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El. knyga: Process Scale Purification of Antibodies

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  • Išleidimo metai: 07-Mar-2017
  • Leidėjas: John Wiley & Sons Inc
  • Kalba: eng
  • ISBN-13: 9781119126935
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Process Scale Purification of AntibodiesDidesnis paveikslėlis
  • Formatas: EPUB+DRM
  • Išleidimo metai: 07-Mar-2017
  • Leidėjas: John Wiley & Sons Inc
  • Kalba: eng
  • ISBN-13: 9781119126935
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Stay on the cutting edge of antibody purification with the insights of industry experts

Biopharmaceutical companies are under extreme pressure to develop robust and economical large-scale processes while consistently meeting regulatory standards for safety and purity. Unfortunately, while upstream productivity has increased in line with demand, downstream processing is mired in a technology crisis resulting in production bottlenecks. Antibody purification is sandwiched between fermentation and drug formulation, two areas that have traditionally received the lion’s share of industry awareness as well as generous research funding and attention in the literature. As a result, improvements in purification technology are needed urgently to meet the challenges of increasing demands without sacrificing product quality.

The second edition of Process Scale Purification of Antibodies continues the legacy of its predecessor to offer scientists, researchers, and engineers an essential resource focused on best practices in manufacturing antibody drugs. It covers different antibody purification strategies, including new developments since the publication of the first edition, and an assembly of top-tier experts in these disparate technologies with the common aim of addressing problems in process-scale antibody purification.

Recognized for providing a fresh perspective on traditional chromatography as well as technologies for the preparation of small molecule drugs, the first edition covered innovative developments in protein purification like smart membranes, bioaffinity mimetics, orthogonal, and integrated strategies and novel platform technologies. The revision updates these topics and also introduces concepts that have gained traction over the ensuing years – including the purification of antibodies produced in novel production systems, novel separation technologies, novel antibody formats and alternative scaffolds, and strategies for ton-scale manufacturing.

