Preface to Third Edition xvii
Preface to First Edition xix
List of Abbreviations xxi
Part I Introduction 1
1 Biopharmaceutical Production: Value Creation, Product Types, and Biological Basics Introduction 3
1.1 Role of Production in Pharmaceutical Biotechnology 3
1.1.1 Relationship Between Production and Development 6
1.1.2 Relationship Between Production and Marketing 8
1.2 Product Groups 10
1.2.1 Vaccines 12
1.2.2 Pharmaceuticals from Blood and Organs 12
1.2.3 Recombinant Therapeutic Proteins 13
1.2.4 Cell and Gene Therapeutics 13
1.2.5 Antibiotics 16
1.3 Basics of Biology 16
1.3.1 Cells and Microorganisms 16
1.3.1.1 Structure and Types of Cells 17
1.3.1.2 Metabolism 19
1.3.1.3 Reproduction and Aging 21
1.3.1.4 Viruses and Bacteriophages 22
1.3.1.5 Protein Biosynthesis 23
1.3.2 The Four Molecular Building Blocks of Biochemistry 25
1.3.2.1 Proteins 25
1.3.2.2 Nucleic Acids 29
1.3.2.3 Polysaccharides 30
1.3.2.4 Lipids 31
Part II Technology 33
2 Manufacturing Process 35
2.1 Role of the Manufacturing Process in Biotechnology 35
2.2 Process Schematic and Evaluation 37
2.2.1 Drug Substance Manufacturing 38
2.2.2 Drug Product Manufacturing 40
2.2.3 Key Factors for Process Evaluation 41
2.3 Cell Bank 43
2.3.1 Expression Systems 43
2.3.2 Microbial Systems 44
2.3.2.1 Mammalian Systems 45
2.3.2.2 Transgenic Systems 46
2.3.3 Manufacturing and Storage of the Cell Bank 46
2.4 Fermentation 48
2.4.1 Basic Principles 48
2.4.1.1 Cell Growth and Product Expression 49
2.4.1.2 Comparison of Batch and Continuous Processes 50
2.4.1.3 Sterility and Sterile Technology 53
2.4.1.4 Comparison of Fermentation with Mammalian Cells and Microorganisms 55
2.4.2 Technologies and Equipment 56
2.4.2.1 Fermentation in Suspension Culture 56
2.4.2.2 Adherent Cell Cultures 57
2.4.2.3 Transgenic Systems 60
2.4.3 Raw Materials and Processing Aids 61
2.4.3.1 Nutrient Media 61
2.4.3.2 Water, Gases, and Other Processing Aids 62
2.4.4 Overview of Fermentation 63
2.5 Purification 64
2.5.1 Basic Principles 65
2.5.1.1 Basic Pattern of Purification 65
2.5.1.2 Types of Impurities 68
2.5.1.3 Principles of Separation Technologies 71
2.5.2 Technologies for Cell Separation and Product Isolation 73
2.5.2.1 Cell Separation 73
2.5.2.2 Cell Disruption, Solubilization, and Refolding 74
2.5.2.3 Concentration and Stabilization 75
2.5.3 Technologies for Final Purification 80
2.5.3.1 Chromatographic Processes 81
2.5.3.2 Precipitation and Extraction 89
2.5.3.3 Sterile Filtration and Virus Removal 90
2.5.4 Raw Materials and Processing Aids 91
2.5.4.1 Gels for Chromatography 91
2.5.4.2 Membranes for TFF 93
2.5.5 Overview of Purification 94
2.6 Formulation and Filling 96
2.6.1 Basic Principles 96
2.6.2 Freeze-Drying 98
2.7 Labeling and Packaging 99
3 Analytics 103
3.1 Role of Analytics in Biotechnology 103
3.2 Product Analytics 105
3.2.1 Identity 107
3.2.2 Content 107
3.2.3 Purity 109
3.2.4 Activity 109
3.2.5 Appearance 112
3.2.6 Stability 112
3.2.7 Quality Criteria of Analytical Methods 114
