Single-use Technology in Biopharmaceutical Manufacture

Authoritative guide to the principles, characteristics, engineering aspects, economics, and applications of disposables in the manufacture of biopharmaceuticals

The revised and updated second edition of Single-Use Technology in Biopharmaceutical Manufacture offers a comprehensive examination of the most-commonly used disposables in the manufacture of biopharmaceuticals. The authors—noted experts on the topic—provide the essential information on the principles, characteristics, engineering aspects, economics, and applications.

This authoritative guide contains the basic knowledge and information about disposable equipment. The author also discusses biopharmaceuticals’ applications through the lens of case studies that clearly illustrate the role of manufacturing, quality assurance, and environmental influences. This updated second edition revises existing information with recent developments that have taken place since the first edition was published. The book also presents the latest advances in the field of single-use technology and explores topics including applying single-use devices for microorganisms, human mesenchymal stem cells, and T-cells. This important book:

•    Contains an updated and end-to-end view of the development and manufacturing of single-use biologics

•    Helps in the identification of appropriate disposables and relevant vendors

•    Offers illustrative case studies that examine manufacturing, quality assurance, and environmental influences

•    Includes updated coverage on cross-functional/transversal dependencies, significant improvements made by suppliers, and the successful application of the single-use technologies

Written for biopharmaceutical manufacturers, process developers, and biological and chemical engineers, Single-Use Technology in Biopharmaceutical Manufacture, 2nd Edition provides the information needed for professionals to come to an easier decision for or against disposable alternatives and to choose the appropriate system.

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 xvii

Preface xxi

Part I Basics 1

1 Single‐Use Equipment in Biopharmaceutical Manufacture: A Brief Introduction 3
Dieter Eibl and Regine Eibl

1.1 Background 3

1.2 Terminology and Features 3

1.3 Single‐Use Systems in Production Processes for Therapeutic Proteins such as mAbs: Product Overview and Classification 5

1.4 Single‐Use Production Facilities 7

1.5 Summary and Conclusions 7

Nomenclature 9

References 9

2 Types of Single‐Use Bag Systems and Integrity Testing Methods 13
Jens Rumsfeld and Regine Eibl

2.1 Introduction 13

2.2 Bags for Fluid and Powder Handling 13

2.3 Bag‐Handling and Container Systems 15

2.4 Single‐Use Bag Systems for Freezing and Thawing 18

2.5 Container Closure Integrity Testing 18

2.6 Summary and Conclusions 22

Nomenclature 22

References 22

3 Mixing Systems for Single‐Use 25
Sören Werner, Matthias Kraume, and Dieter Eibl

3.1 Introduction 25

3.2 The Mixing Process 25

3.3 Single‐Use Bag Mixing Systems 27

3.4 Summary and Conclusions 33

Nomenclature 33

References 33

4 Single‐Use Bioreactors – An Overview 37
Valentin Jossen, Regine Eibl, and Dieter Eibl

4.1 Introduction 37

4.2 SUB History 38

4.3 Comparison of the Current, Most Common SUB Types 40

4.4 Decision Criteria for Selection of the Most Suitable SUB Type 47

4.5 Summary and Future Trends 48

Nomenclature 48

References 48

5 Systems for Coupling and Sampling 53
Cedric Schirmer, Sebastian Rothe, Ernest Jenness, and Dieter Eibl

5.1 Introduction 53

5.2 Components of Single‐Use Transfer Lines 53

5.3 Systems for Aseptic Coupling 57

5.4 Aseptic Disconnection 62

5.5 Systems for Sampling 64

5.6 Summary and Conclusion 66

Nomenclature 66

References 66

6 Sensors for Disposable Bioreactor Systems 69
Tobias Steinwedel, Katharina Dahlmann, Dörte Solle, Thomas Scheper, Kenneth F. Reardon, and Frank Lammers

