A Guide to the GMP requirements

of PS 9000:2001 Pharmaceutical
packaging materials

The Institute of
Quality Assurance

Pharmaceutical
Quality Group
 The Institute of Quality Assurance
Pharmaceutical Quality Group

PS 9004

A Guide to the GMP requirements

of PS 9000:2001 Pharmaceutical packaging materials

September 2004

i
ii
Figure 1. Model of PS 9004: a Guide to the GMP requirements of PS 9000

ide

PS
gu

90

ISO 9000
04

04

+
90

GMP
gu
PS

for Pharmaceutical
ide

packaging materials
=
PS 9000

PS 9004 guide

The symbol is used in Part 1 to identify risk areas.

iii
ISBN 0-906810-79-5

PS 9004: 2004

For further information about the Pharmaceutical Quality Group (PQG) and
any additional information or updates on PS 9000 or PS 9004 visit the PQG
website on: www.pqg.org

PS 9004 is available from:

IQA Information Service
12 Grosvenor Crescent
London SW1X 7EE
Tel: + 44 (0)20 7245 6722
Fax: + 44 (0)20 7245 6788
e-mail: [email protected]
website: www.iqa.org

iv
 COPYRIGHT

PS 9004 copyright
© 2004 Institute of Quality Assurance (IQA)
This PS 9004 guide is copyright protected by IQA/Pharmaceutical Quality
Group(PQG). However in pursuit of their objectives to promote quality
throughout the pharmaceutical manufacturing and supply industries,
permission is given to use the contents for quality system improvement
in education, training, auditing or for certification purposes, provided
acknowledgement of the source of the material (PS 9004 IQA/PQG Copyright)
is given. Reproduction,storage in a retrieval system,transmission in any form
or by any means,electronic, photocopying, recording or otherwise FOR ANY
OTHER PURPOSE without prior permission being secured is prohibited.

Requests for permission to reproduce should be addressed to the IQA at the

address below:

IQA Information Service

12 Grosvenor Crescent
London SW1X 7EE
Tel: + 44 (0)20 7245 6722
Fax: + 44 (0)20 7245 6788
e-mail: [email protected]

Reproduction may be subject to royalty payments or a licensing agreement.

Violators may be prosecuted.

v
vi
 MHRA FOREWORD

The EU Guide to Good Manufacturing Practice (GMP) emphasizes the need for
pharmaceutical manufacturers and assemblers to ensure that the packaging
materials that they use are of the appropriate quality. Not only is this in the
interests of patient safety, but also in the pharmaceutical industry where
the increasing use of automated packaging processes relies heavily on the
consistent quality of packaging components.

Each year the Medicines and Healthcare products Regulatory Agency

(MHRA) receives and investigates a number of reports of quality defects
concerning medicinal products. A significant proportion of these concern
packaging errors, some of which are attributable to the use of packaging
materials not of the desired quality. The introduction of PS 9000 in 2001 by
the Pharmaceutical Quality Group of the Institute of Quality Assurance was
a key step in promoting the understanding of GMPs relevant to the suppliers
of packaging materials to the pharmaceutical industry. PS 9000 focused on
the development and implementation, by suppliers, of a quality management
system designed to provide assurance of the quality of their products and to
enhance customer satisfaction. Its contribution was welcomed by both industry
and the Regulator. PS 9004 is aimed at increasing the awareness of the quality
management system requirements embodied in PS 9000. This comprehensive
and easy to follow guide explains further the GMP requirements of PS 9000.
It adopts a risk assessment approach to the identification and implementation
of preventive action and uses case studies to illustrate areas of GMP risk.

The MHRA encourages the introduction of PS 9004 designed to improve

product and service quality in the supply of packaging materials for medicinal
products, for the benefit of patients and the pharmaceutical industry as a
whole.

John Taylor Quality and Systems Manager

Inspection and Enforcement Division, MHRA

vii
viii
 GENERAL INTRODUCTION

What is PS 9004?
This guide aims to assist suppliers of pharmaceutical packaging materials to
understand and implement the Quality Management System (QMS) of ISO
9001 and the application standard of PS 9000. It supplements the following
documents:
• ISO 9001 which specifies the requirements of the international QMS
standard
• ISO 9004 gives guidance on ISO 9001
• PS 9000 is an application standard written by the PQG for suppliers of
pharmaceutical packaging materials that integrates ISO 9001 and ISO
9004 together with additional Good Manufacturing Practices (GMP)
requirements particular to these suppliers

Companies complying with PS 9000 will comply with ISO 9001 and also the
additional GMP requirements endorsed by the highly regulated pharmaceutical
industry.

This guide is constructed around the clause structure of PS 9000 (and therefore
ISO 9001) to:
• clearly explain the GMP requirements of PS 9000
• list many of the risk areas associated with packaging processes and identify
relevant ISO 9001 and PS 9000 clauses
• provide examples of process inputs and process outputs typical of suppliers
of pharmaceutical packaging materials, and relate these to the QMS
requirements of ISO 9001 and the additional GMP requirements of PS
9000
• give examples of actual case histories of problems arising from the supply of
defective pharmaceutical packaging materials and where the consequences
would have been avoided by correct application of the GMP requirements
of PS 9000. These case histories help to explain the requirements and
provide a valuable training resource

ix
How to use this Guide
PS 9004 has been organized in the following way:
• Part 1 consists of a selection of process schematics, illustrating typical
operations of a packaging supplier, and giving examples of some of the
more significant risks caused by inadequate manufacturing practices
• Part 2 gives guidance on the clauses of PS 9000, by taking the user through
each major section and providing examples to illustrate suggested process
inputs and outputs
• Annex A gives expanded explanatory notes on several key concepts used in
PS 9000
• Annex B gives a listing of other external regulatory references, which are
the background to pharmaceutical GMP and which are directly relevant to
PS 9000 requirements
• the text is primarily black but blue is used for PS 9000 related GMP text
• red text is used to highlight the ‘Risk Areas’

The user can cross refer between the schematics in Part 1 and the process
information in Part 2. In addition, the user can move from Part 2 to the additional
explanations in the annexes.

The annexes contained within this Guide are a stand-alone explanation of key
concepts and external GMP references. The PS 9000 cross-references are for
illustrative purposes and are not a definitive list of clauses or references.

The How to use section, which follows the contents list, shows the user how to
navigate between the different sections of the Guide.

As the range of organizations that may implement PS 9000 is great, both in

terms of size and type of business, the guidance given here is illustrative and
advisory.

Why was the PS 9004 Guide written?

There are three main reasons:
• to guide professional quality specialists towards the implementation and
inspection of a Quality Management System (QMS) in accordance with PS
9000
• to support the training of all the various stakeholders in the PS 9000 process
(top management, quality professionals, staff at all levels of packaging

x
 material suppliers and their customers)
• to provide those people who are not quality specialists with a better
understanding of the aims, objectives and implementation of PS 9000

How was the PS 9004 Guide written?

A group of experienced quality professionals selected from the packaging supply
industry and pharmaceutical customers was recruited by the Pharmaceutical
Quality Group Partners Team and given the task of preparing this Guide.
Many of the people who contributed to the writing of PS 9000 also participated
in the creation of this Guide.

Specific acknowledgements are given for the contributions of the

following people:
Roy Evans PS 9004 Team Leader
David Abraham Supplier
Ian Harwood Pharmaceutical
Jill Jenkins Pharmaceutical
Daniel Peek Supplier
Richard Rowlett Supplier
Mike Shorten Pharmaceutical
Steve Taylor Pharmaceutical

Additional contributions:
Caroline Fowler Pharmaceutical
Peter Gough Pharmaceutical
Ian Holloway Regulator
Steve Merrit Pharmaceutical
Ashley McCraight Consultant
Jeff Monk Training
Dominic Parry Training
Steve Pike Accredited certification
Norman Randall Consultant
Trevor Stabb Consultant
Paul Stockbridge Consultant

QA review:
Tony Harper Consultant and accredited certification
Afshin Hosseiny Consultant

xi
QA review (con’t):
Jean Lanet Consultant
Iain Moore Supplier
Steve Moss Pharmaceutical
Ashok Chand Pharmaceutical
John Turner Consultant

The PQG Partners Team and Steering Committee:

Roy Evans
Tony Harper
Femi Ibironke
Jill Jenkins
Ashley McCraight (PT Chairman)
Steve Moss
Norman Randall (SC Chairman)
Ian Richardson

In addition, the PQG is appreciative of the management of Patheon UK

Limited. for the use of their resources and facilities.

xii
 CONTENTS

Section Page

How to use this guide xv

Part 1 – Process schematics and case studies 1
Overview of business processes 2
Schematic 1 Top level business processes 2
Schematic 2 From the customer 4
Schematic 3 Planning 6
Schematic 3 (a) Warehouse (purchased materials and in-process) 8
Schematic 4 Preparation 10
Schematic 4 (a) Print impression media controls 12
Schematic 5 Production 14
Schematic 6 Checking and final release 16
Schematic 7 Distribution 18
Case studies 21

Part 2 – Guidance on PS 9000 GMP clauses 35

Clause 4 Quality management system 37
Clause 5 Management responsibility 39
Clause 6 Resource management 45
Clause 7 Product realization 49
Clause 8 Measurement, analysis and improvement 59
Clause 9 Contamination control 66
Clause 10 Printed materials 68
Clause 11 Origination/artwork 70
Clause 12 Print impression media 72
Clause 13 Print and conversion processes 74

xiii
Section Page

Annex A – Additional Explanation of Key Concepts 77

Admixture 78
Change control 80
Counterfeit 82
Identification and traceability 84
Line clearance 86
Risk assessment 88
Segregation controls 92
Validation (and Qualification) 94

Annex B – Other external GMP References 99

B1 - US Code of Federal Regulations with
corresponding PS 9000 references 100
B2 - Rules and Guidance for Pharmaceutical Manufacturers and
Distributors 2002 with corresponding PS 9000 references 101
B3 - MHRA Defect Investigation reference table 103

Index 104

xiv
 HOW TO USE THIS GUIDE

STEP 1

Choose a schematic from the ‘Overview of business process’ diagram in Part 1 of

this guide. (e.g. Schematic 3(a) is illustrative)

STEP 2

From your schematic, choose a particular stage of the process to examine, e.g.
Store material (see below).

SCHEMATIC 3 (a) - WAREHOUSE

Delivery Quality Store Issue

checks inspection material material

• Document errors • Labelling errors • Pest • Incorrect

Risk areas • Missing • Incorrect goods Infestation materials
documents
7.4.3 7.4 Case study G 7.5.3
7.5.3 7.4.3 7.5.5:
Preservation
of product
See Part 2
for more 9:
details Contamina-
tion control

STEP 3

Consider the Risk Areas shown in red and the real life case study (if shown) - these
are detailed at the end of Part 1, following the schematics.

xv
STEP 4

Using the references shown in the schematic, move to the corresponding section
in Part 2, entitled ‘Guidance on PS 9000 GMP clauses’. This gives reasons for the
‘extra’ GMPs and shows examples of processes, inputs and outputs.

General synopsis: Clause 9 Contamination control

The capability of facilities and equipment, achieved through their design, location,
etc.

Reasons for the ‘extra’ GMP requirements

The highest priority of the pharmaceutical industry is... etc.
Process inputs Processes Process outputs Cross refer to
and evidence Schematic/Annex

Specification Processes which Records of: Schematic 3(a)

for design of identify/control: • processing
new facilities, • operating areas • cleaning Schematic 4(a)
processes, or • pest control schedules
environment • cleaning proce- • material disposal Schematic 5
dures • incidents/audit
Specialist reports Annex A - all parts
support for
pest control

Standards for
environmental
conditions

STEP 5

Use the cross references to move back to a relevant process schematic, alterna-
tively refer to Annex A or B for further guidance.

ANNEX A

Additional Explanation of Key Concepts

ANNEX B

Other external GMP references.

xvi
 The Institute of Quality Assurance
Pharmaceutical Quality Group

PS 9004

A Guide to the GMP requirements

of PS 9000:2001 Pharmaceutical packaging materials

PART 1 - PROCESS SCHEMATICS

PS 9000 GMP references are reproduced in blue

Risk areas are reproduced in red

1
OVERVIEW OF BUSINESS PROCESSES

Schematic 1: Top level business processes

Schematic 2: Schematic 3: Schematic 4:

From the customer Planning Preparation

Schematic 3 (a): Schematic 4 (a):

Warehouse Print impression
media controls

SCHEMATIC 1: TOP LEVEL BUSINESS PROCESSES

Quality Management Objectives Resource

management commitment allocation
system

• Inadequate • Unclear • Too few people

incorporation business for quality
of PS 9000 targets/goals compliant
requirements • No clear operation
• QMS not direction as • Wrong/
communicated objectives not inadequate
and/or published equipment
supported • Inadequate
by senior premises
Risk areas management • Inadequate
training

4 QMS 5.3 Quality 6.1 Provision of

5.1 Management Policy resources
See Part 2 commitment 5.4 Planning 6.2 Human
for more 5.5 resources
details Responsibility,
authority and
communication

Refer to the hypothetical examples which

are located after the schematics.

2
 Schematic 5: Schematic 6: Schematic 7:
Production Checking and final Distribution
release

This diagram shows the main business processes from customer

requirements through to delivery of final product and provides an index
to the schematics

Feedback/communication

Audit and Management Quality

measurement review management
system

• Inadequate • Quality System

performance measures not
measures reviewed
• Poorly controlled • Lack of senior
processes management
• Unreliable involvement/
information for leadership
management • No continual
decisions process
• Poor compliance to improvement
internally established
processes/
procedures
• Insufficient proof
of continuous
improvement
8.1 Measurement, 5.1 Management
analysis and commitment
improvement - 5.6 Management
general review
8.5 Improvement

3
SCHEMATIC 2: FROM THE CUSTOMER

Feedback

Organization Customer Supply

request/ requirements
requirements (what, how,
when)
Customer
• Requirements design
unclear • Unclearly
• Requirements specified
incorrectly • Failure to meet • Poor design
specified customer • Inadequate detail
• Requirements expectation • Failure to
misunderstood • Rejection by function
• Requirements customer • Poor
Risk areas incorrectly performance at
accepted customers site
• Rejection by
customer
• Potential risk to
patient
• Inadequate
testing/validation
See case study A See case studies
A and B
5.2 Customer 7.2 Customer-related processes
focus 7.3 Design and development
7.2 Customer-
See Part 2
related processes
for more
details

Refer to the case studies

which are located after
the schematics.

4
Assessment Agreed Planning
of capability contract/
agreement
and confirmed
• Incorrect order
assessment
of capability
e.g. resource, • Lack of formal
technology, contract/
systems, agreement
environment • Failure to
• Fail to meet agree contract
delivery/quality requirements
• Poor
communication

6.1 Provision of 7.2.3 Customer-

resources related processes
6.3 Infrastructure
6.4 Work
environment
7.1 Planning
of product
realization

5
SCHEMATIC 3: PLANNING

Receive order Order review and Availability checks

from customer customer feedback on documentation,
(where required) materials, tooling
and equipment

• Incorrect specification
chosen • Incorrect material checked
• Inadequate or issued (e.g. wrong foil
communication with gauge)
customer • Wrong print media
• Order details incorrect (version or item)
• Supply incorrect product • Non-availability of
• Supply error (quantity/ equipment (e.g.
schedule) maintenance/validation
• Proof approval error status)
• Specification not • Unapproved production
Risk areas
approved process (e.g. not
approved by customer)
• Unsuitable/unapproved
material/changes
• Missing/incorrect
documentation (e.g.
missing mould inspection
record)

See case studies

C and D
5.2 Customer focus 7.4 Purchasing
7.2 Customer-related 7.5 Production and service
See Part 2 processes provision
for more 7.3 Design and 11 Origination/artwork
details development 12 Print impression media

Refer to the case studies

which are located after
the schematics.

