REGINE EIBL, PHD, is a professor at the Zurich University of Applied Sciences (Switzerland), where she lectures in biotechnology and cell cultivation techniques. DIETER EIBL, PHD, is a professor at the Zurich University of Applied Sciences, where he lectures in biochemical engineering and the planning of biotechnological production facilities.

• List of Contributors xviiPreface xxiPart I Basics 11 Single‐Use Equipment in Biopharmaceutical Manufacture: A Brief Introduction 3Dieter Eibl and Regine Eibl1.1 Background 31.2 Terminology and Features 31.3 Single‐Use Systems in Production Processes for Therapeutic Proteins such as mAbs: Product Overview and Classification 51.4 Single‐Use Production Facilities 71.5 Summary and Conclusions 7Nomenclature 9References 92 Types of Single‐Use Bag Systems and Integrity Testing Methods 13Jens Rumsfeld and Regine Eibl2.1 Introduction 132.2 Bags for Fluid and Powder Handling 132.3 Bag‐Handling and Container Systems 152.4 Single‐Use Bag Systems for Freezing and Thawing 182.5 Container Closure Integrity Testing 182.6 Summary and Conclusions 22Nomenclature 22References 223 Mixing Systems for Single‐Use 25Sören Werner, Matthias Kraume, and Dieter Eibl3.1 Introduction 253.2 The Mixing Process 253.3 Single‐Use Bag Mixing Systems 273.4 Summary and Conclusions 33Nomenclature 33References 334 Single‐Use Bioreactors – An Overview 37Valentin Jossen, Regine Eibl, and Dieter Eibl4.1 Introduction 374.2 SUB History 384.3 Comparison of the Current, Most Common SUB Types 404.4 Decision Criteria for Selection of the Most Suitable SUB Type 474.5 Summary and Future Trends 48Nomenclature 48References 485 Systems for Coupling and Sampling 53Cedric Schirmer, Sebastian Rothe, Ernest Jenness, and Dieter Eibl5.1 Introduction 535.2 Components of Single‐Use Transfer Lines 535.3 Systems for Aseptic Coupling 575.4 Aseptic Disconnection 625.5 Systems for Sampling 645.6 Summary and Conclusion 66Nomenclature 66References 666 Sensors for Disposable Bioreactor Systems 69Tobias Steinwedel, Katharina Dahlmann, Dörte Solle, Thomas Scheper, Kenneth F. Reardon, and Frank Lammers6.1 Introduction 696.2 Interfaces for Sensor Technology 706.3 Considerations of Extractables and Leachables from Integrated Sensors 716.4 Optical Chemosensors 726.5 Spectroscopic Sensors 736.6 Capacitance Sensors 756.7 Electrochemical Sensors 766.8 Biosensors 786.9 Conclusions and Outlook 78Nomenclature 79References 797 Bioinformatics and Single‐Use 83Barbara A. Paldus7.1 Introduction 837.2 Bioinformatics and Single‐Use 847.3 Smart Sensors 867.4 Intelligent Control Systems 877.5 Continuous Processing 887.6 Conclusions 92Nomenclature 94References 948 Production of Disposable Bags: A Manufacturer’s Report 95Steven Vanhamel and Catherine Piton8.1 Introduction 958.2 Materials 958.4 Bag Manufacturing 1108.5 Summary and Conclusions 113Nomenclature 115References 1169 Single‐Use Downstream Processing for Biopharmaceuticals: Current State and Trends 117Britta Manser, Martin Glenz, and Marc Bisschops9.1 Introduction 1179.2 Single‐Use DSP Today 1179.3 Technologies in Single-Use DSP 1209.4 Single‐Use Continuous Downstream Processing 1219.5 Integrated and Continuous DSP 1249.6 Summary and Conclusions 124Nomenclature 124References 12510 Application of Microporous Filtration in Single‐Use Systems 127Christian Julien and Chuck Capron10.1 Introduction 12710.2 Microporous Filters 12810.3 Filter Selection 13410.4 Final Sterile Filtration 13610.5 Filter Integrity Testing 13810.6 Filter Qualification and Validation 13910.7 Summary and Conclusions 140Nomenclature 140References 14011 Extractables/Leachables from Single‐Use Equipment: Considerations from a (Bio) Pharmaceutical Manufacturer 143Alicja Sobańtka and Christian Weiner11.1 Introduction 14311.2 Regulatory Environment 14411.3 The (Bio)Pharmaceutical Manufacturer’s Approach 14611.4 The (Bio)Pharmaceutical Manufacturer’s Challenges 15311.5 Summary 15511.6 Discussion and Outlook 156Acknowledgments 156Nomenclature 157References 15712 The Single‐Use Standardization 159P.E. James Dean Vogel12.1 