A Practical Guide to Biopharmaceutical Manufacturing
Informa Healthcare, January 2006, Pages: 234
Biomanufacturing is an exciting and fundamentally new science that is constantly changing and yielding novel products from emerging technologies. This report A Practical Guide to Biopharmaceutical Manufacturing provides an in-depth understanding of the biopharmaceutical industry. It consists of 10 chapters and highlights the production technologies and operations that occur in the manufacturing facility.
Chapter 1 provides an overview of the biopharmaceutical industry, highlighting the financial and timescale pressures faced during the drug development and manufacturing process, which in part reflect the regulations surrounding the biotechnology industry.
Chapter 2 and 3 are concerned with the production techniques used for the manufacture of a biopharmaceutical.
Chapter 4 describes the process equipment and operations used to support the main production process.
Chapter 5 provides a brief discussion on the design of the biopharmaceutical manufacturing facility, and the monitoring and control methods performed to ensure that the product meets the approved specifications.
Chapter 6 and 7 discuss the benefits and applications of process and cost modelling, present the frameworks used for the modelling and provides examples of the uses of such tools.
Chapter 8 outlines the typical production methods used in the industry to manufacture biotherapeutics by considering sample processes for therapeutics proteins, vaccines, gene therapies and cellular therapies.
Chapter 9 describes the application of the disposable technology, which has a great impact on the operating costs, validation issues and environment concerns in the biopharmaceutical industry.
Finally in chapter 10, the regulatory issues surrounding biopharmaceutical manufacture.
CHAPTER 1 INTRODUCTION TO BIOPROCESSING 11
1.1 Introduction 11
1.1.1 Special considerations 12
1.2 The biopharmaceutical development process 15
1.2.1 Drug discovery 15
1.2.2 Process development 16
1.2.3 Clinical Trials 17
1.2.4 Time-to-market 18
1.3 The biopharmaceutical manufacturing process 19
1.3.1 Manufacturing capacity 20
1.3.2 Scale-up of production processes 21
1.4 Demand for biologics 22
1.4.1 Historical growth 22
1.4.2 Biologics in clinical trials 23
1.4.3 Approved biological products 27
1.5 Contract manufacturing organisations 28
1.5.1 Clinical Trials Directive 29
1.5.2 CMO Entrant 31
CHAPTER 2 GROWTH OPERATIONS 33
2.1 EXPRESSION SYSTEMS 33
2.1.1 Host organisms 33
2.1.2 Transgenic hosts 36
2.2 Culture type 38
2.2.1 Suspension culture 38
2.2.2 Attachment dependent 41
2.3 Growth characterisitics 46
2.3.1 Product formation 46
2.3.2 Scale-up 47
2.3.3 Culture media 47
2.3.4 Process monitoring and control 48
2.4 Modes of operation 49
2.4.1 Batch operation 50
2.4.2 Fed-batch operation 50
2.4.3 Media exchange operation 51
2.4.4 Perfusion operation 51
2.4.5 Solera 52
CHAPTER 3 RECOVERY & DOWNSTREAMS PROCESSING 53
3.1 Recovery 53
3.1.1 Centrifugation 53
3.1.2 Lysis 55
3.1.3 Filtration 56
3.2 Purification 59
3.2.1 Solubilisation and refolding 60
3.2.2 Chromatography 61
3.2.3 Precipitation 66
3.2.4 Viral clearance 67
3.3 Sterile filtration 68
3.4 Formulation, fill and finish 69
3.4.1 Pre-formulation 69
3.4.2 Stabilisation and formulation 70
3.4.3 Fill finish operations 72
CHAPTER 4 SUPPORT OPERATIONS 75
4.1 Process equipment 75
4.1.1 Standard vessels 75
4.1.2 Jacketed vessels 77
4.1.3 Disposables 78
4.1.4 Pipework 79
4.1.5 Manifolds 80
4.2 Process solutions and waste 81
4.2.1 Process solutions 81
4.2.2 Sampling 84
4.2.3 Waste 84
4.3 Cleaning and sterilisation 85
4.3.1 Clean-in-place (CIP) 85
4.3.2 Sterilisation 88
4.4 Process utilities 91
4.4.1 Purified water (PW) 91
4.4.2 Water for injection (WFI) 92
4.4.3 Clean steam 92
4.4.4 Utility distribution 93
CHAPTER 5 BIOPROCESS DESIGN 97
5.1 Introduction 97
5.2 Bioprocess design 98
5.2.1 Process description 98
5.2.2 GMP philosophy 98
5.2.3 Mass balance 99
5.2.4 Block flow diagrams and process flowsheets 100
5.2.5 Process Simulation 102
5.2.6 Equipment List 102
5.2.7 Piping and instrumentation diagram 103
5.2.8 Process control 104
5.2.9 Scale-up/Scale-down 107
5.3 Facility design 108
5.3.1 Facility products 109
5.3.2 Plant layout 111
5.3.3 Room classifications and HVAC zoning 112