6
 Feedback

Purchasing and print Production schedule Preparation for

media provision and feedback from start of
production production
• Inadequate supplier
control • Inadequately defined
• Nonconforming plan/schedule (e.g.
purchased materials or insufficient time for
service line clearance or
• Inability to obtain raw maintenance)
material • Inadequate programme
• Inadequate security (e.g. time to follow procedures
printing plates) • Problems in production
• Insecure data links (e.g.
validation of ISDN link)
• Incorrectly identified
materials (e.g.
mislabelling of stock
from supplier)

See case study E

4.2 Documentation 7.1 Planning of product

requirements realization
7.4 Purchasing 7.5 Production and service
8.3 Control of provision
nonconforming product 8 Measurement, analysis
11 Origination/artwork and improvement
12 Print impression media

7
SCHEMATIC 3 (a): WAREHOUSE (purchased materials and in-process)

Delivery from Delivery Goods checks and

supplier/sub- documentation and quality inspection
contractor off-loading checks

• Inadequate checks
• Errors not identified performed
between delivery • Labelling errors not
documentation & identified
purchase order • Incorrect goods sent
• Missing delivery/QC • Rogue box within delivery
documentation • Inadequate batch coding
• Transit damage or wet • Non representative sample
boxes not identified taken or provided
Risk areas before off-loading • Transit/water damage not
• Incorrect goods detected
• Inadequate packaging/
sealing not detected
• Incorrect quality status
input to system
See case study F

7.4.3 Verification of 7.4 Purchasing

See Part 2 purchased product 7.4.3 Verification of
for more 7.5.3 Identification and purchased product
details traceability

Refer to the case studies

which are located after
the schematics.

8
 Return of unused material or semi-finished product

Store material Issue material To production

• Water damage • Incorrect materials

• Pest infestation dispensed eg. wrong
• Dirt contamination batch, version
• Mix-up due to • Incorrect quantity issued
inadequate segregation • Mixed batch issued but
• Goods stored incorrectly not identified
(e.g. on the floor,
temperature, humidity)
• Incorrect quantity/
location recorded

See case study G

7.5.5 Preservation of 7.5.3 Identification and

product traceability
9 Contamination control

9
SCHEMATIC 4: PREPARATION

Production Preparation/ Materials

plan pre-production management
checks of
purchased raw Preparation/
materials pre-production Errors in:
checks of • Co-ordination
tooling and of all required
• Error in checking equipment resources
raw material • Combining/
• Quality status assembly/ Bills
incorrect • Error in checking of Material
• Availability status tooling/equipment • Timing/change
incorrect • Change control management
error • Machine
• Validation status allocation
Risk areas
error
• Maintenance
omission/ error
• Availability status
incorrect

See case study H

7.4 Purchasing 7.1 Planning

7.5 Production and service provision of product
See Part 2 realization
10 Printed materials
for more 7.2 Customer
11 Origination/artwork
details related
12 Print impression media
13 Print and conversion process processes

Refer to the case studies

which are located after
the schematics.

10
Issue of tooling Issue of Production
materials
and
documentation
• Issue incorrect tool
• Issued with incorrect
status • Issue incorrect
• Issue in poor materials
condition • Incorrect quantity
• Issue printing plates issued
in insecure manner • Issued with incorrect
status
• Issue incorrect
documentation
• Unapproved
documentation

See case studies

I, J and K
7.5 Production and 4.2 Documentation
service provision requirements
12 Print impression 7.5 Production and
media service provision
11 Origination/artwork
12 Print impression
media

11
SCHEMATIC 4 (a): PRINT IMPRESSION MEDIA CONTROLS

Customer New print Secure

supplied media design storage and
design text Controls controlled
over partial issue of
• Errors in media re-designs plates
undetected by and obsolete
checks designs
• Individual plate • Mix-up with
incorrectly coded plates from
• Set of plates • Incorrect plates another product
incorrectly coded retained • Uncontrolled
• Failure to secure • Insecure disposal access of
customer proof • Superseded plates personnel
approval not rendered • Physical
• Failure to log unusable damage to
customer • Incorrect plate plates
Risk areas
approval identification • Inadequate
• Error in records of issue
replacement plate/ introducing
matching set admixture risk
• Documentation in production
errors
• Customer
approval error

See case study L See case study M

11 Origination/ 12.2 Matched plates

artwork 12.3 Copy / design change
12.1 General 12.5 Quarantine and destruction
12.2 Matched 13.2 Changeover systems
See Part 2 plates
for more
details

Refer to the case studies

which are located after
the schematics.

12
Line use of Line clearance Production
plates and controlled
return of
Controls over plates to store
Failure to : replacement
• Check design plate (same
• Clear line of • Plate left on
design)
previous plates machine in error
• Perform start-up • Inadequate
printing checks • A new first off records of return
• Record checks check is not to store
• Keep samples performed or
recorded (e.g.
plate made
from existing
approved
source)
• New origination
& new batch
checks not
performed or
recorded (e.g.
plate created
from a new
See case source)
study N

9.1.7 Line 13.4 Replacement 9.1.7 Line

clearance print media clearance
12.4 Verification 12.1 General
13.1 Print
machine set-up
(make-ready)
13.2 Changeover
systems
13.3 Retained
samples

13
SCHEMATIC 5: PRODUCTION

Preparation Line clear Documents/ Set up

check materials/ checks and
tooling to line production
start
• Admixture from
previous batch • Use of incorrect
• Erroneous use documents/ • Errors in
of previous materials data input to
documents • Failure to use machine, e.g.
• Use of a plate documents settings
from previous correctly • Setting error
job • Incorrect undetected
quantities • Start up waste
Risk areas • Defective moulds/ inadequately
equipment/plates segregated
from main
batch
• Unauthorized
start up

See case study O

7.5 Production 4.2 Documentation 5.5 Respon-

and service requirements sibility,
provision 7.5 Production and authority and
9.1.7 Line service provision communication
clearance 7.6 Control of
10 Printed monitoring
See Part 2 materials and measuring
for more 11 Origination/ devices
details artwork 9 Contamination
controls
10 Printed
materials
12 Print
impression
media

Refer to the case studies

which are located after
the schematics.

14
 Feedback

Production/in Production completion Checking and

process control and line clearance final release

• Quality variation due Risk to next job due to:

to environment e.g. • lack of GMP training
temperature, humidity • failure to clear line
• Contamination e.g. • inadequate waste disposal
insects, dust • documentation not signed
• Defective / out of spec off therefore status unclear
or wrong materials • clearance of electronic
• Visual defects not files/settings
detected
• Inadequate IPC of transit
packaging
• Labelling errors
• IPC errors
• Material usage error
• Failure to identify/
segregate non
conforming product
• Recording error
See case study R
See case studies P, Q
6.2.2 Competence,
6.4 Work environment awareness and training
7.5 Production and 8.2 Monitoring and
service provision measurement
8.2 Monitoring and 9 Contamination controls
measurement 10 Printed materials
8.3 Control of 13 Print and conversion
nonconforming product processes
11 Origination/artwork

15
SCHEMATIC 6: CHECKING AND FINAL RELEASE

Production End product Review of batch

QC testing documents and QC
testing

• Inadequate training
• Test method not • Missing/incorrect
validated document
• Out of Specification • Missing/incorrect sample
results not investigated • Signature omissions,
• Inadequate procedures unauthorized check
• Release decision signature
contradicts data • Errors of information/data
• Inconsistent sampling/ entry
Risk areas risk • Checks out of sequence
• Equipment/test • Abnormal events not
equipment inadequate reviewed
• Calibration errors/
omissions

See case study S See case study T

6.2.2 Competence, 5.5 Responsibility, authority

awareness and training and communication
See Part 2 7.6 Control of monitoring 6.2 Human resources
for more and measuring devices 4.2 Documentation
details 8 Measurement, analysis requirements
and improvement 13 Print and conversion
8.4 Analysis of data process

Refer to the case studies

which are located after
the schematics.

16
Create certificate of Check box labels Distribution
test or conformance against batch
information

• Errors / omissions • Incorrect/missing label

• Signature invalid • Label data error/
• Inappropriate data omission
supplied • Label reconciliation
• Incorrect specifications/ • Incorrect QC status label
tolerances
• Incorrect release decision
• Certificate text differs
from batch details

See case study U See case studies V and W

8.2 Monitoring and 7.5 Production and service

measurement provision
8.3 Control of
nonconforming product

17
SCHEMATIC 7 - DISTRIBUTION

Checking and Receipt of product Order preparation

final release into storage/holding (picking and transit
(goods out packaging)
warehouse)

• Picking wrong product

• Error in system • Damage to product due
transaction (receipt) to inappropriate transit
• Inadequate segregation packaging
from other goods • Pallets not suitable for
Risk areas • Storage damage customer handling
• Error in transaction (issue)

See case study X

See Part 2 7.5 Production and service 7.5 Production and service
for more provision provision
details 10 Printed materials

Refer to the case studies

which are located after
the schematics.

18
Dispatch area/ Transport to the The customer
goods check and customer
documentation

• Transit damage e.g. poor

• Errors of quantity pallet stacking, poor
• Incorrect labelling weather protection
• Error in dispatch note • Contamination in transit
• Admixture of boxes • Inadequate control of
hauliers

See case study Y See case study Z

7.5 Production and service provision

19
20
 The Institute of Quality Assurance
Pharmaceutical Quality Group

PS 9004

A Guide to the GMP requirements

of PS 9000:2001 Pharmaceutical packaging materials

PART 1 - CASE STUDIES

21
22
 Part 1 – Examples and Case studies

These examples and ‘real life’ case studies should be used with the
relevant Schematic, to illustrate specific GMP risk areas and the
appropriate QMS processes involved.

HYPOTHETICAL EXAMPLE FOR SCHEMATIC 1 –

TOP LEVEL BUSINESS PROCESSES

The senior management of a booklet printing company believes that PS

9000 certification will aid company profitability and smooth throughput
because of consistent demand from the pharmaceutical industry, which
is not adversely affected by recessions. The company has an enthusiastic
Quality Manager who has produced a comprehensive manual with up to
date and relevant procedures. However, the Quality Manager is beginning
to feel like a ‘voice in the wilderness’ as there is little evidence that senior
management is driving the whole organization to become aligned to the
requirements of the standard. The lack of senior management commitment
to the continual improvement philosophy and the Good Manufacturing
Practices of the pharmaceutical industry means that only superficial actions
are taken in areas considered highly visible to visiting auditors. Key individu-
als are unclear about the standards required of them. The level of customer
complaints remains high, some of these complaints being serious mix-ups.
Productivity stays unchanged with a high level of wastage. Workforce moral
is low and many staff are demotivated.

The company is then purchased by another company that already supplies

cartons to the pharmaceutical industry - allowing them to offer a better
product range to the customer. The corporate re-organization results in key
changes in senior management at the booklet factory. The new managers
know their prime objective is to encourage each and every employee to
understand the particular needs of their pharmaceutical customers. They
understand the value of PS 9000 in a competitive market, but know that the
real benefits are much deeper than merely achieving the ‘badge’. The Qual-
ity Manager begins to feel encouraged and genuinely part of the team. The
frequency of management review meetings is increased with the emphasis
changed to progressing preventive actions for nonconformities and review-

23
 ing clear measures of performance for key parameters such as complaint
rates. The senior management commitment begins to permeate throughout
the staff and becomes evident in many areas such as resourcing, training,
customer service, and improved product quality. The board of directors
soon recognises that the PS 9000 implementation process is enabling them
to profitably expand their business, improve relationships with their custom-
ers, whilst still significantly reducing their cost of quality.

CASE STUDIES FOR SCHEMATIC 2 – FROM THE CUSTOMER

A Focus - Customer request/requirements

Bar coded product labels could not be read by customer’s electronic read-
ers due to shading of background colour, caused by inadequate testing
and validation. The packing orders at the pharmaceutical company were
delayed which threatened the availability of the medicinal products to the
end customers. The labels had to be destroyed, incurring the direct expense
of replacement. The product was redesigned with solid background, and all
graphics designers were made aware of the issue and to consider the pos-
sible need for trials on change of design or introduction of a new design.

B Focus – Customer design

A market need for a needle protection mechanism was specified, but
translation of this into a final design was lengthy and complicated. The
component did not perform reliably due to limited experimental validation.
The problems were addressed through increased communication with the
supplier to make the design more robust, involving revalidation and testing.
This extended work caused a delay in providing the improved safety prod-
uct to the patient. An organizational review followed to ensure that in future,
adequate resource is devoted at the design and testing stages of product
development.

CASE STUDIES FOR SCHEMATIC 3 – PLANNING

C Focus – Order review and customer feedback

The wrong material was ordered by the supplier’s UK sales office from their
own factory. Normally, orders were placed for 40 micron PVDC coated PVC

24
 (for tablet blister packing), but on this occasion a new order for 60 micron
coated film was incorrectly notified by the sales office to the factory in Ger-
many as 40 micron; the incorrect material was delivered and used causing
a regulatory noncompliance and potentially inadequately protecting the
tablets from moisture. Significant work was necessary by the pharmaceuti-
cal company to assess stability data to determine the acceptability of the
packed tablet batches. The root cause was established through customer
audit of the ordering system at the sales office. An independent check of
order details was implemented to prevent repetition.

D Focus – Order review and customer feedback

The printer’s proof was incorrectly read by the supplier as ‘approved’ when
it was actually ‘rejected’; also the wrong file was used to make replace-
ment printing plates. Cartons for a heart condition medicinal product were
printed and used showing on one end flap 14 tablets instead of 28. The
consequence of this was that stock had to be recalled from the distribu-
tion centres to enable a rework. This delayed the critical medicinal product
reaching the market. Working together, customer and organization, the
complete sequence of events was reconstructed. In addition to awareness
training, the rules regarding issuing artworks and file management between
organization and platemaker were made more robust.

E Focus – Purchasing and print media provision

Leaflets with a different paper weight were supplied, due to problems with
availability of normal paper. This caused insertion difficulties on the phar-
maceutical packing line, high wastage of components and loss of some
pharmaceutical product. The supplier was advised of the existing change
control clause in the quality agreement/contract and procedures were
revised. The supplier managed to obtain further supplies of normal paper.

CASE STUDIES FOR SCHEMATIC 3 (a) –

WAREHOUSE (PURCHASED MATERIALS & IN-PROCESS)

F Focus – Goods checks and quality inspection

Self-adhesive labels were failing to stick to glass vials at the customer’s
premises because a different adhesive had been used. This had been
caused by the supplier switching their source of unprinted label material.

25
 The raw material was thought to be of equivalent quality and no extra qual-
ity checks were performed at goods-inwards. The change was introduced
without informing the customer therefore no formal change control or a
risk assessment could be performed. The problem caused chaos on the
customer’s packing line and it was not certain how well the labels were
affixed to ‘apparently’ satisfactory packed vials. The label printing company
pursued the quality issue with its supplier and proper trials of alternatives
were subsequently conducted with the pharmaceutical company. In addi-
tion, revisions were made to the change control system.

G Focus – Store material

Two dead mice were found inside the pallet wrapping of a consignment of
plastic bottles to be used for an antiseptic liquid product. This caused major
disruption to the output of the pharmaceutical filling plant. All the stock of
bottles had to be manually inspected for contamination. It was necessary to
audit the supplier and its remote warehouse. Immediate action involved the
relocation of bottle storage back into the main factory. The root cause was
inadequate warehouse pest controls at the supplier’s remote warehouse. It
prompted an extensive programme of work to improve the standards at the
site. The product was a low margin item for the pharmaceutical company
and it has since been sold off to another company. Although many other
factors were involved, this episode only added to the reasons to sell this
part of the business.