6.1 Introduction 69

6.2 Interfaces for Sensor Technology 70

6.3 Considerations of Extractables and Leachables from Integrated Sensors 71

6.4 Optical Chemosensors 72

6.5 Spectroscopic Sensors 73

6.6 Capacitance Sensors 75

6.7 Electrochemical Sensors 76

6.8 Biosensors 78

6.9 Conclusions and Outlook 78

Nomenclature 79

References 79

7 Bioinformatics and Single‐Use 83
Barbara A. Paldus

7.1 Introduction 83

7.2 Bioinformatics and Single‐Use 84

7.3 Smart Sensors 86

7.4 Intelligent Control Systems 87

7.5 Continuous Processing 88

7.6 Conclusions 92

Nomenclature 94

References 94

8 Production of Disposable Bags: A Manufacturer’s Report 95
Steven Vanhamel and Catherine Piton

8.1 Introduction 95

8.2 Materials 95

8.4 Bag Manufacturing 110

8.5 Summary and Conclusions 113

Nomenclature 115

References 116

9 Single‐Use Downstream Processing for Biopharmaceuticals: Current State and Trends 117
Britta Manser, Martin Glenz, and Marc Bisschops

9.1 Introduction 117

9.2 Single‐Use DSP Today 117

9.3 Technologies in Single-Use DSP 120

9.4 Single‐Use Continuous Downstream Processing 121

9.5 Integrated and Continuous DSP 124

9.6 Summary and Conclusions 124

Nomenclature 124

References 125

10 Application of Microporous Filtration in Single‐Use Systems 127
Christian Julien and Chuck Capron

10.1 Introduction 127

10.2 Microporous Filters 128

10.3 Filter Selection 134

10.4 Final Sterile Filtration 136

10.5 Filter Integrity Testing 138

10.6 Filter Qualification and Validation 139

10.7 Summary and Conclusions 140

Nomenclature 140

References 140

11 Extractables/Leachables from Single‐Use Equipment: Considerations from a (Bio) Pharmaceutical Manufacturer 143
Alicja Sobańtka and Christian Weiner

11.1 Introduction 143

11.2 Regulatory Environment 144

11.3 The (Bio)Pharmaceutical Manufacturer’s Approach 146

11.4 The (Bio)Pharmaceutical Manufacturer’s Challenges 153

11.5 Summary 155

11.6 Discussion and Outlook 156

Acknowledgments 156

Nomenclature 157

References 157

12 The Single‐Use Standardization 159
P.E. James Dean Vogel

12.1 Introduction 159

12.2 Alphabet Soup 159

12.3 History 161

12.4 Compare and Contrast 161

12.5 Collaboration and Alignment Lead to Standardization 162

12.6 General SUT Efforts 163

12.7 Leachables and Extractables 164

12.8 Particulates in SUT 164

12.9 Change Notification 165

12.10 SUT System Integrity 165

12.11 SUT User Requirements 165

12.12 Connectors 165

12.13 SUT Design Verification 165

12.14 Summary and Conclusions 166

Nomenclature 166

References 166

Further Reading 166

13 Environmental Impacts of Single‐Use Systems 169
William G. Whitford, Mark A. Petrich, and William P. Flanagan

13.1 Introduction 169

13.2 Sustainability 169

13.3 The Evolution of SU Technologies 169

13.4 Implications in Sustainability 172

13.5 LCA – A Holistic Methodology 172

13.6 LCA Applied to SU Technologies 173

13.7 Sustainability Efforts in the BioPharma Industry 175

13.8 End‐of‐Life (Waste) Management 177

13.9 Summary and Conclusions 178

Nomenclature 178

References 178

14 Design Considerations Towards an Intensified Single‐Use Facility 181
Gerben Zijlstra, Kai Touw, Michael Koch, and Miriam Monge