3.2.8 Analytical Methods 115
3.2.8.1 Amino Acid Analysis 116
3.2.8.2 Protein Sequencing 116
3.2.8.3 Peptide Mapping 117
3.2.8.4 Protein Content 117
3.2.8.5 Electrophoresis 118
3.2.8.6 Western Blot 120
3.2.8.7 HCP Enzyme-Linked Immunosorbent Assay (elisa) 122
3.2.8.8 Analytical Chromatography 123
3.2.8.9 Infrared (IR) Spectroscopy 125
3.2.8.10 UV/Vis Spectroscopy 125
3.2.8.11 Mass Spectrometry 126
3.2.8.12 Glycoanalytics 127
3.2.8.13 Pcr 127
3.2.8.14 DNA/RNA Sequencing 128
3.2.8.15 Endotoxins and Pyrogen Testing 129
3.2.8.16 Bioburden Test 130
3.2.8.17 Virus Testing 130
3.2.8.18 Tem 131
3.2.8.19 Circular Dichroism 131
3.2.8.20 Differential Scanning Calorimetry 131
3.3 Process Analytics 132
3.3.1 Fermentation 132
3.3.2 Purification 133
3.3.3 Formulation and Packaging 134
3.4 Environmental Monitoring 135
3.5 Raw Material Testing 137
3.6 Product Comparability 138
Part III Pharmacy 141
4 Pharmacology and Drug Safety 143
4.1 Action of Drugs in Humans 144
4.1.1 Pharmacokinetics 145
4.1.2 Pharmacodynamics 149
4.1.2.1 Principles of Phenomenological Effects 149
4.1.2.2 Parameters of Drug Effects 150
4.2 Routes and Forms of Administration 152
4.3 Drug Study 153
4.3.1 Pre-Clinical Study 155
4.3.2 Clinical Study 157
4.3.2.1 Phases of Clinical Studies 157
4.3.2.2 Design and Conduct of Clinical Trials 160
4.4 Path of the Drug from the Manufacturer to Patients 162
4.5 Drug Safety 164
4.5.1 Causes and Classification of Side Effects 165
4.5.2 Methods for Supervising Drug Safety (Pharmacovigilance) 167
4.5.3 Measures upon Incidence of Adverse Reactions 168
Part IV Quality Assurance 171
5 Fundamentals of Quality Assurance 173
5.1 Basic Principles 173
5.2 Benefit of Quality Assurance Activities 174
5.3 Quality Management According to ISO 9000 175
5.3.1 Fields of Activity 176
5.4 Structure of Quality Management Systems 178
5.5 Quality Management System Components in the Pharmaceutical Area 180
5.5.1 Documentation 180
5.5.2 Failure Prevention and Correction 181
5.5.3 Responsibility of Management and Training of Personnel 186
5.5.4 Audits 186
5.5.5 External Suppliers 187
5.5.6 Contract Review 188
5.6 Quality Assurance in Development 189
6 Quality Assurance in Manufacturing 191
6.1 Gmp 191
6.1.1 Personnel 196
6.1.2 Premises and Equipment 198
6.1.2.1 Measures to Avoid External Contamination 198
6.1.2.2 Measures to Avoid Cross-Contamination and Product Confusion 201
6.1.3 Equipment Qualification 203
6.1.4 Process Validation 206
6.1.5 Computer Validation 208
6.1.6 Documentation 209
6.2 Operative Workflows under GMP Conditions 210
6.2.1 Product Release and Deviation Management 211
6.2.2 Changes in the Manufacturing Process 213
6.3 Production of Investigational Drugs 216
Appendix A Case Study Part IV: Warning Letters by FDA 219
Part V Pharmaceutical Law 223
7 Pharmaceutical Law and Regulatory Authorities 225
7.1 Fields of Pharmaceutical Law 225
7.2 Bindingness of Regulations 226
7.3 Authorities, Institutions, and Their Regulations 227
7.3.1 Fda 228
7.3.2 Ema 230
7.3.3 German Authorities 233
