VALIDATION OF ACTIVE PHARMACEUTICAL INGREDIENTS

Transcription

1 VALIDATION OF ACTIVE PHARMACEUTICAL INGREDIENTS Second Edition Ira R. Berry Daniel Harpaz Editors ###5 Health Group *> MS-GHOUF Company Your Enterprise Solution for Global Healthcare Knowledge Denver, Colorado

2 CONTENTS PREFACE 2001 xvii AUTHOR BIOGRAPHIES xix 1. INTRODUCTION 1 Daniel Harpaz GMP Concepts 2 Regulatory 3 FDA Site Inspections 4 References 7 2. THE LEGAL FRAMEWORK FOR THE REGULATION OF ACTIVE PHARMACEUTICAL INGREDIENTS 11 David F. Weeda, Arthur Y. Tsien, Neil F. O'Flaherty, and Robert A. Hahn The Regulatory Status of APIs 12 APIs and BPCs 12 APIs as "Drugs" 13 APIs as "New Drugs" or "New Animal Drugs" 14 API Adulteration 14 cgmp Noncompliance 15 Validation as Part of cgmps 16 Other Forms of Adulteration 19 API Misbranding 20 Mi

3 iv Validation of Active Pharmaceutical Ingredients API Inspections 21 History of API Inspections 21 Reasonable Inspections Under Section 374(a) 22 Scope of FDA Inspectional Authority over APIs 23 Inspection Priorities: Active Drug Substances Versus Excipients 25 Foreign Versus Domestic Plant Inspection 26 Other Inspection Issues 30 Enforcement Tools Against APIs 32 Administrative Tools 32 Judicial Tools 34 FDA Import/Export Authority over APIs 37 Drug Master Files for APIs 42 DMF Types 42 DMF Holder Obligations 43 Status of DMFs as Records 44 Conclusion 45 Notes 45 References THE LEGAL BASIS FOR VALIDATION 55 Irving L. Wiesen Current Good Manufacturing Practices 55 The 1962 Food and Drug Amendments 56 Challenges to the cgmps 59 FDA's Analysis of cgmps 59 Judicial Analysis of cgmps 61 "Open-Endedness" of the cgmp Framework 63 Failure to Comply with cgmps Constitutes Product Adulteration 65 Active Pharmaceutical Ingredient Standards 66 Validation 67 FDA's Validation Guideline of Validation of Active Pharmaceutical Ingredients 70 The Ban Laboratories Decision 70 Conclusion 76 Notes 76 References DRUG MASTER FILES 83 Arthur B. Shaw Regulatory Basis for DMFs 84 Guideline 84 Relationship Between Holder and Applicant 84 Filing and Referencing a DMF 85 Review of a DMF 87

4 Contents v Approval of DMFs 89 Types of DMFs 89 Manufacturing Performed at More Than One Site 91 Intermediates 93 Rereview of DMFs for APIs 93 Changing the Manufacturing Procedure in a DMF 95 Summary THE FDA's PERSPECTIVES ON ACTIVE PHARMACEUTICAL INGREDIENT MANUFACTURING, cgmp CONTROLS, AND VALIDATION 97 Edwin Rivera Martinez Development of the FDA's API GMP Draft Guidance 98 "What to Do" Versus "How to Do" in the FDA's API Guidance 100 cgmp Deficiencies Uncovered by the FDA's Inspections Abroad 101 Scope of the FDA's Draft API Guidance 105 Application of cgmps to API Processes 106 Defining and Identifying the Starting Material 107 API Process Validation 110 Defining and Identifying Critical Process Steps 113 Defining Critical Process Parameters 115 Types of Process Validation 116 Equipment Cleaning and Validation 118 Process Water 120 Review of Batch Production and Control Records 123 Reprocessing and Reworking 123 Impurity Testing and Impurity Profiles 124 Initiatives to Develop an Internationally Harmonized GMP Guidance for APIs 127 Conclusions 129 References DOMESTIC AND FOREIGN API MANUFACTURING FACILITY AUDITS AND FINDINGS 133 Peter D. Smith Quality Assurance Functions and Systems 133 Standard Operating Procedures 134 Batch Release Procedure 136 Deviation and Failure Investigations, Reports 136

