Jeffery Odum, CPIP is the Managing Partner of the Strategic Manufacturing Concept Group, and a Global Technology Partner at NNE in the US Office located in Durham, North Carolina and a Teaching Fellow in the BTEC program at North Carolina State University. Michael C. Flickinger, PhD is the Associate Director for Academic Programs at the Golden LEAF Biomanufacturing Training and Education Center (BTEC) and a Professor of Chemical and Biomolecular Engineering at North Carolina State University, Raleigh, North Carolina.

• Contributors xvForeword xviiPreface xix1 Introduction to Biomanufacturing 1Mark F. Witcher1.1 Introduction 11.2 The Basics Constituents of Biopharmaceuticals 21.2.1 Proteins 31.2.2 Nucleic Acids (DNA and RNA) 51.2.3 Cells 61.3 Enterprise Element #1—Manufacturing Processes 81.3.1 Process—Unit Operations 81.3.2 Upstream Processes—Inoculum through Production Bioreactor 91.3.3 Upstream Processes—Harvest and Recovery 121.3.3.1 Normal Filtration 121.3.3.2 Centrifuge 131.3.3.3 Cell Disruption 131.3.4 Downstream Processes 131.3.4.1 Viral Clearance 141.3.4.2 Tangential Flow Filtration 151.3.4.3 Chromatography 161.3.5 Process Performance and Control 191.3.6 Process—Equipment 221.3.7 Process—Materials 231.4 Enterprise Element #2—Manufacturing Facility 231.4.1 Facility—Layout 231.4.2 Facility—Environment 251.4.3 Clean Rooms/CNC Spaces 251.4.4 HVAC—Heating Ventilation and Air-Conditioning 261.4.5 Surfaces 301.4.6 Facility—Utilities Systems 301.4.7 Facility—Control Systems 311.5 Enterprise Element #3—Manufacturing Infrastructure 311.5.1 Infrastructure—People (Operating Staff) 321.5.2 Infrastructure—Enterprise Practices and Procedures 321.6 Controlling the Manufacturing Enterprise 331.7 Summary 35References 362 Product–Process–Facility Relationship 39Jeffery Odum2.1 Introduction 392.2 The Characteristics of Biological Therapeutic Products 402.3 Understanding the Attributes 422.3.1 Product Quality Attributes 442.3.2 Process Parameters 442.3.3 Facility Attributes 452.4 Factors that Impact Facility Design 462.4.1 Facility Types 472.4.1.1 Product Development Facilities 472.4.1.2 Pilot/Clinical 492.4.1.3 Commercial Manufacturing 542.4.2 Comparisons of the Facility Types 54References 543 Regulatory Considerations of Biomanufacturing Facilities 55Kip Priesmeyer3.1 Introduction 553.2 Regulatory “Uncertainty,” A Two-Way Street 563.3 Design with the Patient in Mind: Assess the Patient, Product, Process, and Plant 583.4 Laws, Regulations, and Guidelines: Historical Background 603.5 Global Guidance Documents 643.6 Quality Systems and Risk Management 663.7 Product Changeover and Regulatory Assessment of Cleaning Validation 703.8 Control Strategy 743.9 Contract Manufacturing Organizations 773.10 FDA Inspections of Biopharm Facilities and Regulators’ Priorities 803.11 Regulatory Meetings 843.12 Conclusion 85References 884 Biopharmaceutical Facility Design and Validation 91Jeffery Odum4.1 Introduction 914.2 Designing for Compliance 924.2.1 Facility Considerations 934.2.2 Product–Process–Facility Integration 944.2.3 The Role of Quality by Design 944.3 Risk Management 1024.4 Qualification/Verification 1054.5 Process Validation 1104.6 List of Abbreviations 113References 1155 Closed Systems in Bioprocessing 117Jeffery Odum5.1 Introduction 1175.2 Definition of Closed Systems 1175.3 Closed System Design 1195.4 Impact on Facility Design 1215.5 Impact on Operations 1235.6 Summary 127References 1276 Aseptic Manufacturing Considerations for Biomanufacturing Facility Design 129Jeffery Odum, Hartmut Schaz, and Larry Pressley6.1 Introduction 1296.2 The Relationship to Biological Products 1306.3 Process Attributes—Product