CASE STUDIES FOR SCHEMATIC 4 – PREPARATION

H Focus – Preparation/pre-production checks of tooling and

equipment
Mould tool used to produce parts for a syringe was used in production
when the validation documentation had not been fully approved and signed
off. This contributed to high variability in functional performance of the
assembled syringe with some batches of parts rejected, and it necessitated
ongoing improvement work. It also delayed the launch of the pharmaceuti-
cal product which in this case was a life saving cancer product. The opera-
tional procedures were revised and the operators were retrained.

26
 I Focus – Issue of tooling
Syringe labels were printed correctly, but were cut with corners of the wrong
profile/shape due to the issue of an incorrect cutter to the press. The labels
were rejected by the pharmaceutical company at the expense of the print-
ers. The time needed to replace the labels meant rescheduling of packing
was necessary at the pharmaceutical company. The cutter identification
process was reviewed & storage standards were improved.

J Focus – Issue of tooling

Cartons were produced with a varnish free area in the wrong position due
to the issue of an incorrect varnish plate. The purpose of a varnish free area
is to ensure the printing of variable data (e.g. lot & expiry) is clear and per-
manent. This error was identified at the pharmaceutical company. The risk
existed that variable data applied by the pharmaceutical company could
be easily smudged or erased when in the market and this would clearly be
a critical problem. The supplier reviewed the varnish plate issuing process
and made improvements to the system which linked varnish plate usage to
print plate usage.

K Focus – Issue of tooling

Mould tool for a syringe plunger rod was issued to production despite
being overdue for refurbishment. This resulted in minor plastic ‘flash’ being
present on the mouldings. If this problem became more serious then loose
particles of plastic could break off and contaminate the pharmaceutical
syringe pack. The supplier applied for a concession from the customer and
this was granted for a limited period because of the extent of the problem.
The case highlighted the need for proper planned preventive maintenance
and sufficient resources allocated to facilitate it.

CASE STUDIES FOR SCHEMATIC 4 (a) –

PRINT IMPRESSION MEDIA CONTROLS

L Focus – New print media design

Artwork supplier made a “cut & paste” error which resulted in cards being
part printed with Polish text in the main body of Portuguese text. The cards
were for an anti-cancer injection. Fortunately the error was noticed dur-
ing in-process checks of printing. The error had the potential to become

27
 a product recall if it had reached the end user. An extensive review of the
artwork supplier’s procedures was completed and a further proof-reading
check was introduced.

M Focus – Controls over partial redesigns & obsolete designs

The printed foil for tablet blister strips (used to treat a heart condition) was
incorrectly printed with two different identifying codes on the foil (different
by one digit). The error occurred during the ‘step and repeat’ process to
generate a single replacement cylinder. The error was only found on inspec-
tion at the pharmaceutical company. In this case, no packed stock was lost,
but the error could have been more serious. The supplier took the issue up
with its cylinder manufacturer and reviewed its inspection procedure for first
off sample inspection following cylinder replacement.

N Focus – Line use of plates

A printing plate was left on the leaflet press by the operator after leaving the
area to retrieve a spare part. Upon return the operator continued printing,
but against the job documentation for the next job. The item was visually
very similar and all subsequent checks by operators and QC failed to spot
the admixture that had been created. The problem was found on goods
inwards checks by the customer, and resulted in a detailed audit of proce-
dures by the customer. Line clearance checks were reviewed, procedures
around bar code scanning at the suppliers were enhanced and refresher
training was delivered.

CASE STUDIES FOR SCHEMATIC 5 – PRODUCTION

O Focus – Documents/materials/tooling to line

During the folding stage of leaflet production two orders were mixed up. Job
A was folded, scanned, labelled and released against Job B documenta-
tion, and Job B documentation was folded, scanned, labelled and released
against Job A documentation. The mixed-up orders were then delivered to
the pharmaceutical company where the error was discovered. The potential
for incorrect leaflets to be packed into pharmaceutical packs was increased.
The supplier’s investigation identified the root cause as human failure to fol-
low established procedures. In addition the codes for the bar code scanner
are now input from an independent source (a PS 9000:2001 requirement).

28
 P Focus – Production/in-process control
A delivery of poorly printed foil, used for tablet blister strips, was caused
by inadequate ‘flagging’ of defective material during printing. The ‘flagged’
material is removed during later stages of slitting and rewinding. The defec-
tive material was detected on the customer’s packing line and lead to the
scrapping of some packed pharmaceutical product. The supplier’s printers
and the operators responsible for removal of the ‘flagged’ material were
given refresher training to ensure all defective material is removed, up to
and around the ‘flagged’ point in the reel.

Q Focus – Production/in-process control

Plastic tablet bottles were manufactured with a wall thickness that was
below specification. This was caused by poor appreciation of the cus-
tomer’s requirements, inadequate in-process monitoring and an inability to
segregate product that was out of specification. Packed pharmaceutical
product had to be quarantined until all aspects of the problem had been
assessed by the pharmaceutical company’s QA Department. The issue was
resolved through improved specification regarding the criticality of certain
dimensions, increased in-process measuring regime and enhanced segre-
gation procedures.

R Focus – Production completion & line clearance

On a reel of label/leaflet combinations, six ‘rogue’ components (of similar
appearance) were found at intermittent points in the reel, by the pharmaceu-
tical customer. This was despite a scanning operation being in place at the
supplier. The root cause was human error involving inadequate line clear-
ance and replacing incorrect labels back onto the web during rewinding/
scanning. Although the rule existed which forbade this practice, the
operator had recently been transferred from a department supplying non-
pharmaceutical customers where this rule was not in place. The supplier
commenced a fundamental review of procedures and operator retraining.

CASE STUDIES FOR SCHEMATIC 6 – CHECKING & FINAL RELEASE

S Focus – End product QC testing

An out of specification result on a test machine record was transcribed
incorrectly as satisfactory on the summary sheet, causing an incorrect

29
 release decision of a batch of syringes. Although, in this case no harm was
caused, it highlighted a risk area, should the error have occurred on another
safety related function of the syringe. Refresher training was delivered to the
operator concerned.

T Focus – Review of Batch documents & QC testing

Carton barcode scanner was switched off during the night shift without
QA authorization and not noticed upon review of documentation. This
meant that the product had been made without the safeguards required
by, and contractually agreed with the customer. The product was therefore
inadequately checked for the absence of rogue components. The affected
order was rejected and scrapped. A detailed audit was performed by the
pharmaceutical company and numerous significant procedural enhance-
ments were made.

U Focus – Create Certificate of Test or Conformance

Irradiated syringes were released for use despite radiation dose figures
being omitted from the certificate of test. In this case the dosage was
actually satisfactory, however the omission / error had the potential to
threaten the sterility of the syringes thus endangering the patient, and to
compromise the pharmaceutical sterile filling facility. The certificates are
now double checked before release from the irradiation contractor.

V Focus – Check box labels against batch information

A box of shampoo closures was delivered amongst a consignment of tablet
bottle closures, caused by box labelling error & poor segregation practices.
This resulted in admixture on the filling line at the pharmaceutical company,
line downtime, and some lost product. The supplier had been audited on
numerous occasions but lack of commitment to eliminate such problems
ultimately lead to a change of supplier for the component.

W Focus – Check box labels against batch information

A keying-in error of leaflet product identity code to outer box label printer
caused rejection upon delivery to customer. Apart from the disruption
caused by the rejection, there was a risk that the material could have been
received into stock as a different item, i.e. admixture. The preventive action
eventually implemented was to link the box label printer to the mainframe

30
 computer thus removing the necessity to manually key the data into a
standalone label printer.

CASE STUDIES FOR SCHEMATIC 7 – DISTRIBUTION

X Focus – Order preparation (picking & transit packaging)

An admixture of boxes of labels was found on receipt by the customer
caused by a picking error made due to poor warehouse lighting and lack
of a double check. In another incident an admixture of batch of cartons
occurred, caused by a picking error due to poor batch segregation in
the warehouse. Both batch defectives were found during the customer’s
receipt checking, but they caused disruption to the product scheduling
programmes because of the need to return the material to the supplier for
sorting/replacement. The corrective and preventive actions, in both cases,
involved a fundamental review of the conditions (and checks made) in the
warehouse and implementation of improved lighting and segregation mea-
sures.

Y Focus – Despatch area/goods check & documentation

Despatch note details accompanying the delivery differed from physical
quantity delivered. This resulted in delays in product release and schedul-
ing disruption while the supplier was contacted. The supplier’s despatch
checking procedures were reviewed, no fundamental weaknesses were
found. In this case, a one-off error had occurred and the issue was dis-
cussed with the individual concerned.

Z Focus – Transport to the customer

Goods were damaged in transit due to movement of the load and inade-
quate control while the vehicle was being loaded. In another incident, goods
were damaged by water penetration due to a poorly closed and maintained
“curtain” of a flexible sided vehicle. Both examples resulted in the need for
product inspection at the customer, and the return of damaged material to
the supplier leaving too few components to meet requirements. In the first
case, the checks made on loading were increased and in the second exam-
ple the company decided it was feasible to switch to hard sided vehicles to
eliminate the risk of water penetration.

31
Using the Case Studies - Guidance for Trainers

Introduction

The case studies that have been described here can be used as valuable aides to
training programmes, for use either by a supplier or a pharmaceutical company. It
is recommended that you select one or more of the case studies that are appro-
priate to your business and design an activity that will encourage your trainees to
discuss the particular subject you would like them to understand. An example of a
training exercise protocol is provided below based on a case study selected from
Schematic No. 3. Developing a short set of questions similar to those illustrated
below should help improve understanding. It will probably be beneficial if such Q &
A sets were developed jointly after discussion between pharmaceutical customers
and their suppliers.

It will certainly be helpful to provide explanations and visual aides relevant to the
case study. For example in the example illustrated below it would be helpful if:
i) For a laminate that you use or manufacture explain which illness(es) the tablets,
that are packed within it, are used to treat.
ii) A copy of an analogous page of a Product Authorisation (Licence) was shown
and the legal basis of such licences explained.
iii) The function of PVDC in the laminate was explained.

Training Exercise

Case study No. C

Title: Mix-up in the weight of PVDC on a PVC based blister film
In this case study, the wrong material was ordered from the factory.
Nomally, orders were placed for 40 micron PVDC coated PVC (for tablet
blister packing) - and etc.

Training objectives
Discuss the case study in groups and decide your answers to the following ques-
tions:
Q 1. Which requirement(s) of PS 9000 do you consider had not been effectively
implemented?

State the clause numbers and your reasons.

32
Q 2. Why do you think that the thickness of the PVDC could affect the stability of
the tablets that were to be packed in the laminate?

Q 3. If this mistake had not been detected what do you think the implications
might have been to:
i) The manufacturer of the laminate film?
ii) The pharmaceutical customer?

33
34
 The Institute of Quality Assurance
Pharmaceutical Quality Group

PS 9004

A Guide to the GMP requirements

of PS 9000:2001 Pharmaceutical packaging materials

PART 2 - GUIDANCE ON PS 9000 GMP CLAUSES

PS 9000 GMP related text is reproduced in blue

35
36
 General synopsis - Clause 4 Quality management system

A QMS provides a basis for continuous improvement of the organization’s effectiveness and efficiency, whilst still considering
the various needs of all stakeholders (e.g. customers, suppliers, investors, employees).

Clause 4.1 General requirements

Detailed consideration is required of the needs of stakeholders, the processes to meet those needs and to measure performance.

There are no ‘extra’ PS 9000 GMPs within this clause. There are important GMP principles in this area, but they are adequately
expressed in ISO 9001 and ISO 9004.

Process inputs Processes Process outputs and Cross refer to

evidence Schematic/Annex

• Identified processes Processes which: • Written procedures Schematic 1

that meet organization • define, implement and maintain QMS essential to
strategic objectives processes (including management and Quality System
• Customer requirements operational activities) • Organization structure
• Regulatory • determine personnel required to carry out that supports QMS
requirements processes and training needs • Adequate premises
• provide premises and equipment for the and equipment
processes • Data from processes
• define and implement controls to measure and measurement
performance of QMS processes including systems
outsourcing

37
38
Clause 4.2 Documentation requirements
Documentation is a fundamental part of the QMS that defines what the organization does, provides traceability and evidence of its
activities.

Reasons for the ‘extra’ GMP requirements (refer to PS 9000 clauses 4.2.2; 4.2.3; 4.2.4)

Pharmaceutical companies have, on occasions, experienced problems in the retrieval of accurate historical data from suppliers and
these have been attributed to inadequate data system validation and data controls. The process references above are part of a system
of data traceability that can provide a complete history of the component’s manufacture. This can be vitally important if there is a
problem in the use of the pharmaceutical product in the marketplace.

The pharmaceutical company has a regulatory obligation to retain production and packing data for one year beyond the shelf-life of
the product. There is therefore a corresponding responsibility (see Annex B) upon the component supplier to establish and maintain
accurate and secure data control and retention systems.

Process inputs Processes Process outputs and Cross refer to

evidence Schematic/Annex

• Documents that need Processes which: • Quality manual Schematic 3

to be controlled • control the document and data management • Procedures that
• Standards and for any media type to cover life-cycle support the document Schematic 4
regulatory requirements • ensure the security of electronic documents is and data management
• Customer requirements equal to that of paper documents system Schematic 5
(specified and • provide audit trail for electronic documents and • Clear accountabilities
unspecified) data and responsibilities Schematic 6
• Responsibilities for • control backup and recovery of data
documents (e.g. • control validation of hardware/software used Records of: Annex B
authors, approvers, for document and data management • documentation
etc.) • control archiving/retention of documents and changes
• Process maps data • training
• define the extent to which PS 9000 applies • validation
within the QMS
 General Synopsis - Clause 5 Management responsibility

Management’s responsibility to ensure an effective QMS which recognises the needs of the organization, customers and
other key stakeholders.

Clause 5.1 Management commitment

Top management defines the organization’s strategy and is responsible for demonstrating commitment to the QMS. Continual
improvement of the system and its processes are necessary to ensure customer and regulatory needs are fully satisfied.

There are no ‘extra’ PS 9000 GMP’s within this clause. There are important GMP principles in this area, but they are adequately
expressed in ISO 9001 and ISO 9004.

Process inputs Processes Process outputs and Cross refer to

evidence Schematic/Annex

• Company strategy/ Processes which: • Evidence of staff Schematic 1

purpose • establish quality policy understanding and
• Adequate resources to • establish quality objectives commitment
meet requirements • require a Management Review as a means of • Customer satisfaction
continual improvement measures
• ensures the communication with staff to help
them understand and contribute to QMS Clearly documented:
implementation (e.g. continuous improvement • quality policy
objectives, customer satisfaction targets, etc.) • quality objectives
• improvement plans

39
40
Clause 5.2 Customer focus
A key requirement to provide suitable premises, people, and processes, in order to enhance customer satisfaction.

Reasons for the ‘extra’ GMP requirements

Pharmaceutical Industry experience shows that from the product development stage onwards, compliant pharmaceutical quality
requires facilities and staff to be ‘fit for purpose’, i.e. ‘suitable facilities and competent staff’, and that this GMP requirement is equally
applicable to the supplier of pharmaceutical packaging components.

Product security and the avoidance of cross contamination underpins all pharmaceutical quality, since these are basic issues that can
lead to people taking the wrong medicine, damaging the pharmaceutical company’s business, and public confidence in it. (See also
Annex A, ‘Counterfeit’ that covers in detail the needs for controls in areas involving disposal of artwork, process defectives and waste
materials, etc.).

Beginning with its regulatory inspectors, the whole pharmaceutical industry is compliance driven, using audits as a measure that
GMP practices, as part of a quality system, are in place. Central to this audit focus, is the ‘Rules and Guidance for Pharmaceutical
Manufacturers and Distributors’. Chapter 9, Internal audits, requires self inspection by the pharmaceutical manufacturer and Annex 8.5,
requires that sampling plans for the assessment of packaging material deliveries should, through audits, take into account knowledge
of the supplier’s quality assurance system.

