PHARMACEUTICAL QUALITY - Parenteral Drug Association · Non-Prescription (OTC) Medicines 94 Complementary Medicines 95 Medical Devices, Blood and Tissue Products 96 Regulations Covering

PHARMACEUTICAL QUALITY

Richard PrinceEditor

PDABethesda, MD, USA

DHI Publishing, LLCRiver Grove, IL, USA

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ISBN: 1-930114-61-3Copyright © 2004 Richard Prince. All rights reserved.

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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 10Quality Gap 10Regulatory Capacity Gap 12

WHO's Response to Pharmaceutical Gaps: WHO Medicines Strategy 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, or Regulations; and inspection severity 28Drug Quality—GMP Implementation 30The GMPs 36Quality Management and the Qualified Person 39

iiiwww.pda.org/bookstore

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 52Trend Today, Improve Tomorrow 53

3. 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 599. 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 Flawed Process 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 7616. The Quality Organization: Authority, Responsibility, and Accountability 78

Contentsiv


Quality Management Metrics 7917. Taking Action When Necessary 8018. Internal Audit Program 8019. Contracting and Outsourcing Scrutiny 8120. Modernization: Knowing the Current Science and Employing Contemporary Technology 82Conclusion 83References 84About the Author 87

4. The Australian System of Quality for Medicines and Other Therapeutic Products 89

Paul K. PriscottIntroduction 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 Regulatory Environment 103Value and Purpose of the National Healthcare Product Regulatory System 104The National Healthcare Product Regulatory Vision for the Future 106Acknowledgement 107References 107About the Author 109

5. Quality Assurance of Healthcare Products in the United Kingdom 111John L. Turner

The Government Structures Responsible for the Regulation of the 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 and Environmental Safety of Chemical Substances 114The UK Accreditation Service 114Commission for Health Improvement 114

Medicinal Products 115

Contents v


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 products Regulatory Agency 117The Royal Pharmaceutical Society of Great Britain and Trading Standards Authorities 118Strategic Health Authorities 118

Medicinal Products for Administration to Animals 118Medical Devices 119

The Authority and the Committee on Safety of Devices 119The Medicines and Healthcare products Regulatory Agency 119

Foods and Cosmetics 120General 120Foods Standards Agency 120

UK Regulations and Procedures to Ensure the Quality of Healthcare Products 121

Safety of Chemicals used in Healthcare Products and Good Laboratory Practice 121Medicinal Products 122

General 122Marketing Authorisation 122Exemptions from the Requirement for a Marketing Authorisation 124

Medicinal Products Intended for Export 124Unlicensed 'Special' Medicinal Products 124Medicinal Products Prepared Under the Supervision 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 on Inspection and Authorisation of Manufacturers 128The 'Qualified Person' 128

Contentsvi


Good Manufacturing Practice (GMP) 129Wholesale Dealing 130

Wholesale Dealer's Licence 130Wholesale Dealer's (Import) Licence 131Good Distribution Practice 131

Regulatory Inspection, Testing and Quality Surveillance 132Inspection for Compliance with GMP and GDP 132Inspection for Compliance with GLP and GCP 133Medicines Prepared in Pharmacies and Health Establishments 133Official Sampling and Testing of Medicines 133Suspected Defective Medicines 134Enforcement of the Medicines Act 135

Medical Devices 135Foods and Cosmetics 135

The Relationship Between UK Government and Other Organisations Involved in the Quality Assurance of Healthcare Products,In and Outside the UK 136

UK Organisations 136General 136The British Standards Institute and Quality Certification Bodies 137Professional Bodies 138Academic Institutions 139Trade Associations 139

The European Community (EC) 139General 139Legal Framework 140

Medicinal Products 141Medical Devices 143Cosmetics 143Safety of Chemicals and Good Laboratory Practice 143

The European Commission 143The European Agency for the Evaluation of Medicinal Products 144

Wider Europe 145The European Economic Area 145The Council of Europe, the European Department for the Quality of Medicines and the European Pharmacopoeia 145

Contents vii


Protocol to the European Agreement on Conformity Assessment and Acceptance of Industrial Products within the EC and Associated Countries 146

International 146The World Health Organization 146Organisation for Economic Cooperation and Development 147The Pharmaceutical Inspection Conventionand Pharmaceutical Cooperation Scheme 147

