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PHARMACEUTICAL QUALITY
Richard PrinceEditor
PDA
Bethesda, MD, USA
DHI Publishing, LLC
River Grove, IL, USA
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10 9 8 7 6 5 4 3 2 1
ISBN: 1-930114-61-3Copyright © 2004 Richard Prince. 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.
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CONTENTS
Introduction Richard Prince i
SECTION I : THE INTERNATIONAL LANDSCAPE OF QUALITY
1. Global Disequilibrium of Quality 3Lembit Rägo
Introduction 3WHO's Contribution to Medicines Quality 5Pharmaceutical Gaps 7
Access Gap 7Population/Consumption Gap 8Human Resource Gap 9Research and Development Gap 10
Quality Gap 10Regulatory Capacity Gap 12
WHO's Response to Pharmaceutical Gaps:WHO MedicinesStrategy 13International Conference of Drug Regulatory Authorities (ICDRA) 13Regional Harmonization initiatives: Setting Priorities 15Remaining Challenges 16Conclusions 17References 18About the Author 21
2. Good Manufacturing Practices: An International Perspective 23Michael H. Anisfeld
Introduction 23Drug Quality—Pharmacopeal Testing 24The Advent of GMPs 26GMPs: Codes, Directives, Guidelines, Points to Consider, orRegulations; and inspection severity 28Drug Quality—GMP Implementation 30
The GMPs 36Quality Management and the Qualified Person 39
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Validation 40Self-Inspection 42Contract Manufacture and Contract Analysis 43Future Trends—GMPs and Risk Assessment 43Afterthought 45About the Author 47
3. Quality Management in the American Pharmaceutical Industry 49Richard L. Friedman
Introduction 491. 'Global Quality Assurance' 502. Quality Foundation 51
Quality Leadership and Commitment 52
Trend Today, Improve Tomorrow 533. Good Science 534. Intended Use 555. People: Qualifications, Roles, Responsibilities 566. Reliable Laboratory 577. Suitability of Equipment, Facilities, and Associated Procedures 58
A Day in the Life: Minimizing Variability 58Same way, Each Time 58Quality—Business Synergy 59
8. Raw Material Quality and Surveillance 59
9. Batch Review and Release 6110. Documentation 6311. Effective Development and Process Validation 63
From Development to Commercialization 63Lifecycle Progression: Monitoring Regular Production 65
12. 'Building Quality In' and the Willingness to Fix a FlawedProcess 6613. Effective Use of Risk Assessment 69
Advantages of Risk Assessment Methods 69Quantity of Data Used to Assess Risk 69Quality of Data: Adequacy of the Risk Assessment 70Regulatory Concepts 71
14. Understanding Sources of Variability and Signals of Drift 73Sources of Variability and Risk Mitigation 73Why Drift Occurs 73We've Always Done It That Way 75Testing a Finished Product 75Preventing Drift: Detect, Correct, Prevent 76
15. Awareness of the Link Between Safety, Efficacy, and Quality 76
16. The Quality Organization: Authority, Responsibility, andAccountability 78
Contentsiv
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Quality Management Metrics 7917. Taking Action When Necessary 8018. Internal Audit Program 8019. Contracting and Outsourcing Scrutiny 8120. Modernization: Knowing the Current Science and EmployingContemporary Technology 82Conclusion 83References 84About the Author 87
4. The Australian System of Quality for Medicines and OtherTherapeutic Products 89
Paul K. Priscott
Introduction 89The Government System of Healthcare Product Regulation 90
Prescription Medicines 91Non-Prescription (OTC) Medicines 94Complementary Medicines 95Medical Devices, Blood and Tissue Products 96
Regulations Covering the Quality of Healthcare Products 100The National System in the International RegulatoryEnvironment 103Value and Purpose of the National Healthcare Product
Regulatory System 104The National Healthcare Product Regulatory Vision for theFuture 106Acknowledgement 107References 107About the Author 109
5. Quality Assurance of Healthcare Products in the United Kingdom 111 John L. Turner
The Government Structures Responsible for the Regulation ofthe Quality of Healthcare Products in the United Kingdom 111
General 111Government of the United Kingdom 111Healthcare Products and Medicinal Products 112Health and Safety at Work 112The National Health Service 113Good Laboratory Practice in Relation to Health andEnvironmental Safety of Chemical Substances 114The UK Accreditation Service 114
Commission for Health Improvement 114Medicinal Products 115
Contents v