5 vi Validation of Active Pharmaceutical Ingredients Reworking and Reprocessing 137 Change Control System 138 Annual Product Quality Reviews 139 Raw Materials Handling and Controls/Warehousing 140 Qualification 143 API Production Equipment 145 Equipment Cleaning 146 Commonly Found Problem Areas 146 Equipment Calibration 148 Labeling Controls 149 Recovered Solvents 149 Master Production and Control Records 150 Batch Production and Control Records 151 Personnel Training and Training Program 153 Quality Control Laboratory Operations 154 Common Adverse Observations 155 Research and Development (R&D) 160 Process Validation 161 Reference VALIDATION OF APIs: A CASE STUDY 163 Nirmal Khanna The FDA and the History of Validation 164 What Is Validation? 164 A Successful Validation Program 165 API Validation A Case Study 166 Manufacturing Operations 166 Quality Assurance Systems 167 Validation Program 168 Retrospective Reviews 169 Master Plan 169 Retrospective Review Effort 170 Concurrent/Prospective Validations 172 Master Plan 174 Validation Protocols 175 Summary Report 175 Cleaning Operations 176 Cleaning Validation Concurrent or Prospective Validation 178 Computer Control Systems 179 Concurrent Validation 179

6 Contents vii Executive Summary Concurrent/Prospective Validations 180 Validation File 181 Maintaining a "Validation State" 181 Concurrent or Prospective Validation Effort 182 Conclusions 184 Reference 185 Additional Reading 186 Acknowledgments 186 Appendices 7.1: What Is Concurrent Validation? What Is Prospective Validation? : Events and U.S. Regulations : SOPs Operations, IDEAL Corp : Batch Records A Validation Viewpoint A: Miscellaneous Activities Prospective Validation (Support Systems) B Miscellaneous Activities Prospective Validation (Process Equipment) C Miscellaneous Activities Prospective Validation (Computer System Validation) : Outline of a Typical Retrospective Protocol : Outline of a Typical Concurrent or Prospective Validation Protocol Key Instruments Used in OQ Activities A Retrospective Example B Prospective Example: Process Equipment, Train B (IQs, OQs) C Concurrent Example: Controlled Environment (IQ, OQ) D Concurrent or Prospective Example: Supreme Process (PQ) E Concurrent or Prospective Example: Cleaning F: Concurrent or Prospective Example: Micronization G: Concurrent Example: DCS Summary Report ACTIVE PHARMACEUTICAL INGREDIENT VALIDATION: AN OVERVIEW AND COMPARATIVE ANALYSIS 261 Max S. Lazar FDA Focus 262 Industry Reaction 262 Validation: A Comparison of Dosage Versus APIs 263 Development Documents 264 Considerations During Development 265 Technology Transfer 266 Change Control 266 Defined Critical Steps 267 Well-Defined Purification 267 Types of Validation 268 Retrospective Validation 268

7 viii Validation of Active Pharmaceutical Ingredients Prospective Validation 269 Concurrent Validation 269 The Future Horizon 269 References IMPURITIES IN DRUG SUBSTANCES AND DRUG PRODUCTS 271 Quality Stephen R. Byrn and Joseph G. Stowell A Typical USP Monograph 272 USP Descriptions of Impurities 273 Foreign Substances 273 Toxic Impurities 273 Ordinary Impurities 273 Other Impurities 274 Signal Impurities 274 Organic Volatile Impurities 274 Concomitant Components 275 ICH Documents on Impurities 275 Specifications 276 Qualification of Impurities 276 Analytical Procedures for Degradation Products or Drug-Excipient Reaction Products 278 Specification Limits for Degradation Products or Drug-Excipient Reaction Products 279 Impurities in Drug Products in Abbreviated New Drug Applications (ANDAs) 279 Validation 280 Impurity Issues Related to Manufacturing, Processing, or Holding Drug Substances (APIs) 282 Enantiomers as Impurities 285 Polymorphs as Unwanted Components 285 BACPAC 287 Summary and Conclusion 289 References INVESTIGATING PROCESS DEVIATIONS 293 Frank J. Golden Process Deviations 294 Regulatory Considerations 295 Process Deviation Principles 297 Problem Description 297 Classification of Deviation 297

