VALIDATION MASTER PLAN

Project : Oral Solid Dosage Forms

PRIME PHARMACEUTICALS Document No. : PRIME/VMP/001
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1.0 APPROVAL

This Validation Master Plan (VMP) has been reviewed and approved by following –

Name Position Signature Date

Asst. Quality Control Manager
Written by Md. Atiqullah
& Validation Coordinator
Md. Nasim Ahamad Production Officer
Reviewed by
Md. Nahid Sarour Quality Control Officer
Approved by Md. Boctiar Ahamad (Factory In Manager)

Note : After approvals any revision in this document shall meet all requirements of change control and
necessary history of changes made shall be maintained.

A distribution list of this document with records shall be maintained.

2.0 REVISION HISTORY

Issue Sections Page/ Annexure Summary of Reasons for Date

Changes Changes

00 Initial Document

TABLE OF CONTENTS

Chapter No. Title Page No.

1.0 Approval 01
2.0 Revision History 01
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3.0 Introduction 05
3.1 Overview of the Project 05
3.2 Plant Location 05
3.3 Corporate Head Office 05
3.4 Brief Outline of the Project 05
3.4.1 Processes 06
3.5 Process Stages 06
3.5.1 Bulk Manufacturing 06
3.5.2 Formulation / Mixing / Granulation / Compression / Filling / Packaging 06
3.6 Operations 06
4.0 Building & Facilities 08
5.0 Scope 09
6.0 Validation Strategy 10
7.0 Validation Philosophy 11
7.1 Fundamentals of Qualification / Validation 11
7.2 Concepts of Validation Life Cycle 12
8.0 HVAC Description 13
8.1 Critical Equipment & Systems (Direct Impact Systems) 13
8.1.1 Qualification of Direct Impact (Critical) Equipment & Systems 14
8.2 Indirect Impact & No Impact (Non-Critical) Equipment & Systems 15
8.2.1 Qualification of Indirect Impact & No Impact (Non-Critical) Equipment & 15
Systems
8.3 Premises Qualification 16
8.4 Microbiological Method Validation 16
8.5 Process Validation 16
8.6 Product Validation 16
8.7 Cleaning Validation 16
9.0 Validation Organization 17
Chapter No. Title Page No.
9.1 Validation Board & Team 17
9.1.1 Validation Board 18
9.1.2 Validation Team 18
9.2 Validation Team Responsibility 18
9.2.1 Validation Coordinator 18
9.2.2 Engineering 18
9.2.3 Quality Assurance, Quality Control & Quality Compliance 19
9.2.3.1 Quality Assurance 19
9.2.3.2 Quality Control 19
9.2.3.3 Quality Compliance 19
9.2.4 Production 20
9.2.5 External Validation Support (External Source / Vendors) 20
10.0 Facility Description 21
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10.1 Brief Description of Facility 21

10.2 Zoning Concept 21
10.3 Surfaces 21
11.0 Description of Utilities 22
11.1 Systems with Turn-over Packages (TOPs) 22
11.1.1 HVAC System 22
11.1.2 Purified Water System 22
11.1.3 Pure Steam System 22
11.1.4 Compressed Air 22
11.2 Systems with Certification Packages 23
11.2.1 Compressed Air System 23
11.2.2 Plant Steam 23
11.2.3 Potable Water System 23
11.2.4 Electrical Power 23
12.0 Description of the Process Equipment 24
13.0 Equipment History Files 26
14.0 Qualification and Validation Approach 27
14.1 Validation Master Plan 28
14.2 User Requirement Specification (URS) 30
Chapter No. Title Page No.
14.3 Design Qualification 30
14.4 Functional Specification 30
14.5 Risk Analysis 30
14.6 Installation Qualification 30
14.7 Operational Qualification / Performance Qualification 31
14.8 Analytical Method Validation 31
14.9 Process Validation 31
14.10 Cleaning Validation 32
14.11 Raw Material Qualification 33
14.12 Validation Protocols 34
14.13 Validation Report 34
14.14 Validation Schedule 34
14.15 Revalidation 34
15.0 Validation Support Programs 35
15.1 Standard Operating Procedures 35
15.2 Environment / Water Monitoring Program 36
15.3 Water Quality Monitoring 36
15.4 Calibration Program 36
15.5 Preventive Maintenance Program 37
15.6 Training Program 37
15.7 Out of Specification 38
15.8 Change Control Program 38
15.9 Document Handling 39
16.0 Key Personnel 40
17.0 Production Facility 42
18.0 Quality Control 46
19.0 Product Development 48
20.0 Glossary of Terms Used 51
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21.0 List of Annexures 54

3.0 INTRODUCTION

3.1 Overview of the Project

This VMP relates to the facility of Oral Solid Dosage Forms of products in line with GMP standards. The
facility will provide manufactured tablets and capsules’ products. The facility has been undertaken in view of
increasing number of products, capacity enhancement & compliance with the requirements of GMP.

3.2 Plant Location

Tepirbari, P. O. Sreepur, Gazipur, Bangladesh

Tel : +88-0721-9357257, 8311407
Fax : +88-02-9336875
Email : [email protected]

3.3 Corporate Head Office

City Heart Building (8th Floor),
Suite-9/7,67,Nayapaltan,Motijheel,
Dhaka – 1000, Bangladesh
Tel : +88-0721-9357257, 8311407
Fax : +88-02-9336875
Email : [email protected]

3.4 Brief Outline of the Project

Prime Pharmaeuticals Ltd. installed and commissioned the project for Oral solid dosage manufacturing area
for production of oral solid dosage forms of products at Gazipur manufacturing facility in the year 2007.

The project includes :

 Testing and re-commissioning of HVAC (Heating Ventilation & Air Conditioning).

 Installation, testing & commissioning of new process equipment.
 Testing and re-commissioning of existing process equipment.
 Testing and re-commissioning of process piping and utilities piping.

This Manufacturing facility will be used for the manufacture of –

1. Tablet products of Prime Pharmaceuticals Ltd.
2. Capsule products of Prime Pharmaceuticals Ltd.
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3. Contract manufactured products under the license of Directorate of Drugs, Govt. of Bangladesh

The facility will have in-house formulation and granulation, mixing, compression, coating, encapsulation,
packaging operations. In general, the manufacturing facility design shall take into account certain important
logical considerations such as –

a. Man and material flow considerations so as to eliminate / minimize any chances of unwanted
movements of staff and materials, which could result in issues of cross contamination.
b. Enough working space to be provided depending on the nature and volume of operation to be
handled.
c. Placement of equipments complying with GMP requirements with optimum scope for provision
of necessary utility connections to them.
d. Capacity calculations based on two shift working basis to take care of all future increases in
production.
e. Optimal use of all available resources especially the utilities.

3.4.1 Processes

The facility is, designed as a multi product facility with operation. Within each stream, production will be
made on campaign basis.

The bulk shall be formulated into finished dosage forms as below –

a. Granulation, Compression and Packaging of uncoated tablets.

b. Granulation, Compression, Coating and Packaging of coated tablets.
c. Mixing, Encapsulation and Packaging of Capsules.

3.5 Process Stages

The facility design has provided for the following process stages –

3.5.1 Bulk Manufacturing

Granulation / Mixing

3.5.2 Formulation/Mixing/Granulation/Compression/Filling/Packaging

1. Formulating
2. Mixing / Granulation
3. Encapsulation
4. Packaging

These unit operations are representative of the type of operations carried out in the facility in its lifetime.
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3.6 Operations

The facility is designed to carry out following operations.

1. Receipt of materials.
2. Sampling of materials.
3. Inspection of materials.

4. Dispensing and issue of materials.

5. Manufacturing.
6. Packing.
7. In process and final product quality control.

These operations are supported by other activities like –

1. Utilities generation, storage and distribution.

2. Warehousing.
3. Quality Control and Assurance.
4. Security and Administration.
5. Maintenance & Engineering.
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4.0 BUILDINGS & FACILITIES

Production facilities & equipments are located, designed, constructed, adapted and maintained to suit the
operation to be carried out. Their lay out and design aim to minimize the risk of errors, cross contamination,
to prevent mix-ups between different components, drug products, containers, closures, labelling and permit
effective cleaning and maintenance in order to prevent cross contamination, build up of dust or dirt and, in
general, any adverse effect on the quality of products.
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5.0 SCOPE

The purpose of this VMP is to ensure that the validation policy of CLL is enforced at the project for oral solid
dosage forms production facility. The VMP is intended to facilitate an overview of the entire validation
operation, validation strategy, its organizational structure, its content, planning, schedules and
responsibilities. The core of validation planning is the inventory of items to be qualified, based on a GMP
Risk Assessment.