The Global Harmonisation Taskforce 148The International Committee on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use 148Trade and Professional Bodies 148

The Dominant Values in the Regulation of Quality of Healthcare 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


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 173

Healthcare Products 173'Quality' – The Idea 174

Healthcare Services 175The National Quality System for Healthcare Products 176

Medicinal Products and Medical Devices 176Federal Government Apparatus 176Laender Governments 179

Quality Assurance of Products and Services Provided in Healthcare 180

Part 2: National Regulations covering Quality of Healthcare Products 181

Good Laboratory Practice (GLP): German Chemicals Act and Derived Administrative Provisions 181Enforcement 183

Medicinal Products Regulations: German Medicines Act of 1976 (Law on Trade in Medicinal Products) and Derived Ordinances, Legal Specifications and Administrative Provisions 183

Purpose 183Essential Drug Requirements 184Manufacture 184Drug Evaluation Prior to Market Approval 185

Drug Testing Instructions 185Authorization Documents 187

Pharmaceutical Quality and Good Manufacturing Practices 190

Quality: AMG Definition 192Statutory Rules for Operations in Pharmaceutical Enterprises 192

Contents ix


Pharmacopoeia 194Official Collection of Evaluation Procedures 195Quality Documents/Templates from the International Conference on Harmonization and their Adoption Status 195

Clinical Trials—Good Clinical Practice 195National and Supra-National Authorization Procedures 199

National Procedures 199The European Authorisation Procedures for Medicinal Products 204Distribution of Medicinal Products 207Special Regulations for Veterinary Medicinal Products 208Post-Marketing Drug Surveillance Procedures and Pharmacovigilance 208

Procedures to Ensure Appropriate Conformity and Long-Term Quality,Efficacy and Safety 208Post-Marketing Surveillance 209Drug Risk Management: Observation,Compilation, Evaluation of Drug Risks and Graduate Management Procedure 210Pharmacovigilance: National and Supra-National Mutual Information Exchange 214

Electronic Drug Information Systems 216International Drug Traffic 217Quality of Conformity Summary—From the Viewpoint of Pharmaceutical Entrepreneurs 217

Regulations 217Conformity/Quality Management Standards 219

A Concrete, Actual and Somewhat Complex Example: Quality Approach,Licensing and Surveillance of Gene Therapy Medicinal Products 220

Preclinical Research and Development 220Manufacture 221Clinical Trials 222Licensing 224Probable Future Regulatory Changes 224

Contentsx


Enforcement of AMG Law and PharmBetrV Ordinance 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 Devices Act and Provisions Derived Thereof 226

Purpose, Definitions, Scope and Responsibilities 227Quality and its Assessment 229

Legal Classification of Medical Devices According to Potential Risk 229Notified Bodies 231CE Marking, Conformity Assessment 232Harmonized Standards and Common Technical Specifications 233Conformity Assessment—From the Viewpoint of European and Global Manufacturers 237Statutory Rules for Operations 239Registration 240Biologically Active Medical Devices 240Mandatory Medical Prescription 240Clinical Trials 241Definition of Further National Responsibilities in Context with Quality Assurance 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 Healthcare Quality System to other Systems—Domestic and Supra-National 250

Domestic Systems and Institutions 250Federal/Laender Authority Level 250Statutory (Corporatist, Self-governing) Sickness Funds—the GKV 253Professional Chambers of Care Providers 253Hospitals/Hospital Societies 254

Contents xi


Laender Health Surveillance Authorities Mandating Private Institutions 255Universities 255The Association of the Scientific Medical Societies 255The German Institute for Standardization 256The German Accreditation Council 257Private Associations of Health Insurers,Pharmacists, Pharmaceutical and Allied Industries 259Press/TV and Consumer-protection Associations 260

International Interconnections 261The Pharmaceutical Inspection Convention 261

The International Conference on Harmonization 264The Global Harmonization Task Force 265Bilateral Mutual Recognition Agreements 265

Bilateral MRAs between EU and US,Canada, Switzerland, Australia, New Zealand, Japan 265MRAs with Central and East European Countries 266

Harmonization of Orphan Medicinal Product Legislation 269Increasing Role of Pharmacoeconomics 270Quality Assurance of Healthcare Products and Services ('Technologies') in Other Countries 270