7.3.4 Japanese Authorities 234
7.3.5 Authorities of Growth Markets 235
7.3.5.1 China: National Medical Products Administration (nmpa) 236
7.3.5.2 Brazilian Agência Nacional de Vigilância Sanitária (National Health Surveillance Agency, ANVISA) 236
7.3.6 Other Important Institutions 236
7.3.6.1 US Pharmacopoeia 236
7.3.6.2 Ich 237
7.3.6.3 Iso 237
7.3.6.4 Who 237
7.3.6.5 Pic/s 237
7.3.6.6 Ispe 239
7.3.6.7 Pda 239
7.4 Official Enforcement of Regulations 239
7.5 Drug Approval 241
Appendix B Case Study Part V: Clinical Trials for Protein Products 243
B.1 Mabthera® /Rituxan ® 243
B.2 Enbrel® 244
B.2.1 Adult Patients with Rheumatoid Arthritis 244
B.3 Remicade® Infliximab 245
B.3.1 Adult Rheumatoid Arthritis 245
B.4 Humira® 40 mg 246
B.5 Lucentis® 247
B.5.1 Treatment of Wet AMD 247
B.6 Zaltrap® 247
Part VI Production Facilities 249
8 Facility Design 251
8.1 Basic Principles 251
8.2 GMP-Compliant Plant Design 254
8.2.1 Production Flow Diagram 256
8.2.2 Conceptual Plant Layout 257
8.2.2.1 Is the Facility Fit for the Intended Purpose? 259
8.2.2.2 Is the Facility cGMP Compliant? 259
8.2.2.3 Is the Facility Flexible? 259
8.2.2.4 Can the Facility Be Expanded? 260
8.2.2.5 Is It Possible to Separate the Core Process from the Support Functions? 260
8.2.2.6 Is the Plant Capacity Optimized and Are Synergies with Existing Facilities Used? 261
8.2.3 GMP Flow Analysis 261
8.2.4 Zoning Concept 264
8.3 Basic Concepts for Production Plants 267
8.3.1 Single- and Multiproduct Plants 270
8.3.2 Fractal and Integrated Configuration 271
8.3.3 Flexible and Fixed Piping 273
8.3.4 Steel Tanks and Disposable Equipment 274
8.4 Clean and Plant Utilities 275
8.4.1 Clean Utilities 275
8.4.1.1 Water 275
8.4.1.2 Clean Steam 282
8.4.1.3 Gases and Process Air 282
8.4.2 Plant Utilities 283
8.4.3 Waste Management 285
8.5 Equipment Cleaning 286
8.6 Clean Rooms 288
8.6.1 Separation of Zones by Clean Room Design 289
8.6.2 Finishing of Floors, Walls, and Ceilings 291
8.6.3 HVAC Installations 292
8.6.4 Qualification 293
8.7 Automation 293
8.8 QC Laboratories 295
8.9 Location Factors 295
8.9.1 Cost 295
8.9.2 Personnel 296
8.9.3 Permitting 296
8.9.4 Synergies with Existing Facilities or Units 296
8.9.5 Logistics 297
8.9.6 Know-How and Intellectual Property Protection 297
8.9.7 Other Risks 297
8.9.8 Market Access 297
8.9.9 Language and Culture 298
9 Planning, Construction, and Commissioning of a Manufacturing Plant 299
9.1 Steps of the Engineering Project 299
9.1.1 Planning 300
9.1.2 Construction 301
9.1.3 Commissioning, Qualification, Validation 303
9.2 Project Schedules 306
9.3 Cost Estimates 307
9.4 Organization of an Engineering Project 309
9.4.1 Expert Groups Involved 309
9.4.2 Role and Selection of Contractors 310
9.4.3 Contracts and Scope Changes 310
9.5 Successful Execution of an Engineering Project 314
9.6 Legal Aspects of Facility Engineering 315
9.6.1 Health, Safety, and Environmental Law 316
9.6.2 Building Law 317
Part VII Economy 319
10 Production Costs 321