The VMP shall be the route map and itinerary for the validation of the project. It shall be the formal
documentation of the essential planning and preparation that are pre-requisite to an orderly,
comprehensive, structured, pre-agreed and well managed validation exercise.

The VMP shall present the purpose of conducting the validation and CLL’s intent to comply with regulatory
requirements. The VMP shall describe the Qualification / Validation approach in compliance with company
policy and the validation activities to be completed between the design engineering and start-up of the
project for oral solid production facility of CLL.

The VMP shall direct to the more specific, detailed documents such as protocols, reports and documentation
preparation and their control, SOPs and personnel training records.

The VMP shall also list systems, facilities, critical utility, equipment, analytical methods, test procedures and
processes that are subject to validation, applicable validation and qualification protocols and procedures. It
shall outline test procedures, acceptance criteria and protocols to be followed to complete validation
activities.

This VMP is not limited to qualification of computer system at the plant which will be taken in future plan.

Additional programs such as revalidation, training, calibration and preventive maintenance, which are
necessary for compliance with GMP regulations and ongoing control, shall also be referenced.
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6.0 VALIDATION STRATEGY

The purpose of this VMP is to present in a single coherent document CLL’s plan for those activities, when
completed will result in the list of items (systems, facilities, critical utility, equipment, analytical methods,
test procedures and processes) mentioned above being validated.

This VMP is limited to the Validation / Qualification activities for the new project for multi-purpose solid
dosage production facility.

The VMP shall provide a brief description of the facility, the processes involved and the use of all equipment
and services within the production facility.

The facility shall be used for the manufacturing, processing and primary packaging of oral solid products.

The products to be manufactured in the facility shall employ existing as well as new process equipment.
Personnel, materials and component flow throughout the building shall be described in the VMP.

The VMP will delineate the scope of validation appropriate to each of the areas that need to be validated.

This VMP provides a detailed description of the Qualification and Validation Philosophy that will be used for
the qualification of process equipment, premises and utility systems and for process validations.

The VMP will cover all the requirements for the following qualification stages –

The following components will undergo the qualification and validation activities described in this VMP.

a. Premises inclusive of HVAC system.

b. Process Equipment and Utility systems.
c. Analytical Methods.
d. Processes.
e. Cleaning Validation.

The process equipment and systems are divided into two categories as under based on their impact on the
compliance of the facility to required specifications and regulatory requirements.
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7.0 VALIDATION PHILOSOPHY

The VMP is intended to be a “live” document that initially supports the design and construction of the facility
and subsequently the operation, maintenance and change of the facility for its entire life. It will provide the
basis for validation and quality system activities required for GMP compliance. This will enable the validated
production, processing, storage and distribution of a range of oral solid dosage medicinal products under the
control of an appropriate quality system.

The VMP may be revised as appropriate to incorporate changes and/or additions to the facility and/or
products.

Using current pharmaceutical industry guidelines, the validation steps and activities will be designed to
address all critical product attributes and process steps whilst minimizing un-necessary work. This will be
achieved by employing techniques such as Impact Assessment & Risk assessment, in order to focus
validation activity onto those systems critical to product quality.

The validation process will follow these basic group headings as applicable –

 Quality Plan.
 Design Reviews.
 Factory Acceptance Testing (FAT) / Commissioning.
 Installation Qualification.
 Site Acceptance Testing (SAT) / Operational / Performance Qualification.
 Process Validation.
 Cleaning Validation.
 Analytical Method Validation.

The validation activities will be incorporated into project design, construction programs and production
schedules. The objectives of this are to integrate similar activities, e.g., SAT with OQ, and thus reduce
duplication of tests and checks to a minimum.

7.1 Fundamentals of Qualification / Validation

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The manufacturing equipment requires DQ, IQ, OQ & PQ. The same should be done for support systems
like HVAC, utilities like purified water, compressed air, nitrogen gas.

After successful qualification of Machinery & Utilities support systems, process validation should be
commenced. The process validation should be done in consecutive 3 batches with study of physical,
chemical and/or microbiological tests, as per specification, which must be checked in validation batches.

7.2 Concepts of Validation Life Cycle

The validation life cycle is presented schematically as follows –

VALIDATION MASTER PLAN

Design Cleaning
Revalidation Risk Analysis
Qualification Validation

Installation Operational Performance Process

Qualification Qualification Qualification Validation

Computer
Validation
Monitoring, Maintenance,
Validation Report
Change Control

Fig : Validation Life Cycle

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8.0 HVAC DESCRIPTION

HVAC for oral dosage facilities will have adequate supply of filtered air to the various process zones, must
be grade D in production zone & in surrounding sub-critical work zones. The packing area must be covered
by controlled air as to minimize risk of particle contamination in sub-critical & critical work zones. The supply
air of HVAC must be filtered sequentially through 60%, 90-95% & finally 99.97%. The relative humidity
must be 45±10% in production area & surrounding areas. Temperature in the area must be 22°C±4°C.

Zoning concept for the production of non-sterile oral solid dosage form of products applicable to health care
sectors of Chemico Laboratories Limited is applicable to Production Unit engaged in the production, testing,
packaging or storage of oral solid dosage form of products.

For existing facilities, actual environmental control specification may deviate, as long as they have proven to
have no negative impact on the clean zone requirements (particle counts & microbiological counts) and as
long as product quality is not adversely affected.

8.1 Critical Equipment & Systems (Direct Impact Systems)

The first step in the qualification process is to carry out a System Impact Assessment. This is the process by
which the potential impact on product quality of systems and components is identified.

There are three levels of impact that are defined, ‘direct impact’, ‘indirect impact’ or ‘n impact’. Direct impact
systems require qualification, whilst indirect or no impact systems only require good engineering practice to
be applied, but indirect impact systems should also be subject to documented commissioning.
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The method for identifying system impact is illustrated below –

Identify Systems

Identify System
Boundaries

Does the System YES

have a Direct Impact
on Product Quality ?

Is the System YES “INDIRECT “DIRECT

linked to a Direct IMPACT” IMPACT”
Impact System ? SYSTEM SYSTEM

NO

“NO IMPACT” SYSTEM Document Decisions & Rationale

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Critical components shall be identified within direct impact systems so that these may be assessed for
qualification. A critical component is one where its operation, data, control, alarm or failure may have a
direct impact on the quality of the product.

Participants in the Impact Assessment should be appropriately qualified stakeholders, and their participation
should be noted on the document, which should be approved by the job holders who approve the VMP.

8.1.1 Qualification of Direct Impact (Critical) Equipment & Systems

The Direct Impact (critical) equipment and systems will follow a detailed sequence of activities in order to
achieve the required stages of qualification as follows as applicable.

New Equipment & Systems :

1. User Requirement Specification (URS).
2. URS Verification.
3. Functional Specifications (FS).
4. Vendor Enquiry Sheets.
5. Technical Evaluation of Vendors’ offers.
6. Final Design Qualification Documentation.
7. Review of Vendor Documentation.
8. Inspection Scheduling & Inspection Reports.
9. Factory Acceptance Testing (FAT).
10. Site Acceptance Testing (SAT).
11. Installation Qualification (IQ).
12. Operational Qualification (OQ).
13. Performance Qualification (PQ).
Existing Equipment & Systems :
1. Retrospective User Requirement Specification.
2. URS Verification.
3. Functional Specifications (FS).
4. Final Design Qualification Documentation.
5. Review of Available Vendor Documentation.
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6. Operational Qualification.
7. Performance Qualification.

The documentation generated at each stage will be reviewed, approved and archived so as to achieve
complete traceability and shall be used for the purpose of auditing the equipment and systems. Such
documentation binders will be called as Turn Over Packages (TOPs).

8.2 Indirect Impact & No Impact (Non – Critical) Equipment & Systems

Please refer to the Annexure – III in separate folder for the list of Indirect Impact & No Impact (Non-
Critical) equipments & systems.

8.2.1 Qualification of Indirect Impact & No Impact (Non-Critical)

Equipment & Systems

The Indirect Impact & No Impact (non-critical) equipment and systems will follow a detailed sequence of
activities as per GEP in order to achieve the required stage of qualification as follows as applicable –

1. User Requirement Specification (URS).

2. URS Verification
3. Functional Specifications (FS).
4. Final Design Specification.
5. Review of Available Vendor Documentation.

6. Performance Testing & Certification.

8.3 Premises Qualification

The Premises is a term used to encompass the individual components like the building, surfaces, HVAC
system, drains, doors and windows and other hardware that make up the physical structure of the plant. Of
these, the HVAC system is incorporated in the critical equipment and systems list.

The other critical elements like the surfaces, doors and windows, the drains, the light fixtures etc. shall be
qualified before the HVAC validation is done using a pre-defined Room Specification sheet and procedures.
Room data sheet will be filed in a separate annexure.

