Process Validation in Manufacturing Biopharmaceuticals: Guidelines, Current Practices, and Industrial Case Studies

Preface......Page 10
Editors......Page 14
Contributors......Page 16
Contents......Page 20
1.1 Introduction......Page 24
1.2 Current Validation Citations/Problems......Page 25
1.3.1 Today......Page 30
1.3.2 Tomorrow......Page 31
References......Page 33
Applications of Failure Modes and Effects Analysis to Biotechnology Manufacturing Processes......Page 36
2.2 Risk Analysis Methods......Page 37
2.3 Two Applications of FMEA......Page 38
2.4 FMEA Worksheet......Page 39
2.5.1 Severity......Page 42
2.5.2 Occurrence......Page 45
2.6 Example of FMEA Applied to Process Transfer......Page 46
2.7 Next Steps......Page 50
References......Page 51
Process Characterization......Page 54
3.1 Introduction......Page 55
3.3 Precharacterization Work......Page 56
3.3.1 Historical Data Review and Risk Assessment......Page 57
3.3.2 Scale-Down Model Qualification......Page 62
3.3.2.1 Scaling Down Fermentation and Cell Culture......Page 66
3.3.2.2 Analytical Methods Qualification......Page 68
3.4.1 Impurity Clearance......Page 69
3.4.2 Screening Experiments......Page 70
3.4.3 Interactions between Key Parameters (The Next Round of Process Characterization Experiments)......Page 77
3.4.3.1 Combining Variables......Page 81
3.4.4 Key and Critical Parameters......Page 83
3.4.5 Setting Acceptance Criteria for In-Process Performance Parameters: Using Feed Quality as a Process Input......Page 84
3.6 Future Challenges......Page 87
References......Page 89
Scale-Down Models for Purification Processes: Approaches and Applications......Page 92
4.1 Introduction......Page 93
4.2.2 Evaluation of Scale-Up before Scale-Down......Page 96
4.2.4 Scale-Down Model of an Entire Process Train......Page 97
4.3.1.1 Description of Chromatographic Techniques......Page 98
4.3.1.2 General Scale-Down Principles and Parameters......Page 99
4.3.1.3 Primary End Points......Page 102
4.3.1.4 Scale-Down Validation of Expanded Bed Chromatography......Page 105
4.3.2 Protein Modification Reactions......Page 108
4.3.2.1 Hydroxylamine Cleavage Reactions......Page 109
4.3.2.3 PEGylation......Page 113
4.3.3.1 Description of Precipitation Techniques......Page 114
4.3.3.2 General Scale-Down Principles and Critical Parameters......Page 115
4.3.3.3 Primary End Points......Page 119
4.3.4.1 Description of Microfiltration Techniques......Page 120
4.3.4.2 General Scale-Down Principles and Critical Parameters......Page 121
4.3.4.3 Primary End Points......Page 123
4.3.5.1 Description of Ultrafiltration Techniques......Page 124
4.3.5.2 General Scale-Down Principles and Critical Parameters......Page 125
4.3.5.3 Primary End Points......Page 127
4.3.6.1 Description of Centrifugation Techniques......Page 128
4.3.6.2 General Scale-Down Principles and Critical Parameters......Page 129
4.3.6.3 Primary End Points......Page 130
4.3.7.2 General Scale-Down Principles and Critical Parameters......Page 131
4.3.7.3 Primary End Points......Page 133
4.3.8.1 Description of Unit Operation......Page 134
4.3.8.2 General Scale-Down Principles and Critical Parameters......Page 135
4.3.8.3 Primary End Points......Page 137
4.3.8.4 Example of a Scale-Down Validation of an NFF Virus Removal Filtration System......Page 138
4.4 Evaluation of Suitability of Scale- Down Systems as Models of Full- Scale Operation......Page 140
4.5 Application of Scale-Down Systems......Page 144
4.5.1.1 Assessment and Validation of Impurity Removal......Page 145
4.5.1.2 Process Robustness......Page 147
4.5.1.4 Resin Cleaning, Reuse, and End-of-Life Validation......Page 148
4.5.1.5 Hold Times for Cell Culture Harvest Samples......Page 150
4.5.1.6 Selection of Control Ranges for Cell Culture Processes......Page 151
