Ps9004 Complete for Pharmaceutical

The Institute of Quality Assurance

Pharmaceutical Quality Group

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



PS 9004

A Guide to the GMP requirements

of PS 9000:2001 Pharmaceutical packaging materials

September 2004

i

PS 9

004

guid

e PS 9004 guide

PS 9004 guide

ISO 9000+

GMPfor Pharmaceutical

packaging materials=

PS 9000

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

iii

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

iviv

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

v

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

vii

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

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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

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How to use this GuidePS 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

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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

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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.

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CONTENTS

Section Page

How to use this guide xvPart 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

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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

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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

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.

Delivery checks

• Document errors• Missing documents

7.4.3

7.5.3

Quality inspection

• Labelling errors• Incorrect goods

7.4

7.4.3

Store material

• Pest Infestation

Case study G

7.5.5:Preservation of product

9:Contamina-tion control

Issue material

• Incorrect materials

7.5.3

See Part 2 for more details

Risk areas

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

Reasons for the ‘extra’ GMP requirementsThe highest priority of the pharmaceutical industry is... etc.

Process inputs Processes Process outputs and evidence

Cross refer to Schematic/Annex

Specification for design of new facilities, processes, or environment

Specialist support for pest control

Standards for environmental conditions

Processes which identify/control:• operating areas• pest control• cleaning proce-

dures

Records of:• processing • cleaning

schedules• material disposal• incidents/audit

reports

Schematic 3(a)

Schematic 4(a)

Schematic 5

Annex A - all parts

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.

1



PS 9004



PART 1 - PROCESS SCHEMATICS

PS 9000 GMP references are reproduced in blue Risk areas are reproduced in red

2

OVERVIEW OF BUSINESS PROCESSES

Schematic 1: Top level business processes

Schematic 2: From the customer

Schematic 3: Planning

Schematic 4: Preparation

Schematic 3 (a): Warehouse

Schematic 4 (a): Print impression media controls

SCHEMATIC 1: TOP LEVEL BUSINESS PROCESSES

Qualitymanagementsystem

Management commitment

• Inadequate incorporation of PS 9000 requirements

• QMS not communicated and/or supported by senior management

4 QMS5.1 Management

commitment5.5

Responsibility, authority and communication

Objectives

• Unclear business targets/goals

• No clear direction as objectives not published

5.3 Quality Policy

5.4 Planning

Resource allocation

• Too few people for quality compliant operation

• Wrong/ inadequate equipment

• Inadequate premises

• Inadequate training

6.1 Provision of resources

6.2 Human resources

Refer to the hypothetical examples which are located after the schematics.


Risk areas

3

OVERVIEW OF BUSINESS PROCESSES

Schematic 5: Production

Schematic 6: Checking and final release

Schematic 7: Distribution

This diagram shows the main business processes from customer requirements through to delivery of final product and provides an index to the schematics

Audit and measurement

• Inadequate performance measures

• Poorly controlled processes

• Unreliable information for management decisions

• Poor compliance to internally established processes/procedures

• Insufficient proof of continuous improvement

8.1 Measurement, analysis and improvement - general

Management review

• Quality System measures not reviewed

• Lack of senior management involvement/leadership

• No continual process improvement

5.1 Management commitment

5.6 Management review

8.5 Improvement

Quality management system

Feedback/communication

SCHEMATIC 1: TOP LEVEL BUSINESS PROCESSES

Refer to the hypothetical examples which are located after the schematics.

4

SCHEMATIC 2: FROM THE CUSTOMER

Organization Customer request/requirements

• Requirements unclear

• Requirements incorrectly specified

• Requirements misunderstood

• Requirements incorrectly accepted

See case study A

5.2 Customer focus

7.2 Customer-related processes

Supply requirements (what, how, when)

• Unclearly specified

• Failure to meet customer expectation

• Rejection by customer

Customer design

• Poor design• Inadequate detail• Failure to

function• Poor

performance at customers site

• Rejection by customer

• Potential risk to patient

• Inadequate testing/validation

See case studies A and B

Feedback

7.2 Customer-related processes7.3 Design and development


Risk areas

Refer to the case studies which are located after the schematics.

5

SCHEMATIC 2: FROM THE CUSTOMER

Assessment of capability

• Incorrect assessment of capability e.g. resource, technology, systems, environment

• Fail to meet delivery/quality

6.1 Provision of resources

6.3 Infrastructure6.4 Work

environment7.1 Planning

of product realization

Agreed contract/agreement and confirmed order

• Lack of formal contract/agreement

• Failure to agree contract requirements

• Poor communication

7.2.3 Customer-related processes

Planning


6

SCHEMATIC 3: PLANNING

Receive order from customer

Order review and customer feedback (where required)

• Incorrect specification chosen

• Inadequate communication with customer

• Order details incorrect• Supply incorrect product• Supply error (quantity/

schedule)• Proof approval error• Specification not

approved

See case studies C and D

5.2 Customer focus7.2 Customer-related

processes7.3 Design and

development

Availability checks on documentation, materials, tooling and equipment

• Incorrect material checked or issued (e.g. wrong foil gauge)

• Wrong print media (version or item)

• Non-availability of equipment (e.g. maintenance/validation status)

• Unapproved production process (e.g. not approved by customer)

• Unsuitable/unapproved material/changes

• Missing/incorrect documentation (e.g. missing mould inspection record)

7.4 Purchasing7.5 Production and service

provision11 Origination/artwork12 Print impression media


Risk areas


7

SCHEMATIC 3: PLANNING

Purchasing and print media provision

• Inadequate supplier control

• Nonconforming purchased materials or service

• Inability to obtain raw material

• Inadequate security (e.g. printing plates)

• 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 requirements

7.4 Purchasing8.3 Control of

nonconforming product11 Origination/artwork12 Print impression media

Production schedule and feedback from production

• Inadequately defined plan/schedule (e.g. insufficient time for line clearance or maintenance)

• Inadequate programme time to follow procedures

• Problems in production

7.1 Planning of product realization

7.5 Production and service provision

8 Measurement, analysis and improvement

Preparation for start of production

Feedback

Availability checks on documentation, materials, tooling and equipment

• Incorrect material checked or issued (e.g. wrong foil gauge)

• Wrong print media (version or item)

• Non-availability of equipment (e.g. maintenance/validation status)

• Unapproved production process (e.g. not approved by customer)

• Unsuitable/unapproved material/changes

• Missing/incorrect documentation (e.g. missing mould inspection record)

7.4 Purchasing7.5 Production and service

provision11 Origination/artwork12 Print impression media


8

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

Delivery from supplier/sub-contractor

Delivery documentation and off-loading checks

• Errors not identified between delivery documentation & purchase order

• Missing delivery/QC documentation

• Transit damage or wet boxes not identified before off-loading

• Incorrect goods

7.4.3 Verification of purchased product

7.5.3 Identification and traceability

Goods checks and quality inspection

• Inadequate checks performed

• Labelling errors not identified

• Incorrect goods sent• Rogue box within delivery• Inadequate batch coding• Non representative sample

taken or provided• Transit/water damage not

detected• Inadequate packaging/

sealing not detected• Incorrect quality status

input to system

See case study F

7.4 Purchasing7.4.3 Verification of

purchased product


Risk areas


9

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

Store material

• Water damage• Pest infestation• Dirt contamination• Mix-up due to

inadequate segregation• Goods stored incorrectly

(e.g. on the floor, temperature, humidity)

• Incorrect quantity/ location recorded

See case study G

7.5.5 Preservation of product

9 Contamination control

Issue material

• Incorrect materials dispensed eg. wrong batch, version

• Incorrect quantity issued• Mixed batch issued but

not identified

7.5.3 Identification and traceability

To production

Goods checks and quality inspection

• Inadequate checks performed

• Labelling errors not identified

• Incorrect goods sent• Rogue box within delivery• Inadequate batch coding• Non representative sample

taken or provided• Transit/water damage not

detected• Inadequate packaging/

sealing not detected• Incorrect quality status

input to system

See case study F

7.4 Purchasing7.4.3 Verification of

purchased product


Return of unused material or semi-finished product

10

SCHEMATIC 4: PREPARATION

Production plan

Preparation/pre-production checks of purchased raw materials

• Error in checking raw material

• Quality status incorrect

• Availability status incorrect

Materials management

Errors in:• Co-ordination

of all required resources

• Combining/ assembly/ Bills of Material

• Timing/change management

• Machine allocation

7.1 Planning of product realization

7.2 Customer related processes

Preparation/pre-production checks of tooling and equipment

• Error in checking tooling/equipment

• Change control error

• Validation status error

• Maintenance omission/ error

• Availability status incorrect

See case study H

7.4 Purchasing7.5 Production and service provision10 Printed materials11 Origination/artwork12 Print impression media13 Print and conversion process


Risk areas


11

SCHEMATIC 4: PREPARATION

Issue of tooling

• Issue incorrect tool• Issued with incorrect

status• Issue in poor

condition• Issue printing plates

in insecure manner

See case studies I, J and K


12 Print impression media

Issue of materials and documentation

• Issue incorrect materials

• Incorrect quantity issued

• Issued with incorrect status

• Issue incorrect documentation

• Unapproved documentation



11 Origination/artwork12 Print impression

media

Production


12

SCHEMATIC 4 (a): PRINT IMPRESSION MEDIA CONTROLS

Customer supplied design text

New print media design

• Errors in media undetected by checks

• Individual plate incorrectly coded

• Set of plates incorrectly coded

• Failure to secure customer proof approval

• Failure to log customer approval

See case study L

11 Origination/ artwork

12.1 General12.2 Matched

plates

Secure storage and controlled issue of plates

• Mix-up with plates from another product

• Uncontrolled access of personnel

• Physical damage to plates

• Inadequate records of issue introducing admixture risk in production

Controls over partial re-designs and obsolete designs

• Incorrect plates retained

• Insecure disposal• Superseded plates

not rendered unusable

• Incorrect plate identification

• Error in replacement plate/ matching set

• Documentation errors

• Customer approval error

See case study M

12.2 Matched plates12.3 Copy / design change12.5 Quarantine and destruction13.2 Changeover systems


Risk areas


13

SCHEMATIC 4 (a): PRINT IMPRESSION MEDIA CONTROLS

Line use of plates

Failure to :• Check design• Clear line of

previous plates• Perform start-up

printing checks• Record checks• Keep samples

See case study N

9.1.7 Line clearance

12.4 Verification13.1 Print

machine set-up (make-ready)

13.2 Changeover systems

13.3 Retained samples

Controls over replacement plate (same design)

• A new first off check is not 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 source)

13.4 Replacement print media

Line clearance and controlled return of plates to store

• Plate left on machine in error

• Inadequate records of return to store


12.1 General

Production


14

SCHEMATIC 5: PRODUCTION

Preparation Line clear check

• Admixture from previous batch

• Erroneous use of previous documents

• Use of a plate from previous job



10 Printed materials

11 Origination/ artwork

Documents/materials/tooling to line

• Use of incorrect documents/ materials

• Failure to use documents correctly

• Incorrect quantities

• Defective moulds/equipment/plates

See case study O



Set up checks and production start

• Errors in data input to machine, e.g. settings

• Setting error undetected

• Start up waste inadequately segregated from main batch

• Unauthorized start up

5.5 Respon- sibility, authority and communication

7.6 Control of monitoring and measuring devices

9 Contamination controls


12 Print impression media


Risk areas


15

SCHEMATIC 5: PRODUCTION

Production/in process control

• Quality variation due to environment e.g. temperature, humidity

• Contamination e.g. insects, dust

• Defective / out of spec or wrong materials

• Visual defects not detected

• Inadequate IPC of transit packaging

• Labelling errors• IPC errors• Material usage error• Failure to identify/

segregate non conforming product

• Recording error

See case studies P, Q

6.4 Work environment7.5 Production and

service provision8.2 Monitoring and

measurement8.3 Control of

nonconforming product11 Origination/artwork

Production completion and line clearance

Risk to next job due to:• lack of GMP training• failure to clear line• inadequate waste disposal• documentation not signed

off therefore status unclear• clearance of electronic

files/settings

See case study R

6.2.2 Competence, awareness and training

8.2 Monitoring and measurement

9 Contamination controls10 Printed materials13 Print and conversion

processes

Checking and final release


Feedback

16

SCHEMATIC 6: CHECKING AND FINAL RELEASE

Production End product QC testing

• Inadequate training• Test method not

validated• Out of Specification

results not investigated• Inadequate procedures• Release decision

contradicts data• Inconsistent sampling/

risk• Equipment/test

equipment inadequate• Calibration errors/

omissions

See case study S

6.2.2 Competence, awareness and training

7.6 Control of monitoring and measuring devices

8 Measurement, analysis and improvement

8.4 Analysis of data

Review of batch documents and QC testing

• Missing/incorrect document

• Missing/incorrect sample• Signature omissions,

unauthorized check signature

• Errors of information/data entry

• Checks out of sequence• Abnormal events not

reviewed

See case study T

5.5 Responsibility, authority and communication

6.2 Human resources4.2 Documentation

requirements13 Print and conversion

process


Risk areas


17

SCHEMATIC 6: CHECKING AND FINAL RELEASE

Create certificate of test or conformance

• Errors / omissions• Signature invalid• Inappropriate data

supplied• Incorrect specifications/

tolerances• Incorrect release decision• Certificate text differs

from batch details

See case study U

8.2 Monitoring and measurement

8.3 Control of nonconforming product

Check box labels against batch information

• Incorrect/missing label• Label data error/

omission• Label reconciliation• Incorrect QC status label

See case studies V and W


DistributionReview of batch documents and QC testing

• Missing/incorrect document

• Missing/incorrect sample• Signature omissions,

unauthorized check signature

• Errors of information/data entry

• Checks out of sequence• Abnormal events not

reviewed

See case study T

5.5 Responsibility, authority and communication

6.2 Human resources4.2 Documentation

requirements13 Print and conversion

process


18

SCHEMATIC 7 - DISTRIBUTION

Checking and final release

Receipt of product into storage/holding (goods out warehouse)

• Error in system transaction (receipt)

• Inadequate segregation from other goods

• Storage damage



Order preparation (picking and transit packaging)

• Picking wrong product• Damage to product due

to inappropriate transit packaging

• Pallets not suitable for customer handling

• Error in transaction (issue)

See case study X



Risk areas


19

SCHEMATIC 7 - DISTRIBUTION

Dispatch area/goods check and documentation

• Errors of quantity• Incorrect labelling• Error in dispatch note• Admixture of boxes

See case study Y

Transport to the customer

• Transit damage e.g. poor pallet stacking, poor weather protection

• Contamination in transit• Inadequate control of

hauliers

See case study Z

The customer


Order preparation (picking and transit packaging)

• Picking wrong product• Damage to product due

to inappropriate transit packaging

• Pallets not suitable for customer handling

• Error in transaction (issue)

See case study X



21



PS 9004



PART 1 - CASE STUDIES

23

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-

24

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/requirementsBar 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 designA 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 feedbackThe 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

25

(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 feedbackThe 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 provisionLeaflets 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 inspectionSelf-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.

26

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 materialTwo 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 equipmentMould 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.

27

I Focus – Issue of toolingSyringe 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 toolingCartons 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 toolingMould 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 designArtwork 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

28

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 designsThe 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 platesA 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 lineDuring 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).

29

P Focus – Production/in-process controlA 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 controlPlastic 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 clearanceOn 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

30

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 testingCarton 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 ConformanceIrradiated 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 informationA 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 informationA 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

31

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 & documentationDespatch 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 customerGoods 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.

32

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 objectivesDiscuss 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.

33

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?

35



PS 9004



PART 2 - GUIDANCE ON PS 9000 GMP CLAUSES

PS 9000 GMP related text is reproduced in blue

37

Gen

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syn

op

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- C

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38

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s fa

cilit

ies

and

sta

ff to

be

‘fit

for

pur

pos

e’,

i.e.

‘sui

tab

le f

acili

ties

and

com

pet

ent

staf

f’,

and

tha

t th

is G

MP

req

uire

men

t is

eq

ually

ap

plic

able

to

the

sup

plie

r of

pha

rmac

eutic

al p

acka

ging

com

pon

ents

.

Pro

duc

t se

curit

y an

d t

he a

void

ance

of

cros

s co

ntam

inat

ion

und

erp

ins

all p

harm

aceu

tical

qua

lity,

sin

ce t

hese

are

bas

ic is

sues

tha

t ca

n le

ad t

o p

eop

le t

akin

g th

e w

rong

med

icin

e, d

amag

ing

the

pha

rmac

eutic

al c

omp

any’

s b

usin

ess,

and

pub

lic c

onfid

ence

in it

. (S

ee a

lso

Ann

ex A

, ‘C

ount

erfe

it’ t

hat

cove

rs in

det

ail t

he n

eed

s fo

r co

ntro

ls in

are

as in

volv

ing

dis

pos

al o

f ar

twor

k, p

roce

ss d

efec

tives

and

was

te

mat

eria

ls,

etc.

).

Beg

inni

ng w

ith it

s re

gula

tory

insp

ecto

rs,

the

who

le p

harm

aceu

tical

ind

ustr

y is

com

plia

nce

driv

en,

usin

g au

dits

as

a m

easu

re t

hat

GM

P p

ract

ices

, as

par

t of

a q

ualit

y sy

stem

, ar

e in

pla

ce.