Introduction 15912.2 Alphabet Soup 15912.3 History 16112.4 Compare and Contrast 16112.5 Collaboration and Alignment Lead to Standardization 16212.6 General SUT Efforts 16312.7 Leachables and Extractables 16412.8 Particulates in SUT 16412.9 Change Notification 16512.10 SUT System Integrity 16512.11 SUT User Requirements 16512.12 Connectors 16512.13 SUT Design Verification 16512.14 Summary and Conclusions 166Nomenclature 166References 166Further Reading 16613 Environmental Impacts of Single‐Use Systems 169William G. Whitford, Mark A. Petrich, and William P. Flanagan13.1 Introduction 16913.2 Sustainability 16913.3 The Evolution of SU Technologies 16913.4 Implications in Sustainability 17213.5 LCA – A Holistic Methodology 17213.6 LCA Applied to SU Technologies 17313.7 Sustainability Efforts in the BioPharma Industry 17513.8 End‐of‐Life (Waste) Management 17713.9 Summary and Conclusions 178Nomenclature 178References 17814 Design Considerations Towards an Intensified Single‐Use Facility 181Gerben Zijlstra, Kai Touw, Michael Koch, and Miriam Monge14.1 Introduction 18114.2 Moving Towards Intensified and Continuous Processing 18114.3 Methodologies for Continuous and Intensified Single‐Use Bioprocessing 18314.4 Process Development for Intensified Biomanufacturing Facilities 18414.5 The Intensified Biomanufacturing Facility 18414.6 Process Automation for Commercial Manufacturing Facilities 18714.7 Intensified Upstream Processing 18714.8 Intensified Downstream Processing 18914.9 Summary and Conclusions 191Acknowledgments 191Nomenclature 191References 19115 Single‐Use Technologies in Biopharmaceutical Manufacturing: A 10‐Year Review of Trends and the Future 193Ronald A. Rader and Eric S. Langer15.1 Introduction 19315.2 Background 19315.3 Methods 19415.4 Results 19415.5 Discussion 19715.6 Conclusions 199Nomenclature 200References 200Part II Application Reports and Case Studies 20116 Single‐Use Process Platforms for Responsive and Cost‐Effective Manufacturing 203Priyanka Gupta, Miriam Monge, Amelie Boulais, Nitin Chopra, and Nick Hutchinson16.1 Introduction 20316.2 Standardized Single‐Use Process Platforms for Biomanufacturing 20416.3 Implementing Single‐Use Process Platforms 20416.4 Economic Analysis Comparing Stainless Steel with Single‐Use Process Platforms 20716.5 Summary and Conclusions 209Nomenclature 209References 21017 Considerations on Performing Quality Risk Analysis for Production Processes with Single‐Use Systems 211Ina Pahl, Armin Hauk, Lydia Schosser, and Sonja von Orlikowski17.1 Introduction 21117.2 Quality Risk Assessment 21117.3 Terminology and Features 21217.4 Current Industrial Approach for Leachable Assessment in Biopharmaceutical Processes 21217.5 Holistic Approach to Predict Leachables for Quality Risk Assessment 21417.6 Summary and Conclusions 215Nomenclature 217References 21718 How to Assure Robustness, Sterility, and Performance of Single‐Use Systems: A Quality Approach from the Manufacturer’s Perspective 219Simone Biel and Sara Bell18.1 Introduction 21918.2 Component Qualification 21918.3 Validation of Product Design 22018.4 Manufacturing and Control 22418.5 Operator Training, Performance Culture 22518.6 Particulate Risk Mitigation 22518.7 Change Management 22518.8 Summary and Conclusions 226Nomenclature 227References 22719 How to Design and Qualify an Improved Film for Storage and Bioreactor Bags 229Lucie Delaunay, Elke Jurkiewicz, Gerhard Greller, and Magali Barbaroux19.1 Introduction22919.2 Materials, Process, and Suppliers Selection 22919.3 Biological Properties 22919.4 Specifications and Process Design Space 23119.5 Process Control Strategy 23319.6 Summary and Conclusions 233Nomenclature 233References 23320 An Approach for Rapid Manufacture and Qualification of a Single‐Use Bioreactor Prototype 235Stephan C. Kaiser20.1 Introduction 23520.2 About the Development Process of a Single‐Use Bioreactor 23520.3 Summary and Conclusions 243Nomenclature 244References 24421 Single‐Use Bioreactor Platform for Microbial Fermentation 247Parrish M. Galliher, Patrick Guertin, Ken Clapp, Colin