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The Licensing Authority 115The Enforcement Authority 115The Medicines Commission and Section 4 Committees 116The British Pharmacopoeia 116The National Institute for Biological Standards andControl 117Medicinal Products for Administration to Humans 117
The Medicines and Healthcare productsRegulatory Agency 117The Royal Pharmaceutical Society ofGreat Britain and Trading Standards Authorities 118Strategic Health Authorities 118
Medicinal Products for Administration to Animals 118
Medical Devices 119The Authority and the Committee on Safety ofDevices 119The Medicines and Healthcare productsRegulatory Agency 119
Foods and Cosmetics 120General 120Foods Standards Agency 120
UK Regulations and Procedures to Ensure the Quality ofHealthcare Products 121
Safety of Chemicals used in Healthcare Products andGood Laboratory Practice 121Medicinal Products 122
General 122Marketing Authorisation 122Exemptions from the Requirement for aMarketing Authorisation 124
Medicinal Products Intended for Export 124Unlicensed 'Special' Medicinal Products 124Medicinal Products Prepared Under theSupervision of a Pharmacist 125Herbal Remedies 125Homoeopathic Medicinal Products 126Investigational Medicinal Products 126
Manufacture 127Manufacturer's Licence 127Manufacture Outside the EC or EEA 127Mutual Recognition Agreements onInspection and Authorisation of
Manufacturers 128The 'Qualified Person' 128
Contentsvi
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Good Manufacturing Practice (GMP) 129Wholesale Dealing 130
Wholesale Dealer's Licence 130Wholesale Dealer's (Import) Licence 131Good Distribution Practice 131
Regulatory Inspection, Testing and QualitySurveillance 132Inspection for Compliance with GMP and GDP 132Inspection for Compliance with GLP and GCP 133Medicines Prepared in Pharmacies and HealthEstablishments 133Official Sampling and Testing of Medicines 133Suspected Defective Medicines 134
Enforcement of the Medicines Act 135Medical Devices 135Foods and Cosmetics 135
The Relationship Between UK Government and Other OrganisationsInvolved in the Quality Assurance of Healthcare Products,In and Outside the UK 136
UK Organisations 136General 136The British Standards Institute and QualityCertification Bodies 137
Professional Bodies 138Academic Institutions 139Trade Associations 139
The European Community (EC) 139General 139Legal Framework 140
Medicinal Products 141Medical Devices 143Cosmetics 143Safety of Chemicals and GoodLaboratory Practice 143
The European Commission 143The European Agency for the Evaluationof Medicinal Products 144
Wider Europe 145The European Economic Area 145The Council of Europe, the European Departmentfor the Quality of Medicines and the EuropeanPharmacopoeia 145
Contents vii
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Protocol to the European Agreement on ConformityAssessment and Acceptance of Industrial Productswithin the EC and Associated Countries 146
International 146The World Health Organization 146Organisation for Economic Cooperation andDevelopment 147The Pharmaceutical Inspection Conventionand Pharmaceutical Cooperation Scheme 147
The Global Harmonisation Taskforce 148The International Committee on Harmonisationof Technical Requirements for Registration ofPharmaceuticals for Human Use 148
Trade and Professional Bodies 148The Dominant Values in the Regulation of Quality ofHealthcare Products in the UK 149The Vision of Legislation for Quality 149Author's Comments 150References 151Useful Websites 152
United Kingdom: Government/Quasi-Government 152United Kingdom: Professional and Trade 152European and International 153
About the Author 154
6. Canada's National Healthcare System of Quality 155Suzanne Levesque, Pierre Morin and Leonor FerreiraCanada's Government Organisation 155Canada's Quality Regulatory Environment 156
Regulatory Framework 157Licenses 157International Conference on Harmonisation 158Confidentiality 158The Drug Quality Assessment Program 158The Food and Drugs Act 159The Food and Drugs Regulations 160Posting of Good Manufacturing Practices 161A Radical but Welcome Evolution 161
Quality Management 161Quality Assurance 162Good Manufacturing Practices for Drugs 163Quality Control 164
Enforcement 166Values, Integration and Vision 167
Contentsviii
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Two Basic Values 167Integration 167At Last, A Vision 168
Postscript 169A Business Transformation Initiative 169Quality is the Key Component 169
About the Authors 170
7. Germany's National Quality System for Healthcare Products 171Günter Winkmann and Harald G. Schweim
