Cover
List of Contributors
Preface
Part I: Basics
1. 1 Single‐Use Equipment in Biopharmaceutical Manufacture
  1. 1.1 Background
  2. 1.2 Terminology and Features
  3. 1.3 Single‐Use Systems in Production Processes for Therapeutic Proteins such as mAbs: Product Overview and Classification
  4. 1.4 Single‐Use Production Facilities
  5. 1.5 Summary and Conclusions
  6. Nomenclature
  7. References
2. 2 Types of Single‐Use Bag Systems and Integrity Testing Methods
  1. 2.1 Introduction
  2. 2.2 Bags for Fluid and Powder Handling
  3. 2.3 Bag‐Handling and Container Systems
  4. 2.4 Single‐Use Bag Systems for Freezing and Thawing
  5. 2.5 Container Closure Integrity Testing
  6. 2.6 Summary and Conclusions
  7. Nomenclature
  8. References
3. 3 Mixing Systems for Single‐Use
  1. 3.1 Introduction
  2. 3.2 The Mixing Process
  3. 3.3 Single‐Use Bag Mixing Systems
  4. 3.4 Summary and Conclusions
  5. Nomenclature
  6. References
4. 4 Single‐Use Bioreactors – An Overview
  1. 4.1 Introduction
  2. 4.2 SUB History
  3. 4.3 Comparison of the Current, Most Common SUB Types
  4. 4.4 Decision Criteria for Selection of the Most Suitable SUB Type
  5. 4.5 Summary and Future Trends
  6. Nomenclature
  7. References
5. 5 Systems for Coupling and Sampling
  1. 5.1 Introduction
  2. 5.2 Components of Single‐Use Transfer Lines
  3. 5.3 Systems for Aseptic Coupling
  4. 5.4 Aseptic Disconnection
  5. 5.5 Systems for Sampling
  6. 5.6 Summary and Conclusion
  7. Nomenclature
  8. References
6. 6 Sensors for Disposable Bioreactor Systems
  1. 6.1 Introduction
  2. 6.2 Interfaces for Sensor Technology
  3. 6.3 Considerations of Extractables and Leachables from Integrated Sensors
  4. 6.4 Optical Chemosensors
  5. 6.5 Spectroscopic Sensors
  6. 6.6 Capacitance Sensors
  7. 6.7 Electrochemical Sensors
  8. 6.8 Biosensors
  9. 6.9 Conclusions and Outlook
  10. Nomenclature
  11. References
7. 7 Bioinformatics and Single‐Use
  1. 7.1 Introduction
  2. 7.2 Bioinformatics and Single‐Use
  3. 7.3 Smart Sensors
  4. 7.4 Intelligent Control Systems
  5. 7.5 Continuous Processing
  6. 7.6 Conclusions
  7. Nomenclature
  8. References
8. 8 Production of Disposable Bags
  1. 8.1 Introduction
  2. 8.2 Materials
  3. 8.3 Film Manufacturing and Molding
  4. 8.4 Bag Manufacturing
  5. 8.5 Summary and Conclusions
  6. Nomenclature
  7. References
9. 9 Single‐Use Downstream Processing for Biopharmaceuticals
  1. 9.1 Introduction
  2. 9.2 Single‐Use DSP Today
  3. 9.3 Technologies in Single‐Use DSP
  4. 9.4 Single‐Use Continuous Downstream Processing
  5. 9.5 Integrated and Continuous DSP
  6. 9.6 Summary and Conclusions
  7. Nomenclature
  8. References
10. 10 Application of Microporous Filtration in Single‐Use Systems
  1. 10.1 Introduction
  2. 10.2 Microporous Filters
  3. 10.3 Filter Selection
  4. 10.4 Final Sterile Filtration
  5. 10.5 Filter Integrity Testing
  6. 10.6 Filter Qualification and Validation
  7. 10.7 Summary and Conclusions
  8. Nomenclature
  9. References
11. 11 Extractables/Leachables from Single‐Use Equipment
  1. 11.1 Introduction
  2. 11.2 Regulatory Environment
  3. 11.3 The (Bio)Pharmaceutical Manufacturer's Approach
  4. 11.4 The (Bio)Pharmaceutical Manufacturer's Challenges
  5. 11.5 Summary
  6. 11.6 Discussion and Outlook
  7. Acknowledgments
  8. Nomenclature
  9. References
12. 12 The Single‐Use Standardization
  1. 12.1 Introduction
  2. 12.2 Alphabet Soup
  3. 12.3 History
  4. 12.4 Compare and Contrast
  5. 12.5 Collaboration and Alignment Lead to Standardization
  6. 12.6 General SUT Efforts
  7. 12.7 Leachables and Extractables
  8. 12.8 Particulates in SUT
  9. 12.9 Change Notification
  10. 12.10 SUT System Integrity
  11. 12.11 SUT User Requirements
  12. 12.12 Connectors
  13. 12.13 SUT Design Verification
  14. 12.14 Summary and Conclusions
  15. Nomenclature
  16. References
  17. Further Reading
13. 13 Environmental Impacts of Single‐Use Systems
  1. 13.1 Introduction
  2. 13.2 Sustainability
  3. 13.3 The Evolution of SU Technologies
  4. 13.4 Implications in Sustainability
  5. 13.5 LCA – A Holistic Methodology
  6. 13.6 LCA Applied to SU Technologies
  7. 13.7 Sustainability Efforts in the BioPharma Industry
  8. 13.8 End‐of‐Life (Waste) Management
  9. 13.9 Summary and Conclusions
  10. Nomenclature
  11. References
14. 14 Design Considerations Towards an Intensified Single‐Use Facility
  1. 14.1 Introduction
  2. 14.2 Moving Towards Intensified and Continuous Processing
  3. 14.3 Methodologies for Continuous and Intensified Single‐Use Bioprocessing
  4. 14.4 Process Development for Intensified Biomanufacturing Facilities
  5. 14.5 The Intensified Biomanufacturing Facility
  6. 14.6 Process Automation for Commercial Manufacturing Facilities
  7. 14.7 Intensified Upstream Processing
  8. 14.8 Intensified Downstream Processing
  9. 14.9 Summary and Conclusions
  10. Acknowledgments
  11. Nomenclature
  12. References
15. 15 Single‐Use Technologies in Biopharmaceutical Manufacturing
  1. 15.1 Introduction
  2. 15.2 Background
  3. 15.3 Methods
  4. 15.4 Results