10.1 Drug Life Cycle 321
10.2 Position of the Manufacturing Costs in the Overall Cost Framework 325
10.3 Basic Principles of Cost Calculation 327
10.3.1 Nominal Accounting Actual Accounting 327
10.3.2 Cost Accounting Profit and Loss Accounting 328
10.3.3 Direct Costs Indirect Costs 328
10.3.4 Fixed Costs Variable Costs 329
10.3.5 Relevant and Irrelevant Costs 330
10.3.6 Cost Type, Cost Center, and Cost Unit 331
10.4 Costs of Biotechnological Manufacturing Processes 332
10.4.1 Capital Costs 333
10.4.2 Operating Costs 335
10.5 Accounting Methods 338
10.5.1 Cost Accounting 338
10.5.2 Profit and Loss Accounting 347
11 Investments 351
11.1 Basic Principles 352
11.1.1 Investment Targets 352
11.1.2 Types of Investments 353
11.1.3 Decision Processes 355
11.2 ValueBenefit Analysis 359
11.3 Investment Appraisal 360
11.3.1 Static Methods 364
11.3.1.1 Cost Comparison 364
11.3.1.2 Profit Comparison 365
11.3.1.3 Profitability Comparison 365
11.3.1.4 Static Payback Time 365
11.3.2 Dynamic Methods 365
11.3.2.1 Capital Value 366
11.3.2.2 Internal Rate of Return 366
11.3.2.3 Annuity 367
11.4 Dynamic Payback Time 367
12 Production Concept 369
12.1 Capacity Planning 369
12.2 Dilemma of In-House Manufacturing 372
12.3 Aspects of Manufacturing Outsourcing 375
12.3.1 Types of Cooperation 376
12.3.2 Contractual Agreements 377
12.3.3 Technology Transfer 382
12.3.4 Time Schedules 384
12.4 Make-or-Buy Analysis 385
12.5 Process Optimization 387
12.5.1 Comparability of the Product 387
12.5.2 Operational Excellence 390
12.5.2.1 Lean Management 391
12.5.2.2 Six-Sigma 392
12.6 Supply-Chain Management 396
12.6.1 Security of Supply 398
12.6.2 Performance Management 401
Appendix C Examples Part VII: Manufacturing Cost Calculation 405
C. 1 Introduction 405
C. 2 Basic Assumptions for Both Production Processes 405
C. 3 Step 1: Production of Product 1 in Dedicated Facility 405
C.3. 1 Cost Structure 406
C.3. 2 Product Costs 407
C. 3 Idle Costs 407
C.3.4 Unit Price Based on Facility Usage 407
C.4 Step 2: Addition of a Second Product 408
C.4.1 Costs of Products 409
C.4.2 Evaluation of Manufacturing Options 410
Part VIII Production Organization and Digitalization 413
13 Organization of a Manufacturing Facility 415
13.1 Functional Setup of a Manufacturing Plant 416
13.2 Development of a Plant Organization 416
13.3 Organizational Charts and Cooperation Pathways 421
13.4 Cultural Aspects: The Human Factor 424
14 Digitalization 427
14.1 Operational and Digital Perspective 428
14.2 Digital Maturity 435
14.3 Integration and IT Architecture 440
14.4 Digital Transformation 444
14.5 Digital Applications in the GMP Environment 446
References 451
Further Reading 451
Biotechnology General 451
Fermentation 452
Purification 452
Aseptic Filling and Lyophilization 452
Bioanalytics 452
Regulatory 453
Pharmacy and Clinical Development 453
Quality and Validation 453
Good Manufacturing Practice 454
Facility Design 454
Clean Rooms 454
Project Management 454
Engineering 454
Economy 455
Weblinks 455
Index 457