Tuohey, Rick Damren, Yasser Kehail, Vincent Colombie, and Andreas Castan21.1 Introduction 24721.2 General Design Basis for Microbial SUFs 24721.3 SUF Design Criteria and Approach – Heat Transfer 24721.4 SUF Design Criteria and Approach – Oxygen Transfer 24921.5 SUF Design Criteria and Approach – Mixing 25121.6 Operational Considerations for SUFs 25221.7 Case Studies 25221.8 Summary and Conclusions 256Nomenclature 257References 25822 Engineering Parameters in Single‐Use Bioreactors: Flow, Mixing, Aeration, and Suspension 259Martina Micheletti and Andrea Ducci22.1 Introduction 25922.2 Stirred Bioreactors 25922.3 Orbitally Shaken Bioreactors 26222.4 Rocking Bag 26722.5 Summary and Conclusions 268Nomenclature 268References 26823 Alluvial Filtration: An Effective and Economical Solution for Midstream Application (e.g. Cell and Host Cell Protein Removal) 271Ralph Daumke, Vasily Medvedev, Tiago Albano, and Fabien Rousset23.1 Introduction 27123.2 Case Study 2: Cell Removal 27223.3 Case Study 2: HCP Removal 27523.4 Summary and Conclusions 276Nomenclature 277References 27724 Single‐Use Continuous Downstream Processing for Biopharmaceutical Products 279Marc Bisschops, Britta Manser, and Martin Glenz24.1 Introduction 27924.2 Continuous Multicolumn Chromatography 27924.3 Single‐Use Continuous Downstream Processing 28024.4 Summary and Conclusions 283References 28325 Single‐Use Technology for Formulation and Filling Applications 285Christophe Pierlot, Alain Vanhecke, Kevin Thompson, Rainer Gloeckler, and Daniel Kehl25.1 Introduction 28525.2 Challenges in Formulation and Filling 28525.3 End‐User Requirements 28625.4 Quality by Design 28725.5 Hardware Design and Usability 28825.6 Single‐Use Technology, Arrangement, and Operation 29025.7 Summary and Conclusions 293Nomenclature 294References 29426 Facility Design Considerations for Mammalian Cell Culture 295Sue Walker26.1 Introduction 29526.2 Generic Case Study 29526.3 Summary and Conclusions 301Nomenclature 301References 30127 Progress in the Development of Single‐Use Solutions in Antibody–Drug Conjugate (ADC) Manufacturing 303Diego R. Schmidhalter, Stephan Elzner, and Romeo Schmid27.1 Introduction 30327.2 Challenges for the Use of Disposables in ADC Processes 30427.3 Key Unit Operations 30627.4 Cysteine Conjugation Process – An ADC Production Process Case Study 30827.5 Summary and Conclusions 309Acknowledgment 309Nomenclature 309References 31028 Single‐Use Processing as a Safe and Convenient Way to Develop and Manufacture Moss‐Derived Biopharmaceuticals 311Holger Niederkrüger, Andreas Busch, Paulina Dabrowska‐Schlepp, Nicola Krieghoff, Andreas Schaaf, and Thomas Frischmuth28.1 Introduction 31128.2 Case Study 31128.3 Summary and Outlook 317Nomenclature 317References 31829 Single‐Use Technologies Used in Cell and Gene Therapy Manufacturing Need to Fulfill Higher and Novel Requirements: How Can this Challenge Be Addressed? 319Alain Pralong and Angélique Palumbo29.1 Introduction 31929.2 Promise of Cell and Gene Therapy 32029.3 Considerations for Biopharmaceutical Industry and Conclusion 322Nomenclature 325References 32530 Single‐Use Bioreactors for Manufacturing of Immune Cell Therapeutics 327Ralf Pörtner, Christian Sebald, Shreemanta K. Parida, and Hans Hoffmeister30.1 Introduction 32730.2 The Particular Nature of Immune Cell Therapeutics 32730.3 Uncertain Mass Production of Immune Cells for Therapy 32830.4 Technical Standards Required for Immune Cell ATMP Manufacturing 32930.5 Techniques for Expansion of Immune Cells 32930.6 Case Study ZRP System Consisting of GMP Breeder, Control Unit, and Software 33030.7 Summary and Conclusions 330Nomenclature 332References 332Index 335

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REGINE EIBL, PHD, is a professor at the Zurich University of Applied Sciences (Switzerland), where she lectures in biotechnology and cell cultivation techniques. DIETER EIBL, PHD, is a professor at the Zurich University of Applied Sciences, where he lectures in biochemical engineering and the planning of biotechnological production facilities.