8.4 Microbiological Method Validation

Microbiological methods that are employed to ascertain the microbiological quality of the formulated product
and hence considered critical, shall be subjected to microbiological method validation.

A method specific validation protocol shall be prepared & approved. The test method shall be subjected to
its validation as per the protocol. If the method meets the acceptance criteria as outlined under this protocol
then the data shall be approved and only then this validated microbiological method shall be employed for
its routine microbiological testing purposes.
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8.5 Process Validation

These comprise of the unit operations used in the manufacturing stages as well as stand-alone processes
like cleaning, drying operations. These validations will be performed using pre-defined protocols for the
purpose.

8.6 Product Validation

The product validation will be carried out by manufacturing the products under various challenged
conditions including the worst-case conditions to arrive at the most optimum process parameters. The
exercise will be carried out using pre-defined protocols for the purpose. The product is considered validated
when three consecutive lots of the product comply with all the specifications applicable to the product.

8.7 Cleaning Validation

Using the pre-defined protocol the cleaning validations shall be carried out. A product matrix followed by the
worst-case validation shall be observed. Routine cleaning verification shall be followed thereafter on a
routine basis between product changeovers.

9.0 VALIDATION ORGANIZATION

A team headed by the Validation Coordinator and supported by functional specialists from within the CLL
organization as well as from the consultants to the project shall carry out the validation activities.

9.1 Validation Board & Team (Validation Steering Committee).

The organization of the Validation Steering Committee & team is given below -

Validation Board
(Review & Approval)

1. Md. Bokhtiar Ahama, Factory in Charge.

2. Md. Atiqullah Asst. Quality Control Manager, Operations (Head).
3. Md. Nasim ahamad, Production , (Head).
4.Md.Abul Hasan,QC(Head)
4. Mr. Sajal Das, Engineering (Head).

Validation Coordinator
(Control & Review)

Md. Golam Kibria, Quality Assurance Manager

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Validation Team External Team

(Execution) (Guidance & Support)

1. Md. Anwar Pervez, Asstt. Manager, QC

2. Mr. Ashique Ahmed, Deputy Manager, R & D
3. Mr. Abdul Hye, Deputy Manager, Production
4. Md. Samiul Hossain, QC Officer
5. Md. Mizanur Rahhman, QC Officer
6. Md. Zakir Hassan, Sr. Production Officer
7. Md. Sharifuzzaman Khan, Asstt. QC Officer
8. Md. S. M. Mustafizur Rahman, Sr. Engineering Officer

9.1.1 Validation Board

The members of the board will review and approve the VMP and also provide adequate resources to ensure
that the validation activities are carried out satisfactorily. The members included on the board shall be the
Head, Production, Engineering and Quality Assurance.

9.1.2 Validation Team

For the execution and compilation of all validation activities, the validation team shall comprise of
representatives from Production, Engineering, Quality Control and Quality Assurance (as validation
coordinator).

Besides the above, a validation coordinator from external source and necessary representatives from
concerned vendors shall form a part of the validation team as and when required.

This validation team will carry the responsibility and authority to manage the execution of the validation
program and to complete this program. It will also ensure that the facility remains in a state of validation
and qualification by ensuring that execution of the validation plan and completion of all the listed activities
as scheduled. This also ensures that all the systems are in place to assure the product quality. The board /
team will meet at frequent intervals to review the validation status and execution program.

9.2 Validation Team Responsibility

The responsibilities of the key personnel for validation are as follows –

9.2.1 Validation Coordinator

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1. Coordination of all validation activities from concept till commissioning.

2. Coordination of preparing URS for the Facility / Utility / System / Equipment.
3. Coordination of preparing and checking of VMP and Validation Protocols.
4. To monitor validation activities and track the progress and ensure completion of the validation
program on time.
5. Coordination of compiling and analysis for the validation data and test results.
6. Coordination of preparing for the final report of all validation activities.

9.2.2 Engineering

1. To ensure that there are adequate resources to execute the Engineering aspects of the VMP.
2. To co-ordinate with the consultants for all validation activities and related documents.
3. To review the VMP.
4. To review and approve the facility design for compliance to regulatory norms and required
product, personnel and environment protection needs including the manpower, material, waste and
equipment flows, HVAC and AHU zoning.

5. To prepare URS for utility systems and support systems. To prepare DQ documents in co-
ordination with the user.
6. To conduct DQ / IQ along with vendors and user, prepare reports and support validation
program.
7. To support PQ activity of purified water system and non-lubricated compressed air system.
8. To establish various SOPs for utility systems.
9. To provide training and management of personnel.

9.2.3 Quality Assurance, Quality Control & Quality Compliance

9.2.3.1 Quality Assurance

1. To review and approve the facility design for compliance to regulatory norms and the required
product, personnel and environment protection needs including the manpower, material, waste and
equipment flows, HVAC and AHU zoning.
2. To review the VMP.
3. To review and approve all validation documents, with respect to GMP compliance.
4. To establish QA system SOPs, assure the deployment of quality systems for GMP compliance.
5. To identify, organize and monitor GMP training.

9.2.3.2 Quality Control

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1. To review and approve Cleaning / Process Validation Protocols or Reports.

2. To conduct analytical method validation, if required.
3. Responsible for qualification of laboratory equipment.
4. Establish SOPs required for the operations in QC lab. Responsible for qualification of laboratory
equipment.
5. Establish SOPs required for the operations in QC lab.
6. To provide analytical and microbiological support for Cleaning & Process Validation.
7. To provide analytical and microbiological support for all qualification and validation activities.
8. To support PQ activities for Purified Water System, Non-Lubricated Compressed Air System &
HVAC system, in co-ordination with Engineering.
9. To support Qualification / Validation activities for process equipment in co-ordination with
Manufacturing.

9.2.3.3 Quality Compliance

To provide in-process inspection during process validation of products.

9.2.4 Production

1. To review and approve the facility design for compliance with regulatory norms and the
required product, personnel and environment protection needs including the manpower, material, waste and
equipment flows, HVAC and AHU zoning.
2. To prepare URS for Equipment and the resource to provide inputs for preparing URS for
Purified Water system and HVAC in co-ordination with engineering.
3. To assist Engineering in making DQ documents.
4. To prepare OQ / PQ Protocol / Reports for manufacturing & packing equipment.
5. To support PQ of HVAC system, Purified Water system in co-ordination with engineering.
6. To co-ordinate in preparing Process / Cleaning Validation Protocols & reporting with QA.
7. To execute Process / Cleaning Validation as per the protocol and co-ordinate in preparing the
final report.
8. Establish various SOPs for manufacturing and packing activities.
9. Ensure product processes remain in validated state.
10. To provide training and management of personnel.

9.2.5 External Validation Support (External Source / Vendors)

1. To participate in preparing the VMP.

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2. To support in the compilation of DQ documents.

3. In co-ordination with Validation team, execute FAT / IQ / OQ Protocols (Vendors).
4. To conduct stage-wise inspection of equipment, support systems and utility systems.
5. To participate in and support facility design and qualification of building construction (for GMP
compliance and respective regulatory norms).

10.0 FACILITY DESCRIPTION

10.1 Brief Description of Facility

Annexure – I comprises of the following drawings and schematic diagrams, which have been reviewed and
approved by the concerned persons.

Architectural and structural drawings comprising of –

1. Plot Plan (Oral Solid Plant Positioning).

2. Lay out Plans (Room layout).
3. Air Class Zoning.

10.2 Zoning Concept

The clean room zoning is defined as per the ISO 14644 Part – I classification (equivalence to clean room
classification of Guidance to Validation of Aseptic Processes, CDER, September 2004 is provided).

The localized area within this room where the final product or a component or container is exposed to
external environment will be protected by a Vertical down flow Laminar Flow (VLF) unit to provide an ISO
Class 8 protection equivalent to Class 1,00,000 of the superseded US Federal Standard 209E.
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Areas other than clean rooms will be provided with ventilation systems with or without temperature control
as required. The systems providing control over temperature are called A/C systems while those without
such a control are called Ventilation Systems.

The clean room air handling systems as well as the ventilation systems will serve the objectives of
maintaining the temperature, pressure as well as relative humidity in the pre-defined range in the rooms
served by them.

10.3 Surfaces

In order to achieve and maintain the desired clean room conditions in both the static as well as dynamic
conditions, the surfaces in the manufacturing rooms will be designed so as to minimize generation as well as
accumulation of viable and non-viable particulates. To achieve this, the surfaces shall be designed
accordingly. A brief description of surfaces, the drain types as well as utilities entering the rooms is provided
in the Room Data sheets as shown in separate Annexure.

11.0 DESCRIPTION OF UTILITIES

The following is a brief description of the various utilities that shall be used in the facility. The GMP
impacting systems shall undergo the complete qualification routing.

