Biopharmaceuticals, an Industrial Perspective

Front Matter......Page 1
Contributors......Page 3
Acknowledgements......Page 5
Preface......Page 6
Index......Page 0
Table of Contents......Page 8
1. Biopharmaceuticals, An Overview......Page 11
1. Development of the Pharmaceautical Industry......Page 12
1.1 The Birth of the Biopharmaceutical Industry......Page 13
1.2 Biopharmaceuticals; Market Value......Page 15
2. Sources and Manufacture of Biopharmaceutical Products......Page 16
2.1 Upstream Processing......Page 17
2.2 Downstream Processing......Page 18
3.1.1 Blood Clotting Factors......Page 20
3.1.2 Anticoagulants......Page 21
3.1.3 Thrombolytic Agents......Page 22
3.2 Therapeutic Enzymes......Page 23
3.3 Recombinant Therapeutic Hormones......Page 24
3.4 Haemopoietic Growth Factors......Page 28
3.5 Interferons and Interleukins......Page 30
3.6 Recombinant Vaccines......Page 34
3.7 Monoclonal Antibody Based Products......Page 35
4.1 Gene Therapy......Page 38
5. Future Trends......Page 40
References......Page 41
2. Abciximab: The First Platelet Glycoprotein IIb/IIIa Receptor Antagonist......Page 45
1.1 The GP IIb/IIIa Receptor as a Target for Antithrombotic Therapy......Page 46
1.2 Development of Abciximab......Page 47
2.1 Binding Studies......Page 49
2.2 Dose-Response Studies......Page 51
2.3.1 Abciximab Alone......Page 52
2.3.2 Abciximab Combined with Fibrinolytic Agents......Page 53
2.5.2 Inhibition of Inflammatory Processes......Page 54
3.1 Dose-Response Studies in Humans......Page 55
4.2 Early Studies......Page 59
4.3.1 Methods......Page 60
4.3.2 30-Day Efficacy Results.......Page 61
4.3.3 30-Day Safety Results.......Page 62
4.3.4 6-Month Efficacy Results.......Page 63
4.3.5 3-Year Efficacy Results.......Page 64
4.3.6 Subgroup Analyses.......Page 65
4.3.7 Anticoagulant Effect of Abciximab.......Page 66
4.5 The EPILOG Trial: Low-Risk and High-Risk Patients......Page 67
4.5.2 30-Day Efficacy Results.......Page 68
4.5.3 30-Day Safety Results in Contrast to EPIC Results.......Page 69
4.6 Unstable Angina: The CAPTURE Trial......Page 70
4.6.2 Efficacy Results.......Page 71
4.7.2 30-Day Results.......Page 73
4.8.1 GUSTO-III.......Page 74
4.9.3 TIMI-14.......Page 75
5. Conclusions: Current Indications and Future Prospects......Page 76
References......Page 77
3. Recombinant Coagulation Factor IX (Benefix)......Page 83
1. Introduction......Page 84
2. Mechanism of Action......Page 85
3. Development of the Production Cell Line......Page 86
3.1 Preparation of the rFIX Coding Sequence......Page 88
3.2 Cell Line Development......Page 89
3.4 Preparation of the PACE-SOL Coding Sequence......Page 90
4.1 Characterization of the Cell Banks and End-of-Production Cells......Page 91
4.2.2 Growth Rate......Page 92
4.2.3 Cellular Productivity......Page 93
4.2.5 Characterization of Expression Vectors and Transcripts......Page 94
4.3 Evaluation of Genotypic and Phenotypic Stability......Page 95
5.2.1 Ultrafiltratiod Diafiltration......Page 97
5.2.4 Ceramic Hydroxyapatite Purification......Page 98
5.3 Product Formulation......Page 99
6.1 Primary Structure and Posttranslational Modifications......Page 100
6.3 Specific Activity......Page 102
6.4 Purity......Page 103
7.1.1 Identity......Page 104
7.1.3 Potency......Page 106
7.2.2 Purity......Page 107
7.2.5 Quality......Page 108
8. Preclinical Testing......Page 109
9.2 Efficacy in Surgery......Page 110
9.3 Safety......Page 111
10. Registration Strategy......Page 112
Biography......Page 114
References......Page 115
1. Introduction......Page 119
1.1 Producer Cell Line......Page 121
1.3 Patent Issues......Page 122
2. Preclinical Studies......Page 123
3. Clinical Trial Findings......Page 124
5. Summary of Dossier Preparation and Experience of Getting it Through Regulatory Agencies......Page 127
6. Additional Technical/Business Matters......Page 128