  5. 15.5 Discussion
  6. 15.6 Conclusions
  7. Nomenclature
  8. References
Part II: Application Reports and Case Studies
1. 16 Single‐Use Process Platforms for Responsive and Cost‐Effective Manufacturing
  1. 16.1 Introduction
  2. 16.2 Standardized Single‐Use Process Platforms for Biomanufacturing
  3. 16.3 Implementing Single‐Use Process Platforms
  4. 16.4 Economic Analysis Comparing Stainless Steel with Single‐Use Process Platforms
  5. 16.5 Summary and Conclusions
  6. Nomenclature
  7. References
2. 17 Considerations on Performing Quality Risk Analysis for Production Processes with Single‐Use Systems
  1. 17.1 Introduction
  2. 17.2 Quality Risk Assessment
  3. 17.3 Terminology and Features
  4. 17.4 Current Industrial Approach for Leachable Assessment in Biopharmaceutical Processes
  5. 17.5 Holistic Approach to Predict Leachables for Quality Risk Assessment
  6. 17.6 Summary and Conclusions
  7. Nomenclature
  8. References
3. 18 How to Assure Robustness, Sterility, and Performance of Single‐Use Systems
  1. 18.1 Introduction
  2. 18.2 Component Qualification
  3. 18.3 Validation of Product Design
  4. 18.4 Manufacturing and Control
  5. 18.5 Operator Training, Performance Culture
  6. 18.6 Particulate Risk Mitigation
  7. 18.7 Change Management
  8. 18.8 Summary and Conclusions
  9. Nomenclature
  10. References
4. 19 How to Design and Qualify an Improved Film for Storage and Bioreactor Bags
  1. 19.1 Introduction
  2. 19.2 Materials, Process, and Suppliers Selection
  3. 19.3 Biological Properties
  4. 19.4 Specifications and Process Design Space
  5. 19.5 Process Control Strategy
  6. 19.6 Summary and Conclusions
  7. Nomenclature
  8. References
5. 20 An Approach for Rapid Manufacture and Qualification of a Single‐Use Bioreactor Prototype
  1. 20.1 Introduction
  2. 20.2 About the Development Process of a Single‐Use Bioreactor
  3. 20.3 Summary and Conclusions
  4. Nomenclature
  5. References
6. 21 Single‐Use Bioreactor Platform for Microbial Fermentation
  1. 21.1 Introduction
  2. 21.2 General Design Basis for Microbial SUFs
  3. 21.3 SUF Design Criteria and Approach – Heat Transfer
  4. 21.4 SUF Design Criteria and Approach – Oxygen Transfer
  5. 21.5 SUF Design Criteria and Approach – Mixing
  6. 21.6 Operational Considerations for SUFs
  7. 21.7 Case Studies
  8. 21.8 Summary and Conclusions
  9. Nomenclature
  10. References
7. 22 Engineering Parameters in Single‐Use Bioreactors
  1. 22.1 Introduction
  2. 22.2 Stirred Bioreactors
  3. 22.3 Orbitally Shaken Bioreactors
  4. 22.4 Rocking Bag
  5. 22.5 Summary and Conclusions
  6. Nomenclature
  7. References
8. 23 Alluvial Filtration
  1. 23.1 Introduction
  2. 23.2 Case Study 1: Cell Removal
  3. 23.3 Case Study 2: HCP Removal
  4. 23.4 Summary and Conclusions
  5. Nomenclature
  6. References
9. 24 Single‐Use Continuous Downstream Processing for Biopharmaceutical Products
  1. 24.1 Introduction
  2. 24.2 Continuous Multicolumn Chromatography
  3. 24.3 Single‐Use Continuous Downstream Processing
  4. 24.4 Summary and Conclusions
  5. References
10. 25 Single‐Use Technology for Formulation and Filling Applications
  1. 25.1 Introduction
  2. 25.2 Challenges in Formulation and Filling
  3. 25.3 End‐User Requirements
  4. 25.4 Quality by Design
  5. 25.5 Hardware Design and Usability
  6. 25.6 Single‐Use Technology, Arrangement, and Operation
  7. 25.7 Summary and Conclusions
  8. Nomenclature
  9. References
11. 26 Facility Design Considerations for Mammalian Cell Culture
  1. 26.1 Introduction
  2. 26.2 Generic Case Study
  3. 26.3 Summary and Conclusions
  4. Nomenclature
  5. References
12. 27 Progress in the Development of Single‐Use Solutions in Antibody–Drug Conjugate (ADC) Manufacturing
  1. 27.1 Introduction
  2. 27.2 Challenges for the Use of Disposables in ADC Processes
  3. 27.3 Key Unit Operations
  4. 27.4 Cysteine Conjugation Process – An ADC Production Process Case Study
  5. 27.5 Summary and Conclusions
  6. Acknowledgment
  7. Nomenclature
  8. References
13. 28 Single‐Use Processing as a Safe and Convenient Way to Develop and Manufacture Moss‐Derived Biopharmaceuticals
  1. 28.1 Introduction
  2. 28.2 Case Study
  3. 28.3 Summary and Outlook
  4. Nomenclature
  5. References
14. 29 Single‐Use Technologies Used in Cell and Gene Therapy Manufacturing Need to Fulfill Higher and Novel Requirements
  1. 29.1 Introduction
  2. 29.2 Promise of Cell and Gene Therapy
  3. 29.3 Considerations for Biopharmaceutical Industry and Conclusion
  4. Nomenclature
  5. References
15. 30 Single‐Use Bioreactors for Manufacturing of Immune Cell Therapeutics
  1. 30.1 Introduction
  2. 30.2 The Particular Nature of Immune Cell Therapeutics
  3. 30.3 Uncertain Mass Production of Immune Cells for Therapy
  4. 30.4 Technical Standards Required for Immune Cell ATMP Manufacturing
  5. 30.5 Techniques for Expansion of Immune Cells
  6. 30.6 Case Study ZRP System Consisting of GMP Breeder, Control Unit, and Software
  7. 30.7 Summary and Conclusions
  8. Nomenclature
  9. References
Index
End User License Agreement

