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QUALITY ASSURANCE WORKBOOK

FOR PHARMACEUTICAL

MANUFACTURERS

Michael Jahnke

PDA

Bethesda, MD, USA

DHI Publishing, LLC

River Grove, IL, USA

www.pda.org/bookstore

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10 9 8 7 6 5 4 3 2 1

ISBN: 1-930114-81-8Copyright © 2005 Michael Jahnke. All rights reserved.

All rights reserved. This book is protected by copyright. No part of it may be reproduced, stored in a

retrieval system or transmitted in any means, electronic, mechanical, photocopying, recording, or otherwise,

without written permission from the publisher. Typeset in the United Kingdom by Dolffin. Printed in the United

States of America.

Where a product trademark, registration mark, or other protected mark is made in the text, ownership of

the mark remains with the lawful owner of the mark. No claim, intentional or otherwise, is made by reference to any

such marks in the book.

While every effort has been made by the publisher and the author to ensure the accuracy of the

information contained in this book, the organization accepts no responsibility for errors or omissions. The views

expressed in this book are those of the editors and authors and may not represent those of either Davis Healthcare

International or the PDA, its officers, or directors.

PDA

3 Bethesda Metro Center

Suite 1500

Bethesda, MD 20814

United States

301-986-0293

Davis Healthcare International Publishing, LLC

2636 West Street

River Grove

IL 60171

United States

www.DHIBooks..com


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iii

CONTENTS

Contents iiiPreface xiii

Biography xvii

INTRODUCTION 1

Principles and Duties of Production 3Principles and Duties of Quality Control 3Principles and Duties of Quality Assurance 4Quality Management, Quality Assurance and Quality Control 5

THE QUALITY MANAGEMENT SYSTEM OF A PHARMACEUTICAL COMPANY 9

The Basis of a QM System-The DIN EN ISO 9001 9Quality Management Sections 11

QUALITY MANUAL 13

Quality Manual of the Company 15Table of Contents 16Part 1: Declaration of Principles of the Quality Policy 17Part 2: Definitions 17Part 3: Organisational Structure 18Part 4: Functional Measures 22

SECTION 1: MANAGEMENT RESPONSIBILITY 23Introduction 23

Regulations 23 Job Descriptions 24


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Job Description: Quality Assurance 25Aim of the Position 25Most Important Responsibilities/Duties 26

Job Description: Quality Control Manager (Qualified Person) 27Aim of the Position 27Most Important Responsibilities/Duties 27Organisational Structure 29

SECTION 2: QUALITY MANAGEMENT SYSTEM 31

Introduction 31Regulations 31

First Level: Quality Manual 32Second Level: Quality Management System Procedures 32Third Level: Standard Operating Procedures (SOPs) 33Fourth Level: Rules and Regulations 33

SECTION 3: CONTRACT REVIEW 35


Responsibilities 361. Secrecy Agreement 362. (Contract) Manufacturing Agreement 373. Quality Assurance Agreement 44

SECTION 4: DESIGN AND DEVELOPMENT 53

Responsibilities 53

SECTION 5: CONTROL OF DOCUMENTS AND RECORDS 55

Responsibilities 56SOP: Documentation Requirements-Design and Structure of StandardOperating Procedures (SOPs) and other Quality Manual Documents 56

SOP Header 57Indexing by Central Documentation Unit 57Layout Requirements 57

Identification of Revision Needs 59 Approval and Release of Documents 59

Contentsiv


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Distribution and Identification of the Original Document 60Example of Receipt Form 60Example of a Destroy Form 60Storage and Archiving of Records and Documents 61Distribution of Quality Relevant Documents 61Indexing System 61

SECTION 6: PURCHASING 63

Introduction 63Regulations 63Vendor Evaluation 64

Responsibilities 65SOP: Supplier Evaluation 65

1. Purpose 652. Responsibilities 653. Description/Implementation 67

SOP: Implementation of Supplier Audits 691. Purpose 692. Responsibilities 693. Description/Implementation 71

Supplier Audit Checklist 74

SECTION 7: CONTROL OF CUSTOMER-SUPPLIED PRODUCT 101

Introduction 101Regulations 101Responsibilities 101

Description of Execution 102

SECTION 8: PRODUCT IDENTIFICATION AND TRACEABILITY 103


Example Description of Execution 104

Contents v


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SECTION 9: PROCESS CONTROL 107Introduction 107Regulations 107Responsibilities 108