UK: Quality in Pharmacy 272Netherlands MEB Agency 273

Dominant Values and Underlying Ethical Criteria Associated with the National Quality System in Healthcare 274Vision of Quality Legislation in Healthcare Manufacturing 275References 276

Useful Websites 287Germany (Internet addresses of institutions referred to in this article) 287European Union, Member States, EEA Agreement States 290International 291

Acknowledgements 292About the Authors 292

Contentsxii


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 the Quality 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 to ISO 9000 314Regulation of Pharmaceutical Quality and Organization of Industries in Japan—New Regulation Concerning Quality Assurance, Responsibility of Manufacturing and Marketing 314Newly Revised Pharmaceutical Affairs Law andRelated Regulations in Japan 316Registration Flow of Pharmaceuticals—Development to Approval to Post-marketing Surveillance in Japan 318

Research and Development and New Drug Application Submission 320

New Drug Application and Approval 320New Drug Investigation, Clinical Trial and Quality Assurance 320Regulations from the View Points of Ethics and Safety in Development of New Drugs—Consideration of New Drugs and Creature-derived Products 322

Contents xiii


Procedures for the Review and Approval of New Drugs,and Measures to Make the Review Processes Faster 322Drug Master File System for Simpler and Quicker Review Time 322Good Clinical Practice for the Quality Assurance of Pharmaceuticals Used in Clinical Trials and Higher Quality of Clinical Data 326Good Manufacturing Practice in Investigational New 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 332

Good Vigilance Practice 332Good Post-marketing Surveillance Practice 332Safety for Creature-derived Products and Pharmaceuticals 336Quality and Risk Management Matrix forCreature-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) 353The Infectious Diseases Act (Chapter 137) 353Radiation Protection Act (Chapter 262) 354

Contentsxiv


Governing Authority and Regulatory Structure 355Healthcare Services 355Health-Related Products 355Licensing Requirements 355

Pharmaceutical Products and Import Procedure 355Product Licensing 356Import Licensing 357Wholesale Licensing 357Manufacturing Licensing 358Other Licensing Requirement 358Clinical Drug Trials 359

Environmental Issues 359Economic and Tax Incentives 359

Import Procedures 360Quality Control/Quality Assurance 360

Healthcare Professionals 360Medical Doctors and Traditional Chinese Medicine Practitioners 360Continuous Training of Nurses 362

Quality Assurance for Health-related Products 363Quality Assurance in Medical and Health Laboratories 363Pharmaceuticals and Health-related Products 364

Evaluation and Registration 364Pharmaceuticals 364Complementary Health Products (Chinese Proprietary Medicines and Health Supplements) 364Medical Devices 365Good Manufacturing Practice and Good Distribution Practice 365Product Quality Surveillance 366Pharmacovigilance and Adverse Drug Reactions 367Advanced Preventive Regulations 368Forensic Medicine and Science 368

Blood Supply 368Collection, Processing, Distribution 368

Harmonization of Regulations and Practices in Healthcare Products 369

Regional and Global Harmonization Initiatives 369Harmonization of Pharmaceutical Regulations 369Harmonization of Cosmetic Regulations 370

Contents xv


Western Pacific Regional Forum for Harmonization of Herbal Medicines 370Medical Devices Harmonization 370

Asian and Global Harmonization of Medical Devices Regulations 370

Global Harmonization Task Force 370Regional Harmonization of Radiation Protection Regulations 371

Singapore's National Quality Management System 371Singapore's National Quality System 371

Quality Management in Hospitals and Healthcare Institutions in Singapore 373

Overview 373Quality Management Practices in Hospitals 375

Singapore 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 Crime Laboratory Directors/Laboratory Accreditation Board 382Accreditation by Singapore Accreditation Council—Singapore Laboratory Accreditation Scheme 382

Singapore Quality Class 382Reference Laboratories for the United Nations International 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


WHO Regional Training Centre for Quality Management Project 384WHO Collaborating Centre for Food Contamination Monitoring 384WHO Collaborating Centre for Drug Quality Assurance 384WHO International Advisory Committee on Electromagnetic Fields 385WHO Department of Essential Drugs and Medicines Policy 385WHO International Conference of Drug Regulatory Authorities 385