8 Contents ix Examination of Data Available 298 Review Procedures Utilized 298 Materials Used 298 Suitability of Facilities 298 Suitability of Equipment 299 Employee Training 299 Extent of Deviation 300 Validation Impact 300 Equivalency 300 Testing Required 300 Regulatory Impact 301 Results of Investigation 301 Corrective Action 301 Preventive Actions 301 Conclusions 302 Documentation 302 Signatures and Approvals 302 Periodic Review 302 Investigating Quality Problems 302 Process Deviation Examples 304 Example Example Example References TECHNOLOGY TRANSFER: ACTIVE PHARMACEUTICAL INGREDIENTS 309 B. J. Evanoff and K. L. Hofmann, Jr. Preliminary Considerations 310 The Role of Marketing 310 Defining the Process 311 Categories of Technology Transfer 312 New Chemical Entities 312 Changes to Established Processes 312 Process Development Report 313 Organization for Technology Transfer 317 Technology Transfer Team 317 Intracompany Project 318 External Technology Transfer Project 319 Considerations for Plant Scale-Up 319 Raw Materials 320 Plant Equipment and Utilities 320 Process Control Parameters 321 Process Equipment 322 Cleaning Validation 323 Process Validation 323 Analytical Methods 324

9 x Validation of Active Pharmaceutical Ingredients Ancillary Issues 326 API Container/Closure 326 Stability 327 Regulatory Issues 327 Summary 327 References POSTAPPROVAL CHANGES TO BULK DRUG SUBSTANCES 329 Eric Sheinin, Eric Duffy, Kasturi Srinivasachar, and John Smith BACPAC I 331 Scope 331 Filing Mechanism 332 Assessment of Change 333 Manufacturing Site, Manufacturing Scale, and Equipment Changes 335 Specification Changes 336 Process Changes 336 BACPAC II 337 Scope 338 Principles of Equivalence 338 Filing Mechanisms 339 Types of Changes 339 Summary 339 Conclusion VENDOR QUALIFICATION AND CERTIFICATION 343 Ira R. Berry Definition of Terms 344 Purpose of Vendor Qualification and Certification 345 Qualification/Certification Procedure Overview 346 How to Qualify a Vendor 347 Certifying a Vendor 351 Monitoring a Vendor 352 Vendor Audits 353 Philosophy of Pharmaceutical GMP Compliance 354 Documentation 354 Quality Assurance Program 355 Standard Operating Procedures Manual 355 Change Control Procedure 356 Personnel Training 356 Out-of-Specification Data Handling/Failure Investigation 356 Written Master Production and Control Records with In-Process Controls 357

10 Contents xi Reprocessing and Rework 357 Process Validation Program 357 Cleaning Validation 358 Analytical Methods Validation 358 Stability Program 358 Control of Suppliers 358 Distribution Records 359 Recall Procedure and Capability 359 Product Complaint Handling Procedure 359 Returned Goods Procedure 359 Safety Program 360 Current Drug Master File 360 Internal/External Audit Program 360 Calibration Program 361 Facilities and Equipment Preventive Maintenance Program 361 Materials and Labeling Control 362 The Auditors 362 Be Prepared 363 Some Common Plant Issues 363 Preparation Aids 365 References QUALITY ASSURANCE SYSTEMS 369 Fred C. Radford Definition and Decision 375 FDA Requirements Are Central 380 The Inspection Focus 381 Beyond the Manufacturing Instruction 383 Tangent Considerations 385 Plan, Do, Study, Act 388 References CLEANING FOR ACTIVE PHARMACEUTICAL INGREDIENT MANUFACTURING FACILITIES 397 William E. Hall Regulatory Requirements 397 Multiple Use Versus Dedicated Equipment 399 The Unique Nature of APIs 401 Multiple Levels Approach to Cleaning 402 Level 1 Cleaning 402 Level 2 Cleaning 402 Level 3 Cleaning 402