Protection 1306.3.1 System Closure 1316.3.2 Segregation Strategy 1336.4 Facility Design 1346.5 Critical Area 137References 1417 Facility Control of Microorganisms: Containment and Contamination 143Jonathan Crane7.1 Introduction 1437.2 Design Principles for Controlling Microorganisms 1447.2.1 Planning Concepts 1457.2.2 Physical Barriers 1457.2.3 Engineering Systems 1467.2.4 Containment and Isolation Equipment 1507.2.5 Design to Support Operational Protocols 1517.3 Controlling Viable Environmental Particulates 1517.4 Reducing the Transport of Mold into the Bioprocess Facility 1537.4.1 Environmental Zoning 1537.4.2 Filtration of Molds and Mold Spores from Incoming Air 1557.5 Reducing Mold Sources within the Bioprocess Facility 1567.5.1 Cleaning and Decontamination 1577.6 Biocontainment: An Overlay to Process Design 1577.7 The Biocontainment Regulatory Environment 1597.7.1 Laboratory-Scale Use and Use in Animal Models of Disease 1607.7.2 Large-Scale Use of Pathogens 1617.7.3 Animal and Plant Pathogens 1627.7.4 Genetically Modified Organisms (GMO) and Synthesized Organisms 1637.7.5 Toxins 1637.7.6 Allergens and Biologically Active Products 1647.7.7 Biosecurity 1647.8 Principles of Biosafety 1657.8.1 Risk Groups 1657.8.2 Biosafety Levels 1657.9 Principles of Biocontainment Facility Design 1677.9.1 Risk Assessment 1687.9.2 Primary Containment 1687.9.3 Secondary Containment 1697.9.4 Impact of Scale and Process 1707.10 Design for the Entire Process 1717.10.1 Upstream Process Facilities 1727.10.2 Downstream Process Facilities 1737.10.3 Fill and Finish Facilities 1737.10.4 Quality Control Laboratory Facilities 1737.10.5 Cross-contamination “Live” to “Nonlive” 1737.11 Conclusion 173References 174Further Reading 1768 Process-Based Laboratory Design 177Henriette Schubert and Flemming K. Nielsen8.1 Introduction 1778.2 Areas of Application/Scope 1778.3 Translation of Process Elements into Laboratory Architecture 1798.4 Key Steps in Planning Approach and Methodology 1808.4.1 Laboratory Planning Process 1808.4.1.1 Project Initiation (Analyze Data) 1818.4.1.2 Conceptual Design (Develop Concepts) 1818.4.1.3 Basic Design and Detailed Design (Develop Solutions) 1818.4.2 Creating an Informed Basis for Design 1828.4.2.1 Mapping of Design Drivers and Project Targets 1838.4.2.2 Designing for the Desired Laboratory Work Culture 1858.4.2.3 Risk Assessment (GMP, Biocontainment/High Potent Product Containment) 1888.4.2.4 Operational Workflow Mapping and Visual Planning 1938.4.2.5 Functional Adjacency Analysis (Function/Relation) 1958.4.2.6 Laboratory Typologies as a Planning Tool 1978.5 Laboratory Concept Development 2008.5.1 Planning Considerations for Laboratory Concepts 2008.5.1.1 Area Distribution 2008.5.1.2 Laboratory Concepts 2018.5.1.3 Capacity Considerations 2018.5.1.4 Translating Strategic Project Drivers into Laboratory Concepts 2028.5.1.5 Generic Versus Tailor-Made/Specialized Laboratory Concepts 2038.5.1.6 Typical Objectives for Laboratory Types (R&D, QC) 2048.5.1.7 Laboratory Planning Modules and Floor Height 2068.5.2 Mechanical Considerations 2088.6 SHE Considerations 2098.7 Glossary 2108.8 List of Abbreviations 210References 2119 Case Study: Pharmaceutical Pilot Plant Design and Operation 213Beth H. Junker9.1 Introduction 2139.2 Operational Concepts and Processing Requirements 2159.3 Design 2179.3.1 Process Equipment 2199.3.2 Utilities 2239.3.2.1 Product Contact 2249.3.2.2 Nonproduct Contact 2279.3.2.3 HVAC 2289.3.3 Containment 2309.3.3.1 Product Protection 2319.3.3.2 Environmental Protection 2319.3.3.3 Personnel Protection 2329.3.4 Instrumentation 2329.3.5 Automation and Control 2339.3.6 Data