Cen

tral

to

this

aud

it fo

cus,

is t

he ‘

Rul

es a

nd G

uid

ance

for

Pha

rmac

eutic

al

Man

ufac

ture

rs a

nd D

istr

ibut

ors’

. C

hap

ter

9, In

tern

al a

udits

, re

qui

res

self

insp

ectio

n b

y th

e p

harm

aceu

tical

man

ufac

ture

r an

d A

nnex

8.5

, re

qui

res

that

sam

plin

g p

lans

for

the

ass

essm

ent

of p

acka

ging

mat

eria

l del

iver

ies

shou

ld,

thro

ugh

aud

its,

take

into

acc

ount

kno

wle

dge

of

the

sup

plie

r’s q

ualit

y as

sura

nce

syst

em.

Pro

cess

inp

uts

Pro

cess

esP

roce

ss o

utp

uts

and

evi

den

ceC

ross

ref

er t

o

S

chem

atic

/Ann

ex

• C

usto

mer

inp

ut/

req

uire

men

tsP

roce

sses

whi

ch:

• co

nsid

er c

usto

mer

req

uire

men

ts

in o

rder

to

del

iver

a s

ecur

ely

man

ufac

ture

d p

rod

uct

to s

pec

ifica

tion

• p

erm

it cu

stom

er a

udits

• en

sure

sec

ure

dis

pos

al o

f al

l prin

t re

late

d m

ater

ial

• S

uita

ble

fac

ilitie

s•

Evi

den

ce o

f G

MP

tra

inin

g an

d

task

com

pet

ency

• Im

pro

vem

ent

pla

ns f

rom

cu

stom

er a

udits

•

Phy

sica

l con

trol

and

rec

ord

s of

sec

ure

dis

pos

al o

f sp

ecifi

ed m

ater

ials

Sch

emat

ic 2

Sch

emat

ic 3

Ann

ex A

Ann

ex B

41

Cla

use

5.3

Qua

lity

po

licy

The

qua

lity

pol

icy

is a

top

-lev

el d

ocum

ent,

key

to

com

mun

icat

ing

and

lead

ing

cont

inuo

us im

pro

vem

ent

to s

atis

fy t

he n

eed

s of

the

or

gani

zatio

n, c

usto

mer

s an

d o

ther

sta

keho

lder

s.

Rea

sons

fo

r th

e ‘e

xtra

’ GM

P r

equi

rem

ents

All

ISO

900

1 ce

rtifi

cate

d c

omp

anie

s ar

e re

qui

red

to

have

a ‘

qua

lity

pol

icy’

. Th

e av

oid

ance

of

cont

amin

atio

n an

d m

aint

aini

ng a

co

ntro

lled

env

ironm

ent

in o

rder

to

ensu

re p

rod

uct

secu

rity

and

inte

grity

is o

f su

ch im

por

tanc

e to

the

pha

rmac

eutic

al in

dus

try

that

the

se

two

req

uire

men

ts h

ave

to b

e in

clud

ed in

the

sup

plie

r’s q

ualit

y p

olic

y.

Whi

le P

S 9

000:

2001

is p

rimar

ily f

or s

upp

liers

of

pha

rmac

eutic

al p

acka

ging

mat

eria

ls,

som

e or

gani

zatio

ns s

upp

ly d

iffer

ent

ind

ustr

y se

ctor

s (e

.g.

food

, ag

roch

emic

al,

cosm

etic

s).

Ther

efor

e, f

or t

he p

urp

oses

of

clar

ity,

the

exte

nt t

o w

hich

thi

s ap

plic

atio

n st

and

ard

is

emp

loye

d w

ithin

the

org

aniz

atio

n ne

eds

to b

e d

ocum

ente

d.

Pro

cess

inp

uts

Pro

cess

esP

roce

ss o

utp

uts

and

ev

iden

ceC

ross

ref

er t

o

S

chem

atic

/Ann

ex

• O

rgan

izat

ion

stra

tegy

/p

urp

ose

• C

usto

mer

nee

ds

incl

udin

g p

rod

uct

secu

rity

req

uire

men

ts

and

pre

vent

ion

of

cros

s-co

ntam

inat

ion

• E

xten

t to

whi

ch P

S

9000

is u

sed

with

in t

he

orga

niza

tion

Pro

cess

es w

hich

:•

def

ine

qua

lity

pol

icy

• re

view

pol

icy

to e

nsur

e it

mee

ts u

ser

need

s•

revi

ew q

ualit

y ob

ject

ives

• co

mm

unic

ate

qua

lity

pol

icy,

incl

udin

g co

ntam

inat

ion

cont

rol,

to in

tern

al s

taff

and

ex

tern

al p

eop

le,

as a

pp

rop

riate

• U

p-t

o-d

ate

qua

lity

pol

icy

Rec

ord

s of

:•

awar

enes

s/co

mm

unic

atio

n ac

tiviti

es•

pro

duc

t se

curit

y an

d

envi

ronm

ent

cont

rols

• im

ple

men

tatio

n

Sch

emat

ic 1

42

Cla

use

5.4

Pla

nnin

g

Str

ateg

ic b

usin

ess

pla

nnin

g is

ess

entia

l to

ensu

re t

hat

the

orga

niza

tion

mov

es f

orw

ard

s in

a w

ay t

hat

satis

fies

the

need

s of

all

stak

ehol

der

s. T

his

sect

ion

cove

rs t

he f

orm

al p

lann

ing

pro

cess

es n

eed

ed t

o re

alis

e or

gani

zatio

nal s

trat

egy

thro

ugh

gene

ratio

n of

ob

ject

ives

with

in t

he q

ualit

y m

anag

emen

t sy

stem

.

Ther

e ar

e no

‘ex

tra’

PS

900

0 G

MP

s w

ithin

thi

s cl

ause

. Th

ere

are

imp

orta

nt G

MP

prin

cip

les

in t

his

area

, b

ut t

hey

are

adeq

uate

ly

exp

ress

ed in

ISO

900

1 an

d IS

O 9

004.

Pro

cess

inp

uts

Pro

cess

esP

roce

ss o

utp

uts

and

ev

iden

ceC

ross

ref

er t

o

S

chem

atic

/Ann

ex

• S

hort

and

long

ter

m

orga

niza

tion

stra

tegy

/go

als

• R

egul

ator

y re

qui

rem

ents

• N

eed

s of

the

or

gani

zatio

n an

d

mar

kets

• M

anag

emen

t re

view

fin

din

gs•

Cur

rent

pro

duc

t an

d

pro

cess

per

form

ance

• R

esou

rce

info

rmat

ion

• R

esul

ts f

rom

sel

f-as

sess

men

ts a

nd o

ther

au

dits

• In

dus

try

info

rmat

ion/

ben

chm

arki

ng

Pro

cess

es w

hich

:•

pla

n th

e im

ple

men

tatio

n, a

nd c

ontin

ual

imp

rove

men

t of

the

QM

S•

pro

vid

e a

fram

ewor

k fo

r th

e se

ttin

g of

m

easu

rab

le q

ualit

y ob

ject

ives

, w

hich

sup

por

t th

e q

ualit

y p

olic

y an

d s

trat

egic

goa

ls

• P

erfo

rman

ce

mea

sure

men

t d

ata

Def

ined

and

doc

umen

ted

:•

skill

s an

d k

now

led

ge

• re

spon

sib

ilitie

s an

d a

utho

rity

for

imp

lem

enta

tion

of

imp

rove

men

t p

lans

Qua

lity

obje

ctiv

es:

• at

org

aniz

atio

nal

leve

ls (e

.g.

man

ager

s,

sup

ervi

sors

, op

erat

ives

)•

for

func

tiona

l are

as

(e.g

. p

rod

uctio

n,

adm

inis

trat

ion)

Sch

emat

ic 1

43

Cla

use

5.5

Res

po

nsib

ility

, aut

hori

ty a

nd c

om

mun

icat

ion

All

staf

f sh

ould

kno

w w

hat

thei

r re

spon

sib

ilitie

s ar

e an

d t

o w

hom

the

y ar

e re

spon

sib

le.

Aut

horit

y ne

eds

to b

e p

re-d

efin

ed,

doc

umen

ted

an

d w

ell c

omm

unic

ated

to

ensu

re a

ctiv

ities

tak

e p

lace

in a

con

trol

led

man

ner.

Rea

sons

fo

r th

e ‘e

xtra

’ GM

P r

equi

rem

ents

(re

fer

to P

S 9

000

clau

se 5

.5.3

Int

erna

l co

mm

unic

atio

n)

Sta

ff in

all

orga

niza

tions

wor

k b

ette

r w

hen

they

are

kep

t in

form

ed,

are

app

rop

riate

ly t

rain

ed a

nd h

ave

rele

vant

agr

eed

pro

ced

ures

.A

com

mun

icat

ion

pro

cess

nee

ds

to b

e in

pla

ce t

o en

sure

tha

t st

aff

are

cust

omer

foc

usse

d,

mot

ivat

ed a

nd w

here

ap

plic

able

, ar

e aw

are

of t

he r

egul

ator

y, le

gal,

and

GM

P n

eed

s of

the

pha

rmac

eutic

al in

dus

try

that

may

affe

ct t

hem

.

Pro

cess

inp

uts

Pro

cess

esP

roce

ss o

utp

uts

and

ev

iden

ceC

ross

ref

er t

o

S

chem

atic

/Ann

ex

• E

xist

ing

role

s an

d

resp

onsi

bili

ty d

ata

• R

esou

rce

info

rmat

ion

• P

erso

nnel

dat

a (q

ualif

icat

ions

, ex

per

ienc

e, e

tc.)

• In

dus

try

info

rmat

ion/

ben

chm

arki

ng

Pro

cess

es w

hich

:•

clar

ify r

esp

onsi

bili

ties

and

aut

horit

ies

for

job

el

emen

ts r

elat

ing

to q

ualit

y (e

.g.

stat

e w

ho is

al

low

ed t

o re

leas

e p

rod

ucts

for

des

pat

ch)

• ap

poi

nt a

man

agem

ent

rep

rese

ntat

ive

to

over

see

the

QM

S (e

.g.

the

QA

Man

ager

)•

esta

blis

h in

tern

al c

omm

unic

atio

n (e

.g.

mon

thly

te

am b

riefin

gs,

etc.

)

Pro

cess

es t

o co

mm

unic

ate:

• re

spon

sib

ilitie

s an

d a

utho

ritie

s fo

r q

ualit

y (e

.g.

pos

t or

gani

zatio

n ch

arts

, gi

ve p

eop

le t

heir

key

resp

onsi

bili

ties

to r

ead

and

ap

pro

ve)

• q

ualit

y th

roug

hout

the

org

aniz

atio

n –

all s

taff

shou

ld b

e in

clud

ed,

from

the

mos

t se

nior

m

anag

er t

o th

e m

ost

juni

or s

upp

ort

per

sonn

el•

the

GM

P a

nd r

egul

ator

y re

qui

rem

ents

to

all

app

rop

riate

sta

ff

• E

vid

ence

of

com

mun

icat

ion

Res

pon

sib

ilitie

s an

d

auth

oriti

es w

hich

are

:•

def

ined

and

d

ocum

ente

d•

clea

rly c

omm

unic

ated

th

roug

hout

the

or

gani

zatio

n

Sch

emat

ic 1

Sch

emat

ic 5

Sch

emat

ic 6

44

Cla

use

5.6

Man

agem

ent

revi

ew

Sen

ior

man

agem

ent

mus

t p

erio

dic

ally

rev

iew

the

QM

S t

o en

sure

it r

emai

ns e

ffect

ive

and

to

asse

ss im

pro

vem

ent

opp

ortu

nitie

s.

This

sho

uld

be

don

e in

the

con

text

of

imp

rovi

ng t

he p

erfo

rman

ce o

f th

e w

hole

org

aniz

atio

n.

Ther

e ar

e no

‘ex

tra’

PS

900

0 G

MP

s w

ithin

thi

s cl

ause

. Th

ere

are

imp

orta

nt G

MP

prin

cip

les

in t

his

area

, b

ut t

hey

are

adeq

uate

ly

exp

ress

ed in

ISO

900

1 an

d IS

O 9

004.

Pro

cess

inp

uts

Pro

cess

esP

roce

ss o

utp

uts

and

ev

iden

ceC

ross

ref

er t

o

S

chem

atic

/Ann

ex

• Q

ualit

y p

olic

y an

d

obje

ctiv

es•

Qua

lity

aud

it re

sults

• P

rod

uct

qua

lity

info

rmat

ion

and

co

nfor

mity

dat

a•

Op

por

tuni

ties

to

imp

rove

• Fe

edb

ack

from

cu

stom

ers

• P

roce

ss p

erfo

rman

ce

info

rmat

ion

• C

orre

ctiv

e an

d

pre

vent

ive

actio

ns•

Cha

nges

tha

t m

ight

af

fect

the

QM

S•

Pre

viou

s Q

MS

rev

iew

s

Pro

cess

es w

hich

:•

revi

ew a

nd e

valu

ate

the

per

form

ance

of

the

QM

S•

asse

ss w

heth

er t

he Q

MS

req

uire

s im

pro

vem

ent

• ev

alua

te b

eyon

d t

he Q

MS

itse

lf, t

o th

at o

f th

e w

hole

org

aniz

atio

n –

its a

ctiv

ities

, p

erfo

rman

ce

and

effi

cien

cy

• R

evie

wed

qua

lity

pol

icy

and

ob

ject

ives

• In

form

atio

n fo

r st

rate

gic/

orga

niza

tiona

l d

ecis

ion-

mak

ing

Act

ions

to:

•

com

mun

icat

e fin

din

gs

of r

evie

w•

imp

rove

the

QM

S•

imp

rove

pro

cess

es•

imp

rove

pro

duc

ts•

add

ress

res

ourc

e ne

eds

Sch

emat

ic 1

45

Gen

eral

Syn

op

sis

- C

laus

e 6

Res

our

ce m

anag

emen

t

The

pro

visi

on o

f al

l res

ourc

es, i

nclu

din

g p

eop

le, i

nfra

stru

ctur

e, w

ork

envi

ronm

ent

and

info

rmat

ion,

nee

ded

for

op

erat

ion

and

im

pro

vem

ent

of t

he q

ualit

y sy

stem

to

assu

re c

omp

lianc

e w

ith t

he r

equi

rem

ents

of

cust

omer

s.

Cla

use

6.1

Pro

visi

on

of

reso

urce

s

It is

imp

orta

nt t

o ha

ve p

roce

sses

, w

hich

det

erm

ine

and

pro

vid

e th

e re

sour

ces

need

ed b

y th

e or

gani

zatio

n.

Rea

sons

fo

r th

e ‘e

xtra

’ GM

P r

equi

rem

ents

Gai

ning

cer

tific

atio

n to

PS

900

0 re

qui

res

a fu

ll an

d t

horo

ugh

det

erm

inat

ion

of r

esou

rce

req

uire

men

ts.

This

will

ena

ble

the

im

ple

men

tatio

n of

a Q

MS

tha

t sa

tisfie

s th

e ex

pec

tatio

ns o

f th

e p

harm

aceu

tical

cus

tom

er,

with

the

ben

efits

of

cont

inuo

us im

pro

vem

ent

and

cus

tom

er a

udit

succ

esse

s.

Pro

cess

inp

uts

Pro

cess

esP

roce

ss o

utp

uts

and

evi

den

ceC

ross

ref

er t

o

S

chem

atic

/Ann

ex

• Q

MS

pro

cess

re

qui

rem

ents

• P

roce

ss in

form

atio

n,

dat

a an

d r

equi

rem

ents

(p

eop

le,

pre

mis

es,

equi

pm

ent,

etc

.)•

Cur

rent

org

aniz

atio

n p

eop

le,

pre

mis

es,

equi

pm

ent

• P

S 9

000

spec

ific

add

ition

al r

equi

rem

ents

Pro

cess

es w

hich

:•

iden

tify

and

ap

poi

nt s

uffic

ient

per

sonn

el

• p

rovi

de

reso

urce

s ne

eded

to

imp

rove

cu

stom

er s

atis

fact

ion

• p

rovi

de

enou

gh r

esou

rces

to

fulfi

l the

re

qui

rem

ents

of

PS

900

0

• D

efin

ed o

rgan

izat

ion

stru

ctur

e an

d p

erso

nnel

and

re

spon

sib

ilitie

s•

Ad

equa

te p

erso

nnel

to

enab

le im

pro

vem

ent

pro

gram

mes

and

foc

us o

n cu

stom

er r

equi

rem

ents

• Q

uant

ified

ass

essm

ent

of

reso

urce

nee

ds

• A

utho

risat

ion

to p

rocu

re

reso

urce

Sch

emat

ic 1

Sch

emat

ic 2

46

Cla

use

6.2

Hum

an r

eso

urce

s

Det

erm

ine,

pro

vid

e an

d d

evel

op p

eop

le t

o su

pp

ort

the

orga

niza

tion’

s q

ualit

y p

olic

y an

d o

bje

ctiv

es

Rea

sons

fo

r th

e ‘e

xtra

’ GM

P r

equi

rem

ents

(re

fer

to P

S 9

000

clau

se 6

.2.2

Co

mp

eten

ce, a

war

enes

s an

d t

rain

ing

)

GM

P is

fun

dam

enta

l to

effe

ctiv

e co

ntro

l of

pro

duc

t q

ualit

y an

d r

equi

res

that

GM

P t

rain

ing

be

pro

vid

ed o

n an

ong

oing

bas

is.