4.5.2.1 Qualify Secondary Vendors for Raw Materials......Page 152
4.5.2.3 Evaluate Lot-to-Lot Variability of Raw Materials and Troubleshoot Process Deviations......Page 153
4.6 Summary......Page 154
References......Page 155
Adventitious Agents: Concerns and Testing for Biopharmaceuticals......Page 166
5.1 Introduction......Page 167
5.2 Viruses......Page 169
5.2.2 Cell Banks......Page 171
5.2.3 Unprocessed Bulk......Page 172
5.2.4 Summary of Viral Safety Issues......Page 177
5.3.1 Assays......Page 178
5.3.2 Cell Banks and Unprocessed Bulk......Page 179
5.3.3 In-Process/Raw Materials......Page 180
5.3.4 Final Product......Page 181
5.4 Mycoplasma......Page 182
5.4.1 Test Methods......Page 183
5.5 Transmissible Spongiform Encephalopathies......Page 184
5.6 Summary......Page 186
References......Page 187
Life Span Studies for Chromatography and Filtration Media......Page 192
6.1 Introduction......Page 193
6.2.1 Position of Step in Purification Process......Page 196
6.2.2 Nature of the Feed Stream......Page 197
6.2.3 Mode of Chromatography......Page 198
6.2.5 Column Maintenance......Page 199
6.2.6 Column Packing and Attrition......Page 201
6.2.8 Quality of Raw Materials......Page 202
6.3.1 Small-Scale Models......Page 203
6.3.2 Parameters to Measure......Page 207
6.3.2.1 Chromatographic Profile......Page 208
6.3.2.3 Clearance of Impurities......Page 210
6.3.2.6 Chromatography Media Properties......Page 211
6.3.2.7 Blank Runs......Page 212
6.3.2.8 End of Media Lifespan Testing......Page 213
6.3.3 Concurrent Validation at Pilot or Full Scale......Page 214
6.4.1 Small-Scale Models......Page 216
6.4.2.1 Normalized Water Permeability (NWP)......Page 218
6.4.2.4 Filter Integrity Measurements......Page 219
6.4.2.6 Filter Analysis......Page 220
6.5 Conclusions......Page 221
References......Page 223
Validation of a Filtration Step......Page 228
7.1 Filtration Validation Overview......Page 230
7.2 Scales of Validation......Page 233
7.3.1 Bacterial Retention......Page 234
7.3.2 Bubble Point Integrity Test......Page 236
7.3.3 Diffusion Integrity Test......Page 238
7.3.4 Integrity Test Validation......Page 240
7.3.5 Postuse Integrity Testing and Product Bubble Point Test......Page 242
7.3.6 Grow-Through and Endotoxin......Page 245
7.3.7 Adsorption......Page 246
7.3.8 Extractables......Page 248
7.3.9 Thermal and Hydraulic Stress Resistance......Page 253
7.4.1 Retention Ratings......Page 254
7.4.3 Toxicity and Fiber Shedding......Page 255
7.4.5 Extractables......Page 256
7.4.6 Product Stability......Page 257
7.4.7 Processing Considerations......Page 258
7.5.1 Definitions and Regulatory Requirements......Page 259
7.5.2 Virus Spiking Studies......Page 262
7.5.3 Integrity Testing of Viral Clearance Filters......Page 267
7.5.4 Other Considerations......Page 269
7.6.1 Overview......Page 270
7.6.3 Pressure Profiles......Page 272
7.6.4 Retention......Page 273
7.6.6 Chemical Compatibility......Page 274
7.6.7 Bioburden and Endotoxin......Page 275
7.6.9 Other Considerations......Page 276
7.6.10 Bacterial Cell Harvest and Lysate Clarification......Page 277
7.6.12 Protein Concentration and Diafiltration......Page 278
7.7.1 Cleaning Considerations......Page 280
7.7.2 Chemical Compatibility......Page 282
7.7.3 System Design......Page 283
7.7.4 Cleaning Specifications......Page 284
7.7.5 Membrane Reuse......Page 286
7.7.6 Clean-Water Flux......Page 287
7.7.7 Integrity Testing......Page 288
7.8.1 Swab Testing......Page 289
7.8.2 Solvent Sampling......Page 290
7.8.4 Assays......Page 291
7.8.5 Acceptable Residue Limits......Page 292
7.9 Conclusion......Page 293
References......Page 295
Analytical Test Methods for Biological and Biotechnological Products......Page 300
8.1 Analytical Characterization of Biomolecular Products......Page 301