• List of Contributors xviiPreface xxiPart I Basics 11 Single‐Use Equipment in Biopharmaceutical Manufacture: A Brief Introduction 3Dieter Eibl and Regine Eibl1.1 Background 31.2 Terminology and Features 31.3 Single‐Use Systems in Production Processes for Therapeutic Proteins such as mAbs: Product Overview and Classification 51.4 Single‐Use Production Facilities 71.5 Summary and Conclusions 7Nomenclature 9References 92 Types of Single‐Use Bag Systems and Integrity Testing Methods 13Jens Rumsfeld and Regine Eibl2.1 Introduction 132.2 Bags for Fluid and Powder Handling 132.3 Bag‐Handling and Container Systems 152.4 Single‐Use Bag Systems for Freezing and Thawing 182.5 Container Closure Integrity Testing 182.6 Summary and Conclusions 22Nomenclature 22References 223 Mixing Systems for Single‐Use 25Sören Werner, Matthias Kraume, and Dieter Eibl3.1 Introduction 253.2 The Mixing Process 253.3 Single‐Use Bag Mixing Systems 273.4 Summary and Conclusions 33Nomenclature 33References 334 Single‐Use Bioreactors – An Overview 37Valentin Jossen, Regine Eibl, and Dieter Eibl4.1 Introduction 374.2 SUB History 384.3 Comparison of the Current, Most Common SUB Types 404.4 Decision Criteria for Selection of the Most Suitable SUB Type 474.5 Summary and Future Trends 48Nomenclature 48References 485 Systems for Coupling and Sampling 53Cedric Schirmer, Sebastian Rothe, Ernest Jenness, and Dieter Eibl5.1 Introduction 535.2 Components of Single‐Use Transfer Lines 535.3 Systems for Aseptic Coupling 575.4 Aseptic Disconnection 625.5 Systems for Sampling 645.6 Summary and Conclusion 66Nomenclature 66References 666 Sensors for Disposable Bioreactor Systems 69Tobias Steinwedel, Katharina Dahlmann, Dörte Solle, Thomas Scheper, Kenneth F. Reardon, and Frank Lammers6.1 Introduction 696.2 Interfaces for Sensor Technology 706.3 Considerations of Extractables and Leachables from Integrated Sensors 716.4 Optical Chemosensors 726.5 Spectroscopic Sensors 736.6 Capacitance Sensors 756.7 Electrochemical Sensors 766.8 Biosensors 786.9 Conclusions and Outlook 78Nomenclature 79References 797 Bioinformatics and Single‐Use 83Barbara A. Paldus7.1 Introduction 837.2 Bioinformatics and Single‐Use 847.3 Smart Sensors 867.4 Intelligent Control Systems 877.5 Continuous Processing 887.6 Conclusions 92Nomenclature 94References 948 Production of Disposable Bags: A Manufacturer’s Report 95Steven Vanhamel and Catherine Piton8.1 Introduction 958.2 Materials 958.4 Bag Manufacturing 1108.5 Summary and Conclusions 113Nomenclature 115References 1169 Single‐Use Downstream Processing for Biopharmaceuticals: Current State and Trends 117Britta Manser, Martin Glenz, and Marc Bisschops9.1 Introduction 1179.2 Single‐Use DSP Today 1179.3 Technologies in Single-Use DSP 1209.4 Single‐Use Continuous Downstream Processing 1219.5 Integrated and Continuous DSP 1249.6 Summary and Conclusions 124Nomenclature 124References 12510 Application of Microporous Filtration in Single‐Use Systems 127Christian Julien and Chuck Capron10.1 Introduction 12710.2 Microporous Filters 12810.3 Filter Selection 13410.4 Final Sterile Filtration 13610.5 Filter Integrity Testing 13810.6 Filter Qualification and Validation 13910.7 Summary and Conclusions 140Nomenclature 140References 14011 Extractables/Leachables from Single‐Use Equipment: Considerations from a (Bio) Pharmaceutical Manufacturer 143Alicja Sobańtka and Christian Weiner11.1 Introduction 14311.2 Regulatory Environment 14411.3 The (Bio)Pharmaceutical Manufacturer’s Approach 14611.4 The (Bio)Pharmaceutical Manufacturer’s Challenges 15311.5 Summary 15511.6 Discussion and Outlook 156Acknowledgments 156Nomenclature 157References 15712 The Single‐Use Standardization 159P.E. James Dean Vogel12.1 Introduction 15912.2 Alphabet Soup 15912.3 History 16112.4 Compare and Contrast 16112.5 Collaboration and Alignment Lead to Standardization 16212.6 General SUT Efforts 16312.7 Leachables and Extractables 16412.8 Particulates in SUT 16412.9 Change Notification 16512.10 SUT System Integrity 16512.11 SUT User Requirements 16512.12 Connectors 16512.13 SUT Design Verification 16512.14 Summary and Conclusions 166Nomenclature 166References 166Further Reading 16613 Environmental Impacts of Single‐Use Systems 169William G. Whitford, Mark A. Petrich, and William P. Flanagan13.1 Introduction 16913.2 Sustainability 16913.3 The Evolution of SU Technologies 16913.4 Implications in Sustainability 17213.5 LCA – A Holistic Methodology 17213.6 LCA Applied to SU Technologies 17313.7 Sustainability Efforts in the BioPharma Industry 17513.8 End‐of‐Life (Waste) Management 17713.9 Summary and Conclusions 178Nomenclature 178References 17814 Design Considerations