Pha

rmac

eutic

al c

usto

mer

s lo

ok f

or e

vid

ence

of

this

at

thei

r su

pp

liers

.

Cro

ss c

onta

min

atio

n in

pac

kagi

ng c

an le

ad t

o th

e p

atie

nt b

eing

giv

en t

he w

rong

med

icat

ion

with

fat

al c

onse

que

nces

. W

hen

item

s ar

e no

t m

anuf

actu

red

usi

ng c

ontr

olle

d s

yste

ms

the

chan

ce o

f a

mix

-up

or

prin

t er

ror

is s

igni

fican

tly g

reat

er,

and

the

ris

k ca

nnot

be

acce

pte

d b

y th

e p

harm

aceu

tical

ind

ustr

y.

Pro

cess

inp

uts

Pro

cess

esP

roce

ss o

utp

uts

and

ev

iden

ceC

ross

ref

er t

o

S

chem

atic

/Ann

ex

• Id

entif

ied

bus

ines

s p

roce

sses

• A

vaila

ble

peo

ple

to

carr

y ou

t p

roce

sses

• R

equi

red

co

mp

eten

cies

/leve

l of

tra

inin

g fo

r Q

MS

p

roce

sses

• R

ecru

itmen

t re

qui

rem

ents

: ed

ucat

ion,

tra

inin

g,

skill

s an

d e

xper

ienc

e

Pro

cess

es w

hich

:•

iden

tify

trai

ning

and

aw

aren

ess

need

s (g

ap

anal

ysis

)•

del

iver

tra

inin

g an

d a

war

enes

s p

rogr

ams

• ev

alua

te e

ffect

iven

ess

of t

rain

ing

and

aw

aren

ess

• en

sure

tra

inin

g co

vers

GM

P, t

he r

isk

and

d

ange

r of

cro

ss-c

onta

min

atio

n an

d t

he

imp

orta

nce

of f

ollo

win

g p

roce

dur

es•

ensu

re p

erio

dic

ref

resh

er t

rain

ing

is p

rovi

ded

• D

efin

ed a

nd

doc

umen

ted

GM

P

trai

ning

sch

edul

e

Rec

ord

s of

:•

trai

ning

•

per

sonn

el in

form

atio

n•

curr

icul

a vi

taru

m

(CV

s)•

ind

ivid

ual

dev

elop

men

t p

lans

Sch

emat

ic 1

Sch

emat

ic 6

47

Cla

use

6.3

Infr

astr

uctu

re

Ap

pro

pria

te e

qui

pm

ent,

pre

mis

es,

serv

ices

and

env

ironm

ent

are

fund

amen

tal r

equi

rem

ents

of

GM

P.

Rea

sons

fo

r th

e ‘e

xtra

’ GM

P r

equi

rem

ents

Pac

kagi

ng d

efec

ts,

incl

udin

g m

isla

bel

ling/

mix

-up

s, a

re t

he m

ajor

cau

se o

f ap

pro

xim

atel

y 25

% o

f d

efec

tive

med

icin

es a

nd b

atch

rec

alls

(s

ee A

nnex

B 3

). It

mus

t b

e em

pha

size

d t

hat

the

caus

es o

f th

is p

rob

lem

are

not

sol

ely

attr

ibut

able

to

the

pac

kagi

ng s

upp

ly in

dus

try

sinc

e al

l par

ts o

f th

e su

pp

ly c

hain

and

man

ufac

turin

g p

roce

ss c

an b

e im

plic

ated

. Th

is a

lso

incl

udes

the

dis

trib

utio

n fr

om t

he s

upp

lier

to

the

cust

omer

, d

urin

g us

e in

the

cus

tom

er’s

pro

cess

es a

nd a

lso

the

final

mar

ket

dis

trib

utio

n.

Whi

lst

the

pro

duc

t sh

ould

be

des

igne

d t

o m

inim

ise/

avoi

d c

ontr

ibut

ing

to t

he r

isk,

the

infr

astr

uctu

re o

f m

anuf

actu

ring

and

sup

por

t p

roce

sses

at

the

sup

plie

r m

ust

also

be

des

igne

d,

mai

ntai

ned

and

op

erat

ed in

com

plia

nce

with

the

prin

cip

les

of G

MP

to

assu

re p

rod

uct

secu

rity.

It is

bec

ause

of

the

cont

inui

ng h

igh

pro

por

tion

of m

arke

t re

calls

tha

t ar

e ca

used

by

def

ectiv

e p

acka

ging

tha

t p

harm

aceu

tical

sup

plie

r au

dits

will

alw

ays

asse

ss h

ow t

he in

fras

truc

ture

may

influ

ence

pro

duc

t co

ntam

inat

ion.

Pro

cess

inp

uts

Pro

cess

esP

roce

ss o

utp

uts

and

evi

den

ceC

ross

ref

er t

o

S

chem

atic

/Ann

ex

• B

usin

ess

pro

cess

re

qui

rem

ents

for

p

rem

ises

, eq

uip

men

t,

utili

ties

and

oth

er

serv

ices

incl

udin

g ha

rdw

are

and

sof

twar

e•

Mai

nten

ance

man

uals

an

d s

ched

ules

• R

egul

ator

y re

qui

rem

ents

Pro

cess

es w

hich

:•

iden

tify,

pro

vid

e an

d m

aint

ain

pre

mis

es,

equi

pm

ent,

util

ities

and

ot

her

serv

ices

incl

udin

g ha

rdw

are

and

so

ftw

are

and

tra

nsp

ort

• en

sure

tha

t G

MP

req

uire

men

ts

are

inco

rpor

ated

to

avoi

d p

rod

uct

cont

amin

atio

n

• A

deq

uate

pre

mis

es,

faci

litie

s,

equi

pm

ent

and

ser

vice

s•

Inte

rnal

rev

iew

s an

d c

usto

mer

fe

edb

ack

• R

ecor

ds

of o

ngoi

ng

mai

nten

ance

and

rev

iew

• A

ctio

n p

lans

(sho

rt a

nd lo

ng

term

)•

Cro

ss-c

onta

min

atio

n av

oid

ance

Sch

emat

ic 2

Ann

ex A

:S

egre

gatio

n co

ntro

ls

48

Cla

use

6.4

Wo

rk e

nvir

onm

ent

The

wor

k en

viro

nmen

t is

crit

ical

to

ensu

ring

not

only

pro

duc

t co

nfor

mity

, b

ut a

lso

the

abili

ty a

nd d

esire

of

peo

ple

to

per

form

effe

ctiv

ely.

Rea

sons

fo

r th

e ‘e

xtra

’ GM

P r

equi

rem

ents

Pre

vent

ing

cont

amin

atio

n of

med

icin

al p

rod

ucts

may

req

uire

tha

t th

e co

mp

onen

ts b

e m

anuf

actu

red

und

er p

artic

ular

sta

ndar

ds

of

clea

nlin

ess,

whi

ch c

ould

ulti

mat

ely

invo

lve

clea

nroo

ms

(i.e.

con

trol

led

env

ironm

ents

). Th

ese

enab

le t

he p

harm

aceu

tical

pro

duc

t an

d

pat

ient

to

be

pro

tect

ed.

This

may

ap

ply

eve

n w

hen

the

com

pon

ents

und

ergo

a c

lean

ing

pro

cess

at

the

pha

rmac

eutic

al m

anuf

actu

rer’s

si

te.

For

som

e p

rod

uct

cont

act

com

pon

ents

, m

icro

bia

l con

tam

inat

ion

leve

ls (t

he b

iob

urd

en) n

eed

to

be

kep

t at

the

low

est

leve

ls p

ossi

ble

. Th

is s

till a

pp

lies

even

whe

n th

e p

harm

aceu

tical

pro

cess

ing

invo

lves

a s

teril

izat

ion

oper

atio

n.

Pro

cess

inp

uts

Pro

cess

esP

roce

ss o

utp

uts

and

ev

iden

ceC

ross

ref

er t

o

S

chem

atic

/Ann

ex

• C

ateg

orie

s/st

and

ard

s fo

r en

viro

nmen

tal

cond

ition

s•

Pro

duc

t/m

anuf

actu

ring

pro

cess

es•

Cus

tom

er r

equi

rem

ents

• In

form

atio

n fr

om

ongo

ing

envi

ronm

enta

l m

onito

ring

• P

eop

le n

eed

s/co

nsid

erat

ion

• R

egul

ator

y re

qui

rem

ents

Pro

cess

es w

hich

:•

iden

tify

nece

ssar

y w

ork

envi

ronm

ent

• id

entif

y fa

ctor

s ne

eded

to

ensu

re p

rod

ucts

m

eet

req

uire

men

ts•

man

age

and

mai

ntai

n w

ork

envi

ronm

ent

incl

udin

g cl

eani

ng,

valid

atio

n an

d p

roce

sses

• in

corp

orat

e ap

pro

pria

te ‘

clea

nroo

m’

cond

ition

s fo

r th

e ty

pe

of p

rod

uct

bei

ng m

ade

• A

pp

rop

riate

en

viro

nmen

t fo

r p

rod

uct

bei

ng m

ade

• R

ecor

ds

of

envi

ronm

enta

l m

onito

ring,

val

idat

ion

and

cle

anin

g

Sch

emat

ic 2

Sch

emat

ic 5

Ann

ex A

:R

isk

asse

ssm

ent

49

Gen

eral

Syn

op

sis

- C

laus

e 7

Pro

duc

t re

aliz

atio

n

Mak

ing

pro

duc

t in

volv

es m

any

inte

rrel

ated

pro

cess

es,

the

inp

uts

and

out

put

s of

whi

ch s

houl

d b

e an

alys

ed a

nd m

anag

ed.

Cla

use

7.1

Pla

nnin

g o

f p

rod

uct

real

izat

ion

Man

agem

ent

shou

ld p

lan

the

pro

cess

es n

eed

ed f

or p

rod

uct

real

izat

ion.

Ther

e ar

e no

‘ex

tra’

PS

900

0 G

MP

s w

ithin

thi

s cl

ause

. Th

ere

are

imp

orta

nt G

MP

prin

cip

les

in t

his

area

but

the

y ar

e ad

equa

tely

ex

pre

ssed

in IS

O 9

001

and

ISO

900

4.

Pro

cess

inp

uts

Pro

cess

esP

roce

ss o

utp

uts

and

ev

iden

ceC

ross

ref

er t

o

S

chem

atic

/Ann

ex

• Q

ualit

y re

qui

rem

ents

fo

r th

e p

rod

uct

• P

rod

uct

spec

ifica

tions

• C

usto

mer

req

uire

men

ts•

Pro

duc

t re

qui

rem

ents

–

valid

atio

n, m

onito

ring,

te

st c

riter

ia.

• R

esou

rce

req

uire

men

ts

spec

ific

to t

he p

rod

uct

Pro

cess

es w

hich

:•

pla

n th

e p

rod

uctio

n p

roce

sses

• p

lan

the

sup

por

t p

roce

sses

• m

anag

e ch

ange

s•

cont

rol p

roce

ss/p

rod

uct

valid

atio

n

• Q

ualit

y p

lan

• C

lear

ly id

entif

ied

p

roce

sses

• A

n op

erat

ing

pla

n to

m

anag

e p

roce

sses

• Id

entif

ied

res

ourc

e re

qui

rem

ents

to

sup

por

t th

e op

erat

ion

and

mon

itorin

g of

p

roce

sses

• C

hang

e p

roce

dur

e an

d r

ecor

ds

• Va

lidat

ion

reco

rds

Sch

emat

ic 2

Sch

emat

ic 3

Sch

emat

ic 4

Ann

ex A

:C

hang

e co

ntro

l

Valid

atio

n (a

nd

Qua

lific

atio

n)

50

Cla

use

7.2

Cus

tom

er r

elat

ed p

roce

sses

The

orga

niza

tion

shou

ld h

ave

effe

ctiv

e p

roce

sses

for

com

mun

icat

ing

with

its

cust

omer

s an

d o

ther

inte

rest

ed p

artie

s.

Rea

sons

fo

r th

e ‘e

xtra

’ GM

P r

equi

rem

ents

(re

fer

to P

S 9

000

clau

se 7

.2.3

Cus

tom

er c

om

mun

icat

ion)

The

pha

rmac

eutic

al in

dus

try

is h

eavi

ly r

egul

ated

by

regu

lato

ry a

utho

ritie

s, t

hrou

ghou

t th

e w

orld

. C

omp

anie

s ar

e re

qui

red

to

obta

in a

m

arke

ting

auth

oriz

atio

n (M

A)/

Pro

duc

t Li

cenc

e (P

L) t

o p

lace

a m

edic

inal

pro

duc

t on

the

mar

ket.

The

ap

plic

atio

n fo

r an

MA

/PL

mus

t b

e su

pp

orte

d b

y ex

tens

ive

dat

a in

clud

ing

info

rmat

ion

on t

he p

acka

ging

mat

eria

ls t

o b

e us

ed.

Com

pan

ies

are

not

at li

ber

ty t

o m

ake

any

chan

ges

to t

he p

rod

uct,

its

com

pon

ents

or

its m

etho

d o

f p

rod

uctio

n w

ithou

t ap

pro

val f

rom

the

reg

ulat

ory

auth

ority

. Th

e lic

ensi

ng o

f p

harm

aceu

tical

pro

duc

ts r

equi

res

that

the

pha

rmac

eutic

al c

omp

anie

s in

form

gov

ernm

ent

regu

lato

rs o

f vi

rtua

lly a

ll ch

ange

s. T

hey

are

not

at li

ber

ty t

o ch

ange

any

reg

iste

red

pro

duc

t d

etai

ls w

ithou

t go

ing

thro

ugh

an e

xten

sive

and

leng

thy

sub

mis

sion

pro

cess

.

One

par

ticul

ar r

easo

n fo

r th

is c

omm

unic

atio

n p

roce

ss is

tha

t ch

ange

s ca

n re

qui

re t

rial w

ork

(e.g

. st

abili

ty t

rial)

at t

he p

harm

aceu

tical

co

mp

any

or o

ther

act

ions

, su

ch a

s m

achi

ne a

ltera

tions

, w

ith im

plic

atio

ns f

or d

esig

n an

d p

lann

ing.

In o

rder

to

give

due

con

sid

erat

ion

to e

ach

pro

pos

ed c

hang

e, t

here

sho

uld

be

a cl

ear

agre

emen

t b

etw

een

the

pha

rmac

eutic

al c

usto

mer

and

org

aniz

atio

n of

wha

t co

mm

unic

atio

n is

req

uire

d f

or v

ario

us t

ypes

of

chan

ge.

51

Pro

cess

inp

uts

Pro

cess

esP

roce

ss o

utp

uts

and

ev

iden

ceC

ross

ref

er t

o

Sch

emat

ic/A

nnex

• C

usto

mer

st

ated

re

qui

rem

ents

• E

xter

nal

mar

ket

dat

a•

Sta

tuto

ry a

nd

regu

lato

ry

req

uire

men

ts

Pro

cess

es w

hich

:•

enab

le c

omm

unic

atio

n w

ith c

usto

mer

s (a

bou

t p

rod

uct

info

rmat

ion,

sal

es e

nqui

ries,

com

pla

ints

, et

c.)

• re

view

the

cus

tom

er’s

ord

er,

pro

duc

t re

qui

rem

ents

b

efor

e p

rod

ucts

are

sup

plie

d (e

.g.

cont

ract

rev

iew

)•

req

uire

cha

nge

cont

rol m

easu

res

to b

e in

pla

ce t

o re

cord

and

mon

itor

chan

ges

to p

roce

sses

• re

view

rel

ated

info

rmat

ion

– m

arke

t re

sear

ch,

com

pet

itor

anal

ysis

, st

atut

ory

req

uire

men

ts•

spec

ifica

lly id

entif

y th

ose

typ

es o

f ch

ange

s w

hich

re

qui

re p

rior

app

rova

l by,

or

notif

icat

ion

to t

he

cust

omer

• D

efin

ed p

rod

uct

req

uire

men

ts•

Doc

umen

tatio

n d

enot

ing

cust

omer

ap

pro

val

• E

ffect

ive

dat

a ex

chan

ge

cove

ring

pro

duc

ts,

amen

dm

ents

, fe

edb

ack

and

com

pla

ints

• P

ossi

ble

inp

uts

to

man

agem

ent

pla

nnin

g p

roce

ss

(e.g

. re

sour

ce/

mac

hine

ry im

plic

atio

ns)

Rec

ord

s of

:•

cust

omer

co

mm

unic

atio

n (e

.g.

pro

duc

t sp

ecifi

catio

ns,

ord

er c

onfir

mat

ions

, co

mp

lain

t in

vest

igat

ions

, et

c.)

•

ord

er/p

rod

uct

revi

ew

Sch

emat

ic 2

Sch

emat

ic 3

Sch

emat

ic 4

Ann

ex A

:C

hang

e co

ntro

l

52

Cla

use

7.3

Des

ign

and

dev

elo

pm

ent

Pla

nnin

g an

d c

ontr

ollin

g d

esig

n an

d d

evel

opm

ent

activ

ities

are

fun

dam

enta

l to

mak

ing

pro

duc

t th

at f

ully

mee

ts t

he r

equi

rem

ents

of

cust

omer

s.