List of Tables

Chapter 1
1. Table 1.1 Summary of advantages and limitations of single‐use equipment.
Chapter 2
1. Table 2.1 Summary of findings.
Chapter 3
1. Table 3.1 Overview of currently existing bag mixing systems.
Chapter 4
1. Table 4.1 Overview of often used commercial single‐use bioreactors being inst...
Chapter 5
1. Table 5.1 Different tube materials [6–16].
2. Table 5.2 Tube‐to‐tube fittings.
3. Table 5.3 Different types of connectors.
4. Table 5.4 Steam‐in‐place connectors.
5. Table 5.5 Aseptic connectors.
6. Table 5.6 Tube welding devices.
7. Table 5.7 Tube sealers.
8. Table 5.8 Sampling systems.
Chapter 6
1. Table 6.1 Overview of some commercially available sensors of chemical and bio...
Chapter 8
1. Table 8.1 Mechanical tests used to characterize film and components.
2. Table 8.2 Physical tests used to characterize film and components.
3. Table 8.3 Biological tests used to characterize film and components.
4. Table 8.4 Material dependent tests used for film and/or components in disposa...
5. Table 8.5 Example of solutions for chemical compatibility test.
6. Table 8.6 Test in incoming material.
7. Table 8.7 Test for release of disposable bags.
Chapter 10
1. Table 10.1 Commonly used microporous filter media in single‐use filtration ap...
2. Table 10.2 Common terms used to describe filter design and performance attrib...
3. Table 10.3 Commonly used microporous filter media in single‐use assemblies, o...
Chapter 11
1. Table 11.1 Checklist for extractables studies.
Chapter 12
1. Table 12.1 Brief descriptions of the organizations (in alphabetical order) cu...
Chapter 13
1. Table 13.1 Summary of terms having importance for this chapter.
2. Table 13.2 Parameters for two GE LCA studies.
Chapter 14
1. Table 14.1 Four monoclonal antibody process scenarios modeled in the BioSolve...
Chapter 15
1. Table 15.1 Worldwide capacity and facilities summary data.
2. Table 15.2 Estimates of selected bioprocessing systems/facilities current mar...
Chapter 17
1. Table 17.1 Typical risks related to SUS.
2. Table 17.2 Description of process steps as sources and sinks of leachables in...
3. Table 17.3 Overview about input parameters for leachablesA and B; the calcula...
Chapter 18
1. Table 18.1 Typical manufacture and test procedure for three lots of the Maste...
2. Table 18.2 Typical sample strategy per lot.
3. Table 18.3 Validation of equipment used in SU system manufacturing.
Chapter 19
1. Table 19.1 bDtBPP‐specific EC₅₀ values.
Chapter 20
1. Table 20.1 Radiation stability of selected medical‐grade polymers.
Chapter 21
1. Table 21.1 Heat transfer tests results in a 50 l SUF.
2. Table 21.2 Cool down test results of a 500 l SUF.
3. Table 21.3 Oxygen mass transfer tests of SUFs (XFDR‐500 MO 500 l, four Rushto...
4. Table 21.4 Oxygen mass transfer tests of SUFs (XDR‐500 MO 500 l, two Rushton ...
Chapter 24
1. Table 24.1 Experimental conditions and results for the case study performed o...
Chapter 25
1. Table 25.1 Overview of today's small to mid‐scale combination final filling m...
Chapter 27
1. Table 27.1 SafeBridge product classification categories 1–4.
2. Table 27.2 Typical unit operations for the manufacture of ADCs and specific c...
Chapter 28
1. Table 28.1 Quantity of compounds found in the L&E study and published in bag ...
2. Table 28.2 Quantity of compounds found exclusively in fluorescent tube or LED...
Chapter 30
1. Table 30.1 List of completed clinical studies with selected immune cells.
2. Table 30.2 Immune cell marker.
3. Table 30.3 Single‐use devices used for manufacturing processes of immune cell...