Process inputs Processes Process outputs and evidence Cross refer to

Schematic/Annex

• Customer input/ Processes which: • Suitable facilities Schematic 2

requirements • consider customer requirements • Evidence of GMP training and
in order to deliver a securely task competency Schematic 3
manufactured product to specification • Improvement plans from
• permit customer audits customer audits Annex A
• ensure secure disposal of all print • Physical control and records
related material of secure disposal of Annex B
specified materials
 Clause 5.3 Quality policy
The quality policy is a top-level document, key to communicating and leading continuous improvement to satisfy the needs of the
organization, customers and other stakeholders.

Reasons for the ‘extra’ GMP requirements

All ISO 9001 certificated companies are required to have a ‘quality policy’. The avoidance of contamination and maintaining a
controlled environment in order to ensure product security and integrity is of such importance to the pharmaceutical industry that these
two requirements have to be included in the supplier’s quality policy.

While PS 9000:2001 is primarily for suppliers of pharmaceutical packaging materials, some organizations supply different industry
sectors (e.g. food, agrochemical, cosmetics). Therefore, for the purposes of clarity, the extent to which this application standard is
employed within the organization needs to be documented.

Process inputs Processes Process outputs and Cross refer to

evidence Schematic/Annex

• Organization strategy/ Processes which: • Up-to-date quality Schematic 1

purpose • define quality policy policy
• Customer needs • review policy to ensure it meets user needs
including product • review quality objectives Records of:
security requirements • communicate quality policy, including • awareness/
and prevention of contamination control, to internal staff and communication
cross-contamination external people, as appropriate activities
• Extent to which PS • product security and
9000 is used within the environment controls
organization • implementation

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42
Clause 5.4 Planning
Strategic business planning is essential to ensure that the organization moves forwards in a way that satisfies the needs of all
stakeholders. This section covers the formal planning processes needed to realise organizational strategy through generation of
objectives within the quality management system.

There are no ‘extra’ PS 9000 GMPs within this clause. There are important GMP principles in this area, but they are adequately
expressed in ISO 9001 and ISO 9004.

Process inputs Processes Process outputs and Cross refer to

evidence Schematic/Annex

• Short and long term Processes which: • Performance Schematic 1

organization strategy/ • plan the implementation, and continual measurement data
goals improvement of the QMS
• Regulatory • provide a framework for the setting of Defined and documented:
requirements measurable quality objectives, which support • skills and knowledge
• Needs of the the quality policy and strategic goals • responsibilities
organization and and authority for
markets implementation of
• Management review improvement plans
findings
• Current product and Quality objectives:
process performance • at organizational
• Resource information levels (e.g. managers,
• Results from self- supervisors,
assessments and other operatives)
audits • for functional areas
• Industry information/ (e.g. production,
benchmarking administration)
 Clause 5.5 Responsibility, authority and communication
All staff should know what their responsibilities are and to whom they are responsible. Authority needs to be pre-defined, documented
and well communicated to ensure activities take place in a controlled manner.

Reasons for the ‘extra’ GMP requirements (refer to PS 9000 clause 5.5.3 Internal communication)

Staff in all organizations work better when they are kept informed, are appropriately trained and have relevant agreed procedures.
A communication process needs to be in place to ensure that staff are customer focussed, motivated and where applicable, are aware
of the regulatory, legal, and GMP needs of the pharmaceutical industry that may affect them.

Process inputs Processes Process outputs and Cross refer to

evidence Schematic/Annex

• Existing roles and Processes which: • Evidence of Schematic 1

responsibility data • clarify responsibilities and authorities for job communication
• Resource information elements relating to quality (e.g. state who is Schematic 5
• Personnel data allowed to release products for despatch) Responsibilities and
(qualifications, • appoint a management representative to authorities which are: Schematic 6
experience, etc.) oversee the QMS (e.g. the QA Manager) • defined and
• Industry information/ • establish internal communication (e.g. monthly documented
benchmarking team briefings, etc.) • clearly communicated
throughout the
Processes to communicate: organization
• responsibilities and authorities for quality (e.g.
post organization charts, give people their key
responsibilities to read and approve)
• quality throughout the organization – all staff
should be included, from the most senior
manager to the most junior support personnel
• the GMP and regulatory requirements to all
appropriate staff

43
44
Clause 5.6 Management review
Senior management must periodically review the QMS to ensure it remains effective and to assess improvement opportunities.
This should be done in the context of improving the performance of the whole organization.

There are no ‘extra’ PS 9000 GMPs within this clause. There are important GMP principles in this area, but they are adequately
expressed in ISO 9001 and ISO 9004.

Process inputs Processes Process outputs and Cross refer to

evidence Schematic/Annex

• Quality policy and Processes which: • Reviewed quality Schematic 1

objectives • review and evaluate the performance of the policy and objectives
• Quality audit results QMS • Information
• Product quality • assess whether the QMS requires improvement for strategic/
information and • evaluate beyond the QMS itself, to that of the organizational
conformity data whole organization – its activities, performance decision-making
• Opportunities to and efficiency
improve Actions to:
• Feedback from • communicate findings
customers of review
• Process performance • improve the QMS
information • improve processes
• Corrective and • improve products
preventive actions • address resource
• Changes that might needs
affect the QMS
• Previous QMS reviews
 General Synopsis - Clause 6 Resource management

The provision of all resources, including people, infrastructure, work environment and information, needed for operation and
improvement of the quality system to assure compliance with the requirements of customers.

Clause 6.1 Provision of resources

It is important to have processes, which determine and provide the resources needed by the organization.

Reasons for the ‘extra’ GMP requirements

Gaining certification to PS 9000 requires a full and thorough determination of resource requirements. This will enable the
implementation of a QMS that satisfies the expectations of the pharmaceutical customer, with the benefits of continuous improvement
and customer audit successes.

Process inputs Processes Process outputs and evidence Cross refer to

Schematic/Annex

• QMS process Processes which: • Defined organization Schematic 1

requirements • identify and appoint sufficient personnel structure and personnel and
• Process information, • provide resources needed to improve responsibilities Schematic 2
data and requirements customer satisfaction • Adequate personnel to
(people, premises, • provide enough resources to fulfil the enable improvement
equipment, etc.) requirements of PS 9000 programmes and focus on
• Current organization customer requirements
people, premises, • Quantified assessment of
equipment resource needs
• PS 9000 specific • Authorisation to procure
additional requirements resource

45
46
Clause 6.2 Human resources
Determine, provide and develop people to support the organization’s quality policy and objectives

Reasons for the ‘extra’ GMP requirements (refer to PS 9000 clause 6.2.2 Competence, awareness and training)

GMP is fundamental to effective control of product quality and requires that GMP training be provided on an ongoing basis.
Pharmaceutical customers look for evidence of this at their suppliers.

Cross contamination in packaging can lead to the patient being given the wrong medication with fatal consequences. When items
are not manufactured using controlled systems the chance of a mix-up or print error is significantly greater, and the risk cannot be
accepted by the pharmaceutical industry.

Process inputs Processes Process outputs and Cross refer to

evidence Schematic/Annex

• Identified business Processes which: • Defined and Schematic 1

processes • identify training and awareness needs (gap documented GMP
• Available people to analysis) training schedule Schematic 6
carry out processes • deliver training and awareness programs
• Required • evaluate effectiveness of training and Records of:
competencies/level awareness • training
of training for QMS • ensure training covers GMP, the risk and • personnel information
processes danger of cross-contamination and the • curricula vitarum
• Recruitment importance of following procedures (CVs)
requirements: • ensure periodic refresher training is provided • individual
education, training, development plans
skills and experience
 Clause 6.3 Infrastructure
Appropriate equipment, premises, services and environment are fundamental requirements of GMP.

Reasons for the ‘extra’ GMP requirements

Packaging defects, including mislabelling/mix-ups, are the major cause of approximately 25% of defective medicines and batch recalls
(see Annex B 3). It must be emphasized that the causes of this problem are not solely attributable to the packaging supply industry
since all parts of the supply chain and manufacturing process can be implicated. This also includes the distribution from the supplier to
the customer, during use in the customer’s processes and also the final market distribution.

Whilst the product should be designed to minimise/avoid contributing to the risk, the infrastructure of manufacturing and support
processes at the supplier must also be designed, maintained and operated in compliance with the principles of GMP to assure product
security.

It is because of the continuing high proportion of market recalls that are caused by defective packaging that pharmaceutical supplier
audits will always assess how the infrastructure may influence product contamination.

Process inputs Processes Process outputs and evidence Cross refer to

Schematic/Annex

• Business process Processes which: • Adequate premises, facilities, Schematic 2

requirements for • identify, provide and maintain equipment and services
premises, equipment, premises, equipment, utilities and • Internal reviews and customer Annex A:
utilities and other other services including hardware and feedback Segregation controls
services including software and transport • Records of ongoing
hardware and software • ensure that GMP requirements maintenance and review
• Maintenance manuals are incorporated to avoid product • Action plans (short and long
and schedules contamination term)
• Regulatory • Cross-contamination
requirements avoidance

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Clause 6.4 Work environment
The work environment is critical to ensuring not only product conformity, but also the ability and desire of people to perform effectively.

Reasons for the ‘extra’ GMP requirements

Preventing contamination of medicinal products may require that the components be manufactured under particular standards of
cleanliness, which could ultimately involve cleanrooms (i.e. controlled environments). These enable the pharmaceutical product and
patient to be protected. This may apply even when the components undergo a cleaning process at the pharmaceutical manufacturer’s
site.

For some product contact components, microbial contamination levels (the bioburden) need to be kept at the lowest levels possible.
This still applies even when the pharmaceutical processing involves a sterilization operation.

Process inputs Processes Process outputs and Cross refer to

evidence Schematic/Annex

• Categories/standards Processes which: • Appropriate Schematic 2

for environmental • identify necessary work environment environment for
conditions • identify factors needed to ensure products product being made Schematic 5
• Product/manufacturing meet requirements • Records of
processes • manage and maintain work environment environmental Annex A:
• Customer requirements including cleaning, validation and processes monitoring, validation Risk assessment
• Information from • incorporate appropriate ‘cleanroom’ conditions and cleaning
ongoing environmental for the type of product being made
monitoring
• People needs/
consideration
• Regulatory
requirements
 General Synopsis - Clause 7 Product realization

Making product involves many interrelated processes, the inputs and outputs of which should be analysed and managed.

Clause 7.1 Planning of product realization

Management should plan the processes needed for product realization.

There are no ‘extra’ PS 9000 GMPs within this clause. There are important GMP principles in this area but they are adequately
expressed in ISO 9001 and ISO 9004.

Process inputs Processes Process outputs and Cross refer to

evidence Schematic/Annex

• Quality requirements Processes which: • Quality plan Schematic 2

for the product • plan the production processes • Clearly identified
• Product specifications • plan the support processes processes Schematic 3
• Customer requirements • manage changes • An operating plan to
• Product requirements – • control process/product validation manage processes Schematic 4
validation, monitoring, • Identified resource
test criteria. requirements to Annex A:
• Resource requirements support the operation Change control
specific to the product and monitoring of
processes Validation (and
• Change procedure Qualification)
and records
• Validation records

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Clause 7.2 Customer related processes
The organization should have effective processes for communicating with its customers and other interested parties.

Reasons for the ‘extra’ GMP requirements (refer to PS 9000 clause 7.2.3 Customer communication)

The pharmaceutical industry is heavily regulated by regulatory authorities, throughout the world. Companies are required to obtain a
marketing authorization (MA)/ Product Licence (PL) to place a medicinal product on the market. The application for an MA/PL must be
supported by extensive data including information on the packaging materials to be used. Companies are not at liberty to make any
changes to the product, its components or its method of production without approval from the regulatory authority. The licensing of
pharmaceutical products requires that the pharmaceutical companies inform government regulators of virtually all changes. They are
not at liberty to change any registered product details without going through an extensive and lengthy submission process.

One particular reason for this communication process is that changes can require trial work (e.g. stability trial) at the pharmaceutical
company or other actions, such as machine alterations, with implications for design and planning. In order to give due consideration
to each proposed change, there should be a clear agreement between the pharmaceutical customer and organization of what
communication is required for various types of change.
 Process inputs Processes Process outputs and Cross refer to
evidence Schematic/Annex

• Customer Processes which: • Defined product Schematic 2

stated • enable communication with customers (about product requirements
requirements information, sales enquiries, complaints, etc.) • Documentation denoting Schematic 3
• External • review the customer’s order, product requirements customer approval
market data before products are supplied (e.g. contract review) • Effective data exchange Schematic 4
• Statutory and • require change control measures to be in place to covering products,
regulatory record and monitor changes to processes amendments, feedback Annex A:
requirements • review related information – market research, and complaints Change control
competitor analysis, statutory requirements • Possible inputs to
• specifically identify those types of changes which management planning
require prior approval by, or notification to the process (e.g. resource/
customer machinery implications)

Records of:
• customer
communication (e.g.
product specifications,
order confirmations,
complaint investigations,
etc.)
• order/product review

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Clause 7.3 Design and development
Planning and controlling design and development activities are fundamental to making product that fully meets the requirements of
customers.

Reasons for the ‘extra’ GMP requirements (refer to PS 9000 clauses 7.3.1, 7.3.2, 7.3.5, 7.3.6 and 7.3.7)

The organization often has specialist knowledge regarding product design that can assist in evaluating risks to the end user or patient.
This would normally form part of customer/organization communication at the product development stage. Technical data from the
design and development stages of a component may be required as part of the pharmaceutical company’s submission to regulatory
authorities when applying for permission to market a medicinal product. This is mandatory for a component that will be in physical
contact with the medicinal product, as the composition of the component material can influence the medicinal product’s composition
and stability and the safety of the patient.

The availability of validation documents at this stage gives recorded assurance that the design produced has been thoroughly tested
and is suitable for long-term production. This, in conjunction with the testing and approval of samples by the customer, enables the
design to progress into production in a formal controlled manner.

Similar controls are expected when design and development activities are involved in making modifications to the product or
production methods. It is mandatory that the details of the medicinal product lodged with regulatory authorities are accurate and
maintained (‘The Rules and Guidance for Pharmaceutical Manufacturers and Distributors 2002,’ Article 5 European Commission
Directives 2003/94/EC and 91/412/EEC).
 Process inputs Processes Process outputs and Cross refer to
evidence Schematic/Annex

Internal inputs, e.g. Processes which: • Reports of validation/tests Schematic 2

• competence • control planning the design and • Information for other functions
requirements for people development of products (e.g. purchasing) Schematic 3
performing design and • control product design and • Data to enable verification
development development of design and development Annex A:
• records and data on • control production process design and process outputs to the Change control
existing processes and development process inputs
products • evaluate potential risks of the product • Evidence of customer Risk assessment
• outputs from other design to customer and ultimately the approval of changes
processes patient Validation (and
• provide technical/material data to Identification of: Qualification)
External inputs, e.g. the pharmaceutical customer and/or • review, verification and
• customer/marketplace medicinal regulatory authorities and to validation appropriate to each
needs notify of any changes arising from the design and development
• user input to achieve supply chain stage
robust design and • cover testing, retaining and gaining • responsibilities for design and
development customer approval of samples development
• statutory requirements resulting from new product designs
• international standards • produce and provide validation Documented:
• industry codes of documentation to the customer • change control
practice • control modified or refurbished • risk assessments
• other requirements equipment and tooling and product • specifications for product,
for safe operation, process, material, testing,
handling, storage safety characteristics
• environmental/disposal • training requirements and
constraints for the records
products or processes

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Clause 7.4 Purchasing
Management has a responsibility to define and implement effective purchasing processes to ensure purchased materials meet stated
requirements.

