Contents

Cover

Title Page

List of Contributors

Part One: Overview of State-of-the-Art Technologies and Challenges

Chapter 1: Continuous Bioprocess Development: Methods for Control and Characterization of the Biological System
1. 1.1 Proposed Advantages of Continuous Bioprocessing
2. 1.2 Special Challenges for Continuous Bioprocesses
3. 1.3 Changes Required to Integrate Continuous Processes in Biotech
4. 1.4 Role of Iterative Process Development to Push Continuous Processes in Biotech
5. 1.5 Conclusions
6. References
Chapter 2: Tools Enabling Continuous and Integrated Upstream and Downstream Processes in the Manufacturing of Biologicals
1. 2.1 Introduction
2. 2.2 Continuous Upstream Processes
3. 2.3 Continuous Downstream Processes
4. 2.4 Integrated Continuous Processes
5. 2.5 Concluding Remarks
6. References
Chapter 3: Engineering Challenges of Continuous Biomanufacturing Processes (CBP)
1. 3.1 Introduction
2. 3.2 Analysis of CBP Status
3. 3.3 Case Studies
4. 3.4 Status and Needs for Research and Development
5. 3.5 Engineering Challenges
6. 3.6 Conclusion and Outlook
7. Acknowledgments
8. References

Part Two: Automation and Monitoring (PAT)

Chapter 4: Progress Toward Automated Single-Use Continuous Monoclonal Antibody Manufacturing via the Protein Refinery Operations Lab
1. 4.1 Introduction
2. 4.2 Protein Refinery Operations Lab
3. 4.3 Protein Refinery Operations Lab: Case Studies
4. 4.4 Summary
5. Acknowledgments
6. References

Part Three: Single Use Technologies and Perfusion Technologies

Chapter 5: Single-Use Bioreactors for Continuous Bioprocessing: Challenges and Outlook
1. 5.1 Introduction
2. 5.2 Single-Use Reactor Types
3. 5.3 Material Aspects
4. 5.4 Sensors
5. 5.5 Reactor Design
6. 5.6 Scale-Up Aspects
7. 5.7 Continuous Seed Train
8. 5.8 New Mixer Designs
9. 5.9 Future Outlook
10. References
Chapter 6: Two Mutually Enabling Trends: Continuous Bioprocessing and Single-Use Technologies
1. 6.1 Introduction
2. 6.2 Single-Use Technologies
3. 6.3 Continuous Bioprocessing
4. 6.4 Integrated Single-Use Continuous Bioprocessing: Case Studies
5. 6.5 Regulatory Aspects
6. 6.6 Adoption Rate of Single-Use and Continuous Bioprocessing
7. 6.7 Conclusions
8. References
Chapter 7: Perfusion Formats and Their Specific Medium Requirements
1. 7.1 Introduction
2. 7.2 Characterization of Perfusion Processes
3. 7.3 Perfusion Formats
4. 7.4 Development Strategies for Perfusion Media
5. 7.5 Process Development for Perfusion Processes
6. 7.6 Case Study
7. 7.7 Conclusion
8. Abbreviations
9. References

Part Four: Continuous Upstream Bioprocessing

Chapter 8: Upstream Continuous Process Development
1. 8.1 Introduction
2. 8.2 Upstream Processes in Biomanufacturing
3. 8.3 The Upstream Continuous/Perfusion Process
4. 8.4 Manufacturing Scale-Up Challenges
5. 8.5 Single-Use Technologies: A Paradigm Change
6. 8.6 FDA Supports Continuous Processing
7. 8.7 Making the Switch from Batch/Fed-Batch to Continuous Processing
8. 8.8 Costs and Benefits of Continuous Manufacturing
9. 8.9 Costs of Adoption
10. 8.10 Continuous Downstream Processing
11. 8.11 Integrated Continuous Manufacturing
12. 8.12 Concluding Remark
13. Acknowledgment
14. References
Chapter 9: Study of Cells in the Steady-State Growth Space
1. 9.1 Introduction
2. 9.2 Advanced Continuous Cultivation Methods – Changestats [2]
3. 9.3 Review of the Results Obtained Using the Changestats [2]
4. 9.4 SSGSA Using Parallel-Sequential Cultivations
5. 9.5 Modeling in Steady-State Growth Space Analysis
6. References