SECTION 10: INSPECTION AND TESTING 109


Typical Description of Execution 110

SECTION 11: CONTROL OF INSPECTION, MEASURING ANDTEST EQUIPMENT 113


SECTION 12: INSPECTION AND TEST STATUS 117


SECTION 13: CONTROL OF NON-CONFORMING PRODUCTS 119


Example Description about Management of Defective Products 120SOP: Processing of Complaints 121

Implementation 122Receiving Reports of Medicine-Related Risks 122Essential Initial Information 123Obtaining Information 123Blocking of Remaining Products 124Documentation 124

Checking (Simulation) of the Structured Procedure 124

Contentsvi


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SECTION 14: CORRECTIVE AND PREVENTATIVE ACTION 125


Highlighting Errors and Potential Quality Deviations 126SOP: Deviation Management 127

Deviation Report Form 131

SECTION 15: HANDLING, STORAGE, PACKAGING AND DISTRIBUTION 133

Introduction 133

Regulations 133Responsibilities 133

SOP: Handling, Storage, Packaging and Dispatch of Solid andSterile Products 134

SECTION 16: CONTROL OF QUALITY RECORDS 139


Responsibilities 140

SECTION 17: SELF INSPECTION AND AUDITING 141

Introduction 141Regulations 141Scheduling and Planning Audits 142

Auditors 142Conducting the Audit 142Reporting Findings 142Corrective and Preventive Action 143Review 143SOP: Self Inspection (Quality Audit) 143Planning 144Quality Audit Procedure 144Measures Following a Quality Audit 145SOP: Handling (Regulatory) Inspections 145

Contents vii


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SECTION 18: TRAINING 161


Establishing the Training Requirement 164Internal and External Training Measures 164Types of Training 166Trainer Qualification 167Training Materials 167Stipulating the Content of the Training Programme 168Training Duration and Time 169Outer Framework of the Training Event 169

Monitoring Success 169Documentation 170Organisation of a Training System 170The Efficiency of a Training System 171Summary and Outlook 172

Example Documentation of Training and Instructions Report aboutExecution of Instruction Measures 173

SECTION 19: SERVICING 175

SECTION 20: STATISTICAL TECHNIQUES 177


Comments Regarding the Procedure 178

SECTION 21: HYGIENE 179

Introduction 179Regulations 179Responsibilities 179General Aspects 180

Staff Hygiene 180Production Hygiene 181

Example: Sterile Production Hygiene Protocol 181

Aim of the Hygiene Protocol 181Scope of the Hygiene Protocol 181

Contentsviii


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Health and Safety 181Cleanroom Concept 182Room Layout in Sterile Production 182Requirements for Premises, Ventilation Techniques and Equipment 183Lockers 183Washrooms 183Media 183Staff Hygiene 183

Access Regulations 184Dress Code 184Skin and Hand Hygiene 184Medical Monitoring 184Training 185

Production Hygiene 185The Cleaning and Disinfecting of Equipment and Premises 185

SECTION 22: FACILITIES, UTILITIES AND ENGINEERING (SITE MASTER FILE) 189

Introduction 189Regulations 189Example: Site Master File 189

1. General Information 191

2. Personnel 1943. Premises and Equipment 1954. Documentation 1985. Production 2016. Quality Control 2047. Contract Manufacture and Analysis 2058. Distribution, Complaints and Product Recall 2059. Self Inspection 205

SECTION 23: VALIDATION 207

Introduction 207Validation Master Plan 207

Company Description 208Company Validation Policy 208Legal Regulations and Guidelines 208

Aim of the Validation Master Plan 209Responsibilities 209

Validation Concept 210Process Validation (PV) 213

Contents ix


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Cleaning Validation 217Revalidations 220Maintenance 220Validation Status/Validation Programme 221Technology Transfer 221Risk Analyses 224

ANALYTICAL TRANSFER PROTOCOL 225MANUFACTURING TRANSFER PROTOCOL 233Hazard Analysis and Critical Control Points (HACCP) Risk Analysis inProduct Specific Validation 243

Introduction 243HACCP Analysis 244Product Specific Validation Plan (PVP) 245

Example: Summary Technology Transfer Report of Product 255Introduction 255General Part 255

Analytical Transfer Protocol (ATP) 255Manufacturing Transfer Protocol (MTP) 256Risk Analysis According HACCP 256Final Evaluation of the Technology Transfer Process 257