Reasons for the ‘extra’ GMP processes (refer to PS 9000 clauses 7.4.1 and 7.4.3)

The pharmaceutical company needs to know where all parts of a manufacturing process are performed. These details, including sub-
contracted elements, may be ‘registered’ as part of the marketing authorisation, and thus need customer approval. The pharmaceutical
company must be satisfied that there are no other risks to product security or quality involved with subcontracted parts of the
manufacturing process. Product quality can also be affected by many contracted out services (e.g. cleaning, maintenance, calibration),
and evidence of good management and control of these is expected.

Quarantine of purchased product until approved for use eliminates the risk of using unapproved or unsuitable material.
 Process inputs Processes Process outputs and evidence Cross refer to
Schematic/Annex

• Product specifications • Purchasing process that satisfies the • Co-ordinated purchasing Schematic 3
• Contracts, warranties, organization’s needs whilst considering information, e.g. requirements
prices costs and other appropriate performance for approval of product, Schematic 3 (a)
• Logistic requirements measures supplier’s procedures,
• Product identification processes and equipment, Schematic 4
and traceability Processes which: other personnel or quality
• Supplier performance • control suppliers systems requirements Annex A:
data – quality, price, • enable verification of purchased products Change control
delivery, response Records of:
• Audits of suppliers Processes which: • inspection checks made on
• Commercial • gain customer approval of subcontracted incoming items
dependability of parts of the manufacturing process • the release (for acceptable
suppliers • control contracted out services that can items) or rejection (for
• Supplier’s capabilities affect product quality unacceptable items) of
• Certification • quarantine purchased product until purchased goods
approved for use
Evidence of:
• a supplier approval scheme
in place (e.g. an approved
supplier list and audit reports)
• the monitoring of
subcontractors

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Clause 7.5 Production and service provision
Production (or service provision) where key elements are the control and validation of production conditions, and traceability of
materials and equipment used.

Reasons for the ‘extra’ GMP requirements (refer to PS 9000 clauses 7.5.2, 7.5.3, 7.5.4 and 7.5.5)

The special needs of pharmaceutical packaging mean that certain processes are critical to product quality, safety, and function. These
‘critical’ processes require validation to be certain that they function reliably and consistently. It is important that validation is performed
as necessary during development and on start-up in production and also performed when there are changes to production processes.

Identification and traceability is essential to enable a reconstruction of events when investigating a quality problem. To be able to
investigate any problem with a medicine in the marketplace, the pharmaceutical company is obliged to retain records for (at least) a
year beyond the life of the medicines it is making. There is a corresponding responsibility on the part of the component suppliers to
be able to support any such investigation through its retained records of manufacture e.g. traceability of materials, equipment and
personnel involved in the components manufacture (see Annex A).

The pharmaceutical company places trust in its suppliers to protect its property. The main consideration is protection from theft
and subsequent fraudulent use, unauthorized supply and use in counterfeit medicines. This particularly applies to artwork or data in
electronic form due to its ease of transmission.

Following manufacture under controlled conditions, the continuing protection of the product is important to prevent damage and
contamination.

Accurate identification of the final product is vital in order to minimise risk of admixture both within the organization and during receipt
at the pharmaceutical company. This is always important, but particularly so where there are direct ‘supply to line’ arrangements, with
minimal goods-inwards checking in place at the pharmaceutical site.
 Process Inputs Processes Process outputs and Cross refer to
evidence Schematic/Annex

• Raw material batch Processes which: • Continual Schematic 3

records • ensure production/service provision activity improvement activities
• Specifications is under controlled conditions, i.e. suitable Schematic 4
– product, materials equipment with appropriate monitoring and Records of:
• Manufacturing controls • production (e.g. batch Schematic 5
method/process • ensure validation of processes where the sheets)
instructions resulting output cannot be checked by • process validation/ Schematic 6
• Provision of suitable subsequent measurement revalidation
resources – machinery, • ensure continual improvement of realization • material usage Schematic 7
people processes, e.g. reducing waste, improving • warehouse and
• Training of process methods, preventing problems, improving yield dispatch transactions Annex A:
operators • validate critical processes that could affect • product identification Counterfeit
• Environmental product quality including specific examples and
instructions revalidation requirements Admixture
• Packing instructions • ensure identification and traceability of
• Validation plans materials and equipment used throughout Segregation
production controls
• protect and care for customer property (e.g.
moulds, artwork, electronic data) Validation (and
• protect and clearly identify the final product Qualification)

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Clause 7.6 Control of monitoring and measurement devices
Control of such equipment is critical to good control of manufacturing processes.

There are no ‘extra’ PS 9000 GMPs within this clause. There are important GMP principles in this area but they are adequately
expressed in ISO 9001 and ISO 9004.

Process inputs Processes Process outputs and Cross refer to

evidence Schematic/Annex

• Outputs from design Processes which: • List of monitoring/ Schematic 5

and development • determine the monitoring/measuring and measuring equipment
activities - e.g. design equipment needed • Status labelled Schematic 6
tolerances • ensure identification and protection of equipment
• Product specifications equipment • Calibration records
• Customer • control calibration
requirements • control the monitoring/measuring activities to Procedures for:
• Calibration standards verify products (and production processes) • monitoring
• control nonconforming equipment/device • measuring
• control the checks on computer software when • calibration
used in monitoring and measurement
 General Synopsis - Clause 8 Measurement, analysis and improvement

Measurement information is vital to sound decision making. The organization should monitor its processes, products and all
aspects of the QMS in order to provide data for continual improvement in performance.

Clause 8.1 Measurement, analysis and improvement: General

These activities are of such importance that careful planning is needed on how it shall be performed.

There are no ‘extra’ PS 9000 GMPs within this clause. There are important GMP principles in this area, but they are adequately
expressed in ISO 9001 and ISO 9004.

Process inputs Processes Process outputs and Cross refer to

evidence Schematic/Annex

• Process analysis work Processes which: • Formal measurement Schematic 3

• Company objectives • plan how to monitor/measure processes and systems
• Customer needs products • Statistical techniques Schematic 6
• develop suitable improvement mechanisms • Procedures
• control the implementation of the above • Reports

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Clause 8.2 Monitoring and measurement
Monitoring the satisfaction of customers, other interested parties, monitoring products, processes and systems.

Reasons for the ‘extra’ GMP requirements (refer to PS 9000 clause 8.2.4 Monitoring and measurement of product)

ISO 9001:2000 requires quality designed and system compliant processes, and complimentary to this in PS 9000 is the need for
processes to be operated in a way which maintains product security and avoids contamination (see also 5.2 and 5.3).

Since process assessment is often based upon product samples, these must be representative of the process with the sampling
scheme defined. Whilst samples examined on the line are considered secure, a contamination or admixture risk exists if there are
inadequate controls on the security handling of samples removed from the production area.

To avoid this risk, PS 9000 specifically requires the secure disposal after examination, of all samples that have been removed from the
immediate production area and additionally stipulates they cannot be reincorporated into the product (see also ‘Rules and Guidance
for Pharmaceutical Manufacturers and Distributors 2002’, Chapter 5.54)

It is generally known that processes work better when they have stabilized following start-up and are running continuously. Hence
when equipment breaks down or there is an unscheduled interruption that stops the process, quality variability can occur and
additional quality monitoring is required on recommencement.
 Process inputs Processes Process outputs and Cross refer to
evidence Schematic/Annex

• Customer surveys Processes that identify (and implement) suitable Corrective actions: Schematic 5
• Focus group data methods to: • when processes fail
• Feedback on products • monitor and measure customer satisfaction to achieve planned Schematic 6
• Customer • monitor and measure the satisfaction of results
requirements/contracts interested parties (other than customers) e.g. • in response to
• Market needs employees, investors, suppliers and society customer information
• Delivery data • monitor and measure production processes (complaints, surveys
• Financial data/costs of • verify that product is meeting requirements at etc.)
nonconformities appropriate stages of production
• Market benchmarking Records of:
and best practice Processes which: • product monitoring
• control internal auditing – programme, and measuring
procedures, auditors activities (e.g. test
• define a statistically valid sampling scheme reports)
• prevent samples from being returned to a batch • audit reports/actions/
- keep separate then destroy/dispose securely follow-up actions
• apply additional monitoring, after a machine
breakdown or stoppage Feedback to:
• customers
• other interested
parties

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Clause 8.3 Control of nonconforming product
It is essential that product not meeting specification be segregated from suitable product until corrected, destroyed, or reclassified.

Reasons for the ‘extra’ GMP requirements

There is an assumption that all processes work efficiently without problems and that material will be uniform, consistent and fully
compliant with the specification. In reality problems can occur resulting in short periods when the process may not be in control and
produces nonconforming product. This can result in problems in the market, customer complaints and returned product.

For GMP reasons and good customer relations, the pharmaceutical industry needs to be aware of any quality issues during the
manufacture of its packaging materials. The customer should always be notified of nonconforming or associated product, which may
have already left the organization, so that the pharmaceutical company can consider any implications to processes, stock or packed
product.

Suspect product retained by the supplier or returned from the customer, requires formal GMP controls on its secure storage, handling
and remedial rework actions, including a risk assessment to ensure that the reworking process does not introduce further quality
problems.

All of these issues require good documentation to provide traceability over time and to reconstruct events if required.
 Process inputs Processes Process outputs and Cross refer to
evidence Schematic/Annex

• Products not meeting Processes which: • Documented risk Schematic 3

specification • review identified nonconforming product and assessment for any
• Customer rejects or actions to be determined batches that are Schematic 5
complaints • control the secure physical (or electronic) reworked to recover
• Results of inspections quarantining of items/data stock from a rejected Schematic 6
or in-process testing • control rework or quarantined batch
activities • re-verify or inspect corrected product (e.g. • Records of customer Annex A:
• Observations by following rework) communications/ Risk assessment
members of staff • notify customers if problems are found after notifications
delivery • Defined
• identify and control any batches of product that responsibilities/
are related to any nonconforming product that authorities for dealing
has been returned from the customer with nonconforming
product

Procedures:
• detailing what to
do in the event of
nonconforming
product being
detected
• for handling rejections
and complaints
• for handling recovery/
reworks

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Clause 8.4 Analysis of data
In addition to monitoring activities, the sensible analysis and interpretation of data is critical to enable good decisions to be taken and
business improvements to be made.

There are no ‘extra’ PS 9000 GMPs within this clause. There are important GMP principles in this area, but they are adequately
expressed in ISO 9001 and ISO 9004.

Process inputs Required processes Process outputs and Cross refer to

evidence Schematic/Annex

• Outputs from Processes which determine the data required, Trends, information and Schematic 6
Monitoring and collect and analyse it, to: data about:
Measurement (8.2) and • evaluate the QMS • customers
other processes • monitor and measure its suitability and • suppliers
• Data from relevant effectiveness • products
sources • improve it • processes
• QMS
Processes for:
• root cause analysis of problems
• analysis of data which uses valid methods and
appropriate statistical techniques
• decision-making based on results of logical
analysis, balanced with experience and
knowledge
 Clause 8.5 Improvement
Continual improvement of the QMS is at the heart of the ISO 9001 and PS 9000 philosophy.

There are no ‘extra’ PS 9000 GMPs within this clause. There are important GMP principles in this area, but they are adequately
expressed in ISO 9001 and ISO 9004.

Process inputs Processes Process outputs and Cross refer to

evidence Schematic/Annex

• Audit results Processes to assess potential nonconformities, • Risk assessment Schematic 1

• Quality data study their effects and: reports
• Quality policy and • evaluates the need to take preventive action • Improvement plans Annex A:
objectives • develops suitable actions to eliminate causes • Procedure for Risk assessment
• Management reviews • examines the effectiveness of them nonconformance
• Previous corrective and management
preventive actions Processes to detect actual nonconformities which: • Preventive and
• Validation data • evaluates the need to take corrective action corrective actions
• Process and product • develops suitable actions to eliminate causes taken
measurements • examines the effectiveness of them
• Data from self Records:
assessments Process that plans for losses sustained by the • of these actions
• Requirements from organization in order to mitigate their potential • of the effectiveness of
customers/interested effects (e.g. fire or weather damage) these actions
parties
• Financial and service
data

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General Synopsis - Clause 9 Contamination control

The capability of facilities and equipment, achieved through their design, location, construction, and maintenance, to
minimise the risk of process errors and avoid cross-contamination affecting process and product.

Reasons for the ‘extra’ GMP requirements

The highest quality priority of the pharmaceutical industry is for the component material to meet specifications and meet or exceed
defined GMP controls.

Pharmaceutical product safety, efficacy, and stability can all be compromised by chemical contamination of the primary packaging
material. Particulate contamination may reduce the visual quality of the product as well as interfere with its function; it can also be a
‘carrier medium’ for microbial contamination with a potential infection risk to the patient.

GMP controls and procedures provide the safeguards to prevent cross-contamination (admixture). A single ‘rogue’ component within a
batch could create a life-threatening hazard to the patient (see Annex A - Admixture).

Since contamination can take many forms and be introduced anywhere, preventive measures (e.g. good facility design, Standard
Operating Procedures, training, area clearance, segregation controls, etc.), must be applied throughout the facility. In addition, similar
measures should be included in the design of the process.

PS 9000 specifies GMP requirements across the manufacturing operation as well as the environmental conditions needed for
processing packaging materials for use with medicinal products. Three different cleanliness categories are defined dependent upon the
material and its application.
 Process inputs Processes Process outputs and Cross refer to
evidence Schematic/Annex

• Specification for Processes which identify/control: • Incidents/audit Schematic 3 (a)

design of new facilities, • operating areas/activities that contribute to reports
processes, equipment contamination • Drawings (e.g. floor Schematic 4 (a)
and environment • environmental category appropriate to the plans)
• Specialist pest and product (agree with customer) • Appropriate Schematic 5
contamination control • handling of material and segregation controls environmental
• Customer requirements • good practices to avoid contamination during category established Annex A: all parts
• Standards for operation, support, and maintenance for product (agreed
environmental • pest control with customer)
conditions • cleaning procedures and checks
• training of staff and visitors in contamination Procedures to:
avoidance and standards of dress • control processes
• management and control of waste material • monitor and control
• line clearance environments
• change control
• environmental monitoring Records of:
• processing
• cleaning schedules
• cleaning
• training
• material disposal

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General Synopsis - Clause 10 Printed materials

The application of controls specific to different types of printed materials in order to ensure identity, maximise product
security and prevent cross-contamination. It includes the use and verification of various types of security code systems and
associated software.

Reasons for the ‘extra’ GMP requirements

This section intentionally follows the section on Contamination Control because it covers in depth the specific GMP requirements for
securely printing components to prevent admixture and cross-contamination.

The risk associated with admixture is that an incorrect printed component, often similar in design to the correct component, will be
used to label or contain the pharmaceutical product. This can lead to the patient using the wrong product or using it in an inappropriate
manner.

(For more detail refer to Annex A - Additional Explanations of Key Concepts).

There are many stages in the manufacture of printed materials, all of which can benefit from good control procedures. The advantage
of security bar codes systems is that automated detection checks can be incorporated into key process stages at the supplier
organization and customer.