Part Five: Continuous Downstream Bioprocessing

Chapter 10: Continuous Downstream Processing for Production of Biotech Therapeutics
1. 10.1 Introduction
2. 10.2 Continuous Manufacturing Technologies for Downstream Processing
3. 10.3 Continuous Process Development
4. 10.4 Case Studies Related to Continuous Manufacturing
5. 10.5 Summary
6. References
Chapter 11: Evolving Needs For Viral Safety Strategies in Continuous Monoclonal Antibody Bioproduction
1. 11.1 Introduction
2. 11.2 Batch versus Continuous: Potential Impacts on Virus Safety
3. 11.3 Validation of Viral Reduction Steps in Continuous Manufacturing Processes
4. 11.4 Conclusion
5. References

Part Six: Continuous Chromatography

Chapter 12: Multicolumn Continuous Chromatography: Understanding this Enabling Technology
1. 12.1 Introduction
2. 12.2 Modes of Chromatography
3. 12.3 Interaction Mechanisms Used in Chromatographic Systems
4. 12.4 Batch Chromatography
5. 12.5 Semicontinuous and Continuous Batch Chromatography
6. 12.6 Multicolumn, Countercurrent, Continuous Chromatography
7. 12.7 Risk Assessment of Continuous Chromatography
8. 12.8 Process Design of Continuous Capture Step
9. 12.9 Conclusion
10. References
Chapter 13: Continuous Chromatography as a Fully Integrated Process in Continuous Biomanufacturing
1. 13.1 Introduction
2. 13.2 Continuous Chromatography
3. 13.3 Conclusion and Outlook
4. Symbols
5. References
Chapter 14: Continuous Chromatography in Biomanufacturing
1. 14.1 Introduction to Continuous Chromatography
2. 14.2 Introduction to Manufacturing Aspects of Chromatography
3. 14.3 Trade-Offs in Batch Chromatography
4. 14.4 Capture Applications
5. 14.5 Polishing Applications
6. 14.6 Discovery and Development applications
7. 14.7 Scale-Up of Multicolumn Countercurrent Chromatography Processes
8. 14.8 Multicolumn Countercurrent Chromatography as Replacement for Batch Chromatography Unit Operations
9. 14.9 Multicolumn Countercurrent Chromatography and Continuous Upstream
10. 14.10 Regulatory Aspects and Control of Multicolumn Countercurrent Processes
11. References
Chapter 15: Single-Pass Tangential Flow Filtration (SPTFF) in Continuous Biomanufacturing
1. 15.1 Introduction
2. 15.2 Tangential Flow Filtration in Bioproduction
3. 15.3 Validation
4. 15.4 Conclusion
5. References

Part Seven: Integration of Upstream and Downstream

Chapter 16: Design of Integrated Continuous Processes for High-Quality Biotherapeutics
1. 16.1 Introduction
2. 16.2 Perfusion Cell Culture Development
3. 16.3 Continuous Capture Development
4. 16.4 Operation of the Continuous Integrated Process
5. 16.5 Conclusion
6. Acknowledgment
7. References
Chapter 17: Integration of Upstream and Downstream in Continuous Biomanufacturing
1. 17.1 Introduction
2. 17.2 Background on Upstream Development in Continuous Manufacturing
3. 17.3 Background on Downstream Development in Continuous mAb Manufacturing
4. 17.4 Challenges in Process Development
5. 17.5 Trends and Integration Approaches
6. 17.6 Methodical Approach of Integrating USP and DSP Regarding Impurity Processing
7. 17.7 Conclusion and Outlook
8. References