Rea

sons

fo

r th

e ‘e

xtra

’ GM

P r

equi

rem

ents

(re

fer

to P

S 9

000

clau

ses

7.3.

1, 7

.3.2

, 7.3

.5, 7

.3.6

and

7.3

.7)

The

orga

niza

tion

ofte

n ha

s sp

ecia

list

know

led

ge r

egar

din

g p

rod

uct

des

ign

that

can

ass

ist

in e

valu

atin

g ris

ks t

o th

e en

d u

ser

or p

atie

nt.

This

wou

ld n

orm

ally

for

m p

art

of c

usto

mer

/org

aniz

atio

n co

mm

unic

atio

n at

the

pro

duc

t d

evel

opm

ent

stag

e. T

echn

ical

dat

a fr

om t

he

des

ign

and

dev

elop

men

t st

ages

of

a co

mp

onen

t m

ay b

e re

qui

red

as

par

t of

the

pha

rmac

eutic

al c

omp

any’

s su

bm

issi

on t

o re

gula

tory

au

thor

ities

whe

n ap

ply

ing

for

per

mis

sion

to

mar

ket

a m

edic

inal

pro

duc

t. T

his

is m

and

ator

y fo

r a

com

pon

ent

that

will

be

in p

hysi

cal

cont

act

with

the

med

icin

al p

rod

uct,

as

the

com

pos

ition

of

the

com

pon

ent

mat

eria

l can

influ

ence

the

med

icin

al p

rod

uct’s

com

pos

ition

an

d s

tab

ility

and

the

saf

ety

of t

he p

atie

nt.

The

avai

lab

ility

of

valid

atio

n d

ocum

ents

at

this

sta

ge g

ives

rec

ord

ed a

ssur

ance

tha

t th

e d

esig

n p

rod

uced

has

bee

n th

orou

ghly

tes

ted

an

d is

sui

tab

le f

or lo

ng-t

erm

pro

duc

tion.

Thi

s, in

con

junc

tion

with

the

tes

ting

and

ap

pro

val o

f sa

mp

les

by

the

cust

omer

, en

able

s th

e d

esig

n to

pro

gres

s in

to p

rod

uctio

n in

a f

orm

al c

ontr

olle

d m

anne

r.

Sim

ilar

cont

rols

are

exp

ecte

d w

hen

des

ign

and

dev

elop

men

t ac

tiviti

es a

re in

volv

ed in

mak

ing

mod

ifica

tions

to

the

pro

duc

t or

p

rod

uctio

n m

etho

ds.

It is

man

dat

ory

that

the

det

ails

of

the

med

icin

al p

rod

uct

lod

ged

with

reg

ulat

ory

auth

oriti

es a

re a

ccur

ate

and

m

aint

aine

d (‘

The

Rul

es a

nd G

uid

ance

for

Pha

rmac

eutic

al M

anuf

actu

rers

and

Dis

trib

utor

s 20

02,’

Art

icle

5 E

urop

ean

Com

mis

sion

D

irect

ives

200

3/94

/EC

and

91/

412/

EE

C).

53

Pro

cess

inp

uts

Pro

cess

esP

roce

ss o

utp

uts

and

ev

iden

ceC

ross

ref

er t

o

S

chem

atic

/Ann

ex

Inte

rnal

inp

uts,

e.g

. •

com

pet

ence

re

qui

rem

ents

for

peo

ple

p

erfo

rmin

g d

esig

n an

d

dev

elop

men

t•

reco

rds

and

dat

a on

ex

istin

g p

roce

sses

and

p

rod

ucts

• ou

tput

s fr

om o

ther

p

roce

sses

Ext

erna

l inp

uts,

e.g

. •

cust

omer

/mar

ketp

lace

ne

eds

• us

er in

put

to

achi

eve

rob

ust

des

ign

and

d

evel

opm

ent

• st

atut

ory

req

uire

men

ts•

inte

rnat

iona

l sta

ndar

ds

• in

dus

try

cod

es o

f p

ract

ice

• ot

her

req

uire

men

ts

for

safe

op

erat

ion,

ha

ndlin

g, s

tora

ge•

envi

ronm

enta

l/dis

pos

al

cons

trai

nts

for

the

pro

duc

ts o

r p

roce

sses

Pro

cess

es w

hich

:•

cont

rol p

lann

ing

the

des

ign

and

d

evel

opm

ent

of p

rod

ucts

• co

ntro

l pro

duc

t d

esig

n an

d

dev

elop

men

t•

cont

rol p

rod

uctio

n p

roce

ss d

esig

n an

d

dev

elop

men

t•

eval

uate

pot

entia

l ris

ks o

f th

e p

rod

uct

des

ign

to c

usto

mer

and

ulti

mat

ely

the

pat

ient

• p

rovi

de

tech

nica

l/mat

eria

l dat

a to

th

e p

harm

aceu

tical

cus

tom

er a

nd/o

r m

edic

inal

reg

ulat

ory

auth

oriti

es a

nd t

o no

tify

of a

ny c

hang

es a

risin

g fr

om t

he

sup

ply

cha

in•

cove

r te

stin

g, r

etai

ning

and

gai

ning

cu

stom

er a

pp

rova

l of

sam

ple

s re

sulti

ng f

rom

new

pro

duc

t d

esig

ns•

pro

duc

e an

d p

rovi

de

valid

atio

n d

ocum

enta

tion

to t

he c

usto

mer

• co

ntro

l mod

ified

or

refu

rbis

hed

eq

uip

men

t an

d t

oolin

g an

d p

rod

uct

• R

epor

ts o

f va

lidat

ion/

test

s•

Info

rmat

ion

for

othe

r fu

nctio

ns

(e.g

. p

urch

asin

g)•

Dat

a to

ena

ble

ver

ifica

tion

of d

esig

n an

d d

evel

opm

ent

pro

cess

out

put

s to

the

p

roce

ss in

put

s•

Evi

den

ce o

f cu

stom

er

app

rova

l of

chan

ges

Iden

tific

atio

n of

:•

revi

ew,

verif

icat

ion

and

va

lidat

ion

app

rop

riate

to

each

d

esig

n an

d d

evel

opm

ent

stag

e•

resp

onsi

bili

ties

for

des

ign

and

d

evel

opm

ent

Doc

umen

ted

:•

chan

ge c

ontr

ol•

risk

asse

ssm

ents

• sp

ecifi

catio

ns f

or p

rod

uct,

p

roce

ss,

mat

eria

l, te

stin

g,

safe

ty c

hara

cter

istic

s•

trai

ning

req

uire

men

ts a

nd

reco

rds

Sch

emat

ic 2

Sch

emat

ic 3

Ann

ex A

:C

hang

e co

ntro

l

Ris

k as

sess

men

t

Valid

atio

n (a

nd

Qua

lific

atio

n)

54

Cla

use

7.4

Pur

chas

ing

Man

agem

ent

has

a re

spon

sib

ility

to

def

ine

and

imp

lem

ent

effe

ctiv

e p

urch

asin

g p

roce

sses

to

ensu

re p

urch

ased

mat

eria

ls m

eet

stat

ed

req

uire

men

ts.

Rea

sons

fo

r th

e ‘e

xtra

’ GM

P p

roce

sses

(re

fer

to P

S 9

000

clau

ses

7.4.

1 an

d 7

.4.3

)

The

pha

rmac

eutic

al c

omp

any

need

s to

kno

w w

here

all

par

ts o

f a

man

ufac

turin

g p

roce

ss a

re p

erfo

rmed

. Th

ese

det

ails

, in

clud

ing

sub

-co

ntra

cted

ele

men

ts,

may

be

‘reg

iste

red

’ as

par

t of

the

mar

ketin

g au

thor

isat

ion,

and

thu

s ne

ed c

usto

mer

ap

pro

val.

The

pha

rmac

eutic

al

com

pan

y m

ust

be

satis

fied

tha

t th

ere

are

no o

ther

ris

ks t

o p

rod

uct

secu

rity

or q

ualit

y in

volv

ed w

ith s

ubco

ntra

cted

par

ts o

f th

e m

anuf

actu

ring

pro

cess

. P

rod

uct

qua

lity

can

also

be

affe

cted

by

man

y co

ntra

cted

out

ser

vice

s (e

.g.

clea

ning

, m

aint

enan

ce,

calib

ratio

n),

and

evi

den

ce o

f go

od m

anag

emen

t an

d c

ontr

ol o

f th

ese

is e

xpec

ted

.

Qua

rant

ine

of p

urch

ased

pro

duc

t un

til a

pp

rove

d f

or u

se e

limin

ates

the

ris

k of

usi

ng u

nap

pro

ved

or

unsu

itab

le m

ater

ial.

55

Pro

cess

inp

uts

Pro

cess

esP

roce

ss o

utp

uts

and

evi

den

ceC

ross

ref

er t

o

Sch

emat

ic/A

nnex

• P

rod

uct

spec

ifica

tions

• C

ontr

acts

, w

arra

ntie

s,

pric

es•

Logi

stic

req

uire

men

ts•

Pro

duc

t id

entif

icat

ion

and

tra

ceab

ility

• S

upp

lier

per

form

ance

d

ata

– q

ualit

y, p

rice,

d

eliv

ery,

res

pon

se•

Aud

its o

f su

pp

liers

• C

omm

erci

al

dep

end

abili

ty o

f su

pp

liers

• S

upp

lier’s

cap

abili

ties

• C

ertif

icat

ion

• P

urch

asin

g p

roce

ss t

hat

satis

fies

the

orga

niza

tion’

s ne

eds

whi

lst

cons

ider

ing

cost

s an

d o

ther

ap

pro

pria

te p

erfo

rman

ce

mea

sure

s

Pro

cess

es w

hich

:•

cont

rol s

upp

liers

• en

able

ver

ifica

tion

of p

urch

ased

pro

duc

ts

Pro

cess

es w

hich

:•

gain

cus

tom

er a

pp

rova

l of

sub

cont

ract

ed

par

ts o

f th

e m

anuf

actu

ring

pro

cess

• co

ntro

l con

trac

ted

out

ser

vice

s th

at c

an

affe

ct p

rod

uct

qua

lity

• q

uara

ntin

e p

urch

ased

pro

duc

t un

til

app

rove

d f

or u

se

• C

o-or

din

ated

pur

chas

ing

info

rmat

ion,

e.g

. req

uire

men

ts

for

app

rova

l of

pro

duc

t,

sup

plie

r’s p

roce

dur

es,

pro

cess

es a

nd e

qui

pm

ent,

ot

her

per

sonn

el o

r q

ualit

y sy

stem

s re

qui

rem

ents

Rec

ord

s of

:•

insp

ectio

n ch

ecks

mad

e on

in

com

ing

item

s•

the

rele

ase

(for

acce

pta

ble

ite

ms)

or

reje

ctio

n (fo

r un

acce

pta

ble

item

s) o

f p

urch

ased

goo

ds

Evi

den

ce o

f:•

a su

pp

lier

app

rova

l sch

eme

in p

lace

(e.g

. an

ap

pro

ved

su

pp

lier

list

and

aud

it re

por

ts)

• th

e m

onito

ring

of

sub

cont

ract

ors

Sch

emat

ic 3

Sch

emat

ic 3

(a)

Sch

emat

ic 4

Ann

ex A

:C

hang

e co

ntro

l

56

Cla

use

7.5

Pro

duc

tio

n an

d s

ervi

ce p

rovi

sio

n

Pro

duc

tion

(or

serv

ice

pro

visi

on) w

here

key

ele

men

ts a

re t

he c

ontr

ol a

nd v

alid

atio

n of

pro

duc

tion

cond

ition

s, a

nd t

race

abili

ty o

f m

ater

ials

and

eq

uip

men

t us

ed.

Rea

sons

fo

r th

e ‘e

xtra

’ GM

P r

equi

rem

ents

(r

efer

to

PS

900

0 cl

ause

s 7.

5.2,

7.5

.3, 7

.5.4

and

7.5

.5)

The

spec

ial n

eed

s of

pha

rmac

eutic

al p

acka

ging

mea

n th

at c

erta

in p

roce

sses

are

crit

ical

to

pro

duc

t q

ualit

y, s

afet

y, a

nd f

unct

ion.

The

se

‘crit

ical

’ p

roce

sses

req

uire

val

idat

ion

to b

e ce

rtai

n th

at t

hey

func

tion

relia

bly

and

con

sist

ently

. It

is im

por

tant

tha

t va

lidat

ion

is p

erfo

rmed

as

nec

essa

ry d

urin

g d

evel

opm

ent

and

on

star

t-up

in p

rod

uctio

n an

d a

lso

per

form

ed w

hen

ther

e ar

e ch

ange

s to

pro

duc

tion

pro

cess

es.

Iden

tific

atio

n an

d t

race

abili

ty is

ess

entia

l to

enab

le a

rec

onst

ruct

ion

of e

vent

s w

hen

inve

stig

atin

g a

qua

lity

pro

ble

m.

To b

e ab

le t

o in

vest

igat

e an

y p

rob

lem

with

a m

edic

ine

in t

he m

arke

tpla

ce,

the

pha

rmac

eutic

al c

omp

any

is o

blig

ed t

o re

tain

rec

ord

s fo

r (a

t le

ast)

a ye

ar b

eyon

d t

he li

fe o

f th

e m

edic

ines

it is

mak

ing.

The

re is

a c

orre

spon

din

g re

spon

sib

ility

on

the

par

t of

the

com

pon

ent

sup

plie

rs t

o b

e ab

le t

o su

pp

ort

any

such

inve

stig

atio

n th

roug

h its

ret

aine

d r

ecor

ds

of m

anuf

actu

re e

.g.

trac

eab

ility

of

mat

eria

ls,

equi

pm

ent

and

p

erso

nnel

invo

lved

in t

he c

omp

onen

ts m

anuf

actu

re (s

ee A

nnex

A).

The

pha

rmac

eutic

al c

omp

any

pla

ces

trus

t in

its

sup

plie

rs t

o p

rote

ct it

s p

rop

erty

. Th

e m

ain

cons

ider

atio

n is

pro

tect

ion

from

the

ft

and

sub

seq

uent

fra

udul

ent

use,

una

utho

rized

sup

ply

and

use

in c

ount

erfe

it m

edic

ines

. Th

is p

artic

ular

ly a

pp

lies

to a

rtw

ork

or d

ata

in

elec

tron

ic f

orm

due

to

its e

ase

of t

rans

mis

sion

.

Follo

win

g m

anuf

actu

re u

nder

con

trol

led

con

diti

ons,

the

con

tinui

ng p

rote

ctio

n of

the

pro

duc

t is

imp

orta

nt t

o p

reve

nt d

amag

e an

d

cont

amin

atio

n.

Acc

urat

e id

entif

icat

ion

of t

he f

inal

pro

duc

t is

vita

l in

ord

er t

o m

inim

ise

risk

of a

dm

ixtu

re b

oth

with

in t

he o

rgan

izat

ion

and

dur

ing

rece

ipt

at t

he p

harm

aceu

tical

com

pan

y. T

his

is a

lway

s im

por

tant

, b

ut p

artic

ular

ly s

o w

here

the

re a

re d

irect

‘su

pp

ly t

o lin

e’ a

rran

gem

ents

, w

ith

min

imal

goo

ds-

inw

ard

s ch

ecki

ng in

pla

ce a

t th

e p

harm

aceu

tical

site

.

57

Pro

cess

Inp

uts

Pro

cess

esP

roce

ss o

utp

uts

and

ev

iden

ceC

ross

ref

er t

o

S

chem

atic

/Ann

ex

• R

aw m

ater

ial b

atch

re

cord

s•

Sp

ecifi

catio

ns

– p

rod

uct,

mat

eria

ls•

Man

ufac

turin

g m

etho

d/p

roce

ss

inst

ruct

ions

• P

rovi

sion

of

suita

ble

re

sour

ces

– m

achi

nery

, p

eop

le•

Trai

ning

of

pro

cess

op

erat

ors

• E

nviro

nmen

tal

inst

ruct

ions

• P

acki

ng in

stru

ctio

ns•

Valid

atio

n p

lans

Pro

cess

es w

hich

:•

ensu

re p

rod

uctio

n/se

rvic

e p

rovi

sion

act

ivity

is

und

er c

ontr

olle

d c

ond

ition

s, i.

e. s

uita

ble

eq

uip

men

t w

ith a

pp

rop

riate

mon

itorin

g an

d

cont

rols

• en

sure

val

idat

ion

of p

roce

sses

whe

re t

he

resu

lting

out

put

can

not

be

chec

ked

by

sub

seq

uent

mea

sure

men

t•

ensu

re c

ontin

ual i

mp

rove

men

t of

rea

lizat

ion

pro

cess

es,

e.g.

red

ucin

g w

aste

, im

pro

ving

m

etho

ds,

pre

vent

ing

pro

ble

ms,

imp

rovi

ng y

ield

• va

lidat

e cr

itica

l pro

cess

es t

hat

coul

d a

ffect

p

rod

uct

qua

lity

incl

udin

g sp

ecifi

c ex

amp

les

and

re

valid

atio

n re

qui

rem

ents

• en

sure

iden

tific

atio

n an

d t

race

abili

ty o

f m

ater

ials

and

eq

uip

men

t us

ed t

hrou

ghou

t p

rod

uctio

n•

pro

tect

and

car

e fo

r cu

stom

er p

rop

erty

(e.g

. m

ould

s, a

rtw

ork,

ele

ctro

nic

dat

a)•

pro

tect

and

cle

arly

iden

tify

the

final

pro

duc

t

• C

ontin

ual

imp

rove

men

t ac

tiviti

es

Rec

ord

s of

:•

pro

duc

tion

(e.g

. b

atch

sh

eets

) •

pro

cess

val

idat

ion/

re

valid

atio

n•

mat

eria

l usa

ge

• w

areh

ouse

and

d

isp

atch

tra

nsac

tions

• p

rod

uct

iden

tific

atio

n

Sch

emat

ic 3

Sch

emat

ic 4

Sch

emat

ic 5

Sch

emat

ic 6

Sch

emat

ic 7

Ann

ex A

:C

ount

erfe

it

Ad

mix

ture

Seg

rega

tion

cont

rols

Valid

atio

n (a

nd

Qua

lific

atio

n)

58

Cla

use

7.6

Co

ntro

l of

mo

nito

ring

and

mea

sure

men

t d

evic

es

Con

trol

of

such

eq

uip

men

t is

crit

ical

to

good

con

trol

of

man

ufac

turin

g p

roce

sses

.