List of Illustrations

Chapter 1
1. Figure 1.1 Schematic of a typical manufacturing process for therapeutic prot...
2. Figure 1.2 Primary categories of disposables utilizable for the development ...
3. Figure 1.3 Questions concerning security of supply.
4. Figure 1.4 Process flow diagram of a mid‐scale production for a mAb in which...
5. Figure 1.5 Types of single‐use facilities: (a) single‐use facility of the cl...
Chapter 2
1. Figure 2.1 Summary of single‐use bag applications in biopharmaceutical manuf...
2. Figure 2.2 Tank liner in a drum.
3. Figure 2.3 Examples of 2D bags: (a) end‐ported bag and (b) face‐ported bag....
4. Figure 2.4 Thermo Scientific Powdertainer II with clamp and wash down line....
5. Figure 2.5 Examples of 3D bags: (a) 3D Flexsafe bag for rectangular tank, (b...
6. Figure 2.6 Selected bag‐handling systems for liquids: (a) plastic Flexsafe/F...
7. Figure 2.7 Bag‐handling system for frozen liquids.
8. Figure 2.8 Bioprocess container for in‐house applications: (a) 3D Stainless ...
9. Figure 2.9 Flexel 3D Palletank for shipping.
10. Figure 2.10 Sartorius Stedim freeze–thaw system: (a) 1 and 2 l Celsius‐Pak, ...
11. Figure 2.11 Single Use Support RoSS shell (a) and RoSS.pFTU for up to 240 l ...
12. Figure 2.12 Relationship between liquid leak and microbial ingress. DI, dist...
13. Figure 2.13 Sartorius Stedim integrity testing approach for single‐use assem...
Chapter 3
1. Figure 3.1 Mixing conditions describing mixing quality. (a) Completely unmix...
2. Figure 3.2 Classification of single‐use bag mixing systems.
3. Figure 3.3 Stirred mixing systems. (a) Levitated stirrer. The superconductin...
4. Figure 3.4 Mixing system with a tumbling stirrer. Due to the tumbling motion...
5. Figure 3.5 Oscillating mixing systems. (a) Oscillating wand in sleeve. A wan...
6. Figure 3.6 Hydraulically driven mixing systems. An external pump moves the f...
Chapter 4
1. Figure 4.1 Common features of single‐use bioreactors.
2. Figure 4.2 Differences and categorization of single‐use bioreactors.
3. Figure 4.3 Phases and milestones in single‐use bioreactor development.
4. Figure 4.4 Schematic diagrams of wave‐mixed bioreactors with 1‐D, 2‐D, or 3‐...
5. Figure 4.5 HyPerforma S.U.B 2000 L bioreactor.
6. Figure 4.6 OrbShake bioreactor series.
7. Figure 4.7 Main criteria for selection of the most suitable disposable biore...
Chapter 5
1. Figure 5.1 Different types of clamps: (a) Pinch clamp, (b) Ratchet clamp, (c...
2. Figure 5.2 Steam‐in‐place connectors: (a) Lynx ST Connectors and (b) CPC Ste...
3. Figure 5.3 Installation process for a steam‐in‐place connector.
4. Figure 5.4 Different types of aseptic connectors: (a) AseptiQuik G, (b) Asep...
5. Figure 5.5 Application of a Kleenpak™ Sterile Connector to integrate a probe...
6. Figure 5.6 Functional principle of a tube welder: Welding steps (a)–(e).
7. Figure 5.7 Aseptic transfer systems: (a) Single‐use aseptic transfer device ...
8. Figure 5.8 Aseptic disconnecting device: (a) tube sealer with (b) a sealed t...
9. Figure 5.9 Crimping tools and aseptic disconnectors: (a) Clipster Aseptic Di...
10. Figure 5.10 Sampling systems: (a) NovaSeptum Sterile Sampling System and (b)...
11. Figure 5.11 Manifold sampling system, equipped with a weldable connection tu...
Chapter 6
1. Figure 6.1 General interface categories for disposable reactors. Three diffe...
2. Figure 6.2 Schematic of optical ports of an optical chemosensor that could b...
3. Figure 6.3 Schematic of optical ports for different spectroscopic sensor typ...
4. Figure 6.4 Schematic of a capacitance sensor. Only living cells are detected...
5. Figure 6.5 Schematic of a pH‐ISFET. By immobilizing biomolecules on the gate...
Chapter 7
1. Figure 7.1 Diagram illustrating different types of vessels integrated into a...
2. Figure 7.2 Single‐use element (Smartsheath) which comes pre‐inserted into th...
3. Figure 7.3 Single‐use virtual transmitter windows in TruBio control software...
4. Figure 7.4 Main graphic screens of a Delta V‐based bioreactor automation pla...
5. Figure 7.5 Pump calibration page (top) and pump multi‐feed process control s...
6. Figure 7.6 TruBio bioreactor automation platform that is optimized for singl...
7. Figure 7.7 Fully single‐use continuous process train concept.
Chapter 8
1. Figure 8.1 Chemical structure of PE.
2. Figure 8.2 Different PE structures: LDPE, LLDPE, and HDPE.
3. Figure 8.3 Chemical structure of PP.
4. Figure 8.4 Chemical structure of EVA.
5. Figure 8.5 Chemical structure of PA6.
6. Figure 8.6 Chemical structure of PA6,6.
7. Figure 8.7 Chemical structure of PET.
8. Figure 8.8 Chemical structure of EVOH.
9. Figure 8.9 Chemical structure of PVDC.
10. Figure 8.10 Schematic drawing of an extruder.
11. Figure 8.11 Monolayer film structure.
12. Figure 8.12 Multilayer film structure with sandwiched barrier layer.