Part Eight: Quality, Validation, and Regulatory Aspects

Chapter 18: Quality Control and Regulatory Aspects for Continuous Biomanufacturing
1. 18.1 Introduction
2. 18.2 FDA Support for Continuous Manufacturing
3. 18.3 PAT as a Facilitator for Continuous Manufacturing Implementation
4. 18.4 PAT Applications in the Pharmaceutical Industry
5. 18.5 Process Validation for Continuous Manufacturing Processes
6. 18.6 Regulatory Documents Related to Process Validation
7. 18.7 ICH
8. 18.8 FDA
9. 18.9 EMA
10. 18.10 ASTM
11. 18.11 Special Considerations for Continuous Manufacturing Process Validation
12. 18.12 Scale-Down for Continuous Bioprocessing
13. 18.13 Impact of Single-Use Systems in Process Validation
14. 18.14 Batch and Lot Definition
15. 18.15 Conclusion
16. References
Chapter 19: Continuous Validation For Continuous Processing
1. 19.1 Quality Management
2. 19.2 Regulatory Considerations
3. 19.3 Setting Specifications
4. 19.4 Sequence of Events
5. 19.5 Verification of Validated States
6. 19.6 Choice of Test Methods
7. 19.7 Types of Monitoring
8. 19.8 Process Stream Analyzers
9. 19.9 Validation/Qualification of Process Stream Analyzers
10. 19.10 Control Charting
11. 19.11 The Moving Range Chart
12. 19.12 Continuous Validation
13. 19.13 Choosing Other Control Charts
14. 19.14 Information Awareness
15. 19.15 Cost Issues
16. 19.16 Revalidations
17. 19.17 Management and Personnel
18. References
Chapter 20: Validation, Quality, and Regulatory Considerations in Continuous Biomanufacturing
1. 20.1 Introduction
2. 20.2 Quality
3. 20.3 Validation
4. 20.4 Regulatory
5. 20.5 Conclusion
6. Further Reading

Part Nine: Industry Perspectives

Chapter 21: Evaluation of Continuous Downstream Processing: Industrial Perspective
1. 21.1 Biogen mAb Downstream Platform Process
2. 21.2 Potential Platform Process Bottlenecks Pertaining to Large Scale Manufacturing
3. 21.3 Continuous Downstream Process
4. 21.4 Productivity Comparison of Batch and Continuous Downstream Process
5. References

