatures present manufacturing deviations,
yield accountability vs. SOPs, sampling plan / retention samples) ?
5. Review the plan/protocol for sampling and testing the pivotal lot. qYes qNo
6. Examine intended production documentation. qYes qNo
7. Review Manufacturing Deviation Report relevant to each pivotal qYes qNo
batch.
8. Review conformance and compliance to manufacturing time qYes qNo
limitations.
9. Review excipient monographs vs. CoAs; routine and full testing qYes qNo
procedures and test dates?
10.Review overall disbursement of pivotal batch - e.g. QC release, qYes qNo
retention, stability, biostudy samples and full reconciliation of product
trail for each pack type used, and packs placed on stability?
11.Identify contract manufacturers or packages for documentation and qYes qNo
compliance auditing?

TECHNOLOGY TRANSFER PROCESS

12. Review the technology transfer process/ SOPs from development to qYes qNo
production facilities ?
13. Review data supporting rework or reprocessing procedures in qYes qNo
development and process qualification batches to insure that the rework
process are adequately supported and scientifically justified?

333

Handbook of Pharmaceutical Sect: 19.

19 11 Generic Development
 TABLETS ORAL P R E - A P P R O V A L S CHAPTER 19

Ø CHECKLIST×
CL # HPGD-03-01Y2K

Pre-approval Inspection Team’s Audit Activities

‘…Pre-approval inspection preparation is a team work affair…

…All departments must pull their weight equally…
…its not a QC or RA one man show… '

SCALE-UP TO COMMERCIAL
15. Review scale-up documentation and ensure all changes are within qYes qNo
SUPAC rules ?
16. Review ANDA formula and manufacturing variations are within qYes qNo
SUPAC limits?
17. Review side-by-side comparison of pivotal vs. commercial process, qYes qNo
facilities and equip.?
18. Review SOPs relating to issue and review of batch records, receipt, qYes qNo
handling and processing of raw materials, packaging components and
labeling, cleaning procedures, maintenance, HVAC, calibration and
equipment use, change control and manufacture.
19. Review site (manufacturing and labs) personnel training procedures qYes qNo
and training records
qYes qNo
PROCESS VALIDATION
20. Validation protocol for first three consecutive commercial lots on- qYes qNo
site ?
21. Review the side-by-side comparison between pivotal and validation qYes qNo
equipment /facilities ?
22. Review the protocol for sampling and testing the validation lots qYes qNo
(part of validation protocol)

ANALYTICAL
23. Perform a thorough check on the lab notebook referencing all qYes qNo
pivotal tests ?
24. Review method validation for in-house assays, impurities and qYes qNo
dissolution test?
25. Review stability-indicating assay and the impact of any placebo qYes qNo
effect ?
26. Review all out-of-specification results (log) on analytical or product qYes qNo
failures?

Handbook of Pharmaceutical Sect: 19.

19 12 Generic Development
 TABLETS ORAL P R E - A P P R O V A L S CHAPTER 19

ØC H E C K L I S T ×
CL # HPGD-03-01Y2K

Pre-approval Inspection Team’s Audit Activities

STABILITY
27. Does pivotal batch remains in check specifications after 3 months qYes qNo
accelerated (40oC) testing ?
28. Have samples been placed on stability within 30 days of qYes qNo
manufacturing release CoA ?
29. Insure stability testing is performed according to stability protocol ? qYes qNo
30. Statement on proposed expiration period in accordance with qYes qNo
obtained test results ?
31. Review all stability data, in-out dates, exposure times, temperatures qYes qNo
and humidity (RH) including control of environmental parameters
(recording devices, graphs and any OOS conditions) ?
32. Review Stability SOPs and equipment; Are chambers, probes and qYes qNo
monitors calibrated ?

MICROBIOLOGICAL
33. Microbial parameters in compendial excipients are retested every qYes qNo
12 months ?
34. Preservative containing excipients are tested for preservative qYes qNo
efficacy ?
35. Appropriate use of validated in-house methods with proper method qYes qNo
controls ?
36. Review of microbial testing facilities, test methods, calibration and qYes qNo
laboratory SOPs?

CONTRACT FACILITIES qYes qNo

37. Full GMP review (on-site/mail audit) of contract facilities used ? qYes qNo

38. Review of analytical testing facilities methods, validation and qYes qNo
laboratory SOPs ?
39. All facilities listed in file submission are fully capable of performing qYes qNo
designated tasks ?
40. Review of packaging and labeling procedures, in-process controls qYes qNo
and SOPs ?
333

Handbook of Pharmaceutical Sect: 19.

19 13 Generic Development
 TABLETS ORAL STABILITY TESTING & STABILITY SOPs CHAPTER 20

Stability Testing of Drug

Substances and Drug Products
OVERVIEW - PART I

N ew draft 'stability testing of drug

substance and drug products'
guidance issued in June 1998, provides,
The purpose of stability testing is to
provide evidence on how the quality of a
drug substance or drug product varies
recommendations and guidance in a with time under the influence of a variety
comprehensive document that covers of environmental factors such as:-
some 110 pages, including glossary, and l Temperature
provides information on all aspects of
l Humidity
stability data generation and use.
l Light.
It references and incorporates
substantial text from the following five
Stability testing permits the
International Conference on establishment of recommended storage
Harmonization (ICH) guidances: conditions, retest periods, and shelf
lives. [ICH Q1A]
Ø ICH Harmonized Tripartite Guideline This guidance provides recommen-
for Stability Testing of New Drug dations regarding the design, conduct
Substances and Products, September and use of stability studies that should
23, 1994 - [ICH Q1A] be performed to support all the following
categories:-
Ø ICH Guideline for Stability Testing of
New Dosage Forms - [ICH Q1C] Ø Investigational New Drug
Applications (INDs) (21CFR 312.23(a)(7))
Ø ICH Guideline for Photostability
Testing of New Drug Substances and Ø New Drug Applications (NDAs) for
Products - [ICH Q1B] both new molecular entities (NMEs)
and non-NMEs
Ø ICH Guideline for Stability Testing of
Biotechnological / Biological Products Ø New Dosage Forms (21CFR 314.50(d)(1))
- [ICH Q5C] Ø Abbreviated New Drug
Where text from one of these Applications (ANDAs) (21CFR 314.92-314.99)
documents has been incorporated in this Ø Supplements and Annual Reports
guidance, it has been denoted by the (21CFR 314.70, and 601.12)

use of a reference in square brackets Ø Biologics License Application

[i.e.] in the beginning of a particular (BLAs) and Product License
section or at the end of an individual
Applications (PLAs) (21 CFR 601.2)
paragraph.

Handbook of Pharmaceutical Sect: 20.

20 1 Generic Development
 TABLETS ORAL STABILITY TESTING & STABILITY SOPs CHAPTER 20

The principle established in ICH Q1A -- kinetic temperature in any region of the
that information on stability generated in world can be derived from climatic data.
any one of the three areas of the EU, (Grimm, W., Drugs Made in Germany, 28:196-202,
1985, and 29:39-47,1986). Referenced in [ICH Q1A]
Japan, and the USA would be mutually
acceptable in both of the other two areas The recommendations in this guidance
--- is incorporated in this guidance are effective upon publication of the
document. final guidance and should be followed in
In fact, much of the text of the guidance preparing new applications, re-
on drug substances and drug products is submissions, and supplements.
incorporated directly from the ICH Q1A This guidance represents FDA’s current
text (e.g. II.A. and II.B.). thinking on how the stability section of
The guidance is intended to replace the drug and biologics applications should
be prepared. An applicant may choose to
12 year old, Guideline For Submitting
use alternative procedures.
Documentation for the Stability of Human
Drugs and Biologics, published in If an applicant chooses to depart from
February 1987. the recommendations set forth in this
guidance, the applicant is encouraged to
It applies to all drug substances and discuss the matter with FDA prior to
products submitted to the Center for initiating studies that may later be
Drug Evaluation and Research (CDER). determined to be unacceptable.
This guidance also applies to biological
FDA recognizes that the time necessary
products that are included in the scope
for applicants to establish new
of the ICH Q5C Stability Annex, Stability
procedures, install, and commission the
Testing of Biotechnology Drug Products
new temperature and relative humidity-
(July 1996) and all other products
controlled rooms / cabinets, carry out
submitted to the Center for Biologics
appropriate stability studies on batches
Evaluation and Research (CBER).
of product, and submit the information in
The draft guidance provides an application may prevent some
recommendations for the design of applicants from generating data
stability studies for drug substances and consistent with the recommendations in
drug products that should result in a the guidance for some time.
statistically acceptable level of However, since this guidance represents
confidence for the established retest or FDA’s current thinking, recommendations
expiration dating period for each type of regarding stability data submission not
application. conforming with this guidance is possible
The applicant is responsible for with justification.
confirming the originally established Applications withdrawn prior to
retest and expiration dating periods by publication of this guidance should not
continual assessment of stability normally have to include stability data in
properties (21 CFR 211.166). conformance with the guidance upon
resubmission. However, if new stability
Continuing confirmation of these dating studies are conducted to support the
periods should be an important submission, such studies should be
consideration in the applicant’s stability conducted as per guidance.
program.
The choice of test conditions defined in A comprehensive glossary is included,
this guidance is based on an analysis of and contains definitions of the major
the effects of climatic conditions in the terms and origins of the definitions
EU, Japan, and the USA. The mean derived either from ICH, CFR, or USP.

Handbook of Pharmaceutical Sect: 20.

20 2 Generic Development
 TABLETS ORAL STABILITY TESTING & STABILITY SOPs CHAPTER 20

STABILITY TESTING FOR ABBREVIATED If not previously generated or available

NEW DRUG APPLICATIONS by reference, stress testing studies
M uch of the general information
provided for NDAs in the guidance
is applicable and at times referenced to
should be conducted to establish the
inherent stability characteristics of the
drug substance, and support the
Abbreviated New Drug Applications. suitability of the proposed analytical
However, depending upon the procedures.
availability of significant information on, The detailed nature of the studies will
and the complexity of, these drug depend on the individual drug substance,
products / dosage forms, the amount of type of drug product and available
information necessary to support these supporting information. Any necessary
applications may vary from that testing may be carried out as described
proposed for NDAs. in the NDA section (II. A.)
This section (III, A-G) is intended to provide
specific recommendations on abbreviated [C] Drug Product
applications - ANDAs. Original ANDAs should contain stability
[A] Drug Substance Stability Data data generated under the long-term and
Submission accelerated stability storage conditions.
For drug products submitted under an (delineated in V.E. of the ICH Q1A guidance or
ANDA, including antibiotics, supporting Section II. B. of this guidance).
information may be provided directly to ANDAs are divided into
the drug product ANDA or by reference
to an appropriately referenced drug Simple Dosage Forms
master file (DMF). Publications may be and
provided or referenced as supportive Complex Dosage Forms
information.
For ANDA bulk drug substances, stability
The data package for ANDAs (e.g.,
number of batches, length of studies
data should be generated on a minimum
needed at submission and at approval,
of one pilot-scale batch. All batches
and accelerated, intermediate and long-
should be made using equipment of the
term stability data) should be based on
same design and operating principle as
several factors:
the manufacturing-scale production
þ including the complexity of the dosage
equipment with the exception of capacity.
form (i.e. MR, Aerosol, Patch),
For ANDA bulk drug substances þ the existence of a significant body of
produced by fermentation, stability data information for the dosage form,
should be provided on three production þ the existence of an approved
batches, at least two of which should be application for a particular dosage form.
generated from different starter cultures.
[D] ANDA Data Package
[B] Drug Substance Testing
Recommendations
A program for stability assessment may
For Simple Dosage Forms the
include storage at accelerated, long-
following stability data package is
term, and, if applicable, intermediate
recommended:
stability study storage conditions
(refer to IV.G. of the ICH Q1A 711 Guidance and Section II.A
[i.e NDAs] of this guidance).
ð Accelerated stability data at 0, 1, 2,
and 3 months. A tentative expiration
Stability samples should be stored in the dating period of up to 24 months will be
bulk storage container equivalent (e.g.,
granted based on satisfactory
same composition and type of container,
accelerated stability data unless not
closure and liner, but smaller in size).

Handbook of Pharmaceutical Sect: 20.

20 3 Generic Development
 TABLETS ORAL STABILITY TESTING & STABILITY SOPs CHAPTER 20

supported by the available long-term

stability data. Ø 3-month accelerated stability studies.
Ø Long-term stability studies (available
Ø Long-term stability data (available
data at the time of original filing and
data at the time of original filing and subsequent amendments).
subsequent amendments).
Ø A minimum of one batch; pilot scale. The expiration dating period for complex
Ø Additional stability studies (12 months dosage forms will be determined based
at the intermediate conditions, or long- on available long-term stability data
term data through the proposed submitted in the application.
expiration date) if significant change is Ø A minimum of THREE batches
seen after 3 months during the manufactured in accordance with the ICH
accelerated stability study. Q1A batch size recommendations. These
batch sizes are TWO pivotal (100 000 or
Simple Solid Forms 10% etc.) plus one small scale lot (1/2 or
¼ Pivotal)
- mean IR (Refer to V.B. of the ICH Q1A guidance and Section
II.B. of new stability guidance).
Complex Solid
Simple Solid Forms
Forms One Pivotal Batch
- mean MR Complex Solid Forms
The tentative expiration dating period will Two Pivotal Batches
be determined based on the available
data from the additional study.
+ one small scale lot
[E] Exceptions - ANDA Data Ø Additional stability studies (12 months
at the intermediate conditions or long-
Package Recommendations term stability testing through the
(MR/CR, MDI and TDPs) proposed expiration date) if significant
change is seen after 3 months during the
The following may be considered accelerated stability studies (the
exceptions to the general ANDA tentative expiration dating period will be
recommendations: determined based on the available data
Ø Complex dosage forms, such as from the additional studies).
modified-release products, transdermal
patches, metered-dose inhalers. [F] Data Package for Approval
Ø Drug products without a significant Full-term stability testing of the primary
stability batch(es) is suggested.
body of information.
However, in the absence of full-term
Ø New dosage forms submitted through stability data for the drug product,
the ANDA suitability petition process adequate accelerated stability data
(Q1C applications). combined with available long-term data
Ø Other exceptions may exist and can be used as the basis for granting a
should be discussed with the Office of tentative expiration dating period.
Generic Drugs.
Batches for Stability
An ANDA that is determined to be one
of the above categories should contain a should have Release Assays
modified ICH Q1A stability data package, close to 100%
including:

Handbook of Pharmaceutical Sect: 20.

20 4 Generic Development
 TABLETS ORAL STABILITY TESTING & STABILITY SOPs CHAPTER 20

The batch(es) used for stability testing appropriate expiration dating period is
should comply fully with the proposed determined.
specifications for the product and be Extension of the tentative expiration
packaged in the market package, and
dating period should be based on data
the release assay should be within
generated on at least three production
reasonable variation (taking into account
batches tested according to the
inherent assay variability) from the
approved protocol outlined in the stability
labeled strength or theoretical strength of
commitment. Reporting of the data
the reference listed drug.
should follow Section VI. of this guidance
Overages must mimic ANDA STABILITY
the RLD Product COMMITMENT on THREE
If formulated with an overage, the commercial lots until long
overage should be justified as necessary term testing is complete
to match that of the reference listed ANDAs withdrawn prior to publication of
drug.
this guidance should not normally have
Other supportive stability data may be
to include stability data in conformance
submitted on drug product batches that
with the guidance upon resubmission if
may or may not meet the above criteria.
the original application was withdrawn
In Modified Release due to non-stability related issues.
However, if new stability studies are
Solid Dosage Forms conducted to support the submission,
the PQ batch can be such studies should be conducted as
recommended in the guidance.
the third stability batch
Data on relevant research batches, NEW RULES SUMMARY
investigational formulations, alternate
container/closure systems, or from other
related studies may also be submitted to SIMPLE ANDAs
support the stability of the drug product. Ø One batch of 100 000 (net) for 1, 2, &
The supportive stability data should be 3 months at 40oC ± 2oC / 75% RH ± 5%.
clearly identified. Ø Long Term Study started i.e. 3 or 6
months - whatever is available.
[G] Stability Study Acceptance
Ø Commitment to THREE production
If the results are satisfactory, a tentative
lots until long term data complete.
expiration dating period of up to 24
months at the labeled storage conditions Ø Significant Change clause effective.
may be granted. COMPLEX ANDAs
Where data from accelerated studies Ø TWO batches of 100 000 net for 1, 2,
are used to project a tentative expiration & 3 months at 40oC ± 2oC / 75% RH ±
dating period that is beyond a date 5% PLUS Small scale (e.g. PQ) lot.
supported by actual long-term studies on Ø Long Term Study started i.e. 3 or 6
production batches, then the application months - whatever is available.
should include a commitment to conduct Ø Commitment to THREE production
long-term stability studies on the first lots until long term data complete.
three production batches and annual Ø Significant Change clause effective.
batches until the tentative expiration
dating period is verified, or the

Handbook of Pharmaceutical Sect: 20.

20 5 Generic Development
 TABLETS ORAL STABILITY TESTING & STABILITY SOPs CHAPTER 20

Stability of Finished Dosage Form

[EXAMPLE OF SECTION 16 (STABILITY) OF AN ANDA]

TABLE OF CONTENTS
The following example highlights the Overall ANDA Guideline Requirements for the
Stability Section of an application. Only two out of the required sixteen stability
tabulations (stability profiles) are shown. A separate profile is required for each
strength, pack size and challenge temperature and humidity. The stability section is
divided into seven essential parts, as follows:

17.1 Section Page and Title.

17.2 Expiration Dating Period Statement

17.3 Stability Protocol for Post Approval Production Batches (This is the ANDA
stability commitment on what will be done after approval of the file)

17.4 Individual Stability Reports (stability profiles) indicating results obtained from
the Pivotal lot after [3] months accelerated and [X] months controlled room
temperature / humidity studies

17.5 Package Configuration and sizes (largest and smallest) used in stability
studies.

17.6 Stability Protocol used for (two) Pivotal Batch lots consisting of one
PIVOTAL Lot for each marketed strength.

17.7 Stability Data Summary Report (plus graphical presentations, graphs of assay
values vs. time ).

Handbook of Pharmaceutical Sect: 20.

20 6 Generic Development
 TABLETS ORAL STABILITY TESTING & STABILITY SOPs CHAPTER 20

Stability of Finished Dosage Form

[EXAMPLE OF SECTION 16 (STABILITY) OF AN ANDA]

This section contains:

♦ Proposed expiration date and stability commitment

♦ Stability protocol for post-approval production batches
♦ Summary of Stability Profile on ONE Batch (IR)
♦ Stability reports containing data from 3 month accelerated and 6 months controlled
room temperature studies
♦ Package Characteristic of pivotal batch

Overview
Stability testing is performed on each strength of three batches in the largest and
smallest container-closure systems proposed for marketing; i.e. in each material type,
namely plastic (HDPE/HDPP), or glass packs.

When more than one closure for the same container material type (e.g. HDPE
container) is used in the proposed marketing containers, the largest and smallest
container-closure configuration is tested, - for both accelerated and long term studies.

In cases where plastic bottles of the same size range and shape are manufactured
from different thermoplastic resins, they exhibition different storage characteristics and
thus are considered as completely separate container-closure systems.

The number of stability tests conducted can be quite large in such cases. The example
below for the following packaging configuration highlights the number of stability tests
needed. Tests can be significantly reduced using a matrix stability protocol.
1. HDPE (s/s & l/s) container with inner liner and HDPE CRC cap.
2. HDPE (s/s & l/s) container with inner liner and metal cap.

When testing TWO strengths with 4 container-closure configuration1 at accelerated

and long term testing (2), the stability Program will produce 16 separate stability
protocols as calculated below.

CALCULATING THE NUMBER OF STUDIES REQUIRED:

Calculation is for 1 pivotal batch lot per strength (2 strengths manufactured.)
i.e. (2 container / sizes x [1 lots] x 2 closures x 2 strength x [25ÐC + 40ÐC] = 16
studies).
1
Largest and smallest size only, of each container-closure configuration to be
marketed.

Handbook of Pharmaceutical Sect: 20.

20 7 Generic Development
 TABLETS ORAL STABILITY TESTING & STABILITY SOPs CHAPTER 20

Stability of Finished Dosage Form

[EXAMPLE OF SECTION 16 (STABILITY) OF AN ANDA]

Proposed Expiration Date

and Stability Commitment

A ll stability data support the proposed expiration period of 2 years when the product
is stored at room temperatures.

Stability commitment
Long term commercial stability studied in accordance with the approved stability
protocol shall be carried out by [Generic Company Name Inc. / Ltd.] The stability
results of these studies shall be submitted in the annual ANDA Reports filed on the
anniversary date of the submitted product.

[Generic Company Name Inc. / Ltd.] commits to remove any batch promptly from the
market place any material falling outside the products check specifications.

Extensions to the expiration date will be made via the annual ANDA Reports as
acceptable long term stability data is obtained,

Rework procedures may be submitted for batches that fail to meet established specifications. Prior
to implementation, these procedures will be submitted in a supplement in accord with: 21 CFR
314.70 (b)(2)(x) on a lot by lot basis.

[Signature of Responsible Person]

------------------------------------------------ -----------------------------------------
[Name of Responsible Person] Date
Regulatory Affairs Director

Handbook of Pharmaceutical Sect: 20.

20 8 Generic Development
 TABLETS ORAL STABILITY TESTING & STABILITY SOPs CHAPTER 20

Stability of Finished Dosage Form

[EXAMPLE OF SECTION 16 (STABILITY) OF AN ANDA]

Stability Protocol for Post-approval Production Batches

[Generic name] TABLET [USP] [000.0] mg. [Batch No: 000]

FINISHED PRODUCT STABILITY PROTOCOL

Package sizes: Smallest and largest containers
Storage Conditions
Controlled Room Temperature: 25-30°C.
Test Intervals: 0,3,6,9,12,18,24 and 36 months.
Samples: First three marketable production batches and annual batch thereafter.
Storage Conditions
Accelerated Temperature: 40°C / 75%RH.
Test Intervals: 1, 2, 3 months.
Samples: To be submitted as appropriate in supplements to the approved application
Stability Testing.
All test results will be subjected to compliance with current official requirements of the
approved applications and all supplements approved thereafter.
Test parameters will include:
TEST PROCEDURE TEST METHOD SPECIFICATION
& ED. NUMBER
1 Appearance / ID SI-5-000-01 Conforms

2 Assay SI-5-000-01 90.0 - 110.0% of labeled amount

IMPURITIES / DEGRADATION PRODUCTS

3 - Each Individual SI-5-000-01 NMT 0.5% of the labeled amount

- Any other Individual SI-5-000-01 NMT 0.5% of the labeled amount
- Total: SI-5-000-01 NMT 2.0% of the labeled amount

4 Dissolution SI-5-000-01 NLT 80% (Q) in 45 minutes

Report Format
Results will be tabulated in the format of the Stability Report Form:
1) Product Name, and Strength 9) Stability Start Date
2) Batch Number and Batch size 10) Manufacturing Site
3) Storage Conditions and Intervals 11) Manufacturer of Bulk Drug
4) Container/Closure Systems - Description 12) Inventory Control Number of (11)
5) Inventory Control Number of (4) 13) Manufacturer of Container/Closure
6) Fill Size and No of units on stability 14) Formulation
7) Batch Manufacturing Date 15) Data profile
8) Batch Packaging Date 16) Methodology and Specifications

Handbook of Pharmaceutical Sect: 20.