Acquisition and Archiving 2359.3.7 Warehousing 2369.3.8 Back-Up Systems/Redundancy 2379.3.9 Future Expansion/Modification 2379.4 Operation 2389.4.1 Maintenance 2389.4.1.1 Preventative 2389.4.1.2 Ongoing 2409.4.1.3 Calibrations 2409.4.1.4 Modifications/Change Control 2419.4.2 Staffing 2429.4.3 Laboratory Support 2439.4.4 Standard Operating Procedures (SOPs) 2439.4.5 Safety 2479.4.6 Training 2499.4.7 Validation 2509.4.8 Facility Records and Manufacturing Execution Systems (MES) 251References 25310 Addressing Sustainability in Biomanufacturing Facility Design 259Josh Capparella, Samuel Colucci, Daniel Conner, Robert Dick, and Amanda Weko10.1 Introduction 25910.1.1 Economics of Sustainability 26110.1.2 Energy Benchmarking in the Biopharmaceutical Industry 26110.1.3 Integrating Sustainability into the Design Process 26110.1.3.1 Building Sustainability into the Process Early 26110.1.3.2 Building Information Modeling 26210.1.3.3 Integrated Utilities Approach 26210.1.4 Sustainable Building Benchmarking 26310.1.4.1 Commercial Building Benchmarking 26310.1.4.2 Biopharmaceutical Building Benchmarking 26510.1.4.3 Variations in Benchmarking Data 26610.1.4.4 Making a Meaningful Impact to Facility Energy Reductions 26710.1.4.5 Energy Efficiency: Current Trends 26810.1.5 Cost of Utilities 26910.1.6 Is Net Zero a Possibility? 27110.1.7 Process Drives the Design 27210.1.8 Risk-Based Approach to Sustainability 27210.1.9 Risk in a Closed Process 27310.2 Process Architecture 27310.2.1 Process Technology Impact on Footprint 27310.2.2 Tech Transfer and Scale Up 27410.2.3 Water 27610.3 Water and Water Treatment 27610.3.1 Incoming City Water 27710.3.2 Filtration and Softening 27710.3.3 Deionization and Reverse Osmosis 27810.3.4 Water for Injection (WFI) 27910.3.4.1 Ambient, Intermediate, and Hot WFI Requirements 27910.3.5 Clean Steam 27910.3.6 Black Utilities 28010.3.7 Wastewater Treatment 28010.4 Energy Efficiency 28110.4.1 Building Envelope and Materials 28110.4.2 Heating, Ventilation, and Air Conditioning (HVAC) 28210.4.2.1 Once-Through HVAC Versus Recirculation 28310.4.2.2 Filtration 28310.4.2.3 Primary–Secondary Air 28310.4.2.4 Setback Strategies 28310.4.3 Chilled Water 28510.4.3.1 Chilled Water and the HVAC System 28610.4.3.2 Chilled Water Generation 28610.4.3.3 Chilled Water Analysis and Design 28610.4.3.4 Free Cooling Opportunities 28810.4.3.5 Cooling Tower Design 28910.4.4 Steam 28910.4.4.1 Steam Optimization 28910.4.5 Compressed Air 29110.4.5.1 Air- and Water-Cooled Air Compressors 29310.4.5.2 Drier Technology 29310.4.6 Nitrogen 29410.4.7 Retro Commissioning 29410.4.8 Maintenance and Operations Best Practices 29710.5 Conclusion 300Acknowledgments 301References 30111 Technology’s Impact on the Biomanufacturing Facility of the Future 305Jeffery Odum and Mark F. Witcher11.1 Introduction 30511.2 The Enabling Technologies 30711.2.1 Process Platform Improvements 30711.2.2 Single-Use Technology 30811.2.3 Process Automation 31111.3 Elements of a Biomanufacturing Enterprise 31111.4 Evolution of the Facility of the Future 31311.5 The Future—Summary and Conclusions 320References 321Glossary 323Index 329

Jeffery Odum, CPIP is the Managing Partner of the Strategic Manufacturing Concept Group, and a Global Technology Partner at NNE in the US Office located in Durham, North Carolina and a Teaching Fellow in the BTEC program at North Carolina State University. Michael C. Flickinger, PhD is the Associate Director for Academic Programs at the Golden LEAF Biomanufacturing Training and Education Center (BTEC) and a Professor of Chemical and Biomolecular Engineering at North Carolina State University, Raleigh, North Carolina.