8.2 Physiochemical Profile of Biotechnological/Biological Products......Page 303
8.3 Analytical Methods Used in Production Operations......Page 305
8.3.1 Raw Material Methods......Page 306
8.3.2 In-Process Methods......Page 307
8.4 Methods Used for Product Characterization, Release, and Stability Testing......Page 309
8.4.1 QC Release Tests - Thumbs Up or Thumbs Down?......Page 312
8.4.2 Stability Tests - Looking for Ghosts with Metal Detectors?......Page 313
8.5 Methods Used for Comparability Assessment......Page 316
8.6 Development, Qualification, and Validation of an Analytical Method......Page 318
8.7 Typical Assay Development Strategy......Page 319
8.8 Conclusion......Page 340
References......Page 342
Facility Design Issues - A Regulatory Perspective......Page 350
9.1 Introduction......Page 352
9.2 Regulatory Requirements......Page 353
9.3.1 Chemistry Manufacturing and Controls......Page 355
9.3.2 Establishment Description......Page 357
9.4.1 General Considerations......Page 358
9.4.1.1 Cell Inoculum Suites......Page 359
9.4.1.2 Fermentation/Harvest Areas......Page 360
9.4.1.4 Bulk Filtration Areas......Page 361
9.4.1.5 Support Areas......Page 362
9.4.2.1 Closed Systems......Page 364
9.4.2.3 Good Large-Scale Practice......Page 365
9.5 Utilities: Design and Operation......Page 366
9.5.1.2 Water Purification Systems......Page 367
9.5.1.4 Storage and Distribution Systems......Page 369
9.5.1.5 Materials of Construction......Page 370
9.5.2 Heating Ventilation and Air-Conditioning (HVAC) Systems......Page 371
9.5.2.2 Recirculated versus Once-Through Systems......Page 373
9.5.2.4 HVAC System Qualification and Monitoring......Page 374
9.6.1 Cleaning Procedures......Page 375
9.6.2 Cleaning Agents and Equipment......Page 376
9.6.4 Recommissioning Activities......Page 377
9.7.1 Nonviable Particulate Monitoring......Page 378
9.7.2 Airborne Viable Microbial Monitoring......Page 379
9.7.3 Contact Plates and Swabs......Page 380
9.7.4 Temperature and Humidity Monitoring......Page 381
9.7.6 Water Monitoring......Page 382
9.7.7 Data Management and Trending......Page 384
9.8.1 Types of Multiproduct Facilities......Page 386
9.8.2 Design Considerations......Page 388
9.8.3 Product Changeover Procedures......Page 390
9.8.4 Cleaning Validation......Page 391
9.8.4.1 Goals of a Cleaning Validation......Page 392
9.8.4.2 Common Inspectional Pitfalls......Page 396
9.8.5 Introduction of New Products into a Multiproduct Facility......Page 397
9.9 Contract Manufacturing......Page 399
9.9.1.1 Compliance Issues......Page 400
9.10.1 History and Statutory Requirements for Facility Inspections......Page 404
9.10.2 Current Focus of Inspections......Page 406
9.10.2.1 Process Validation......Page 407
9.10.2.2 Contamination and Cross- Contamination......Page 408
9.10.2.3 Quality Assurance Functions......Page 409
9.11 Summary......Page 410
REFERENCES......Page 411
Validation of Computerized Systems......Page 418
10.2 Historical Overview......Page 420
10.3 Creating a Corporate Culture for Computerized Systems Compliance......Page 429
10.3.1 Develop a Global Computing Vision with Short-Term and Long-Term Milestones, and Implement Technologies to Fully Automate All Functional Areas in Accordance with the Firm’s Global Computing Vision......Page 430
10.3.3 Train All Personnel to Shift Their Mental Paradigm from a Paper-Based World to Thinking in Terms of Paperless Operations, and Build Internal Expertise in Computerized Systems Compliance......Page 431
10.3.4.1 Centralized/Distributed Quality Model......Page 433
10.3.4.2 Centralized/Distributed IT/IS Model......Page 435
10.3.5 Centralize and Automate Quality Systems Support Operations......Page 436
10.3.5.1 Document Management......Page 437