11 xli Validation of Active Pharmaceutical Ingredients Level 4 Cleaning 403 Philosophy of Cleaning 403 Nature of Contaminants 404 Product Groupings and Selection of a Worst Case 405 Cleaning Techniques 406 Sampling 407 Analytical Methods 409 Visual Examination 411 Analytical Techniques for Biotechnology Cleaning Validation 412 High Performance Liquid Chromatography 412 Microbial and Endotoxin Testing 413 Total Organic Carbon Analysis 413 Limits and Acceptance Criteria 414 Calculation of Limit Based on Smallest Therapeutic Dose 416 Calculation of Limit Based on Toxicity 417 Cleaning Validation Documentation 420 Protocols 421 Final Validation Report 425 Emerging Trends in Cleaning in the Pharmaceutical Industry 425 References VALIDATION OF STERILE APIs 429 Robert V. Kasubick Regulatory Aspects 431 Validation Protocol Format 431 General Manufacturing Process Description 432 Facility 432 Room Classification 434 Airflow Patterns and Pressure Differentials 435 Personnel Row 437 Material Flow 439 Support Systems 439 Water Systems 439 Air Systems 442 Equipment Sterilization 444 Clean Steam System 445 Filtration Systems 445 Heat Exchangers 447 Vacuum Systems 447 Manufacturing Process Validation 447 Validation Maintenance 449 References 449

12 Contents xiii 17. VALIDATION OF BIOTECHNOLOGY ACTIVE PHARMACEUTICAL INGREDIENTS 451 Rob Murphy and Robert J. Seely Master Planning 452 Equipment Qualification 453 Installation Qualification 453 Operational Qualification 454 Performance Qualification 454 Cleaning Validation 454 Equipment Sterilization 456 Process Validation 457 Timing 458 Process Variables 459 Impurity Profile 462 Additional Studies 463 The Final Package 463 Process Monitoring 464 Change Control 466 Revalidation 468 References 469 Appendix 17.1: Process Validation Protocol PV MICROBIOLOGICAL ATTRIBUTES OF ACTIVE PHARMACEUTICAL INGREDIENTS 475 Karen link McCullough and John Shirtz Preliminary Issues 478 Standard Operating Procedures 478 Microbiological Quality of Water 479 Validation/Qualification and Maintenance of the Water Purification, Storage, and Distribution System 482 Bioburden 484 API Processing 486 Facility and Equipment Considerations for the Production of Sterile APIs 488 Use of Isolator Systems to Minimize Human Contact with Sterile APIs 493 Containment 493 Monitoring the Environment in API Manufacturing Facilities 494 Monitoring of Classified and Critical Areas: Manufacturing and Support for Products and APIs Produced Aseptically 495 Monitoring of Unclassified Areas: Nonsterile Dosage Forms and APIs 496 Site Selection and Frequency of Testing 496

13 xiv Validation of Active Pharmaceutical Ingredients Microbiological Monitoring of Air 49 7 Microbiological Monitoring of Surfaces 499 Microbiological Monitoring of Operators 501 Trending Data Obtained from Environmental Monitoring 501 Microbiological Testing of Finished Sterile APIs 502 Sterility Testing 502 Testing of APIs for the Presence of Endotoxin 503 Endotoxin Limits 506 Summary 510 Glossary 511 References EXCIPIENTS: FACILITY, EQUIPMENT, AND PROCESSING CHANGES 519 Irwin Silverstein Identification of Significant Process Change 524 Facility 531 Equipment 534 Processing 537 Conclusion 540 Glossary 541 References API TERMINOLOGY AND DOCUMENTATION 543 Robert A. Nash Active Pharmaceutical Ingredient 548 Compendial Standards 549 Chiral APIs 550 Chemical Control Regulations 551 The Validation of APIs 553 Process Validation Options 554 Process Description 554 Impurity Profile 559 Retrospective Validation 559 Revalidation 560 Change Control 560 Bulk Actives Postapproval Changes 561 Reprocessing 562

14 Contents xv Validation Master Plan 563 Cleaning Validation 563 Explosion Suppression Validation 566 Validation Documentation 566 Recommended Reading 569 References 570 INDEX 573