13. Figure 8.13 Multilayer structure with barrier layer and protective outer lay...
14. Figure 8.14 Blown film extrusion line.
15. Figure 8.15 Air cooling of the bubble with blown film extrusion.
16. Figure 8.16 Three‐layer blown film co‐extrusion die.
17. Figure 8.17 Cooling system of cast film extrusion.
18. Figure 8.18 Principle of extrusion lamination.
19. Figure 8.19 Raw material arrives in bulks.
20. Figure 8.20 Raw material arrives in bags.
21. Figure 8.21 Blown film extrusion cleanroom setup.
22. Figure 8.22 Cast film extrusion cleanroom setup.
23. Figure 8.23 Injection molding installation.
24. Figure 8.24 The relationship between extractables and leachables.
25. Figure 8.25 Lloyd LRX force tester, setup for defining the pull‐off force of...
26. Figure 8.26 DSC of a polymer.
27. Figure 8.27 Two‐dimensional bag design.
28. Figure 8.28 FTIR spectrum from outside of bioreactor film.
29. Figure 8.29 FTIR spectrum from inside of bioreactor film.
30. Figure 8.30 Pressure drop integrity system used for standard release of disp...
31. Figure 8.31 Principle of Helium Integrity testing in a disposable bag.
Chapter 9
1. Figure 9.1 Comparison of a batch downstream process (top) using single‐use t...
2. Figure 9.2 Cost in $ per gram of antibody throughout the downstream processi...
3. Figure 9.3 Annual cost of a monoclonal antibody (mAb) DSP platform at commer...
4. Figure 9.4 Working principle of single‐use continuous harvesting strategies ...
5. Figure 9.5 Schematic of parallel switch‐in and ‐out for continuous filtratio...
6. Figure 9.6 Working principle of disposable continuous virus inactivation str...
Chapter 10
1. Figure 10.1 Description of the sieving mechanism under consideration of size...
2. Figure 10.2 Cutaway view of a microporous capsule filter with pleated membra...
3. Figure 10.3 Microporous PTFE filter, 0.2 μm rated at 2000×
4. Figure 10.4 Microporous isotropic PVDF membrane, 0.2 μm rated at 3500×
5. Figure 10.5 Microporous highly asymmetric PES membrane, 0.2 μm rated at 1000...
6. Figure 10.6 Single‐use filter device configurations from left to right: inli...
Chapter 11
1. Figure 11.1 Direct and indirect health risk from leachables.
2. Figure 11.2 General illustration of migration of leachables in the course of...
3. Figure 11.3 Responsibility chart regulatory compliance of single‐use equipme...
4. Figure 11.4 Pharmaceutical manufacturing process including low‐ and high‐ris...
5. Figure 11.5 Illustration of the local distribution of potential leachables a...
6. Figure 11.6 Proposed workflow for chemical safety assessment.
7. Figure 11.7 Guidance on how to deal with unknown extractables.
8. Figure 11.8 Illustration of the supply chain of a plastic component that for...
Chapter 12
1. Figure 12.1 Regulation vs. flexibility.
Chapter 13
1. Figure 13.1 Schematic diagram of the product life cycle (left) and environme...
2. Figure 13.2 Impact comparison for traditional, hybrid, and single‐use techno...
3. Figure 13.3 Comparison of climate change impact (y‐axis) between traditional...
4. Figure 13.4 Potential environmental impact of AdV production for traditional...
Chapter 14
1. Figure 14.1 An intensified single‐use process platform.
2. Figure 14.2 Model outputs for the different mAb‐process scenarios as describ...
3. Figure 14.3 Excerpt of mass balance sheet.
4. Figure 14.4 Example of a process flow diagram for 6× 2000 l USP setup.
5. Figure 14.5 ISA S95 structure: Four‐level concept for manufacturing faciliti...
6. Figure 14.6 Cell density profile of a rocking motion bioreactor run in perfu...
7. Figure 14.7 3D representation of the upstream suite from the intensified sin...
8. Figure 14.8 S88‐compliant recipe‐based control system.
Chapter 15
1. Figure 15.1 Usage of disposables in biopharmaceutical manufacturing, at any ...
2. Figure 15.2 12‐Year percentage‐point change in first‐usage of disposables, 2...
Chapter 16
1. Figure 16.1 A single‐use process platform for viral vectors.
2. Figure 16.2 Process flow diagrams for three different process platforms.
3. Figure 16.3 Cost modeling data to show that single‐use platforms are capable...
4. Figure 16.4 Breakdown of annual costs for a stainless‐steel mAb process and ...
5. Figure 16.5 Reduction in COGs attributed to USP and DSP.
6. Figure 16.6 NPV of three mAb platform processes.
Chapter 17
1. Figure 17.1 Exemplary scheme of evaluation of E/L information in the biophar...
2. Figure 17.2 Elements of a dynamic box‐model including subsequent process ste...
Chapter 18
1. Figure 18.1 Risk‐based approach to assembly manufacture and use involves SU ...
2. Figure 18.2 SU supplier's responsibility from component qualification to lot...
3. Figure 18.3 Integrity assurance risk factors and mitigation proposals throug...
4. Figure 18.4 Manufacturing process flow diagram. IPA, isopropyl alcohol; QA, ...
