Contributors xv
Foreword xvii
Preface xix
1 Introduction to Biomanufacturing 1
Mark F. Witcher
1.1 Introduction 1
1.2 The Basics Constituents of Biopharmaceuticals 2
1.2.1 Proteins 3
1.2.2 Nucleic Acids (DNA and RNA) 5
1.2.3 Cells 6
1.3 Enterprise Element #1-Manufacturing Processes 8
1.3.1 Process-Unit Operations 8
1.3.2 Upstream Processes-Inoculum through Production Bioreactor 9
1.3.3 Upstream Processes-Harvest and Recovery 12
1.3.3.1 Normal Filtration 12
1.3.3.2 Centrifuge 13
1.3.3.3 Cell Disruption 13
1.3.4 Downstream Processes 13
1.3.4.1 Viral Clearance 14
1.3.4.2 Tangential Flow Filtration 15
1.3.4.3 Chromatography 16
1.3.5 Process Performance and Control 19
1.3.6 Process-Equipment 22
1.3.7 Process-Materials 23
1.4 Enterprise Element #2-Manufacturing Facility 23
1.4.1 Facility-Layout 23
1.4.2 Facility-Environment 25
1.4.3 Clean Rooms/CNC Spaces 25
1.4.4 HVAC-Heating Ventilation and Air-Conditioning 26
1.4.5 Surfaces 30
1.4.6 Facility-Utilities Systems 30
1.4.7 Facility-Control Systems 31
1.5 Enterprise Element #3-Manufacturing Infrastructure 31
1.5.1 Infrastructure-People (Operating Staff) 32
1.5.2 Infrastructure-Enterprise Practices and Procedures 32
1.6 Controlling the Manufacturing Enterprise 33
1.7 Summary 35
References 36
2 Product-Process-Facility Relationship 39
Jeffery Odum
2.1 Introduction 39
2.2 The Characteristics of Biological Therapeutic Products 40
2.3 Understanding the Attributes 42
2.3.1 Product Quality Attributes 44
2.3.2 Process Parameters 44
2.3.3 Facility Attributes 45
2.4 Factors that Impact Facility Design 46
2.4.1 Facility Types 47
2.4.1.1 Product Development Facilities 47
2.4.1.2 Pilot/Clinical 49
2.4.1.3 Commercial Manufacturing 54
2.4.2 Comparisons of the Facility Types 54
References 54
3 Regulatory Considerations of Biomanufacturing Facilities 55
Kip Priesmeyer
3.1 Introduction 55
3.2 Regulatory "Uncertainty," A Two-Way Street 56
3.3 Design with the Patient in Mind: Assess the Patient, Product, Process, and Plant 58
3.4 Laws, Regulations, and Guidelines: Historical Background 60
3.5 Global Guidance Documents 64
3.6 Quality Systems and Risk Management 66
3.7 Product Changeover and Regulatory Assessment of Cleaning Validation 70
3.8 Control Strategy 74
3.9 Contract Manufacturing Organizations 77
3.10 FDA Inspections of Biopharm Facilities and Regulators' Priorities 80
3.11 Regulatory Meetings 84
3.12 Conclusion 85
References 88
4 Biopharmaceutical Facility Design and Validation 91
Jeffery Odum
4.1 Introduction 91
4.2 Designing for Compliance 92
4.2.1 Facility Considerations 93
4.2.2 Product-Process-Facility Integration 94
4.2.3 The Role of Quality by Design 94
4.3 Risk Management 102
4.4 Qualification/Verification 105
4.5 Process Validation 110
4.6 List of Abbreviations 113
References 115
5 Closed Systems in Bioprocessing 117
Jeffery Odum
5.1 Introduction 117
5.2 Definition of Closed Systems 117
5.3 Closed System Design 119
5.4 Impact on Facility Design 121
5.5 Impact on Operations 123
5.6 Summary 127
References 127
6 Aseptic Manufacturing Considerations for Biomanufacturing Facility Design 129
Jeffery Odum, Hartmut Schaz, and Larry Pressley
6.1 Introduction 129
6.2 The Relationship to Biological Products 130
6.3 Process Attributes-Product Protection 130
6.3.1 System Closure 131
6.3.2 Segregation Strategy 133
6.4 Facility Design 134
6.5 Critical Area 137
References 141
7 Facility Control of Microorganisms: Containment and Contamination 143