11.1 Systems with Turn – Over – Packages (TOPs)

11.1.1 HVAC System

This system is used to supply environmental treated air to the various processing areas and to maintain
appropriate pressure differentials as per the class of the room as specified in the room data sheets. There
are separate Air Handling Units as shown in the drawing attached to this VMP as Annexure – I, catering to
the various areas requiring the attainment of the desired classification.

All the Air Handling Systems shall be validated through Design, Installation and Operational qualification.
The protocols for the same shall be developed to correctly assess the performance of the systems so as to
assure that the areas do comply with the specification as identified in the room data sheets.

The HVAC systems shall be designed to assure adequate control over temperature, humidity and air
pressurization. Sufficient number of air changes per hour shall be designed to assure the achievement and
maintenance of air cleanliness levels over a long period of time.
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All the systems shall be designed, installed and commissioned under proper controls and all documentation
generated to trace the Qualification Processes.

11.1.2 Purified Water System

The purified water required for the processing is generated through a RO system. The system shall be
validated through a design, installation and operational qualification procedure as per pre-defined protocols.
This water shall meet the requirements for purified water as specified in BP. The water shall be produced
from Potable Water & Purified Water generated shall be received in a storage tank. The sanitization of this
system shall be achieved through hot water / chlorination at regular frequencies and also be provided with
adequate number and types of filters and UV stations to ensure that the process objectives are complied
with.

11.1.3 Pure Steam System

The pure steam required for the processes like the paste making for granulation operations shall be
generated through a Pure Steam Generator. This system shall be validated through a design, installation
and operational qualification procedure as per pre-defined protocols. The pure steam shall be produced
from Purified Water USP and it will be supplied to the points of use through a piping system.

11.1.4 Compressed Air

The compressed air that will come in contact with the product or product containing equipment at any point
of time shall be generated using an oil free compressor and will be appropriately filtered before use to
achieve the desired level of cleanliness. The system for generation, storage and distribution of oil free
compressed air shall undergo the design, installation, operational and performance qualification.

11.2 Systems with Certification Packages (CP)

11.2.1 Compressed Air System

This system shall be used to generate compressed air, which is utilized for product non-contact applications
like the pneumatic systems. The system shall be qualified through a design and installation qualification
process.

11.2.2 Plant Steam

This system shall be used to generate steam for product non-contact operations like heating of liquids in
Jacketed Vessels etc.

Boiler shall be installed to generate house or raw steam and shall be distributed as and where needed in the
manufacturing block and in utility generations.

11.2.3 Potable Water System

The Potable Water System shall be designed to meet the input as per WHO / EPA requirements for the
Purified Water System. The Potable Water may be utilized for drinking purposes, plant washings, pre-
washes of the laboratory equipment and other product non-contact operations. A suitable filtration, re-
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circulation and drainage system shall be designed to ensure the compliance of process objectives. The
system shall be qualified through design, installation and operational qualification as per a predetermined
protocol.

11.2.4 Electrical Power

Electrical power will be used through generator operated by oil and in the event of any power failure;
electrical power shall be put into use from the State Board. These systems shall be certified for operating
within the predefined specifications for power supply and stability etc.

12.0 DESCRIPTION OF THE PROCESS EQUIPMENT

An impact assessment exercise shall be carried out to ascertain the impact of the equipment on the quality
of the final product. Based on this scientific rationale these equipments shall be classified as “Direct Impact”
(critical) or “Indirect Impact” or “No Impact” (non-critical).

Impact Assessment is the process by which the impact of a system on product quality is evaluated and the
critical components associated with those systems are identified. Those systems having a direct impact on
product quality are termed as “Direct Impact” and are subjected to Qualification Process.

Others which do not have any direct impact on product quality are termed as “Indirect Impact” or “No
Impact” systems and are designed, installed and commissioned according to Good Engineering Practice, but
need not be subjected to a similar kind of Qualification Process as practiced for “Direct Impact” systems.
This process allows appropriate effort and focus to be concentrated on the quality impacting systems and
components.

IMPACT ASSESSMENT PROCESS

Prior to assessing system impact, the scope outlining the design, objective and boundaries of each shall be
clearly defined. Evaluation of the impact of a system on product quality has to be carried out by a group of
people from different departments mainly user, Engineering and Quality Assurance. The scientific rationale
behind each assessment needs to be well documented with mutual consensus.
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Applicability of any of the following criteria will provide an indication that a system has a “Direct Impact”

1. The system has direct contact with the product.

2. The system provides or produces an ingredient or excipient, which forms a part of the final
product formulation.
3. The system is used in cleaning or sterilizing.
4. The system preserves product status.
5. The system produces data, which is used to accept or reject product.
6. The system is a process control system that may affect product quality and for which there is
no alternative independent verification available.

The components within “Direct Impact” system should be assessed for criticality.

Applicability of any of the following criteria to a given component will provide an indication that the
component is critical.

1. The component is used to demonstrate compliance with the registered process.

2. The normal operation or control of the component will have a direct effect on product quality.
3. Failure or alarm of the component will have a direct effect on product quality.
4. Information from this component is recorded as part of the batch record; lot release data or
other GMP related documentation.
5. The component has direct contact with the product or product components.

6. The component is used to create or preserve a critical status of a system.

7. The component controls critical process elements that may affect product quality, without
independent verification of the control system performance.

Note : “Indirect Impact” or “No Impact” systems are comprised of non-critical components only. Should an
“Indirect Impact” or “No Impact” system incorporate one or more critical components, either the system has
been misclassified, or the component wrongly assessed.

The Annexure – II & Annexure – III in separate folders give the details of this approach and the list of
critical and non-critical equipments being used in the manufacturing.

The following ancillary equipment / accessories also shall be used in the performance of various unit
operations. This list is only indicative and not all inclusive.

1. Air curtains at various man and material entry points.

2. Clothes washing machine for process clothing.
3. Pallet stackers, Fork lifts.
4. Balances of various capacities and accuracies.
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5. Analytical instruments for testing at QC.

6. In process testing instruments at shop floor.

13.0 EQUIPMENT HISTORY FILES

Equipment history files shall support all the critical as well as non-critical equipment. The history files of
critical equipment shall have the following documents in them.
1. Specifications.
2. Purchase Orders.
3. Invoices.
4. Certificates.
5. Performance Guarantees.
6. Manuals.
7. Drawings.
8. Installation Qualification Report.
9. Operational Qualification Report.
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10. Performance Qualification Report.

11. List of Essential Spares.
12. Preventive Maintenance Schedule.
13. Preventive Maintenance Record.
14. Breakdown Maintenance Record.
15. Annual Performance Reviews.
The non-critical equipment history files shall have the following documents in them –
1. Specifications.
2. Purchase Orders.
3. Invoices.
4. Certificates.
5. Manuals.
6. Drawings.
7. Installation Qualification Report.
8. Commissioning Report.
9. List of Essential Spares.
10. Preventive Maintenance Schedule.
11. Preventive Maintenance Record.
12. Breakdown Maintenance Record.
13. Annual Performance Reviews.

14.0 QUALIFICATION AND VALIDATION APPROACH

The validation program for the facility will be in concurrence with the Good Manufacturing Practices (GMPs).

The validation activities are divided into the following steps.

1. Validation Master Plan (VMP)

2. User Requirement Specification (URS)
3. Design Qualification (DQ)
4. Risk Analysis (RA)
5. Installation Qualification (IQ)
6. Operational Qualification (OQ)
7. Performance Qualification (PQ)
8. Process Validation (PV)
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9. Cleaning Validation (CV)

10. Validation Report (VR)
11. Revalidation (ReV)

A schematic representation of the interrelationships of these components of Validation Philosophy is given

below –

14.1 Validation Master Plan

VALIDATION MASTER PLAN

DESIGN QUALIFICATION

REVALIDATION

INSTALLATION
QUALIFICATION
MONITORING
MAINTENANCE
CHANGE CLEANING PERFORMANCE
OPERATIONAL
PROCESS
CONTROL VALIDATIONVALIDATION MASTER PLAN
QUALIFICATION
VALIDATION
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Validation Master Plan (VMP) Execution Methodology

The execution of entire validation and documentation project will be executed by CLL project execution
teams. In order to execute the entire plan with least complications, it is essential to define the execution
plan and responsibilities very carefully. The scope, responsibilities and sequence of the validation &
documentation project execution plan are illustrated in the following process flow chart –

Protocol Preparation & Review

Yes

Protocol Approval
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Protocol Execution, Data

Collection & Compilation
and Preparation of Report

No
Report Review

Yes

OK ?
No

Report Approval

Implementation

14.2 User Requirement Specifications (URS)

Based on the Process / GMP / Safety requirements, an approved User Requirement Specifications (URS) will
be prepared specific to an equipment / system.