Part 1: Germany's Government Structure for Regulating Quality 171Structure: General Remarks 171Quality of Healthcare Products and Services:
Definitions and Regulatory Scope 173Healthcare Products 173
'Quality' – The Idea 174Healthcare Services 175
The National Quality System for Healthcare Products 176Medicinal Products and Medical Devices 176
Federal Government Apparatus 176Laender Governments 179
Quality Assurance of Products and ServicesProvided in Healthcare 180
Part 2: National Regulations covering Quality ofHealthcare Products 181
Good Laboratory Practice (GLP): GermanChemicals Act and Derived AdministrativeProvisions 181Enforcement 183
Medicinal Products Regulations: German Medicines Actof 1976 (Law on Trade in Medicinal Products) andDerived Ordinances, Legal Specifications andAdministrative Provisions 183
Purpose 183Essential Drug Requirements 184Manufacture 184Drug Evaluation Prior to Market Approval 185
Drug Testing Instructions 185Authorization Documents 187
Pharmaceutical Quality and Good ManufacturingPractices 190
Quality: AMG Definition 192
Statutory Rules for Operations inPharmaceutical Enterprises 192
Contents ix
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Pharmacopoeia 194Official Collection of EvaluationProcedures 195Quality Documents/Templates from theInternational Conference onHarmonization and their AdoptionStatus 195
Clinical Trials—Good Clinical Practice 195National and Supra-National AuthorizationProcedures 199
National Procedures 199The European Authorisation Procedures forMedicinal Products 204
Distribution of Medicinal Products 207Special Regulations for Veterinary MedicinalProducts 208Post-Marketing Drug Surveillance Proceduresand Pharmacovigilance 208
Procedures to Ensure AppropriateConformity and Long-Term Quality,Efficacy and Safety 208Post-Marketing Surveillance 209Drug Risk Management: Observation,
Compilation, Evaluation of Drug Risksand Graduate Management Procedure 210Pharmacovigilance: National andSupra-National Mutual InformationExchange 214
Electronic Drug Information Systems 216International Drug Traffic 217Quality of Conformity Summary—From theViewpoint of Pharmaceutical Entrepreneurs 217
Regulations 217Conformity/Quality ManagementStandards 219
A Concrete, Actual and SomewhatComplex Example: Quality Approach,Licensing and Surveillance of Gene TherapyMedicinal Products 220
Preclinical Research and Development 220Manufacture 221Clinical Trials 222
Licensing 224Probable Future Regulatory Changes 224
Contentsx
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Enforcement of AMG Law and PharmBetrVOrdinance 224
Regulations Concerning Narcotics and their Precursors:German Narcotics Act of 1981 and Derived Ordinances,Supplemented by Precursors Control Act of 1994 225Medical Devices Regulations: German Medical DevicesAct and Provisions Derived Thereof 226
Purpose, Definitions, Scope and Responsibilities 227Quality and its Assessment 229
Legal Classification of Medical DevicesAccording to Potential Risk 229Notified Bodies 231CE Marking, Conformity Assessment 232
Harmonized Standards and CommonTechnical Specifications 233Conformity Assessment—From theViewpoint of European and GlobalManufacturers 237Statutory Rules for Operations 239Registration 240Biologically Active Medical Devices 240Mandatory Medical Prescription 240Clinical Trials 241
Definition of Further NationalResponsibilities in Context with QualityAssurance 241
Surveillance 242Procedure and Enforcement 242Notification of Incidents 243Risk Management 244Electronic Information System 247
Enforcement 248Statutory Quality Assurance in Healthcare 248
The Statutory Sickness Insurance—Social Code,Section V 248
Part 3: Relation of German Governmental HealthcareQuality System to other Systems—Domestic andSupra-National 250
Domestic Systems and Institutions 250Federal/Laender Authority Level 250Statutory (Corporatist, Self-governing)Sickness Funds—the GKV 253
Professional Chambers of Care Providers 253Hospitals/Hospital Societies 254
Contents xi
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Laender Health Surveillance AuthoritiesMandating Private Institutions 255Universities 255The Association of the Scientific MedicalSocieties 255The German Institute for Standardization 256The German Accreditation Council 257Private Associations of Health Insurers,Pharmacists, Pharmaceutical andAllied Industries 259Press/TV and Consumer-protectionAssociations 260
International Interconnections 261