Acknowledgements......Page 129
1. Introduction......Page 134
2.2 Gene Cloning......Page 136
2.3 Construction of the Expression Vector and Selector Plasmid......Page 137
3. Production and Purification of Recombinant FSH......Page 138
4. Characterisation: Purity and Identity......Page 139
4.2 Identity......Page 140
5.2.2 In Vivo Studies......Page 141
5.3.1 Introduction......Page 142
5.3.2 Single-Dose Studies......Page 143
5.3.3 Multiple-Dose Studies......Page 144
5.4.1.1 Pilot Efficacy Study in IVF......Page 145
5.4.1.2 Pivotal Trial......Page 146
5.4.1.3 Supportive Trials......Page 148
5.4.2 Ovulation in Clomiphene Resistant Normogonadotropic Anovulatory Women......Page 149
5.5 Discussion of Findings in the Development......Page 151
6. Quality Control......Page 152
7. Final Product Formulation and Format......Page 153
8. Conclusion......Page 154
References......Page 155
1. Introduction......Page 158
1.1 Biotechnology Leading to Insulin Lispro......Page 160
1.2 Manufacturing Process for Insulin Lispro......Page 165
1.3 Toxicopharmacologic Effects......Page 166
1.4 Reproduction and Teratology Studies......Page 168
1.5.1 Pharmacokinetics and Glucodynamics......Page 169
1.5.2 Global Registration Studies......Page 170
1.5.3 Insulin Lispro In Continuous Subcutaneous Infusion Therapy......Page 171
1.5.5 Paediatric Use......Page 172
1.6 Summary......Page 173
References......Page 174
1. Multiple Sclerosis and Interferon Beta-1B......Page 181
2. Clinical Trials......Page 183
3. Product Approval......Page 184
4. Adverse Effects......Page 185
5. Mode of Action......Page 187
Biography......Page 190
References......Page 191
1. Introduction......Page 193
2.1 Molecular Structure......Page 194
2.3 Molecular Weight......Page 195
3.2 The Open-Artery Theory and Thrombolytic Therapy......Page 196
3.3 Problems with First- and Second-Generation Thrombolytics......Page 197
3.4 Profile of the Ideal Thrombolytic......Page 198
4.1 Analysing Structure-Function Relationships Within the t-PA Molecule......Page 199
5. Comparison of the Biochemical Properties of Reteplase and Alteplase......Page 200
5.1 Cleavage by Plasmin......Page 201
5.4 Inhibition by PAI-1......Page 202
5.5 Affinity for Fibrin and Lysine......Page 203
5.6 Expression of Reteplase in E. Coli......Page 204
6.1 Clot Lysis in Vitro: Static Model......Page 205
6.2 Dynamic Plasma Clot Lysis Model......Page 206
6.3 Clot Penetration Studies in Vitro......Page 207
6.6 Animal Pharmacokinetics......Page 208
7.1.1 Healthy Subjects......Page 209
7.2.2 Following AMI......Page 210
8. Clinical Data......Page 211
8.2 GRECO-DB......Page 213
8.4 RAPID-2 Study......Page 214
8.6 GUSTO-III Trial......Page 215
8.7 Safety Profile of Reteplase......Page 216
9.2 Relative Contraindications (61)......Page 217
10.2.1 Organoleptic Characteristics......Page 218
10.2.7 Stability......Page 219
Biography......Page 220
References......Page 221
1. Introduction to Biopharmaceuticals......Page 225
2. Why is Stabilisation Important?......Page 226
3. Strategies for Stability Evaluations......Page 227
4.1.1 Unfolding......Page 228
4.1.2 Aggregation and Precipitation......Page 229
4.1.3 Adsorption......Page 230
4.2.1 Deamidation......Page 231
4.2.2 Oxidation......Page 232
5. Overview of Production Processes for Proteins......Page 233
6.2 Bulk Drug Substance......Page 235
6.3.1 Storage Conditions......Page 236
6.3.2 Storage Containers......Page 237
7.1.1 Clinical Considerations......Page 238
7.1.2 Regulatory Considerations......Page 239
7.2.1 Solution Stabilisation......Page 240
7.2.1.1 pH Stabilisation......Page 241
7.2.1.3 Stabilisation Through Non-Specific Interactions......Page 242
7.2.1.4 Other Stabilisers and Additives for Solution Formulations......Page 243
7.2.2.1 Stabilisation Within a Glassy Matrix......Page 244
7.2.3 Stabilisation in Novel Drug Delivery Systems......Page 246