For existing equipment / systems, a “Retrospective URS” shall be prepared. This will be done in conjunction
with Process Development, Production, Engineering and Quality Assurance and will take into account the
type of product and their intended use.

The URS will highlight the critical design specifications e.g., capacity, material of construction, elements and
parameters as appropriate. The supporting data like process flow sheet, layout drawings, Room data sheets,
Engineering / Functional specifications will be provided as appropriate. The URS will be updated as
appropriate to incorporate modifications and enhancements made during discussions with suppliers. The
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final URS will be used for the placement of the order and as the basis for controlling subsequent changes to
the design.

14.3 Design Qualification

A design review protocol will be created in which the key GMP issues, derived from the URS and the
rationale for the assessment methodology will be defined. The equipment design will be systematically
assessed against the protocol, with respect to any aspect, which might cause failure to attain the quality
requirements. The review will also highlight any GMP or safety issues inherent in the design that are not
specifically defined by the protocol. The evaluations will be compiled in the DQ document.

14.4 Functional Specification

An approved document translating the URS into a specification detailing how the requirements are to be
achieved. Together with the URS, this will provide the objectives and acceptance criteria for the subsequent
validation protocols.

14.5 Risk Analysis

The purpose of risk analysis is to identify critical and non-critical parts of processes and equipment. This risk
analysis also identifies the activities necessary for validation, maintenance and calibration. Risk analysis
performed may be documented as a part of Qualification / Validation protocols or as a separate document.

14.6 Installation Qualification

The purpose of this phase is to ensure that all equipment / systems are received and installed according to
the approved Design Qualification & Good Engineering Practices. This activity will be done in phases and
following points will be ensured as applicable.

1. Equipment / system is constructed as per the approved design / technical specifications.

Materials of construction conform to the specifications.
2. Installation Qualification (IQ) drawings and other documentation provided by vendors during
and after the construction are accurate and complete.
3. Equipment, piping, instrumentation have been clearly identified in the field and conform to the
descriptions provided in the Process and Instrumentation Diagram (PID) or other documentation.

4. Electrical and instrumentation wiring has been completed in accordance with the specification.
5. Where appropriate, instruments have been calibrated.
6. Piping and equipment intended to operate under pressure have been tested and certified.
7. The system has been installed according to the approved engineering documents and
drawings.

14.7 Operational / Performance Qualification

The purpose of this phase is to check that all the equipment / systems operate and perform as expected
with reference to DQ.
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OQ / PQ will be done as per the pre-approved protocol. The protocol will deliberate the functional test(s) to
be performed specific to an equipment / system and the acceptance criteria & critical parameters to be met.

The functional tests planned in the protocols will be adequate to demonstrate that equipment / systems
operate and perform throughout the specified operating range. It will cover operations of automated
sequences, interlocks, alarms, timers, counters etc. as applicable. The performance qualification of the key
manufacturing equipment will be done (on applicability basis), by producing placebo batch or operations.

The change control program immediately following the completion of the OQ test functions will cover each
system / equipment / process. Any change(s) made to the system during OQ must be documented in the
final report. Any changes proposed after OQ (i.e., during cycle development, performance qualification, or
manufacturing) must be pre-approved and follow the change control procedure. If changes are made prior
to approval of the final report, the change control documentation will be included in the validation exercises.
The change and its justification will be documented in the final report.

At the end of OQ / PQ approved Standard Operating Procedures for the Operation, Calibration, Preventive
Maintenance etc. will be established.

14.8 Analytical Method Validation

The analytical testing procedures utilized for the input and finished product testing shall be validated as
defined in the protocols developed for the same. Non-pharmacopoeial testing procedures shall be developed
through a validation protocol and shall further be applied in process validation exercises.

The analytical method validation will be done wherein an appropriate SOP will be established for validation
of analytical methods. The SOP will also consider the approach towards validation of pharmacopoeial
methods & transfer of a validated method. These procedures shall be applied for routine QA testing as well
as for process validation exercises. The pharmacopoeial procedures shall be applied as per the methodology
described in the respective pharmacopoeias.

14.9 Process Validation

Process Validation is establishing documented evidence, which provides a high degree of assurance, that a
specific process will consistently produce a product meeting its pre-determined specifications and quality
attributes.

Approach to process validation will be in-line with various regulatory guidelines like “guide to validation of
aseptic processes”. These guidelines will be recorded as a basis in the protocols for the respective
validations.

Prospective Validation

Validation conducted prior to the distribution of either a new product, or product made under a revised
manufacturing process, where the revisions may affect the product’s characteristics.
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Prospective validation involves the collection and analysis of data from at least three consecutive batches of
a product. If three production batches of a product in a span of a year are not feasible due to justified
reasons, then in such cases Concurrent Validation approach will be adopted.

Concurrent Validation approach will also be adopted in case of site-to-site process transfer. Before initiating
process validation exercise, it will be ensured that all the pre-requisites for the process are in the qualified /
validated status with respect to equipments and analytical testing methods.

The validations will be executed as per the approved Process Validation Protocols. The protocol will mainly
consider the monitoring of critical process parameters by enhanced sampling and analysis of In-process /
Finished Product. Only validated analytical methods will be used. The critical parameters will be assessed on
the basis of scientific judgments / experience during development or scale-up batches / experience with
similar product / theoretical considerations. The data collected will be evaluated against the acceptance
criteria defined in the protocol for the respective parameter.

In case of new product developments / production scale-up batches, the acceptance criteria defined can be
substantiated from the data of laboratory scale or pilot scale batches, unless the parameter can be
determined from production scale batches. In case of site-to-site process transfer, the acceptance criteria
will be defined based on the data available from previous site.

Samples of validation batches will be kept for stability studies to evaluate the influence of scale up / change
in site, on the stability of product. Also, a system will be established for follow-up stability testing. For
contract manufacturing products, the process validation activities will be conducted by either CLL or jointly
conducted by both contract giver and acceptor.

14.10 Cleaning Validation

Approach to cleaning validation will be in-line with guidelines from regulatory agencies for validation of
cleaning processes. These guidelines will be cross-referred in the protocols of cleaning validations for each
equipment, system cleaning validation protocol.

Cleaning procedures to be adopted during product change over which involve cleaning of product contact
surfaces of the equipment will be validated.

The cleaning procedures developed may be based on preliminary cleaning studies performed under
laboratory or experimental conditions. Scientific judgment and experience shall also be used in the
development of cleaning procedures. The SOP will also address the maximum duration within which the
cleaning should be done after use and the duration for use after cleaning. The equipment cleaning
procedures will be developed for all the equipment installed where the product comes in direct contact.

Cleaning Validation will be performed as per the approved protocol. The protocol will be prepared &
approved in advance for each cleaning validation study. The equipment will be cleaned at the completion of
the manufacturing process by following the cleaning SOP and the cleaning validation exercise will be
performed as per the protocol. The protocol will provide the details for visual inspection, sampling points,
sampling technique (swab / rinse), reference to analytical / microbiology testing method and acceptance
criteria.

Only validated analytical methods will be used. It will be ensured from the limit of detection & quantification
that the method is sensitive enough for the desired level of detection. Sampling methods will be validated in
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advance by conducting recovery experiments. The acceptance criteria for % recovery will be set to
minimum 50%. Recovery experiment will be done at the level of acceptance limit and in triplicate. The
recovery values will be used to apply the correction factor while calculating actual amount of the residues.

The limits for previous product residues, cleaning agent residues & microbial contamination will be
established based on scientific rationale so that probable level of contamination to the next product will be
within justified limits.

The cleaning procedure will be considered validated if the acceptance criteria are achieved for three
consecutive cleaning operations. If contamination levels exceed established limits in the protocol, the SOP
will be modified with appropriate changes.

Cleaning validation studies will be then repeated. The modification and validation study will be continued till
the SOP stands validated. On completion of the validation exercise, a Cleaning Validation Report will be
prepared.

Since the facility will be used for multiple products, a matrix approach will be used. A matrix will be formed
by product categories based on solubility, potency & toxicity. The “worst case” with respect to cleaning will
be assessed from the matrix and the cleaning validation will be done for the “worst case”. For a new
product, which may fall within the matrix for solubility, potency & toxicity, the same procedure may be used
without validation. However, the cleaning procedures will be fully validated for the new products, which fall
out of matrix.

For contract manufacturing products, the cleaning validation activities will be conducted by Chemico
Laboratories Limited or jointly conducted by both contract giver and acceptor.