The Pharmaceutical Inspection Convention 261The International Conference on Harmonization 264The Global Harmonization Task Force 265Bilateral Mutual Recognition Agreements 265
Bilateral MRAs between EU and US,Canada, Switzerland, Australia, NewZealand, Japan 265MRAs with Central and East EuropeanCountries 266
Harmonization of Orphan Medicinal Product
Legislation 269Increasing Role of Pharmacoeconomics 270Quality Assurance of Healthcare Products andServices ('Technologies') in Other Countries 270
UK: Quality in Pharmacy 272Netherlands MEB Agency 273
Dominant Values and Underlying Ethical Criteria Associatedwith the National Quality System in Healthcare 274Vision of Quality Legislation in Healthcare Manufacturing 275References 276
Useful Websites 287Germany (Internet addresses of institutionsreferred to in this article) 287European Union, Member States, EEAAgreement States 290International 291
Acknowledgements 292About the Authors 292
Contentsxii
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8. Israeli System of Quality: Emphasis on Medicines 295Karen Ginsbury
National System of Quality—Governmental Structure 295Regulation and Enforcement 297Affiliations and Interactions with Other Organizations 305
The Israel Society for Quality 305The Standards Institute of Israel 306The National Physical Laboratory of Israel 306The National Accreditation Authority 306Dominant Values and Fundamentals of theQuality System 308
The Vision 308About the Author 309
9. Japanese National System of Quality: Emphasis on Medicines 311Kunio Kawamura, Katutoshi Mise and Sadayoshi TomitaConcept of Quality Assurance of Pharmaceuticals—Revision of Pharmaceutical Affairs Law in Japan 311
Background and History of Revision 311Need for Legal Framework 311Safety and Efficacy 312Risk-based Management for Quality 312What is Pharmaceutical Quality? 313
Quality Assurance in Japan 313Definition of Terms Related to Quality According toISO 9000 314Regulation of Pharmaceutical Quality andOrganization of Industries in Japan—New RegulationConcerning Quality Assurance, Responsibility ofManufacturing and Marketing 314Newly Revised Pharmaceutical Affairs Law andRelatedRegulations in Japan 316Registration Flow of Pharmaceuticals—Developmentto Approval to Post-marketing Surveillance in Japan 318
Research and Development and New Drug ApplicationSubmission 320
New Drug Application and Approval 320New Drug Investigation, Clinical Trial andQuality Assurance 320Regulations from the View Points of Ethics andSafety in Development of New Drugs—Consideration of New Drugs and Creature-
derived Products 322
Contents xiii
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Procedures for the Review and Approval of New Drugs,and Measures to Make the Review Processes Faster 322Drug Master File System for Simpler and QuickerReview Time 322Good Clinical Practice for the Quality Assuranceof Pharmaceuticals Used in Clinical Trials and HigherQuality of Clinical Data 326Good Manufacturing Practice in InvestigationalNew Drugs 328
Manufacturing, Good Manufacturing Practice 329GMP in Japan 329Biological Products and Creature-derived Products 329
Marketing and Post-marketing, Good Vigilance Practice and
Good Post-marketing Surveillance 332Good Vigilance Practice 332Good Post-marketing Surveillance Practice 332Safety for Creature-derived Products andPharmaceuticals 336Quality and Risk Management Matrix for Creature-derived Pharmaceuticals 336
References 340About the Authors 341
10. Singapore's National Healthcare System of Quality 343Teng-Heng Chan and Hesan-Ahmad Quazi
Introduction 343General Overview of the Healthcare Delivery System 344
Role of MOH 345Role of HSA 345Public Sector/Private Sector 346Hospitals 346Key Statistics 346
Government System Responsible for Regulating Quality 347Ministry of Health (MOH) 347Clusters—Hospitals and Institutions 349Health Services Authority (HSA) 350
Professional Centres under HSA 350Associated Regulations that Cover Healthcare Quality 351
Medicines Act (Chapter 176) 351Poisons Act (Chapter 234) 353Private Hospitals and Medical Clinics Act(Chapter 248) 353
The Infectious Diseases Act (Chapter 137) 353Radiation Protection Act (Chapter 262) 354
Contentsxiv
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Governing Authority and Regulatory Structure 355Healthcare Services 355Health-Related Products 355Licensing Requirements 355
Pharmaceutical Products and ImportProcedure 355Product Licensing 356Import Licensing 357Wholesale Licensing 357Manufacturing Licensing 358Other Licensing Requirement 358Clinical Drug Trials 359