Ther

e ar

e no

‘ex

tra’

PS

900

0 G

MP

s w

ithin

thi

s cl

ause

. Th

ere

are

imp

orta

nt G

MP

prin

cip

les

in t

his

area

but

the

y ar

e ad

equa

tely

ex

pre

ssed

in IS

O 9

001

and

ISO

900

4.

Pro

cess

inp

uts

Pro

cess

esP

roce

ss o

utp

uts

and

ev

iden

ceC

ross

ref

er t

o

Sch

emat

ic/A

nnex

• O

utp

uts

from

des

ign

and

dev

elop

men

t ac

tiviti

es -

e.g

. d

esig

n to

lera

nces

• P

rod

uct

spec

ifica

tions

• C

usto

mer

re

qui

rem

ents

• C

alib

ratio

n st

and

ard

s

Pro

cess

es w

hich

:•

det

erm

ine

the

mon

itorin

g/m

easu

ring

and

eq

uip

men

t ne

eded

• en

sure

iden

tific

atio

n an

d p

rote

ctio

n of

eq

uip

men

t•

cont

rol c

alib

ratio

n •

cont

rol t

he m

onito

ring/

mea

surin

g ac

tiviti

es t

o ve

rify

pro

duc

ts (a

nd p

rod

uctio

n p

roce

sses

)•

cont

rol n

onco

nfor

min

g eq

uip

men

t/d

evic

e•

cont

rol t

he c

heck

s on

com

put

er s

oftw

are

whe

n us

ed in

mon

itorin

g an

d m

easu

rem

ent

• Li

st o

f m

onito

ring/

mea

surin

g eq

uip

men

t•

Sta

tus

lab

elle

d

equi

pm

ent

• C

alib

ratio

n re

cord

s

Pro

ced

ures

for

:•

mon

itorin

g•

mea

surin

g •

calib

ratio

n

Sch

emat

ic 5

Sch

emat

ic 6

59

Gen

eral

Syn

op

sis

- C

laus

e 8

Mea

sure

men

t, a

naly

sis

and

imp

rove

men

t

Mea

sure

men

t in

form

atio

n is

vita

l to

soun

d d

ecis

ion

mak

ing.

The

org

aniz

atio

n sh

ould

mon

itor

its p

roce

sses

, pro

duc

ts a

nd a

ll as

pec

ts o

f th

e Q

MS

in o

rder

to

pro

vid

e d

ata

for

cont

inua

l im

pro

vem

ent

in p

erfo

rman

ce.

Cla

use

8.1

Mea

sure

men

t, a

naly

sis

and

imp

rove

men

t: G

ener

al

Thes

e ac

tiviti

es a

re o

f su

ch im

por

tanc

e th

at c

aref

ul p

lann

ing

is n

eed

ed o

n ho

w it

sha

ll b

e p

erfo

rmed

.

Ther

e ar

e no

‘ex

tra’

PS

900

0 G

MP

s w

ithin

thi

s cl

ause

. Th

ere

are

imp

orta

nt G

MP

prin

cip

les

in t

his

area

, b

ut t

hey

are

adeq

uate

ly

exp

ress

ed in

ISO

900

1 an

d IS

O 9

004.

Pro

cess

inp

uts

Pro

cess

esP

roce

ss o

utp

uts

and

ev

iden

ceC

ross

ref

er t

o

Sch

emat

ic/A

nnex

• P

roce

ss a

naly

sis

wor

k•

Com

pan

y ob

ject

ives

• C

usto

mer

nee

ds

Pro

cess

es w

hich

:•

pla

n ho

w t

o m

onito

r/m

easu

re p

roce

sses

and

p

rod

ucts

• d

evel

op s

uita

ble

imp

rove

men

t m

echa

nism

s•

cont

rol t

he im

ple

men

tatio

n of

the

ab

ove

• Fo

rmal

mea

sure

men

t sy

stem

s•

Sta

tistic

al t

echn

ique

s•

Pro

ced

ures

• R

epor

ts

Sch

emat

ic 3

Sch

emat

ic 6

60

Cla

use

8.2

Mo

nito

ring

and

mea

sure

men

t

Mon

itorin

g th

e sa

tisfa

ctio

n of

cus

tom

ers,

oth

er in

tere

sted

par

ties,

mon

itorin

g p

rod

ucts

, p

roce

sses

and

sys

tem

s.

Rea

sons

fo

r th

e ‘e

xtra

’ GM

P r

equi

rem

ents

(re

fer

to P

S 9

000

clau

se 8

.2.4

Mo

nito

ring

and

mea

sure

men

t o

f p

rod

uct)

ISO

900

1:20

00 r

equi

res

qua

lity

des

igne

d a

nd s

yste

m c

omp

liant

pro

cess

es,

and

com

plim

enta

ry t

o th

is in

PS

900

0 is

the

nee

d f

or

pro

cess

es t

o b

e op

erat

ed in

a w

ay w

hich

mai

ntai

ns p

rod

uct

secu

rity

and

avo

ids

cont

amin

atio

n (s

ee a

lso

5.2

and

5.3

).

Sin

ce p

roce

ss a

sses

smen

t is

oft

en b

ased

up

on p

rod

uct

sam

ple

s, t

hese

mus

t b

e re

pre

sent

ativ

e of

the

pro

cess

with

the

sam

plin

g sc

hem

e d

efin

ed.

Whi

lst

sam

ple

s ex

amin

ed o

n th

e lin

e ar

e co

nsid

ered

sec

ure,

a c

onta

min

atio

n or

ad

mix

ture

ris

k ex

ists

if t

here

are

in

adeq

uate

con

trol

s on

the

sec

urity

han

dlin

g of

sam

ple

s re

mov

ed f

rom

the

pro

duc

tion

area

.

To a

void

thi

s ris

k, P

S 9

000

spec

ifica

lly r

equi

res

the

secu

re d

isp

osal

aft

er e

xam

inat

ion,

of

all s

amp

les

that

hav

e b

een

rem

oved

fro

m t

he

imm

edia

te p

rod

uctio

n ar

ea a

nd a

dd

ition

ally

stip

ulat

es t

hey

cann

ot b

e re

inco

rpor

ated

into

the

pro

duc

t (s

ee a

lso

‘Rul

es a

nd G

uid

ance

fo

r P

harm

aceu

tical

Man

ufac

ture

rs a

nd D

istr

ibut

ors

2002

’, C

hap

ter

5.54

)

It is

gen

eral

ly k

now

n th

at p

roce

sses

wor

k b

ette

r w

hen

they

hav

e st

abili

zed

fol

low

ing

star

t-up

and

are

run

ning

con

tinuo

usly

. H

ence

w

hen

equi

pm

ent

bre

aks

dow

n or

the

re is

an

unsc

hed

uled

inte

rrup

tion

that

sto

ps

the

pro

cess

, q

ualit

y va

riab

ility

can

occ

ur a

nd

add

ition

al q

ualit

y m

onito

ring

is r

equi

red

on

reco

mm

ence

men

t.

61

Pro

cess

inp

uts

Pro

cess

esP

roce

ss o

utp

uts

and

ev

iden

ceC

ross

ref

er t

o

S

chem

atic

/Ann

ex

• C

usto

mer

sur

veys

• Fo

cus

grou

p d

ata

• Fe

edb

ack

on p

rod

ucts

• C

usto

mer

re

qui

rem

ents

/con

trac

ts•

Mar

ket

need

s•

Del

iver

y d

ata

• Fi

nanc

ial d

ata/

cost

s of

no

ncon

form

ities

• M

arke

t b

ench

mar

king

an

d b

est

pra

ctic

e

Pro

cess

es t

hat

iden

tify

(and

imp

lem

ent)

suita

ble

m

etho

ds

to:

• m

onito

r an

d m

easu

re c

usto

mer

sat

isfa

ctio

n•

mon

itor

and

mea

sure

the

sat

isfa

ctio

n of

in

tere

sted

par

ties

(oth

er t

han

cust

omer

s) e

.g.

emp

loye

es,

inve

stor

s, s

upp

liers

and

soc

iety

• m

onito

r an

d m

easu

re p

rod

uctio

n p

roce

sses

•

verif

y th

at p

rod

uct

is m

eetin

g re

qui

rem

ents

at

app

rop

riate

sta

ges

of p

rod

uctio

n

Pro

cess

es w

hich

:•

cont

rol i

nter

nal a

uditi

ng –

pro

gram

me,

p

roce

dur

es,

aud

itors

• d

efin

e a

stat

istic

ally

val

id s

amp

ling

sche

me

• p

reve

nt s

amp

les

from

bei

ng r

etur

ned

to

a b

atch

-

keep

sep

arat

e th

en d

estr

oy/d

isp

ose

secu

rely

• ap

ply

ad

diti

onal

mon

itorin

g, a

fter

a m

achi

ne

bre

akd

own

or s

top

pag

e

Cor

rect

ive

actio

ns:

• w

hen

pro

cess

es f

ail

to a

chie

ve p

lann

ed

resu

lts•

in r

esp

onse

to

cust

omer

info

rmat

ion

(com

pla

ints

, su

rvey

s et

c.)

Rec

ord

s of

:•

pro

duc

t m

onito

ring

and

mea

surin

g ac

tiviti

es (e

.g.

test

re

por

ts)

• au

dit

rep

orts

/act

ions

/fo

llow

-up

act

ions

Feed

bac

k to

:•

cust

omer

s•

othe

r in

tere

sted

p

artie

s

Sch

emat

ic 5

Sch

emat

ic 6

62

Cla

use

8.3

Co

ntro

l of

nonc

onf

orm

ing

pro

duc

t

It is

ess

entia

l tha

t p

rod

uct

not

mee

ting

spec

ifica

tion

be

segr

egat

ed f

rom

sui

tab

le p

rod

uct

until

cor

rect

ed,

des

troy

ed,

or r

ecla

ssifi

ed.

Rea

sons

fo

r th

e ‘e

xtra

’ GM

P r

equi

rem

ents

Ther

e is

an

assu

mp

tion

that

all

pro

cess

es w

ork

effic

ient

ly w

ithou

t p

rob

lem

s an

d t

hat

mat

eria

l will

be

unifo

rm,

cons

iste

nt a

nd f

ully

co

mp

liant

with

the

sp

ecifi

catio

n. In

rea

lity

pro

ble

ms

can

occu

r re

sulti

ng in

sho

rt p

erio

ds

whe

n th

e p

roce

ss m

ay n

ot b

e in

con

trol

and

p

rod

uces

non

conf

orm

ing

pro

duc

t. T

his

can

resu

lt in

pro

ble

ms

in t

he m

arke

t, c

usto

mer

com

pla

ints

and

ret

urne

d p

rod

uct.

For

GM

P r

easo

ns a

nd g

ood

cus

tom

er r

elat

ions

, th

e p

harm

aceu

tical

ind

ustr

y ne

eds

to b

e aw

are

of a

ny q

ualit

y is

sues

dur

ing

the

man

ufac

ture

of

its p

acka

ging

mat

eria

ls.

The

cust

omer

sho

uld

alw

ays

be

notif

ied

of

nonc

onfo

rmin

g or

ass

ocia

ted

pro

duc

t, w

hich

may

ha

ve a

lread

y le

ft t

he o

rgan

izat

ion,

so

that

the

pha

rmac

eutic

al c

omp

any

can

cons

ider

any

imp

licat

ions

to

pro

cess

es,

stoc

k or

pac

ked

p

rod

uct.

Sus

pec

t p

rod

uct

reta

ined

by

the

sup

plie

r or

ret

urne

d f

rom

the

cus

tom

er,

req

uire

s fo

rmal

GM

P c

ontr

ols

on it

s se

cure

sto

rage

, ha

ndlin

g an

d r

emed

ial r

ewor

k ac

tions

, in

clud

ing

a ris

k as

sess

men

t to

ens

ure

that

the

rew

orki

ng p

roce

ss d

oes

not

intr

oduc

e fu

rthe

r q

ualit

y p

rob

lem

s.

All

of t

hese

issu

es r

equi

re g

ood

doc

umen

tatio

n to

pro

vid

e tr

acea

bili

ty o

ver

time

and

to

reco

nstr

uct

even

ts if

req

uire

d.

63

Pro

cess

inp

uts

Pro

cess

esP

roce

ss o

utp

uts

and

ev

iden

ceC

ross

ref

er t

o

S

chem

atic

/Ann

ex

• P

rod

ucts

not

mee

ting

spec

ifica

tion

• C

usto

mer

rej

ects

or

com

pla

ints

•

Res

ults

of

insp

ectio

ns

or in

-pro

cess

tes

ting

activ

ities

• O

bse

rvat

ions

by

mem

ber

s of

sta

ff

Pro

cess

es w

hich

:•

revi

ew id

entif

ied

non

conf

orm

ing

pro

duc

t an

d

actio

ns t

o b

e d

eter

min

ed•

cont

rol t

he s

ecur

e p

hysi

cal (

or e

lect

roni

c)

qua

rant

inin

g of

item

s/d

ata

• co

ntro

l rew

ork

• re

-ver

ify o

r in

spec

t co

rrec

ted

pro

duc

t (e

.g.

follo

win

g re

wor

k)•

notif

y cu

stom

ers

if p

rob

lem

s ar

e fo

und

aft

er

del

iver

y•

iden

tify

and

con

trol

any

bat

ches

of

pro

duc

t th

at

are

rela

ted

to

any

nonc

onfo

rmin

g p

rod

uct

that

ha

s b

een

retu

rned

fro

m t

he c

usto

mer

• D

ocum

ente

d r

isk

asse

ssm

ent

for

any

bat

ches

tha

t ar

e re

wor

ked

to

reco

ver

stoc

k fr

om a

rej

ecte

d

or q

uara

ntin

ed b

atch

• R

ecor

ds

of c

usto

mer

co

mm

unic

atio

ns/

notif

icat

ions

• D

efin

ed

resp

onsi

bili

ties/

auth

oriti

es f

or d

ealin

g w

ith n

onco

nfor

min

g p

rod

uct

Pro

ced

ures

: •

det

ailin

g w

hat

to

do

in t

he e

vent

of

nonc

onfo

rmin

g p

rod

uct

bei

ng

det

ecte

d•

for

hand

ling

reje

ctio

ns

and

com

pla

ints

• fo

r ha

ndlin

g re

cove

ry/

rew

orks

Sch

emat

ic 3

Sch

emat

ic 5

Sch

emat

ic 6

Ann

ex A

:R

isk

asse

ssm

ent

64

Cla

use

8.4

Ana

lysi

s o

f d

ata

In a

dd

ition

to

mon

itorin

g ac

tiviti

es,

the

sens

ible

ana

lysi

s an

d in

terp

reta

tion

of d

ata

is c

ritic

al t

o en

able

goo

d d

ecis

ions

to

be

take

n an

d

bus

ines

s im

pro

vem

ents

to

be

mad

e.

Ther

e ar

e no

‘ex

tra’

PS

900

0 G

MP

s w

ithin

thi

s cl

ause

. Th

ere

are

imp

orta

nt G

MP

prin

cip

les

in t

his

area

, b

ut t

hey

are

adeq

uate

ly

exp

ress

ed in

ISO

900

1 an

d IS

O 9

004.