20 9 Generic Development
 TABLETS ORAL STABILITY TESTING & STABILITY SOPs CHAPTER 20

Stability of Finished Dosage Form

[EXAMPLE OF SECTION 16 (STABILITY) OF AN ANDA]

SUMMARY OF STABILITY STUDIES

The 3 months accelerated (40° ±2°C / 75 RH ±5% ) and 6 months room temperature
(25° ±2°C / 60 RH ±5%) stability data were examined for [Generic name] TABLET
[USP] [000.0] mg.

The data indicate that the formulation is stable, with no observed degradation peaks,
under test conditions. There were no significant changes in either the physical
chemical, or microbiological specifications in any samples evaluated after the exposed
storage test conditions.

The attached tables and graphs are summaries of the results for the parameters used
to establish the stability profile of [Generic name] TABLETS [USP] [000.0] mg. for the
pivotal batch per dosage strength, where applicable.
Included, are assay chromatogram spectra of the stability tests for zero time (T0) and
the three (3) months accelerated test conditions.
[Generic name] TABLETS [USP] [000.0] mg were stored at accelerated conditions
(40o ±2 o C / 75% RH ± 5%) and at room temperature (25° ±2°C/ 60% RH ±5%) in the
proposed market container/closure system. All stability data supports the proposed
expiration period of 2 years when the product is stored at room temperatures.
SIGNIFICANT CHANGE CLAUSE:
Where PRODUCTS fail the accelerated testing, Intermediate testing is performed
according to the following specification.
Intermediate testing 300 ±20C/60 ±5%RH
0,1,2,3,6, 9 and 12 months

Significant change at the accelerated conditions is defined as:

1. Ø A 5 % potency loss from the initial assay value of a batch.
2. Ø Any specified degradant exceeding its specification limit.
3. Ø The product exceeding its pH limits.
4. Ø Dissolution exceeding the specification limits for 12 capsules or tablets (USP
Stage 2).
5. Ø Failure to meet specifications for appearance and physical properties (e.g., color,
hardness)
Should significant change occur at 40oC/75% RH, the initial application should include
a minimum of 6 months’ data from an ongoing 1-year study at 30oC/60 percent RH; the
same significant change criteria shall then apply.

Handbook of Pharmaceutical Sect: 20.

20 10 Generic Development
 TABLETS ORAL STABILITY TESTING & STABILITY SOPs CHAPTER 20

Stability of Finished Dosage Form

[EXAMPLE OF SECTION 16 (STABILITY) OF AN ANDA]

SUMMARY OF STABILITY STUDY RESULTS

FOR MODIFIED RELEASE DOSAGE FORMS.

HDPE Container Closure liner system 25°C 60%RH 40°C 75%RH

Container Size (cc) Ü Smallest Largest Smallest Largest

HDPE Container with (CRC HDPE Cap)1 þ þ þ þ

HDPE Container with (Metal Cap)1 þ þ þ þ

2
Glass Container Closure Liner System
ý ý
ý ý
Bulk Packaging
ý ý
Number of Pivotal Batches ('100 000+' rule) [1]
New for
Number of NON-Pivotal Batches (i.e. PQ Lot) [0]
MR
TOTAL NUMBER OF STABILITY BATCHES 1
Dosage
Number of Temperature/RH Levels 2 Forms
Number of Dosage Strengths 2 only
Number of Container-Closure Sizes 2
Number of Resins present in Containers 1
Number of Closure Systems 2
Number of Resins present in Closures 1
Number of Stability Studies Performed 16
Number of resins used in the HDPE containers = one resin from same supplier.
1
Typical Assembly : HDPE container with HDPE CRC / METAL SCREW CAP and inner LINER.
2
Typical Assembly : Glass bottle with HDPE CRC / METAL SCREW CAP and inner LINER

Handbook of Pharmaceutical Sect: 20.

20 11 Generic Development
 TABLETS ORAL STABILITY TESTING & STABILITY SOPs CHAPTER 20

Stability of Finished Dosage Form

[EXAMPLE OF SECTION 16 (STABILITY) OF AN ANDA]

STABILITY REPORT
1 Product name, dosage form and strength. Generic name] [000] mg.
2 Fill size 000 [USP]
3 Site of Manufacture NJ MNF SITE
4 Batch or lot number 000
5 Batch size (type) 000 000
6 Batch manufacturing Date and Packaging Date Month DD, 199Y / Month DD, 199Y
7 Manufacturer of Active Material (approved supplier) LEK Chemical Co. dd
8 Date placed on stability Month DD, 199Y
9 Batch number or receiving number of Active Material LK 2323
10 Full details of container/closure system (type, material, resin) 100cc HDPP (LR-7340-43) CRC
HDPP white cap (resin LR-7340-43)
11 Goods Receiving number of container-liner GRN 96-2-02234 (body)
Goods Receiving number of closure GRN 96-2-02237 (cap)
12 Manufacturer of container/closure Wheeler Cap Co PA USA.
13 Objective of the stability program þ Pivotal Batch
14 Site where stability test conducted US PA MAN Site
15 Number of units to be sent for testing in each time interval 2 x 000
16 Analytical method number and Edition Number for each stability indicating test S-I 555-03 / S-I 1234 Ed . 03
17 Stability specifications indicating names of test required. Tabulated
18 Number of packages placed on stability 70
19 Testing intervals required 0, 1, 2, 3 (6) months
20 Stability storage conditions 40 degrees C / 75% RH
HPLC/TLC
Period Date of Contents ASSAY DISSOLUTION
Analysis Appearance Impurity
% Profile Percentage of label claim dissolved in 45 minutes
Impurities I
White to
Month 90.0 % - Impurities II NLT 80% (Q) in 45 minutes
Creamish
110.0% Impurities III
Powder
Total < 3.0
Method # S-I-000 -01 S-I-000 -02 S-I 000 -03 S-I 000-04 Mean C.V.
0 1/6/97 conforms 100.3 conforms 15: 00.0; 00.0; 00.0; 00.0; 00.0; 00.0 00.0 0.0
30: 00.0; 00.0; 00.0; 00.0; 00.0; 00.0 00.0 0.0
45: 00.0; 00.0; 00.0; 00.0; 00.0; 00.0 00.0 0.0

3 5/9/97 conforms 99.8 conforms 15: 00.0; 00.0; 00.0; 00.0; 00.0; 00.0 00.0 0.0
30: 00.0; 00.0; 00.0; 00.0; 00.0; 00.0 00.0 0.0
45: 00.0; 00.0; 00.0; 00.0; 00.0; 00.0 00.0 0.0

6 9/12/97 conforms 101.3 conforms 15: 00.0; 00.0; 00.0; 00.0; 00.0; 00.0 00.0 0.0
30: 00.0; 00.0; 00.0; 00.0; 00.0; 00.0 00.0 0.0
45: 00.0; 00.0; 00.0; 00.0; 00.0; 00.0 00.0 0.0
9 15/3/98 conforms 101.4 conforms 15: 00.0; 00.0; 00.0; 00.0; 00.0; 00.0 00.0 0.0
30: 00.0; 00.0; 00.0; 00.0; 00.0; 00.0 00.0 0.0
45: 00.0; 00.0; 00.0; 00.0; 00.0; 00.0 00.0 0.0
STABILITY PARAMETERS
21. Product Formula On Stability (Formula No: 000- Identical to ANDA Sections 6, 7, 11, & 12
1. Active material BP 7. Anhydrous Lactose NF 230.00
2. Povidone USP 9.00 8. Magnesium Stearate NF 3.00
3. Colloidal Silicon Dioxide NF 2.10 9. Opadry OY-S-20000 (light Color)
4. Starch NF 5.30
5. Starch NF (Redried) 27.00
6. Purified Water USP NF (Processing Solvent Only)

Handbook of Pharmaceutical Sect: 20.

20 12 Generic Development
 TABLETS ORAL STABILITY TESTING & STABILITY SOPs CHAPTER 20

Stability of Finished Dosage Form

[EXAMPLE OF SECTION 16 (STABILITY) OF AN ANDA]

STABILITY REPORT
1 Product name, dosage form and strength. [Generic name] [000.0] mg.
2 Fill size 00 [USP]
3 Site of Manufacture NJ MNF SITE
4 Batch or lot number P-5432
5 Batch size (type) 000
6 Batch manufacturing Date and Packaging Date Month DD, 1998 / Month DD, 1998
7 Manufacturer of Active Material (approved supplier) LEK Chemical Co. dd
8 Date placed on stability June 15, 199Y
9 Batch number or receiving number of Active Material LK 2323
10 Full details of container/closure system (type, material, resin) 200cc HDPP (LR-7340-43) CRC
HDPP white cap (resin LR-7340-43)
11 Goods Receiving number of container-liner GRN 96-2-02234 (body)
Goods Receiving number of closure GRN 96-2-02237 (cap)
12 Manufacturer of container/closure Wheeler Cap Co PA USA.
13 Objective of the stability program þ Pivotal Batch
14 Site where stability test conducted US PA MNF Site
15 Number of units to be sent for testing in each time interval 2 x 00
16 Analytical method number and Edition Number for each stability indicating test S-I 555-03 / S-I 1234 Ed . 03
17 Stability specifications indicating names of test required. Tabulated
18 Number of packages placed on stability 70
19 Testing intervals required 0, 3, 6, 9, 12, 18, 24, 36… months
20 Stability storage conditions 25 degrees C / 60% RH
Contents HPLC/TLC
Period Date of Appearance DISSOLUTION
Analysis ASSAY Impurity
ID
% Profile Percentage of label claim dissolved in 45 minutes
Impurities I
White to
Month Lab book 90.0 % - Impurities II NLT 80% (Q) in 45 minutes
Creamish
Ref. No 110.0% Impurities III
Powder
Total < 3.0
Method # S-I-000 -01 S-I-000 -02 S-I 000 -03 S-I 000-04 Mean C.V.
0 1/6/97 conforms 100.3 conforms 15: 00.0; 00.0; 00.0; 00.0; 00.0; 00.0 00.0 0.0
L/Book 30: 00.0; 00.0; 00.0; 00.0; 00.0; 00.0 00.0 0.0
N0: ___
Page___ 45: 00.0; 00.0; 00.0; 00.0; 00.0; 00.0 00.0 0.0

3 5/9/97 conforms 99.8 conforms 15: 00.0; 00.0; 00.0; 00.0; 00.0; 00.0 00.0 0.0
L/Book 30: 00.0; 00.0; 00.0; 00.0; 00.0; 00.0 00.0 0.0
N0: Page
45: 00.0; 00.0; 00.0; 00.0; 00.0; 00.0 00.0 0.0

6 9/12/97 conforms 101.3 conforms 15: 00.0; 00.0; 00.0; 00.0; 00.0; 00.0 00.0 0.0
L/Book 30: 00.0; 00.0; 00.0; 00.0; 00.0; 00.0 00.0 0.0
N0: Page
45: 00.0; 00.0; 00.0; 00.0; 00.0; 00.0 00.0 0.0

9 15/3/98 conforms 101.4 conforms 15: 00.0; 00.0; 00.0; 00.0; 00.0; 00.0 00.0 0.0
L/Book
N0: Page 30: 00.0; 00.0; 00.0; 00.0; 00.0; 00.0 00.0 0.0
45: 00.0; 00.0; 00.0; 00.0; 00.0; 00.0 00.0 0.0
STABILITY PARAMETERS
Additional Tests performed Annually: Microbial Limit Test USP and Residual Solvents.
21. Product Formula On Stability (Formula No: 000- Identical to ANDA Sections 6, 7, 11, & 12.
1. Active material BP 7. Anhydrous Lactose NF 230.00
2. Povidone USP 9.00 8. Magnesium Stearate NF 3.00
3. Colloidal Silicon Dioxide NF 2.10 9. Opadry OY-S-20000 (light Color)
4. Starch NF 5.30
5. Starch NF (Redried) 27.00
6. Purified Water USP NF (Processing Solvent Only)

Handbook of Pharmaceutical Sect: 20.

20 13 Generic Development
 TABLETS ORAL STABILITY TESTING & STABILITY SOPs CHAPTER 20

MODEL EXAMPLE OF SECTION 16 (STABILITY) AN ANDA

Stability of Finished Dosage Form

PACKAGE CHARACTERISTICS

[Generic name] TABLET [USP] [000.0] mg. [Batch No: 000]

Pivotal Lot Packaging Material Characteristics

ITEM Pack 1 Pack 2 Pack 3 Pack 4

Container Drug Plastics & Drug Plastics & Drug Plastics & Drug Plastics &
manufacturer Glass Co. Inc. Glass Co. Inc. Glass Co. Inc. Glass Co. Inc.

Container size 00 / 000cc round, 00 / 000cc round, 00 / 000cc round, 00 / 000cc round,
White HDPE White HDPE White HDPE White HDPE
container container container container
Resin Type HDPE HDPE HDPE HDPE
Quantum LR-7340-43 Quantum LR-7340-43 Quantum LR-7340-43 Quantum LR-7340-43
Cap U.S. CAN U.S. CAN U.S. CAN U.S. CAN
Manufacturer (Penn-Wheeling (Penn-Wheeling (Penn-Wheeling (Penn-Wheeling
Closure Corp.) Closure Corp.) Closure Corp.) Closure Corp.)
11087 PE White Ampacet White Ampacet White Ampacet White Ampacet
White Master 11078 Polyethylene 11078 Polyethylene 11078 Polyethylene 11078 Polyethylene
batch
Cap Type ROPP HDPE Cap ROPP HDPE Cap ROPP HDPE Cap ROPP HDPE Cap
CRC HDPE Cap CRC HDPE Cap CRC HDPE Cap CRC HDPE Cap
Cap Size 00 / 00 mm 00 / 00 mm 00 / 00 mm 00 / 00 mm
Closure Liner Tekni-Plex Inc. Tekni-Plex Inc. Tekni-Plex Inc. Tekni-Plex Inc.
Foam seal Mfg Foamseal PS 22 Foamseal PS 22 Foamseal PS 22 Foamseal PS 22

Inner liner TEKNISEAL RVT TEKNISEAL X-14 TEKNISEAL RVT TEKNISEAL X-14
composition + LF (polyethylene/Kraft + LF (polyethylene/Kraft
Paper laminate) Paper laminate)
CONTAINER Lot #00000 Lot #00000 Lot #00000 Lot #00000
CoA #0000 CoA #0000 CoA #0000 CoA #0000
CONTAINER Lot #00000 Lot #00000 Lot #00000 Lot #00000
CoA #0000 CoA #0000 CoA #0000 CoA #0000
CAP Lot #00000 Lot #00000 Lot #00000 Lot #00000
CoA #0000 CoA #0000 CoA #0000 CoA #0000
CAP Lot #00000 Lot #00000 Lot #00000 Lot #00000
CoA #0000 CoA #0000 CoA #0000 CoA #0000
LINER Lot #00000 Lot #00000 Lot #00000 Lot #00000
CoA #0000 CoA #0000 CoA #0000 CoA #0000
SEAL Lot #00000 Lot #00000 CoA #00000 CoA #00000
CoA = Certificate of Analysis/Compliance.

Handbook of Pharmaceutical Sect: 20.

20 14 Generic Development
 TABLETS ORAL STABILITY TESTING & STABILITY SOPs CHAPTER 20

Stability Testing of Drug

Substances and Drug Products II
INTRODUCTION TO ANDAs
STABILITY TESTING FOR Much of the general information for
New Drug Applications provided in the
ABBREVIATED NEW DRUG guidance is also applicable to
APPLICATIONS Abbreviated New Drugs Applications

I n June 1998 the FDA issued for

comment, a lengthy draft guidance
titled 'stability testing of drug substance
(ANDAs). However, depending upon
the availability of significant information
on, and the complexity of, these drug
and drug products', The guidance products / dosage forms, the amount of
interweaves the requirements of NDAs information necessary to support these
and ANDAs for both drug substance applications may vary from that
and drug product and borrows heavily proposed for NDAs.
from the European Stability Guidelines. This section is intended to provide
FDA Draft Guidance specific recommendations on abbre-
viated (ANDAs) applications only.
harmonizes the DRUG SUBSTANCE STABILITY
requirements for DATA SUBMISSION
US, EU & Japan For drug products submitted under an
ANDA, including antibiotics, supporting
The New Draft Guidance to industry is active material information may be
extremely comprehensive and is provided directly to the drug product
intended to replace the ageing 1987 ANDA or by reference to an appropriate
guidelines, thus harmonising the drug master file (DMF). Publications
requirements for US, EU and Japan may be provided or referenced as
They contain detailed recommendations supportive information.
on all current aspects of stability For ANDA bulk drug substances,
testing, photostability, including stability data should be generated on a
reduced testing procedures via the use minimum of one pilot-scale batch.
of bracketing and matrixing protocols.
Pilot-scale
This Part II article deals only in part
(with Section III) of the proposed
or Pilot Plant Scale
guidance namely aspects affecting the means100 000 units
stability testing in ANDA dosage forms.
The guidance to industry covers all
or 10% of full size
drug types namely INDs, NDAs and production batch
ANDAs.

Handbook of Pharmaceutical Sect: 20.

20 15 Generic Development
 TABLETS ORAL STABILITY TESTING & STABILITY SOPs CHAPTER 20

Definition of Pilot-Plant Scale suitability of the proposed analytical

procedures. The detailed nature of the
The manufacture of either drug
studies will depend on the individual
substance or drug product by a drug substance, type of drug product
procedure fully representative of and and available supporting information.
simulating that to be applied on a full Any necessary testing may be carried
manufacturing scale. out as described in Section II-A which
For oral solid dosage forms this is pertains to new drug applications.
generally taken to be at a minimum
DRUG PRODUCTS
scale of one tenth that of full production
or 100,000 tablets or capsules, Original ANDAs should contain stability
whichever is the larger. [Q1A] 3222. data generated under the long-term and
For biotechnology products, the methods of cell accelerated stability storage conditions
expansion, harvest, and product purification delineated in Section II-B of the
should be identical except for the scale of
guidance (Section II B deals with the
production.
stability testing of the drug products in
All batches should be made using New Drug Applications i.e. NDAs.)
equipment of the same design and
operating principle as the
The data package for ANDAs (e.g.,
manufacturing-scale production number of batches, length of studies
equipment with the sole exception of needed at submission and at approval,
capacity. and accelerated, intermediate and long-
term stability data) should be based on
For ANDA bulk drug substances several factors, including the complexity
produced by fermentation, stability data of the dosage form, the existence of a
should be provided on three production significant body of information for the
batches, at least two of which should be dosage form, and the existence of an
generated from different starter approved application for a particular
cultures. dosage form.
DRUG SUBSTANCE TESTING STABILITY DATA PACKAGE
A program for stability assessment may RECOMMENDATIONS.
include storage at:-
× Simple Dosage Forms Ø
Ø accelerated, The following stability data package is
Ø long-term, , recommended: (excludes controlled /
Ø intermediate stability study storage modified release dosage forms)
conditions (where applicable)
(Refer the stability Section II A. of the Guidance).
Ü Accelerated stability data at 0, 1,
2, and 3 months. A tentative expiration
Section II-A deals with the stability dating period of up 24 months will be
testing of the drug substance in New granted based on satisfactory
Drug Applications (i.e. NDAs) Stability accelerated stability data unless not
samples should be stored in the bulk supported by the available long-term
storage container equivalent (e.g., stability data.
same composition and type of Ü Long-term stability data (available
container, closure and liner, but smaller data at the time of original filing and
in size). subsequent amendments).
If not previously generated or available Ü A minimum of one batch; pilot scale.
by reference, stress testing studies Ü Additional stability studies (12
should be conducted to establish the months at the intermediate conditions,
inherent stability characteristics of the or long-term data through the proposed
drug substance, and support the expiration date) if significant change is

Handbook of Pharmaceutical Sect: 20.

20 16 Generic Development
 TABLETS ORAL STABILITY TESTING & STABILITY SOPs CHAPTER 20

seen after 3 months during the determined based on the available data
accelerated stability study. from the additional studies)
Ü The tentative expiration dating Complex Dosage Forms
period will be determined based on the
available data from the additional study. MR/CR/ER/DR/MDIs
×COMPLEX DOSAGE FORMSØ
Ø require THREE
Exceptions to the ANDA Data Package
Recommendations.
Stability batches
The following may be considered Data Package for Approval
exceptions to the general ANDA
recommendations:- ◊ Full-term stability testing of the
primary stability batch(es) is suggested.
Complex dosage forms, such as However, in the absence of full-term
Ü Modified-release products. stability data for the drug product,
Ü Transdermal patches. adequate accelerated stability data
Ü Metered-dose inhalers. combined with available long-term data
can be used as the basis for granting a
Ü Drug products without a tentative expiration dating period.
significant body of information.
Ü New dosage forms submitted
◊ The batch(es) used for stability
testing should comply fully with the
through the ANDA suitability petition
proposed specifications for the product
process
(Other exceptions may exist and should be
and be packaged in the market
discussed with the Office of Generic Drugs. package, and the release assay should
Refer Q1C applications). be within reasonable variation (taking
An ANDA that is determined to be one into account inherent assay variability)
of the above categories should contain from the labeled strength or theoretical
a modified ICH Q1A stability data strength of the reference listed drug.
package, including: ◊ If formulated with an overage, the
◊ 3-month accelerated stability studies. overage should be justified as
necessary to match that of the
◊ Long-term stability studies (available reference listed drug.
data at the time of original filing and
subsequent amendments). The ◊ Other supportive stability data may
expiration dating period for complex be submitted on drug product batches
dosage forms will be determined based that may or may not
on available long-term stability data ◊ meet the above criteria. Data on
submitted in the application. relevant research batches,
◊A minimum of three batches investigational formulations, alternate
manufactured in accordance with the container / closure systems, or from
ICH Q1A batch size recommendations other related studies may also be
(refer Section II B of this guidance -NDA Drug submitted to support the stability of the
Products or to V.B. of the ICH Q1A guidance). drug product. The supportive stability
Additional stability studies (12 months data should be clearly identified.
at the intermediate conditions or long-
term stability testing through the
Stability Study Acceptance
proposed expiration date) if significant If the results are satisfactory, a
change is seen after 3 months during tentative expiration dating period of up
the accelerated stability studies (the to 24 months at the labeled storage
tentative expiration dating period will be conditions may be granted.

Handbook of Pharmaceutical Sect: 20.