Towards an Intensified Single‐Use Facility 181Gerben Zijlstra, Kai Touw, Michael Koch, and Miriam Monge14.1 Introduction 18114.2 Moving Towards Intensified and Continuous Processing 18114.3 Methodologies for Continuous and Intensified Single‐Use Bioprocessing 18314.4 Process Development for Intensified Biomanufacturing Facilities 18414.5 The Intensified Biomanufacturing Facility 18414.6 Process Automation for Commercial Manufacturing Facilities 18714.7 Intensified Upstream Processing 18714.8 Intensified Downstream Processing 18914.9 Summary and Conclusions 191Acknowledgments 191Nomenclature 191References 19115 Single‐Use Technologies in Biopharmaceutical Manufacturing: A 10‐Year Review of Trends and the Future 193Ronald A. Rader and Eric S. Langer15.1 Introduction 19315.2 Background 19315.3 Methods 19415.4 Results 19415.5 Discussion 19715.6 Conclusions 199Nomenclature 200References 200Part II Application Reports and Case Studies 20116 Single‐Use Process Platforms for Responsive and Cost‐Effective Manufacturing 203Priyanka Gupta, Miriam Monge, Amelie Boulais, Nitin Chopra, and Nick Hutchinson16.1 Introduction 20316.2 Standardized Single‐Use Process Platforms for Biomanufacturing 20416.3 Implementing Single‐Use Process Platforms 20416.4 Economic Analysis Comparing Stainless Steel with Single‐Use Process Platforms 20716.5 Summary and Conclusions 209Nomenclature 209References 21017 Considerations on Performing Quality Risk Analysis for Production Processes with Single‐Use Systems 211Ina Pahl, Armin Hauk, Lydia Schosser, and Sonja von Orlikowski17.1 Introduction 21117.2 Quality Risk Assessment 21117.3 Terminology and Features 21217.4 Current Industrial Approach for Leachable Assessment in Biopharmaceutical Processes 21217.5 Holistic Approach to Predict Leachables for Quality Risk Assessment 21417.6 Summary and Conclusions 215Nomenclature 217References 21718 How to Assure Robustness, Sterility, and Performance of Single‐Use Systems: A Quality Approach from the Manufacturer’s Perspective 219Simone Biel and Sara Bell18.1 Introduction 21918.2 Component Qualification 21918.3 Validation of Product Design 22018.4 Manufacturing and Control 22418.5 Operator Training, Performance Culture 22518.6 Particulate Risk Mitigation 22518.7 Change Management 22518.8 Summary and Conclusions 226Nomenclature 227References 22719 How to Design and Qualify an Improved Film for Storage and Bioreactor Bags 229Lucie Delaunay, Elke Jurkiewicz, Gerhard Greller, and Magali Barbaroux19.1 Introduction22919.2 Materials, Process, and Suppliers Selection 22919.3 Biological Properties 22919.4 Specifications and Process Design Space 23119.5 Process Control Strategy 23319.6 Summary and Conclusions 233Nomenclature 233References 23320 An Approach for Rapid Manufacture and Qualification of a Single‐Use Bioreactor Prototype 235Stephan C. Kaiser20.1 Introduction 23520.2 About the Development Process of a Single‐Use Bioreactor 23520.3 Summary and Conclusions 243Nomenclature 244References 24421 Single‐Use Bioreactor Platform for Microbial Fermentation 247Parrish M. Galliher, Patrick Guertin, Ken Clapp, Colin Tuohey, Rick Damren, Yasser Kehail, Vincent Colombie, and Andreas Castan21.1 Introduction 24721.2 General Design Basis for Microbial SUFs 24721.3 SUF Design Criteria and Approach – Heat Transfer 24721.4 SUF Design Criteria and Approach – Oxygen Transfer 24921.5 SUF Design Criteria and Approach – Mixing 25121.6 Operational Considerations for SUFs 25221.7 Case Studies 25221.8 Summary and Conclusions 256Nomenclature 257References 25822 Engineering Parameters in Single‐Use Bioreactors: Flow, Mixing, Aeration, and Suspension 259Martina Micheletti and Andrea Ducci22.1 Introduction 25922.2 Stirred Bioreactors 25922.3 Orbitally Shaken Bioreactors 26222.4 Rocking Bag 26722.5 Summary and Conclusions 268Nomenclature 268References 26823 Alluvial Filtration: An Effective and Economical Solution for Midstream Application (e.g. Cell and Host Cell Protein Removal) 271Ralph Daumke, Vasily Medvedev, Tiago Albano, and Fabien Rousset23.1 Introduction 27123.2 Case Study 2: Cell Removal 27223.3 Case Study 2: HCP Removal 27523.4 Summary and Conclusions 276Nomenclature 277References 27724 Single‐Use Continuous Downstream Processing for Biopharmaceutical Products 279Marc Bisschops, Britta Manser, and Martin Glenz24.1 Introduction 27924.2 Continuous Multicolumn Chromatography 27924.3 Single‐Use Continuous Downstream Processing 28024.4 Summary and Conclusions 283References 28325 Single‐Use Technology for Formulation and Filling Applications 285Christophe Pierlot, Alain Vanhecke, Kevin Thompson, Rainer Gloeckler, and Daniel Kehl25.1 Introduction 28525.2 Challenges