Pro

cess

inp

uts

Req

uire

d p

roce

sses

Pro

cess

out

put

s an

d

evid

ence

Cro

ss r

efer

to

Sch

emat

ic/A

nnex

• O

utp

uts

from

M

onito

ring

and

M

easu

rem

ent

(8.2

) and

ot

her

pro

cess

es•

Dat

a fr

om r

elev

ant

sour

ces

Pro

cess

es w

hich

det

erm

ine

the

dat

a re

qui

red

, co

llect

and

ana

lyse

it,

to:

• ev

alua

te t

he Q

MS

• m

onito

r an

d m

easu

re it

s su

itab

ility

and

ef

fect

iven

ess

• im

pro

ve it

Pro

cess

es f

or:

• ro

ot c

ause

ana

lysi

s of

pro

ble

ms

• an

alys

is o

f d

ata

whi

ch u

ses

valid

met

hod

s an

d

app

rop

riate

sta

tistic

al t

echn

ique

s•

dec

isio

n-m

akin

g b

ased

on

resu

lts o

f lo

gica

l an

alys

is,

bal

ance

d w

ith e

xper

ienc

e an

d

know

led

ge

Tren

ds,

info

rmat

ion

and

d

ata

abou

t:•

cust

omer

s •

sup

plie

rs•

pro

duc

ts•

pro

cess

es•

QM

S

Sch

emat

ic 6

65

Cla

use

8.5

Imp

rove

men

t

Con

tinua

l im

pro

vem

ent

of t

he Q

MS

is a

t th

e he

art

of t

he IS

O 9

001

and

PS

900

0 p

hilo

sop

hy.

Ther

e ar

e no

‘ex

tra’

PS

900

0 G

MP

s w

ithin

thi

s cl

ause

. Th

ere

are

imp

orta

nt G

MP

prin

cip

les

in t

his

area

, b

ut t

hey

are

adeq

uate

ly

exp

ress

ed in

ISO

900

1 an

d IS

O 9

004.

Pro

cess

inp

uts

Pro

cess

esP

roce

ss o

utp

uts

and

ev

iden

ceC

ross

ref

er t

o

Sch

emat

ic/A

nnex

• A

udit

resu

lts•

Qua

lity

dat

a•

Qua

lity

pol

icy

and

ob

ject

ives

• M

anag

emen

t re

view

s •

Pre

viou

s co

rrec

tive

and

p

reve

ntiv

e ac

tions

• Va

lidat

ion

dat

a•

Pro

cess

and

pro

duc

t m

easu

rem

ents

• D

ata

from

sel

f as

sess

men

ts•

Req

uire

men

ts f

rom

cu

stom

ers/

inte

rest

ed

par

ties

• Fi

nanc

ial a

nd s

ervi

ce

dat

a

Pro

cess

es t

o as

sess

pot

enti

al n

onco

nfor

miti

es,

stud

y th

eir

effe

cts

and

:•

eval

uate

s th

e ne

ed t

o ta

ke p

reve

ntiv

e ac

tion

• d

evel

ops

suita

ble

act

ions

to

elim

inat

e ca

uses

• ex

amin

es t

he e

ffect

iven

ess

of t

hem

Pro

cess

es t

o d

etec

t ac

tual

non

conf

orm

ities

whi

ch:

• ev

alua

tes

the

need

to

take

cor

rect

ive

actio

n•

dev

elop

s su

itab

le a

ctio

ns t

o el

imin

ate

caus

es•

exam

ines

the

effe

ctiv

enes

s of

the

m

Pro

cess

tha

t p

lans

for

loss

es s

usta

ined

by

the

orga

niza

tion

in o

rder

to

miti

gate

the

ir p

oten

tial

effe

cts

(e.g

. fir

e or

wea

ther

dam

age)

• R

isk

asse

ssm

ent

rep

orts

• Im

pro

vem

ent

pla

ns•

Pro

ced

ure

for

nonc

onfo

rman

ce

man

agem

ent

• P

reve

ntiv

e an

d

corr

ectiv

e ac

tions

ta

ken

Rec

ord

s:•

of t

hese

act

ions

• of

the

effe

ctiv

enes

s of

th

ese

actio

ns

Sch

emat

ic 1

Ann

ex A

:R

isk

asse

ssm

ent

66

Gen

eral

Syn

op

sis

- C

laus

e 9

Co

ntam

inat

ion

cont

rol

The

cap

abili

ty o

f fa

cilit

ies

and

eq

uip

men

t, a

chie

ved

thr

ough

the

ir d

esig

n, l

ocat

ion,

con

stru

ctio

n, a

nd m

aint

enan

ce,

to

min

imis

e th

e ris

k of

pro

cess

err

ors

and

avo

id c

ross

-con

tam

inat

ion

affe

ctin

g p

roce

ss a

nd p

rod

uct.

Rea

sons

fo

r th

e ‘e

xtra

’ GM

P r

equi

rem

ents

The

high

est

qua

lity

prio

rity

of t

he p

harm

aceu

tical

ind

ustr

y is

for

the

com

pon

ent

mat

eria

l to

mee

t sp

ecifi

catio

ns a

nd m

eet

or e

xcee

d

def

ined

GM

P c

ontr

ols.

Pha

rmac

eutic

al p

rod

uct

safe

ty,

effic

acy,

and

sta

bili

ty c

an a

ll b

e co

mp

rom

ised

by

chem

ical

con

tam

inat

ion

of t

he p

rimar

y p

acka

ging

m

ater

ial.

Par

ticul

ate

cont

amin

atio

n m

ay r

educ

e th

e vi

sual

qua

lity

of t

he p

rod

uct

as w

ell a

s in

terf

ere

with

its

func

tion;

it c

an a

lso

be

a ‘c

arrie

r m

ediu

m’

for

mic

rob

ial c

onta

min

atio

n w

ith a

pot

entia

l inf

ectio

n ris

k to

the

pat

ient

.

GM

P c

ontr

ols

and

pro

ced

ures

pro

vid

e th

e sa

fegu

ard

s to

pre

vent

cro

ss-c

onta

min

atio

n (a

dm

ixtu

re).

A s

ingl

e ‘r

ogue

’ co

mp

onen

t w

ithin

a

bat

ch c

ould

cre

ate

a lif

e-th

reat

enin

g ha

zard

to

the

pat

ient

(see

Ann

ex A

- A

dm

ixtu

re).

Sin

ce c

onta

min

atio

n ca

n ta

ke m

any

form

s an

d b

e in

trod

uced

any

whe

re,

pre

vent

ive

mea

sure

s (e

.g.

good

fac

ility

des

ign,

Sta

ndar

d

Op

erat

ing

Pro

ced

ures

, tr

aini

ng,

area

cle

aran

ce,

segr

egat

ion

cont

rols

, et

c.),

mus

t b

e ap

plie

d t

hrou

ghou

t th

e fa

cilit

y. In

ad

diti

on,

sim

ilar

mea

sure

s sh

ould

be

incl

uded

in t

he d

esig

n of

the

pro

cess

.

PS

900

0 sp

ecifi

es G

MP

req

uire

men

ts a

cros

s th

e m

anuf

actu

ring

oper

atio

n as

wel

l as

the

envi

ronm

enta

l con

diti

ons

need

ed f

or

pro

cess

ing

pac

kagi

ng m

ater

ials

for

use

with

med

icin

al p

rod

ucts

. Th

ree

diff

eren

t cl

eanl

ines

s ca

tego

ries

are

def

ined

dep

end

ent

upon

the

m

ater

ial a

nd it

s ap

plic

atio

n.

67

Pro

cess

inp

uts

Pro

cess

esP

roce

ss o

utp

uts

and

ev

iden

ceC

ross

ref

er t

o

S

chem

atic

/Ann

ex

• S

pec

ifica

tion

for

des

ign

of n

ew f

acili

ties,

p

roce

sses

, eq

uip

men

t an

d e

nviro

nmen

t•

Sp

ecia

list

pes

t an

d

cont

amin

atio

n co

ntro

l•

Cus

tom

er r

equi

rem

ents

• S

tand

ard

s fo

r en

viro

nmen

tal

cond

ition

s

Pro

cess

es w

hich

iden

tify/

cont

rol:

• op

erat

ing

area

s/ac

tiviti

es t

hat

cont

ribut

e to

co

ntam

inat

ion

• en

viro

nmen

tal c

ateg

ory

app

rop

riate

to

the

pro

duc

t (a

gree

with

cus

tom

er)

• ha

ndlin

g of

mat

eria

l and

seg

rega

tion

cont

rols

• go

od p

ract

ices

to

avoi

d c

onta

min

atio

n d

urin

g op

erat

ion,

sup

por

t, a

nd m

aint

enan

ce•

pes

t co

ntro

l•

clea

ning

pro

ced

ures

and

che

cks

• tr

aini

ng o

f st

aff

and

vis

itors

in c

onta

min

atio

n av

oid

ance

and

sta

ndar

ds

of d

ress

• m

anag

emen

t an

d c

ontr

ol o

f w

aste

mat

eria

l•

line

clea

ranc

e•

chan

ge c

ontr

ol•

envi

ronm

enta

l mon

itorin

g

• In

cid

ents

/aud

it re

por

ts•

Dra

win

gs (e

.g.

floor

p

lans

)•

Ap

pro

pria

te

envi

ronm

enta

l ca

tego

ry e

stab

lishe

d

for

pro

duc

t (a

gree

d

with

cus

tom

er)

Pro

ced

ures

to:

•

cont

rol p

roce

sses

• m

onito

r an

d c

ontr

ol

envi

ronm

ents

Rec

ord

s of

:•

pro

cess

ing

• cl

eani

ng s

ched

ules

• cl

eani

ng•

trai

ning

• m

ater

ial d

isp

osal

Sch

emat

ic 3

(a)

Sch

emat

ic 4

(a)

Sch

emat

ic 5

Ann

ex A

: al

l par

ts

68

Gen

eral

Syn

op

sis

- C

laus

e 10

Pri

nted

mat

eria

ls

The

app

licat

ion

of c

ontr

ols

spec

ific

to d

iffer

ent

typ

es o

f p

rinte

d m

ater

ials

in

ord

er t

o en

sure

id

entit

y, m

axim

ise

pro

duc

t se

curit

y an

d p

reve

nt c

ross

-con

tam

inat

ion.

It in

clud

es t

he u

se a

nd v

erifi

catio

n of

var

ious

typ

es o

f se

curit

y co

de

syst

ems

and

as

soci

ated

sof

twar

e.

Rea

sons

fo

r th

e ‘e

xtra

’ GM

P r

equi

rem

ents

This

sec

tion

inte

ntio

nally

fol

low

s th

e se

ctio

n on

Con

tam

inat

ion

Con

trol

bec

ause

it c

over

s in

dep

th t

he s

pec

ific

GM

P r

equi

rem

ents

for

se

cure

ly p

rintin

g co

mp

onen

ts t

o p

reve

nt a

dm

ixtu

re a

nd c

ross

-con

tam

inat

ion.

The

risk

asso

ciat

ed w

ith a

dm

ixtu

re is

tha

t an

inco

rrec

t p

rinte

d c

omp

onen

t, o

ften

sim

ilar

in d

esig

n to

the

cor

rect

com

pon

ent,

will

be

used

to

lab

el o

r co

ntai

n th

e p

harm

aceu

tical

pro

duc

t. T

his

can

lead

to

the

pat

ient

usi

ng t

he w

rong

pro

duc

t or

usi

ng it

in a

n in

app

rop

riate

m

anne

r.

(For

mor

e d

etai

l ref

er t

o A

nnex

A -

Ad

diti

onal

Exp

lana

tions

of

Key

Con

cep

ts).

Ther

e ar

e m

any

stag

es in

the

man

ufac

ture

of

prin

ted

mat

eria

ls,

all o

f w

hich

can

ben

efit

from

goo

d c

ontr

ol p

roce

dur

es.

The

adva

ntag

e of

sec

urity

bar

cod

es s

yste

ms

is t

hat

auto

mat

ed d

etec

tion

chec

ks c

an b

e in

corp

orat

ed in

to k

ey p

roce

ss s

tage

s at

the

sup

plie

r or

gani

zatio

n an

d c

usto

mer

.

The

pha

rmac

eutic

al in

dus

try

bel

ieve

s th

at,

alth

ough

sec

urity

bar

cod

e sy

stem

s ca

n ap

pro

ach

100%

sec

urity

con

fiden

ce,

they

are

not

a

sub

stitu

te f

or o

ther

goo

d m

anuf

actu

ring

pra

ctic

es.

69

Pro

cess

inp

uts

Pro

cess

esP

roce

ss o

utp

uts

and

ev

iden

ceC

ross

ref

er t

o

S

chem

atic

/Ann

ex

• P

rod

uct

req

uire

men

ts

incl

udin

g le

afle

ts,

cart

ons,

re

el-f

ed m

ater

ials

, la

bel

s an

d p

rod

uct

prin

ting

usin

g d

igita

l tec

hnol

ogy

• A

ll p

rod

ucts

mad

e b

y as

sem

bly

of

sub

-co

mp

onen

ts (e

.g.

lab

el/

leaf

let

com

bin

atio

ns)

• G

rap

hic

des

ign

(e.g

. in

clus

ion

of s

ecur

ity

bar

cod

e in

orig

inat

ion/

artw

ork)

• M

achi

ne d

esig

n/op

erat

iona

l set

tings

• C

usto

mer

req

uire

men

ts

and

agr

eem

ent

on

qua

ntity

tol

eran

ces

• S

pec

ifica

tions

for

ree

l-fe

d m

ater

ials

incl

udin

g sp

lice

join

s an

d h

ow

reel

mat

eria

ls s

hall

be

iden

tifie

d•

Ele

ctro

nic

and

/or

mec

hani

cal m

achi

ne

enha

ncem

ents

(e.g

. op

tical

, d

oub

le s

heet

d

etec

tors

)•

Pac

king

and

sto

rage

sp

ecifi

catio

ns

Pro

cess

es w

hich

con

trol

:•

the

issu

e an

d a

lloca

tion

of s

ecur

ity

bar

cod

es

• th

e se

t-up

and

use

of

scan

ners

to

reje

ct

unsu

itab

le m

ater

ial

• eq

uip

men

t th

at c

an,

und

er c

erta

in c

ond

- iti

ons

prin

t w

ith m

issi

ng c

olou

rs o

r te

xt

• an

y ov

erp

rintin

g p

roce

ss a

nd it

s ve

rific

atio

n •

the

scan

ning

and

off-

line

verif

icat

ion

of

bar

cod

es w

hen

nece

ssar

y an

d c

halle

nge

of t

he e

ffect

iven

ess

of s

cann

ing

• th

e ch

ecki

ng o

f sp

lices

in r

eels

• co

untin

g/se

que

ntia

l num

ber

ing

Pro

cess

es w

hich

:•

pro

hib

it th

e re

pla

cem

ent

of m

issi

ng la

bel

s on

a r

eel

• p

reve

nt p

artia

lly p

rinte

d o

r b

lank

leaf

lets

• en

sure

tha

t th

e lin

e cl

eara

nce

pro

cess

es

incl

ude

com

put

er a

rtw

ork

file

rem

oval

(w

here

ap

plic

able

) •

ensu

re t

hat

dig

ital f

ile a

cces

s is

sec

ure,

va

lidat

ed a

nd p

reve

nts

acci

den

tal u

se o

f in

corr

ect

orig

inat

ion/

artw

ork

files

•

ensu

re s

ecur

e as

sem

bly

(e

.g.

lab

el/

leaf

lets

) with

sec

ure

pro

duc

tion

of a

ll su

b-

com

pon

ents

•

cont

rol v

alid

atio

n ac

tiviti

es•

cont

rol p

acki

ng a

nd s

tora

ge a

ctiv

ities

• R

egis

ter

of s

ecur

ity

bar

cod

es•

Acc

urat

e co

unts

det

aile

d

on t

he o

uter

car

ton

lab

els

• Tr

acea

bili

ty o

f p

rod

uct

(aud

it tr

ail)

• G

ood

pac

king

line

p

erfo

rman

ce o

f co

mp

onen

ts w

hen

in u

se

by

cust

omer

(com

pla

ints

/fe

edb

ack)

• E

stab

lishe

d s

ettin

gs t

o en

sure

rep

rod

ucib

ility

Verif

ied

and

sec

urel

y p

rinte

d

pro

duc

t th

at is

:•

free

fro

m a

dm

ixtu

re•

free

fro

m m

issi

ng p

rint/

erro

rs•

accu

rate

ly c

ount

ed•

corr

ectly

ass

emb

led

(e.g

. la

bel

/leaf

lets

)

Sys

tem

s p

rove

n to

be

effe

ctiv

e, r

ecor

ds

of:

• va

lidat

ion

and

qua

lific

atio

n•

verif

icat

ion

chec

ks•

scan

ning

rej

ects

and

re

view

of

them

• eq

uip

men

t te

stin

g

Sch

emat

ic 4

Sch

emat

ic 5

Sch

emat

ic 7

Ann

ex A

:A

dm

ixtu

re

Iden

tific

atio

n an

d

trac

eab

ility

Line

cle

aran

ce

Valid

atio

n (a

nd

Qua

lific

atio

n)

70

Gen

eral

Syn

op

sis

– C

laus

e 11

Ori

gin

atio

n/ar

two

rk

The

gene

ratio

n of

new

or

amen

ded

orig

inat

ion

is th

e st

art o

f the

man

ufac

turin

g p

roce

ss fo

r p

rinte

d it

ems

and

req

uire

s co

ntro

l fr

om c

once

pts

to

orig

inat

ion

and

thr

ough

to

final

prin

ting.

A

ll or

igin

atio

n an

d p

rinte

d m

edia

mus

t b

e co

ntro

lled

to

ensu

re

secu

rity

and

inte

grity

of

the

final

prin

ted

pro

duc

t.