The pharmaceutical industry believes that, although security bar code systems can approach 100% security confidence, they are not a
substitute for other good manufacturing practices.
 Process inputs Processes Process outputs and Cross refer to
evidence Schematic/Annex

• Product requirements Processes which control: • Register of security Schematic 4

including leaflets, cartons, • the issue and allocation of security barcodes
reel-fed materials, labels barcodes • Accurate counts detailed Schematic 5
and product printing • the set-up and use of scanners to reject on the outer carton labels
using digital technology unsuitable material • Traceability of product Schematic 7
• All products made • equipment that can, under certain cond- (audit trail)
by assembly of sub- itions print with missing colours or text • Good packing line Annex A:
components (e.g. label/ • any overprinting process and its performance of Admixture
leaflet combinations) verification components when in use
• Graphic design (e.g. • the scanning and off-line verification of by customer (complaints/ Identification and
inclusion of security barcodes when necessary and challenge feedback) traceability
barcode in origination/ of the effectiveness of scanning • Established settings to
artwork) • the checking of splices in reels ensure reproducibility Line clearance
• Machine design/ • counting/sequential numbering
operational settings Verified and securely printed Validation (and
• Customer requirements Processes which: product that is: Qualification)
and agreement on • prohibit the replacement of missing labels • free from admixture
quantity tolerances on a reel • free from missing print/
• Specifications for reel- • prevent partially printed or blank leaflets errors
fed materials including • ensure that the line clearance processes • accurately counted
splice joins and how include computer artwork file removal • correctly assembled (e.g.
reel materials shall be (where applicable) label/leaflets)
identified • ensure that digital file access is secure,
• Electronic and/or validated and prevents accidental use of Systems proven to be
mechanical machine incorrect origination/artwork files effective, records of:
enhancements (e.g. • ensure secure assembly (e.g. label/ • validation and qualification
optical, double sheet leaflets) with secure production of all sub- • verification checks
detectors) components • scanning rejects and
• Packing and storage • control validation activities review of them

69
specifications • control packing and storage activities • equipment testing
70
General Synopsis – Clause 11 Origination/artwork

The generation of new or amended origination is the start of the manufacturing process for printed items and requires control
from concepts to origination and through to final printing. All origination and printed media must be controlled to ensure
security and integrity of the final printed product.

Reasons for the ‘extra’ GMP requirements

Both packaging suppliers and pharmaceutical companies have experience of common problems that occur in the preparation of
origination/artwork, which could be avoided by good manufacturing practices.

Origination problems occur in the same way as those for printing of the packaging material and GMP preventive controls to address
these, follow the same pattern, (e.g. defined work areas, segregation, line clearance, recorded checks, etc.).

Electronic systems are widely used to produce pharmaceutical origination; it is important that the systems are secure and have
controlled access (see PS 9000 4.2.3). Since origination/artwork is comparable to a design process, errors built into the design
cannot be removed by later inspection and therefore quality, i.e. GMP, must be built into the creation process. This starts with unique
identification of the material and identity checks at all process stages within the organization and during transfer to the customer.
 Process inputs Processes Process outputs and Cross refer to
evidence Schematic/Annex

• All origination material Processes which: • A system of Schematic 3

• Customer • seek agreement with customer (where required) control for artwork
requirements to sign off a copy of the final proof before that prevents the Schematic 4
• Customer designs/ production is authorized inadvertent use of
specifications • require the identification of all origination incorrect items Schematic 4 (a)
• Customer component material (e.g. ensuring that proofs are marked
codes with component numbers and issue dates) Records of: Schematic 5
• control origination materials and covers storage, • approval by customer
issue, return and line clearances (e.g. approval of Annex A:
• ensure understanding of how codes are used artwork) Change control
by customers and application of appropriate • in-process checks
control measures performed on Identification and
• require the checking of copy (electronic or artworks traceability
hard output) against original specifications and • line clearances
customer approved versions • checks made on Line clearance
in-house produced
items against a
customer approved
master
• customer approved
masters

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General Synopsis – Clause 12 Print impression media

Life-cycle management of print impression media is essential and should incorporate good communication with the customer
to understand the design and application of the product. Key is the traceability from customer design through to delivery of
all printed items.

Reasons for the ‘extra’ GMP requirements

Printing of packaging materials is normally a three-stage process, involving creation of the origination/artwork, production of the print
impression media, i.e. ‘the plates’ and lastly use of the plates to create the text and images on the packaging material.

The GMP requirements for all these stages must therefore be very similar since they have the same objective, i.e. compliance with the
customer’s specification and avoidance of cross contamination/mix-ups.

Print designs can be very similar and difficult to differentiate, particularly with modern company ‘house’ designs or for a family range
of product presentations. Print impression media must therefore be strictly controlled with unique identification codes, and checks
incorporated into all usage, together with secure and controlled disposal of impression media when eventually superseded. For more
information see Annex A - Additional Explanations of Key Concepts. Also ‘Rules and Guidance for Pharmaceutical Manufacturers and
Distributors 2002’, Chapter 5.43.
 Process inputs Processes Process outputs and Cross refer to
evidence Schematic/Annex

• All printed items Processes which: • Documentary Schematic 3

• All origination material • control all media (e.g. identification, checking, evidence (e.g.
(e.g. films, electronic issue and return of plates) that a full set of Schematic 4
files) • ensure that all plates of the set are identified and matched plates
• Print impression media used was signed out Schematic 4 (a)
(e.g. plates, gravures, • ensure that where one or more plates in a set to the job, or in-
etc.) are common to several items (e.g. a patterned process checks Schematic 5
• All sets of printing plates background that is used for a range of label that all colours
• Customer approved designs), controls exist to ensure that shared and are present in the Annex A:
design (e.g. customer unique parts of a set are used appropriately printed item) Admixture
issued specification, or • check all printed output against approved
a customer approved specifications during set-up, to ensure that the Records of: Change control
proof) correct item is being made at the correct quality • checks carried out
• Design requirements for • control change including records of changes or on media Segregation controls
a multi-plate set (e.g. revisions • plate issue and
a two colour design, • ensure that identification and authorisation of return
or a design that, for print media changes is as rigorous as the initial • identity changes
production reasons. origination and item revisions
needs to be split across • prevent use of print media whilst undergoing or • approval to run
two print stations) awaiting change (e.g. a signed pass
• Requirement for a design • render unusable any print media declared sheet, first off
change obsolete samples etc.)
• Any revised printed • ensure that when plates are replaced within a • revision of items
products/designs set, adequate controls exist to prevent error • disposal of
(e.g. a new customer • control the quarantine and destruction of plates obsolete items
specification) and other print media (e.g. segregated storage, once revised
• All revised or obsolete quarantine labels, etc.)
items • require a formal approval before the operator is
allowed to run the press

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General Synopsis – Clause 13 Print and conversion processes

This clause covers the GMPs required to ensure adequate control throughout the make-ready and production processes of
printed materials

Reasons for the ‘extra’ GMP requirements

This clause addresses a number of specific aspects of the print process that are associated with known risk areas, i.e. risk of serious
print errors and/or cross-contamination.

The details in this section of PS 9000 represent current best practice, routinely seen by pharmaceutical auditors during audits of
progressive suppliers who are aware of the GMP needs of the pharmaceutical industry. This means that the most dangerous of
practices, for example ‘Gang printing’, is excluded because of the historical association with mix-ups. While it is accepted that the
risk might now be statistically low, it is not zero and the consequences cannot be accepted by the pharmaceutical industry. (For more
information see Annex A - Additional Explanations of Key Concepts).

However, in certain situations for example, using printed material to set-up the machine, or where total line clearance may be
impractical due to the machine technology, an approach involving a documented assessment of risk with suitable alternative security
checks introduced, is allowed.
 Process inputs Processes Process outputs and Cross refer to
evidence Schematic/Annex

• Customer Processes which: • Good logical flow of Schematic 4

specification/design • limit the use of printed material for machine materials and clear
requirements set-up purposes segregation Schematic 4 (a)
• Any special customer • involve a risk assessment of changeover
agreed requirements systems (e.g. where the nature of the Records of: Schematic 6
• Suitable equipment, machinery does not permit a total line- • production controls/
materials, trained staff clearance) checks Annex A:
• Braille specifications • control any samples taken • all replacement of Admixture
where required • verify any changes of print media before plates
continuing production, to ensure consistent • samples taken and Risk assessment
quality disposition
• ensure when new plates are made from a new Segregation
source file, the subsequent work is treated as controls
a new batch
• ensure when new plates are made from a
fixed/approved file, the subsequent work must
undergo a first off check
• ensure any Braille symbols meet specification
• control storage to ensure security, integrity and
traceability
• control the holding of stock (when
contractually agreed)
• exclude gang printing due to potential for
cross-contamination

75
76
 The Institute of Quality Assurance
Pharmaceutical Quality Group

PS 9004

A Guide to the GMP requirements

of PS 9000:2001 Pharmaceutical packaging materials

ANNEX A - ADDITIONAL
EXPLANATION OF KEY CONCEPTS

PS 9000 GMP related text is reproduced in blue

77
 Admixture

Ref: Definition/References Explanation

PS 9000 Definition Data supplied by the MHRA on their investigations

3.1 The presence within the into defective medicine shows that 12 % involve
batch of one or more mislabelling in its widest sense (i.e. the product
items not of the nature container is printed, or labelled, cartoned or has a
of that specified by the descriptive leaflet which is either incorrect or has
product description, i.e. text which is not compatible with the use of the
cross contamination. product), see Table Annex B3.
Other terms used
include ‘mix-up’, ‘rogue’ The source of admixture can originate at the
or ‘stranger’ supplier, the pharmaceutical manufacturer and the
distribution chain or at the point of dispensing.
Some causes might be outside the control of the
PS 9000 References pharmaceutical manufacturer, e.g. the pharmacist
3.14 Cross-contamination dispensing the product. However the pharmaceutical
manufacturer needs to take all possible precautions
6.2.2 Competence, to prevent mix-up, including:
awareness and training • bar coded items (and detectors)
• visual codes
6.3 Infrastructure • colour/text differentiation
• procedural controls at supplier (i.e. the
8.3 Control of non- focus of PS 9000) and at the pharmaceutical
conforming product manufacturer (i.e. GMP)
• physical segregation
9.1.7 Line clearance (cross-
contamination control) Mislabelling of the medicinal product introduces the
risk that the patient will:
9.1.8 Segregation controls • use the wrong product
(cross-contamination • use the product in an inappropriate manner
control)
Furthermore, there can be serious damage to
9.1.11 Personal hygiene and market confidence in the company’s products or
security pharmaceutical products in general. Product recalls
are very serious, and may cause withdrawal of a
10.1.5 Converter’s flap code critical medicinal product, otherwise urgently needed
in the market. However, the risk of causing patient
10.2 Reel fed materials harm cannot be over-emphasised and should never
(general) be forgotten.

10.3 Reel fed self-adhesive One historically recognised cause of admixtures

labels is via ‘gang printed’ sources where two or more
different designs are printed on the same matrix at
13.5 Gang Printing the same time.

This conflicts with a strict GMP principle, which can

78
Ref: Definition/References Explanation

be paraphrased, as “it is bad practice for a process

to deliberately mix product in the expectation
that technology or procedures can and will later
differentiate and separate them”. In the USA gang
printing can be permitted according to 21 CFR
211.122(f) where “the labelling from gang printed
sheets is adequately differentiated by size, shape
or color”.

This contrasts with the view in Europe where it

is known that colour differences have proved
inadequate to prevent mix-ups and best practice
therefore prohibits gang printing.

These two approaches might seem contradictory

but the requirement detailed in PS 9000 is strictly
in keeping with Europe’s view of ‘Risk Assessment’
where the possibility of a critical admixture, even
though small, cannot be accepted.

79
 Change control

Ref: Definition/References Explanation

PS 9000 Definition The development of a new component or material is

3.7 A process that ensures a period of extensive design change, with controls
changes to materials, and liaison between customer and supplier. This
methods, equipment results in specifications approved by customer and
and software are prop- supplier, covering raw materials, sources, processes,
erly documented, vali- and tests.
dated, approved and
traceable. Later in the product life-cycle, variability can occur
through uncontrolled changes.
PS 9000 References
3.31 Risk Assessment The following are examples of changes which
could affect component dimensions, constituents
4.2.3 Control of documents or other characteristics (e.g. surface finish),
(electronic) creating operational problems for the customer, or
incompatibility during the shelf-life of the medicinal
7.2.3 Customer product:
communication • refurbishment of injection moulds
• use of a different production line
7.3.2 Design and • raw materials sourced from a new supplier
development inputs • reprogramming of equipment controlling
computers
7.3.7 Control of design and • replacement equipment
development changes
To avoid the risk of uncontrolled changes PS 9000
7.5.2 Validation of processes requires the use of a Change Control process which:
for production and • documents all planned changes
service provision • assesses potential problems (e.g. Risk
Assessment)
9.1.6(b) Materials (starting, • revalidates where required
ancillary and • includes an independent change review and
intermediate) authorisation
• notifies the customer and schedules the
12.3 Copy/design change introduction of the change
• provides traceability on the change
13.4 Replacement print • retains a record
media
The bottom line of Change Control is to plan and
PS 9004 References document change to avoid potential issues that
Annex A Risk assessment could affect supplier and/or customer.

Annex A Validation For further information see ‘Rules and Guidance

for Pharmaceutical Manufacturers and Distributors
2002’, Section A15.43, A15.44.

80
Ref: Definition/References Explanation

81
 Counterfeit

Ref: Definition/References Explanation

PS 9000 Definition Most people will have heard of counterfeit consumer

3.13 A copy produced products, such as watches and perfumes, but may
without authority not be aware that in some parts of the world there
with the intention of is a serious problem involving counterfeit medicinal
deceiving a user as to products.
its true origin
The scale of the problem can amount to many
PS 9000 References billions of dollars, and governments are even
5.2 Customer focus sensitive that this practice might eventually pose
a serious risk to the normal commercial supply of
5.3 Quality Policy medicinal products. This is evidenced by the May
2003 FDA directive to pharmaceutical companies
7.4.1 Purchasing process supplying the US market, requiring notification within
five days of the detection of a counterfeit product.
9.1.10 Waste material (cross-
contamination control) In the UK the practice is rare but not unknown, as
“the last example of a counterfeit product entering
11.1 Origination procedures the legal supply chain was approximately 20
and work areas years ago”. However data from the World Health
Organisation, (WHO), shows that “between 1984 and
12.1 Print impression media 1999, there were 771 reports of counterfeit drugs,
– General the majority (78%) of these reports came from
developing countries”. Similarly “a recent report from
12.5 Quarantine and Russia showed that 12% of medicines in circulation
destruction were counterfeit products and it was as high as 40%
in the Ukraine”. (Reference 1).

To illustrate the risk posed to the patient by

counterfeit drugs, it is necessary not only to
consider the level of incidents but also the lack of
drug efficacy or potential toxicity of these products,
e.g. for the years 2000-01, of the cases reported
to the WHO, “43% had no active ingredients, while
a further 21% had low content, 7% had the wrong
ingredient and 24% were of generally poor quality”
(Reference 2).

It will be easy to understand that while the possible

consequences of buying a counterfeit watch are
simply disappointment or embarrassment, using a
counterfeit drug may carry serious, or even fatal,
health risks. Some counterfeit drugs are very crude
copies of the original product while others are less
so. However the counterfeiter is always keen to

82
Ref: Definition/References Explanation

use ‘quality image’ packaging that is as close as

possible to the original pharmaceutical packaging
because people usually believe what is printed on
the carton or label.

For obvious reasons there is pressure from

enforcement agencies that “the pharmaceutical
industry, importers, distributors and consumer
organization should adopt a shared responsibility in
the fight against counterfeit drugs”. (Reference 2).

In some markets “a variety of anti-counterfeiting

measures have been put into place by
pharmaceutical manufacturers, for example, the use
of holograms and other devices on the packaging”.
(Reference 1).

It is therefore clear why the pharmaceutical industry

attaches such importance to basic security of print
media at the suppliers, to ensure that:
• all print media is securely stored.
• there is controlled access to the print media
stores
• obsolete and no longer required media is made
unusable and disposed of securely
• all waste and scrap material is stored securely
and rendered unusable prior to disposal. (see
21CFR 211.122)

By preventing access to legitimate print media,

the packaging supplier removes the opportunity
for the counterfeiter to use authentic and genuine
materials, for the good of the pharmaceutical
supplier, customer and product user.

Reference 1 British Pharmaceutical Conference,

Harrogate, UK, September 2003.
Reference 2 International Pharmaceutical
Federation Congress, Sydney, Australia, September
2003.

Acknowledgement for the above quotations is

made to The Pharmaceutical Journal (Volume 271,
pages 453-454, 465-466).