Index

End User License Agreement

List of Illustrations

Figure 1.1

Figure 1.2

Figure 2.1

Figure 2.2

Figure 2.3

Figure 2.4

Figure 2.5

Figure 2.6

Figure 2.7

Figure 2.8

Figure 2.9

Figure 2.10

Figure 3.1

Figure 3.2

Figure 3.3

Figure 3.4

Figure 3.5

Figure 3.6

Figure 3.7

Figure 3.8

Figure 3.9

Figure 3.10

Figure 3.11

Figure 3.12

Figure 3.13

Figure 3.14

Figure 3.15

Figure 3.16

Figure 3.17

Figure 3.18

Figure 3.19

Figure 3.20

Figure 3.21

Figure 3.22

Figure 3.23

Figure 3.24

Figure 3.25

Figure 4.1

Figure 4.2

Figure 4.3

Figure 4.4

Figure 4.5

Figure 4.6

Figure 4.7

Figure 4.8

Figure 4.9

Figure 4.10

Figure 4.11

Figure 4.12

Figure 4.13

Figure 4.14

Figure 4.15

Figure 4.16

Figure 4.17

Figure 5.1

Figure 5.2

Figure 5.3

Figure 5.4

Figure 5.5

Figure 5.6

Figure 5.7

Figure 6.1

Figure 6.2

Figure 6.3

Figure 6.4

Figure 6.5

Figure 6.6

Figure 7.1

Figure 7.2

Figure 7.3

Figure 7.4

Figure 7.5

Figure 7.6

Figure 7.7

Figure 7.8

Figure 8.1

Figure 8.2

Figure 8.3

Figure 8.4

Figure 9.1

Figure 9.2

Figure 9.3

Figure 9.4

Figure 10.1

Figure 10.2

Figure 10.3

Figure 10.4

Figure 10.5

Figure 10.6

Figure 10.7

Figure 10.8

Figure 10.9

Figure 11.1

Figure 11.2

Figure 11.3

Figure 11.4

Figure 11.5

Figure 11.6

Figure 11.7

Figure 11.8

Figure 12.1

Figure 12.2

Figure 12.3

Figure 12.4

Figure 12.5

Figure 12.6

Figure 12.7

Figure 12.8

Figure 12.9

Figure 12.10

Figure 12.11

Figure 12.12

Figure 12.13

Figure 12.14

Figure 12.15

Figure 12.16

Figure 12.17

Figure 12.18

Figure 12.19

Figure 12.20

Figure 12.21

Figure 12.22

Figure 12.23

Figure 12.24

Figure 12.25

Figure 12.26

Figure 12.27

Figure 12.28

Figure 12.29

Figure 12.30

Figure 12.31

Figure 13.1

Figure 13.2

Figure 13.3

Figure 13.4

Figure 13.5

Figure 13.6

Figure 13.7

Figure 13.8

Figure 13.9

Figure 13.10

Figure 13.11

Figure 13.12

Figure 13.13

Figure 13.14

Figure 13.15

Figure 14.1

Figure 14.2

Figure 14.3

Figure 14.4

Figure 14.5

Figure 14.6

Figure 14.7

Figure 14.8

Figure 14.9

Figure 14.10

Figure 14.11

Figure 14.12

Figure 14.13

Figure 14.14

Figure 14.15

Figure 14.16

Figure 15.1

Figure 15.2

Figure 15.3

Figure 15.4

Figure 15.5

Figure 15.6

Figure 15.7

Figure 15.8

Figure 15.9

Figure 15.10

Figure 15.11

Figure 15.12

Figure 15.13

Figure 15.14

Figure 15.15

Figure 15.16

Figure 15.17

Figure 15.18

Figure 15.19

Figure 15.20

Figure 15.21

Figure 16.1

Figure 16.2

Figure 16.3

Figure 16.4

Figure 16.5

Figure 16.6

Figure 16.7

Figure 16.8

Figure 16.9

Figure 17.1

Figure 17.2

Figure 17.3

Figure 17.4

Figure 17.5

Figure 17.6

Figure 17.7

Figure 17.8

Figure 20.1

Figure 20.2

Figure 21.1

Figure 21.2

Figure 21.3

Figure 21.4

Figure 21.5

Figure 21.6

Figure 21.7

Figure 21.8

Figure 21.9

Figure 21.10

Figure 21.11

List of Contributors

Kristo Abner

Competence Center of Food and Fermentation Technologies

Akadeemia tee 15

12618 Tallinn

Estonia

Kaarel Adamberg

Tallinn University of Technology