in Formulation and Filling 28525.3 End‐User Requirements 28625.4 Quality by Design 28725.5 Hardware Design and Usability 28825.6 Single‐Use Technology, Arrangement, and Operation 29025.7 Summary and Conclusions 293Nomenclature 294References 29426 Facility Design Considerations for Mammalian Cell Culture 295Sue Walker26.1 Introduction 29526.2 Generic Case Study 29526.3 Summary and Conclusions 301Nomenclature 301References 30127 Progress in the Development of Single‐Use Solutions in Antibody–Drug Conjugate (ADC) Manufacturing 303Diego R. Schmidhalter, Stephan Elzner, and Romeo Schmid27.1 Introduction 30327.2 Challenges for the Use of Disposables in ADC Processes 30427.3 Key Unit Operations 30627.4 Cysteine Conjugation Process – An ADC Production Process Case Study 30827.5 Summary and Conclusions 309Acknowledgment 309Nomenclature 309References 31028 Single‐Use Processing as a Safe and Convenient Way to Develop and Manufacture Moss‐Derived Biopharmaceuticals 311Holger Niederkrüger, Andreas Busch, Paulina Dabrowska‐Schlepp, Nicola Krieghoff, Andreas Schaaf, and Thomas Frischmuth28.1 Introduction 31128.2 Case Study 31128.3 Summary and Outlook 317Nomenclature 317References 31829 Single‐Use Technologies Used in Cell and Gene Therapy Manufacturing Need to Fulfill Higher and Novel Requirements: How Can this Challenge Be Addressed? 319Alain Pralong and Angélique Palumbo29.1 Introduction 31929.2 Promise of Cell and Gene Therapy 32029.3 Considerations for Biopharmaceutical Industry and Conclusion 322Nomenclature 325References 32530 Single‐Use Bioreactors for Manufacturing of Immune Cell Therapeutics 327Ralf Pörtner, Christian Sebald, Shreemanta K. Parida, and Hans Hoffmeister30.1 Introduction 32730.2 The Particular Nature of Immune Cell Therapeutics 32730.3 Uncertain Mass Production of Immune Cells for Therapy 32830.4 Technical Standards Required for Immune Cell ATMP Manufacturing 32930.5 Techniques for Expansion of Immune Cells 32930.6 Case Study ZRP System Consisting of GMP Breeder, Control Unit, and Software 33030.7 Summary and Conclusions 330Nomenclature 332References 332Index 335

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REGINE EIBL, PHD, is a professor at the Zurich University of Applied Sciences (Switzerland), where she lectures in biotechnology and cell cultivation techniques. DIETER EIBL, PHD, is a professor at the Zurich University of Applied Sciences, where he lectures in biochemical engineering and the planning of biotechnological production facilities.

• List of Contributors xviiPreface xxiPart I Basics 11 Single‐Use Equipment in Biopharmaceutical Manufacture: A Brief Introduction 3Dieter Eibl and Regine Eibl1.1 Background 31.2 Terminology and Features 31.3 Single‐Use Systems in Production Processes for Therapeutic Proteins such as mAbs: Product Overview and Classification 51.4 Single‐Use Production Facilities 71.5 Summary and Conclusions 7Nomenclature 9References 92 Types of Single‐Use Bag Systems and Integrity Testing Methods 13Jens Rumsfeld and Regine Eibl2.1 Introduction 132.2 Bags for Fluid and Powder Handling 132.3 Bag‐Handling and Container Systems 152.4 Single‐Use Bag Systems for Freezing and Thawing 182.5 Container Closure Integrity Testing 182.6 Summary and Conclusions 22Nomenclature 22References 223 Mixing Systems for Single‐Use 25Sören Werner, Matthias Kraume, and Dieter Eibl3.1 Introduction 253.2 The Mixing Process 253.3 Single‐Use Bag Mixing Systems 273.4 Summary and Conclusions 33Nomenclature 33References 334 Single‐Use Bioreactors – An Overview 37Valentin Jossen, Regine Eibl, and Dieter Eibl4.1 Introduction 374.2 SUB History 384.3 Comparison of the Current, Most Common SUB Types 404.4 Decision Criteria for Selection of the Most Suitable SUB Type 474.5 Summary and Future Trends 48Nomenclature 48References 485 Systems for Coupling and Sampling 53Cedric Schirmer, Sebastian Rothe, Ernest Jenness, and Dieter Eibl5.1 Introduction 535.2 Components of Single‐Use Transfer Lines 535.3 Systems for Aseptic Coupling 575.4 Aseptic Disconnection 625.5 Systems for Sampling 645.6 Summary and Conclusion 66Nomenclature 66References 666 Sensors for Disposable Bioreactor Systems 69Tobias Steinwedel, Katharina Dahlmann, Dörte Solle, Thomas Scheper, Kenneth F. Reardon, and Frank Lammers6.1 Introduction 696.2 Interfaces for Sensor Technology 706.3 Considerations of Extractables and Leachables from Integrated Sensors 716.4 Optical Chemosensors 726.5 Spectroscopic Sensors 736.6 Capacitance Sensors 756.7 Electrochemical Sensors 766.8 Biosensors 786.9 Conclusions and Outlook 78Nomenclature 79References 797 Bioinformatics and Single‐Use 83Barbara A. Paldus7.1 Introduction 837.2 Bioinformatics