20 17 Generic Development
 TABLETS ORAL STABILITY TESTING & STABILITY SOPs CHAPTER 20

Where data from accelerated studies Additional data from ongoing studies
are used to project a tentative and regular annual batches should be
expiration dating period that is beyond included in the application’s annual
a date supported by actual long-term report. Annual reports should include
studies on production batches, the new or updated stability data generated
application should include a in accordance with the approved
commitment to conduct long-term stability protocol.
stability studies on the first three The data may include accelerated and
production batches and annual batches long-term studies for each product to
until the tentative expiration dating satisfy the standard stability
period is verified, or the appropriate commitment made in the original or
expiration dating period is determined. supplemental application, including the
Final Expiration Dating annual batch(es), and to support post-
approval changes.
means long term The data should be presented in an
stability studies on organized, comprehensive, and
three production lots cumulative format.
CONTENT OF STABILITY REPORTS
For Complex Dosages It is suggested that stability reports
Extension of the tentative expiration include the following information and
dating period should be based on data data to facilitate decisions concerning
generated on at least three production drug product stability:
batches tested according to the
GENERAL PRODUCT INFORMATION
approved protocol outlined in the
stability commitment. • Product Name
Reporting of the data should follow • Source
Section VI format of the guidance which • Manufacturing site(s)
applies to all application types • Date of manufacture of drug
ANDAs withdrawn prior to publication substance and drug/biological product.
of this guidance should not normally • Dosage form and strength,
have to include stability data in
conformance with the guidance upon • Product formulation.
resubmission if the original application • Composition, type, source, size, and
was withdrawn due to non-stability adequate description of container and
related issues. closure., seals, and desiccants (cotton
However, if new stability studies are coil / stuffers) should be identified.
conducted to support the submission, The application should provide a table
such studies should be conducted as of specific formulations under study.
recommended in the guidance. When more than one formulation has
been studied, the formulation number is
REPORTING STABILITY DATA acceptable.
A. General
Stability data should be included in the SPECIFICATIONS AND TEST
ANDA application (or supplement) they METHODOLOGY INFORMATION
are intended to support. The extent of • Physical, chemical, and
stability data expected at the time of microbiological regulatory specifications
submission is discussed at length and attributes/limits (or specific
throughout the guidance. references to ANDA or USP).

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20 18 Generic Development
 TABLETS ORAL STABILITY TESTING & STABILITY SOPs CHAPTER 20

• Individual data as well as mean and

• Test methodology used (or specific
standard deviation should be reported.
reference to ANDA, prior submissions,
or USP) for each sample tested. • Tabulated data by storage condition.
• Summary of information on previous
• Information on accuracy, precision, formulations during product
and suitability of the methodology (cited development. This summary may be
by reference to appropriate sections). referenced (if previously submitted) and
• Where applicable, a description of should include other containers and
the potency test(s) for measuring closures investigated.
biological activity, including speci- DATA ANALYSIS
fications for potency determination. The following data analysis of
STUDY DESIGN AND STUDY quantitative parameters should be
CONDITIONS provided:
• Description of the sampling plan, • Evaluation of data, plots, and/or
including: graphics.
• Batches and number selected. • Documentation of appropriate
statistical methods and formulas used.
• Container and closures and number
• Results of statistical analysis and
selected.
estimated expiration dating period.
• Number of dosage units selected and • Results of statistical tests used in
whether tests were conducted on arriving at microbiological potency
individual units or on composites of estimates.
individual units.
• Sampling time points.
CONCLUSIONS
• Proposed expiration dating period
• Testing of drug or biological products
and its justification.
for reconstitution at the time of
• Regulatory specifications set.
reconstitution (as directed on the
labeling) as well as through their (Note: Establishment of acceptable minimum
recommended use periods. potency at the time of initial release for full
expiration dating period to be fully justified).
• Expected duration of the study.
Complex Dosage Form Definition
• Conditions of storage of the product A complex dosage form is one where
under study (e.g., temperature, quality and/or stability is more likely to
humidity, light, container orientation). be affected by changes because the
A Sampling Protocol release mechanism, delivery system,
identifying sampling and manufacturing process are more
complicated and thus more susceptible
points is necessary to variability.
STABILITY DATA/INFORMATION Examples of complex dosage forms
• Batch number (research, pilot, include ♦modified-release dosage forms,
production) and associated ♦metered-dose inhalers, ♦transdermal
manufacturing date. patches, ♦ liposome preparations.
• For antibiotic drug products, the age Due to the diversity of currently marketed
of the bulk active drug substance(s) dosage forms and the ever-increasing
used in manufacturing the batch. complexity of new delivery systems, it is
impossible to clearly identify simple vs.
• Analytical data, source of each data complex dosage forms in an exhaustive
point, and date of analysis (e.g., batch, manner.
container composite, etc.) Pooled Applicants are advised to consult with the
estimates may be submitted if individual appropriate FDA chemistry review team when
data points are provided. questions arise.

Handbook of Pharmaceutical Sect: 20.

20 19 Generic Development
 TABLETS ORAL STABILITY TESTING & STABILITY SOPs CHAPTER 20

ANDA à STABILITY
DRUG PRODUCT à FLOWCHART
SIMPLE DOSAGE FORMS COMPLEX DOSAGE FORMS
× IR Ø × CR/MR/ER/DR/MDIs…Ø
Formulation for Simple Dosage Forms Formulation for Complex Dosage Forms
Immediate Release Solids & Liquids Modified Release Solids & MDIs

Sampling Protocol Sampling Protocol

& &
Sampling Points Sampling Points

Stability Check Specifications

Stability Check Specifications
and Limits
and Limits (Additional Guidance for complex dosage forms in the
(Refer Guidance for each dosage form)
FDA Pipeline)

Stability Protocol Stability Protocol

Bracketing & Bracketing &
Matrixing Permitted Matrixing Permitted

THREE BATCHES PER STRENGTH

ONE BATCH PER STRENGTH/SITE Two Pivotal 100 000 (net) or 10% rule
100 000 (net) or 10% rule plus one small scale lot
(i.e. could be PQ or Scale-UP lots)

ACCELERATED CONDITIONS ACCELERATED CONDITIONS

1, 2, & 3 months @ 40 oC 75% RH 1, 2, & 3 months @ 40 oC 75% RH
plus Real Time @ 25 oC

SIGNIFICANT CHANGE CLAUSE SIGNIFICANT CHANGE CLAUSE

applies if accelerated specifications go applies if accelerated specifications go
OUT-OF-LIMITS OUT-OF-LIMITS
5% potency 5% potency
Rule A Problematic Rule Rule

Reporting of Stability Data Reporting of Stability Data

A minimum data set and format A minimum data set and format
is required. is required.

Expiration based on ACCELERATED Expiration based on REAL TIME data

data

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20 20 Generic Development
 TABLETS ORAL STABILITY TESTING & STABILITY SOPs CHAPTER 20

Stability Testing of Drug

Substances and Drug Products III
SIGNIFICANT
CHANGE
CLAUSE

THE MEANING OF 'SIGNIFICANT photostability, including reduced testing

procedures via the use of bracketing
CHANGE' … IN ANDAs and matrixing protocols.
S ignificant change alters the overall
planning concept of a drug product
stability study. It play a dominant part in
This Part III article deals with the
significant change at accelerated
the FDAs draft guidance titled 'Stability conditions and the possible pitfalls
testing of drug substance and drug arising from this rule, during stability
products' which inter-weaves the testing in finished drug dosage forms.
requirements of INDs, NDAs and Past experience shows that in many
ANDAs for both the active drug stability programs, the proposed one
substance and finished drug product. It year, 30oC study, may well be needed,
references and borrows heavily from in addition to the normal accelerated
the European Stability Guidelines. and real time studies, as a 5%
Comprehensive potency/assay loss, frequently occurs
during the initial three month
US Draft Guidance accelerated study period.
partly harmonizes Neither the ICH or Draft FDA guidance
US, EU & Japan takes into account of the intermediate
precision RSD of the validated stability
Stability Requirements indicating assay. This means that the
The New Draft Guidance to industry is 5% is net and overlooks a standard 2.0-
extremely comprehensive and detailed. 4.0% intermediate precision RSD
It is intended to replace the aging, thereby reducing the actual 5% assay
twelve year old, 1987 guidelines, value in real terms.
thereby in one step partially Significant Change
harmonising the requirements for US,
EU and Japan while not deviating too clause simple means:
much from the current ANDA START a 30oC / 60%RH
requirements. The EU stability
requirements are adequately met with
one year study
additional existing US ANDA from DAY ONE of the
requirements. The document contain Stability Program
detailed recommendations on all
current aspects of stability testing, Just-in-Case it's Needed

Handbook of Pharmaceutical Sect: 20.

20 21 Generic Development
 TABLETS ORAL STABILITY TESTING & STABILITY SOPs CHAPTER 20

Where significant change occurs due Alternatively, the study at the

to accelerated testing, additional testing
intermediate condition should
at an intermediate condition (e.g.,
30oC± 2oC / 60% RH ±5%) should be be started from the initial time
conducted. point.
Significant change at the accelerated Where a significant change occurs
conditions is defined as:
during 12 months of storage at
Ü 5 percent potency loss from the 30ºC/60%RH, it may not be appropriate
initial assay value of a batch. to label the drug product for Controlled
Ü Any specified degradant exceeding Room Temperature (CRT) storage with
its specification limit. the proposed expiration dating period,
even if the stability data from the full
Ü The product exceeding its pH limits. long-term studies at 25ºC/60%RH
appear satisfactory.
Ü Dissolution exceeding the specific-
ation limits for 12 capsules or tablets
(USP Stage 2).
Significant Change
may occur during the
Ü Failure to meet specifications for
30oC / 60%RH
appearance and physical properties
(e.g., color, phase separation, re-
suspendability, delivery per actuation,
intermediate study
caking, hardness) [ICH Q1A]. - as well
FIVE Criteria exist In such cases, alternate approaches,
requiring an additional should be considered during drug
development. such as the following:-
30oC / 60%RH
Ü Qualifying higher acceptance
one year study criteria for a degradant

Should significant change occur at Ü Shorter expiration dating period,

o or refrigerator temperature storage
40 C/75% RH, the initial application
should include a minimum of 6 months’
data from an ongoing 1-year study at
Ü More protective container and/or
closure
30oC/60 percent RH; the same
significant change criteria shall then Ü Modification to the formulation
apply. [ICH Q1A]
If any parameter fails significant change Ü Modification of the manufacturing
process.
criteria during the accelerated stability
study, testing of all parameters during ADDITIONAL LABELLING
the intermediate stability study should If CRT storage is ultimately justified, it
be performed. may be necessary to add to the product
If stability samples have been put into labeling a cautionary statement against
the intermediate condition, but have not prolonged exposure at or above 30ºC.
been tested, testing these samples may The long-term testing will be continued
begin as soon as the accelerated study for a sufficient period of time beyond 12
shows significant change in the drug months to cover shelf life at appropriate
product specifications. test periods.

Handbook of Pharmaceutical Sect: 20.

20 22 Generic Development
 TABLETS ORAL STABILITY TESTING & STABILITY SOPs CHAPTER 20

ADDITIONAL DATA STABILITY TESTING PROTOCOL

The additional or further accumulated
data should be submitted to the FDA
during the assessment period of the Place sufficient stability samples for
drug application. [ICH Q1A.] all three temperature ranges within
The first three production batches 30 days from manufacturing date
manufactured post approval, if not
submitted in the original application,
should be placed on accelerated and
250C 300C 400C
long-term stability studies using the
same stability protocol as in the
approved drug application. [ICH Q1A.] PLACE & HOLD
FOUR TEST STATIONS
A minimum of 4 test stations (e.g., 0, 2, Test for 0, 1, 2, 3
4, and 6 months) are recommended for months
the 6-month accelerated stability study.

DEFINITION (FDA / ICH) Start testing if any FAIL

of the 5 accelerated
Significant Change [ICH-Q1A] conditions fail. PASS
Significant change for a drug product at TEST for up to
12 months
the accelerated stability condition and
the intermediate stability condition is Full Monograph 0, 2, 4, 6, 12 months
testing required sampling periods
defined as:
[1] 5 percent potency loss from the
initial assay value of a batch
Continue All
[2] Any specified degradant until If 400C
exceeding its specification limit either significant
400C tests
[3] The product exceeding its pH or change pass for
limits any occurs Three
300C again months
[4] Dissolution exceeding the study Re-formulate
specification limits for 12 capsules or FAILS
then
Re-qualify þ
tablets Re-view
STOP Product
[5] Failure to meet specifications for all Test alternative OK
appearance and physical properties, for approaches
example.
Tablets:- Color, hardness
Suspensions:- Color, phase separation
Re-suspendibility, caking If Real Time 25 oC PASS
Semisolids:- Color, phase separation but additional 30 oC study
Liquids:- Color, shows Significant Change
Aerosols:- Delivery per actuation as well - then cautionary
phase separation. Labeling Statement is required

Handbook of Pharmaceutical Sect: 20.

20 23 Generic Development
 TABLETS ORAL STABILITY TESTING & STABILITY SOPs CHAPTER 20

When Applicable

1 2 3 4 +5
Dissolution
Initial To Specification Drug Product
Limit of any exceeds 12
Assay decreases exceeds it pH
drug product dosage unit
> 5% during limits during
degradant is o specification
1, 2, or 3 months the 30 or 40 C or
exceeded during Study
of 30/40o C Study o Appearance
30/40 C Study
Initial assay must be or
'close to 100% rule' Physical
SIGNIFICANT CHANGE properties

IMPACT ON TESTING

Ü Three Study Temperatures in stability protocol

Ü Evaluate stability profile in PQ batch to access and eliminate significant change
Ü Qualify and document check specifications precisely accounting for relevant
aging (e.g. white to off-white, or cream colored tablet)
Ü Hardness Qualification Protocol for PQ or Pivotal Batch Lot
Ü pH range Qualification Protocol for liquids, suspensions and semisolids
Ü Rugged Assays with low RSD values for intermediate precision (day-to-day)
Ü SOP to define 5% change as meaning net value change (i.e. 5% ± RSD1)
Ü More detailed Investigation procedures to evaluate, if >5% change is not due to
an analytical procedure or technician error.
RSD1 values for actual full assay method's intermediate precision calculated on
different days, with different lab technicians and equipment, under routine
conditions.
IMPACT ON DRUG DEVELOPMENT

Ü Longer times required for overall stability study evaluation - more costly studies.
Ü Formulations to be rugged / robust to withstand potential 5% assay change.
Ü Enhanced antioxidant / chelating formula optimization studies1 necessary
during product development stages.
Ü Tablet Hardness Qualification Study 2
essential in either PQ or Pivotal Batch
lots.
Ü Full Analytical Assay Validation must be performed at the PQ stage or earlier to
sufficiently evaluate potential significant change parameters.
Courtesy: International Journal of Generic Drugs, Volume 01, No 08 ,1997.
Courtesy: International Journal of Generic Drugs, Volume 01 ,No 06, 1997.

Handbook of Pharmaceutical Sect: 20.

20 24 Generic Development
 TABLETS ORAL STABILITY TESTING & STABILITY SOPs CHAPTER 20

SOP # S-435-01-01Y2K STANDARD OPERATING Total Pages 4.

PROCEDURES

EVALUATION OF SIGNIFICANT CHANGE

RESULTS IN STABILITY TESTING PROCEDURES

PURPOSE

T he purpose of this Standard Operating Procedure is to define the procedure to

be observed in the case of questionable laboratory results being obtained due to
significant change occurring during stability testing programs. This SOP is designed
to fully address the impact of potential significant change in stability analytical results
due to laboratory error causes (Ref. Draft Stability Guidance to Industry, June 1998.)

Significant change analytical results are defined as the following:

[1]. Analytical results which falls outside of the Stability Check Specifications.
[[2]. >5 percent potency loss1 from the initial analytical assay value of the batch
(i.e. values outside the >5% ± RSD2 range)
[3]. Any specified drug product degradant exceeding its specification limit.
[4]. Dissolution assay results for capsules/tablets or suspensions exceeding the
specification limits for 12 dosage forms (USP Stage 2 criteria).
[5]. Failure to meet product CHECK specifications for appearance and physical
properties or where the product exceeds its CHECK SPECIFICATION pH limits.
RESPONSIBILITY
◊ Laboratory Analysts are responsible for immediately informing their supervisor of
any significant change or questionable analytical result obtained.
◊ Laboratory Supervisors are responsible for conducting a laboratory investigation
together with the appropriate analyst.
◊ After such investigation is complete the supervisor shall determining whether
repeat analytical testing is necessary and the Quality Assurance Manager
(Development) shall be informed of the investigation's conclusions.
FREQUENCY
Applies to laboratory analysis where a questionable stability result or a significant
change in a previous test result has been obtained.
PROCEDURE (Ref. - Appendix 1 - GENERAL FLOW CHART)
[1]. The Analytical testing Laboratory shall maintain and keep current a Significant
Change Logbook. The Logbook shall record all Significant Change results and retest
procedures and investigations.
1 2
Adjusted Significant Change that includes analytical variance value. Relative Standard Deviation
(RSD) values for test assay method's intermediate precision. Calculated from assays performed on
different days, with different lab technicians and equipment, under routine testing conditions.

ED. N0: 01 Effective Date: APPROVED:

Replaces NEW
Ed. Status : 01 DD/MM/200Y
Department R&D RA QC / QA
Handbook of Pharmaceutical Sect: 20.
20 25 Generic Development
 TABLETS ORAL STABILITY TESTING & STABILITY SOPs CHAPTER 20

SOP # S-435-01-01Y2K STANDARD OPERATING Total Pages 4.

PROCEDURES

EVALUATION OF SIGNIFICANT CHANGE

RESULTS IN STABILITY TESTING PROCEDURES

[2]. Where a questionable analytical result is obtained during routine laboratory

testing, the testing analyst shall immediate inform the appropriate supervisor.

[3]. The supervisor and the analyst shall then conduct a laboratory investigation
which shall include a review of the analytical principles using the “Checklist For
Laboratory Investigation Report” (See “Out of Specification Result SOP.”)

[4]. Where the laboratory investigation reveals that the cause of the questionable
result is a LABORATORY ERROR, i.e. one of the principles mentioned in the
checklist was at fault, the supervisor shall invalidate the original test results. The
supervisor shall record the conclusions and scientific rationale in the analyst's
laboratory notebook. The comments shall be signed and dated.

[5]. Where the cause is found to be faulty analytical technique, the test is repeated
(in duplicate from the beginning) on the same sample (i.e. from the same stability
sample container initially used for sampling and testing).

Ü If the sample passes the retest, then the result may be released and accepted.
Ü In cases of retest failure, proceed as per paragraph [9].
[6]. Where the cause is due to faulty analytical methodology, a new edition
methodology revision shall be prepared.

[7]. Where the laboratory investigation is INCONCLUSIVE, and the cause cannot
definitely be ascribed to laboratory error, proceed as follows:

[8]. If the relevant pharmacopoeia specifies acceptance criteria guidelines for the
particular type of test involved (dissolution, microbial limits etc.), the analyst shall
proceed with the testing according to the official method. If the retest passes, it is
reported according to the pharmacopoeial requirements. If the compendial retest
fails, the Quality Assurance Unit inform for further investigation, where appropriate.

[9]. Where, the relevant pharmacopoeia does not specify retesting procedures for
the particular type of test involved, TWO re-tests will be performed by TWO analysts
(that is, the sample shall be tested in duplicate).
The final result is calculate as the average of the THREE analysis (e.g. 6 results
which include the results from two re-tests and the original test result). No individual
analysis of the retest results shall fail the specifications.

ED. N0: 01 Effective Date: APPROVED:

Replaces NEW
Ed. Status : 01 DD/MM/200Y
Department R&D RA QC / QA
Handbook of Pharmaceutical Sect: 20.
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 TABLETS ORAL STABILITY TESTING & STABILITY SOPs CHAPTER 20

SOP # S-435-01-01Y2K STANDARD OPERATING Total Pages 4.

PROCEDURES

EVALUATION OF SIGNIFICANT CHANGE

RESULTS IN STABILITY TESTING PROCEDURES

[10]. In cases that the results are within the specified limits, the results are accepted.

[11]. If the retest result still remains questionable, the supervisor will inform the
Quality Assurance Unit for further investigation, if so required.

[12]. The Quality Assurance Unit shall fully review the data and decide if the test
results should be reported as is, or additional action is required.

LIMITS & LIMITATIONS

Retesting may not be performed until an investigation is completed or the laboratory
supervisor's permission has been given. The results of the investigation shall
determine at what point re-testing is appropriate (if, at all).
In the case of a proposed analytical methodology revision, retesting with the new
edition method may proceed, but the results shall not be accepted or utilized until
the method is fully validated, approved and duly authorized.

CORRECTIVE ACTION
Retesting is performed on the same sample container originally used, (obtaining
new samples, new sample stock or performing new sampling procedures from bulk
material or stability stock is prohibited.)

DOCUMENTATION
Laboratory investigations shall be fully documented, and the conclusions signed and
dated by the Laboratory Manager.

In case where the investigation is passed on to the Quality Assurance Unit Manager,
an Investigation Report shall be prepared.

All analytical re-testing of stability tests is to be reported and documented in the

Significant Change Log. The Log book is held under the responsibility of the
Analytical Laboratory Manager and the Stability Unit Manager.

A “Checklist For Laboratory Investigation Reports” is filed in all cases of

questionable or significant change results following a laboratory investigation.

The Investigation Report Number is recorded in the Significant Change Log.

ED. N0: 01 Effective Date: APPROVED:

Replaces NEW
Ed. Status : 01 DD/MM/200Y
Department R&D RA QC / QA
Handbook of Pharmaceutical Sect: 20.
20 27 Generic Development
 TABLETS ORAL STABILITY TESTING & STABILITY SOPs CHAPTER 20

SOP # S-435-01-01Y2K STANDARD OPERATING Total Pages 4.

PROCEDURES

EVALUATION OF SIGNIFICANT CHANGE

RESULTS IN STABILITY TESTING PROCEDURES

Appendix 1 FLOW CHART

Significant Change with
Questionable Lab Result

Immediate Notification
Investigation Started

LABORATORY INVESTIGATION
FINDINGS in LOGBOOK

NON CONCLUSIVE LABORATORY ERROR

RESULTS
Invalidate original results
Specific Pharmacopoeial
and RETEST on the SAME
Retest Procedures allowed
sample in duplicate.