14.1 Introduction 181

14.2 Moving Towards Intensified and Continuous Processing 181

14.3 Methodologies for Continuous and Intensified Single‐Use Bioprocessing 183

14.4 Process Development for Intensified Biomanufacturing Facilities 184

14.5 The Intensified Biomanufacturing Facility 184

14.6 Process Automation for Commercial Manufacturing Facilities 187

14.7 Intensified Upstream Processing 187

14.8 Intensified Downstream Processing 189

14.9 Summary and Conclusions 191

Acknowledgments 191

Nomenclature 191

References 191

15 Single‐Use Technologies in Biopharmaceutical Manufacturing: A 10‐Year Review of Trends and the Future 193
Ronald A. Rader and Eric S. Langer

15.1 Introduction 193

15.2 Background 193

15.3 Methods 194

15.4 Results 194

15.5 Discussion 197

15.6 Conclusions 199

Nomenclature 200

References 200

Part II Application Reports and Case Studies 201

16 Single‐Use Process Platforms for Responsive and Cost‐Effective Manufacturing 203
Priyanka Gupta, Miriam Monge, Amelie Boulais, Nitin Chopra, and Nick Hutchinson

16.1 Introduction 203

16.2 Standardized Single‐Use Process Platforms for Biomanufacturing 204

16.3 Implementing Single‐Use Process Platforms 204

16.4 Economic Analysis Comparing Stainless Steel with Single‐Use Process Platforms 207

16.5 Summary and Conclusions 209

Nomenclature 209

References 210

17 Considerations on Performing Quality Risk Analysis for Production Processes with Single‐Use Systems 211
Ina Pahl, Armin Hauk, Lydia Schosser, and Sonja von Orlikowski

17.1 Introduction 211

17.2 Quality Risk Assessment 211

17.3 Terminology and Features 212

17.4 Current Industrial Approach for Leachable Assessment in Biopharmaceutical Processes 212

17.5 Holistic Approach to Predict Leachables for Quality Risk Assessment 214

17.6 Summary and Conclusions 215

Nomenclature 217

References 217

18 How to Assure Robustness, Sterility, and Performance of Single‐Use Systems: A Quality Approach from the Manufacturer’s Perspective 219
Simone Biel and Sara Bell

18.1 Introduction 219

18.2 Component Qualification 219

18.3 Validation of Product Design 220

18.4 Manufacturing and Control 224

18.5 Operator Training, Performance Culture 225

18.6 Particulate Risk Mitigation 225

18.7 Change Management 225

18.8 Summary and Conclusions 226

Nomenclature 227

References 227

19 How to Design and Qualify an Improved Film for Storage and Bioreactor Bags 229
Lucie Delaunay, Elke Jurkiewicz, Gerhard Greller, and Magali Barbaroux

19.1 Introduction229

19.2 Materials, Process, and Suppliers Selection 229

19.3 Biological Properties 229

19.4 Specifications and Process Design Space 231

19.5 Process Control Strategy 233

19.6 Summary and Conclusions 233

Nomenclature 233

References 233

20 An Approach for Rapid Manufacture and Qualification of a Single‐Use Bioreactor Prototype 235
Stephan C. Kaiser

20.1 Introduction 235

20.2 About the Development Process of a Single‐Use Bioreactor 235

20.3 Summary and Conclusions 243

Nomenclature 244

References 244

21 Single‐Use Bioreactor Platform for Microbial Fermentation 247
Parrish M. Galliher, Patrick Guertin, Ken Clapp, Colin Tuohey, Rick Damren, Yasser Kehail, Vincent Colombie, and Andreas Castan

21.1 Introduction 247

21.2 General Design Basis for Microbial SUFs 247

21.3 SUF Design Criteria and Approach – Heat Transfer 247

21.4 SUF Design Criteria and Approach – Oxygen Transfer 249

21.5 SUF Design Criteria and Approach – Mixing 251

21.6 Operational Considerations for SUFs 252

21.7 Case Studies 252

21.8 Summary and Conclusions 256

Nomenclature 257

References 258

22 Engineering Parameters in Single‐Use Bioreactors: Flow, Mixing, Aeration, and Suspension 259
Martina Micheletti and Andrea Ducci