5.3.4 Clean air 114
5.3.5 People, material and waste flows 114
5.3.6 Change rooms and airlocks 115
5.3.7 Waste management 116
5.4 Design lifecycle 118
5.4.1 Conceptual design 118
5.4.2 Front end engineering 118
5.4.3 Detail design 119
5.4.4 Construction 120
5.4.5 Commissioning and qualification 120
CHAPTER 6 PROCESS SIMULATION 123
6.1 Introduction 123
6.1.1 Simulation models 123
6.1.2 Simulation study 125
6.2 Overview of process simulation 126
6.2.1 Challenges of bioprocess simulation 126
6.2.2 Benefits of process simulation 126
6.2.3 Simulators for the bioprocess industry 127
6.3 Bioprocess simulation 128
6.3.1 Domain description 128
6.3.2 Modelling scope of a bioprocess simulator 129
6.3.3 Bioprocess simulation software packages 130
6.4 A simulation case study 132
6.4.1 An example of a modelling framework 132
6.4.2 Case study set-up 137
6.4.3 Simulation results and discussion 139
6.4.4 Conclusion 142
CHAPTER 7 COST MODELLING 143
7.1 Introduction 143
7.2 Cost performance metrics 144
7.2.1 Capital costs 144
7.2.2 Operating costs 146
7.2.3 Net Present Value (NPV) 147
7.3 Framework of a cost model 148
7.3.1 An example of a cost model framework 148
7.3.2 Data collection 149
7.3.3 COG modules 149
7.4 A COG case study 156
7.4.1 Case study set-up 156
7.4.2 Simulation results and discussion 159
CHAPTER 8 SAMPLE PROCESSES 161
8.1 Therapeutic proteins 161
8.1.1 Monoclonal antibodies (MAbs) 161
8.1.2 Recombinant interferons 161
8.1.3 Recombinant interleukins 161
8.1.4 Recombinant hormones 162
8.1.5 Recombinant growth factors 162
8.1.6 Monoclonal antibodies 162
8.1.7 Growth 163
8.1.8 Recovery 164
8.1.9 Purification 164
8.2 Vaccines 166
8.2.1 Types of vaccines 166
8.2.2 Whooping cough 168
8.2.3 Growth and Recovery 169
8.2.4 Solid Fraction Lysis and Purification 170
8.2.5 Supernatant Purification 171
8.2.6 Polishing and combined purification 171
8.3 Gene therapy 172
8.3.1 Genetic Vectors 173
8.3.2 Growth 174
8.3.3 Recovery 175
8.3.4 Purification 176
8.4 Cellular therapy 176
8.4.1 Dendritic white blood cells 177
8.4.2 Purification & transformation 178
8.4.3 Recovery and Growth 179
CHAPTER 9 DISPOSABLES 181
9.1 Disposable application evaluation 181
9.1.1 Quantitative analysis 181
9.1.2 Benefits of disposable technology 187
9.1.3 Disadvantages of disposable technology 187
9.2 Design guide: bag handling 188
9.2.1 Empty bioprocess bags & disposable equipment 188
9.2.2 Filled bioprocess bags 188
9.2.3 Tubing 190
9.3 Systems 191
9.3.1 Cell culture 192
9.3.2 Chromatography 194
9.3.3 Mixer systems 195
9.3.4 Freezing systems 196
9.4 Components 197
9.4.1 Bags 197
9.4.2 Connectors 197
9.4.3 Rapid transfer ports 198
9.4.4 Tubing 198
9.4.5 Filling 199
9.5 Instrumentation and control 199
CHAPTER 10 REGULATORY ENVIRONMENT 201
10.1 Product licensing 201
10.1.1 Clinical development and product approval 201
10.1.2 Clinical trials 202
10.1.3 Regulatory authorities 203
10.2 Good manufacturing practice 206
10.2.1 Defining the regulatory requirements 207
10.2.2 Regulatory framework 207
10.2.3 Scope Process areas 208
10.2.4 Assessing requirements 209
10.2.5 Design considerations 209
10.2.6 Viral clearance of biotechnology products 210
10.2.7 Good Automated Manufacturing Practices (GAMPs) 213
10.3 Biosafety 213
10.3.1 Defining the regulatory requirements 213
10.3.2 Risk 214
10.3.3 Biosafety & GMP 215
10.4 Validation approach 215
10.4.1 Validation requirements 216
10.4.2 Validation life cycle 217
10.5 Quality: The role of QA/QC 221
10.5.1 Quality Assurance 222
10.5.2 Quality Control 224
LIST OF TABLES
Table 1.1 Average figures for number of subjects, success rates and trial durations in clinical phases
Table 1.2 Mean total phase lengths for biopharmaceuticals
Table 1.3 Typical dosage figures for a selection of approved products
Table 1.4 Typical therapeutic antibodies approved, and their indications
Table 4.1 Typical mixing time for media and buffer preparation
Table 4.2 System requirements for solution preparation stations
Table 5.1 Environmental classification
Table 5.2 Classification of cleanrooms
Table 6.1 Comparison of SuperPro/SchedulePro Designer and BPS Simulation
Table 6.2 Major equipment specification
Table 7.1 A typical worksheet for presenting the annual cash flow, the discounted present value and the net present value of a project.