5. Figure 18.5 Purpose of each change qualification step. The science of Managi...
Chapter 19
1. Figure 19.1 Test procedure and parameters for leachable screening.
2. Figure 19.2 Dose–response effect of bDtBPP on CHO‐DG4 (‐‐), CHO XM111–10 (⋅⋅...
3. Figure 19.3 CHO‐DG44 cell growth in the presence of media extracts of two di...
4. Figure 19.4 Model variation of puncture resistance in function to variation ...
5. Figure 19.5 QbD scaling approach with description of limits for extrusion pr...
Chapter 20
1. Figure 20.1 Schematic of the workflow used in this study.
2. Figure 20.2 CFD‐predicted flow pattern of the final bioreactor prototype: (a...
3. Figure 20.3 Schematics of injection molding (a), the additive manufacturing ...
4. Figure 20.4 Pictures of the rapid prototyping parts of the new single‐use bi...
5. Figure 20.5 Summary of engineering parameters for one of the bioreactor prot...
6. Figure 20.6 Picture of a sample part made of Steralloy FDG before (left) and...
Chapter 21
1. Figure 21.1 SUFs: Xcellerex XDR‐50 MO single‐use fermenter (a) and Xcellerex...
2. Figure 21.2 CFD modeling of a 500 L SUF for two impeller configurations (fou...
3. Figure 21.3 Rate of temperature drop in a cool down test in a 500 l SUF.
4. Figure 21.4 50 l SUF oxygen transfer rate as a function of oxygen enrichment...
5. Figure 21.5 50 l SUF oxygen transfer rate as a function of agitator's revolu...
6. Figure 21.6 Kinetics of E. coli growth in a XDR‐50 MO single‐use fermenter....
7. Figure 21.7 Kinetics of S. cerevisiae growth in a XDR‐50 MO single‐use ferme...
8. Figure 21.8 Increase in cell density of P. fluorescens growth in a XDR‐50 MO...
9. Figure 21.9 Kinetics of E. coli cell growth in a XDR‐500 l SUF.
10. Figure 21.10 Kinetics of H. influenzae growth in a XDR‐500 MO compared with ...
11. Figure 21.11 Kinetics of capsular polysaccharide production in a XDR‐500 MO ...
Chapter 22
1. Figure 22.1 Time evolution of the mixing dynamics inside the CellReady 3 l S...
2. Figure 22.2 Variation of the mixing number in the CellReady with increasing ...
3. Figure 22.3 (a) Sketch visualizing the action of the centrifugal and gravita...
4. Figure 22.4 Velocity flow fields for h = 3 cm (i.e. V_f =235 ml), d_i = 10 cm,...
5. Figure 22.5 Flow transitional region (gray shaded) in the Fr–h/d_i plane [25]...
6. Figure 22.6 Variation of the nondimensional interfacial area, I_a, with incre...
7. Figure 22.7 Scaling of the mixing numbers with the Froude number ratio, Fr/F...
8. Figure 22.8 Variation of the suspended to critical Froude number ratio, Fr_s
9. Figure 22.9 Flow visualization in the structural mimic. (a) Image of the flu...
Chapter 23
1. Figure 23.1 Pressure profiles as a function of throughput for different dosa...
2. Figure 23.2 Pressure profiles (inlet) as a function of process time (through...
3. Figure 23.3 IgG recoveries in different filtration experiments performed.
4. Figure 23.4 Static depletion at 5 min CT (HCP: black, DNA: dark gray, IgG: g...
5. Figure 23.5 Static depletion at 1 : 50 mix ratio.
6. Figure 23.6 Dynamic depletion at 1 min RT (a) and at 2 min RT (b).
Chapter 24
1. Figure 24.1 Conceptual diagram of a multicolumn chromatography process: (a) ...
2. Figure 24.2 Cadence BioSMB Process response curve: above the curve, complete...
3. Figure 24.3 Experimental data on the Cadence BioSMB PD system to challenge t...
Chapter 25
1. Figure 25.1 Supportive hardware for the Pall Biotech final filtration single...
2. Figure 25.2 Single‐use isolator for safe operator handling of toxic active p...
3. Figure 25.3 Swissfillon's shadow board indicating the installation points of...
4. Figure 25.4 Allegro final filling needle into Optima final filling machine....
5. Figure 25.5 Schematic concept of an Alpha/Beta‐Port system. (a) Approach, (b...
6. Figure 25.6 Swissfillon isolator final filling machine equipment from Optima...
Chapter 26
1. Figure 26.1 Generic mAb process map.
2. Figure 26.2 Generic mAb process flow diagram.
3. Figure 26.3 Example of a master “wish” list.
Chapter 27
1. Figure 27.1 Typical antibody modification followed by conjugation for cystei...
2. Figure 27.2 Example of a site‐selective cysteine conjugation process as exec...
Chapter 28
1. Figure 28.1 Process overview.
2. Figure 28.2 Schematic overview of USP dominated by single‐use technology.
3. Figure 28.3 Pictures of the USP unit. (a) Cleanroom Class D equipped with th...
4. Figure 28.4 Illumination spectra and intensities used in the L&E study in ca...
Chapter 29
1. Figure 29.1 Cancer treatment options and modalities since the nineteenth cen...
2. Figure 29.2 Autologous high‐level process architecture including processing ...
3. Figure 29.3 Allogeneic high‐level process architecture including processing ...
Chapter 30
1. Figure 30.1 Zellwerk's ZRP platform: GMP Z®RP Cell BREEDER equipped with M‐t...