Retesting Not Specified

PASS
FAIL
Retest TWICE (duplicates) on
Same Sample - TWO analysts

PASS
FAIL
PASS
FAIL

LOG Report Average of all LOG

RESULT three analysis (6 results) RESULT
QA INVESTIGATION

Courtesy: International Journal of Generic Drugs

ED. N0: 01 Effective Date: APPROVED:

Replaces NEW
Ed. Status : 01 DD/MM/200Y
Department R&D RA QC / QA
Handbook of Pharmaceutical Sect: 20.
20 28 Generic Development
 TABLETS ORAL STABILITY TESTING & STABILITY SOPs CHAPTER 20

Stability Testing Storage

Conditions STORAGE
PARAMETERS
TEMPERATURE/HUMIDITY

NEW STABILITY GUIDELINES - General Storage

LONG TERM, INTERMEDIATE & ACCELERATED CONDITIONS
CONTAINER-CLOSURE SYSTEMS The comparison between upright and
inverted or on-the-side position is
S tability data should be developed for
the drug product in each type of
immediate container and closure
important to determine whether contact
of the drug product (or solvent) with the
proposed for marketing, promotion, or closure results in extraction of chemical
bulk storage. substances from the closure
components or adsorption and
The possibility of interaction between absorption of product components into
the drug and the container and closure the container/closure.
and the potential introduction of
extractables into the drug product The evaluation should include the set
formulations during storage should be of test parameters (check
assessed during container/closure specifications) that are listed in
qualification studies using sensitive and Considerations for Specific Dosage
quantitative procedures. Forms in Section VIII of the draft
Guidance
These studies are recommended even
if the container-closure meet Development Stability
compendial suitability tests, such as
those outlined in the USP for plastic Studies Include Upright
containers and elastomeric or plastic
closures. & Inverted Positions
A draft guidance is available on this Upright versus inverted/on-the-side
topic entitled; Submission of Documentation
in Drug Applications for Container Closure stability studies should be performed
Systems Used for the Packaging of Human during the pre-approval and post-
Drugs and Biologics (June 1997). approval verification stages of the
stability program.
Solutions (i.e., oral, SVPs, LVPs, oral and Once it has been demonstrated that the
nasal inhalations, and topical preparations),
dispersed systems (oral, MDIs, injectables), product in maximum contact with the
and semi-solid drug products (topical, primary pack does not have a
ophthalmics, and otics) should be stored in significantly greater impact on drug
both the upright and either inverted or on- product quality than the upright
the-side positions until contact with the orientation, stability studies may be
container/closure system has been shown continued only in the most stressful
not to impact on drug product quality. orientation, which is generally the
inverted or on-the-side position.

Handbook of Pharmaceutical Sect: 20.

20 29 Generic Development
 TABLETS ORAL STABILITY TESTING & STABILITY SOPs CHAPTER 20

LONG TERM, INTERMEDIATE & ACCELERATED CONDITIONS

Tabulated storage conditions detailing temperature, humidity and orientation as
recommended in the proposed June 1998 stability testing guidance document.

Container-Closure CONDITIONS TIME at File

Storage Orientation áâ Submission
Long Term Stability Optional NDA ANDA

Solid Oral Dosage Forms 25oC ±2oC 60% RH ±5% 12+ 3+

o o
Glass Containers (solid oral) 25 C ±2 C [60%RH ±5%] 12 3+
Glass Containers (liquids) áâ 25oC ±2oC [60%RH ±5%] 12+ 3+
Semi Permeable á â 25oC ±2oC 40% RH ±5% 12+ 3+
Accelerated Stability Optional NDA ANDA
Solid Dosage Forms 40oC ±2oC 75% RH ±5% 6 3
Glass Containers (solid oral) 40oC ±2oC [75%RH ±5%] 3
Glass Containers (liquids) áâ 40oC ±2oC [75%RH ±5%] 6 3
Semi Permeable Containers á â 40oC ±2oC 15% RH ±5% 6 3
Intermediate Stability Optional NDA ANDA
Solid Dosage Forms 30oC ±2oC 60% RH ±5% 6+ 6+
Glass Containers (solid oral) 30oC ±2oC [60%RH ±5%] 6+ 6+
Glass Containers (liquids) áâ 30oC ±2oC [60%RH ±5%] 6+ 6+
Semi Permeable (SP) áâ 30oC ±2oC 40% RH ±5% 6+ 6+
Ophthalmics + Otics (SP) áâ 30oC ±2oC 40% RH ±5% 6+ 6+
Nasal Sprays (SP) áâ 30oC ±2oC 40% RH ±5% 6+ 6+
Stability Storage Conditions for container-closures which may be susceptible to
water loss are defined as: Semi-Permeable & Permeable containers for: þ Large
volume parenterals (LVPs); þ Small volume parenterals (SVPs); þ Ophthalmics;
þ Otics, & þ Nasal sprays packaged in semi-permeable containers, such as plastic
bags, or semi-rigid plastic containers e.g., ampules, vials and bottles with or without
droppers or applicators.
LOW TEMPERATURE - LONG TERM & ACCELERATED
CONDITIONS
DOSAGE FORM CONDITIONS TIME
Container-Closure At Submission
Long Term Stability - Refrigerator NDA ANDA
o o
5 C ±5 C No Control 12+ 3+
Accelerated Stability - Refrigerator NDA ANDA
25oC ±2oC 60% RH ±5% 6 3
Long Term Stability - Freezer NDA ANDA
-15oC ±5oC No Control 12+ 3+
Accelerated Stability - Freezer NDA ANDA
5oC ±3oC Ambient RH 6 3

Handbook of Pharmaceutical Sect: 20.

20 30 Generic Development
 TABLETS ORAL STABILITY TESTING & STABILITY SOPs CHAPTER 20

STABILITY TESTING

P hotostability
in New Drug Products
‘…evaluating photostability is foremost for new chemical entities only - not in
g e n e r i c d r u g s , p r o v i d e d t h e c o n t a i n e r - c l o s u r e p r o t e c t i o n i s t h e s a m e …'

INTRODUCTION light is equal or better than the reference

and one of the two standardized caution

I n June 1998 the FDA issued for

comment, a lengthy 110 page draft
guidance titled 'Stability Testing of
phrases 'PROTECT FROM LIGHT'
appears on the package labeling.
GENERAL
Drug Substance and Drug Products' The ICH Harmonized Tripartite
The stability guidance interweaves the Guideline on Stability Testing of New
requirements of NDAs and ANDAs for Drug Substances and Products
both drug substance and drug product (hereafter referred to as the parent
and borrows heavily from the European guidance) notes that light testing should
Stability Guidelines. be an integral part of stress testing.
The ICH Q1B guidance Photo-stability
Photostability Testing of New Drug Substances and
Draft Guidelines Products primarily addresses the
do not readily affect generation of photostability information
for new molecular entities and
Generic Development associated drug products and the use of
the data in determining whether
The New Draft Guidance to industry is precautionary measures in
extremely comprehensive and is manufacturing, labeling, or packaging
intended to replace the ageing 1987 are needed to mitigate exposure to light.
guidelines, thus harmonising the
requirements for US, EU and Japan Generic Developers
They contain detailed recommendations should at least
on all current aspects of stability testing,
photostability, including reduced testing
be aware of the
procedures via the use of bracketing Draft Photostability
and matrixing protocols. Guidelines
This Part III article deals with the Q1B does not specifically address other
proposed guidance namely aspects photostability studies that may be
affecting the photostability stability needed to support, for example, the
testing in New Drug Applications photostability of a product under in-use
Photostability Draft Guidelines do not conditions or the photostability of
readily affect generic development analytical samples.
providing that the packaging
configuration and protection against

Handbook of Pharmaceutical Sect: 20.

20 31 Generic Development
 TABLETS ORAL STABILITY TESTING & STABILITY SOPs CHAPTER 20

Because data are generated on a For example, if initial studies

directly exposed drug substance alone demonstrate that an active moiety in a
and/or in simple solutions and drug simple solution degrades upon exposure
products when studies are conducted as to light and the tablet drug product is
described in the Q1B guidance, stable, a subsequent filing requesting
knowledge of photostability approval of a liquid dosage form may
characteristics may be useful in warrant additional studies to
determining when additional studies may characterize the photostability
be needed or in providing justification for characteristics of the new dosage form.
not performing additional studies.
Light stress testing
Generic Developers is part of
should check the the stress testing
reference drug's in ANY stability indicating
labelling and literature assay development
for photo-instability
Photostability studies need not be
For example, if a product has been conducted for products that duplicate a
determined to photodegrade upon direct commercially available listed drug
exposure but is adequately protected by product provided that the packaging
packaging, an in-use study may be (immediate container/closure and market
needed to support the use of the product pack) and labeling storage statements
(e.g., a parenteral drug that is infused regarding light duplicate those of the
over a period of time). reference listed drug.
The test conditions for in-use studies If deviations in packaging or labeling
will vary depending on the product and statements are made, additional studies
use but should depend on and relate to may be recommended.
the directions for use of the particular The decision as to whether additional
product. studies should be conducted will be
Photostability studies are usually made on a case-by-case basis by the
conducted only in conjunction with the agencies chemistry review team.
first approval of a new molecular entity.
Under some circumstances, The intrinsic photostability
photostability studies should be characteristics of new drug substances
repeated if certain post-approval or and products should be evaluated to
supplemental changes, such as changes demonstrate that, as appropriate, light
in formulation or packaging, are made to exposure does not result in
the product, or if a new dosage form is unacceptable change. Normally,
proposed. photostability testing is carried out on a
single batch of material selected as
Whether these studies should be described in the section Selection of
repeated depends on the photostability Batches, in the parent guidance.
characteristics determined at the time of
initial filing and the type of changes Under some circumstances, these
made. studies should be repeated if certain
variations and changes are made to

Handbook of Pharmaceutical Sect: 20.

20 32 Generic Development
 TABLETS ORAL STABILITY TESTING & STABILITY SOPs CHAPTER 20

the product (e.g., formulation, LIGHT SOURCES

packaging). The light sources described below may
Whether these studies should be be used for photostability testing. The
repeated depends on the photo-stability applicant should either maintain an
characteristics determined at the time of appropriate control of temperature to
initial filing and the type of variation and minimize the effect of localized
/ or change made. [ICH Q1B] 1992. temperature changes or include a dark
control in the same environment unless
Four Stages for otherwise justified.
For both options 1 and 2, a
Light Stress Testing exist:: pharmaceutical manufacturer / applicant
Exposed Active material can rely on the spectral distribution
specification of the light source
Drug Product - outside pack manufacturer. [ICH Q1B]
Drug Product - in Primary Pack Standard Light Sources
Drug Product - Final Marketing Pack for light chambers
A systematic approach to photo-stability are set with controlled
testing is recommended covering, as
appropriate, studies such as: exposure temperatures
(See flow chart attached.) Option 1
n Tests on the drug substance; Any light source that is designed to
produce an output similar to the D65 /
n Tests on the exposed drug product ID65 emission standard such as an
outside of the immediate pack; and if artificial daylight fluorescent lamp
necessary, combining visible and ultraviolet (UV)
n Tests on the drug product in the outputs, xenon, or metal halide lamp.
immediate pack; and if necessary, D65 is the internationally recognized standard
for outdoor daylight as defined in ISO 10977
n Tests on the drug product in the (1993).
marketing pack (with secondary carton ID65 is the equivalent indoor indirect daylight
and label - where required). [ICH Q1B] standard.
The extent of drug product testing For a light source emitting significant
should be established by assessing radiation below 320 nanometers (nm),
whether or not acceptable change has an appropriate filter(s) may be fitted to
occurred at the end of the light exposure eliminate such radiation. [ICHQ1B]
testing as described in the Decision Option 2
Flow Chart for Photostability Testing For option 2 the same sample should be
of Drug Products. Acceptable change is exposed to both the cool white
change within limits justified by the fluorescent and near ultraviolet lamp.
applicant. [ICH Q1B] n A cool white fluorescent lamp
The formal labeling requirements for designed to produce an output similar to
photolabile drug substances and drug that specified in ISO10977 (1993); and;
products are established by national / n A near UV fluorescent lamp having a
regional requirements. [ICH Q1B] spectral distribution from 320 nm to 400
nm with a maximum energy

Handbook of Pharmaceutical Sect: 20.

20 33 Generic Development
 TABLETS ORAL STABILITY TESTING & STABILITY SOPs CHAPTER 20

emission between 350 nm and 370 nm; studies, the samples should be in
a significant proportion of UV should be chemically inert and transparent
in both bands of 320 to 360 nm and 360 containers.
to 400 nm. [ICH Q1B] In these forced degradation studies, a
variety of exposure conditions may be
PROCEDURE [ICH Q1B] used, depending on the photosensitivity
For confirmatory studies, samples of the drug substance involved and the
should be exposed to light providing an intensity of the light sources used.
overall illumination of not less than 1.2 For development and validation
million lux hours and an integrated near purposes, it is appropriate to limit
ultraviolet energy of not less than 200 exposure and end the studies if
watt hours/square meter to allow direct extensive decomposition occurs.
comparisons to be made between the
drug substance and drug product. For photostable materials, studies may
be terminated after an appropriate
Samples may be exposed side-by-side exposure level has been used.
with a validated chemical actinometric The design of these experiments is left
system to ensure the specified light to the applicant’s discretion although the
exposure is obtained, or for the exposure levels used should be justified.
appropriate duration of time when Under forcing conditions, decomposition
conditions have been monitored using products may be observed that are
calibrated radiometers/lux meters. unlikely to be formed under the
An example of an actinometric conditions used for confirmatory studies.
procedure is provided. This information may be useful in
If protected samples (e.g., wrapped in developing and validating suitable
aluminum foil) are used as dark controls analytical methods.
to evaluate the contribution of thermally
induced change to the total observed If in practice it has been demonstrated
change, these should be placed they are not formed in the confirmatory
alongside the authentic sample. [ICH studies, these degradation products
Q1B]. need not be examined further.
Confirmatory studies should then be
undertaken to provide the information
DRUG SUBSTANCE [ICH Q1B] necessary for handling, packaging, and
For drug substances, photostability labeling (see Presentation of Samples,
testing should consist of two parts: for information on the design of these
Forced degradation testing and studies Section VIII.J.3., Procedure, and
confirmatory testing. 4.a. in guidelines).
The purpose of forced degradation Normally, only one batch of drug
testing studies is to evaluate the overall
substance is tested during the
photosensitivity of the material for
development phase, and then the
method development purposes and/or
photostability characteristics should be
degradation pathway elucidation.
confirmed on a single batch selected as
This testing may involve the drug described in the parent guidance if the
substance alone and/or in simple drug is clearly photostable or
solutions / suspensions to validate the photolabile.
analytical procedures. In these

Handbook of Pharmaceutical Sect: 20.

20 34 Generic Development
 TABLETS ORAL STABILITY TESTING & STABILITY SOPs CHAPTER 20

Ifthe results of the confirmatory study in physical properties (e.g.,

are equivocal, testing of up to two appearance, clarity, color of solution)
additional batches should be conducted. or assay and degradants by a method
Samples should be selected as suitably validated for products likely to
described in the parent guidance. arise from photochemical degradation
processes.
[a.] Presentation of Samples [ICH Q1B]
Care should be taken to ensure that the
Where solid drug substance samples
physical characteristics of the samples are involved, sampling should ensure
under test are taken into account, and that a representative portion is used in
efforts should be made, such as cooling individual tests. Similar sampling
and/or placing the samples in sealed considerations, such as homogenization
containers, to ensure that the effects of of the entire sample, apply to other
the changes in physical states such as materials that may not be homogeneous
sublimation, evaporation, or melting are after exposure.
minimized. The analysis of the exposed sample
All such precautions should be chosen should be performed concomitantly with
to provide minimal interference with the that of any protected samples used as
exposure of samples under test. dark control if these are used in the test.
Possible interactions between the [c.] Judgement of Results
samples and any material used for The forced degradation studies should
containers or for general protection of be designed to provide suitable
the sample should also be considered information to develop and validate test
and eliminated wherever not relevant to methods for the confirmatory studies.
the test being carried out. These test methods should be capable
As a direct challenge for samples of of resolving and detecting photolytic
solid drug substances, an appropriate degradants that appear during the
amount of sample should be taken and confirmatory studies.
placed in a suitable glass or plastic dish When evaluating the results of these
and protected with a suitable studies, it is important to recognize that
transparent cover if considered they form part of the stress testing and
necessary. are not therefore designed to establish
Spread Active Materials qualitative or quantitative limits for
change.
3 mm thick in a covered Generic Developers
glass petri dish. must perform light
(plastics can affect wavelength)
stress studies on the
Solid drug substances should be spread
across the container to give a thickness stability indicating assay
of typically not more than 3 millimeters. The confirmatory studies should identify
precautionary measures needed in
Drug substances that are liquids should manufacturing or in formulation of the
be exposed in chemically inert and drug product and if light resistant
transparent containers. packaging is needed.
[b.] Analysis of Samples - At the end of
the exposure period, the samples should When evaluating the results of
be examined for any changes confirmatory studies to determine
whether change due to exposure to

Handbook of Pharmaceutical Sect: 20.

20 35 Generic Development
 TABLETS ORAL STABILITY TESTING & STABILITY SOPs CHAPTER 20

light is acceptable, it is important to [a.] Presentation of Samples

consider the results from other formal Care should be taken to ensure that the
stability studies to ensure that the drug physical characteristics of the samples
will be within justified limits at time of under test are taken into account, and
use (see the relevant ICH stability and efforts, such as cooling and/or placing
impurity guidance). the samples in sealed
DRUG PRODUCTS [ICH Q1B] containers, should be made to ensure
that the effects of the changes in
Normally, the studies on drug products
physical states are minimized, such as
should be carried out in a sequential
manner starting with testing the fully sublimation, evaporation, or melting. All
exposed product then progressing as precautions should be chosen to provide
necessary to the product in the minimal interference with the irradiation
immediate pack and then in the of samples under test.
marketing pack. Possible interactions between the
samples and any material used for
Testing should progress until the results containers or for general protection of
demonstrate that the drug product is
the sample should also be considered
adequately protected from exposure to
and eliminated wherever not relevant to
light.
the test being carried out.
The drug product should be exposed to
the light conditions described. Where practicable when testing
samples of the drug product outside of
Normally, only one batch of drug the primary pack, these should be
product is tested during the development
presented in a way similar to the
phase, and then the photostability
conditions mentioned for the drug
characteristics should be confirmed on a
substance.
single batch selected as described in the
parent guidance if the product is clearly Spread Tablets & Capsules
photostable or photolabile. in a single layer
If the results of the confirmatory study
are equivocal, testing of up to two
in a covered glass petri dish
additional batches should be conducted. for maximum exposure
For some products where it has been The samples should be positioned to
demonstrated that the immediate pack is
provide maximum area of exposure to
completely impenetrable to light, such as
the light source.
aluminum tubes or cans, testing should
For example, tablets and capsules
normally only be conducted on directly
should be spread in a single layer.
exposed drug product.
It may be appropriate to test certain If direct exposure is not practical (e.g.,
due to oxidation of a product), the
products, such as infusion liquids or
sample should be placed in a suitable
dermal creams, to support their
protective inert transparent container
photostability in-use. The extent of this
(e.g., quartz).
testing should depend on and relate to
the directions for use, and is left to the If testing of the drug product in the
applicant’s discretion. immediate container or as marketed is
The analytical procedures used should needed, the samples should be placed
be suitably validated. horizontally or transversely with respect
to the light source, whichever provides
for the most uniform exposure of the
samples.

Handbook of Pharmaceutical Sect: 20.

20 36 Generic Development
 TABLETS ORAL STABILITY TESTING & STABILITY SOPs CHAPTER 20

Some adjustment of testing conditions specifications during the shelf life (Ref.
are when testing large volume ICH stability and impurity guidance).
containers (e.g., dispensing packs). QUININE CHEMICAL ACTINOMETRY
[b.] Analysis of Samples Details of an actinometric procedure for
monitoring exposure to a near UV
At the end of the exposure period, the
fluorescent lamp, based on the draft
samples should be examined for any
guidance are provided in the attached
changes in physical properties (e.g.,
Standard Operating Procedure.
n appearance
ACCEPTABLE & UNACCEPTABLE
n clarity of solution
PHOTOSTABILITY CHANGE
n color of solution
n dissolution / disintegration for dosage The extent of the drug product
forms such as capsules) photostability testing depends on the
n assay change that has occurred a the end of
n degradants each test tier described in the Decision
Suitably validated methods for Flow Chart for Photostability.
degradants likely to arise from Testing of Drug Products.
photochemical degradation processes Test results that are outside the
should be used. proposed acceptance criteria for the
product would not be considered
When powder samples are involved, acceptable change.
sampling should ensure that a
representative portion is used in This is a stress test designed to
individual tests. determine the intrinsic photostability
characteristics of new drug substances
For solid oral dosage form products, and products, and no correlation has
testing should be conducted on an been developed to equate a within
appropriately sized composite of, for specification result to an expiration
example, 20 tablets or capsules. Similar dating period.
sampling considerations, such as
homogenization or solubilization of the Evaluate Light Stress and Heat
entire sample, apply to other materials Stress Degradation Separately
that may not be homogeneous after
exposure (e.g., creams, ointments,
The acceptability of any observed
changes should be justified in the
suspensions).
application. It may be important to
The analysis of the exposed sample is consider other degradative processes
performed concomitantly with that of any (e.g., thermal) when justifying a
protected samples used as dark controls photostability change as acceptable
if these are used in the test. because the processes may be
[c.] Judgement of Results independent and additive.
Depending on the extent of change, For example, a 5 percent loss in
special labeling or packaging may be potency due to photodegradation may
needed to mitigate exposure to light. be considered acceptable if that is the
When evaluating the results of only type of degradation observed.
photostability studies to determine If the product is also expected to
whether change due to exposure to light degrade 5 percent over the shelf-life
is acceptable, it is important to consider due to thermal degradation, the photo-
the results obtained from other formal degradation may then be considered
stability studies to ensure that the unacceptable based on the potential
product will be within proposed additive effect of the changes.

Handbook of Pharmaceutical Sect: 20.

20 37 Generic Development
 TABLETS ORAL STABILITY TESTING & STABILITY SOPs CHAPTER 20

In this case, precautions should be the product being removed from the
taken to mitigate the product’s exposure immediate package during the
to light. distribution process.
n For those products that are unlikely to
Under the intense light exposure be removed from the immediate
conditions included in the Q1B guidance, container, such as creams or ointments
certain colors in solid dosage forms may in tubes dispensed directly to the
fade. patient, and ophthalmic products, the
Quantitative analysis of the color change use of a labeling storage statement
is not recommended as these changes regarding light is optional.
are not likely to occur under actual
storage conditions. n For products that may be removed
In the absence of change in other from the immediate pack, such as
parameters such as assay, these color pharmacy bulk packs, a light storage
changes may be acceptable. statement should be included such as
“PROTECT FROM LIGHT. Dispense in
Two Standardized labeling a light-resistant container.”
instructions recommended to Change after exposure in the market
PROTECT FORM LIGHT pack:
PHOTOSTABILITY LABELING If changes that are observed are
acceptable only when the product in the
The data generated using the procedure market pack is exposed under the
described in the ICH Q1A guidance is conditions described in the Q1B
useful in determining when special guidance, labeling storage statements
handling or storage statements regarding light should be included.
regarding exposure to light should be
included in the product labeling (21 CFR
Examples of typical labeling cautions for
single-dose and multiple-dose products
201.57(k)(4)).
The labeling guidance provided below pertains respectively are either,
only to products as packaged for distribution.
Labeling Caution - Type Single Dose
Instructions and stability statements that may be
needed to address in-use conditions pursuant to
21 CFR 201.57(j) are not covered. n “PROTECT FROM LIGHT.
Retain in carton until time of use.”
Change after direct exposure:
If changes that are observed when the Labeling Caution - Type Single Dose
product is directly exposed under the
light conditions described in the Q1B n “PROTECT FROM LIGHT.
guidance are acceptable, no labeling Retain in carton until contents are used.”
storage statement regarding light is
needed. SOPS and 'Guidance for Industry'
n Violating an in-house SOP is a GMP
Change after exposure in the
violation and you can be cited for SOP
immediate container/closure: violations.
If changes observed when the product is n Violating a agency 'Guidance for
directly exposed are unacceptable, but Industry' in NOT a GMP violation and you
are acceptable when the product is cannot be cited for a violation.
tested in the immediate container / n Violating an in-house SOP which is
closure under the conditions described based on a 'Guidance for Industry' is a
in the Q1B guidance, the inclusion of a standard GMP violation.
labeling storage statement regarding The photostability SOP supplied is based
light would depend on the likelihood of on the current draft guidelines.