7.3.1 Shear Damage......Page 247
7.3.3 Adsorptive Losses......Page 249
9. Conclusion......Page 252
References......Page 253
10. Patent Law for Biopharmaceuticals......Page 257
1.1 Natural Product Patents......Page 258
2.1 Factor VIII Litigation......Page 259
2.2 Erythropoietin Litigation......Page 260
3.1 Nerve Growth Factor Case......Page 261
3.2 Genentech\'s UK patent 2,119,904 on Tissue Plasminogen Activator (t-PA)......Page 262
3.4 The Erythropoietin Litigation (Further Developments)......Page 263
4. The Enabling Disclosure Requirement......Page 266
4.1 Erythropoietin in the European Patent Office (Appeal case T412/93)......Page 267
4.2 Recombinant Factor VII Patent......Page 268
5. Therapeutic Antibodies......Page 269
6. Patent Infringement......Page 271
6.1 Genentech v Wellcome Foundation and Genetics Institute (1990)......Page 272
7. Issues for the Future......Page 274
References......Page 275
11. The Development of New Medicines: An Overview......Page 276
1. Discovery of New Medicines......Page 277
1.2 Toxicology Testing......Page 278
1.4 Formulation Development......Page 280
2. From Animals to Humans......Page 281
2.1 Clinical Trial Design......Page 283
2.2 First Clinical Trials in Patients......Page 285
2.3 Surrogate Markers......Page 286
2.4 Phase 3 Clinical Trials......Page 287
3. Regulatory Approval......Page 288
3.1 Marketing......Page 289
3.2 Phase 4 Clinical Trials......Page 290
4. Pharmacoeconomics......Page 291
5. Pharmacovigilance......Page 292
7. Conclusion......Page 293
References......Page 294
1. General Introduction......Page 295
1.2 The European Commission and European Law......Page 296
1.3 Pharmaceutical Law within the EU......Page 298
1.4 The Rules Governing Medicinal Products in the European Union......Page 300
2.1 Structure and Role of the EMEA......Page 303
2.2 Centralized Procedure for Marketing Authorization Applications......Page 305
2.3 Mutual Recognition......Page 307
2.5 Additional EMEA Activities......Page 309
3. New Centralized System......Page 312
4. Conclusion......Page 315
References......Page 316
1. Introduction......Page 317
2.1 The Validation Master Plan (VMP)......Page 318
2.6 Change Control......Page 319
2.13 Retrospective Validation......Page 320
3.1 Design Qualification (DQ)......Page 321
3.2 Installation Qualification (IQ)......Page 322
3.3 Operational Qualification (OQ)......Page 323
3.4 Performance Qualification (PQ)......Page 324
3.6 Methods Validation......Page 325
3.7 Cleaning Validation......Page 326
3.8 Computerised Systems Validation......Page 327
4.1 Procurement......Page 328
4.3 Reviewing Computer System Documents for Compliance with Life Cycle Requirements......Page 329
4.5 Turnover Package......Page 330
4.7 Installation and Construction......Page 331
4.9 Validation Protocols......Page 332
4.12 Gap Analysis......Page 334
4.15 Action Plans......Page 335
5. Biopharmaceutical Facility Characteristics......Page 336
5.2 Sterility......Page 337
5.5 Clean-In-Place (CIP) and Steam-In-Place (SIP)......Page 338
5.6 Utilities......Page 339
5.8 Automation......Page 340
References......Page 341
14. Validation of Biopharmaceutical Chromatography Systems......Page 342
2.1 Typical Processing Steps......Page 343
2.3 Typical Control System......Page 344
2.5 Support Operations......Page 345
2.6 Design Considerations......Page 346
3.1 Prospective and Retrospective Validation......Page 347
3.2 Validation Master Plan......Page 348
3.4 Change Control......Page 350
3.5.2 Control Systems......Page 351
3.7 Design Qualification (DQ)......Page 352
3.7.2 Control System......Page 353
3.8.1 Process Equipment......Page 354
3.10 Operational Qualification......Page 355
4. Summary......Page 357
References......Page 358
Appendix 1: Methods for the Determination of Column Quality Parameters......Page 360