83
 Identification and traceability

Ref: Definition/References Explanation

PS 9000 Definition A fundamental requirement when an operational

There is no PS problem occurs at the pharmaceutical manufacturer,
9000 definition for (e.g. material usage problem, market complaint,
identification etc.), is an effective QMS, which assists problem
resolution. Operational problems can occur for many
3.35 Traceability - The ability reasons, but should the problem be related to a
to follow data/records supplier’s material, then it is essential that the total
logically forwards or inter-company record system enables traceability
backwards within and of the material on site from delivery and during
between organizations, manufacture at the supplier organization.
to allow reconstruction
of events. Through GMP guidance via the regulatory
organizations, e.g. Medicines and Healthcare
products Regulatory Agency (MHRA), all
PS 9000 References pharmaceutical companies are required to use
3.29 Quality Records unique and unambiguous lot numbers and material
identification codes, since it is the cornerstone
7.5.3 Identification and of traceability, avoids potential confusion or
traceability misunderstanding and allows referral to:
• the delivery date and supplier
7.5.5 Preservation of product • the quantity received
• receipt check results
8.3 Control of non- • remaining stock
conforming product • batch and market usage

9.1.10 Waste material (cross- A requirement for medicinal products is that records
contamination control) are retained for at least one year after the expiry of
the batch in which they were used. For this reason,
10.1.1 Security barcode and that packaging materials may not be used
systems - General immediately, PS 9000 requires suppliers to keep
quality records for at least “5 years from the last
10.2 Reel fed materials date of supply of the batch of packaging material”.
(General) Similarly, to provide complete traceability, supplier’s
documented quality systems require:
11.1 Origination procedures • unique material identifications, for raw materials
and work areas used in the product, as well as for the product
itself
12.1 Print impression media • records showing batch history (e.g. process
- General dates, quantity made, in-process test results)
• change control records
12.2 Matched plates • record retention system

12.3 Copy/design change This system can then allow tracking back to the
same quality data as that for the pharmaceutical

84
Ref: Definition/References Explanation

13.3 Retained samples manufacturer detailed above, e.g.

• raw material data, quantity received, receipt test
13.7 Batched production data
and stock holding • supply source details
• where else the same batch of raw material may
have been used
• how it was stored
• personnel employed on processing and testing
• possible environmental monitoring data, (if
relevant)
• customer shipment data

Whilst the main purposes of an effective

identification and traceability system are to control
use and to assist in problem analysis, the supplier
also possesses the means to operate a continual
improvement process, which aids company financial
and quality efficiency.

85
 Line clearance

Ref: Definition/References Explanation

PS 9000 Definition A fundamental requirement in the practice of

3.19 The assurance that a avoiding mix-ups is ensuring that only the materials,
production facility (line), documents, etc. as required for that product, are
and its associated on a line or machine, or in a working area at any
working area is one time. This material or document has to be that
completely cleared of allocated and issued for that particular batch or job.
all materials, waste, Virtually all investigations following a mix-up, focus
products, samples, on the batch that preceded the incident product, or
documentation, etc. was being processed or handled in the vicinity, e.g.
associated with the an adjacent line.
current production, prior
to the introduction of The obvious risk of inadequate line clearance is that
new documentation and once a rogue material is introduced into a batch it
materials required for is virtually impossible to reliably detect and remove
commencement of the in subsequent operations. The only practical quality
next production run. measure is therefore not detection, but prevention,
using procedures, checks, counterchecks and
PS 9000 References training.
9.1.7 Line clearance (cross-
contamination control) The least serious effect of a mix-up is processing
difficulties on the pharmaceutical manufacturer’s
10.7 Digital printing packaging line, e.g. the rogue components are too
large or too small to process properly and they
11.1 Origination procedures block hoppers and feed chutes. However, even this
and work areas can disrupt a smooth running process and cause
product variability.
13.2 Changeover systems
The most serious consequences involve a rogue
PS 9004 Reference component or material, which is incorporated
Annex A Admixture into the pharmaceutical manufacturer’s product,
with potential implications ranging from product
instability to patient confusion on usage instructions
and market recall.

Line clearance is an essential element in product

mix-up prevention and needs to focus on:
• input materials on the line from the previous
batch
• samples and waste from the previous batch
• documents on the line from the previous batch
(e.g. process instructions or test procedures)

Line clearance activities need to be documented

and cover all areas, not just the machine or line, i.e.

86
Ref: Definition/References Explanation

• the whole machine, including hoppers,

conveyors, reject stations, etc.
• the floor around the line
• benches, cupboards, shelves, etc. around the
line
• pallets, etc.

PS 9000 calls for a dual approach to line

clearance, i.e.
• a recorded line clearance at the end of each
production run
• an independent recorded check immediately
prior to the next run.

Similar security precautions are needed when there

are temporary line stoppages to ensure that other
operations, e.g. maintenance, do not accidentally
introduce rogue materials, which, because the
process is in the middle of a run, is thought to be
secure.

87
 Risk assessment

Ref: Definition/References Explanation

PS 9000 Definition Most companies will have experienced the

3.31 A documented situation where a response to a process problem,
assessment of potential or a change, results in a second, sometimes more
failures or faults serious problem. Often, the secondary problem
arising from new or could have been avoided if the change or the
changed processes, original process problem had been given proper
materials, equipment or consideration and planning.
facilities, which could
affect product quality, This consideration is known as Risk Assessment,
performance or use and its application is best explained by two typical
examples:
PS 9000 References
(References to 1. Batch Reworking/Sorting
risk and/or risk
assessment) When tests revealed a ‘cosmetic’ defect in a printed
component, reworking the batch introduced a critical
4.2.3 (d) Control of documents ‘rogue’ component, due to inadequate rework area
(electronic) cleandown from the previous job.

7.3.1 Design and The initial defect was minor, but the ultimate
development planning consequences of an undetected rogue component
reaching the patient could be fatal.
8.3 Control of non-
conforming product A risk assessment of the rework process must
cover the areas specified in PS 9000 Clause 8.3.
9.1.1 General However, the rework/sorting process may introduce
other GMP risks related to, e.g. infrastructure,
9.1.2 Facilities design competency, work environment, and so an
assessment should consider risks of:
9.1.4 Cleaning • a mix-up with other materials
• contamination or damage from further handling
9.1.5 Pest Control • incomplete rework due to poor training
• difficulty in detecting the difference between
9.1.10 Waste material (cross- good and bad product
contamination control) • inadequate defect description
• poor lighting, poor job separation, poor labelling
9.1.11 Personal hygiene and in inspection area
security • discontinuous sorting process (over several days
or by different staff)
9.2.1 d) Minimum environmental • poor separation between sorted/unsorted
conditions material
• poor labelling of sorted/unsorted product
13.2 Changeover systems
The risk assessment should include complete batch

88
Ref: Definition/References Explanation

ISO 9004 Reference documentation, i.e. details of the product and

7.1.3.3 Product and process problems, lot number and quantity, defects involved,
validation and deadline, etc. From this a suitable plan of rework
changes can be generated which includes:
• identification and segregation of the batch,
PS 9004 References (before, during and after sorting)
Annex A Change control • inspection area cleandown checks
• special lighting needs, tools and equipment to
Annex A Validation assist rework
• documentation of the sorting process, the
objective and data collection form
• training of staff (using a controlled example of
the defective to illustrate the problem)
• secure area for removed defectives
• repackaging (and relabelling) of sorted product
• area clean down, on completion and recorded
defectives disposal
• final process release check (matching that for a
new batch)
• records (of rework details included in batch file)
• process revision (where practical)
• notification to customers (where required)
• completion reviews

It is important that management ensures that the

urgency to act quickly to rectify defective product
does not compromise documented procedures
designed to avoid admixtures or introduce other
risks to product quality.

2. Process Change

A refurbished or replacement tool/mould is returned

to production use without a “full” examination
of its potential effect on the product, resulting in
surface finish differences compared with pre-change
product. This change affected the customer’s
process, e.g. the fit with other components,
processing at normal speed.

This type of ongoing change or upgrade is not

uncommon, and it is known that a similar surface
finish problem can be triggered by supplier
changes to running speeds, cycling conditions, the

89
Ref: Definition/References Explanation

software of process controllers, i.e. computers or

programmable logic controllers (PLC’s).

As for the first example, assessment of the change

should involve:
• documentation details of the change including
hardware, software, reasons for change etc.
• risk assessment technique to be used, e.g.
failure mode and effect analysis (FMEA)
• plan of controlled change to include risk
assessment of both the supplier’s process and
customer’s process, e.g.
i. Implications to the supplier’s process:
- installation/changeover
- process speeds
- process conditions
- yield wastage
- staff retraining
- tool identification
- specification and procedural revisions

ii. Implications to the customer’s process:

- phase in (old and new requirement)
- compatibility (with product, other
components)
- differences (visual, performance,
dimensions)
- change schedule (old stock, etc.)
- notification (to regulators, market, etc.)
- specification (revisions to documents)
- machine set-up (changes)

Details of the eventual change introduction can

include:
• management (responsibility for change
implementation and customer notification)
• documentation (details of the change, reason or
purpose e.g. what, how, when, why)
• review (past specification, performance
characteristics, issues, requirements, change
schedule)
• reference or involvement of customer
• risks (documented, classified, with responses,
actions and cures)

90
Ref: Definition/References Explanation

• compliance of the ‘agreed’ specification, to

meet:
- organizational needs
- customer’s needs
• change implementation plan

Outputs from the change implementation can

include:
• testing (at customer or supplier)
• trials and/or revalidation (at customer or supplier,
in market)
• revisions (and additions to requirements)
• records (of performance, new specification,
controls, etc.)
• modifications (details)
• phase in (changeover schedules)
• phase in (controls and schedule to monitor and
measure performance compliance)
• change of identification numbers (reference
numbers to control new item)
• revised specifications (supplier and customer
agreed)
• completion review

For further information see 21CFR 211.115

Reprocessing

91
 Segregation controls

Ref: Definition/References Explanation

PS 9000 Definition To avoid the risk of product cross-contamination, it

Note: is essential that, in addition to normal good material
There is no definition in handling disciplines, there is adequate process
PS 9000 segregation during manufacture.

PS 9000 References PS 9000 states, “working areas should be defined

3.37 Working (work) areas and segregated”.

8.3 Control of Often in practice, a separation gap between

nonconforming product processes of 1 – 2 metres is maintained, with the
actual process areas identified by lines marked
9.1.2 Facilities Design on the floor. This can be wasteful of space and is
often abused when pallet materials straddle the
9.1.8 Segregation controls delineating segregation lines.
(cross-contamination
control) A more absolute method, routinely used in the
pharmaceutical industry, is to use a physical barrier
11.1 Origination procedures between processes - PS 9000 states:
and work areas • “Where physical barriers are used to segregate
working areas they shall be a minimum of 1.5
13.1 Print machine set up metres high and continuous from floor level.”
(make-ready). • “Inspection and sorting areas shall be defined
and segregated by physical barriers of a
minimum of 1.5 metres high and continuous
from floor level.”

The purpose behind these requirements is that

most working conveyor belts are about 1m high
and similarly pallets are stacked to about 1m high,
hence, a 1.5 metre barrier effectively prevents
items falling over the barrier. Making it continuous
from floor level, i.e. sealed to the floor prevents
the transfer of items passing under the barrier.
Making the barrier solid, with no openings or holes,
prevents passage of items through the barrier (if
mesh barriers are used, the hole size needs to
be sufficiently small to prevent product passing
through).

These measures have been proven effective in

preventing cross transfer i.e. preventing admixture,
mix-ups, rogues or strangers.

For further information see 21 CFR 211.130(a).

92
Ref: Definition/References Explanation

93
 Validation (and Qualification)

Ref: Definition/References Explanation

PS 9000 Definition Qualification

3.36 Documented Before implementing a validation program it is
confirmation that a necessary to link into the more comprehensive
procedure, process, ‘qualification system’ which is shown in the diagram
equipment, material, below:
activity or system,
performs as intended Specification
and achieves the Qualification (SQ) Determine what is required
expected results Specify requirement
in accordance with
predefined acceptance Installation
criteria. Qualification (IQ) Check on receipt
Install as appropriate
PS 9000 References
4.2.3 Control of documents Operation
(electronic) Qualification (OQ) Trial processes

7.3.6 Design and

development validation Performance
Qualification (PQ) Evaluate first three
7.5.2 Validation of processes batches for:
for production and • process performance
service provision • process compliance
• product compliance
9.2.3 Enhanced cleanroom
conditions Validation
Through experience of operational and in-market
10.2 Reel fed materials problems, the pharmaceutical industry has found
(general) that validation is the only dependable method
to fully understand the process capability and to
10.4 Leaflets ensure process control. It should be an essential tool
at the supply organization and is a requirement of
10.5 Board products PS 9000, for reasons detailed below.
(cartons, cards, wallets,
catch cards etc.) Inconsistent product quality can often be traced to
an inadequately controlled process which has not
10.6 Combination products been validated and where process parameters have
not been fully defined.
10.7 Digital printing
Validation can be viewed as a key part of a defect
prevention system and as such requires no
justification when management objectives are for an
efficient process. However, the sound operational

94
Ref: Definition/References Explanation

PS 9004 References reasons for validation includes ensuring:

Annex A Change control • the process is controllable and operates
consistently with defined control settings
Annex A Risk assessment • compliance with the product requirements,
i.e. variability only occurs within the agreed
specification
• compliance with known regulatory requirements,
(where applicable)
• change is controlled
• prevention of problems for the organization and/
or customer

Validation is not simply for production processes,

but is relevant to test equipment used on line or in
the laboratory, as well as computer hardware and
software.

From the above detail it is clear that there is a

need for a validation protocol before introducing
new equipment. To establish a comprehensive and
focused programme, it is beneficial but not essential
for the organization to liaise with the pharmaceutical
customer. Here there is a wealth of validation
experience and the motivation exists to assist
suppliers in defect and problem prevention.

A general validation procedure is practical and

often used, (e.g. an across the process Validation
Master Plan or VMP), which can define the broad
scope of the validation approach. This can then
be customised for any specific item needing
assessment. The VMP can cover:
1. The scope
• New process or test equipment that contributes
to product quality or process efficiency, e.g.
i. a new machine (e.g. an injection blow
moulding machine)
ii. a new machine tool, (e.g. a 24 impression
mould replacing a 16 impression mould)
• New process software (e.g. new process
software from the existing supplier)
• New starting materials, (e.g. replacement
equivalent grade from a new supplier)
• Others where appropriate

95
Ref: Definition/References Explanation

PS 9000, reference 7.5.2 identifies specific examples

where validation and revalidation are required.

Similarly, control of change (see Annex A-Change

Control), needs to be incorporated within the
validation system, when the risk assessment, (see
Annex A-Risk Assessment), identifies that change
may introduce a significant risk of problems (to
organization or customer).

The VMP should include changes to, e.g.:

• equipment hardware, e.g.
i. refurbished moulds or tools
ii. full maintenance strip down and rebuild
iii. relocation of equipment to a new position
• process materials, e.g.
i. revised specification material from the
existing supplier
ii. the same specification material but made
through a different process.
iii. process materials delivered in a different
format, (e.g. quantity, presentation etc.)

2. Responsibilities for, e.g.:

• the validation protocol
• the trials
• the testing
• final acceptance authorisation

3. Equipment parameters, e.g.:

• operating conditions - according to theory or
practice
• control settings - running speeds/cycle times,
e.g. temperature/pressure

4. Product Specification, e.g.:

• confirmation - against existing specification
• compliance - against a draft specification
• variability - inside or outside specification

5. Trial conditions, e.g.:

• duration
• output quantity/units to be produced
• environmental controls

96
Ref: Definition/References Explanation

6. Sample evaluation, e.g.:

• Tests, (e.g. visual/measurement/function)
• units examined, e.g. from beginning, middle and
end of trial)
• test comparison with previous data
• test location, e.g. on site and/or at customer
• numbers retained, e.g. for future reference

7. Documentation responsibilities, e.g.:

• validation protocol preparation
• report preparation
• report circulation (to customer where
appropriate)
• report and protocol archiving
• revised operating/test procedures (where
applicable)

8. Training, e.g.:
• revised training where applicable, (and revised
training documentation)

9. Revision authorisation, e.g.:

• to process conditions and settings (organization)
• to product specification (organization and
customer)
• to procedures

10. Validation review, e.g.:

• completion review including any lessons from
the validation process

The success of an operational validation system

can be measured through the lack of problems
encountered following the introduction of new
hardware /software or after a change.