and Single‐Use 847.3 Smart Sensors 867.4 Intelligent Control Systems 877.5 Continuous Processing 887.6 Conclusions 92Nomenclature 94References 948 Production of Disposable Bags: A Manufacturer’s Report 95Steven Vanhamel and Catherine Piton8.1 Introduction 958.2 Materials 958.4 Bag Manufacturing 1108.5 Summary and Conclusions 113Nomenclature 115References 1169 Single‐Use Downstream Processing for Biopharmaceuticals: Current State and Trends 117Britta Manser, Martin Glenz, and Marc Bisschops9.1 Introduction 1179.2 Single‐Use DSP Today 1179.3 Technologies in Single-Use DSP 1209.4 Single‐Use Continuous Downstream Processing 1219.5 Integrated and Continuous DSP 1249.6 Summary and Conclusions 124Nomenclature 124References 12510 Application of Microporous Filtration in Single‐Use Systems 127Christian Julien and Chuck Capron10.1 Introduction 12710.2 Microporous Filters 12810.3 Filter Selection 13410.4 Final Sterile Filtration 13610.5 Filter Integrity Testing 13810.6 Filter Qualification and Validation 13910.7 Summary and Conclusions 140Nomenclature 140References 14011 Extractables/Leachables from Single‐Use Equipment: Considerations from a (Bio) Pharmaceutical Manufacturer 143Alicja Sobańtka and Christian Weiner11.1 Introduction 14311.2 Regulatory Environment 14411.3 The (Bio)Pharmaceutical Manufacturer’s Approach 14611.4 The (Bio)Pharmaceutical Manufacturer’s Challenges 15311.5 Summary 15511.6 Discussion and Outlook 156Acknowledgments 156Nomenclature 157References 15712 The Single‐Use Standardization 159P.E. James Dean Vogel12.1 Introduction 15912.2 Alphabet Soup 15912.3 History 16112.4 Compare and Contrast 16112.5 Collaboration and Alignment Lead to Standardization 16212.6 General SUT Efforts 16312.7 Leachables and Extractables 16412.8 Particulates in SUT 16412.9 Change Notification 16512.10 SUT System Integrity 16512.11 SUT User Requirements 16512.12 Connectors 16512.13 SUT Design Verification 16512.14 Summary and Conclusions 166Nomenclature 166References 166Further Reading 16613 Environmental Impacts of Single‐Use Systems 169William G. Whitford, Mark A. Petrich, and William P. Flanagan13.1 Introduction 16913.2 Sustainability 16913.3 The Evolution of SU Technologies 16913.4 Implications in Sustainability 17213.5 LCA – A Holistic Methodology 17213.6 LCA Applied to SU Technologies 17313.7 Sustainability Efforts in the BioPharma Industry 17513.8 End‐of‐Life (Waste) Management 17713.9 Summary and Conclusions 178Nomenclature 178References 17814 Design Considerations Towards an Intensified Single‐Use Facility 181Gerben Zijlstra, Kai Touw, Michael Koch, and Miriam Monge14.1 Introduction 18114.2 Moving Towards Intensified and Continuous Processing 18114.3 Methodologies for Continuous and Intensified Single‐Use Bioprocessing 18314.4 Process Development for Intensified Biomanufacturing Facilities 18414.5 The Intensified Biomanufacturing Facility 18414.6 Process Automation for Commercial Manufacturing Facilities 18714.7 Intensified Upstream Processing 18714.8 Intensified Downstream Processing 18914.9 Summary and Conclusions 191Acknowledgments 191Nomenclature 191References 19115 Single‐Use Technologies in Biopharmaceutical Manufacturing: A 10‐Year Review of Trends and the Future 193Ronald A. Rader and Eric S. Langer15.1 Introduction 19315.2 Background 19315.3 Methods 19415.4 Results 19415.5 Discussion 19715.6 Conclusions 199Nomenclature 200References 200Part II Application Reports and Case Studies 20116 Single‐Use Process Platforms for Responsive and Cost‐Effective Manufacturing 203Priyanka Gupta, Miriam Monge, Amelie Boulais, Nitin Chopra, and Nick Hutchinson16.1 Introduction 20316.2 Standardized Single‐Use Process Platforms for Biomanufacturing 20416.3 Implementing Single‐Use Process Platforms 20416.4 Economic Analysis Comparing Stainless Steel with Single‐Use Process Platforms 20716.5 Summary and Conclusions 209Nomenclature 209References 21017 Considerations on Performing Quality Risk Analysis for Production Processes with Single‐Use Systems 211Ina Pahl, Armin Hauk, Lydia Schosser, and Sonja von Orlikowski17.1 Introduction 21117.2 Quality Risk Assessment 21117.3 Terminology and Features 21217.4 Current Industrial Approach for Leachable Assessment in Biopharmaceutical Processes 21217.5 Holistic Approach to Predict Leachables for Quality Risk Assessment 21417.6 Summary and Conclusions 215Nomenclature 217References 21718 How to Assure Robustness, Sterility, and Performance of Single‐Use Systems: A Quality Approach from the Manufacturer’s Perspective 219Simone Biel and Sara Bell18.1 Introduction 21918.2 Component Qualification 21918.3 Validation of Product Design 22018.4 Manufacturing and Control 