SECTION 24: CHANGE CONTROL AND ANNUAL PRODUCT REVIEW 259


Example: Change Control Management 260Formal Procedure for Changes 263

Application of a Change (Section 1 and 2) 263SOP Annual Product Review 270

Scope 270 Abbreviations 270Responsibilities 270Regulations 271

SECTION 25: CONTINUOUS IMPROVEMENT SYSTEM 275


Quality System 276Design Control 277

Contentsx


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Document Control 277Purchasing 277Change Control 277Control of Customer-Supplied Products 277Process Control 277Inspection and Test Status 277Control of Non-conforming Product 278Corrective and Preventive Action 278Handling, Storage, Packaging, Preservation and Delivery 278Internal Quality Audit 278Training 278Statistical Techniques 278Hygiene 279

Facilities, Engineering 279Validation 279

FURTHER READING 281

INDEX 287

LIST OF FIGURES

Figure 1 Interrelationship between QA, QC and Pharmaceutical Production 2Figure 2 Model of a Quality Management System 5Figure 3 Process Oriented Quality Management System 7Figure 4 Possible Organisation Chart within a Quality Management System 29Figure 5 Document Structure of a Quality Management System 33Figure 6 GMP Training in the Form of a Lecture 172Figure 7 Documentation SOP Flow Chart 199Figure 8 Flow Diagram of Manufacturing and In-Process Controls - Site 1 238Figure 9 Flow Diagram of Manufacturing and In-Process Controls - Site 2 239

LIST OF TABLES

Table 1 Basis of a Quality Management System-Comparison between DIN ENISO 9001 and PIC-GMP Guideline 10Table 2 Matrix Example to Define Functions and Responsibilities 49Table 3 The Layout Requirements for SOP Documentation 57

Table 4 An Example of Indexing of Relevant Documents 61Table 5 Summary Self-Inspection Report 146

Contents xi


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Table 6 Example of Actions on Corrective or Preventative Measures 148Table 7 Allocation of Areas to Clean Categories 182Table 8 Number of Employees Engaged in Various Activities 192Table 9 List of Contact Details and Outside Activities 193Table 10 Preparation, Revision and Control of Documents 200Table 11 Risk Analysis According to HACCP (Hazard Analysis andCritical Control Points) 246

Contentsxii


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PREFACE

This Quality Assurance Workbook for Pharmaceutical Manufacturers presents

strategies for the set up and management of a Quality Management system within the

pharmaceutical industry. Based on the structure of DIN EN ISO 9000, a series of Quality Management sections are shown and it is made clear that these must be

realised and continuously improved. These sections regulate the responsibility for

quality, show how necessary it is to plan processes at an early stage, what is required

in order to attain a high production standard and how it may be maintained. All

chapters are presented individually and partly supplemented with practiced order-of-

events experience (Standard Operation Procedures [SOPs]).

Starting with the close relationship of Quality Assurance with Good

Manufacturing Practice (GMP) and Quality Control and Pharmaceutical Production, a

Quality Management system for the pharmaceutical industry is presented and anexample Quality Manual is described. Within the 25 chapters the key issues of a good

Quality Manual are presented and practices are described that have been developed

within a pharmaceutical manufacturing company.

Starting with Management Responsibility, advice is presented on how to provide

job descriptions and define management responsibilities. The Quality Management

System chapter deals with the establishment, documentation, implementation and

maintenance of a Quality Management system, e.g., how to handle manufacturing

protocols, testing instructions, measures for calibration and maintenance, etc.

A detailed description of the set up and review of contracts such as Secrecy

Agreement , (Contract) Manufacturing Agreement and Quality Assurance Agreement

and the measures for amendments thereof are provided. This is followed by

descriptions of the process of the planned and documented Research and Development

(R&D), ranging from planning, definition of inputs, documentation of the results and

inspection and certification of the design, to design validation, which defines the

transition into the field of process control.

Control of documents and records is of paramount importance, thusdocumentation requirements, e.g., design and structure of SOPs and other Quality

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Manual documents are described. Measures for Purchasing are presented and

supplemented by SOPs dealing with vendor qualification programs and audit

checklists. The next chapter deals with Control of Customer-Supplied Product in

which specification requirements of starting materials, packaging materials, etc., and

systematic verification, storage and control are described.