List of Contributors

Tiago Albano
Univercells SA, Gosselies, Belgium

Magali Barbaroux
Sartorius Stedim FMT S.A.S., Aubagne, France

Sara Bell
MilliporeSigma, Bedford, MA, USA

Simone Biel
Merck Chemicals GmbH, an affiliate of Merck KGaA, Darmstadt, Germany

Marc Bisschops
Pall International Sàrl, Fribourg, Switzerland

Amelie Boulais
Sartorius Stedim Biotech GmbH, Göttingen, Germany

Andreas Busch
Greenovation Biotech GmbH, Freiburg im Breisgau, Germany

Chuck Capron
Meissner Filtration Products, Camarillo, CA, USA

Andreas Castan
GE Healthcare Life Sciences, Uppsala, Sweden

Nitin Chopra
Sartorius Stedim Biotech GmbH, Göttingen, Germany

Ken Clapp
GE Healthcare Life Sciences, Marlborough, MA, USA

Vincent Colombie
Sanofi Pasteur, Campus Merieux, Marcy l’Etoile, France

Paulina Dabrowska‐Schlepp
Greenovation Biotech GmbH, Freiburg im Breisgau, Germany

Katharina Dahlmann
Institut für Technische Chemie, Gottfried Wilhelm Leibniz Universität Hannover, Germany

Rick Damren
GE Healthcare Life Sciences, Marlborough, MA, USA

Ralph Daumke
FILTROX AG, St. Gallen, Switzerland

Lucie Delaunay
Sartorius Stedim FMT S.A.S., Aubagne, France

Andrea Ducci
University College London, London, UK

Dieter Eibl
School of Life Sciences and Facility Management, Institute of Chemistry and Biotechnology, Zurich University of Applied Sciences, Wädenswil, Switzerland

Regine Eibl
School of Life Sciences and Facility Management, Institute of Chemistry and Biotechnology, Zurich University of Applied Sciences, Wädenswil, Switzerland

Stephan Elzner
Lonza AG, Visp, Switzerland

William P. Flanagan
Aspire Sustainability, Albany, NY, USA

Thomas Frischmuth
Greenovation Biotech GmbH, Freiburg im Breisgau, Germany

Parrish M. Galliher
GE Healthcare Life Sciences, Marlborough, MA, USA

Martin Glenz
Pall International Sàrl, Fribourg, Switzerland

Rainer Gloeckler
Swissfillon AG, Visp, Switzerland

Gerhard Greller
Sartorius Stedim Biotech GmbH, Göttingen, Germany

Patrick Guertin
GE Healthcare Life Sciences, Marlborough, MA, USA

Priyanka Gupta
Sartorius Stedim Biotech GmbH, Göttingen, Germany

Armin Hauk
Sartorius Stedim Biotech GmbH, Göttingen, Germany

Hans Hoffmeister
Zellwerk GmbH, Oberkrämer, Germany

Nick Hutchinson
Sartorius Stedim Biotech GmbH, Göttingen, Germany

Ernest Jenness
MilliporeSigma, Bedford, MA, USA

Valentin Jossen
School of Life Sciences and Facility Management, Institute of Chemistry and Biotechnology, Zurich University of Applied Sciences, Wädenswil, Switzerland