22418.5 Operator Training, Performance Culture 22518.6 Particulate Risk Mitigation 22518.7 Change Management 22518.8 Summary and Conclusions 226Nomenclature 227References 22719 How to Design and Qualify an Improved Film for Storage and Bioreactor Bags 229Lucie Delaunay, Elke Jurkiewicz, Gerhard Greller, and Magali Barbaroux19.1 Introduction22919.2 Materials, Process, and Suppliers Selection 22919.3 Biological Properties 22919.4 Specifications and Process Design Space 23119.5 Process Control Strategy 23319.6 Summary and Conclusions 233Nomenclature 233References 23320 An Approach for Rapid Manufacture and Qualification of a Single‐Use Bioreactor Prototype 235Stephan C. Kaiser20.1 Introduction 23520.2 About the Development Process of a Single‐Use Bioreactor 23520.3 Summary and Conclusions 243Nomenclature 244References 24421 Single‐Use Bioreactor Platform for Microbial Fermentation 247Parrish M. Galliher, Patrick Guertin, Ken Clapp, Colin Tuohey, Rick Damren, Yasser Kehail, Vincent Colombie, and Andreas Castan21.1 Introduction 24721.2 General Design Basis for Microbial SUFs 24721.3 SUF Design Criteria and Approach – Heat Transfer 24721.4 SUF Design Criteria and Approach – Oxygen Transfer 24921.5 SUF Design Criteria and Approach – Mixing 25121.6 Operational Considerations for SUFs 25221.7 Case Studies 25221.8 Summary and Conclusions 256Nomenclature 257References 25822 Engineering Parameters in Single‐Use Bioreactors: Flow, Mixing, Aeration, and Suspension 259Martina Micheletti and Andrea Ducci22.1 Introduction 25922.2 Stirred Bioreactors 25922.3 Orbitally Shaken Bioreactors 26222.4 Rocking Bag 26722.5 Summary and Conclusions 268Nomenclature 268References 26823 Alluvial Filtration: An Effective and Economical Solution for Midstream Application (e.g. Cell and Host Cell Protein Removal) 271Ralph Daumke, Vasily Medvedev, Tiago Albano, and Fabien Rousset23.1 Introduction 27123.2 Case Study 2: Cell Removal 27223.3 Case Study 2: HCP Removal 27523.4 Summary and Conclusions 276Nomenclature 277References 27724 Single‐Use Continuous Downstream Processing for Biopharmaceutical Products 279Marc Bisschops, Britta Manser, and Martin Glenz24.1 Introduction 27924.2 Continuous Multicolumn Chromatography 27924.3 Single‐Use Continuous Downstream Processing 28024.4 Summary and Conclusions 283References 28325 Single‐Use Technology for Formulation and Filling Applications 285Christophe Pierlot, Alain Vanhecke, Kevin Thompson, Rainer Gloeckler, and Daniel Kehl25.1 Introduction 28525.2 Challenges in Formulation and Filling 28525.3 End‐User Requirements 28625.4 Quality by Design 28725.5 Hardware Design and Usability 28825.6 Single‐Use Technology, Arrangement, and Operation 29025.7 Summary and Conclusions 293Nomenclature 294References 29426 Facility Design Considerations for Mammalian Cell Culture 295Sue Walker26.1 Introduction 29526.2 Generic Case Study 29526.3 Summary and Conclusions 301Nomenclature 301References 30127 Progress in the Development of Single‐Use Solutions in Antibody–Drug Conjugate (ADC) Manufacturing 303Diego R. Schmidhalter, Stephan Elzner, and Romeo Schmid27.1 Introduction 30327.2 Challenges for the Use of Disposables in ADC Processes 30427.3 Key Unit Operations 30627.4 Cysteine Conjugation Process – An ADC Production Process Case Study 30827.5 Summary and Conclusions 309Acknowledgment 309Nomenclature 309References 31028 Single‐Use Processing as a Safe and Convenient Way to Develop and Manufacture Moss‐Derived Biopharmaceuticals 311Holger Niederkrüger, Andreas Busch, Paulina Dabrowska‐Schlepp, Nicola Krieghoff, Andreas Schaaf, and Thomas Frischmuth28.1 Introduction 31128.2 Case Study 31128.3 Summary and Outlook 317Nomenclature 317References 31829 Single‐Use Technologies Used in Cell and Gene Therapy Manufacturing Need to Fulfill Higher and Novel Requirements: How Can this Challenge Be Addressed? 319Alain Pralong and Angélique Palumbo29.1 Introduction 31929.2 Promise of Cell and Gene Therapy 32029.3 Considerations for Biopharmaceutical Industry and Conclusion 322Nomenclature 325References 32530 Single‐Use Bioreactors for Manufacturing of Immune Cell Therapeutics 327Ralf Pörtner, Christian Sebald, Shreemanta K. Parida, and Hans Hoffmeister30.1 Introduction 32730.2 The Particular Nature of Immune Cell Therapeutics 32730.3 Uncertain Mass Production of Immune Cells for Therapy 32830.4 Technical Standards Required for Immune Cell ATMP Manufacturing 32930.5 Techniques for Expansion of Immune Cells 32930.6 Case Study ZRP System Consisting of GMP Breeder, Control Unit, and Software 33030.7 Summary and Conclusions 330Nomenclature 332References 332Index 335

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