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20 38 Generic Development
 TABLETS ORAL STABILITY TESTING & STABILITY SOPs CHAPTER 20

Decision Flowchart for

Photostability of Drug Products

Formula
Change may
include OPAQUE
film coatings or
capsule shells Start of
Decision Tree
Drug Product
spread in a
CHANGE
mono layer
FORMULA YES glass petridish
Dosage Form
(Coating) Directly Exposed

ACCEPTABLE YES TEST

CHANGE END
NO

NO
Drug Product in
Primary
CHANGE container-
Dosage Form in
Primary closure system
Primary Pack (without carton)
Pack YES

ACCEPTABLE YES TEST

NO CHANGE END

NO
CHANGE Drug Product
Marketing Dosage Form in in Primary &
Pack Marketing Pack Secondary
packaging
system

ACCEPTABLE YES TEST

CHANGE END

NO

Redesign package or
reformulate

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20 39 Generic Development
 TABLETS ORAL STABILITY TESTING & STABILITY SOPs CHAPTER 20

Setting-up
a Functional
Stability Unit
Each area is fundamental to the long-

I
n setting-up a stability unit it is
necessary to highlight some current term success of the firms products,
deficiencies found in Pharmaceutical whether the products are New Drugs
Stability Departments, as well as (NDAs), ANDAs or simply OTCs.
indicating the necessary control Departments Impacted
structures required for the efficient The stability department(s) must service
operation of a functional Stability the Development Department (or
Department. The structure of a practical R&D), the Regulatory Batches (those
and operational proven stability submitted to the authorities) and the
department is herewith described. Production Department (where each
Stability Control. commercial product is placed on
Stability control is achieved through stability once a year - i.e. only one
standard operational systems - namely batch of each strength and largest pack
proper stability documentation, size).
sufficient control SOPs and acceptable The Stability Requirements
monitoring equipment and laboratory The main stability operations are:
facilities. ⇒ Development Stability
The analytical testing section • Stability testing during the key
(personnel and equipment) must be of product development stages (i.e.
sufficient size to adequately perform the stability testing prior to the pivotal
stability tests in the required time. batch used for regulatory filing).
Stability testing depends on good ⇒ Regulatory Stability
timing. Consistently late drug product Stability testing of ANDA / AADA FDA
testing is of little scientific or regulatory filed batch(es):-
value. ♦ Original Generic Applications
Number of SOPs required submitted to FDA.
Stability SOPs number about 45 to 50 ♦ Amended Applications (before file
for a well managed and organized approval.)
stability department to operate ♦ Supplementary Applications
efficiently within current GMP. (changes after approval.)
A comprehensive list of the stability
⇒ Production Stability
control SOPs and some SOP
Stability testing - annually on a
summaries, controlling key functions
representative full production batch.
are included in this issue to highlight
the many operational details required. ♦ One production batch per product,
In Generic and Researched-based per strength, per year.
analytical laboratories, stability testing ♦ Annual Reports - ongoing stability
is performed in three target areas. commitments per filed application.

Handbook of Pharmaceutical Sect: 20.

20 41 Generic Development
 TABLETS ORAL STABILITY TESTING & STABILITY SOPs CHAPTER 20

Stability Facilities tape or disc system).

• A rapid/high speed printer with
Adequate stability facilities are continuous paper or sheet feed .
required. The number of stability tests
increase every year. Thus facilities are This is a minimum acceptable system.
required to be sufficiently large in order Review chemists and Scientific Officers
to accommodate the annual growth. conducting GMP or pre-approval
Firms need to invest adequately in the inspections regard a suitable structured
stability department facilities and and efficiently established stability
equipment. department as a critical factor in the
evaluation program. Therefore the
The stability data on development, following areas should be properly
regulatory, or production lots constitute reviewed:
critical review data during ANDA file
review and Pre-approval Inspections ♦ correctly formatted Stability Reports
(PAIs.) (for agency review chemists).
The minimum stability facilities required ♦ adequate environmental control on
are: temperature and humidity (review of
The Environmental System: recording graphs) - reviewed by PAI
site inspectors.
◊ A large 25oC - 30oC controlled
environment stability room with ♦ skillfully written Stability SOPs - for
generous multilevel shelving. efficient daily operation (reviewed
◊ dedicated controlled temperature during PAI site visits).
room(s) Meticulous care is necessary to pass a
ANDA product specific pre-approval
◊ continuous recording of temperature site inspection.
and humidity in the stability room(s)
◊ a validated environment - (room
probes and periodic room validation)
77
◊ 30o and 40oC climatic chamber Do’s & Don’ts
cabinets with automatic recorders.
◊ a light chamber cabinet (optional)
for Managing
[Drug Products need to be properly Stability
exposed to the controlled environment
- this requires orderly storage on Departments.
appropriate and spacious shelving.
Products may not be stored Formal SOP monitoring
indiscriminately in cardboard boxes]. Do - insure that Stability SOPs are
The Minimum regularly updated annually or bi-
annually.
Set-up Do - monitor and approve proposed
Requirements changes to Stability SOPs.
(Avoid stability and quality control
The Computer system laboratory personnel displaying a non-
• A stability computer (Pentium) with a awareness of the departmental SOPs in
validated stability software program. their essential day-to-day work).
• A computer back-up system (e.g.

Handbook of Pharmaceutical Sect: 20.

20 42 Generic Development
 TABLETS ORAL STABILITY TESTING & STABILITY SOPs CHAPTER 20

Do - train and re-train staff in the Don’t - allow the stability room to be
correct use and understanding of used as a stability office, where
current SOPs. personnel are continually entering and
Do - check the firms SOPs adequately leaving the controlled facility.
cover all aspects of stability operations Don’t - allow an air-conditioned 22o -
required by the FDA or Agency. 25oC stability office to function as a
Do - insure the instructions and details 25oC climatic room.
in the SOPs are adequate and sufficient
Don’t - store the 25oC long term
to assure consistent and repeated
stability samples in an office.
operation by staff, reading the SOPs.
(In terms of GMP compliance such a
Do - check staff are aware of latest facility is inadequate and the
edition of the Stability SOPs, affecting environment cannot be controlled).
their day-to-day work.
Don’t - install unreadable chart
Do - provide frequent departmental temperature recorders due to the
training in ‘reviewing and under- smallness of the rotating chart.
standing’ the principles of the SOPs. (Out-of-specifications temperatures are
not adequately shown on these charts,
ALWAYS KEEP as the range divisions on the chart are
DEPT. SOPs cramped and often too small. Narrow
ON SITE chart sensitivity scales are generally
( E l e c t r o n i c a l l y unsuitable and unreadable. The
I f p o s s i b l e ) compliance value of such a temperature
recording system is of minimal value
Do - insure operational personnel are and open to agency challenge).
aware of the latest editions of the SOPs Do - insist that current recording
and where they can be located in their devices are fitted with larger chart
stability department (All SOPs on Site). recorder so that the daily temperatures
Do - insure they are able to refer to the and OOS values can be read with
SOPs for rapid guidance in performing accuracy and precision.
their routine daily duties and tasks. Do - insure there is a system for 60%
Do - insure supervisors and personnel RH control (environmental humidity).
have signed a ‘Read and Understood’ Do - insure the stability room has
form annually indicating full awareness sufficient temperature probes at the
of the SOP contents. upper and lower levels of the room
Do - insure SOP distribution is where the stability samples are being
adequate and the SOP Change Control stored.
System really works and is consistently Do - construct a dedicated stability
on time. room with controlled environmental
Do - insure the 25oC climatic area for facilities that maintain the temperature
storing the ANDA / NDA and OTC at 25o C (± 2o C) and the relative
stability samples at 25o C (± ± 2o) is a humidity at 60% RH (± 5%).
controlled environment room. Do - install the 30o and 40o C climatic
Do - insure access is through an chamber units inside the controlled
controlled-access door, that does not stability areas or rooms.
affect the environmental temperature - Don’t - allow stability samples for
every time the door is opened.
ANDA/NDA and OTC (development, or

Handbook of Pharmaceutical Sect: 20.

20 43 Generic Development
 TABLETS ORAL STABILITY TESTING & STABILITY SOPs CHAPTER 20

production samples) to be stored in Do - insure temperature/RH charts are

cardboard boxes on cramped shelving reviewed for out-of-specification (OOS)
(i.e. stacked one on top of the other). temperature and RH values.
(Reason - the samples are not exposed
to the environment uniformly as they Review Recording
are protected by the insulating Charts for OOS
cardboard boxes in which they are
stored. Values - Daily
Thus the lower samples are screened Do - insure the monitoring control
by the newer samples and a uniform charts are adequately signed and filed
controlled exposure to temperature and in an rapid retrieval system.
humidity is not generally achieved. Do - insure adequate quality
The older stability samples at the assurance evaluation is performed on
bottom of the cardboard box will be the recording charts.
temperature and humidity screened by
the several upper sample layers.)
Do - insure there is corrective action
taken when the stability temperature
Do - avoid product exposure to large goes out of the specifications (OOS).
seasonal variations which do not keep
the temperature in (non-insulated)
Do - insure that is possible for the firm
to conclusively assure the FDA that the
stability rooms within a ±2o C range of
filed drugs were held at 25o C, 40o C (
25o C, in either winter or summer.
±2o C) for the required storage periods
Do - avoid uneven room of 3, 6, 9, 12, 18, + etc. months.
temperature exposures (near doorways,
vents, fans.)
Do - insure a corrective action SOP
exists - to determine the procedures to
Do - insure the samples are arranged follow after a failure of the recording
on the shelving in a neat, orderly equipment or power supply during an
manner. ongoing stability study.
Do - insure there is not a large across Do - insure corrective actions are
room-variation in temperature and carried out, documented and closed.
humidity. Both these variables must be
adequately controlled (<5 %). Have emergency
Do - insure the upper and lower
shelves have been challenged for procedures in place
temperature compliance. (A single
chart recorder probe does not record Do - insure there are written
the temperature accurately at which all emergency procedures for the use of
the stability samples are stored. calibrated hand-thermometers and
Multiple probes are necessary - i.e. > 2 recording logbooks due to recorder or
upper and 2 lower. stability probe failures.
Do - insure the room temperature Do - insure air-condition failures or
validation studies have been conducted equipment shutdowns are recorded.
to insure the firm is aware of the actual
storage parameters of the stability
Do - insure periodic revalidation and
temperature distribution studies of the
ANDA/NDA and OTC test samples.
climatic chambers are carried out
Do - insure there is a substantive (every two years or when there is a
review and control of stability change).
temperature recorders or charts.

Handbook of Pharmaceutical Sect: 20.

20 44 Generic Development
 TABLETS ORAL STABILITY TESTING & STABILITY SOPs CHAPTER 20

Do - insure Original Data Summary Do - insure established procedures

Sheets are never replaced with for investigating abnormal assay
unauthorized "corrected versions". fluctuations or out-of-specification
Do - outlaw the use of "White-Out (OOS) results in the analytical and
tapes or liquids" in stability and other microbial stability testing program, is
reports. both operational and functional.
Do - review of the annual report Investigate OOS
prepared for the FDA to show that the Results
ongoing stability testing has been met,
as per the filed ANDA commitment. - Daily
Agency Case-History I. - Data values Do - insure OOS SOPs are written
go unrecorded. and the principles of the Judge Wolin’s
Investigations highlighted that one set decisions are followed and properly
of data values had not been recorded. investigated.
The appearance that the stability data
sheets are a direct and accurate
Do - review and audit stability
transfer procedure of the raw data in documentation in order to establish the
the laboratory notebooks is open to authenticity of the stability test results
question and further investigation. reported to the FDA in ANDAs or
This technique appears to be used to Supplements or Annual Reports.
alter raw data when the original Insure there is a formal pre-submission
worksheet data was not in compliance. internal auditing program.
Case History II - Lost raw data Do - insure the firms does verify the
The 6 month data point for the product transfer of raw data values from the
potency was required to be evaluated laboratory workbooks to the final
by microbial assay. However the raw computer stability print-out reports.
data to support this assay value in the (Where intermediate summary sheets
stability data sheet was not able to be and analysis request forms are used,
found. Further investigation highlighted these intermediate data sheets should
that this raw data was untraceable. be signed and stamped as bona fide
Do - insure there is no lost data and and accurate by Quality Assurance).
full traceability of stability test points. Do - insure the final stability study is
Do - insure summary data sheets signed off by the Director of Quality
containing ‘failed analysis results’ are Control and the firm has a SOP
meticulously signed and filed. specifying the acceptance and sign-off
procedure for a completed stability
Do - insure there exists a well study, to ensure that the study is
documented reporting system for the complete and accurate.
repeat testing of stability data,
according to written SOPs.
Do - insure that no laboratory raw
data is unavailable or missing in
Do - insure traceability of ALL tests support of the Stability Summary Data
performed via the laboratory work- Reports.
sheets, resulting in full credibility of the
laboratory test results.
Do - insure proper cross-referencing
of laboratory notebooks and
Do - investigate thoroughly if it worksheets with computerized
appears that the stability data is tested documentation prior to data being
and repeat tested until it passes. submitted to the FDA.

Handbook of Pharmaceutical Sect: 20.

20 45 Generic Development
 TABLETS ORAL STABILITY TESTING & STABILITY SOPs CHAPTER 20

Do - insure retrospective audits trails the computerized stability reports.

of ANDA stability reports to summary Do - insure the need to prepare an
data sheets and back to laboratory SOP for cross-referencing laboratory
workbooks clarify that the FDA filed note-book data with computerized
data can be supported by the raw stability test result documentation.
laboratory test data. Do insure all repeating testing
Do - insure the firm does have a performed at the same test interval
comprehensive and functional labor- must be cross-referenced - all together.
atory data reporting system for test Note: a reviewer requires to audit all
results. testing performed on the stability test
Do - insure that data points are not sample and not only the raw data in the
missing (e.g. pH values; missing laboratory notebooks that have passed
potency from crimp-end of semi solid the stability check specifications.
tubes etc.). Do - insure all stability data points are
Do - insure stability test values are present and are in full compliance with
not different from the filed values. the pre-written stability protocol.
Do - insure the use of bound and Do - insure a full review of the stability
numbered laboratory notebooks. protocol and a comparison of the test
Note - The use of unnumbered procedures carried out on the stability
analytical worksheets for recording samples - at each test station - to
analytical data should be discontinued highlight any incidence where stability
and is not in GMP compliance). data points may be absent or OOS.
Do - insure that stability data is not Do - insure that no raw data is
selectively screened prior to omitted from the stability reports or in
computerisation. the Annual Reports submitted to the
FDA.
Do - insure the absence of
discrepancies and different values in Review and Audit
ANDA Annual Reports and the original SOPs
laboratory raw data.
[Case study:- Review of the annual - Annually
report prepared for the FDA showed Do - insure stability SOPs are
that the ongoing stability testing as per adequate and routinely reviewed for
ANDA commitment showed an original GMP compliance by written in-house
report in the stability files with a test audits.
data line covered with “white tape”.
This data report was photocopied and
Do - insure the existing SOPs do
sent to the FDA. The photocopy did control the functions of the stability
department. (45-50 SOPs presented
not reveal the ‘white-out’ data in
question.] are a prerequisite to operate a stability
department for an innovative or generic
Do - insure traceability of workbook drug manufacturing company).
reference page numbers and dates
relating to the original raw data in
Do - insure is that SOPs are not
laboratory workbooks. deficient both in the content and detail.
The lack of suitable SOPs in a stability
Do - insure the traceability of any department may result that much of the
repeat testing performed on the stability stability management and testing of the
samples is clearly referenced on the stability samples are erratic and out-of-
stability documentation used to prepare control - resulting in a failed PAI review

Handbook of Pharmaceutical Sect: 20.

20 46 Generic Development
 TABLETS ORAL STABILITY TESTING & STABILITY SOPs CHAPTER 20

Do
ØPAI×
- insure that SOPs are readily
available and routinely followed and
updated (i.e. after a change or
annually). OBSERVATIONS
on
(The lack of a full set of stability SOPs
and the fact that the SOPs are

Stability
incomplete or that stability personnel
are poorly trained on the contents of the
SOPs is strong evidence to an agency
that the firm’s stability testing program ♦ Traceability of retested stability
is not in current GMP compliance). samples difficult and inconsistent.
Do - insure that it is not possible, for a
sample in a stability program to remain ♦ Traceably of raw data inconsistent.
untested after the ‘due date’ and thus
skip the designated ‘testing interval’. ♦ No written procedures for reporting
stability results precisely.
Do - insure the Certificate of Analyses
are not out of date for time zero when ♦ ‘Corrected’data substituted on FDA
the sample is eventually placed on summary data sheets.
stability at a ‘start date’ several months
after the initial C. of A. was performed. ♦ Use of ‘white-out liquid’ in stability
[Reason - the sample assay value reports to obscure test results.
potency may have degraded by several
months aging which would not be ♦ Annual reports to FDA not accurate
reflected by the initial certificate of or authentic.
analysis - some time earlier].
♦ Lack of stability and analytical SOPs
Insure to insure GMP compliance.
all Avoid
C of A's any
are White-0uts
in-date ♦ Stability data reports not internally
audited and reviewed.
Do - insure the presence of stability
SOPs controlling the maximum time ♦ Data transfer from raw documents to
period [30 days] between initial testing final report not verified.
(Certificate of Analysis at time zero)
and the ‘Start Date’ of the stability study ♦ No review of temperature/RH charts.
in order not to invalidate the initial
stability results. ♦ Uncontrolled storage of charts makes
retrospective temperature/RH chart
Do - insure that all the stability SOPs review, difficult and time consuming.
are updated according to the firm’s
No written emergency procedures
SOP index.
after equipment breakdowns.
3

Handbook of Pharmaceutical Sect: 20.

20 47 Generic Development
 TABLETS ORAL STABILITY TESTING & STABILITY SOPs CHAPTER 20

Stability Room for 25o C samples

♦ No corrective action taken after
used as a working office with
stability system failures.
inadequate environmental controls.
♦ Stability storage recording
♦ No substantive review of stability
temperature procedures not in cGMP
temperature recorders or charts.
compliance.
♦ Original Data Summary Sheets
♦ Stability climatic room must be
replaced with "corrected versions" -
dedicated to stability sample storage.
including the use of "White-Out tape"
in stability reports.
♦ Stability room general office area
for multipurpose use.
♦ LIMS (Laboratory Information
management System) data not
♦ Single-probe recorders are not accurately reported.
suitable for temperature control.
♦ LIMS data excluded from Annual
♦ No periodic revalidation of stability reports and selectively screened in
chambers. ANDA Applications.

♦ Inadequate temperature validation ♦ Ignoring LIMS data results at specific

studies performed in stability room. intervals when OOS results obtained

♦ Uneven temperature distribution - ♦ Out-of-Specifications LIMS stability

and temperatures are out of the results not reported after a full
stated specification range in stability investigation performed.
rooms.
♦ Laboratory raw data unavailable or
♦ No controlled storage of stability missing to support the Stability
samples before testing. Summary Data Reports.

♦ Upper and lower sample room ♦ Rewriting stability protocol testing

temperatures have not been requirements retrospectively to
validated. remove unwanted results obtained

♦ Overall stability facilities in violation ♦ Discrepancies and different values in

GMP compliance. Annual Reports and laboratory raw
data of ANDA tested product.
♦ Absent pH values and missing data
test points. ♦ Stability data points are not in
compliance with stability protocol.
♦ Sample re-tests and to-be-repeated
procedures violate Wolin’s rules. ♦ Missing accelerated stability data
points on impurities at 3 and 6 month
♦ Missing data points with only passing intervals.
stability test values selected.
♦ Inadequate controls on the overall
♦ Stability reports not signed of by QA stability testing program.
Director.

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20 48 Generic Development
 TABLETS ORAL STABILITY TESTING & STABILITY SOPs CHAPTER 20

Stability
SOP
Development
‘…operating a functional stability unit…

T
his section summarizes the Handling the standard procedures
Stability Units’ foremost Standard correctly may well establish the validity
Operating Procedures (SOPs). or non-validity of the firms stability
Handling SOPs in an ordered manner programs and the actual stability
may well be the solution to the effective results obtained.
development of a generic or innovative The following SOP summaries,
drug development program, not only to represent a minimum number of
place the newly formulated drug essential stability study SOPs required
product on the fast track to approval but to maintain an operational stability
hopefully to save embarrassing department for either a generic or
moments during a pre-approval innovative (researched-based) drug
inspection (PAI) should the agency development program and in full GMP
investigator stumble onto failing drug compliance for the stability testing of
product stability results in a product- developmental, regulatory and once a
specific PAI review. year commercial production batch lots.
Key Standard Operating Procedures 4
are summarized to highlight the myriad S-005-02-01YY Indexing
of procedures required for the correct procedure for Stability Studies.
handling of stability results and stability
The purpose of this standard operating
failures in an ongoing drug stability
procedure is to establish an index and
study, - be it a developmental or a final
an annual supplementary index for
formula i.e. a finished product ready to
stability study SOPs. The
go for submission.
supplementary index allows for new
How does your firm shape up in this SOPs, or updated existing SOPs, to be
stability line-up? If you don’t have the indexed in the supplement and
Stability SOP in place, - what is the firm distributed in real time.
doing about it? How is the stability 4
department handling the specific S-010-02-01YY Index for
stability requirements? Have all
Stability Studies.
stability programs and protocols
The purpose of this standard operating
involving the following subject matters
procedure is to index the Stability SOPs
been thoroughly aired and discussed
as shown above. 4
in your firms stability unit ?

Handbook of Pharmaceutical Sect: 20.