Christian Julien
Meissner Filtration Products, Camarillo, CA, USA

Elke Jurkiewicz
Sartorius Stedim Biotech GmbH, Göttingen, Germany

Stephan C. Kaiser
Thermo Fisher Scientific, Santa Clara, CA, USA

Frank Lammers Sanofi, Frankfurt am Main, Germany

Yasser Kehail
GE Healthcare Life Sciences, Marlborough, MA, USA

Daniel Kehl
Swissfillon AG, Visp, Switzerland

Michael Koch
Sartorius Stedim Biotech GmbH, Göttingen, Germany

Matthias Kraume
Technische Universität Berlin, Fakultät III Verfahrenstechnik, Lehrstuhl Verfahrenstechnik, Berlin, Germany

Nicola Krieghoff
Greenovation Biotech GmbH, Freiburg im Breisgau, Germany

Eric S. Langer
BioPlan Associates, Inc., Rockville, MD, USA

Britta Manser
Pall International Sàrl, Fribourg, Switzerland

Vasily Medvedev
Univercells SA, Gosselies, Belgium

Martina Micheletti
University College London, London, UK

Miriam Monge
Sartorius Stedim Biotech GmbH, Göttingen, Germany

Holger Niederkrüger
Greenovation Biotech GmbH, Freiburg im Breisgau, Germany

Ina Pahl
Sartorius Stedim Biotech GmbH, Göttingen, Germany

Barbara A. Paldus
Sekhmet Ventures, Portola Valley, CA, USA

Angélique Palumbo
Science & Tech ENABLE GmbH, Solothurn, Switzerland

Shreemanta K. Parida
Zellwerk GmbH, Oberkrämer, Germany

Mark A. Petrich
Merck & Co., Inc., West Point, PA, USA

Christophe Pierlot
Pall Biotech, Hoegaarden, Belgium

Catherine Piton
Pall Biotech, Saint‐Germain‐en‐Laye, France

Alain Pralong
Pharma‐Consulting ENABLE GmbH, Solothurn, Switzerland

Ralf Pörtner
Institute of Bioprocess and Biosystems Engineering, Hamburg University of Technology, Hamburg, Germany

Ronald A. Rader
BioPlan Associates, Inc., Rockville, MD, USA

Kenneth F. Reardon
Department of Chemical and Biological Engineering, Colorado State University, Fort Collins, CO, USA

Sebastian Rothe
GE Healthcare Europe GmbH, Freiburg, Germany

Fabien Rousset
DAICEL Bioseparations – Chiral Technologies Europe SAS, Illkirch, France

Jens Rumsfeld
Sartorius Stedim Biotech GmbH, Göttingen, Germany

Andreas Schaaf
Greenovation Biotech GmbH, Freiburg im Breisgau, Germany

Thomas Scheper
Institut für Technische Chemie, Gottfried Wilhelm Leibniz Universität Hannover, Germany

Cedric Schirmer
School of Life Sciences and Facility Management, Institute of Chemistry and Biotechnology, Zurich University of Applied Sciences, Wädenswil, Switzerland

Romeo Schmid
Lonza AG, Visp, Switzerland

Diego R. Schmidhalter
Lonza AG, Visp, Switzerland

Lydia Schosser
Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany

Christian Sebald
Zellwerk GmbH, Oberkrämer, Germany

Alicja Sobańtka
Octapharma Pharmazeutika Produktionsges.m.b.H, Vienna, Austria

Dörte Solle
Institut für Technische Chemie, Gottfried Wilhelm Leibniz Universität Hannover, Germany

Tobias Steinwedel
Institut für Technische Chemie, Gottfried Wilhelm Leibniz Universität Hannover, Germany

Kevin Thompson
Pall Biotech, Portsmouth, UK

Kai Touw
Sartorius Stedim Biotech GmbH, Göttingen, Germany

Colin Tuohey
GE Healthcare Life Sciences, Marlborough, MA, USA

Steven Vanhamel
Pall Biotech, Port Washington, NY, USA

Alain Vanhecke
Pall Biotech, Hoegaarden, Belgium

P.E. James Dean VogelThe BioProcess Institute, North Kingstown, RI, USA

Sonja von Orlikowski
Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany

Sue Walker
Engineering Consultant, Portsmouth, NH, USA

Christian Weiner
Octapharma Pharmazeutika Produktionsges.m.b.H, Vienna, Austria

Sören Werner
School of Life Sciences and Facility Management, Institute of Chemistry and Biotechnology, Zurich University of Applied Sciences, Wädenswil, Switzerland

William G. Whitford
GE Healthcare, South Logan, UT, USA

Gerben Zijlstra
Sartorius Stedim Biotech GmbH, Göttingen, Germany

Single‐Use Technology in Biopharmaceutical Manufacture

List of Contributors

Preface

Part I
Basics