Environmental Issues 359
Economic and Tax Incentives 359Import Procedures 360
Quality Control/Quality Assurance 360Healthcare Professionals 360
Medical Doctors and Traditional ChineseMedicine Practitioners 360Continuous Training of Nurses 362
Quality Assurance for Health-related Products 363Quality Assurance in Medical and HealthLaboratories 363
Pharmaceuticals and Health-related Products 364Evaluation and Registration 364Pharmaceuticals 364Complementary Health Products(Chinese Proprietary Medicinesand Health Supplements) 364Medical Devices 365Good Manufacturing Practice and GoodDistribution Practice 365Product Quality Surveillance 366Pharmacovigilance and Adverse DrugReactions 367Advanced Preventive Regulations 368Forensic Medicine and Science 368
Blood Supply 368Collection, Processing, Distribution 368
Harmonization of Regulations and Practices inHealthcare Products 369
Regional and Global Harmonization Initiatives 369
Harmonization of Pharmaceutical Regulations 369Harmonization of Cosmetic Regulations 370
Contents xv
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Western Pacific Regional Forum for Harmonization ofHerbal Medicines 370Medical Devices Harmonization 370
Asian and Global Harmonization of MedicalDevices Regulations 370
Global Harmonization Task Force 370Regional Harmonization of Radiation ProtectionRegulations 371
Singapore's National Quality Management System 371Singapore's National Quality System 371
Quality Management in Hospitals and Healthcare Institutionsin Singapore 373
Overview 373
Quality Management Practices in Hospitals 375Singapore General Hospital 375Changi General Hospital 376National University Hospital (NUH) 377Kandang Kerbau Hospital 377
Private Sector Participation in Quality Management Programs 378Pharmaceutical Industry in Singapore 379
Governing Legislation 379Singapore Association of Pharmaceutical Industries 380
Role of the Singapore Association of
Pharmaceutical Industries 380Board of Directors 381Working Committees 381International Affiliation 381
Attaining Professional Accreditation And Recognition 382Accreditation by American Society of CrimeLaboratory Directors/Laboratory AccreditationBoard 382Accreditation by Singapore AccreditationCouncil—Singapore Laboratory AccreditationScheme 382
Singapore Quality Class 382Reference Laboratories for the United NationsInternational Drug Control Programmes 383Pharmaceutical Inspection Cooperation Scheme 383Permanent Forum on International Pharmaceutical 383Training Centre for Radiation Protection 383Collaboration with the World Health Organization 384
WHO Collaborating Centre for Transfusion
Medicine 384
Contentsxvi
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WHO Regional Training Centre for QualityManagement Project 384WHO Collaborating Centre for FoodContamination Monitoring 384WHO Collaborating Centre for Drug QualityAssurance 384WHO International Advisory Committee onElectromagnetic Fields 385WHO Department of Essential Drugs andMedicines Policy 385WHO International Conference of DrugRegulatory Authorities 385
Summary and Conclusions 385
Acknowledegment 388Useful Websites 388References 389About the Authors 390
SECTION II: INDUSTRIAL QUALITY SYSTEMATICS: THE INTERPLAYOF QUALITY SYSTEMS IN COMMERCIAL MANUFACTURING
11. Quality Systems and Pharmaceutical cGMP Compliance 395
William S. HitchingsBackground and History 395Quality Regulations for Medical Products 397Quality System Definitions and Framework 398Medical Product Quality System Development 400
Quality System 401Management Responsibility 402Quality Audits 405Personnel 406Design Controls 406Document Controls 408Purchasing Control 408Identification and Traceability 409Production and Process Controls 409Inspection, Measuring, and Test Equipment 410Process Validation 411Receiving/In-process/Finished Product Acceptance 411Acceptance Status 412Non-Conforming Product 413
Corrective and Preventative Action 413Labeling and Packaging Control 414
Contents xvii
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Handling, Storage and Distribution 415Records 415Master Records, Device History Record/BatchProduction Record 416Quality System Records 417Complaint Files 417Statistical Procedures 418Laboratory Controls 418
Summary 419Systems Approach 419
Bibliography and References 422About the Author 422
12. Quality Systematics for Contract Service Users 423Diane M. Petitti
Introduction 423Quality Manual 424
Quality Policy 424Responsibility of Senior Management Team 425Organization and Responsibility of the Quality Unit 425Employee Responsibilities 425Management Review 426