Table 7.2 An example of a production worksheet
Table 7.3 An example of an equipment list worksheet.
Table 7.4 Cost factors included in the capital charge
Table 7.5 Lang factors used in the capital estimate (contingencies excluded)
Table 7.6 Labour benchmarking factors and estimated headcount
Table 7.7 Capital breakdown for the traditional and concept facility
Table 7.8 Cost of goods (COG) comparison (including capital) (€/g)
Table 9.1 Tubing pass-through options
Table 9.2 Disposable bioreactors
Table 9.3 Disposable flasks, bottles and other containers
Table 9.4 Mixer systems
Table 9.5 Disposable connectors
Table 9.6 Instrumentation and control components
Table 10.1 Average figures for number of subjects, success rates and trial durations in clinical phases
Table 10.2 Regulatory bodies
Table 10.3 ICH documents
Table 10.4 EU Directives and Guidelines
Table 10.5 US Regulations and Guidelines
Table 10.6 System Classifications
Biomanufacturing is an exciting and fundamentally new science that is constantly changing and yielding novel products from emerging technologies. This report A Practical Guide to Biopharmaceutical Manufacturing, provides an excellent introduction for anyone interested in developing an in-depth understanding of the biopharmaceutical industry. The report is written to highlight the production technologies and operations that occur in the manufacturing facility.
Chapter 1 provides an overview of the biopharmaceutical industry, highlighting the financial and timescale pressures faced during the drug development and manufacturing process, which in part reflect the regulations surrounding the biotechnology industry. An introductory background to the biopharmaceutical drug development and manufacturing pathway has been presented. This chapter also provides an analysis of the biological entities in the clinical pipeline of commercial organisations and the companies offering contract manufacturing services for mammalian cell lines.
Chapters 2 and 3 are concerned with the production techniques used for the manufacture of a biopharmaceutical. The production stage of the biological entity involves the various expression system (e.g. mammalian, microbial, yeast etc.) used to generate the desired product, the type of culture (e.g. suspension or attachment) and the mode of operations (e.g. batch, fedbatch etc.). The subsequent stage includes the recovery of the crude product and the purification process to obtain the product to meet any required standards.
Chapter 4 describes the process equipment and operations used to support the main production process. The process equipment consists of the standard vessels, jacketed vessels, disposable replacements for the vessels, pipework and manifolds for distribution systems. The support operations include solution preparation and storage, cleaning and sterilisation, generation and distribution of process utilities. Chapter 5 provides a brief discussion on the design of the biopharmaceutical manufacturing facility, and the monitoring and control methods performed to ensure that the product meets the approved specifications.
Global competition is driving the need to improve manufacturing efficiency through the need to achieve the following objectives: accelerated time-to-market, maximised resource utilisation and reduced cost of goods. The need for computer-aided design tools to act in support of making the best decisions relating to biomanufacture is becoming increasingly critical. Chapters 6 and 7 discuss the benefits and applications of process and cost modelling, present the frameworks used for the modelling and provide examples of the uses of such tools.
Chapter 8 outlines the typical production methods used in the industry to manufacture biotherapeutics by considering sample processes for therapeutic proteins, vaccines, gene therapies and cellular therapies. Chapter 9 describes the application of the disposable technology, which has a great impact on the operating costs, validation issues and environment concerns in the biomanufacturing industry. The advantages and disadvantages of such single-use approach as compared to traditional stainless steel facilities are also identified.
In Chapter 10, the regulatory issues surrounding biopharmaceutical manufacture are discussed further in details.
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