• Contributors xvForeword xviiPreface xix1 Introduction to Biomanufacturing 1Mark F. Witcher1.1 Introduction 11.2 The Basics Constituents of Biopharmaceuticals 21.2.1 Proteins 31.2.2 Nucleic Acids (DNA and RNA) 51.2.3 Cells 61.3 Enterprise Element #1—Manufacturing Processes 81.3.1 Process—Unit Operations 81.3.2 Upstream Processes—Inoculum through Production Bioreactor 91.3.3 Upstream Processes—Harvest and Recovery 121.3.3.1 Normal Filtration 121.3.3.2 Centrifuge 131.3.3.3 Cell Disruption 131.3.4 Downstream Processes 131.3.4.1 Viral Clearance 141.3.4.2 Tangential Flow Filtration 151.3.4.3 Chromatography 161.3.5 Process Performance and Control 191.3.6 Process—Equipment 221.3.7 Process—Materials 231.4 Enterprise Element #2—Manufacturing Facility 231.4.1 Facility—Layout 231.4.2 Facility—Environment 251.4.3 Clean Rooms/CNC Spaces 251.4.4 HVAC—Heating Ventilation and Air-Conditioning 261.4.5 Surfaces 301.4.6 Facility—Utilities Systems 301.4.7 Facility—Control Systems 311.5 Enterprise Element #3—Manufacturing Infrastructure 311.5.1 Infrastructure—People (Operating Staff) 321.5.2 Infrastructure—Enterprise Practices and Procedures 321.6 Controlling the Manufacturing Enterprise 331.7 Summary 35References 362 Product–Process–Facility Relationship 39Jeffery Odum2.1 Introduction 392.2 The Characteristics of Biological Therapeutic Products 402.3 Understanding the Attributes 422.3.1 Product Quality Attributes 442.3.2 Process Parameters 442.3.3 Facility Attributes 452.4 Factors that Impact Facility Design 462.4.1 Facility Types 472.4.1.1 Product Development Facilities 472.4.1.2 Pilot/Clinical 492.4.1.3 Commercial Manufacturing 542.4.2 Comparisons of the Facility Types 54References 543 Regulatory Considerations of Biomanufacturing Facilities 55Kip Priesmeyer3.1 Introduction 553.2 Regulatory “Uncertainty,” A Two-Way Street 563.3 Design with the Patient in Mind: Assess the Patient, Product, Process, and Plant 583.4 Laws, Regulations, and Guidelines: Historical Background 603.5 Global Guidance Documents 643.6 Quality Systems and Risk Management 663.7 Product Changeover and Regulatory Assessment of Cleaning Validation 703.8 Control Strategy 743.9 Contract Manufacturing Organizations 773.10 FDA Inspections of Biopharm Facilities and Regulators’ Priorities 803.11 Regulatory Meetings 843.12 Conclusion 85References 884 Biopharmaceutical Facility Design and Validation 91Jeffery Odum4.1 Introduction 914.2 Designing for Compliance 924.2.1 Facility Considerations 934.2.2 Product–Process–Facility Integration 944.2.3 The Role of Quality by Design 944.3 Risk Management 1024.4 Qualification/Verification 1054.5 Process Validation 1104.6 List of Abbreviations 113References 1155 Closed Systems in Bioprocessing 117Jeffery Odum5.1 Introduction 1175.2 Definition of Closed Systems 1175.3 Closed System Design 1195.4 Impact on Facility Design 1215.5 Impact on Operations 1235.6 Summary 127References 1276 Aseptic Manufacturing Considerations for Biomanufacturing Facility Design 129Jeffery Odum, Hartmut Schaz, and Larry Pressley6.1 Introduction 1296.2 The Relationship to Biological Products 1306.3 Process Attributes—Product Protection 1306.3.1 System Closure 1316.3.2 Segregation Strategy 1336.4 Facility Design 1346.5 Critical Area 137References 1417 Facility Control of Microorganisms: Containment and Contamination 143Jonathan Crane7.1 Introduction 1437.2 Design Principles for Controlling Microorganisms 1447.2.1 Planning Concepts 1457.2.2 Physical Barriers 1457.2.3 Engineering Systems 1467.2.4 Containment and Isolation Equipment 1507.2.5 Design to Support Operational Protocols 1517.3 Controlling Viable Environmental Particulates 1517.4 Reducing the Transport of Mold into the Bioprocess Facility 1537.4.1 Environmental Zoning 1537.4.2 Filtration of Molds and Mold Spores from Incoming Air 1557.5 Reducing Mold Sources within the Bioprocess Facility 1567.5.1 Cleaning and Decontamination 1577.6 Biocontainment: An Overlay to Process Design 1577.7 The Biocontainment Regulatory Environment 1597.7.1 Laboratory-Scale Use and Use in Animal Models of