However even where a minor problem might be

encountered, the details can be reviewed and the
lessons built into the validation practice, as an
example of continual improvement.

97
98
 The Institute of Quality Assurance
Pharmaceutical Quality Group

PS 9004

A Guide to the GMP requirements

of PS 9000:2001 Pharmaceutical packaging materials

ANNEX B - OTHER EXTERNAL GMP REFERENCES

99
 B1. Code of Federal Regulations 21 Part 211
Current Good Manufacturing Practice for Finished Pharmaceuticals
(www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch.cfm
(select CFR Part No. 211 and search))

Ref. Summary PS 9000 Cross Reference

21 CFR
211.42(a) Building design to facilitate 9.1 Facilities, equipment and
cleaning and maintenance operating conditions
9.1.2 Facilities design
211.42(b) Adequate building space for orderly 9.1.2 Facilities design
placement of equipment and
material to prevent mix-ups
211.63 Equipment design to facilitate 9.1.3 Equipment and maintenance
cleaning and maintenance
211.67 Equipment cleaning and 9.1.4 Cleaning
maintenance
211.68(b) Electronic equipment change 4.2.3 Control of documents
control (Electronic)
4.2.4 Control of records
211.80(b) Off floor material storage 9.1.2 Facilities design
211.115 Procedures for reprocessing 9.1.10 Waste material (cross-
contamination control)
8.3 Control of non-conforming
product
211.122(e) Disposal of obsolete material 9.1.10 Waste material (cross-
contamination control)

12.5 Quarantine and destruction

211.122(f) Use of gang printed materials 13.5 Gang printing
211.130(a) Prevention of mix-ups and cross- 9.1.2 Facilities design
contamination by physical or 9.1.8 Segregation controls (cross-
spatial separation contamination control)
211.180 General Requirements (records and 4.2.4 Control of records
reports)
211.182 Equipment cleaning and use log 9.1.7 Line clearance (cross-
contamination control)
11.1 Origination procedures and
work areas
211.204 Returned products 8.3 Control of non-conforming
product

100
 B2. Rules and Guidance for Pharmaceutical
Manufacturers and Distributors 2002
(http://pharmacos.eudra.org/F2/eudralex/vol-4/home.htm)

EU Guide to Summary PS 9000 Cross Reference

Pharmaceutical GMP General information
Chapter 3.4 Protection against 9.1.5 Pest control
infestation
Chapter 3.8 Avoidance of cross- 9.1 Facilities, equipment and
contamination operating conditions
9.1.1 General
9.1.2 Facilities design
Chapter 3.36 Equipment cleaning 9.1.7 Line clearance (cross-
contamination control)
9.1.4 Cleaning
Chapter 4.8 Retention of records 4.2.4 Control of records
Chapter 4.22 Sampling procedures 8.2.4 Monitoring and measurement of
and precautions product
Chapter 5.22/5.23 Process changes 7.5.2 Validation of processes for
production and service provision
Chapter 5.35/5.45 Line clearance checks 9.1.7 Line clearance control (cross-
contamination control)
Chapter 5.54 Sample disposal 8.2.4 Monitoring and measurement of
product
Chapter 5.43 Obsolete material 9.1.10 Waste control (cross-
disposal contamination control)
Chapter 5.44 Physical segregation to 9.1.2 Facilities design
minimise risk of cross 9.1.8 Segregation controls (cross-
contamination contamination control)
Chapter 5.62 Reprocessing of 8.3 Control of nonconforming product
rejected product
Chapter 6.14 Sample retention 8.2.4 Monitoring and measurement of
product
Chapter 8 Complaints 8.3 Control of nonconforming product
Annex 8 (3) and (5) Supplier GMP 5.2 Customer focus
Annex 11 (2) Computer system 4.2.3 Control of documents (electronic)
validation 7.3.6 Design and development
validation
7.5.2 Validation of processes for
production and service provision

101
EU Guide to Summary PS 9000 Cross Reference
Pharmaceutical GMP General information
Annex 15 (43) and (44) Change control 4.2.3 Control of documents (electronic)
7.2.3 Customer communication
7.3.2 Design and development inputs
7.5.2 Validation of processes for
production and service provision
Annex 16 (8) Finished product 7.2 Customer related processes
batch certification 7.4 Purchasing
that manufacture
and testing are in
compliance with the
marketing authorisation
Annex 18 (9) Labelling of active 7.4.3 Verification of purchased product
pharmaceutical 7.5.3 Identification and traceability
ingredients 7.5.5 Preservation of product

102
 B3. MHRA Defect Investigations

Defect Type Report Received

Year 02/03 Year 01/02 Year 00/01
Noncompliance to product 6 19 16 This table includes
specification (stability) all formal defect
ADR (adverse drug 9 16 23 investigations
reaction) carried out by
the MHRA,
Product mix-up 3 14 18 whether they
Noncompliance to product 11 12 9 were confirmed
specification (analytical) as quality defects
or not. Some of
Other 77 10 29
these investigations
Other particulates 15 9 14 resulted in batch
recalls.
Wrong data 0 9 18
Label mix-up 6 8 13 It does not include
Container 5 7 6 all defects reported
to the MHRA or
Leaflet Missing/mix-up 12 5 9 all investigations
Closure Fault 1 4 3 carried out by
licence holders and
Precipitation 2 4 1
not reported to the
Label details missing 6 4 0 MHRA.
Lack of efficacy 12 4 0
Some headings are
Lack of sterility assurance 5 3 2 very similar, and in
Re-labelling error 21 3 5 most cases could
be combined, e.g.
Glass particulates 6 2 2 product mix-up is
Adulteration 1 2 0 usually where the
wrong tablets are
Under fill 1 2 5
found in a pack.
Wrong data/poor print 3 1 0
Acknowledgement
Fibre particles 1 1 0
to:
Solubility 0 1 0 The Defective
Wrong fill 3 0 3 Medicines Report
Centre
Bacteria contamination 3 0 2 MHRA
Mould Contamination 1 0 1 May 2003
Label Missing 2 0 1
Poor Print 0 0 3
Total 212 140 183

103
INDEX PAGE

A
Admixture 12, 14, 28, 30, 31, 56, 60, 66, 68, 69, 78,
79, 86, 89, 92
Agreements 5, 25, 50, 69, 71
Archive 38
Artwork 12, 25, 27, 56, 57, 69, 70, 71, 72, 92
Audit 23, 25, 26, 28, 30, 38, 40, 42, 44, 45, 47,
55, 61, 65, 67, 69, 74

B
Bar code (see also codes) 24, 29, 69, 68
Bar code (readers, scanners) 28, 30, 69, 78, 83
Batch samples (see also samples)
Bench mark 42, 43, 61
Bioburden 48
Blister (pack) 25, 28, 29, 32
Business processes xv, 2
Bottles 26, 29, 30

C
Calibration 16, 54, 58
Case studies ix, 21-32
Certificate/certification 17, 30, 41, 45, 55
Change (control) 6,10, 24, 25, 26, 49, 50, 51, 53, 56, 67, 73,
80, 84, 88, 89, 90,91, 94, 95, 96, 97, 100,
101
Clearance (see also line clearance) 13, 15
Clean areas (rooms) 48, 94
Cleaning xvi, 48, 54, 67, 88, 89, 100, 101
Closures 30
Codes (see also bar codes) 28, 30, 68, 71 , 72
Code of Federal Regulations (CFR) xiv, 79, 83, 91, 92, 100
Complaints 24, 51, 61, 62, 63, 69, 84, 101
Contaminate (contamination) 15, 26, 27, 47,48, 56, 60, 66, 67, 68, 69,
70, 88

104
 INDEX PAGE

Continual improvement 3, 23, 39, 41, 42, 45, 57, 59, 65, 85, 97
Contract 5, 25, 30, 51, 61, 75
Corrective (action) 31, 44, 61, 65
Counterfeit 40, 56, 82, 83
Cross contamination 40, 41, 46, 47, 65, 66, 68, 72, 74, 78, 82,
83, 86, 88, 92, 100, 101

D
Defective Medicines Report Centre 103
Defect (prevention) 94
Design 4, 13, 24, 50, 52, 53, 58, 66, 67, 68, 70,
71, 72, 73, 80, 84, 88, 94, 100, 101, 102
Development 40, 52, 53, 56, 58, 80, 94
Disposal (dispose) 40, 72, 73, 83, 100, 101
Distribution 18, 19

E
Efficiency 44, 68, 85, 94,95
Environment xvi, 5, 48, 53, 57, 67, 87
Environmental (conditions/control) 41, 57, 66, 67, 85, 87, 88, 96
Errors 8, 10, 12, 14, 16, 17, 18, 27, 28, 29, 30,
31, 46, 66, 69, 70, 73, 74, 103
European Commission 52
Expiry (see shelf life) 84

F
Film 24, 32, 33
FMEA (Failure mode and effect
analysis) 90
Feedback 61, 69
Foil 6, 28, 29
Food and Drug Administration (FDA) 82

G
Gang printing 74, 75, 78, 79, 100

105
 INDEX PAGE

Gap analysis 46
Good Manufacturing Practice (GMP) iii, vii, ix, xvi, 15, 23, 40, 43, 46, 47, 62, 66,
68, 70, 72, 74, 78, 84, 88, 100, 101

I
Identification (see also traceability) 7, 8, 27, 51, 55, 56, 57, 58, 67, 69, 70, 72,
73, 84, 85, 89, 91, 102
Improve/improvement 32, 44, 45, 59, 64, 65
Incidents 31, 67,
Infestation xv, 9, 101
In process controls 15, 27, 29, 63, 71, 73
Insects 15
Institute of Quality Assurance (IQA) iv, v, vii
ISO (International Standards
Organization) ii, ix

L
Labels/labelling xv, 7, 8, 15, 17, 19, 24, 25, 26, 27, 28, 29,
30, 31, 58, 69, 78, 83, 89, 102
Laminate 32, 33
Leaflets 25, 28, 29, 30, 69
Line clearance (see also cleaning) 7, 13, 15, 28, 29, 66, 67, 69, 70, 71, 74,
75, 78, 86, 87, 100, 101

M
Maintenance 6, 7, 10, 27, 47, 54, 66, 67, 87, 96, 100
Management review 23, 39, 42, 44, 65
Marketing Authorisation (MA) 50, 54, 102
Material disposal 67,73, 83

106
 INDEX PAGE

Media (print) 6, 12, 38, 70, 72, 73, 75, 82, 83, 84
MHRA (Medicines and Healthcare
products Regulatory Agency) vii, xiv, 78, 84, 103
Microbial contamination (moulds) 48, 66, 103
Mislabelling 7, 78
Mix-ups 9, 12, 23, 28, 46, 72, 74, 78, 79, 86,
88, 92, 100, 103
Moulds (see also tooling) 6, 14, 26, 27, 57, 89, 95, 96

O
Orange Guide
(see Rules and Guidance for
Pharmaceutical Manufacturers
and Distributors 2002)

P
Partners Team xi, xii
Pests xv, xvi, 9, 26, 67, 88, 101
Pharmaceutical Quality Group i, iv, v, vii, xii
Plan/planning 7, 42, 80
Preparation 10
Preventive (actions) vii, 23, 27, 30, 31, 44, 65, 66, 70, 86, 94
Print (Printing) 12, 13, 14, 15, 18, 25, 26, 27, 28, 29, 68,
69, 70
Print impression/ media 12, 13, 70, 72, 73
Product Authorisation/
Licence (PL) 32, 50
Project team (PS 9004) xi, xii
Procedures (see also SOPs) 3, 16, 26, 28, 29, 30, 31, 37, 38, 43, 46,
55, 61, 63, 66, 67, 86, 90, 97, 100

Q
Qualification (and validation) 69, 94

107
 INDEX PAGE

Quality Assurance (QA) 29, 30, 40, 43

Quality Control (QC) 8, 17, 28
Quality Management System (QMS) ix, x, 2, 37, 38, 39, 42, 43, 44, 45, 46, 59,
64, 65, 84
Quality manual 38
Quality plan 49
Quality policy 39, 41, 42, 44, 65, 82
Quarantine 29, 54, 55, 63, 73, 82, 100

R
Recall 25, 28, 47, 78, 86, 103
Reconciliation 17
Records xvi, 12, 13, 29, 40, 49, 51, 53, 55, 56, 57,
58, 61, 63, 65, 67, 69, 71, 73, 75, 80, 84, 87,
89, 91, 100, 101
Recovery (reprocessing/rework) 25, 62, 63, 88, 89, 101
Regulations/regulatory vii, x, 25, 38, 40, 42, 43, 47, 48, 50, 51, 52,
53, 84, 90, 95
Registered product 50
Returned product 62, 63, 100
Risk vii, 4, 27, 30, 47, 52, 53, 54, 56, 60, 66, 68,
74, 78, 82 ,89, 90
Risk areas ix, x, xv, 46, 52, 53, 60, 74, 92
Risk assessment 26, 53, 62, 63, 65, 75, 79, 80, 88, 89, 90, 96
Rogues (see also admixture,
mix-ups, strangers) 8, 29, 30, 66, 78, 86, 87, 88, 92
Rules and Guidance for
Pharmaceutical Manufacturers
and Distributors 2002 xiv, 52, 60, 72, 80, 101

S
Safety 24, 52, 53, 56, 66
Samples/sampling 8, 13, 16, 28, 52, 53, 60, 61, 73, 75, 86,
97, 101

108
INDEX PAGE

Security 7, 40, 41, 47, 54, 60, 61, 62, 63, 68, 69,
70, 72, 74, 75, 87
Segregate/segregation 14, 15, 18, 29, 30, 31, 47, 62, 66, 67, 70,
73, 75, 78, 89, 92, 100, 101
Separation 88, 992, 100
Shelf life 38, 56, 80
Specification xvi, 6, 17, 29, 40, 49, 51, 53, 55, 57, 58,
63, 66, 69, 71, 72, 73, 75, 80, 90, 91, 96,
97, 103
Stability 25, 33, 50, 52, 66, 86
Standard Operating Procedures
(SOPs) (see also procedures) 3, 66
Storage 18, 26, 27, 53, 62, 69, 71, 75, 83, 100
Sterile/sterilization 30, 48
Syringe 26, 27, 30
Sub-contract 54, 55

T
The Pharmaceutical Journal 83
Tool/tooling 10, 11, 26, 27, 53, 89, 90, 95, 96
Traceability (see also identification) 38, 56, 57, 62, 69, 71, 72, 75, 80, 84, 85
Training ix, x, 2, 15 ,16, 24, 25, 28, 29, 30, 32, 37,
38, 40, 43, 46, 53, 57, 67, 75, 78, 86, 89,
90, 97
Transit (damage) 8, 9, 18, 19, 31

V
Validation (see also qualification) 4, 10, 16, 24, 26, 38, 48, 49, 52, 53, 56,
57, 65, 69, 80, 89, 91, 94, 95, 96, 97, 101,
102
Vials 25, 26

109
INDEX PAGE

W
Warehouse 8, 26, 31, 57
Waste (materials) 14, 15, 23, 25, 40, 57, 67, 82, 83, 84, 86,
88, 90, 101
World Health Organisation (WHO) 82

110
A Guide to the GMP requirements
of PS 9000:2001 Pharmaceutical
packaging materials

The Institute of Quality Assurance

Pharmaceutical Quality Group