Department of Chemistry and Biotechnology

Akadeemia tee 15

12618 Tallinn

Estonia

and

Competence Center of Food and Fermentation Technologies

Akadeemia tee 15

12618 Tallinn

Estonia

Harshit Agarwal

Indian Institute of Technology

Department of Chemical Engineering

Hauz Khas

110016 New Delhi

India

Paul Beckett

Millipore SAS

Process Solution Technologies

39 Route Industrielle de la Hardt

67124 Molsheim

France

Helge Berg

Technology Management

Millipore SAS

39 Route Industrielle de la Hardt

67124 Molsheim

France

Torsten Bisschop

Millipore SAS

Process Solution Technologies

39 Route Industrielle de la Hardt

67124 Molsheim

France

Marc Bisschops

Pall Life Sciences

Scientific Laboratory Services

Nijverheidsweg 1

1671 GC Medemblik

The Netherlands

Mathilde Bourguignat

Technology Management

Millipore SAS

39 Route Industrielle de la Hardt

67124 Molsheim

France

Mark Brower

Merck & Co Inc

Biologics & Vaccines

2000 Galloping Hill Road

Kenilworth, NJ 07033

USA

Rimenys J. Carvalho

Federal University of Rio de Janeiro

COPPE

Cell Culture Engineering Laboratory

C.P. 68502

21941-972 Rio de Janeiro, RJ

Brazil

Leda R. Castilho

Federal University of Rio de Janeiro

COPPE

Cell Culture Engineering Laboratory

C.P. 68502

21941-972 Rio de Janeiro, RJ

Brazil

Cedric Geyer

Technology Management

Millipore SAS

39 Route Industrielle de la Hardt

67124 Molsheim

France

Andrew Clutterbuck

Millipore SAS

Process Solution Technologies

39 Route Industrielle de la Hardt

67124 Molsheim

France

M. Nicolas Cruz-Bournazou

Technische Universität Berlin

Department of Biotechnology

Ackerstrasse 76

ACK 24

13355 Berlin

Germany

Michael A. Cunningham

Technology Management

EMD Millipore Corporation

290 Concord Road

Billerica, MA 01821

USA

Reinhard Ditz

Clausthal University of Technology

Institute for Separation and Process Technology

Leibnizstr 15

38678 Clausthal-Zellerfeld

Germany

Sten Erm

Tallinn University of Technology

Department of Chemistry and Biotechnology

Akadeemia tee 15

12618 Tallinn

Estonia

and

Competence Center of Food and Fermentation Technologies

Akadeemia tee 15

12618 Tallinn

Estonia

Guillermina Forno

Ciudad Universitaria

Cell Culture Laboratory

UNL

FBCB

Paraje el Pozo

CC 242 Santa Fe

Argentina

and

Ciudad Universitaria

R&D Zelltek S.A.

UNL

FBCB

Paraje el Pozo

CC 242 Santa Fe

Argentina

Paul Genest

Technology Management

EMD Millipore Corporation

290 Concord Road

Billerica, MA 01821

USA

Sanchayita Ghose

Bristol-Myers Squibb

Downstream Process Development

38 Jackson Road

Danvers, MA 01923

USA

Julie Grace

Pall Life Sciences

Scientific Laboratory Services

20 Walkup Drive

Westborough, MA 01581

USA

Petra Gronemeyer

Clausthal University of Technology

Institute for Separation and Process Technology

Leibnizstr 15

38678 Clausthal-Zellerfeld

Germany

Sanjeev K. Gupta

Ipca Laboratories Ltd.

Advanced Biotech Lab

Kandivli Industrial Estate

Kandivli (west)