Disease 1607.7.2 Large-Scale Use of Pathogens 1617.7.3 Animal and Plant Pathogens 1627.7.4 Genetically Modified Organisms (GMO) and Synthesized Organisms 1637.7.5 Toxins 1637.7.6 Allergens and Biologically Active Products 1647.7.7 Biosecurity 1647.8 Principles of Biosafety 1657.8.1 Risk Groups 1657.8.2 Biosafety Levels 1657.9 Principles of Biocontainment Facility Design 1677.9.1 Risk Assessment 1687.9.2 Primary Containment 1687.9.3 Secondary Containment 1697.9.4 Impact of Scale and Process 1707.10 Design for the Entire Process 1717.10.1 Upstream Process Facilities 1727.10.2 Downstream Process Facilities 1737.10.3 Fill and Finish Facilities 1737.10.4 Quality Control Laboratory Facilities 1737.10.5 Cross-contamination “Live” to “Nonlive” 1737.11 Conclusion 173References 174Further Reading 1768 Process-Based Laboratory Design 177Henriette Schubert and Flemming K. Nielsen8.1 Introduction 1778.2 Areas of Application/Scope 1778.3 Translation of Process Elements into Laboratory Architecture 1798.4 Key Steps in Planning Approach and Methodology 1808.4.1 Laboratory Planning Process 1808.4.1.1 Project Initiation (Analyze Data) 1818.4.1.2 Conceptual Design (Develop Concepts) 1818.4.1.3 Basic Design and Detailed Design (Develop Solutions) 1818.4.2 Creating an Informed Basis for Design 1828.4.2.1 Mapping of Design Drivers and Project Targets 1838.4.2.2 Designing for the Desired Laboratory Work Culture 1858.4.2.3 Risk Assessment (GMP, Biocontainment/High Potent Product Containment) 1888.4.2.4 Operational Workflow Mapping and Visual Planning 1938.4.2.5 Functional Adjacency Analysis (Function/Relation) 1958.4.2.6 Laboratory Typologies as a Planning Tool 1978.5 Laboratory Concept Development 2008.5.1 Planning Considerations for Laboratory Concepts 2008.5.1.1 Area Distribution 2008.5.1.2 Laboratory Concepts 2018.5.1.3 Capacity Considerations 2018.5.1.4 Translating Strategic Project Drivers into Laboratory Concepts 2028.5.1.5 Generic Versus Tailor-Made/Specialized Laboratory Concepts 2038.5.1.6 Typical Objectives for Laboratory Types (R&D, QC) 2048.5.1.7 Laboratory Planning Modules and Floor Height 2068.5.2 Mechanical Considerations 2088.6 SHE Considerations 2098.7 Glossary 2108.8 List of Abbreviations 210References 2119 Case Study: Pharmaceutical Pilot Plant Design and Operation 213Beth H. Junker9.1 Introduction 2139.2 Operational Concepts and Processing Requirements 2159.3 Design 2179.3.1 Process Equipment 2199.3.2 Utilities 2239.3.2.1 Product Contact 2249.3.2.2 Nonproduct Contact 2279.3.2.3 HVAC 2289.3.3 Containment 2309.3.3.1 Product Protection 2319.3.3.2 Environmental Protection 2319.3.3.3 Personnel Protection 2329.3.4 Instrumentation 2329.3.5 Automation and Control 2339.3.6 Data Acquisition and Archiving 2359.3.7 Warehousing 2369.3.8 Back-Up Systems/Redundancy 2379.3.9 Future Expansion/Modification 2379.4 Operation 2389.4.1 Maintenance 2389.4.1.1 Preventative 2389.4.1.2 Ongoing 2409.4.1.3 Calibrations 2409.4.1.4 Modifications/Change Control 2419.4.2 Staffing 2429.4.3 Laboratory Support 2439.4.4 Standard Operating Procedures (SOPs) 2439.4.5 Safety 2479.4.6 Training 2499.4.7 Validation 2509.4.8 Facility Records and Manufacturing Execution Systems (MES) 251References 25310 Addressing Sustainability in Biomanufacturing Facility Design 259Josh Capparella, Samuel Colucci, Daniel Conner, Robert Dick, and Amanda Weko10.1 Introduction 25910.1.1 Economics of Sustainability 26110.1.2 Energy Benchmarking in the Biopharmaceutical Industry 26110.1.3 Integrating Sustainability into the Design Process 26110.1.3.1 Building Sustainability into the Process Early 26110.1.3.2 Building Information Modeling 26210.1.3.3 Integrated Utilities Approach 26210.1.4 Sustainable Building Benchmarking 26310.1.4.1 Commercial Building Benchmarking 26310.1.4.2 Biopharmaceutical Building Benchmarking 26510.1.4.3 Variations in Benchmarking Data 26610.1.4.4 Making a Meaningful Impact to Facility Energy Reductions 26710.1.4.5 Energy Efficiency: Current Trends 26810.1.5 Cost of Utilities 26910.1.6 Is Net Zero a Possibility? 