14.11 Raw Material Qualification

This section will be concerned with the raw materials and their testing before their acceptance for use in the
manufacturing process. The procedures for qualification of chemical and biological raw materials, filters,
consumables and packaging material, which will cover the following aspects :
1. Vendor Qualification
2. Specifications.
3. Test Procedures.
4. Handling & Storage.
5. Material Safety Data.
6. Sampling.
7. Control & Release.
8. Re-testing.

14.12 Validation Protocols

The validation protocol is a detailed plan for conducting a validation study. It is drafted by the individual
responsible for the project, checked for content and completeness and approved by undersigned individuals.
It describes purpose, scope, system description, the responsibilities of each individual involved in the
project, pre-requisites, list of tests and methods, acceptance criteria, list of deviations, personnel
undertaking the tests.
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14.13 Validation Report

The report summarizes the Validation / Qualification test results and a conclusion about the ability of the
equipment or system to consistently perform within acceptable operating ranges.

A compilation of the results from process, analytical method validation, cleaning, drying, computer system
validations will be included in separate summary reports to facilitate review. Deviations and/or exceptions to
approved test procedures along with appropriate explanations, through Approved Deviation Form will also
be documented in the final report.

14.14 Validation Schedule

Validation program will be applicable to –

1. Process Equipment, which will have direct impact on the product quality, safety and/or efficacy.
(Refer Annexure No – II for Critical Equipment List – Production).
2. Purified Water System.
3. Pure Steam System.
4. HVAC System.
5. Compressed Air System.
6. Civil Constructions.
7. Laboratory Instruments.

(Refer Annexure No – II for Critical Equipment & Instruments List – Chemical Lab)
(Refer Annexure No – II for Critical Equipment & Instruments List – Microbiology Lab)

A validation schedule is made for the above, in order to carry out the entire validation exercises
prospectively.

14.15 Revalidation

Re-validation / Re-qualification of equipments required due to intentional changes will be considered

through change control. Revalidation / Re-qualification may be necessary due to un-intentional changes that
might have occurred over the period where the necessity of revalidation will be assessed based on the data
of Annual Process and Product Review.

Besides this, a revalidation / re-qualification needs to be carried out on a yearly basis or at a predefined
interval as necessary case wise.

15.0 VALIDATION SUPPORT PROGRAMS

15.1 Standard Operating Procedure (SOP)

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The validation team shall develop Standard Operating Procedures / Instructions / Standard Microbiological
Method for each activity and unit operation including equipment operations, maintenance and cleaning.
These procedures shall evolve from the following sources.

1. Validation studies.
2. Regulatory guidelines.
3. Supplier’s recommendations.
4. Historical data available with manufacturer.
5. Reports of internal audits / self-inspections / external inspections.

The major types of SOP’s that shall be developed will facilitate following operations and activities.

1. Unit processing operations like dispensing, entry & exist, transfer, washing, drying, cleaning,
disinfection, sanitization etc.
2. Logistical sequences like receipt, storage, sampling, testing etc.
3. Operation of equipment like homogenizer, oven etc.
4. Testing like measurement of pH, conductivity, microbial limit etc.
5. Personnel practices like gowning, hygiene etc.
6. Preventive maintenance of equipment.
7. Change control due to changes in any of the parameters or changes in procedures that can
affect the validation status of the processes, equipment, utilities etc.
8. Calibration of instruments, gauges etc.
9. Quality systems such as vendor qualification, change control, market handling and recalls, non-
conformity / deviations, self inspections, labelling, document preparation, distribution and control, out of
specifications and stability, product quality review, batch documentation, review of batch records & release
etc.
10. Administrative purposes such as Housekeeping, Pest & Rodent control, training, fire fighting,
medical check-ups, security and visitor handling.

A list of critical SOP’s that shall be developed as per the types mentioned above will be maintained in
Separate Folder. This list shall undergo additions, deletions or updations based on additions of operations or
changes in any of the critical parameters affecting their definitions.

15.2 Environment / Water Monitoring Program

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The environmental monitoring program shall cover the critical i.e., the classified areas and the controlled
i.e., the ventilated areas.

The environmental monitoring shall consist of the following as per predefined schedules.
1. Revalidation of HVAC system and comprising of filter leak tests, particle counting, velocity
measurement and computation of air change rates. This shall be done once or twice a year depending upon
the clean room classification served by the system.
2. Microbiological monitoring of classified areas as per a predefined procedure.
3. Monitoring of temperature and humidity at predefined interval and areas.
4. Monitoring of differential pressure at predefined interval and areas in classified areas.

All these environmental monitoring activities shall be carried out as per a protocol developed and
acceptance criteria established as per the limits suggested by the regulatory guidelines.

15.3 Water Quality Monitoring

Water systems viz Purified Water shall be covered under initial validation program. However, a continuous
monitoring program shall be established on a routine basis thereafter.

The SOP for this shall specify :

1. Parameters to monitor.
2. Test or measurement methods.
3. Monitoring instrument or equipment.
4. Number of test or measurement.
5. Test or measurement schedule.
6. Acceptance criteria.
7. Water treatment schedule.
8. System maintenance for HVAC system / Purified water system.

15.4 Calibration Program

All the instruments and other measuring devices shall be calibrated as per a predefined calibration program
and it’s SOP. The initial calibration may be performed in-house by the validation group or by the instrument
supplier. If the contractor is to perform the initial calibration, the validation requirements must be supplied
in the request for bid. The record of calibration is made a part of the OQ. The calibration method should be
the same procedure that validation plans to use after installation. The calibration program shall define the
method, frequency, actions to be taken in case of out of calibration situation and documentation of the
calibration program.

These devices shall be identified in two categories :

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Controlling Devices

These are the devices that control the process / premises or equipment and can have a direct effect on the
quality of product or the compliance status of the facility.

Measuring Devices

These are indicative instruments and do not have a direct effect on the quality of the product.

As per the identification, all the devices shall be calibrated based on defined for specific instrument. All
measuring instruments must be calibrated for accuracy.

The calibration program shall define the method, frequency, actions to be taken in case of out of calibration
situation, and documentation of the calibration program.

15.5 Preventive Maintenance Program

The critical process equipment and systems shall be subjected to a preventive maintenance program, which
shall be defined based on the following inputs.
1. Recommendations of the suppliers of the equipment and systems.
2. Results of the validation exercises.
3. Trend analysis of various critical parameters.

The preventive maintenance program shall be dynamic in nature and shall undergo revisions on the basis of
the live data generated during the operation of the plant. SOP’s shall be defined for the preventive
maintenance of the various systems and equipment.

The preventive maintenance program shall define the method, frequency, equipment specific checklist and
documentation of the preventive maintenance program.

15.6 Training Program

All the employees shall be trained in the following areas as per their role in the operations.

Induction Training :

Training shall be imparted to all persons at the time of joining briefing them about the company
background, history, its policies, procedures and arrange their meeting with key people of the organization.
This training shall be the responsibility of Production / Quality Assurance / Engineering / Quality Control /
Ware House Department.

Job Related Training :

Specific job related training on the shop floor related to SOP’s and regarding general procedures shall be
imparted to all new employees in a particular section. This SOP related training should also be done on a
yearly basis conducted as refresher.
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A proper training program or SOP shall be available, that describe the plan for training of the concerned
operating, maintenance, quality control and other personnel on successful completion of each validation
activity and/or after overall qualification / validation exercise.

Training in GMP :

All the personnel from Production, Quality Assurance, Quality Control, Engineering and Warehouse should
undergo training in GMP. This shall encompass the following elements.
1. Basics of microbiology.
2. Sanitation.
3. Clean room operations, maintenance and control.
4. Process control.
5. Labelling control.
6. Safety procedures.
7. Documentation.

There shall be various levels of training imparted to the operating personnel based on their role in the
manufacturing activities. The content of training programs shall be derived from the role of the employee in
the operations. The training program content will be revised based on changes in products, processes,
equipment and utilities as well as revision in regulatory guidelines and requirements.

Assessment of personnel on a routine basis on his/her technical skills, knowledge base and compliance to
procedures and practices shall be carried out based on the key observations during periodic audits and
through periodic performance appraisal.

Training in Safety and Logistics :

This shall be undertaken for all the employees of the plant. Similar to GMP training programs, audit of
personnel for compliance to safety norms, practices shall be carried out as per predefined protocol.

15.7 Out of Specification

If any test results are out of specification (OOS), follow up actions, including a documented failure
investigation must be taken to address the failure. The failure investigation must address the impact of the
failing results on the validity of the equipment / system and the validation effort.

15.8 Change Control Program

The operating procedures as well as all other master documents may undergo a change necessitated by the
following factors.

1. Change in the specification of the products or inputs or addition of the products.

2. Enhancement in capacity of plant, change in processes, test methods revalidation studies suggesting any
such change.
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3. Major product failures requiring re-assessment of the processes.