Quality Agreements 426
Quality System Elements 427The Structure of a Comprehensive Quality System 427
Annual Product Quality Review 428Audits 429Batch Disposition 431Buildings and Facilities 432Change Control 434Complaint Handling 435Contract Service Providers and Consultants 436Corrective and Preventive Action 437Deviations 438Documentation Control 439Equipment 440Label and Labeling Control 442Labeling, Packaging, Storage, Shipping and Distribution 443Laboratory Control 444Management and Employee Quality Responsibilities 447Materials Management and Purchasing Control 448Production and Process Controls 449
Qualification,Verification and Validation 450Recalls and Quality Failures 452
Contentsxviii
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Records and Records Retention 453Returned and Salvaged Goods 455Specifications 456Stability 458Training 459Conclusion 460Acknowledgements 461References 461About the Author 461
13. Quality for Computerized Systems and Electronic Data inRegulated Environments 463
Teri Stokes
Introduction 463Defining Quality for Computerized Systems andElectronic Data 464Management Control 466System Reliability 467Data Integrity and Privacy 471Auditable Quality 473Conclusion 476References 478About the Author 479
14. Quality Control of Pharmaceutical and Biological Products 481Effie Michalopoulos
The Quality Control Laboratory 481Architecture of Quality Control Laboratory Systems 483
Handling Out of Specification Results 486Test Methods Development/Validation/Transfer 486Stability Testing 487Management and Inventory Control of LaboratoryReference Standards 487Management of Laboratory Reagents 487Laboratory Sample Management 488Sample Labeling 488Rounding of Data and Reporting of Significant Figures 488Notebook/Worksheet Management andDocumentationPractices 489Calibration and Preventative Maintenance for GMPLaboratory Instruments 489Contract Laboratories 489
Laboratory Training 490Renovation of Laboratory Facilities 490
Contents xix
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Internal Audits 490The Life Cycle of the Laboratory Systems 491
The Stages of The Life Cycle 496An Example of a Laboratory Life Cycle Journey 497
Concluding Remarks 506Acknowledgements 507References 507About the Author 509
15. Using Statistics to Measure and Improve Quality 511
Lynn D. TorbeckPreface 511
Why Statistics Matter 511
Statistics' Vital Role in Total [Ideal] Quality 512Training New Staff in Applied Statistics for thePharmaceutical Industry 513
Introduction 513History of Statistics 513Statistical Practice in Pharmaceuticals as Comparedto Other Industries 514Defining Quality 515Defining Quality for the Pharmaceutical Industry 515Cost of Quality 516
Statistical Thinking 517Statistics in Context with Pharmaceutical Quality 518
Simple Statistics Well Used 519Summarize the Data 520Plot the Data 520Inferential Statistics 521The Role of Statistical Significance Tests 521
Statistical Tools 522Exploratory Data Analysis 522
The Role of Quality Assurance and Statistics 524The Role of Quality Control and Statistics 524The Role of Manufacturing and Statistics 524Definitions of Quality 525
Quality Control 526Definition 1 526Definition 2 526Quality Assurance 526Quality Engineering 526Statistical Quality Control 526
Statistical Process Control 527
Contentsxx
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Total Quality Management (TQM) or Company-WideQuality Control 527Six Sigma 527
Fads in Quality 527Data Collection 528
Reportable Values 528Good Data Collection 529Poor Data Collection 529Representative versus Random Samples 530
Period Sampling 530Beginning, Middle and End Sampling 530Grab Sampling 530Expert or Judgment Selection 531
Standards versus Specifications 531Philosophy of Standards versus Specifications 531USP/NF as a Compendial Standard 531Specifications 532Specifications as a Go/No-Go Gauge 534Reportable Values versus Specifications 535
Setting Specifications 535Using Historical Data to Set Specifications andTolerances 535
Out of Specifications 536
Incoming Inspection 537In-Process Inspection 538Finished Product Inspection 538Process Validation 538Process Control 539Method Validation 540Stability Program 541Annual Review Program and Trending 541
Process Analytical Technologies 542Resources 543Software for Statistics 543
Minitab 544The Excel Dilemma 544
Summary 545Future Vision 545References 545About the Author 551
Contents xxi
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16. Pharmaceutical Quality Auditing 553Mary Moriva and Steve Iland