Rea

sons

fo

r th

e ‘e

xtra

’ GM

P r

equi

rem

ents

Bot

h p

acka

ging

sup

plie

rs a

nd p

harm

aceu

tical

com

pan

ies

have

exp

erie

nce

of c

omm

on p

rob

lem

s th

at o

ccur

in t

he p

rep

arat

ion

of

orig

inat

ion/

artw

ork,

whi

ch c

ould

be

avoi

ded

by

good

man

ufac

turin

g p

ract

ices

.

Orig

inat

ion

pro

ble

ms

occu

r in

the

sam

e w

ay a

s th

ose

for

prin

ting

of t

he p

acka

ging

mat

eria

l and

GM

P p

reve

ntiv

e co

ntro

ls t

o ad

dre

ss

thes

e, f

ollo

w t

he s

ame

pat

tern

, (e

.g.

def

ined

wor

k ar

eas,

seg

rega

tion,

line

cle

aran

ce,

reco

rded

che

cks,

etc

.).

Ele

ctro

nic

syst

ems

are

wid

ely

used

to

pro

duc

e p

harm

aceu

tical

orig

inat

ion;

it is

imp

orta

nt t

hat

the

syst

ems

are

secu

re a

nd h

ave

cont

rolle

d a

cces

s (s

ee P

S 9

000

4.2.

3).

Sin

ce o

rigin

atio

n/ar

twor

k is

com

par

able

to

a d

esig

n p

roce

ss,

erro

rs b

uilt

into

the

des

ign

cann

ot b

e re

mov

ed b

y la

ter

insp

ectio

n an

d t

here

fore

qua

lity,

i.e.

GM

P, m

ust

be

bui

lt in

to t

he c

reat

ion

pro

cess

. T

his

star

ts w

ith u

niq

ue

iden

tific

atio

n of

the

mat

eria

l and

iden

tity

chec

ks a

t al

l pro

cess

sta

ges

with

in t

he o

rgan

izat

ion

and

dur

ing

tran

sfer

to

the

cust

omer

.

71

Pro

cess

inp

uts

Pro

cess

esP

roce

ss o

utp

uts

and

ev

iden

ceC

ross

ref

er t

o

S

chem

atic

/Ann

ex

• A

ll or

igin

atio

n m

ater

ial

• C

usto

mer

re

qui

rem

ents

• C

usto

mer

des

igns

/sp

ecifi

catio

ns•

Cus

tom

er c

omp

onen

t co

des

Pro

cess

es w

hich

: •

seek

agr

eem

ent

with

cus

tom

er (w

here

req

uire

d)

to s

ign

off

a co

py

of t

he f

inal

pro

of b

efor

e p

rod

uctio

n is

aut

horiz

ed•

req

uire

the

iden

tific

atio

n of

all

orig

inat

ion

mat

eria

l (e.

g. e

nsur

ing

that

pro

ofs

are

mar

ked

w

ith c

omp

onen

t nu

mb

ers

and

issu

e d

ates

)•

cont

rol o

rigin

atio

n m

ater

ials

and

cov

ers

stor

age,

is

sue,

ret

urn

and

line

cle

aran

ces

• en

sure

und

erst

and

ing

of h

ow c

odes

are

use

d

by

cust

omer

s an

d a

pp

licat

ion

of a

pp

rop

riate

co

ntro

l mea

sure

s

• re

qui

re t

he c

heck

ing

of c

opy

(ele

ctro

nic

or

hard

out

put

) aga

inst

orig

inal

sp

ecifi

catio

ns a

nd

cust

omer

ap

pro

ved

ver

sion

s

• A

sys

tem

of

cont

rol f

or a

rtw

ork

that

pre

vent

s th

e in

adve

rten

t us

e of

in

corr

ect

item

s

Rec

ord

s of

:•

app

rova

l by

cust

omer

(e

.g.

app

rova

l of

artw

ork)

•

in-p

roce

ss c

heck

s p

erfo

rmed

on

artw

orks

• lin

e cl

eara

nces

•

chec

ks m

ade

on

in-h

ouse

pro

duc

ed

item

s ag

ains

t a

cust

omer

ap

pro

ved

m

aste

r •

cust

omer

ap

pro

ved

m

aste

rs

Sch

emat

ic 3

Sch

emat

ic 4

Sch

emat

ic 4

(a)

Sch

emat

ic 5

Ann

ex A

:C

hang

e co

ntro

l

Iden

tific

atio

n an

d

trac

eab

ility

Line

cle

aran

ce

72

Gen

eral

Syn

op

sis

– C

laus

e 12

Pri

nt im

pre

ssio

n m

edia

Life

-cyc

le m

anag

emen

t of p

rint i

mp

ress

ion

med

ia is

ess

entia

l and

sho

uld

inco

rpor

ate

good

com

mun

icat

ion

with

the

cust

omer

to

und

erst

and

the

des

ign

and

ap

plic

atio

n of

the

pro

duc

t.

Key

is t

he t

race

abili

ty f

rom

cus

tom

er d

esig

n th

roug

h to

del

iver

y of

al

l prin

ted

item

s.

Rea

sons

fo

r th

e ‘e

xtra

’ GM

P r

equi

rem

ents

Prin

ting

of p

acka

ging

mat

eria

ls is

nor

mal

ly a

thr

ee-s

tage

pro

cess

, in

volv

ing

crea

tion

of t

he o

rigin

atio

n/ar

twor

k, p

rod

uctio

n of

the

prin

t im

pre

ssio

n m

edia

, i.e

. ‘t

he p

late

s’ a

nd la

stly

use

of

the

pla

tes

to c

reat

e th

e te

xt a

nd im

ages

on

the

pac

kagi

ng m

ater

ial.

The

GM

P r

equi

rem

ents

for

all

thes

e st

ages

mus

t th

eref

ore

be

very

sim

ilar

sinc

e th

ey h

ave

the

sam

e ob

ject

ive,

i.e.

com

plia

nce

with

the

cu

stom

er’s

sp

ecifi

catio

n an

d a

void

ance

of

cros

s co

ntam

inat

ion/

mix

-up

s.

Prin

t d

esig

ns c

an b

e ve

ry s

imila

r an

d d

iffic

ult

to d

iffer

entia

te,

par

ticul

arly

with

mod

ern

com

pan

y ‘h

ouse

’ d

esig

ns o

r fo

r a

fam

ily r

ange

of

pro

duc

t p

rese

ntat

ions

. P

rint

imp

ress

ion

med

ia m

ust

ther

efor

e b

e st

rictly

con

trol

led

with

uni

que

iden

tific

atio

n co

des

, an

d c

heck

s in

corp

orat

ed in

to a

ll us

age,

tog

ethe

r w

ith s

ecur

e an

d c

ontr

olle

d d

isp

osal

of

imp

ress

ion

med

ia w

hen

even

tual

ly s

uper

sed

ed.

For

mor

e in

form

atio

n se

e A

nnex

A -

Ad

diti

onal

Exp

lana

tions

of

Key

Con

cep

ts.

Als

o ‘R

ules

and

Gui

dan

ce f

or P

harm

aceu

tical

Man

ufac

ture

rs a

nd

Dis

trib

utor

s 20

02’,

Cha

pte

r 5.

43.

73

Pro

cess

inp

uts

Pro

cess

esP

roce

ss o

utp

uts

and

ev

iden

ceC

ross

ref

er t

o

S

chem

atic

/Ann

ex

• A

ll p

rinte

d it

ems

• A

ll or

igin

atio

n m

ater

ial

(e.g

. fil

ms,

ele

ctro

nic

files

)•

Prin

t im

pre

ssio

n m

edia

(e

.g.

pla

tes,

gra

vure

s,

etc.

)•

All

sets

of

prin

ting

pla

tes

• C

usto

mer

ap

pro

ved

d

esig

n (e

.g.

cust

omer

is

sued

sp

ecifi

catio

n, o

r a

cust

omer

ap

pro

ved

p

roof

)•

Des

ign

req

uire

men

ts f

or

a m

ulti-

pla

te s

et (e

.g.

a tw

o co

lour

des

ign,

or

a d

esig

n th

at,

for

pro

duc

tion

reas

ons.

ne

eds

to b

e sp

lit a

cros

s tw

o p

rint

stat

ions

) •

Req

uire

men

t fo

r a

des

ign

chan

ge

• A

ny r

evis

ed p

rinte

d

pro

duc

ts/d

esig

ns

(e.g

. a

new

cus

tom

er

spec

ifica

tion)

•

All

revi

sed

or

obso

lete

ite

ms

Pro

cess

es w

hich

:•

cont

rol a

ll m

edia

(e.g

. id

entif

icat

ion,

che

ckin

g,

issu

e an

d r

etur

n of

pla

tes)

•

ensu

re t

hat

all p

late

s of

the

set

are

iden

tifie

d a

nd

used

• en

sure

tha

t w

here

one

or

mor

e p

late

s in

a s

et

are

com

mon

to

seve

ral i

tem

s (e

.g.

a p

atte

rned

b

ackg

roun

d t

hat

is u

sed

for

a r

ange

of

lab

el

des

igns

), co

ntro

ls e

xist

to

ensu

re t

hat

shar

ed a

nd

uniq

ue p

arts

of

a se

t ar

e us

ed a

pp

rop

riate

ly•

chec

k al

l prin

ted

out

put

aga

inst

ap

pro

ved

sp

ecifi

catio

ns d

urin

g se

t-up

, to

ens

ure

that

the

co

rrec

t ite

m is

bei

ng m

ade

at t

he c

orre

ct q

ualit

y•

cont

rol c

hang

e in

clud

ing

reco

rds

of c

hang

es o

r re

visi

ons

• en

sure

tha

t id

entif

icat

ion

and

aut

horis

atio

n of

p

rint

med

ia c

hang

es is

as

rigor

ous

as t

he in

itial

or

igin

atio

n •

pre

vent

use

of

prin

t m

edia

whi

lst

und

ergo

ing

or

awai

ting

chan

ge•

rend

er u

nusa

ble

any

prin

t m

edia

dec

lare

d

obso

lete

•

ensu

re t

hat

whe

n p

late

s ar

e re

pla

ced

with

in a

se

t, a

deq

uate

con

trol

s ex

ist

to p

reve

nt e

rror

• co

ntro

l the

qua

rant

ine

and

des

truc

tion

of p

late

s an

d o

ther

prin

t m

edia

(e.g

. se

greg

ated

sto

rage

, q

uara

ntin

e la

bel

s, e

tc.)

• re

qui

re a

for

mal

ap

pro

val b

efor

e th

e op

erat

or is

al

low

ed t

o ru

n th

e p

ress

• D

ocum

enta

ry

evid

ence

(e.g

. th

at a

ful

l set

of

mat

ched

pla

tes

was

sig

ned

out

to

the

job

, or

in-

pro

cess

che

cks

that

all

colo

urs

are

pre

sent

in t

he

prin

ted

item

)

Rec

ord

s of

:•

chec

ks c

arrie

d o

ut

on m

edia

• p

late

issu

e an

d

retu

rn

• id

entit

y ch

ange

s an

d it

em r

evis

ions

•

app

rova

l to

run

(e.g

. a

sign

ed p

ass

shee

t, f

irst

off

sam

ple

s et

c.)

• re

visi

on o

f ite

ms

• d

isp

osal

of

obso

lete

item

s on

ce r

evis

ed

Sch

emat

ic 3

Sch

emat

ic 4

Sch

emat

ic 4

(a)

Sch

emat

ic 5

Ann

ex A

:A

dm

ixtu

re

Cha

nge

cont

rol

Seg

rega

tion

cont

rols

74

Gen

eral

Syn

op

sis

– C

laus

e 13

Pri

nt a

nd c

onv

ersi

on

pro

cess

es

This

cla

use

cove

rs t

he G

MP

s re

qui

red

to

ensu

re a

deq

uate

con

trol

thr

ough

out

the

mak

e-re

ady

and

pro

duc

tion

pro

cess

es o

f p

rinte

d m

ater

ials

Rea

sons

fo

r th

e ‘e

xtra

’ GM

P r

equi

rem

ents

This

cla

use

add

ress

es a

num

ber

of

spec

ific

asp

ects

of

the

prin

t p

roce

ss t

hat

are

asso

ciat

ed w

ith k

now

n ris

k ar

eas,

i.e.

ris

k of

ser

ious

p

rint

erro

rs a

nd/o

r cr

oss-

cont

amin

atio

n.

The

det

ails

in t

his

sect

ion

of P

S 9

000

rep

rese

nt c

urre

nt b

est

pra

ctic

e, r

outin

ely

seen

by

pha

rmac

eutic

al a

udito

rs d

urin

g au

dits

of

pro

gres

sive

sup

plie

rs w

ho a

re a

war

e of

the

GM

P n

eed

s of

the

pha

rmac

eutic

al in

dus

try.

Thi

s m

eans

tha

t th

e m

ost

dan

gero

us o

f p

ract

ices

, fo

r ex

amp

le ‘

Gan

g p

rintin

g’,

is e

xclu

ded

bec

ause

of

the

hist

oric

al a

ssoc

iatio

n w

ith m

ix-u

ps.

Whi

le it

is a

ccep

ted

tha

t th

e ris

k m

ight

now

be

stat

istic

ally

low

, it

is n

ot z

ero

and

the

con

seq

uenc

es c

anno

t b

e ac

cep

ted

by

the

pha

rmac

eutic

al in

dus

try.

(For

mor

e in

form

atio

n se

e A

nnex

A -

Ad

diti

onal

Exp

lana

tions

of

Key

Con

cep

ts).

How

ever

, in

cer

tain

situ

atio

ns f

or e

xam

ple

, us

ing

prin

ted

mat

eria

l to

set-

up t

he m

achi

ne,

or w

here

tot

al li

ne c

lear

ance

may

be

imp

ract

ical

due

to

the

mac

hine

tec

hnol

ogy,

an

app

roac

h in

volv

ing

a d

ocum

ente

d a

sses

smen

t of

ris

k w

ith s

uita

ble

alte

rnat

ive

secu

rity

chec

ks in

trod

uced

, is

allo

wed

.

75

Pro

cess

inp

uts

Pro

cess

esP

roce

ss o

utp

uts

and

ev

iden

ceC

ross

ref

er t

o

Sch

emat

ic/A

nnex

• C

usto

mer

sp

ecifi

catio

n/d

esig

n re

qui

rem

ents

• A

ny s

pec

ial c

usto

mer

ag

reed

req

uire

men

ts•

Sui

tab

le e

qui

pm

ent,

m

ater

ials

, tr

aine

d s

taff

• B

raill

e sp

ecifi

catio

ns

whe

re r

equi

red

Pro

cess

es w

hich

:•

limit

the

use

of p

rinte

d m

ater

ial f

or m

achi

ne

set-

up p

urp

oses

• in

volv

e a

risk

asse

ssm

ent

of c

hang

eove

r sy

stem

s (e

.g.

whe

re t

he n

atur

e of

the

m

achi

nery

doe

s no

t p

erm

it a

tota

l lin

e-

clea

ranc

e)

• co

ntro

l any

sam

ple

s ta

ken

• ve

rify

any

chan

ges

of p

rint

med

ia b

efor

e co

ntin

uing

pro

duc

tion,

to

ensu

re c

onsi

sten

t q

ualit

y•

ensu

re w

hen

new

pla

tes

are

mad

e fr

om a

new

so

urce

file

, th

e su

bse

que

nt w

ork

is t

reat

ed a

s a

new

bat

ch•

ensu

re w

hen

new

pla

tes

are

mad

e fr

om a

fix

ed/a

pp

rove

d f

ile,

the

sub

seq

uent

wor

k m

ust

und

ergo

a f

irst

off

chec

k•

ensu

re a

ny B

raill

e sy

mb

ols

mee

t sp

ecifi

catio

n•

cont

rol s

tora

ge t

o en

sure

sec

urity

, in

tegr

ity a

nd

trac

eab

ility

•

cont

rol t

he h

old

ing

of s

tock

(whe

n co

ntra

ctua

lly a

gree

d)

• ex

clud

e ga

ng p

rintin

g d

ue t

o p

oten

tial f

or

cros

s-co

ntam

inat

ion

• G

ood

logi

cal f

low

of

mat

eria

ls a

nd c

lear

se

greg

atio

n

Rec

ord

s of

:•

pro

duc

tion

cont

rols

/ch

ecks

• al

l rep

lace

men

t of

p

late

s•

sam

ple

s ta

ken

and

d

isp

ositi

on

Sch

emat

ic 4

Sch

emat

ic 4

(a)

Sch

emat

ic 6

Ann

ex A

:A

dm

ixtu

re

Ris

k as

sess

men

t

Seg

rega

tion

cont

rols

77



PS 9004



ANNEX A - ADDITIONAL EXPLANATION OF KEY CONCEPTS

PS 9000 GMP related text is reproduced in blue

78

Ref: Definition/References Explanation

3.1

3.14

6.2.2

6.3

8.3

9.1.7

9.1.8

9.1.11

10.1.5

10.2

10.3

13.5

PS 9000 Definition The presence within the batch of one or more items not of the nature of that specified by the product description, i.e. cross contamination. Other terms used include ‘mix-up’, ‘rogue’ or ‘stranger’

PS 9000 ReferencesCross-contamination

Competence, awareness and training

Infrastructure

Control of nonconforming product

Line clearance (cross-contamination control)

Segregation controls (cross-contamination control)

Personal hygiene and security

Converter’s flap code

Reel fed materials (general)

Reel fed self-adhesive labels

Gang Printing

Data supplied by the MHRA on their investigations into defective medicine shows that 12 % involve mislabelling in its widest sense (i.e. the product container is printed, or labelled, cartoned or has a descriptive leaflet which is either incorrect or has text which is not compatible with the use of the product), see Table Annex B3.