Summary and Conclusions 385Acknowledegment 388Useful Websites 388References 389About the Authors 390

SECTION II: INDUSTRIAL QUALITY SYSTEMATICS: THE INTERPLAY OF QUALITY SYSTEMS IN COMMERCIAL MANUFACTURING

11. Quality Systems and Pharmaceutical cGMP Compliance 395William S. Hitchings

Background 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 413Corrective and Preventative Action 413Labeling and Packaging Control 414

Contents xvii


Handling, Storage and Distribution 415Records 415Master Records, Device History Record/Batch Production 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 426Quality System Elements 427

The Structure of a Comprehensive Quality System 427Annual 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 449Qualification, Verification and Validation 450Recalls and Quality Failures 452

Contentsxviii


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 in Regulated Environments 463

Teri StokesIntroduction 463Defining Quality for Computerized Systems and Electronic 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 Laboratory Reference Standards 487Management of Laboratory Reagents 487Laboratory Sample Management 488Sample Labeling 488Rounding of Data and Reporting of Significant Figures 488Notebook/Worksheet Management and DocumentationPractices 489Calibration and Preventative Maintenance for GMP Laboratory Instruments 489Contract Laboratories 489Laboratory Training 490Renovation of Laboratory Facilities 490

Contents xix


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 511Lynn D. Torbeck

Preface 511Why Statistics Matter 511Statistics' Vital Role in Total [Ideal] Quality 512Training New Staff in Applied Statistics for the Pharmaceutical 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 526Statistical Process Control 527

Contentsxx


Total Quality Management (TQM) or Company-Wide Quality 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 536Incoming 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


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 562Issues to Manage 563

Division 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 for Quality Auditing 566

Implementing and Managing a Quality Audit Program 568Selling 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 Pharmaceutical Quality Systems 589

Contentsxxii


Key Quality System Aspects to be Reviewed in a Quality Audit of Pharmaceutical Manufacturing 591

Quality System 591Facilities and Equipment System 592Materials System 592Production System 593Packaging and Labeling System 593Laboratory Control System 593

Conclusions 598References 599Additional Reading 599About the Authors 600

SECTION III: PERSPECTIVES ON QUALITY

17. Industrial Quality for the Start-Up Biotech Company 603Steven S. Kuwahara

The Real Meaning of Quality 603Quality is Meeting Specifications 604Quality is Meeting Customer Requirements 606Quality is Fitness for Use 609Quality Before the Customer is Involved 611Quality from the Viewpoint of the Leaders 613

1. Quality is a Company-Wide Process 6142. Quality is What the Customer Says it is 6153. Quality and Cost are a Sum Not a

Difference 6154. Quality Requires Both Individual and Teamwork Zealotry 6155. Quality is a Way of Management 6156. Quality and Innovation are Mutually Dependent 6167. Quality is an Ethic 6168. Quality Requires Continuous Improvement 6169. Quality is the Most Effective, LeastCapital Intensive Route to Productivity 61710. Quality is Implemented With a Total System Connected with Customers and Suppliers 617

GMPs 618Quality from the Manufacturer's Point of View 618Quality from the Customer's Point of View 620

Contents xxiii


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 637

Gregory BobrowiczDogma and Reality 637

Dogma 637Reality 638Scope 638

Evidence 639FDA Documents Encourage Creative Reading of the Regulation 639Language of the Different Paradigms 639Paperwork Without Value 641

Training 641FDA Inspections 641Industry Training Programs 642Conclusion 643

Audits 644FDA Inspections 644Industry Audit Programs 644Conclusion 646

Product Development Reports 647FDA Inspections 647Product Development Reports in Industry 647Conclusion 648

Deviations, Investigations, and CAPA 648FDA Inspections 648Deviation Programs in Industry 650Conclusions 651

Validation 652FDA Inspections 652Validation in the Industry 654

Contentsxxiv


Conclusions 655Other Examples 655

Causes 656Senior Management is Generally Inexperienced and Uninterested 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 Emphasize Effectiveness 659The FDA is Driven to Avoid Embarrassment and Criticism: 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 665James L. Vesper

Introduction 665Defining Terms 666Training as an Element of a Quality System 667

Employee Learning and Motivation (25 pts.) 670Employee 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 and Organizational 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


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