27110.1.7 Process Drives the Design 27210.1.8 Risk-Based Approach to Sustainability 27210.1.9 Risk in a Closed Process 27310.2 Process Architecture 27310.2.1 Process Technology Impact on Footprint 27310.2.2 Tech Transfer and Scale Up 27410.2.3 Water 27610.3 Water and Water Treatment 27610.3.1 Incoming City Water 27710.3.2 Filtration and Softening 27710.3.3 Deionization and Reverse Osmosis 27810.3.4 Water for Injection (WFI) 27910.3.4.1 Ambient, Intermediate, and Hot WFI Requirements 27910.3.5 Clean Steam 27910.3.6 Black Utilities 28010.3.7 Wastewater Treatment 28010.4 Energy Efficiency 28110.4.1 Building Envelope and Materials 28110.4.2 Heating, Ventilation, and Air Conditioning (HVAC) 28210.4.2.1 Once-Through HVAC Versus Recirculation 28310.4.2.2 Filtration 28310.4.2.3 Primary–Secondary Air 28310.4.2.4 Setback Strategies 28310.4.3 Chilled Water 28510.4.3.1 Chilled Water and the HVAC System 28610.4.3.2 Chilled Water Generation 28610.4.3.3 Chilled Water Analysis and Design 28610.4.3.4 Free Cooling Opportunities 28810.4.3.5 Cooling Tower Design 28910.4.4 Steam 28910.4.4.1 Steam Optimization 28910.4.5 Compressed Air 29110.4.5.1 Air- and Water-Cooled Air Compressors 29310.4.5.2 Drier Technology 29310.4.6 Nitrogen 29410.4.7 Retro Commissioning 29410.4.8 Maintenance and Operations Best Practices 29710.5 Conclusion 300Acknowledgments 301References 30111 Technology’s Impact on the Biomanufacturing Facility of the Future 305Jeffery Odum and Mark F. Witcher11.1 Introduction 30511.2 The Enabling Technologies 30711.2.1 Process Platform Improvements 30711.2.2 Single-Use Technology 30811.2.3 Process Automation 31111.3 Elements of a Biomanufacturing Enterprise 31111.4 Evolution of the Facility of the Future 31311.5 The Future—Summary and Conclusions 320References 321Glossary 323Index 329

Jeffery Odum, CPIP is the Managing Partner of the Strategic Manufacturing Concept Group, and a Global Technology Partner at NNE in the US Office located in Durham, North Carolina and a Teaching Fellow in the BTEC program at North Carolina State University. Michael C. Flickinger, PhD is the Associate Director for Academic Programs at the Golden LEAF Biomanufacturing Training and Education Center (BTEC) and a Professor of Chemical and Biomolecular Engineering at North Carolina State University, Raleigh, North Carolina.

• Contributors xvForeword xviiPreface xix1 Introduction to Biomanufacturing 1Mark F. Witcher1.1 Introduction 11.2 The Basics Constituents of Biopharmaceuticals 21.2.1 Proteins 31.2.2 Nucleic Acids (DNA and RNA) 51.2.3 Cells 61.3 Enterprise Element #1—Manufacturing Processes 81.3.1 Process—Unit Operations 81.3.2 Upstream Processes—Inoculum through Production Bioreactor 91.3.3 Upstream Processes—Harvest and Recovery 121.3.3.1 Normal Filtration 121.3.3.2 Centrifuge 131.3.3.3 Cell Disruption 131.3.4 Downstream Processes 131.3.4.1 Viral Clearance 141.3.4.2 Tangential Flow Filtration 151.3.4.3 Chromatography 161.3.5 Process Performance and Control 191.3.6 Process—Equipment 221.3.7 Process—Materials 231.4 Enterprise Element #2—Manufacturing Facility 231.4.1 Facility—Layout 231.4.2 Facility—Environment 251.4.3 Clean Rooms/CNC Spaces 251.4.4 HVAC—Heating Ventilation and Air-Conditioning 261.4.5 Surfaces 301.4.6 Facility—Utilities Systems 301.4.7 Facility—Control Systems 311.5 Enterprise Element #3—Manufacturing Infrastructure 311.5.1 Infrastructure—People (Operating Staff) 321.5.2 Infrastructure—Enterprise Practices and Procedures 321.6 Controlling the Manufacturing Enterprise 331.7 Summary 35References 362 Product–Process–Facility Relationship 39Jeffery Odum2.1 Introduction 392.2 The Characteristics of Biological Therapeutic Products 402.3 Understanding the Attributes 422.3.1 Product Quality Attributes 442.3.2 Process Parameters 442.3.3 Facility Attributes 452.4 Factors that Impact Facility Design 462.4.1 Facility Types 472.4.1.1 Product Development Facilities 472.4.1.2 Pilot/Clinical 492.4.1.3 Commercial Manufacturing 542.4.2 Comparisons of the Facility Types 54References 543 Regulatory Considerations of Biomanufacturing Facilities 55Kip Priesmeyer3.1 