Jonathan Crane
7.1 Introduction 143
7.2 Design Principles for Controlling Microorganisms 144
7.2.1 Planning Concepts 145
7.2.2 Physical Barriers 145
7.2.3 Engineering Systems 146
7.2.4 Containment and Isolation Equipment 150
7.2.5 Design to Support Operational Protocols 151
7.3 Controlling Viable Environmental Particulates 151
7.4 Reducing the Transport of Mold into the Bioprocess Facility 153
7.4.1 Environmental Zoning 153
7.4.2 Filtration of Molds and Mold Spores from Incoming Air 155
7.5 Reducing Mold Sources within the Bioprocess Facility 156
7.5.1 Cleaning and Decontamination 157
7.6 Biocontainment: An Overlay to Process Design 157
7.7 The Biocontainment Regulatory Environment 159
7.7.1 Laboratory-Scale Use and Use in Animal Models of Disease 160
7.7.2 Large-Scale Use of Pathogens 161
7.7.3 Animal and Plant Pathogens 162
7.7.4 Genetically Modified Organisms (GMO) and Synthesized Organisms 163
7.7.5 Toxins 163
7.7.6 Allergens and Biologically Active Products 164
7.7.7 Biosecurity 164
7.8 Principles of Biosafety 165
7.8.1 Risk Groups 165
7.8.2 Biosafety Levels 165
7.9 Principles of Biocontainment Facility Design 167
7.9.1 Risk Assessment 168
7.9.2 Primary Containment 168
7.9.3 Secondary Containment 169
7.9.4 Impact of Scale and Process 170
7.10 Design for the Entire Process 171
7.10.1 Upstream Process Facilities 172
7.10.2 Downstream Process Facilities 173
7.10.3 Fill and Finish Facilities 173
7.10.4 Quality Control Laboratory Facilities 173
7.10.5 Cross-contamination "Live" to "Nonlive" 173
7.11 Conclusion 173
References 174
Further Reading 176
8 Process-Based Laboratory Design 177
Henriette Schubert and Flemming K. Nielsen
8.1 Introduction 177
8.2 Areas of Application/Scope 177
8.3 Translation of Process Elements into Laboratory Architecture 179
8.4 Key Steps in Planning Approach and Methodology 180
8.4.1 Laboratory Planning Process 180
8.4.1.1 Project Initiation (Analyze Data) 181
8.4.1.2 Conceptual Design (Develop Concepts) 181
8.4.1.3 Basic Design and Detailed Design (Develop Solutions) 181
8.4.2 Creating an Informed Basis for Design 182
8.4.2.1 Mapping of Design Drivers and Project Targets 183
8.4.2.2 Designing for the Desired Laboratory Work Culture 185
8.4.2.3 Risk Assessment (GMP, Biocontainment/High Potent Product Containment) 188
8.4.2.4 Operational Workflow Mapping and Visual Planning 193
8.4.2.5 Functional Adjacency Analysis (Function/Relation) 195
8.4.2.6 Laboratory Typologies as a Planning Tool 197
8.5 Laboratory Concept Development 200
8.5.1 Planning Considerations for Laboratory Concepts 200
8.5.1.1 Area Distribution 200
8.5.1.2 Laboratory Concepts 201
8.5.1.3 Capacity Considerations 201
8.5.1.4 Translating Strategic Project Drivers into Laboratory Concepts 202
8.5.1.5 Generic Versus Tailor-Made/Specialized Laboratory Concepts 203
8.5.1.6 Typical Objectives for Laboratory Types (R&D, QC) 204
8.5.1.7 Laboratory Planning Modules and Floor Height 206
8.5.2 Mechanical Considerations 208
8.6 SHE Considerations 209
8.7 Glossary 210
8.8 List of Abbreviations 210
References 211
9 Case Study: Pharmaceutical Pilot Plant Design and Operation 213
Beth H. Junker
9.1 Introduction 213
9.2 Operational Concepts and Processing Requirements 215
9.3 Design 217
9.3.1 Process Equipment 219
9.3.2 Utilities 223
9.3.2.1 Product Contact 224
9.3.2.2 Nonproduct Contact 227
9.3.2.3 HVAC 228
9.3.3 Containment 230