The source of admixture can originate at the supplier, the pharmaceutical manufacturer and the distribution chain or at the point of dispensing. Some causes might be outside the control of the pharmaceutical manufacturer, e.g. the pharmacist dispensing the product. However the pharmaceutical manufacturer needs to take all possible precautions to prevent mix-up, including:• bar coded items (and detectors)• visual codes• colour/text differentiation• procedural controls at supplier (i.e. the

focus of PS 9000) and at the pharmaceutical manufacturer (i.e. GMP)

• physical segregation

Mislabelling of the medicinal product introduces the risk that the patient will:• use the wrong product• use the product in an inappropriate manner Furthermore, there can be serious damage to market confidence in the company’s products or pharmaceutical products in general. Product recalls are very serious, and may cause withdrawal of a critical medicinal product, otherwise urgently needed in the market. However, the risk of causing patient harm cannot be over-emphasised and should never be forgotten.

One historically recognised cause of admixtures is via ‘gang printed’ sources where two or more different designs are printed on the same matrix at the same time.

This conflicts with a strict GMP principle, which can

Admixture

79


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.

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Change control

The development of a new component or material is a period of extensive design change, with controls and liaison between customer and supplier. This results in specifications approved by customer and supplier, covering raw materials, sources, processes, and tests.

Later in the product life-cycle, variability can occur through uncontrolled changes.

The following are examples of changes which could affect component dimensions, constituents or other characteristics (e.g. surface finish), creating operational problems for the customer, or incompatibility during the shelf-life of the medicinal product:• refurbishment of injection moulds• use of a different production line• raw materials sourced from a new supplier• reprogramming of equipment controlling

computers• replacement equipment

To avoid the risk of uncontrolled changes PS 9000 requires the use of a Change Control process which:• documents all planned changes• assesses potential problems (e.g. Risk

Assessment)• revalidates where required• includes an independent change review and

authorisation• notifies the customer and schedules the

introduction of the change • provides traceability on the change• retains a record

The bottom line of Change Control is to plan and document change to avoid potential issues that could affect supplier and/or customer.

For further information see ‘Rules and Guidance for Pharmaceutical Manufacturers and Distributors 2002’, Section A15.43, A15.44.

PS 9000 Definition A process that ensures changes to materials, methods, equipment and software are prop-erly documented, vali-dated, approved and traceable.

PS 9000 ReferencesRisk Assessment

Control of documents (electronic)

Customer communication

Design and development inputs

Control of design and development changes

Validation of processes for production and service provision

Materials (starting, ancillary and intermediate)

Copy/design change

Replacement print media

PS 9004 ReferencesRisk assessment

Validation

3.7

3.31

4.2.3

7.2.3

7.3.2

7.3.7

7.5.2

9.1.6(b)

12.3

13.4

Annex A

Annex A

81


82


3.13

5.2

5.3

7.4.1

9.1.10

11.1

12.1

12.5

PS 9000 DefinitionA copy produced without authority with the intention of deceiving a user as to its true origin

PS 9000 ReferencesCustomer focus

Quality Policy

Purchasing process

Waste material (cross-contamination control)

Origination procedures and work areas

Print impression media – General

Quarantine and destruction

Most people will have heard of counterfeit consumer products, such as watches and perfumes, but may not be aware that in some parts of the world there is a serious problem involving counterfeit medicinal products.

The scale of the problem can amount to many billions of dollars, and governments are even sensitive that this practice might eventually pose a serious risk to the normal commercial supply of medicinal products. This is evidenced by the May 2003 FDA directive to pharmaceutical companies supplying the US market, requiring notification within five days of the detection of a counterfeit product.

In the UK the practice is rare but not unknown, as “the last example of a counterfeit product entering the legal supply chain was approximately 20 years ago”. However data from the World Health Organisation, (WHO), shows that “between 1984 and 1999, there were 771 reports of counterfeit drugs, the majority (78%) of these reports came from developing countries”. Similarly “a recent report from Russia showed that 12% of medicines in circulation 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

Counterfeit

83


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).

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Identification and traceability

A fundamental requirement when an operational problem occurs at the pharmaceutical manufacturer, (e.g. material usage problem, market complaint, etc.), is an effective QMS, which assists problem resolution. Operational problems can occur for many reasons, but should the problem be related to a supplier’s material, then it is essential that the total inter-company record system enables traceability of the material on site from delivery and during manufacture at the supplier organization.

Through GMP guidance via the regulatory organizations, e.g. Medicines and Healthcare products Regulatory Agency (MHRA), all pharmaceutical companies are required to use unique and unambiguous lot numbers and material identification codes, since it is the cornerstone of traceability, avoids potential confusion or misunderstanding and allows referral to:• the delivery date and supplier• the quantity received• receipt check results• remaining stock• batch and market usage

A requirement for medicinal products is that records are retained for at least one year after the expiry of the batch in which they were used. For this reason, and that packaging materials may not be used immediately, PS 9000 requires suppliers to keep quality records for at least “5 years from the last date of supply of the batch of packaging material”.Similarly, to provide complete traceability, supplier’s documented quality systems require:• unique material identifications, for raw materials

used in the product, as well as for the product itself

• records showing batch history (e.g. process dates, quantity made, in-process test results)

• change control records• record retention system

This system can then allow tracking back to the same quality data as that for the pharmaceutical

PS 9000 Definition There is no PS 9000 definition for identification

Traceability - The ability to follow data/records logically forwards or backwards within and between organizations, to allow reconstruction of events.

PS 9000 ReferencesQuality Records

Identification and traceability

Preservation of product



Security barcode systems - General

Reel fed materials (General)


Print impression media - General

Matched plates

Copy/design change

3.35

3.29

7.5.3

7.5.5

8.3

9.1.10

10.1.1

10.2

11.1

12.1

12.2

12.3

85


manufacturer detailed above, e.g.• raw material data, quantity received, receipt test

data • 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.

Retained samples

Batched production and stock holding

13.3

13.7

86


Line clearance

3.19

9.1.7

10.7

11.1

13.2

Annex A

PS 9000 Definition The assurance that a production facility (line), and its associated working area is completely cleared of all materials, waste, products, samples, documentation, etc. associated with the current production, prior to the introduction of new documentation and materials required for commencement of the next production run.

PS 9000 ReferencesLine clearance (cross-contamination control)

Digital printing


Changeover systems

PS 9004 ReferenceAdmixture

A fundamental requirement in the practice of avoiding mix-ups is ensuring that only the materials, documents, etc. as required for that product, are on a line or machine, or in a working area at any one time. This material or document has to be that allocated and issued for that particular batch or job. Virtually all investigations following a mix-up, focus on the batch that preceded the incident product, or was being processed or handled in the vicinity, e.g. an adjacent line.

The obvious risk of inadequate line clearance is that once a rogue material is introduced into a batch it is virtually impossible to reliably detect and remove in subsequent operations. The only practical quality measure is therefore not detection, but prevention, using procedures, checks, counterchecks and training.

The least serious effect of a mix-up is processing difficulties on the pharmaceutical manufacturer’s packaging line, e.g. the rogue components are too large or too small to process properly and they block hoppers and feed chutes. However, even this can disrupt a smooth running process and cause product variability.

The most serious consequences involve a rogue component or material, which is incorporated 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.

87


• 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.

88


Risk assessment

3.31

4.2.3 (d)

7.3.1

8.3

9.1.1

9.1.2

9.1.4

9.1.5

9.1.10

9.1.11

9.2.1 d)

13.2

PS 9000 DefinitionA documented assessment of potential failures or faults arising from new or changed processes, materials, equipment or facilities, which could affect product quality, performance or use

PS 9000 References(References to risk and/or risk assessment)

Control of documents (electronic)

Design and development planning


General

Facilities design

Cleaning

Pest Control


Personal hygiene and security

Minimum environmental conditions

Changeover systems

Most companies will have experienced the situation where a response to a process problem, or a change, results in a second, sometimes more serious problem. Often, the secondary problem could have been avoided if the change or the original process problem had been given proper consideration and planning.

This consideration is known as Risk Assessment, and its application is best explained by two typical examples: 1. Batch Reworking/Sorting

When tests revealed a ‘cosmetic’ defect in a printed component, reworking the batch introduced a critical ‘rogue’ component, due to inadequate rework area cleandown from the previous job.

The initial defect was minor, but the ultimate consequences of an undetected rogue component reaching the patient could be fatal.

A risk assessment of the rework process must cover the areas specified in PS 9000 Clause 8.3. However, the rework/sorting process may introduce other GMP risks related to, e.g. infrastructure, competency, work environment, and so an assessment should consider risks of:• a mix-up with other materials• contamination or damage from further handling• incomplete rework due to poor training• difficulty in detecting the difference between

good and bad product• inadequate defect description• poor lighting, poor job separation, poor labelling

in inspection area• discontinuous sorting process (over several days

or by different staff)• poor separation between sorted/unsorted

material• poor labelling of sorted/unsorted product

The risk assessment should include complete batch

89


ISO 9004 ReferenceProduct and process validation and changes

PS 9004 ReferencesChange control

Validation

7.1.3.3

Annex A

Annex A

documentation, i.e. details of the product and problems, lot number and quantity, defects involved, deadline, etc. From this a suitable plan of rework can be generated which includes:• identification and segregation of the batch,

(before, during and after sorting)• inspection area cleandown checks• special lighting needs, tools and equipment to

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

90


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)

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• 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

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3.37

8.3

9.1.2

9.1.8

11.1

13.1

PS 9000 Definition Note: There is no definition in PS 9000

PS 9000 ReferencesWorking (work) areas

Control of nonconforming product

Facilities Design

Segregation controls (cross-contamination control)


Print machine set up (make-ready).

To avoid the risk of product cross-contamination, it is essential that, in addition to normal good material handling disciplines, there is adequate process segregation during manufacture.

PS 9000 states, “working areas should be defined and segregated”.

Often in practice, a separation gap between processes of 1 – 2 metres is maintained, with the actual process areas identified by lines marked on the floor. This can be wasteful of space and is often abused when pallet materials straddle the delineating segregation lines.

A more absolute method, routinely used in the pharmaceutical industry, is to use a physical barrier between processes - PS 9000 states:• “Where physical barriers are used to segregate

working areas they shall be a minimum of 1.5 metres high and continuous from floor level.”

• “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).

Segregation controls

93


94


Validation (and Qualification)

QualificationBefore implementing a validation program it is necessary to link into the more comprehensive ‘qualification system’ which is shown in the diagram below:

ValidationThrough experience of operational and in-market problems, the pharmaceutical industry has found that validation is the only dependable method to fully understand the process capability and to ensure process control. It should be an essential tool at the supply organization and is a requirement of PS 9000, for reasons detailed below.

Inconsistent product quality can often be traced to an inadequately controlled process which has not been validated and where process parameters have not been fully defined.

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

3.36

4.2.3

7.3.6

7.5.2

9.2.3

10.2

10.4

10.5

10.6

10.7

PS 9000 Definition Documented confirmation that a procedure, process, equipment, material, activity or system, performs as intended and achieves the expected results in accordance with predefined acceptance criteria.

PS 9000 ReferencesControl of documents (electronic)

Design and development validation

Validation of processes for production and service provision

Enhanced cleanroom conditions

Reel fed materials (general)

Leaflets

Board products (cartons, cards, wallets, catch cards etc.)

Combination products

Digital printing

Specification Qualification (SQ)

Installation Qualification (IQ)

Operation Qualification (OQ)

PerformanceQualification (PQ)

Determine what is requiredSpecify requirement

Check on receiptInstall as appropriate

Trial processes

Evaluate first three batches for:• process performance• process compliance• product compliance

95


reasons for validation includes ensuring:• the process is controllable and operates

consistently with defined control settings• 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

PS 9004 ReferencesChange control

Risk assessment

Annex A

Annex A

96


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 toolsii. full maintenance strip down and rebuildiii. relocation of equipment to a new position

• process materials, e.g.i. revised specification material from the

existing supplierii. 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

97


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.

99



PS 9004



ANNEX B - OTHER EXTERNAL GMP REFERENCES

100

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.21 CFR

Summary PS 9000 Cross Reference

211.42(a) Building design to facilitate cleaning and maintenance

9.1 Facilities, equipment and operating conditions

9.1.2 Facilities design

211.42(b) Adequate building space for orderly placement of equipment and material to prevent mix-ups

9.1.2 Facilities design

211.63 Equipment design to facilitate cleaning and maintenance

9.1.3 Equipment and maintenance

211.67 Equipment cleaning and maintenance

9.1.4 Cleaning

211.68(b) Electronic equipment change control

4.2.3 Control of documents (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-contamination by physical or spatial separation

9.1.2 Facilities design 9.1.8 Segregation controls (cross-

contamination control)

211.180 General Requirements (records and reports)

4.2.4 Control of records

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

101

EU Guide to Pharmaceutical GMP

Summary PS 9000 Cross ReferenceGeneral information

Chapter 3.4 Protection against infestation

9.1.5 Pest control

Chapter 3.8 Avoidance of cross-contamination

9.1 Facilities, equipment and operating conditions

9.1.1 General9.1.2 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 and precautions

8.2.4 Monitoring and measurement of 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 disposal

9.1.10 Waste control (cross-contamination control)

Chapter 5.44 Physical segregation to minimise risk of cross contamination

9.1.2 Facilities design9.1.8 Segregation controls (cross-

contamination control)

Chapter 5.62 Reprocessing of rejected product

8.3 Control of nonconforming 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 validation

4.2.3 Control of documents (electronic)7.3.6 Design and development

validation 7.5.2 Validation of processes for

production and service provision

B2. Rules and Guidance for Pharmaceutical Manufacturers and Distributors 2002

(http://pharmacos.eudra.org/F2/eudralex/vol-4/home.htm)

102

EU Guide to Pharmaceutical GMP

Summary PS 9000 Cross ReferenceGeneral information

Annex 15 (43) and (44) Change control 4.2.3 Control of documents (electronic)7.2.3 Customer communication7.3.2 Design and development inputs7.5.2 Validation of processes for

production and service provision

Annex 16 (8) Finished product batch certification that manufacture and testing are in compliance with the marketing authorisation

7.2 Customer related processes7.4 Purchasing

Annex 18 (9) Labelling of active pharmaceutical ingredients

7.4.3 Verification of purchased product7.5.3 Identification and traceability7.5.5 Preservation of product

103

Defect Type Report Received

This table includes all formal defect investigations carried out by the MHRA, whether they were confirmed as quality defects or not. Some of these investigations resulted in batch recalls.

It does not include all defects reported to the MHRA or all investigations carried out by licence holders and not reported to the MHRA.

Some headings are very similar, and in most cases could be combined, e.g. product mix-up is usually where the wrong tablets are found in a pack.

Acknowledgement to:The Defective Medicines Report CentreMHRAMay 2003

Year 02/03 Year 01/02 Year 00/01

Noncompliance to product specification (stability)

6 19 16

ADR (adverse drug reaction)

9 16 23

Product mix-up 3 14 18

Noncompliance to product specification (analytical)

11 12 9

Other 77 10 29

Other particulates 15 9 14

Wrong data 0 9 18

Label mix-up 6 8 13

Container 5 7 6

Leaflet Missing/mix-up 12 5 9

Closure Fault 1 4 3

Precipitation 2 4 1

Label details missing 6 4 0

Lack of efficacy 12 4 0

Lack of sterility assurance 5 3 2

Re-labelling error 21 3 5

Glass particulates 6 2 2

Adulteration 1 2 0

Under fill 1 2 5

Wrong data/poor print 3 1 0

Fibre particles 1 1 0

Solubility 0 1 0

Wrong fill 3 0 3

Bacteria contamination 3 0 2

Mould Contamination 1 0 1

Label Missing 2 0 1

Poor Print 0 0 3

Total 212 140 183

B3. MHRA Defect Investigations

104

INDEX PAGE

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

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

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

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

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

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

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

GGang printing 74, 75, 78, 79, 100

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

H

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

J

K

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

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

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Media (print) 6, 12, 38, 70, 72, 73, 75, 82, 83, 84MHRA (Medicines and Healthcare products Regulatory Agency) vii, xiv, 78, 84, 103Microbial contamination (moulds) 48, 66, 103Mislabelling 7, 78Mix-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

N

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

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

QQualification (and validation) 69, 94

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Quality Assurance (QA) 29, 30, 40, 43Quality Control (QC) 8, 17, 28Quality Management System (QMS) ix, x, 2, 37, 38, 39, 42, 43, 44, 45, 46, 59, 64, 65, 84Quality manual 38Quality plan 49Quality policy 39, 41, 42, 44, 65, 82Quarantine 29, 54, 55, 63, 73, 82, 100

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

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

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

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

U

VValidation (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, 102Vials 25, 26

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

The Institute of Quality AssurancePharmaceutical Quality Group

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

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Ps9004 Complete for Pharmaceutical

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