Introduction 553.2 Regulatory “Uncertainty,” A Two-Way Street 563.3 Design with the Patient in Mind: Assess the Patient, Product, Process, and Plant 583.4 Laws, Regulations, and Guidelines: Historical Background 603.5 Global Guidance Documents 643.6 Quality Systems and Risk Management 663.7 Product Changeover and Regulatory Assessment of Cleaning Validation 703.8 Control Strategy 743.9 Contract Manufacturing Organizations 773.10 FDA Inspections of Biopharm Facilities and Regulators’ Priorities 803.11 Regulatory Meetings 843.12 Conclusion 85References 884 Biopharmaceutical Facility Design and Validation 91Jeffery Odum4.1 Introduction 914.2 Designing for Compliance 924.2.1 Facility Considerations 934.2.2 Product–Process–Facility Integration 944.2.3 The Role of Quality by Design 944.3 Risk Management 1024.4 Qualification/Verification 1054.5 Process Validation 1104.6 List of Abbreviations 113References 1155 Closed Systems in Bioprocessing 117Jeffery Odum5.1 Introduction 1175.2 Definition of Closed Systems 1175.3 Closed System Design 1195.4 Impact on Facility Design 1215.5 Impact on Operations 1235.6 Summary 127References 1276 Aseptic Manufacturing Considerations for Biomanufacturing Facility Design 129Jeffery Odum, Hartmut Schaz, and Larry Pressley6.1 Introduction 1296.2 The Relationship to Biological Products 1306.3 Process Attributes—Product Protection 1306.3.1 System Closure 1316.3.2 Segregation Strategy 1336.4 Facility Design 1346.5 Critical Area 137References 1417 Facility Control of Microorganisms: Containment and Contamination 143Jonathan Crane7.1 Introduction 1437.2 Design Principles for Controlling Microorganisms 1447.2.1 Planning Concepts 1457.2.2 Physical Barriers 1457.2.3 Engineering Systems 1467.2.4 Containment and Isolation Equipment 1507.2.5 Design to Support Operational Protocols 1517.3 Controlling Viable Environmental Particulates 1517.4 Reducing the Transport of Mold into the Bioprocess Facility 1537.4.1 Environmental Zoning 1537.4.2 Filtration of Molds and Mold Spores from Incoming Air 1557.5 Reducing Mold Sources within the Bioprocess Facility 1567.5.1 Cleaning and Decontamination 1577.6 Biocontainment: An Overlay to Process Design 1577.7 The Biocontainment Regulatory Environment 1597.7.1 Laboratory-Scale Use and Use in Animal Models of Disease 1607.7.2 Large-Scale Use of Pathogens 1617.7.3 Animal and Plant Pathogens 1627.7.4 Genetically Modified Organisms (GMO) and Synthesized Organisms 1637.7.5 Toxins 1637.7.6 Allergens and Biologically Active Products 1647.7.7 Biosecurity 1647.8 Principles of Biosafety 1657.8.1 Risk Groups 1657.8.2 Biosafety Levels 1657.9 Principles of Biocontainment Facility Design 1677.9.1 Risk Assessment 1687.9.2 Primary Containment 1687.9.3 Secondary Containment 1697.9.4 Impact of Scale and Process 1707.10 Design for the Entire Process 1717.10.1 Upstream Process Facilities 1727.10.2 Downstream Process Facilities 1737.10.3 Fill and Finish Facilities 1737.10.4 Quality Control Laboratory Facilities 1737.10.5 Cross-contamination “Live” to “Nonlive” 1737.11 Conclusion 173References 174Further Reading 1768 Process-Based Laboratory Design 177Henriette Schubert and Flemming K. Nielsen8.1 Introduction 1778.2 Areas of Application/Scope 1778.3 Translation of Process Elements into Laboratory Architecture 1798.4 Key Steps in Planning Approach and Methodology 1808.4.1 Laboratory Planning Process 1808.4.1.1 Project Initiation (Analyze Data) 1818.4.1.2 Conceptual Design (Develop Concepts) 1818.4.1.3 Basic Design and Detailed Design (Develop Solutions) 1818.4.2 Creating an Informed Basis for Design 1828.4.2.1 Mapping of Design Drivers and Project Targets 1838.4.2.2 Designing for the Desired Laboratory Work Culture 1858.4.2.3 Risk Assessment (GMP, Biocontainment/High Potent Product Containment) 1888.4.2.4 Operational Workflow Mapping and Visual Planning 1938.4.2.5 Functional Adjacency Analysis (Function/Relation) 1958.4.2.6 Laboratory Typologies as a Planning Tool 1978.5 Laboratory Concept Development 2008.5.1 Planning Considerations for Laboratory Concepts 2008.5.1.1 Area