4. Major equipment or system modifications for any reason.

Following a decision to modify a equipment / system, the affected drawings, manuals and procedures
should be revised.

All such changes shall be brought following a predefined change control procedure. This procedure shall
ensure that such a change is fully understood, studied, tested for robustness and documented in order to
achieve full traceability.

All changes shall be formally requested, documented and accepted by representatives of respective
functions. The likely impact of the change shall be evaluated and the need and the extent of revalidation
discussed. The change control system will ensure that all notified or requested changes are satisfactorily
investigated, documented and authorized.

15.9 Document Handling

All the documents shall be controlled through a proper generation, issue, updation, storage, distribution and
retrieval procedures developed for the same. Necessary document distribution and history of changes in
these documents shall be maintained.

These documents shall be reviewed at predefined intervals to assess if they need changes. Storage of these
documents shall be primarily with QA, but some of the department related documents should be placed in
their respective department storage cabinets preferably of fire resistant nature.
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16.0 KEY PERSONNEL

The following are defined as the key personnel in the plant and their responsibilities are mentioned against
their positions. These are described generally in the following paragraphs.

16.1 The Head of Quality Assurance

1. To approve or reject starting materials, analytical reagents, packing materials, secondary

packing materials at any stage as he deems fit.
2. To evaluate manufacturing records.
3. To ensure that all necessary testing is carried out.
4. To approve specifications, sampling instructions, test methods and other QC procedures.
5. To approve and monitor contract analysis, if any.
6. To check the maintenance of his department, premises and equipment.
7. To ensure that the appropriate validations are done.
8. To ensure that the required initial and continuing training of his department personnel is
carried out and adapted according to need.

16.2 The Head of Production

1. To ensure that products are manufactured and stored according to the appropriate.
2. Documentation in order to obtain the required quality.
3. To approve the instructions relating to manufacturing operations and to ensure their
implementation.
4. To ensure that the manufacturing records are evaluated and signed by an authorized person
before they are sent to QA.
5. To check the maintenance of his department, premises and equipment.
6. To ensure that appropriate validations are done.
7. To ensure that the required initial and continuing training of his department personnel is
carried out and adapted according to need.
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16.3 The Head of Production & QA Together shall Perform the Following
Duties :

1. The authorization of written procedures and other documents including changes relating to
production.
2. The monitoring and control of manufacturing environment.
3. Plant hygiene.
4. Process validation.
5. Training.
6. Approval and monitoring of suppliers of materials.
7. Designation and monitoring of storage conditions for materials and products.
8. Retention of records.
9. Monitoring of compliance with the requirements of GMP.
10. Inspection, investigation and taking of samples, in order to monitor factors, which may affect
product quality.

These responsibilities shall be further elaborated out in the individual standard operating procedures as well
as protocols.

The responsibilities of other personnel will be defined based on their functional responsibilities and recorded
in the personnel files.
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17.0 PRODUCTION FACILITY

Both single and combination products will be produced. The critical production area for oral solid dosage is
manufacturing, compression / filling & packing room. The critical process machineries of the project are –

 Balances.
 Planetary Mixer.
 Fluid Bed Dryer.
 Wet Granulator.
 Cone Blender.
 THAI Coater (15 Kg).
 THAI Coater (45 Kg).
 BG – 150E Coater (150 Kg).
 JAGUAR 16 Punch Compression Machine.
 YU LEE 16 Punch Compression Machine.
 JAGUAR 27 Punch Compression Machine.
 KEB 35 Punch Compression Machine.
 Hoong – A Blister Packaging Machine.
 Pharma Pack Blister Packaging Machine.
 SJN Blister Packaging Machine.
 Strip Packaging Machine.
 Automatic Capsule Filling Machine.
 Hand Filling Machine.
 Multi Mill.
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Critical Steps for Manufacturing Operations are –

 Dispensing.
 Mixing.
 Granulation.
 Shifting.
 Drying.
 Blending.
 Compression.
 Coating.
 Encapsulation.
 Blister / Strip Packing.
 Filling.
 Cartooning.
 Final Packaging.
 Weight Check.
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17.1 Flow Chart of Production

TABLETS

DISPENSING

DRY MIXING / WET MIXING

SHIFTING

DRYING

SHIFTING

BLENDING

COMPRESSION COATING
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PACKAGING

CAPSULES

DISPENSING

MIXING

ENCAPSULATION

PACKAGING
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18.0 QUALITY CONTROL

Extensive testing will be required for oral solid dosage products, the sampling & testing scheme must be
carefully reviewed before starting validation. The testing includes –

18.1 Stability Test

Uncoated Tablets

 Physical Appearance.
 Loss on Drying / Water Content.
 Hardness.
 Friability.
 Disintegration Time / Dissolution Rate.
 Assay.

Coated Tablets

 Physical Appearance.
 Disintegration Time / Dissolution Rate.
 Assay

18.2 Calibration
 Balance.
 Temperature, RH measuring.
 HPLC.
 UV-Visible Spectrophotometer.
 PH Meter.
 Conductivity Meter.
 Karl Fischer Titrator.
 Hardness Tester.
 Verniers.
 Friability Tester.
 Disintegration Tester.
 Dissolution Tester.
 Atomic Absorption Spectrophotometer.
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 Oven.
 Autoclave.

 Incubators.

18.3 Physical / Chemical Test

Uncoated Tablets

 Physical Appearance
 Identification
 LOD / Water Content by KF
 Length / Width / Diameter / Thickness
 Hardness
 Friability
 Average Weight & Uniformity of Weight
 Disintegration Test / Dissolution Rate
 Assay

Coated Tablets

 Physical Appearance
 Identification
 Length / Width / Diameter / Thickness
 Average Weight & Uniformity of Weight
 Disintegration Test / Dissolution Rate
 Assay

Capsules

 Physical Appearance
 Identification
 Average Weight & Uniformity of Weight
 Disintegration Test / Dissolution Rate
 Assay

18.4 In Process Test

 Physical appearance of tablets / capsules.

 Average weight of tablets / capsules & uniformity of weight.
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 Hardness, thickness & friability loss of tablets.

List of QC Equipments, Specifications, Testing Methods and Method Development, Method Validation etc.
will be kept in separate folders.

19.0 PRODUCT DEVELOPMENT

Product Development of oral solid dosage forms of products will be undertaken according to design &
development protocol which takes account of the following activities & time schedule.

Initiation of Product Proposal by Marketing

Evaluation of Product Proposal by Product Development

Evaluation of Product Brief by Product Development

Final Recipe

Product Cost Estimation

Recipe Submission

Identify Raw / Packaging Material

Purchase Specification
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Laboratory Batch

Analytical Method Development & Validation

Order for Change Parts

Packaging Material Specification

Draft / Final Packaging Design

Pilot Batch

Stability Studies

Approval of Stability Data & Shelf Life

Annexure Submission
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Approval of Inclusion

Approval of MRP / INDP

Quantification of Raw / Packaging Material for Trial Batch

Trial Batch Manufacturing Validation

Studies

Product Launching

Product Manual

Post Marketing Validation

Trial batch will be manufactured at least for 3 batches. The batches will be studied (0, 1, 2, 3, 6) as per
scheme in storage condition 40°C±75% RH. For 6 months & 12 months under storage condition 25°C±65%
RH. The stability study will be carried out by PD analyst & a report will be generated after complete stability
studies of 3 batches. After getting a good stability report the batch manufacturing can be initiated.
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20.0 GLOSSARY OF TERMS USED

The product specifications and acceptance / rejection criteria, such as acceptable

Acceptance quality level and unacceptable quality level, with an associated sampling plan and
Criteria testing methodology that are necessary for making a decision to accept or reject a lot
of equipment, product or systems.
Levels or ranges, which, when deviated from, signal a potential drift from normal
Action Levels operating conditions. These ranges are not perceived as being detrimental to end
product quality.
An audit is a formal review of a product, manufacturing process, equipment, facilities
Audit
or systems for conformance with regulations and quality standards.
Comparison of a measurement standard or instrument of known accuracy with
Calibration another standard or instrument to detect, correlate, report or eliminate by adjustment
any variation in the accuracy of the item being compared.
Documented statement by qualified authorities that a qualification / validation study
Certification has been done appropriately and that the results are acceptable. Certification is also
used to denote the acceptance of the entire manufacturing facility as validated.
A format monitoring system by which qualified representatives of appropriate
disciplines review proposed or actual changes that might affect validated status and
Change Control
take preventive or corrective action to ensure that the system retains its validated
state of control.
Establishing documented evidence that the process, which is being implemented, can
consistently produce a product meeting its predetermined specifications and quality
Concurrent
attributes. This phase of validation activities typically necessitates careful monitoring /
Validation
recording of the process parameters and extensive sampling / testing of the in process
and finished product during the initial implementation of the process.
The documented evaluation of the construction or assembly of a piece of equipment,
process or system to assure that construction or assembly agrees with the approved
Installation specification, applicable codes and regulations, and good engineering practices. The
conclusion of the evaluation should decidedly state that the equipment, process or
system was or was not constructed in conformance with the specifications.
Critical Process Those process variables that are deemed important to quality of the product being
Variables produced.
Areas where a clean or sterilized or sanitized product or containers or closures are
Critical Areas
exposed to environment.
Surfaces, which come into contact with, cleaned or sterilized or sanitized product or
Critical Surfaces
containers or closures.
Facilities Facilities are areas, rooms, spaces such as receiving, shipping, quarantine, rejected
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materials, approved materials, staging areas, process areas etc.