22.1 Introduction 259

22.2 Stirred Bioreactors 259

22.3 Orbitally Shaken Bioreactors 262

22.4 Rocking Bag 267

22.5 Summary and Conclusions 268

Nomenclature 268

References 268

23 Alluvial Filtration: An Effective and Economical Solution for Midstream Application (e.g. Cell and Host Cell Protein Removal) 271
Ralph Daumke, Vasily Medvedev, Tiago Albano, and Fabien Rousset

23.1 Introduction 271

23.2 Case Study 2: Cell Removal 272

23.3 Case Study 2: HCP Removal 275

23.4 Summary and Conclusions 276

Nomenclature 277

References 277

24 Single‐Use Continuous Downstream Processing for Biopharmaceutical Products 279
Marc Bisschops, Britta Manser, and Martin Glenz

24.1 Introduction 279

24.2 Continuous Multicolumn Chromatography 279

24.3 Single‐Use Continuous Downstream Processing 280

24.4 Summary and Conclusions 283

References 283

25 Single‐Use Technology for Formulation and Filling Applications 285
Christophe Pierlot, Alain Vanhecke, Kevin Thompson, Rainer Gloeckler, and Daniel Kehl

25.1 Introduction 285

25.2 Challenges in Formulation and Filling 285

25.3 End‐User Requirements 286

25.4 Quality by Design 287

25.5 Hardware Design and Usability 288

25.6 Single‐Use Technology, Arrangement, and Operation 290

25.7 Summary and Conclusions 293

Nomenclature 294

References 294

26 Facility Design Considerations for Mammalian Cell Culture 295
Sue Walker

26.1 Introduction 295

26.2 Generic Case Study 295

26.3 Summary and Conclusions 301

Nomenclature 301

References 301

27 Progress in the Development of Single‐Use Solutions in Antibody–Drug Conjugate (ADC) Manufacturing 303
Diego R. Schmidhalter, Stephan Elzner, and Romeo Schmid

27.1 Introduction 303

27.2 Challenges for the Use of Disposables in ADC Processes 304

27.3 Key Unit Operations 306

27.4 Cysteine Conjugation Process – An ADC Production Process Case Study 308

27.5 Summary and Conclusions 309

Acknowledgment 309

Nomenclature 309

References 310

28 Single‐Use Processing as a Safe and Convenient Way to Develop and Manufacture Moss‐Derived Biopharmaceuticals 311
Holger Niederkrüger, Andreas Busch, Paulina Dabrowska‐Schlepp, Nicola Krieghoff, Andreas Schaaf, and Thomas Frischmuth

28.1 Introduction 311

28.2 Case Study 311

28.3 Summary and Outlook 317

Nomenclature 317

References 318

29 Single‐Use Technologies Used in Cell and Gene Therapy Manufacturing Need to Fulfill Higher and Novel Requirements: How Can this Challenge Be Addressed? 319
Alain Pralong and Angélique Palumbo

29.1 Introduction 319

29.2 Promise of Cell and Gene Therapy 320

29.3 Considerations for Biopharmaceutical Industry and Conclusion 322

Nomenclature 325

References 325

30 Single‐Use Bioreactors for Manufacturing of Immune Cell Therapeutics 327
Ralf Pörtner, Christian Sebald, Shreemanta K. Parida, and Hans Hoffmeister

30.1 Introduction 327

30.2 The Particular Nature of Immune Cell Therapeutics 327

30.3 Uncertain Mass Production of Immune Cells for Therapy 328

30.4 Technical Standards Required for Immune Cell ATMP Manufacturing 329

30.5 Techniques for Expansion of Immune Cells 329

30.6 Case Study ZRP System Consisting of GMP Breeder, Control Unit, and Software 330

30.7 Summary and Conclusions 330

Nomenclature 332

References 332

Index 335

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