Appendix 2: A Typical Document Matrix......Page 363
1. Introduction......Page 368
2.1.2 Water for Injection......Page 369
3.1 Deep Bed Filtration......Page 370
3.3 Water Softening and Deionisation......Page 371
4.1 Reverse Osmosis......Page 372
5.1 Materials of Construction......Page 373
5.2 Holding and Distribution Systems......Page 374
6.2 Installation Qualification......Page 377
6.4 Performance Qualification......Page 379
6.5 Validation Approach for a New System......Page 381
6.5.1 System Description......Page 382
6.5.4 Operational Qualification......Page 383
6.6.1 System Description......Page 384
6.6.2 System Audit......Page 385
6.6.3 System Review and Sampling......Page 386
6.6.5 Mechanical Modifications......Page 389
7. Conclusions and Recommendations......Page 390
References......Page 391
1. Introduction......Page 393
2.1 Development......Page 395
2.3 CD-ROM......Page 397
3. Information Needs of the Biopharmaceutical Industry......Page 398
3.1 What is Contained in a Bibliographic Database?......Page 399
3.2.1 Define the Search or Information Need......Page 401
3.2.4 Choose Search Terms and Define a Search Strategy or Profle......Page 402
3.2.6 Print or Download the Results......Page 403
3.3 Examples of Database Services that Index Information of Interest to Biopharmaceutical Research:......Page 404
3.4 Some Pertinent Web Addresses......Page 405
4. The Future......Page 407
Biography......Page 408
1. Introduction......Page 409
2. Information in the Corporate Environment......Page 410
2.1 Lab Notebooks - What to Do With Them?......Page 411
2.2 Managing Multiple Sources of Information......Page 412
2.3 Groupware for Intranets and Extranets......Page 413
3.1 Brief History of Bioinformation on the Internet......Page 414
3.2.1 Public Sites......Page 415
3.2.1.2 Nucleic Acid and Protein Sequence Searching......Page 416
3.2.1.3 Public Domain Software......Page 418
3.2.1.4 Journals and Patents......Page 419
3.2.2 Commercial Sites......Page 421
3.3 Search Engines......Page 422
References......Page 423
1. Introduction......Page 424
3. Marketing Plan......Page 425
3.1 Marketing Mix......Page 427
3.2 Differentiation and Product Positioning......Page 430
3.4 Pre-Launch Planning......Page 432
3.4.1 Regional Rollouts......Page 433
4. Primary Market Messages......Page 434
5. Economic Considerations......Page 435
5.1 Product Pricing......Page 438
7. Branding......Page 439
7.1 Creating Market Demand......Page 440
7.2 Product Positioning......Page 441
9. Importance of Training......Page 442
10. Pre-Launch Market Planning......Page 443
References......Page 444
1. Introduction......Page 445
2. Categories of Viral Vectors......Page 447
2.1 Retroviral Vectors......Page 448
2.2 Lentiviral-Based Retroviral Vectors......Page 451
2.3 Adenoviral Vectors......Page 452
2.4 Adeno-Associated Virus Vectors......Page 456
2.5 Additional Virus Vectors......Page 458
2.5.1 Limited Replication Competent Vectors......Page 459
3. Therapeutic Gene Targeting Using Viral Vectors......Page 460
4.1 Gene Therapy and Genetic Disorders.......Page 462
4.2 Gene Therapy and Cancer......Page 464
4.3 Gene Therapy for Infectious Disease: The Aids Model......Page 466
5. Summary......Page 467
References......Page 468
1. Somatic Gene Therapy Myth or Reality?......Page 472
1.1 Plasmid-Based Gene Medicines......Page 474
1.2 Quality of DNA and Manufacture Scale......Page 479
1.2.1 Lipid-Mediated Gene Transfer......Page 480
1.2.2 Polypeptide-Based Gene Delivery......Page 485
1.2.3 Polymer-Based Gene Delivery......Page 487
2. Clinical Perspective of Gene Therapy......Page 489
2.1 Gene Therapy and Genetic Disease......Page 491
2.2 Gene Therapy and Cancer......Page 493
2.3 An Additional Application......Page 496
3. Conclusion......Page 497
References......Page 498
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