The minimum requirements by law for the manufacture, processing, packaging,
Good
holding or distribution of a material as established by various regulatory agencies like
Manufacturing
the WHO, USFDA, MCA of UK, or the revised schedule M of the Indian Drugs and
Practices (GMP)
Cosmetics act or similar regulatory directives of other regulatory agencies.
The installation qualification protocol contains the documented plans and details of
procedures, which are intended to verify specific static attributes of facility, utility,
Installation
system or process equipment. Installation Qualification (IQ) when executed is also a
Qualification
documented verification that all key aspects of the installation adhere to the approved
Protocol
design intentions and that the manufacturer’s recommendations are suitable
considered.
The purpose of a VMP is to provide FDA or other such regulatory agencies or other
Validation Master external auditors a document, which demonstrates a company’s responsibility and
Plan (VMP) intent to comply with GMPs, and itemises the elements, which will be completed
between the design engineering and plant start up.
Operational Qualification (OQ) Protocol contains the plan and details of procedures to
Operational verify specific dynamic attributes of a utility / system or process equipment
Qualification throughout it’s operated range including worst-case conditions. OQ when executed is
Protocol documented verification that the system or subsystem performs as intended
throughout all anticipated operating ranges.
A range of values for a given process parameter that lie at or below a specified
Operating Range maximum operating value and/or at or above a specified minimum operating value,
and are specified on the production worksheet or the standard operating instruction.
Processes are those activities which are repeated frequently such as P H adjustment,
including the preparation of solutions which are to be used for adjusting the P H;
Processes cleaning in place, the preparation of CIP solutions, the various piping adjustments,
sanitizing, sterilization and supportive activities like component cleaning etc. and any
electromechanical or computer assisted processes associated with them.
Process equipment means such items such as scales, load cells, flow meters, reaction
vessels, processing vessels, centrifuges, filters, washers, driers, packaging equipment
Process
including electromechanical or computer assisted instruments, controls, monitors,
Equipment
recorders, alarms, displays, interlocks etc. which are used in the manufacture of
pharmaceutical products.
Process parameters are the properties or features that can be assigned values that are
Process used as control levels or operating limits. Process parameters assure that the product
Parameters meets the desired specifications and quality. Examples might be, Pressure at 1.15 Kg /
square cm; Temperature at 75±2°C etc.
Process variables are the properties or features of a process which are not controlled
Process Variable or which change in time or by demand; they do have an effect on product
specifications or quality.
Establishing documented evidence, which provides a high degree of assurance that a
Process Validation specific process will consistently produce a product meeting it’s predetermined
specifications and quality attributes.
A product is considered validated after completion of three successful full lot size
Product Validation
attempts.
Process Validation Process Validation Protocol (PV) is a documented plan and details of procedures to
Protocol verify specific capabilities of a process equipment / system through the use of
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simulation materials such as for example, the use of a nutrient broth in the validation
of an aseptic filling process, or the use of a placebo formulation in a freeze drying
process. However, the product as the material can also be used to validate the
process.
Validation conducted prior to the distribution of either a new product or product made
Prospective under a revised manufacturing process, where the revisions may have affected the
Validation product’s characteristics, to ensure that the finished product meets all release
requirements for functionality and safety.
Protocol A protocol is defined as a written plan stating how validation will be conducted.
The activity of providing evidence that all the information necessary to determine that
Quality Assurance the product is fit for the intended use is gathered, evaluated and approved. The
quality assurance department executes the function.
Quality attributes refers to those properties of the product or a utility or a system such
Quality Attributes as conductivity of purified water, particulate matter per unit surface area, endotoxin
content per unit volume, total bioburden per unit weight or volume etc.
The activity of measuring process and product parameters for comparison with the
specified standards to assure that they are within predetermined limits and therefore
Quality Control
the product is acceptable for use. The quality control department executes this
function.
Repetition of the validation process or a specific portion of it may be necessitated by a
Revalidation change in the product input specifications, process equipment modifications, utility
system changes or a change in finished product specification.
Documents, which define what something is by quantitatively, measured values.
Specifications Specifications are used to define inputs of a process, in process materials, products,
equipment and systems.
Standard Written procedures followed by trained operators to perform a step, operation,
Operating process or any other discrete function in the manufacture or production of a drug or
Procedure (SOP) drug product or any other end product of such processes or operations.
A condition in which all process parameters that can affect performance remain within
State of Control
such ranges that the process performs consistently and as intended.
Utilities / systems include such things as Heating, Ventilation and Air Conditioning
(HVAC) systems, process water, product water, clean steam. Process air, vacuum,
Utilities / Systems gases etc. and the electromechanical or computer assisted instruments, controls,
monitors, recorders, alarms, displays and interlock etc. which are associated with
them.
Establishing documented evidence, which provided a high degree of assurance that a
Validation specific process will consistently produce a product meeting it’s predetermined
specifications and quality attributes.
Validation The collective activities that are related to validation.
Program
Validation protocols are written plans stating how validation will be conducted,
including test parameters, product characteristics and production equipment and
Validation decision points on what constitutes acceptance criteria. These include the installation
Protocols qualification, operation qualification, performance qualification, process validation and
product validation. When the protocols have been executed it is intended to produce
documented evidence that the system has been validated.
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The validation scope includes the elements that impact critically on the quality of the
Validation Scope product. These elements are facilities, utilities, systems, process equipment, process &
product.
A set of conditions encompassing upper and lower processing limits and circumstances
including those within standard operating procedures, which pose the greatest chance
Worst Case
of process or product failure when compared to ideal conditions. Such conditions do
not necessarily induce product or process failure.

21.0 LIST OF ANNEXURES

Annexure – I : Architectural and structural drawings comprising of –

a. Plot Plan (Oral Solid Dosage Plant Position)

b. Lay out Plans (Room Layout)
c. Air Class Zoning

Annexure – II : List of critical equipment and systems (Direct Impact Systems) – Oral solid dosage
plant.

Annexure – III : List of non-critical equipment and systems (Indirect Systems & No Impact
Systems) – Oral solid dosage plant.

Annexure – I : Architectural and Structural Drawings Comprising of –

a. Plot Plan (New Solid Dosage Form)
b. Lay out Plans (Room Layout)
c. Air Class Zoning

Annexure – II : List of Critical Equipment & Systems (Direct Impact System)

Sl. No. Direct Impact Systems

Oral Solid Plant
01 HVAC
02 Facility Premises
03 Compressed System
04 Plant Steam
05 Balances
06 Temperature Gauge
07 Pressure Gauge
08 Purified Water
09 Planetary Mixer
10 Fluid Bed Dryer
11 Wet Granulator
12 Cone Blender
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13 THAI Coater (15 Kg)

14 THAI Coater (45 Kg)
15 BG – 150E Coater (150 Kg)
16 JAGUAR 16 Punch Compression Machine
17 YU LEE 16 Punch Compression Machine
18 JAGUAR 27 Punch Compression Machine
19 KEB 35 Punch Compression Machine
20 Hoong – A Blister Packaging Machine
21 Pharma Pack Blister Packaging Machine
22 SJN Blister Packaging Machine
23 Strip Packaging Machine
24 Automatic Capsule Filling Machine
25 Hand Filling Machine
26 Multi Mill

Quality Control
01 HPLC
02 UV – VIS Spectrophotometer
03 Karl Fischer Titrator
04 Atomic Absorption Spectrophotometer
05 Balances
06 Drying Oven
07 PH Meter
08 LAF Work Station
09 Conductivity Meter
10 Purified Water
11 Autoclave
12 Hot Air Oven
13 Incubator
14 Microscope

Annexure – III : List of Non Critical Equipment & Systems (Indirect Impact Systems & No
Impact Systems)

Sl. No. Indirect Impact Systems & No Impact Systems

Oral Solid Plant
01 Electrical Power
02 Oven
03 Potable Water System
04 Stirrer
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Quality Control
01 Electrical Power
02 Refrigerator
03 Vacuum Pump
04 Oven