9.3.3.1 Product Protection 231
9.3.3.2 Environmental Protection 231
9.3.3.3 Personnel Protection 232
9.3.4 Instrumentation 232
9.3.5 Automation and Control 233
9.3.6 Data Acquisition and Archiving 235
9.3.7 Warehousing 236
9.3.8 Back-Up Systems/Redundancy 237
9.3.9 Future Expansion/Modification 237
9.4 Operation 238
9.4.1 Maintenance 238
9.4.1.1 Preventative 238
9.4.1.2 Ongoing 240
9.4.1.3 Calibrations 240
9.4.1.4 Modifications/Change Control 241
9.4.2 Staffing 242
9.4.3 Laboratory Support 243
9.4.4 Standard Operating Procedures (SOPs) 243
9.4.5 Safety 247
9.4.6 Training 249
9.4.7 Validation 250
9.4.8 Facility Records and Manufacturing Execution Systems (MES) 251
References 253
10 Addressing Sustainability in Biomanufacturing Facility Design 259
Josh Capparella, Samuel Colucci, Daniel Conner, Robert Dick, and Amanda Weko
10.1 Introduction 259
10.1.1 Economics of Sustainability 261
10.1.2 Energy Benchmarking in the Biopharmaceutical Industry 261
10.1.3 Integrating Sustainability into the Design Process 261
10.1.3.1 Building Sustainability into the Process Early 261
10.1.3.2 Building Information Modeling 262
10.1.3.3 Integrated Utilities Approach 262
10.1.4 Sustainable Building Benchmarking 263
10.1.4.1 Commercial Building Benchmarking 263
10.1.4.2 Biopharmaceutical Building Benchmarking 265
10.1.4.3 Variations in Benchmarking Data 266
10.1.4.4 Making a Meaningful Impact to Facility Energy Reductions 267
10.1.4.5 Energy Efficiency: Current Trends 268
10.1.5 Cost of Utilities 269
10.1.6 Is Net Zero a Possibility? 271
10.1.7 Process Drives the Design 272
10.1.8 Risk-Based Approach to Sustainability 272
10.1.9 Risk in a Closed Process 273
10.2 Process Architecture 273
10.2.1 Process Technology Impact on Footprint 273
10.2.2 Tech Transfer and Scale Up 274
10.2.3 Water 276
10.3 Water and Water Treatment 276
10.3.1 Incoming City Water 277
10.3.2 Filtration and Softening 277
10.3.3 Deionization and Reverse Osmosis 278
10.3.4 Water for Injection (WFI) 279
10.3.4.1 Ambient, Intermediate, and Hot WFI Requirements 279
10.3.5 Clean Steam 279
10.3.6 Black Utilities 280
10.3.7 Wastewater Treatment 280
10.4 Energy Efficiency 281
10.4.1 Building Envelope and Materials 281
10.4.2 Heating, Ventilation, and Air Conditioning (HVAC) 282
10.4.2.1 Once-Through HVAC Versus Recirculation 283
10.4.2.2 Filtration 283
10.4.2.3 Primary-Secondary Air 283
10.4.2.4 Setback Strategies 283
10.4.3 Chilled Water 285
10.4.3.1 Chilled Water and the HVAC System 286
10.4.3.2 Chilled Water Generation 286
10.4.3.3 Chilled Water Analysis and Design 286
10.4.3.4 Free Cooling Opportunities 288
10.4.3.5 Cooling Tower Design 289
10.4.4 Steam 289
10.4.4.1 Steam Optimization 289
10.4.5 Compressed Air 291
10.4.5.1 Air- and Water-Cooled Air Compressors 293
10.4.5.2 Drier Technology 293
10.4.6 Nitrogen 294
10.4.7 Retro Commissioning 294
10.4.8 Maintenance and Operations Best Practices 297
10.5 Conclusion 300
Acknowledgments 301
References 301
11 Technology's Impact on the Biomanufacturing Facility of the Future 305
Jeffery Odum and Mark F. Witcher
11.1 Introduction 305
11.2 The Enabling Technologies 307
11.2.1 Process Platform Improvements 307
11.2.2 Single-Use Technology 308
11.2.3 Process Automation 311
11.3 Elements of a Biomanufacturing Enterprise 311
11.4 Evolution of the Facility of the Future 313
11.5 The Future-Summary and Conclusions 320
References 321
Glossary 323
Index 329