Introduction 553Background 554Considerations in the Design of Quality Audit Programs 557
Requirements for a Quality Audit 557An Overview of Quality Audit Programs 558Tiers That Make Up a Company-Wide Audit Program 560Audit Client 560First, Second, and Third Party Audits 561Corporate Quality Audit Programs 562
Intent and Scope 562Program Deliverables 562
Issues to Manage 563Division Quality Audit Programs 563Site (Internal) Quality Audit Programs 564
Intent and Scope 564Program Deliverables 564Issues to Manage 565
Coordinating a Company-Wide Quality Audit Program 566A Range of Approaches that can be used forQuality Auditing 566
Implementing and Managing a Quality Audit Program 568
Selling the Audit Program to Company Management 570Establishing the Scope of the Audit Program 571Prioritizing the Audit Schedule 572Auditors 575Selecting Auditors 576Auditors Need Improvement 577Basic Auditing Skills—Conducting an Audit Interview 578Auditor Credibility 580Developing the Program's Team of Auditors 580Audit Program Policy and Operating Procedures 581Improving the Audit Program 583Periodic Audit Program Reporting to Management 583
Performing Quality Audits 584Planning and Preparation 584
Important Points about the Audit Plan 585Conducting the Audit 586Preparing the Draft Audit Report 587Audit Exit Meeting 588The Audit Report 589
Areas of Audit Focus when Reviewing PharmaceuticalQuality Systems 589
Contentsxxii
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Competition 621What Quality Is Not 621
Quality Control, Assurance, and Systems 621Why Do Things Go Wrong? 625
Dichotomy of Goals 627Toleration of Deviation 628Conceptual Problems 629So What Do We Need To Do? 631
Conclusions About Quality 631References 632About the Author 634
18. Quality at the Threshold of Enforcement:
Perspectives from Industry and FDA 637Gregory Bobrowicz
Dogma and Reality 637Dogma 637Reality 638Scope 638
Evidence 639FDA Documents Encourage Creative Reading of theRegulation 639Language of the Different Paradigms 639
Paperwork Without Value 641Training 641
FDA Inspections 641Industry Training Programs 642Conclusion 643
Audits 644FDA Inspections 644Industry Audit Programs 644Conclusion 646
Product Development Reports 647FDA Inspections 647Product Development Reports inIndustry 647Conclusion 648
Deviations, Investigations, and CAPA 648FDA Inspections 648Deviation Programs in Industry 650Conclusions 651
Validation 652
FDA Inspections 652Validation in the Industry 654
Contentsxxiv
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Conclusions 655Other Examples 655
Causes 656Senior Management is Generally Inexperienced andUninterested in Quality Except as an Enforcement Risk 656The Cost of Manufacturing Pharmaceuticals isIrrelevant 657
Enforcement is Spotty and Unpredictable 657Rules are Known Only by Legend 658The Words of the Regulations do not EmphasizeEffectiveness 659The FDA is Driven to Avoid Embarrassment andCriticism: Public Health is Only One Piece of This 660
Consequences and Recommendations 661References 663About the author 663
19. Training and Learning: Critical Contributors to Quality 665 James L. Vesper
Introduction 665Defining Terms 666Training as an Element of a Quality System 667
Employee Learning and Motivation (25 pts.) 670
Employee Education, Training, and Development 671Motivation and Career Development 671
Qualitative and Quantitative Measures 672Training Measures 672
Quality Measures 674Cost of Quality 675Integrated Measures 675
The Impact of Training on Quality 676Training, Learning, and the Quality of the Organization 676
Training and its Connection to Profitability 677Training and its Connection to Compliance andOrganizational Quality 679They Must Know Something… 679
Training and the Quality of Processes, Products and Services 680Training on Tasks 681Training and Investigating Deviations 682When Training is Not the Answer 685The Learning Curve 687Anecdotal Comments from Learners 687
Training and the Quality of Personnel 688Optimizing Training to Obtain Quality Outcomes 690
Contents xxv
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Conclusion 693References 694About the Author 696
20. Quality Management for Legal/Regulatory Programs 699Gary Gamerman
Introduction 699Quality Management System Elements 700
1. Policy Management 7002. People and Vendor Management 7013. Program Management 7024. Product Management 7035. Performance Management 703
Conclusion 706About the Author 707
Index 708
Contentsxxvi