Classification of products is important in all phases of production, quality control,

and delivery. The requirements for identification and recording for traceability are

presented within the topic of Product Identification and Traceability. Quality relevant

instructions for process steering and Process Control are provided. All manufacturing

processes need to be conducted under fully validated conditions and following

established specifications. The purpose of the chapter on Inspection and Testing is to

describe the systematic testing procedure for compliance with stipulated quality

requirements. This ensures that tested materials are used in the manufacturing processand are subsequently processed and released as an end-product for launch provided

that they satisfy the specifications stipulated in advance. The status of the materials

and products must be considered in relation to the results of past and future quality

tests.

The chapter about Control of Non-conforming Products is provided to show how

to process complaints and to trace back raw data. Practical advice is also provided

about Corrective and Preventive Action dealing with deviation management and

deviation report form. The provisions for identifying, collecting, recording and

archiving quality records are described in the chapter about Control of Quality Records.

Since auditing is a fundamental element of a Quality Management system a

company must have an audit procedure and program in place to verify conformity of

operations with the principles of Quality Assurance, and the relevant regulatory

requirements. The chapter on Self Inspections and Auditing deals with regulations

about how to conduct audits from the point of view of Quality Assurance, Regulatory

Agencies (legal authorities) and contractors. Detailed SOPs are provided for

adaptation.

In addition to the need for qualified equipment in the pharmaceutical industry,

international and national conditions also demand and regulate staff qualifications

(training). The chapter on Training provides detailed information about

responsibilities, practical aspects on training, e.g., qualification of trainer, training

materials, example documentation of training and instructions, etc.

Subsequent chapters deal with the important topics of Servicing and Statistical

Techniques and this is followed by a chapter on Hygiene and maintaining Hygienic

Conditions with regard to the regulations governing personnel and production hygiene.

Prefacexiv


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The chapter on Facilities, Utilities, and Engineering details the regulations and

gives an example of the content and structure of a Site Master File and also

information about Validation of both manufacturing and analytical methods. The

structure of a Validation Master Plan and required contents of chapters is discussed

followed by introduction into risk analysis according to the HACCP (Hazard Analysis

and Critical Control Points) concept and measures for Analytical and Manufacture

Transfer Protocols.

Change is inevitable and if there is to be improvement it must be planned,

controlled and coordinated if chaos and confusion are to be avoided. Measures to

adequately control change are provided within the chapter on Change Control and

Annual Product Review, which contains example SOPs and formulae dealing with

change control management and annual product reviews. Finally a philosophy of the

Continuous Improvement of a Quality Management system is discussed.

Preface xv


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AUTHOR BIOGRAPHY

Dr Michael Jahnke was born on 4 August 1961 in Gronau (Leine) near Hanover in

Germany. He is married and has two children. His scientific career started in 1981 at

the Technical University of Braunschweig, Germany, and University of Bielefeld,where he passed his Diploma – Pre examination in Biology. Between 1984–1987 he

studied Microbiology at the University of Hanover, Germany, where he achieved his

Diploma in Biology (B.Sc. Biol.). In 1990 he obtained his doctorate on natural

sciences (Dr. rer. nat./Ph.D.) at the Institute of Microbiology/University of Hanover on

the topic of mineralisation of xenobiotics.

Dr Jahnke started his professional career in 1990 when he became the Head of

Department (Biology) at the IBR Forschungs GmbH , working on ecotoxicology,

biology, and Quality Assurance. From 1994–2002 he became Head of Department

Quality Control/Microbiology at Hameln Pharmaceuticals GmbH , a contractmanufacturer of parenteral pharmaceutical drugs. In 2001 Dr Jahnke started

publishing workbooks about Environmental Monitoring in Pharmaceutical Areas,

Media Fill Validation and Environmental Monitoring during Aseptic Processing and

Microbiological Monitoring of Pharmaceutical Process Water .

At present he is Head of Quality Assurance at Wülfing Pharma GmbH , a contract

manufacturer of sterile and non-sterile pharmaceutical drugs. He continues his work

on risk analysis in pharmaceutical drug manufacturing, hygienic risks caused by

microorganisms and topics about Quality Assurance.

Dr Jahnke has achieved certification as a Specialist Microbiologist SM (AAM)

Consumer and Industrial Microbiology – Pharmaceutical/Medical Device/Cosmetics,

is a member of the Parenteral Society and Deutsche Gesellschaft für Hygiene und

Mikrobiologie (DGHM) and contributes to the Editorial Board of European Journal

of Parenteral & Pharmaceutical Sciences of the Parenteral Society, UK and the

Editorial Board of Journal of Pharmaceutical Science and Technology of the

Parenteral Drug Association, USA.

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