10.3.5.4 Computerized Systems Validation......Page 438
10.3.5.5 Change Control......Page 439
10.3.5.7 Security......Page 440
10.3.5.8 Electronic Signatures Management......Page 441
10.3.6 Qualify All Networks......Page 442
10.3.7 Use Technology to Facilitate Efficient and Effective Communications between Centers of Knowledge......Page 443
10.4 Validation of Individual Computerized Systems......Page 446
10.4.1 Risk Assessment and Management......Page 450
10.4.2 Planning Phase/Personnel Responsibilities for CSV......Page 452
10.4.2.1 System Owner and System Users......Page 453
10.4.2.3 Quality Assurance and Compliance......Page 454
10.4.3 System Specification Phase......Page 455
10.4.5 Implementation and Testing Phase......Page 460
10.4.5.1 Validation Summary Report......Page 463
10.4.5.2 System Maintenance Phase......Page 464
10.4.5.3 System Retirement Phase......Page 465
Definitions......Page 466
References......Page 470
Process Optimization and Characterization Studies for Purification of an E. coli-Expressed Protein Product......Page 474
11.1 Introduction......Page 475
11.2 An Approach to Process Development......Page 476
11.2.2 Process Characterization Studies......Page 477
11.3.1 Process Chromatography Procedures......Page 478
11.3.2.3 Anion-Exchange HPLC (AE HPLC)......Page 480
11.3.2.4 Cation-Exchange HPLC (CE HPLC)......Page 481
11.4 Process Optimization Studies......Page 482
11.5 Process Characterization STudies......Page 485
11.6 Summary......Page 488
Acknowledgment......Page 489
References......Page 490
Validation of the ZEVALIN® Purification Process - A Case Study......Page 492
12.1 Introduction and Scope......Page 493
12.2.1 Outline and Definitions......Page 495
12.2.2 Operating Parameter Ranges......Page 497
12.2.3 Small-Scale Characterization Study Results......Page 498
12.2.4 Small-Scale Process Validation Studies......Page 502
12.2.5.2 Hydrophobic Interaction Chromatography......Page 503
12.2.5.3 Nanofiltration......Page 505
12.3.1 Introduction......Page 507
12.3.2.1 Low-pH Treatment Subsequent to PROSEP A Column Chromatography......Page 510
12.3.3.2 Chromatographic Viral Reduction......Page 511
12.3.4 Summary......Page 514
12.3.5 Estimating the Viral Load for the Process......Page 517
12.4 Chromatographic Adsorbent Use Life......Page 518
12.5.1 Process-Related Impurity Removal......Page 521
12.5.1.1 Host Cell Protein and DNA......Page 522
12.5.2.1 Human Recombinant Insulin and Methotrexate......Page 524
12.5.2.2 Urea......Page 525
12.5.2.3 Endotoxins......Page 526
12.5.2.4 Protein A......Page 529
12.5.4 In-Process Hold Times......Page 530
12.6.1 Compatibility......Page 532
12.6.2 Extractables......Page 535
12.7 Conclusions......Page 539
References......Page 543
Process Validation of a Multivalent Bacterial Vaccine: A Novel Matrix Approach......Page 546
13.2 Worst-Case Challenges......Page 547
13.3 Family and Matrix Approaches to Process Validation......Page 548
13.4 Case Study: Matrix Validation of PNEUMOVAX®23, a 23-Valent Polysaccharide-Based Pneumococcal Vaccine......Page 550
13.4.1 Process Development......Page 551
13.4.2 Matrix Validation Plan......Page 553
13.4.3 Regulatory Buy-In and Study Execution......Page 560
13.4.4 Conclusions......Page 562
Acknowledgments......Page 563
References and Notes......Page 564
Viral Clearance Validation: A Case Study......Page 568
14.1 Strategy and Planning......Page 569
14.2 Logistical Considerations......Page 572
14.3 Protocol Development and Execution......Page 574
14.4.2 Laboratory-Scale Process Evaluation......Page 576
14.4.3.3 Heat......Page 578
14.4.3.5 Chromatography Step #2......Page 580
14.4.4 General Comments on Viral Clearance......Page 582
14.5 Conclusion......Page 583
References......Page 585
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