20 49 Generic Development
 TABLETS ORAL STABILITY TESTING & STABILITY SOPs CHAPTER 20

S-015-02-01YY Initiating a S-040-02-01YY Storage

Stability Study. configuration of samples in a
The purpose of this standard operating stability environment.
procedure is to define the stages and The purpose of this standard operating
documentation required in order to start procedure is to determine the storage
or initiate a development, pivotal, or configuration of the stability samples in
commercial stability study. the climatic controlled rooms or
4 chambers during the course of the
S-020-02-01YY Contents of a stability study.
Stability Protocol. 4
The purpose of this standard operating S-045-02-01YY Stress testing
procedure is to define the parameters the bulk drug substance for
needed in the stability protocol that stability analysis.
meet the specific FDA regulatory The purpose of this standard operating
requirements. procedure is to determine the stress
4 testing procedures and parameters for
S-025-02-01YY Setting limits for an approved supplier of the active drug
check specifications in a substance. The data is used for
Stability Study. impurity evaluation and method
The purpose of this standard operating validation.
procedure is to establish the 4
development procedures for setting S-050-02-01YY Intervals and
upper and lower specification limits for climatic and storage conditions
the release and stability (check) for a US development Stability
specifications for a Stability Study.
Study.
4 The purpose of this standard operating
S-030-02-01YY Number and size procedure is to define the intervals and
of batches for stability testing. storage conditions for conducting
The purpose of this standard operating formulation stability studies intended for
procedure is to establish the procedure ANDA/OTC formulations for US
for determining the number and sizes of approval in accordance with the FDA-
batches commonly required from EU-Japan ICH Guidelines.
development to commercial batch, 4
stability study purposes. S-055-02-01YY Intervals and
4 climatic conditions for a US
S-035-02-01YY Number of Pivotal /Bioequivalence Stability
samples required for performing Study.
stability tests. The purpose of this standard operating
The purpose of this standard operating procedure is to define the intervals and
procedure is to establish the number of storage conditions for conducting,
samples required for performing the Pivotal and commercial stability studies
analytical tests in a Stability Study. This intended for ANDA and OTC
SOP is specific for each dosage form formulations for US approval in
under evaluation. accordance with the FDA-EU-Japan
4 ICH Guidelines.
4

Handbook of Pharmaceutical Sect: 20.

20 50 Generic Development
 TABLETS ORAL STABILITY TESTING & STABILITY SOPs CHAPTER 20

S-060-02-01YY - Intervals and S-080-02-01YY - The initial

climatic conditions for a US Certificate of Analysis at To for a
validation/PM Stability Study. Stability Study.
The purpose of this standard operating The purpose of this standard operating
procedure is to define the intervals and procedure is to initiate appropriate time
storage conditions for conducting frames for starting a Stability Study not
Validation and Post Marketing stability later than 30 days (according to current
studies intended for ANDA / OTC guidelines), after the sample has been
formulations for US approval. fully QC tested and a regulatory valid
4 certificate of analysis (C-of-A at time
S-065-02-01YY - Placing the zero (To)) has been issued. Where
Reference Listed Drug (RLB) on samples exceed this period new C-of-A
are issued
Stability.
The purpose of this standard operating
4
procedure is to establish the procedure S-085-02-01YY - Packaging
for placing batch lots of the reference procedures on Formulation lots
listed drug on stability in order to for a stability study.
evaluate the RLD’s analytical The purpose of this standard operating
parameters, aging and impurity profile procedure is to determine the
at different time intervals and different packaging procedures and quality
RLB manufacturing dates in order to control functions on development
produce an overview of the reference formulation lots for a Stability Study.
drugs stability parameters (e.g. The number of units packed and the
especially dissolution and impurities) sampling protocol is clearly established.
(produces a set of mean curves over a 4
year). S-090-02-01YY - Packaging
4
procedures on the Process
S-070-02-01YY - Determining the
Qualification Batch for a
‘Due dates’ for a Stability Study
stability study.
protocol. The purpose of this standard operating
The purpose of this standard operating procedure is to determine the
procedure is to determine the ‘due packaging procedures and quality
dates’ (individual testing stations) at control functions on the final process
which samples are taken from the qualification lots for a Stability Study.
controlled storage environment for the The number of units packed and the
purpose of analytical testing according sample protocol is clearly established.
to the stability protocol.
4
4
S-095-02-01YY - Representative
S-075-02-01YY - Setting the
sampling procedures during
‘Start date’ for a Stability Study.
The purpose of this standard operating batch packaging of stability
procedure is to determine the ‘start samples.
dates’ at which samples are placed in The purpose of this standard operating
controlled climatic condition according procedure is to define the sampling
to the stability protocol. This procedure protocol used during packaging
determines the time limitations between procedures in order to accomplish a
each step in the procedure.
4

Handbook of Pharmaceutical Sect: 20.

20 51 Generic Development
 TABLETS ORAL STABILITY TESTING & STABILITY SOPs CHAPTER 20

fully representative sampling operation S-120-02-01YY Reporting test

of the entire batch. results of a Stability Study.
4 The purpose of this standard operating
S-100-02-01YY - Container- procedure is to determine the
Liner-Closure systems for a procedure for reporting and recording
of the stability test results at each test
Stability Study. interval in the analytical laboratory. The
The purpose of this standard operating procedure for averaging, reviewing and
procedure is to specify the container- distributing the test results are
closure-liner parameters required for documented.
product testing from product 4
development to the process S-125-02-01YY Procedures for
qualification stage and the final
handling abnormal or OOS results
validation/commercial lots.
in a Stability Study.
4 The purpose of this standard operating
S-105-02-01YY - Certification of procedure is to establish the procedure
a Container -Liner-Closure for investigation into abnormal assay
system. fluctuations or out-of-specification
The purpose of this standard operating (OOS) results in the analytical and
procedure is to establish the vendor microbiological stability program
and in-house documentation testing.
requirements in order to meet the FDA 4
documentation filing requirements for S-130-02-01YY The control of
container-liner-closure systems. The Analytical methods #’s and
contents of each document is briefly Edition #’s in stability
described.
documentation.
4
The purpose of this standard operating
S-000-02-01YY Labeling of procedure is to ensure that the correct
Stability Study Samples. analytical methods numbers and edition
The purpose of this standard operating numbers are used in the analytical and
procedure is to specify the procedure microbiological testing laboratory, and
and exact label data requirements for are specified in the stability
labeling stability study samples. documentation during the course of a
4 Stability Study. This SOP insures that
S-115-02-01YY Storing the method changes are updated in the
stability documentation.
stability study samples under
4
controlled conditions prior to
S-135-02-01YY Cross-
analysis.
referencing laboratory
The purpose of this standard operating
notebooks with computerized
procedure is to establish the storage
conditions under which stability stability documentation.
samples are kept during the interim The purpose of this standard operating
period between the sample “due date” procedure is to cross-reference
and the time prior to laboratory laboratory analytical and
analysis to prevent sample spoilage. microbiological notebooks containing
4 the raw data at each specific test
interval with the computerized stability
documentation.
4

Handbook of Pharmaceutical Sect: 20.

20 52 Generic Development
 TABLETS ORAL STABILITY TESTING & STABILITY SOPs CHAPTER 20

S-145-02-01YY Auditing stability The purpose of this standard operating

data in laboratory notebooks. procedure is to specify appropriate
The purpose of this standard operating sanitation and house-keeping practices,
procedure is to determine the method of conditions and requirements of climatic
auditing the stability testing raw data in chambers and controlled environment
the laboratory notebooks (analytical rooms.
and microbiological) and to ensure the 4
precise computerization of the stability S-175-02-01YY Fault correcting
data reports. procedures (after breakdowns)
4 during a Stability Study.
S-150-02-01YY Recording The purpose of this standard operating
stability study climatic procedure is to determine the
conditions procedures to follow after a breakdown
The purpose of this standard operating or failure of the equipment or power
procedure is to ensure the correct supply during an ongoing stability
recording procedures, of temperature study. The use of hand thermometers
and humidity control charts for the and recording logbooks and the
climatic chambers or controlled corrective action procedure is
environment rooms. Breakdown documented.
procedures of chart recorders and 4
corrective action are documented. S-180-02-01YY - Emergency
4 procedures during a Stability
S-155-02-01YY Review and Study.
control of temperature and The purpose of this standard operating
humidity recording charts. procedure is to is to determine the
The purpose of this standard operating procedures to follow after a permanent
procedure is to ensure the correct breakdown or failure of the climatic
review, audit and record keeping of chambers equipment (motor
temperature and humidity control charts burnout/probe failure) during an
for a climatic chambers or controlled ongoing stability study. Corrective
environment rooms. action procedures are documented.
4 4
S-160-02-01YY Periodic S-185-02-01YY Reserved.
The purpose of this standard operating
revalidation of climatic rooms
procedure is to identify specific in-
and chambers. house SOPs due to unique conditions,
The purpose of this standard operating methods or equipment operating within
procedure is to ensure the periodic the companies development operational
revalidation of the climatic rooms and procedure.
chambers to secure that the 4
temperature and humidity is within limits
at all points where samples are stored
S-190-02-01YY Conditions for
in the controlled area. stopping a Stability Study.
4 The purpose of this standard operating
procedure is to define the precise
S-170-02-01YY Sanitation and
conditions subject to which an ongoing
house-keeping requirements of stability study will be terminated.
climatic chambers. 4

Handbook of Pharmaceutical Sect: 20.

20 53 Generic Development
 TABLETS ORAL STABILITY TESTING & STABILITY SOPs CHAPTER 20

S-200-02-01YY - The layout and detailing specific training programs and

format of a Regulatory Stability frequency for the stability department
personnel.
Report
(i.e. the filed FDA report)
4
The purpose of this standard operating S-235-02-01YY - Documentation
procedure is to define the contents and requirements for a Stability
data fields as well as the document Study - contents of a Stability
layout and format of a regulatory Dossier
stability report ready for filing with an
FDA agency.
The purpose of this standard operating
procedure is to provide a check list and
4 explanation of all the documentation
S-210-02-01YY- Self inspection and data forms required to make up the
procedures in a stability complete contents of a Stability Study
department. Dossier.
The purpose of this standard operating 4
procedure is to provide for self S-240-02-01YY - Job description
inspection procedures according to the of stability department
written in-house compliance program
personnel
specific for the stability department.
4 The purpose of this standard operating
S-220-02-01YY - Using stability procedure is to document and provide
SOPs and compliance program appropriate job descriptions (and a
training outline) for the personnel in the
as stability training tools. stability department or personnel
The purpose of this standard operating involved in the performance of stability
procedure is to highlight the training related functions.
tools established in order that
4
appropriate training procedures are
provided to the departmental personnel
S-245-02-01YY - Review and
with specific respect to standard auditing stability study
operating procedures and in-house documentation.
compliance programs. The purpose of this standard operating
4 procedure is to review and audit and
S-225-02-01YY - The Do’s and review each stability study performed in
Don’ts of a Stability Study - a order to ensure that all documentation
departmental training tool. from laboratory Notebooks to
The purpose of this standard operating computerized stability reports are
procedure is to document a check list accurate and complete.
for departmental training purposes of 4
common practice to follow and to avoid S-250-02-01YY- Accepting and
when performing stability studies. Signing-off a Completed
4 Stability Study.
S-230-02-01YY - Stability The purpose of this standard operating
department compliance staff procedure is to specify the acceptance
training and signing-off procedure by the
The purpose of this standard operating Quality Assurance Unit for a completed
procedure is to provide a written stability study to ensure that the study
Compliance and stability procedure, is in fact complete.
4

Handbook of Pharmaceutical Sect: 20.

20 54 Generic Development
 ORAL DOSAGE FORM DEVELOPMENT SOPs CHAPTER 21

SOP # S-225-01-2000 STANDARD OPERATING Total Pages: 6.

PROCEDURES

DO’S AND DON’TS OF A STABILITY STUDY - A DEPARTMENT

TRAINING TOOL.

1. PURPOSE
The purpose of this Standard Operating Procedure is to document an audit check list for
departmental training purposes of common practice to follow and pitfalls to avoid when
performing stability studies.
2. RESPONSIBILITY
ˆ Symbol indicates work is performed by Stability Manager.
‰ Symbol indicates work is performed by Stability Technicians.
3. FREQUENCY
Performed in the stability department.
4. PROCEDURE
In setting-up a stability unit it is necessary to highlight common deficiencies found in
Pharmaceutical Stability Departments, as well as indicating the necessary control structures
required for the efficient operation of a functional Stability Department.
The structure of a practical and operational proven stability department is emphasized with:
• correctly formatted Stability Reports (for agency review chemists).
• adequate environmental control on temperature and humidity (review of recording
graphs) - reviewed by PAI site inspectors.
• skillfully written SOPs - for efficient daily operation (reviewed during PAI site visits).

Do & Don’ts to follow in your training program:-

Do - insure that Stability SOPs are regularly updated annually or bi-annually.
Do - insure the instructions and details in the SOPs are adequate and sufficient to assure
consistent and repeated operation by staff, reading the SOPs.
Do - train and re-train staff in the correct use and understanding of current SOPs.
(Avoid stability and quality control laboratory personnel displaying a non-awareness of the
departmental SOPs in their essential day-to-day work).
Do - provide frequent departmental training in ‘reviewing and under-standing’ the principles
of the SOPs.
Do - check the firms SOPs adequately cover all aspects of stability operations required by
the FDA or Agency.
Do - check staff are aware of latest edition of the Stability SOPs, affecting their day-to-day
work.
Do - insure operational personnel are aware of the latest editions of the SOPs and where
they can be located in their stability department (All SOPs on Site).
Do - insure they are able to refer to the SOPs for rapid guidance in performing their
routine daily duties and tasks.
Do - insure supervisors and personnel have signed a ‘Read and Understood’ form
indicating full awareness of the SOP contents.

ED. N0: 02 Effective Date : APPROVED:

Replaces Ed 01.
Ed. Status: DD/MM/Y2K
Operational QC Laboratory Stability Unit Development QA
Handbook of Pharmaceutical Sect: 21.
21 240 Generic Development
 ORAL DOSAGE FORM DEVELOPMENT SOPs CHAPTER 21

SOP # S-225-01-2000 STANDARD OPERATING Total Pages: 6.

PROCEDURES

DO’S AND DON’TS OF A STABILITY STUDY - A DEPARTMENT

TRAINING TOOL.

Do - insure SOP distribution is adequate and the SOPs Change Control System really
works - and on time.
Do - monitor and approve proposed changes to Stability SOPs.
Do - insure the 25 oC climatic area for storing the ANDA and OTC stability samples at
25oC (± 2o) is a controlled environment room.
Do - insure access is through an controlled-access door, that does not affect the
environmental temperature - every time the door is opened.
Don’t - allow the stability room to be used as a stability office, where personnel are
continually entering and leaving the controlled facility.
Don’t - allow an air-conditioned 22o -25o C stability office to function as a 25o C climatic
room.
Don’t - store the 25o C long term stability samples in an office.
(In terms of GMP compliance such a facility is inadequate and the environment cannot be
controlled).
Don’t - install unreadable chart temperature recorders due to the smallness of the rotating
chart. (Reason: out-of-specifications temperatures are not adequately shown on the charts, as the
range divisions on the chart are cramped and often too small. Narrow chart sensitivity scales are
generally unsuitable and unreadable. The compliance value of such a temperature recording system
is of minimal value and open to agency challenge).
Do - insist that current recording devices are fitted with larger chart recorder so that the
daily temperatures and OOS values can be read with accuracy and precision.
Do - insure there is a system for 60% RH control (environmental humidity).
Do - insure the stability room has sufficient temperature probes at the upper and lower
levels of the room where the stability samples are being stored.
Do - construct a dedicated stability room with controlled environmental facilities that
maintain the temperature at 25o C (± 2o C) and the relative humidity at 60 % RH (± 5%).
Do - install the 30o and 40o C climatic chamber units inside the controlled stability areas or
rooms.
Don’t - allow stability samples for ANDA and OTC (development, or production samples) to
be stored in cardboard boxes on cramped shelving (i.e. stacked one on top of the other.
Drug Products need to be properly exposed to the controlled environment - this requires
orderly storage on appropriate and spacious shelving. Products may not be stored
indiscriminately in cardboard boxes). The samples are not exposed to the environment
uniformly as they are protected by the insulating cardboard boxes in which they are stored.
Thus the lower samples are screened by the newer samples and a uniform controlled
exposure to temperature and humidity is not generally achieved.

ED. N0: 02 Effective Date : APPROVED:

Replaces Ed 01.
Ed. Status: DD/MM/Y2K
Operational QC Laboratory Stability Unit Development QA
Handbook of Pharmaceutical Sect: 21.
21 241 Generic Development
 ORAL DOSAGE FORM DEVELOPMENT SOPs CHAPTER 21

SOP # S-225-01-2000 STANDARD OPERATING Total Pages: 6.

PROCEDURES

DO’S AND DON’TS OF A STABILITY STUDY - A DEPARTMENT

TRAINING TOOL.

The older stability samples at the bottom of the cardboard box will be temperature and
humidity screened by the several upper sample layers.
Do - avoid product exposure to large seasonal variations which do not keep the
temperature in (non-insulated) stability rooms within a 2o C range of 25o C, in either
winter or summer.
Do - avoid uneven room temperature exposures (near doorways, vents, fans.)
Do - insure the samples are arranged on the shelving in a neat, orderly manner.
Do - insure there is not a large across room-variation in temperature and humidity. Both
these variables must be adequately controlled (< 5%).
Do - insure the upper and lower shelves have been challenged for temperature
compliance. (A single chart recorder probe does not record the temperature accurately at
which all the stability samples are stored. Multiple probes are necessary - i.e. > 2 upper and
2 lower.
Do - insure the room temperature validation studies have been conducted to insure the
firm is aware of the actual storage parameters of the stability ANDA and OTC test samples.
Do - insure there is a substantive review and control of stability temperature recorders or
charts.
Do - insure temperature / RH charts are reviewed for out-of-specification (OOS)
temperature and RH values.
Do - insure the stability room charts are adequately signed and filed in an rapid retrieval
system.
Do - insure adequate quality assurance evaluation is performed on the recording charts.
Do - insure there is corrective action taken when the stability temperature goes out of the
specifications (OOS).
Do - insure that is possible for the firm to conclusively assure the FDA that the filed
ANDAs were held at 25o C, 40o C (±2o C) for the required storage periods of 3, 6, 9, 12,
18, 24, 36, etc. months.
Do - insure a corrective action SOP exists - to determine the procedures to follow after a
failure of the recording equipment or power supply during an ongoing stability study.
Do - insure corrective actions are carried out, documented and closed.
Do - insure there are written emergency procedures for the use of calibrated hand-
thermometers and recording logbooks due to recorder or stability probe failures.

ED. N0: 02 Effective Date : APPROVED:

Replaces Ed 01.
Ed. Status: DD/MM/Y2K
Operational QC Laboratory Stability Unit Development QA
Handbook of Pharmaceutical Sect: 21.
21 242 Generic Development
 ORAL DOSAGE FORM DEVELOPMENT SOPs CHAPTER 21

SOP # S-225-01-2000 STANDARD OPERATING Total Pages: 6.

PROCEDURES

DO’S AND DON’TS OF A STABILITY STUDY - A DEPARTMENT

TRAINING TOOL.

Do - insure air-condition failures or equipment shutdowns are recorded.

Do - insure periodic revalidation and temperature distribution studies of the climatic

chambers are carried out (every two years or when there is a change).
Do - insure Original Data Summary Sheets are never replaced with unauthorized
"corrected versions".
Do - outlaw the use of "White-Out tapes or liquids" in stability and other reports.
Do - review of the annual report prepared for the FDA to show that the ongoing stability
testing has been met, as per the filed ANDA commitment.
Agency Case-History I. - Data values go unrecorded.
Investigations highlighted that one set of data values had not been recorded. The appearance that the stability
data sheets are a direct and accurate transfer procedure of the raw data in the laboratory notebooks is further
open to question and investigation.
This technique appears to be used to alter raw data when the original worksheet data was not in compliance.
Case History II - Lost raw data
The 6 month data point for the product potency was required to be evaluated by microbial assay. However the
raw data to support this assay value in the stability data sheet was not able to be found. Further investigation
highlighted that this raw data was untraceable.

Do - insure there is no lost data and full traceability of stability test points.
Do - insure summary data sheets containing ‘failed analysis results’ are meticulously
signed and filed.
Do - insure there exists a well documented reporting system for the repeat testing of
stability data, according to written SOPs.
Do - insure traceability of ALL tests performed via the laboratory work-sheets, resulting in
full credibility of the laboratory test results.
Do - investigate thoroughly if it appears that the stability data is tested and repeat tested
until it passes.
Do - insure established procedures for investigating abnormal assay fluctuations or out-of-
specification (OOS) results in the analytical and microbial stability testing program, is both
operational and functional.
Do - insure OOS SOPs are written and the principles of the Judge Wolin’s decisions are
followed and properly investigated.
Do - review and audit stability documentation in order to establish the authenticity of the
stability test results reported to the FDA in ANDAs, Supplements or Annual Reports. Insure
there is a formal pre-submission internal auditing program .

ED. N0: 02 Effective Date : APPROVED:

Replaces Ed 01.
Ed. Status: DD/MM/Y2K
Operational QC Laboratory Stability Unit Development QA
Handbook of Pharmaceutical Sect: 21.
21 243 Generic Development
 ORAL DOSAGE FORM DEVELOPMENT SOPs CHAPTER 21

SOP # S-225-01-2000 STANDARD OPERATING Total Pages: 6.

PROCEDURES

DO’S AND DON’TS OF A STABILITY STUDY - A DEPARTMENT

TRAINING TOOL.

Do - insure the firms does verify the transfer of raw data values from the laboratory
workbooks to the final computer stability print-out reports.
(Where intermediate summary sheets and analysis request forms are used, these
intermediate data sheets should be signed and stamped as bona fide and accurate by
Quality Assurance).
Do - insure the final stability study is signed off by the Director of Quality Control and the
firm has a SOP specifying the acceptance and sign-off procedure for a completed stability
study, to ensure that the study is complete and accurate.
Do - insure that no laboratory raw data is unavailable or missing in support of the Stability
Summary Data Reports.
Do - insure proper cross-referencing of laboratory notebooks and worksheets with
computerized documentation prior to data being submitted to the FDA.
Do - insure retrospective audits trails of ANDA stability reports to summary data sheets and
back to laboratory workbooks clarify that the FDA filed data can be supported by the raw
laboratory test data.
Do - insure the firm does have a comprehensive and functional laboratory data reporting
system for test results.
Do - insure that data points are not missing (e.g. pH values; missing potency from crimp-
end of semi solid tubes etc.).
Do - insure stability test values are not different from the filed values.
Do - insure the use of bound and numbered laboratory notebooks.
Note - The use of unnumbered analytical worksheets for recording analytical data should be
discontinued and is not in GMP compliance.
Do - insure that stability data is not selectively screened prior to computerization.
Do - insure the absence of discrepancies and different values in ANDA Annual Reports
and the original laboratory raw data.
[Case study:- Review of the annual report prepared for the FDA showed that the ongoing
stability testing as per ANDA commitment showed an original report in the stability files with
a test data line covered with “white tape”. This data report was photocopied and sent to
the FDA. The photocopy did not reveal the ‘white-out’ data in question.]
Do - insure traceability of workbook reference page numbers and dates relating to the
original raw data in laboratory workbooks.
Do - insure the traceability of any repeat testing performed on the stability samples is
clearly referenced on the stability documentation used to prepare the computerized stability
reports.
Do - insure the need to prepare an SOP for cross-referencing laboratory notebook data
with computerized stability test result documentation.