Distribution 2008.5.1.2 Laboratory Concepts 2018.5.1.3 Capacity Considerations 2018.5.1.4 Translating Strategic Project Drivers into Laboratory Concepts 2028.5.1.5 Generic Versus Tailor-Made/Specialized Laboratory Concepts 2038.5.1.6 Typical Objectives for Laboratory Types (R&D, QC) 2048.5.1.7 Laboratory Planning Modules and Floor Height 2068.5.2 Mechanical Considerations 2088.6 SHE Considerations 2098.7 Glossary 2108.8 List of Abbreviations 210References 2119 Case Study: Pharmaceutical Pilot Plant Design and Operation 213Beth H. Junker9.1 Introduction 2139.2 Operational Concepts and Processing Requirements 2159.3 Design 2179.3.1 Process Equipment 2199.3.2 Utilities 2239.3.2.1 Product Contact 2249.3.2.2 Nonproduct Contact 2279.3.2.3 HVAC 2289.3.3 Containment 2309.3.3.1 Product Protection 2319.3.3.2 Environmental Protection 2319.3.3.3 Personnel Protection 2329.3.4 Instrumentation 2329.3.5 Automation and Control 2339.3.6 Data Acquisition and Archiving 2359.3.7 Warehousing 2369.3.8 Back-Up Systems/Redundancy 2379.3.9 Future Expansion/Modification 2379.4 Operation 2389.4.1 Maintenance 2389.4.1.1 Preventative 2389.4.1.2 Ongoing 2409.4.1.3 Calibrations 2409.4.1.4 Modifications/Change Control 2419.4.2 Staffing 2429.4.3 Laboratory Support 2439.4.4 Standard Operating Procedures (SOPs) 2439.4.5 Safety 2479.4.6 Training 2499.4.7 Validation 2509.4.8 Facility Records and Manufacturing Execution Systems (MES) 251References 25310 Addressing Sustainability in Biomanufacturing Facility Design 259Josh Capparella, Samuel Colucci, Daniel Conner, Robert Dick, and Amanda Weko10.1 Introduction 25910.1.1 Economics of Sustainability 26110.1.2 Energy Benchmarking in the Biopharmaceutical Industry 26110.1.3 Integrating Sustainability into the Design Process 26110.1.3.1 Building Sustainability into the Process Early 26110.1.3.2 Building Information Modeling 26210.1.3.3 Integrated Utilities Approach 26210.1.4 Sustainable Building Benchmarking 26310.1.4.1 Commercial Building Benchmarking 26310.1.4.2 Biopharmaceutical Building Benchmarking 26510.1.4.3 Variations in Benchmarking Data 26610.1.4.4 Making a Meaningful Impact to Facility Energy Reductions 26710.1.4.5 Energy Efficiency: Current Trends 26810.1.5 Cost of Utilities 26910.1.6 Is Net Zero a Possibility? 27110.1.7 Process Drives the Design 27210.1.8 Risk-Based Approach to Sustainability 27210.1.9 Risk in a Closed Process 27310.2 Process Architecture 27310.2.1 Process Technology Impact on Footprint 27310.2.2 Tech Transfer and Scale Up 27410.2.3 Water 27610.3 Water and Water Treatment 27610.3.1 Incoming City Water 27710.3.2 Filtration and Softening 27710.3.3 Deionization and Reverse Osmosis 27810.3.4 Water for Injection (WFI) 27910.3.4.1 Ambient, Intermediate, and Hot WFI Requirements 27910.3.5 Clean Steam 27910.3.6 Black Utilities 28010.3.7 Wastewater Treatment 28010.4 Energy Efficiency 28110.4.1 Building Envelope and Materials 28110.4.2 Heating, Ventilation, and Air Conditioning (HVAC) 28210.4.2.1 Once-Through HVAC Versus Recirculation 28310.4.2.2 Filtration 28310.4.2.3 Primary–Secondary Air 28310.4.2.4 Setback Strategies 28310.4.3 Chilled Water 28510.4.3.1 Chilled Water and the HVAC System 28610.4.3.2 Chilled Water Generation 28610.4.3.3 Chilled Water Analysis and Design 28610.4.3.4 Free Cooling Opportunities 28810.4.3.5 Cooling Tower Design 28910.4.4 Steam 28910.4.4.1 Steam Optimization 28910.4.5 Compressed Air 29110.4.5.1 Air- and Water-Cooled Air Compressors 29310.4.5.2 Drier Technology 29310.4.6 Nitrogen 29410.4.7 Retro Commissioning 29410.4.8 Maintenance and Operations Best Practices 29710.5 Conclusion 300Acknowledgments 301References 30111 Technology’s Impact on the Biomanufacturing Facility of the Future 305Jeffery Odum and Mark F. Witcher11.1 Introduction 30511.2 The Enabling Technologies 30711.2.1 Process Platform Improvements 30711.2.2 Single-Use Technology 30811.2.3 Process Automation 31111.3 Elements of a Biomanufacturing Enterprise 31111.4 Evolution of the Facility of the Future 31311.5 The Future—Summary and Conclusions 320References 321Glossary 323Index 329