400067 Mumbai

India

Josselyn Haas

Millipore SAS

Process Solution Technologies

39 Route Industrielle de la Hardt

67124 Molsheim

France

Daniel Karst

ETH Zurich

Institute for Chemical and Bioengineering

Department of Chemistry and Applied Biosciences

Vladimir-Prelog-Weg 1

8093 Zurich

Switzerland

Nikhil Kateja

Indian Institute of Technology

Department of Chemical Engineering

Hauz Khas

110016 New Delhi

India

Steven S. Kuwahara

GXP BioTechnology LLC

Tucson, AZ 85741

USA

Renato Lorenzi

Millipore SAS

Process Solution Technologies

39 Route Industrielle de la Hardt

67124 Molsheim

France

Kathleen Mihlbachler

Lewa Process Technologies Inc. Separations Development

8 Charlestown Street

Devens, MA 01434

USA

Massimo Morbidelli

ETH Zurich

Institute for Chemical and Bioengineering

Department of Chemistry and Applied Biosciences

Vladimir-Prelog-Weg 1

8093 Zürich

Switzerland

Thomas Müller-Späth

ChromaCon AG

Process Development

Technoparkstrasse 1

8005 Zurich

Switzerland

and

ETH Zurich

Institute for Chemical and Bioengineering

Department of Chemistry and Applied Biosciences

Vladimir-Prelog-Weg 1

8093 Zürich

Switzerland

Venkatesh Natarajan

Biogen

Engineering & Technology

225 Binney Street

Cambridge, MA 02142

USA

Peter Neubauer

Technische Universität Berlin

Department of Biotechnology

Ackerstrasse 76

ACK 24

13355 Berlin

Germany

Laura Okhio-Seaman

Sartorius Stedim North America

Validation Services

5 Orville Drive

Bohemia, NY 11716

USA

Nico M.G. Oosterhuis

Celltainer Biotech BV

Bothoekweg 9

7115AK Winterswijk

The Netherlands

Eduardo Ortí

Ciudad Universitaria

R&D Zelltek S.A.

UNL

FBCB

Paraje el Pozo

CC 242 Santa Fe

Argentina

John Pieracci

Biogen

Engineering & Technology

225 Binney Street

Cambridge, MA 02142

USA

David Pollard

Merck & Co Inc

Biologics & Vaccines 2000 Galloping Hill Road

Kenilworth, NJ 07033

USA

Anurag S.Rathore

Indian Institute of Technology

Department of Chemical Engineering

Hauz Khas

110016 New Delhi

India

Douglas Richardson

Merck & Co Inc

Biologics & Vaccines 2000 Galloping Hill Road

Kenilworth, NJ 07033

USA

Christian Schild

Merck Life Science (a business of Merck KGaA) Process Solutions

Cell Culture Media R&D

Frankfurter Strasse 250

64291 Darmstadt

Germany

Mark Schofield

Pall Life Sciences

Applications R&D

20 Walkup Drive

Westborough, MA 01581

USA

Andrus Seiman

Tallinn University of Technology

Department of Chemistry and Biotechnology

Akadeemia tee 15

12618 Tallinn

Estonia

and

Competence Center of Food and Fermentation Technologies

Akadeemia tee 15

12618 Tallinn

Estonia

Frederic Sengler

Millipore SAS

Process Solution Technologies

39 Route Industrielle de la Hardt

67124 Molsheim

France

Jochen B. Sieck

Merck Life Science (a business of Merck KGaA)

Process Solutions

Cell Culture Media R&D

Frankfurter Strasse 250

64291 Darmstadt

Germany

Fabian Steinebach

ETH Zurich

Institute for Chemical and Bioengineering

Department of Chemistry and Applied Biosciences

Vladimir-Prelog-Weg 1

8093 Zurich

Switzerland

Jochen Strube

Clausthal University of Technology

Institute for Separation and Process Technology

Leibnizstr 15

38678 Clausthal-Zellerfeld

Germany

Holger Thiess

Clausthal University of Technology

Institute for Separation and Process Technology

Leibnizstr 15

38678 Clausthal-Zellerfeld

Germany

Raivo Vilu

Tallinn University of Technology

Department of Chemistry and Biotechnology

Akadeemia tee 15

12618 Tallinn

Estonia

and

Competence Center of Food and Fermentation Technologies,

Akadeemia tee 15

12618 Tallinn

Estonia

Jörg von Hagen

Merck Life Science (a business of Merck KGaA) Process Solutions

Cell Culture Media R&D

Frankfurter Strasse 250

64291 Darmstadt

Germany

Steffen Zobel-Roos

Clausthal University of Technology

Institute for Separation and Process Technology

Leibnizstr 15

38678 Clausthal-Zellerfeld

Germany

Continuous Biomanufacturing

Innovative Technologies and Methods

List of Contributors

Part One
Overview of State-of-the-Art Technologies and Challenges