ED. N0: 02 Effective Date : APPROVED:

Replaces Ed 01.
Ed. Status: DD/MM/Y2K
Operational QC Laboratory Stability Unit Development QA
Handbook of Pharmaceutical Sect: 21.
21 244 Generic Development
 ORAL DOSAGE FORM DEVELOPMENT SOPs CHAPTER 21

SOP # S-225-01-2000 STANDARD OPERATING Total Pages: 6.

PROCEDURES

DO’S AND DON’TS OF A STABILITY STUDY - A DEPARTMENT

TRAINING TOOL.

Do - insure all repeating testing performed at the same test interval must be cross-
referenced - all together.
Note: a reviewer requires to audit all testing performed on the stability test sample and not
only the raw data in the laboratory notebooks that have passed the stability check
specifications.
Do - insure all stability data points are present and are in full compliance with the pre-
written stability protocol.
Do - insure a full review of the stability protocol and a comparison of the test procedures
carried out on the stability samples - at each test station - to highlight any incidence where
stability data points may be absent or OOS.
Do - insure that no raw data is omitted from the stability reports or in the Annual Reports
submitted to the FDA.
Do - insure stability SOPs are adequate and routinely reviewed for GMP compliance by
written in-house audits.
Do - insure the existing SOPs do control the functions of the stability department. (45-50
Stability SOPs are a minimum prerequisite to operate a stability department for an
innovative or generic drug manufacturing company).
Do - insure is that SOPs are not deficient both in the content and detail.
The lack of suitable SOPs in a stability department may result that much of the stability management
and testing of the stability samples as erratic and out-of-control - resulting in a failed PAI review.
Do - insure that SOPs are readily available and routinely followed and updated (i.e. after a
change or annually - The lack of a full set of stability SOPs and the fact that the SOPs are
incomplete or that stability personnel are poorly trained on the contents of the SOPs is
strong evidence to an agency that the firm’s stability testing program is not in current GMP
compliance).
Do - insure samples are analyzed on- time using; First-In-First-Out (FIFO).
Do - insure that it is not possible, for a sample in a stability program to remain untested
after the ‘due date’ and thus skip the designated ‘testing interval’.
Do - insure the Certificate of Analyses are not out of date for time zero when the sample is
eventually placed on stability at a ‘start date’ several months after the initial C. of A. was
performed.
[Reason - the sample assay value potency may have degraded by several months aging which would
not be reflected by the initial certificate of analysis - some time earlier].
Do - insure the presence of stability SOPs controlling the maximum time period [30 days]
between initial testing (Certificate of Analysis at time zero) and the ‘Start Date’ of the
stability study in order not to invalidate the initial stability results.
Do - insure that all the stability SOPs are updated according to the firm’s SOP index.
3
•‚ƒ„…†‡Œ•Ž
[End of Document]

ED. N0: 02 Effective Date : APPROVED:

Replaces Ed 01.
Ed. Status: DD/MM/Y2K
Operational QC Laboratory Stability Unit Development QA
Handbook of Pharmaceutical Sect: 21.
21 245 Generic Development
 TABLETS ORAL DEVELOPMENT SOPs CHAPTER 21

Development
SOPs
‘…the essential internal standard system of a
successful drug development unit…'

S tandard Operating Procedures

(SOPs) for drug development Distribute
applies to individuals or groups
responsible for the management and
e-SOPs
operation of the innovative/generic drug electronically
development unit. It is equally valuable
for the operation and control of the
A researcher conducts work according
to a documented set of procedures -
CMC (chemistry, manufacturing and
which hopefully represents the best and
control) section of a NDA researched-
most current methods available i.e.
based unit.
drug development via “state-of-the-art”
All pharmaceutical companies techniques.
conducting drug research and A drug researcher must keeps a record
development must have of every detail of the product
understandable SOPs. The primary development - both the advances and
purpose of the SOP is to translate the the failures of the experimental batch
various regulations and guidelines, lots. SOPs also demonstrate that you
which are open to interpretation, into are following a key rule of a good
clear and concise sets of instructions. researcher - that the research
Don't Do procedures are fully described so that
they can be replicated where
Without necessary.
Remote-US Drug Development.
Development The Standard Operation Procedures
SOPs that govern Non-US drug development
of the innovative/generic dosage form
Essentially generic development can must be carefully structured to insure
be distilled into standard development that the development procedures are
procedures which any development fully understood and interfaced with the
scientist could apply. US manufacturing facility.
These procedures may be electronically Manufacturing equipment and scale-up
circulated as a read-only documents. procedures require dove-tailing at both
Master copies authorized and stored by facilities. Analytical and microbial
QA using the new electronic signature laboratory test methods need to be
procedure (e-sig rule of 20 October rugged and operational in both
1997). facilities.

Handbook of Pharmaceutical Sect: 21.

21 1 Generic Development
 TABLETS ORAL DEVELOPMENT SOPs CHAPTER 21

Great care needs to be taken to insure Generic Development of

and demonstrate the robustness of pharmaceutical drugs may take place in
these laboratory tests and analyses. a Non-US development laboratory
facility. Where product development
Testing procedure methods should be
occurs in a remote development unit
chosen in close cooperation with the (i.e. not attached to the proposed
production laboratory facilities to insure manufacturing site - special SOPs
a smooth transfer of technical dovetailing the procedures at the
documentation (TTD requirements). remote and manufacturing site are
The Standard Operation Procedures necessary for such a separated
chosen, must fully represent a cross- situation.
section of the SOPs needed for a drug Emphasis has been placed in certain
development unit to operate efficiently SOPs on external development (outside
and to produce drug products on time. the US) while commercial
The SOP index in this journal supplies manufacturing is targeted at a US
all the major procedures required, while commercial site. In the majority of the
the summary SOPs chosen describe SOP examples the regulatory ‘Pivotal’
the purpose and the principles batch for regulatory inclusion into the
generally needed to meet the scientific, NDA/ANDA submission file, is targeted
regulatory and at times GMP objectives for manufacture at the US commercial
of a well run stability unit. manufacturing site.
Carefully written SOPs will save Oversees developers who have FDA
research based firms and generic inspected / approved commercial
developers time and hard pressed manufacturing facilities may produce
development dollars. the pivotal batch at a non-US small or
large scale manufacturing facility. The
Standard Operation Procedures manufacturing and testing facility must
The SOP index of about three hundred be in full GMP compliance, as if it were
development SOPs provides the reader a US based operation.
with a full overview of the written SOP
requirements for functional drug
Non-GMP R&D or drug development
development departments, namely facilities are not suitable for clinical or
pharmaceutical, analytical, pivotal drug manufacturing. Full cGMP
microbiological and lastly the key pilot plants or to use the more
stability unit. appropriate terminology ‘small scale
manufacturing’ facilities are the correct
Regulatory Audit venue for manufacturing clinical
SOPs are batches.
Although this procedure may be within
an Essential the OGD framework of regulations, it is
Pre-submission not a recommended route, if the object
is to routinely manufacture at an
Requirement approved US commercial production
Regulatory SOPs are a specialized site.
area and should cover all regulatory Pivotal batches for regulatory
aspects of Drug Development. Pre- submission to the authorities should
submission file review and presentation always be manufactured at the US
of the Product Annual Report are two commercial site - if the intended generic
key examples of Regulatory SOPs. market is the USA.3

Handbook of Pharmaceutical Sect: 21.

21 2 Generic Development
ORAL DOSAGE FORM DEVELOPMENT SOPs INDEX

INDEX OF

PHARMACEUTIC
PHARMACEUTICAL
AL

STANDARD

OPERATING

PROCEDURES

Drug Development

Handbook of Pharmaceutical Generic Development [email protected] Index.

Index 1
 ORAL DOSAGE FORM DEVELOPMENT SOPs INDEX

S tandard
O perating
P rocedures

T
his year 2000 SOP INDEX A drug researcher must keeps a
SUMMARY is intended for record of every detail of the product
individuals or groups development - both the advances
responsible for the and the failures of the experimental
management and operation of the batch lots. SOPs also demonstrate
generic drug development units. It is that you are following a key rule of
divided into four sections, a good researcher: The research
pharmaceutical, analytical, procedures must be fully described
microbiological and stability and in order that the methods can be
equally valuable for the operation duplicated and replicated as
and control of the CMC (chemistry, necessary by various unit personnel.
manufacturing and control) section
of a NDA researched-based unit. The Standard Operation
Procedures chosen fully represent a
All pharmaceutical companies cross-section of the SOPs needed
conducting drug research and for a drug development unit to
development must have SOPs. The operate efficiently and to produce
primary purpose of the SOP is to drug products on time.
translate the various regulations and
guidelines, which are open to The updated index supplies all the
interpretation, into clear and major procedures required, while
concise sets of instructions. the selected 45 summary SOPs
describe the purpose and the
Essentially generic development principles generally needed to meet
can be distilled into standard the scientific, regulatory and at
development procedures which any times GMP objectives of a well run
good drug developer would apply. A stability unit.
researcher conducts work according
to a documented set of procedures - Carefully written and structured
which hopefully represent the best SOPs will save research-based
and most current methods available firms and generic developers both
i.e. drug development using “state- time and development dollars.
of-the-art” techniques.

Handbook of Pharmaceutical Generic Development [email protected] Index.

Index 2
 ORAL DOSAGE FORM DEVELOPMENT SOPs INDEX

INDEX OF
PHARM A C E U T I C A L D E V E L O P M E N T
SOPS

SOP Number Development Study Procedure:-

SOP CONTROL
P-000-01-2000 Template for Pharmaceutical Development SOPs.
P-005-01-2000 Indexing procedure for Pharmaceutical Development SOPs.
P-010-01-2000 Index for Pharmaceutical Development SOPs.
P-015-01-2000 Signing procedures for Pharmaceutical Development SOPs.
P-020-01-2000 Numbering and format of Pharmaceutical Development SOPs.
P-025-01-2000 Circulation of Pharmaceutical Development SOPs.
P-030-01-2000 Annual Review of Pharmaceutical Development SOPs.

DEVELOPMENT NOTEBOOKS
P-035-01-2000 Issue and use of pharmaceutical development notebooks
P-040-01-2000 Signing procedures for development notebooks
P-045-01-2000 Recording pre-formulation and development formula in
development notebooks.
P-050-01-2000 Recording manufacturing instruction in development notebooks
P-055-01-2000 Recording IPQC specifications in development notebooks
P-060-01-2000 Recording finished product specifications in development
notebooks.
P-065-01-2000 Review & auditing of pharmaceutical development notebooks
P-070-01-2000 Correction procedures in development notebooks &
documentation
P-075-01-2000 Archiving of development notebooks.

DEVELOPMENT QUALITY ASSURANCE

P-080-01-2000 Procedures For Development Change Control

DEVELOPMENT FORMULA
P-085-01-2000 Operating procedures for product development.
P-090-01-2000 Formulation of ANDA topical preparations
P-095-01-2000 Formulation of ANDAs to Q1Q2 Status (semisolids)
P-100-01-2000 Validation requirements for Product Development
P-105-01-2000 Vendor Certification requirements for Product Development
P-110-01-2000 Check list for a pharmaceutical Development Report
P-115-01-2000 SOP for Development Reports

Handbook of Pharmaceutical Generic Development [email protected] Index.

Index 3
 ORAL DOSAGE FORM DEVELOPMENT SOPs INDEX

OF INDEX
PHARMACEUTICAL DEVELOPMENT SOPS

SOP Number Development Study Procedure

DEVELOPMENT FORMULA
P-120-01-2000 Formulation of CR / ER ANDA Oral Tablet Preparations
P-125-01-2000 Establishing an IVIVC in Extended Release Oral Dosage Forms
P-130-01-2000 Establishing a level A IN-VITRO IN-VIVO correlation
P-135-01-2000 Establishing a level B IN-VITRO IN-VIVO correlation
P-140-01-2000 Establishing a level C IN-VITRO IN-VIVO correlation
P-145-01-2000 Establishing a level A IN-VITRO IN-VIVO correlation
P-150-01-2000 Evaluating the predictability of a level A - IVIV Correlation
P-155-01-2000 Development and Evaluation of a level C IVIV Correlation

DEVELOPMENT REPORTS
P-160-01-2000 List of FDA Guidance documents impacting on product IR and
CR development dosage forms.
P-165-01-2000 Setting up a general Development SOPs.
P-170-01-2000 Standard Procedures for Generic Product Development
P-175-01-2000 Setting up a Product Specific Development SOPs.
P-180-01-2000 Product Specific Development SOPs for CR Tablets - Contents.
P-185-01-2000 Setting up a Product Specific ER Development SOP.
P-190-01-2000 Setting up IVIVC for Extended Release Oral Dosage Forms
P-195-01-2000 Contents of a Development SOP - ER Oral Tablets.

Active materials
P-200-01-2000 Active Drug Substances for Generic Drugs
P-205-01-2000 Developing Product Formula with approved Actives
P-210-01-2000 R&D Inventory Records for the Active Drug Substance
P-215-01-2000 Vendor Certification Requirements for Approved Actives.
P-230-01-2000 Decision tree for establishing impurity acceptance criteria.
P-235-01-2000 Decision tree for establishing degradation acceptance criteria
P-240-01-2000 Decision tree for establishing particle size acceptance criteria
P-245-01-2000 Decision tree for establishing polymorphism existence
P-250-01-2000 Decision tree for establishing microbiological testing
P-255-01-2000 Decision tree for evaluating chiral actives

Handbook of Pharmaceutical Generic Development [email protected] Index.

Index 4
 ORAL DOSAGE FORM DEVELOPMENT SOPs INDEX

OF INDEX
PHARMACEUTICAL DEVELOPMENT SOPS

SOP Number Development Study Procedure

Semi-Active raw materials

P-260-01-2000 Developing Product Formula with Approved Actives.
P-265-01-2000 Inventory Records for the Active Drug Substance.
P-270-01-2000 Investigating and handling abnormal batch results.
P-275-01-2000 Choosing the Antioxidant
P-280-01-2000 Antioxidant Qualification during Process Optimization

Non-Active materials
P-285-01-2000 Non-active ingredients for ANDA formula development
P-290-01-2000 Use of Purified Water USP in Product Development
P-295-01-2000 Checking excipients in the FDA ‘Inactive Ingredient Guide’
P-300-01-2000 Evaluation and Requirements of Release Controlling Excipients
P-305-01-2000 Justification and functionality of the Release Controlling
Excipient

Container-Liner-Closure systems
P-310-01-2000 Container-Liner-Closure systems for Generic Development
P-315-01-2000 Documentation requirements for Container/Closure systems
P-320-01-2000 Check list for Container-Liner-Closure Documents

In-process controls
P-325-01-2000 Choice of IPQC limits.
P-330-01-2000 Qualification of IPQC limits.
P-335-01-2000 Qualification of manufacturing process specification limits.
P-340-01-2000 In process control on bulk products
P-345-01-2000 Time limitations on manufacturing processing stages

Finished Product Controls

P-355-01-2000 Choice of Finished Product Specification limits
P-360-01-2000 Qualification of Finished Product Specification limits

Handbook of Pharmaceutical Generic Development [email protected] Index.

Index 5
 ORAL DOSAGE FORM DEVELOPMENT SOPs INDEX

Contract laboratories

OF INDEX
PHARMACEUTICAL DEVELOPMENT SOPS
SOP Number Development Study Procedure

Process Optimization Batch

P-375-01-2000 Documentation requirements for a Process Optimization Batch
P-380-01-2000 LOD Qualification during Process Optimization
P-385-01-2000 Tablet lubricant Qualification during Process Optimization

Process Qualification Batch

P-390-01-2000 Documentation requirements for a Process Qualification Batch
P-395-01-2000 Side-by-side comparison for Process Qualification and Pivotal
Batch
P-400-01-2000 Granule Content Uniformity Qualification
P-405-01-2000 Tablet Hardness Qualification

Scale-Up and TTD

P-410-01-2000 Preparing the scale-up report for pivotal batch manufacturing
P-415-01-2000 Check list of a TTD file

Pivotal Batch
P-420-01-2000 Pivotal Batch requirements
P-425-01-2000 In-process sampling & testing procedures of tablets, caplets
and capsules for pivotal batches
P-430-01-2000 Do’s and Don’ts when preparing for pivotal batches
P-435-01-2000 Check list for Pivotal Batch Documentation
P-440-01-2000 Side by side comparison for Pivotal and Validation Batch

Handbook of Pharmaceutical Generic Development [email protected] Index.

Index 6
 ORAL DOSAGE FORM DEVELOPMENT SOPs INDEX

OF INDEX
PHARMACEUTICAL DEVELOPMENT SOPS
SOP Number Development Study Procedure

Biostudy
P-445-01-2000 Do’s and Don’ts when preparing for pivotal Biostudies
P-450-01-2000 Dissolution requirements for Biostudies
P-455-01-2000 Dissolution Testing for Solid Oral Dosage Forms
P-460-01-2000 Dissolution Testing for Suspended Oral Dosage Forms
P-465-01-2000 Check List & Documentation for and IVIVC/Pilot Study
P-470-01-2000 Check List for Biostudy Documentation

Sanitation
P-475-01-2000 Good House Keeping Practice in a Small Scale Development
Unit
P-480-01-2000 Cleaning and Sanitation Procedures for Small Scale
Development Unit
P-485-01-2000 Validation of Cleaning procedures for Small Scale
Manufacturing Equipment
P-490-01-2000 Garmenting procedures for development personnel

Chart Control
P-495-01-2000 Routine signing and checking of temperature charts
P-500-01-2000 Review & control of temperature & humidity recording charts

Calibration, validation and qualification

P-505-01-2000 Itemized List of Small Scale Development Equipment
P-515-01-2000 IQ/OQ Requirements for Small Scale Manufacturing Equipment
P-520-01-2000 Calibration Requirements for Small Scale Mfg. Equipment
P-525-01-2000 Operational Instructions for Small Scale Mfg. Equipment
P-530-01-2000 Annual qualification program for Small Scale Mfg. Equipment
P-535-01-2000 Annual qualification program for Laboratory Equipment
P-540-01-2000 Preventative maintenance for Small Scale Mfg. Equipment
P-545-01-2000 Preventative maintenance for laboratory Analytical Equipment
P-550-01-2000 Reserved SOPs for specialized equipment and test methods

Handbook of Pharmaceutical Generic Development [email protected] Index.

Index 7
 ORAL DOSAGE FORM DEVELOPMENT SOPs INDEX

OF INDEX
PHARMACEUTICAL DEVELOPMENT SOPS
SOP Number Development Study Procedure

Contract laboratories
P-555-01-2000 Auditing procedures for a contract laboratory.
P-560-01-2000 Mail / fax auditing procedures for a contract laboratory.

Self-inspection and auditing

P-565-01-2000 Cross- referencing laboratory notebooks with computerized
development report sheets.
P-570-01-2000 Auditing development data in laboratory notebooks.
P-575-01-2000 Self inspection procedures in a generic development Lab.

Job descriptions and training

P-580-01-2000 Using Development SOPs and compliance program as training
tools.
P-585-01-2000 The do’s and don’ts of a development study as a department
training tool.
P-590-01-2000 R&D Compliance Staff Training
P-595-01-2000 Job description of Pharmaceutical R&D personnel
P-600-01-2000 Operator Certification Procedures of Development Personnel
P-605-01-2000 Maintenance of development personnel training records

Reviewing documentation
P-610-01-2000 Review And Auditing Development Documentation.
P-615-01-2000 Review And Auditing The Process Qualification Batch
Documentation.
P-620-01-2000 Review And Auditing The Pivotal Batch Documentation.

Closing a study
P-625-01-2000 Accepting and signing-off a completed development study.

Handbook of Pharmaceutical Generic Development [email protected] Index.

Index 8
ORAL DOSAGE FORM DEVELOPMENT SOPs INDEX

INDEX
OF

ANALYTICAL

STANDARD
OPERATING
PROCEDURES

Drug Development

Handbook of Pharmaceutical Generic Development [email protected] Index 9

 ORAL DOSAGE FORM DEVELOPMENT SOPs INDEX

INDEX OF
ANA L Y T I C A L D E V E L O P M E N T
SOPS

SOP Number ANALYTICAL STUDY PROCEDURE

INDEX No SOPs
A-001-01-2000 Indexing procedure for analytical SOPs.
A-010-01-2000 Index of analytical SOPs.
A-012-01-2000 Authorization signatures for analytical SOPs.
A-015-01-2000 Numbering and format of analytical SOPs.
A-020-01-2000 Circulation of analytical SOPs.
A-025-01-2000 Annual Review of analytical SOPs.
A-030-01-2000 Reserved.

Development Notebooks
A-035-01-2000 Issue and use of analytical development notebooks
A-040-01-2000 Signing procedures for analytical notebooks
A-045-01-2000 Entering raw data in laboratory notebooks
A-050-01-2000 Using USP terminology in analytical methods
A-055-01-2000 Verifying analytical calculations performed by (in-house)
computer programs
A-060-01-2000 Release of Results from the Analytical R&D Laboratories.
A-060-02-2000 Reviewer Checklist .

Auditing
A-065-01-2000 Review and auditing of analytical laboratory notebooks
A-070-01-2000 Correction procedures in laboratory notebooks
A-075-01-2000 Archiving of laboratory notebooks
A-080-01-2000 Laboratory Note Book Checklist.

Development Quality Assurance

A-085-01-2000 Procedures for Analytical Change Control
A-090-01-2000 Reserved.

Incoming samples
A-095-01-2000 General Analytical Sample Preparation.
A-100-01-2000 Receipt and logging-in of analytical laboratory samples
A-105-01-2000 Storage of samples prior to testing
A-110-01-2000 Storage time limits of samples prior to testing.
A-115-01-2000 Disposition of tested laboratory samples (including time limits).
A-120-01-2000 Reserved.

Handbook of Pharmaceutical Generic Development [email protected] Index 10

 ORAL DOSAGE FORM DEVELOPMENT SOPs INDEX

INDEX OF
AN A L Y T I C A L D E V E L O P M E N T
SOPS

SOP Number ANALYTICAL STUDY PROCEDURE

INDEX No SOPs
Reagent and solutions
A-125-01-2000 Handling and preparation of analytical standards
A-130-01-2000 Handling and preparation of volumetric solutions
A-135-01-2000 Labeling requirements of reagents and solutions
A-140-01-2000 Preparation and storage of analytical glassware.
A-145-01-2000 Reserved.

Test methods
A-150-01-2000 Availability and control of approved test methods.
A-155-01-2000 Updating Pharmacopeial methods with supplemental
monographs.
A-160-01-2000 Abbreviated Raw Materials testing Procedures.
A-165-01-2000 Approval signatures for Raw materials and Approved suppliers.
A-170-01-2000 Retesting Procedures.

Calculations
A-175-01-2000 Recording and checking of method calculations
A-180-01-2000 Procedures for rounding off analytical numbers

Active materials
A-190-01-2000 Active Drug Substances for Generic Drugs
A-195-01-2000 Developing Product Formula with approved Actives
A-200-01-2000 Development Inventory Records for the Active Drug Substance
A-205-01-2000 Reserved.

Drug substance
A-210-01-2000 Drug substance impurity assays
A-215-01-2000 Drug substance impurities profiles
A-220-01-2000 Drug substance specifications
A-225-01-2000 Drug substance approval procedures
A-235-01-2000 Drug substance approved suppliers

The Reference Listed Drug

A-240-01-2000 Reserved
A-245-01-2000 Testing the Reference Listed Drug (RLD)

Handbook of Pharmaceutical Generic Development [email protected] Index 11

 ORAL DOSAGE FORM DEVELOPMENT SOPs INDEX

INDEX OF
AN A L Y T I C A L D E V E L O P M E N T
SOPS

SOP Number ANALYTICAL STUDY PROCEDURE

INDEX No SOP
Drug Product
A-250-01-2000 Drug substance impurity assays
A-255-01-2000 Drug substance impurities profiles
A-260-01-2000 Drug substance Specifications
A-265-01-2000 Limit test on impurities
A-270-01-2000 Validation of limit tests for impurities
A-272-01-2000 Validation of Assay and/or Impurities Determination
A-275-01-2000 Assay determination by HPLC and GC methods.
A-276-02-2000 Assay determination by HPLC and GC methods -Details.

Container-liner-closure systems
A-280-01-2000 Testing Container-Liner-Closure systems for Generic
Development

Sample preparation
A-290-01-2000 General analytical sample preparation
A-295-01-2000 Number of samples and injections for assays
A-300-01-2000 Standards and system suitability for HPLC testing
A-304-01-2000 Working and Impurity Standards - Use and Qualification
A-305-01-2000 Working with Reference Standards and In-house Standards.

Validation
A-310-01-2000 Using ID numbers for identifying laboratory instrumentation.
A-315-01-2000 Validation of stability-indicating (S-I) methods
A-320-01-2000 Validation of in-house analytical methods
A-325-01-2000 Using stability indicating (S-I) methods
A-335-01-2000 Analytical methods not requiring (full) validation
A-340-01-2000 Contents of an analytical validation protocol
A-345-01-2000 Standardizing and transferring S-I methods and assay
validations.
A-350-01-2000 Change Control Procedures.

Contract laboratories
A-355-01-2000 Auditing procedures for a contract analytical laboratory.
A-365-01-2000 Mail/fax auditing procedures for a contract laboratory.

Handbook of Pharmaceutical Generic Development [email protected] Index 12

 ORAL DOSAGE FORM DEVELOPMENT SOPs INDEX

INDEX OF
AN A L Y T I C A L D E V E L O P M E N T
SOPS

SOP Number ANALYTICAL STUDY PROCEDURE

Process Qualification Batch (Scaled-up)

A-375-01-2000 Process Qualification Batch analytical requirements
A-380-01-2000 Side-by-side analytical comparison for process qualification
and pivotal batch
A-385-01-2000 Reserved.
Pivotal Batch
A-390-01-2000 Pivotal Batch analytical requirements
A-395-01-2000 Do’s and Don’ts when preparing for pivotal testing
A-400-01-2000 Checklist for pivotal batch analytical documentation
A-405-01-2000 Side-by-side analytical comparison for pivotal and validation
batch
Investigations
A-415-01-2000 Procedures for handling OOS results
A-420-01-2000 Procedures for repeat testing (using two stages)
A-425-01-2000 Procedures for invalidating test results and graphs
A-430-01-2000 Investigation reports after repeat testing
A-435-01-2000 Evaluation of Significant Change in Stability Test Results.
Analytical Development reports
A-440-01-2000 Checklist for an analytical development report
A-445-01-2000 Analytical Development Reports
A-448-01-2000 Preparing a standard Certificate of Analysis
Analytical transfer documentation (TTDs)
A-450-01-2000 Check list of an analytical TTD file
A-455-01-2000 Analytical transfer from development to QC of mnf. facility.
A-460-01-2000 Change Control Form.
Chart Control
A-465-01-2000 Routine signing and checking of temperature recording charts
A-470-01-2000 Review & control of temperature & humidity recording charts.
A-475-01-2000 Handling of Instrument Graphs, Charts and Print-outs
Sanitation
A-480-01-2000 Good House Keeping Practice in an analytical laboratory.
A-485-01-2000 Cleaning and sanitation procedures for laboratory equipment.
A-490-01-2000 Garmenting procedures for laboratory personnel

Handbook of Pharmaceutical Generic Development [email protected] Index 13

 ORAL DOSAGE FORM DEVELOPMENT SOPs INDEX

INDEX OF
AN A L Y T I C A L D E V E L O P M E N T
SOPS

SOP Number ANALYTICAL STUDY PROCEDURE

Calibration , validation and qualification

A-495-01-2000 Itemized list of laboratory equipment
A-500-01-2000 IQOQ requirements for laboratory equipment
A-505-01-2000 Calibration requirements for laboratory equipment
A-510-01-2000 Corrective action procedures for out-of-calibration
instrumentation.
A-515-01-2000 Operational Instructions for laboratory equipment
A-516-01-2000 Calibration of pH meters
A-517-01-2000 Instrument performance checks p r o t o c o l calibration of pH
meter electrode system
A-518-02-2000 Calibration of pH meters - Detailed
A-519-01-2000 Performance Checks GC Integrator HP 3396 Series II, HP
3393-A Varian 4270
A-520-01-2000 Annual qualification program for laboratory equipment
A-524-01-2000 Performance verification of Bausch & Lomb and Milton Roy
spectrophotometers
A-525-01-2000 Spectronic Standards - Test Calibration Form # [001]
A-526-01-2000 Wavelength Accuracy Form - # [005]
A-527-01-2000 Control of Absorbances Form - #[010]
A-527-02-2000 Control of Absorbances Form - #[015]
A-528-01-2000 Performance verification of dissolution apparatus
A-529-01-2000 Preventative maintenance programs for laboratory equipment
A-529-01-2000 Apparatus Suitability Prednisone Paddle method
A-530-01-2000 Dissolution Apparatus - Eccentricity of Shafts
A-531-01-2000 Apparatus Suitability Salicylic Acid Basket method
A-532-01-2000 Apparatus Suitability Salicylic Acid Paddle method
A-533-01-2000 Apparatus Suitability Prednisone Basket method
A-534-01-2000 Dissolution Apparatus - Routine Checking & Calibration
A-535-01-2000 Daily Balance Calibration - #[020]
A-540-01-2000 Monthly Analytical Balance Check - Tolerance 1.0mg
A-541-01-2000 Monthly Analytical Balance Check - Tolerance 0.1mg

A-580-01-2000 Reserved SOPs for specialized equipment and test methods

A-590-01-2000 Operation of specific laboratory analytical equipment - #[030]
A-595-01-2000 Operation of specific laboratory analytical equipment - #[040]
A-600-01-2000 Operation of specific laboratory analytical equipment - #[050]

Handbook of Pharmaceutical Generic Development [email protected] Index 14

 ORAL DOSAGE FORM DEVELOPMENT SOPs INDEX

INDEX OF
AN A L Y T I C A L D E V E L O P M E N T
SOPS
SOP Number ANALYTICAL STUDY PROCEDURE

Job descriptions and training

A-605-01-2000 Using analytical SOPs & compliance program as training tools.
A-610-01-2000 The do’s and don’ts of an analytical study - as a department
training tool.
A-615-01-2000 Analytical laboratory compliance staff training
A-620-01-2000 Qualification of analytical laboratory personnel
A-625-01-2000 Operator Certification Procedures of laboratory personnel
A-630-01-2000 Maintenance of laboratory personnel training records

Self-inspection and auditing

A-635-01-2000 Cross-referencing laboratory notebooks with printed reports.
A-640-01-2000 Auditing development data in laboratory notebooks.
A-642-01-2000 Laboratory Notebook Checklist.
A-645-01-2000 Self inspection procedures in an analytical laboratory.

Reviewing documentation
A-650-01-2000 Review and Auditing analytical data.
A-655-01-2000 Auditing the Process Qualification Batch analytical data.
A-660-01-2000 Review and Auditing the Pivotal Batch analytical data.
A-665-01-2000 Review and Auditing Stability Batch analytical data.
Closing a study
A-670-01-2000 Accepting and signing-off a completed analytical study.

During The New Millennium

International Journal of
Drug Development
and the
International Journal of
Generic Drugs
will be sponsoring the Years Key Generic Conferences
THE OFFICIAL REVIEWERS FOR
PHARMACEUTICAL CONFERENCES PUBLISHED in the International Journals

Handbook of Pharmaceutical Generic Development [email protected] Index 15

ORAL DOSAGE FORM DEVELOPMENT SOPs INDEX

INDEX OF

MICROBIOLOGICAL

STANDARD

OPERATING

PROCEDURES

Drug Development

Handbook of Pharmaceutical Generic Development [email protected] Index 16

 ORAL DOSAGE FORM DEVELOPMENT SOPs INDEX

INDEX OF
MICROBIOLOGY DEVELOPMENT
SOPS

SOP Number Microbiology Study Procedure

SOP Control
M-005-01-2000 Indexing procedure for Microbiology SOPs.
M-010-01-2000 Index for Microbiology SOPs.

Notebooks
M-015-01-2000 Issue, use, and disposition of microbiological laboratory
notebooks
Samples and Sampling
M-020-01-2000 The use of sterile sampling containers.
M-025-01-2000 Representative sampling procedures.
M-030-01-2000 Labeling of sample containers.
M-035-01-2000 Receipt and logging of laboratory samples.
M-040-01-2000 Storage of samples before and after testing.
M-045-01-2000 Storing the Microbiology study samples under refrigerated
conditions prior to analysis.
M-050-01-2000 Number of samples required for performing microbiology tests.
M-055-01-2000 Storage time limitations of samples prior to testing

Bioburden of starting materials

M-060-01-2000 Microbial testing of non active raw materials.
M-065-01-2000 Total microbial Count specifications in Purified Water USP
M-070-01-2000 Microbial testing in Container-Liner-Closure systems

Media
M-075-01-2000 Labeling and expiration dating of prepared media
M-080-01-2000 Disposition of microbiological media and samples
M-085-01-2000 Preparation, storage and use of microbiological media.

Purified Water USP

M-090-01-2000 Sampling sites and procedures for monitoring Purified Water
USP
M-095-01-2000 Total Microbial Count specifications in Purified Water USP
M-100-02-2000 Microbial Limit Test specifications in Purified Water USP
M-105-01-2000 Alert and Action limits on TMC in Purified Water USP
M-110-01-2000 Frequency of microbial testing in Purified Water USP

Handbook of Pharmaceutical Generic Development [email protected] Index 17

 ORAL DOSAGE FORM DEVELOPMENT SOPs INDEX

INDEX OF
MICROBIOLOGY DEVELOPMENT
SOPS

SOP Number Microbiology Study Procedure

In-process controls
M-115-01-2000 Representative sample procedures on bulk products
M-120-01-2000 In process control on bulk products
M-125-01-2000 Time limitations on bulk product in process controls

Finished Product testing

M-130-02-2000 Total microbial Count specifications in drug products.
M-135-01-2000 Fungal Limit Test specifications in drug products.
M-140-01-2000 Microbial Limit Test specifications in drug products.
M-145-01-2000 Preservative efficacy testing and specifications in topical
semi-solids
M-150-01-2000 Microbial Assay testing in topical semi-solids

Laboratory House-keeping
M-155-01-2000 Procedures for reduction of bioburden in the microbiological
laboratory
M-160-01-2000 The use and rotation of disinfectant swabbing solutions.
M-165-01-2000 Prevention of contamination of media plates
M-170-01-2000 Preparation, sterilization and storage of laboratory glassware
and equipment

Culture control
M-175-01-2000 Procedures for receipt, storage and handling of ATCC cultures
M-180-01-2000 Handling Certificate of Analysis for ATCC cultures
M-185-01-2000 Limitation on transfer procedures for ATCC cultures

Test Method control

M-190-01-2000 Control and use of supplemental monographs in
pharmacopoeial methods
M-195-01-2000 The control of test methods #s and Edition #s in microbiology
documentation.
M-200-01-2000 Distribution of approved test method procedures
M-205-01-2000 Validation of in-house test method procedures

Handbook of Pharmaceutical Generic Development [email protected] Index 18

 ORAL DOSAGE FORM DEVELOPMENT SOPs INDEX

INDEX OF
MICROBIOLOGY DEVELOPMENT
SOPS

SOP Number Microbiology Study Procedure

Formula Control
M-210-01-2000 Recording and checking of method calculations
M-215-01-2000 Procedures for rounding-off recorded numbers

Investigation reports
M-220-01-2000 Procedures for handling abnormal or OOS results in a
microbiology study.
M-220-01-2000 Procedures for repeat testing
M-230-01-2000 Investigation reports after repeat testing
M-230-01-2000 Procedures for invalidating test results

Aseptic practice
M-240-01-2000 Periodic monitoring of lamina flow units
M-240-01-2000 Aseptic working practice and techniques for laminar flow units

Environmental monitoring
M-250-01-2000 Bioburden mapping of laboratory environment
M-250-01-2000 Bioburden mapping of manufacturing environment
M-260-01-2000 Bioburden evaluation of manufacturing equipment
M-260-01-2000 Bioburden sampling and evaluation of the environment air
M-270-01-2000 The operation and use of Biotest Hycon air RCS sampler
M-270-01-2000 Bioburden evaluation of personnel hands and clothing
M-280-01-2000 Swabbing procedures for surface evaluation.

Chart Control
M-290-01-2000 Routine signing and checking of temperature charts
M-290-01-2000 Review and control of temperature and humidity recording
charts.

Calibration , validation and qualification

M-300-01-2000 Itemized list of microbiology laboratory equipment
M-300-01-2000 Validation of laboratory autoclaves
M-310-01-2000 Periodic revalidation of autoclaves and incubators.
M-310-01-2000 Calibration schedule for microbiology laboratory instruments
M-320-01-2000 Annual qualification program for laboratory instruments
M-325-01-2000 Preventative maintenance programs for laboratory equipment
M-330-01-2000 Reserved SOPs for specialized equipment and test methods

Handbook of Pharmaceutical Generic Development [email protected] Index 19

 ORAL DOSAGE FORM DEVELOPMENT SOPs INDEX

INDEX OF
MICROBIOLOGY DEVELOPMENT
SOPS

SOP Number Microbiology Study Procedure

Sanitation
M-335-01-2000 Sanitation and housekeeping requirements of incubators.
M-340-01-2000 Good House Keeping practice in a microbiological laboratory
M-345-01-2000 Cleaning and sanitation procedures for incubators and
refrigerators
M-350-01-2000 Garmenting procedures for microbiological personnel

Job descriptions and training

M-355-01-2000 Using Microbiology SOPs and compliance program as a
microbiology training tools.
M-360-01-2000 The Do’s and Don’ts of a microbiology study - as a department
training tool.
M-365-01-2000 Microbiology department compliance staff training
M-370-01-2000 Job description of microbiology department personnel
M-375-01-2000 Maintenance of microbiological personnel training records

Contract laboratories
M-380-01-2000 Auditing procedures for a contract laboratory.
M-385-01-2000 Mail/fax auditing procedures for a contract laboratory.

Development SOP
M-390-01-2000 Microbiology development procedures for new products.

Self-inspection and auditing

M-395-01-2000 Cross- referencing laboratory notebooks with computerized
microbiology report sheets.
M-400-01-2000 Auditing microbiology data in laboratory notebooks.
M-400-01-2000 Self inspection procedures in a microbiology laboratory.

Reviewing documentation
M-410-01-2000 Review and auditing microbiology documentation.
M-415-01-2000 Reporting the test results of a microbiology study.

Closing a study
M-420-01-2000 Accepting and signing-off a completed microbiology study.

Handbook of Pharmaceutical Generic Development [email protected] Index 20

ORAL DOSAGE FORM DEVELOPMENT SOPs INDEX

INDEX
OF

STABILITY

STANDARD

OPERATING

PROCEDURES

Drug Development

Handbook of Pharmaceutical Generic Development [email protected] Index .20

 ORAL DOSAGE FORM DEVELOPMENT SOPs INDEX

INDEX OF
STABILITY
SOPS

SOP Number Stability Study Procedure

The following index represents an adequate set of standard operating procedures for a stability
department. In order for a stability department to function efficiently the principles described in
these over +45 standard operating procedures are required to conduct a functional stability
study. SOP examples are provided as a base. All SOPs listed are not provided.
SOP CONTROL
S-001-01-2000 Format and Layout of Standard Operating Procedures
S-005-01-2000 Indexing procedure for Stability Studies.
S-010-01-2000 Index for Stability SOPs.

STARTING A STUDY
S-015-01-2000 Initiating a Stability Study.
S-020-01-2000 Contents of a Stability Protocol.
S-025-01-2000 Setting the ‘Start date’ for a Stability Study.
S-030-01-2000 Determining the ‘Due dates’ for a Stability Study protocol.
S-035-01-2000 The initial Certificate of Analysis at T o for a Stability Study.

STUDY PARAMETERS
S-040-01-2000 Setting limits for check specifications in a Stability Study.
S-045-01-2000 Number and size of batches for stability testing.

SAMPLING
S-050-01-2000 Number of samples required for performing stability tests.
S-060-01-2000 Labeling of Stability Study Samples.
S-065-01-2000 Storage configuration of samples in a stability environment.
S-070-01-2000 Storing the stability study samples under controlled conditions prior to analysis.

ACTIVE DRUG
S-075-01-2000 Stress testing the bulk drug substance for stability analysis.

STUDY CONDITIONS
S-080-01-2000 Intervals and climatic conditions for a US development Stability Study.
S-085-01-2000 Intervals and climatic conditions for a US Pivotal/Bioequivalence Stability Study.
S-090-01-2000 Intervals and climatic conditions for a US validation/PM Stability Study.
S-095-01-2000 Placing the Reference Listed Drug (RLB) on Stability.

PACKAGING PROCEDURES
S-100-01-2000 Sampling and Testing of Pivotal Batches - Tablet and Capsule Dosage Forms.
S-105-01-2000 Sampling and Testing of Pivotal Batches - Powder and Syrups for Reconstitution.

CONTAINER SYSTEMS
S-110-01-2000 Container-Liner-Closure systems for a Stability Study.
S-115-01-2000 Certification of a Container-Liner-Closure system.

TEST RESULTS
S-120-01-2000 Reporting test results of a Stability Study.
S-125-01-2000 Procedures for handling abnormal or OOS results in a Stability Study.

Handbook of Pharmaceutical Generic Development [email protected] Index .21

 ORAL DOSAGE FORM DEVELOPMENT SOPs INDEX

INDEX OF
STABILITY
SOPS

SOP Number STABILITY STUDY PROCEDURE

TEST METHODS
S-130-01-2000 The control of Analytical methods #’s and Edition #’s in stability documentation.

AUDIT AND REVIEW RAW DATA

S-145-01-2000 Auditing stability data in laboratory notebooks.
S-140-01-2000 Cross-referencing laboratory notebooks with computerized stability documentation.

CHART CONTROL
S-150-01-2000 Recording stability study climatic conditions
S-155-01-2000 Review and control of temperature and humidity recording charts.

VALIDATION AND SANITATION

S-160-01-2000 Periodic revalidation of climatic rooms and chambers.
S-170-01-2000 Sanitation and housekeeping requirements of climatic chambers.

CORRECTIVE ACTION
S-175-01-2000 Fault correcting procedures (after breakdowns) during a Stability Study.
S-180-01-2000 Emergency procedures during a Stability Study.

IN HOUSE METHODS
S-185-01-2000 Reserved.

STOPPING A STUDY
S-190-01-2000 Conditions for stopping a Stability Study.

SELF INSPECTION
S-210-01-2000 Self inspection procedures in a stability department.

JOB DESCRIPTION AND TRAINING

S-215-01-2000 Job description of stability department personnel
S-220-01-2000 Using stability SOPs and compliance program as stability training tools.
S-225-01-2000 The Do’s and Don’ts of a Stability Study - a department training tool.
S-230-01-2000 Stability department compliance staff training

REVIEWING DOCUMENTATION
S-245-01-2000 Review and auditing stability study documentation.
S-250-01-2000 The layout and format of a regulatory stability report (a filed report)
S-255-01-2000 Documentation requirements for a Stability Study - contents of a stability dossier

CLOSING A STUDY
S-260-01-2000 Accepting and signing-off a completed stability study.

3
[End of Document]

Handbook of Pharmaceutical Generic Development [email protected] Index .22

 ORAL DOSAGE FORM DEVELOPMENT SOPs INDEX

I n t e r n a t i o n a l A s s o c i a t i o n o f G e n e r i c & I n n o v a t i v e D r u g M a n u f a c t u r e r s

Pharmaceutical Researchers and Consultants

Generic Drug Development Departments
CMC Innovative & Research-based Units.

IAGIM - Drug Development Association.

IAGIM regularly connects with Pharmaceutical Manufacturing Companies, Pharmaceutical

Associations, Health Depts., Regulatory Agencies and University Affiliations World wide.

◊ The Association’s Objectives

To provide an International flow of know-how Technology on Innovative and Generic Drug
Development.
◊ The Association’s Publications
Publishes a member's technical bimonthly Drug Letter “Development Do’s and Don’ts”
Publishes the 24 volume authoritative Handbook Series on Generic Drug Development.
Publishes the 120+ READY-TO-GO™ Series on Top Generic Drug Product Development.
Publishes the well-known International Journal of Generic Drugs.
Publishes the Electronic International Journal of Generic Drugs.
Publishes the International Journal of Drug Development.
Publishes the Electronic International Journal of Drug Development.
Maintains and updates the US ANDA Electronic Template Drug Registration System
Maintains and updates the EC EURO Electronic Template Drug Registration System
Publishes PRINT, DISKETTE, CD ROM and Electronic e-mail versions of all publications
◊ The Association’s Archives
The Association maintains a working Drug Development Archive on the World Wide Web dealing with
all aspects of drug development, process validation and analytical aspects. Keep informed of the
important regulations, FDA will adopt this year, so you can plan your drug development and
manufacturing operations ahead.
◊ The Association’s Benefits
²Drug Development Reports ²Membership Discounts and Journals, Handbooks and Publications.
²The Association maintains Comprehensive Drugs Off-Patent™ Files & lists to year 2016 on its popular
On-line Drug Development Archives.² ²New unpublished analytical methods; ²Free monthly SOPs;²
Analytical, Process and Cleaning Validation, and more - e-mailed to your firm's address. ²Essential Key
SOPs ² Ready-To-Go™ Handbooks ²Û Ready-To-Go™ CMCs know-how technology Ü ² All print
issues available by diskette, CD ROM or via e-mail attachment in PDF™.
The Association’s Membership
v Annual Membership: - $ 4 6 0 - ' l e s s t h a n a t w o d o l l a r s a d a y ' v

JOIN NOW - IT’S IN YOUR DRUG RESEARCH INTERESTS !

Handbook of Pharmaceutical Generic Development [email protected] Index .23