Process Scale Purification of Antibodies, therefore, consolidates the unique niche occupied by its predecessor and maintains interest in this neglected subject area by promoting the continued, much-needed renaissance in antibody purification.
Preface xxiii
List Of Contributors xxvii
1 Downstream Processing of Monoclonal Antibodies: Current Practices and Future Opportunities 1(22)
Brian Kelley
1.1 Introduction
1(1)
1.2 A Brief History of Current Good Manufacturing Process mAb and Intravenous Immunoglobulin Purification
2(2)
1.3 Current Approaches in Purification Process Development: Impact of Platform Processes
4(3)
1.4 Typical Unit Operations and Processing Alternatives
7(3)
1.5 VLS Processes: Ton-Scale Production and Beyond
10(2)
1.6 Process Validation
12(1)
1.7 Product Life Cycle Management
13(3)
1.8 Future Opportunities
16(2)
1.9 Conclusions
18(1)
Acknowledgments
19(1)
References
19(4)
2 The Development of Antibody Purification Technologies 23(32)
John Curling
2.1 Introduction
23(2)
2.2 Purification of Antibodies by Chromatography Before Protein A
25(3)
2.3 Antibody Purification After 1975
28(3)
2.4 Additional Technologies for Antibody Purification
31(3)
2.5 Purification of mAbs Approved in North America and Europe
34(6)
2.6 Current Antibody Process Technology Developments
40(5)
Acknowledgments
45(1)
References
46(9)
3 Harvest and Recovery of Monoclonal Antibodies: Cell Removal and Clarification 55(26)
Abhinav A. Shukla
Eric Suda
3.1 Introduction
55(4)
3.2 Centrifugation
59(3)
3.3 Microfiltration
62(5)
3.4 Depth Filtration
67(3)
3.5 Flocculation
70(1)
3.6 Absolute Filtration
71(2)
3.7 Expanded Bed Adsorption Chromatography
73(1)
3.8 Harvesting in Single-Use Manufacturing
74(1)
3.9 Comparison of Harvest and Clarification Unit Operations
74(2)
References
76(5)
4 Next-Generation Clarification Technologies for the Downstream Processing of Antibodies 81(32)
Nripen Singh
Srinivas Chollangi
4.1 Introduction
81(2)
4.2 Impurity Profiles in Cell Cultures
83(1)
4.3 Precipitation
84(5)
4.3.1 Acid Precipitation
84(3)
4.3.2 Caprylic Acid Precipitation
87(1)
4.3.3 PEG Precipitation
88(1)
4.3.4 Cold Ethanol Precipitation
89(1)
4.4 Affinity Precipitation
89(1)
4.5 Flocculation
90(6)
4.5.1 Anionic Flocculation
91(1)
4.5.2 Cationic Flocculation
92(3)
4.5.3 Multimodal Flocculation
95(1)
4.6 Toxicity of Flocculants and Precipitants and Their Residual Clearance
96(1)
4.7 Depth Filtration
97(5)
4.7.1 Improvements in Depth Filtration Technology
97(1)
4.7.2 Impurity Removal by Depth Filtration
98(1)
4.7.3 Virus Clearance by Depth Filtration
99(3)
4.8 Considerations for the Implementation of New Clarification Technologies
102(1)
4.9 Conclusions and Future Perspectives
103(1)
Acknowledgments
104(1)
References
104(9)
5 Protein A-Based Affinity Chromatography 113(22)
Suresh Vunnum
Ganesh Vedantham
Brian Hubbard
5.1 Introduction
113(1)
5.2 Properties of Protein A and Commercially Available Protein A Resins
114(4)
5.2.1 Protein A Structure
114(1)
5.2.2 Protein A-Immunoglobulin G Interaction
114(1)
5.2.3 Stoichiometry of Protein A-IgG Binding
115(1)
5.2.4 Protein A Stability
115(1)
5.2.5 Commercial Protein A Resins
115(1)
5.2.6 Static Capacity
116(1)
5.2.7 Dynamic Binding Capacity
116(1)
5.2.8 Leaching
117(1)
5.2.9 Production Rates
118(1)
5.3 Protein A Chromatography Step Development
118(5)
5.3.1 Loading/Binding
119(1)
5.3.2 Wash Development
120(1)
5.3.3 Elution
121(1)
5.3.4 Stripping
122(1)
5.3.5 Regeneration and CIP
122(1)
5.4 Additional Considerations During Development and Scale-Up
123(4)
5.4.1 Controlling HMW Aggregate Formation
123(1)
5.4.2 Removal of Soluble HMW Contaminants
124(1)
5.4.3 Turbidity
124(3)
5.5 Virus Removal/Inactivation
127(1)
5.5.1 Virus Removal
127(1)
5.5.2 Low-pH Inactivation
127(1)
5.5.3 Prion Clearance
128(1)
5.6 Validation and Robustness
128(1)
5.6.1 Validation
128(1)
5.6.2 Robustness
129(1)
5.7 Conclusions
129(1)
Acknowledgment
130(1)
References
130(5)
6 Purification of Human Monoclonal Antibodies: Non-Protein A Strategies 135(20)
Alahari Arunakumari
Jue Wang
6.1 Introduction
135(1)
6.2 Integrated Process Design for Human Monoclonal Antibody Production
136(1)
6.3 Purification Process Designs for HuMabs
136(13)
6.3.1 Protein A Purification Schemes
136(3)
6.3.2 Non-Protein A Purification Schemes
139(1)
6.3.3 Host Cell Protein Exclusion Approach for IEX Purification Schemes
139(17)
6.3.3.1 Primary Recovery
141(2)
6.3.3.2 Optimization of CEX Capture Chromatography
143(5)
6.3.3.3 Two-Column Nonaffinity Purification Processes
148(1)
6.4 Conclusions
149(2)
Acknowledgments
151(1)
References
152(3)
7 Hydrophobic Interaction Chromatography for the Purification of Antibodies 155(26)
Judith Vajda
Egbert Muller
7.1 Introduction
155(1)
7.2 HIC With mAbs
156(17)
7.2.1 Stationary Phases
157(2)
7.2.2 Dynamic Binding Capacities
159(4)
7.2.2.1 Salts and Electrolytes
159(3)
7.2.2.2 Buffer pH
162(1)
7.2.2.3 Dual Salt Mixtures
162(1)
7.2.2.4 Resin Screening
162(1)
7.2.3 Selectivity and Impurity Removal
163(1)
7.2.4 Antibody Capturing
163(2)
7.2.5 Aggregate Removal
165(7)
7.2.6 mAb Fragments and Other Formats
172(1)
7.2.7 Antibody-Drug Conjugates
173(1)
7.2.8 Analytical HIC for mAbs
173(1)
7.3 HIC with Membrane Adsorbers
173(1)
7.4 Future Perspectives
174(1)
References
175(6)
8 Purification of Monoclonal Antibodies by Mixed-Mode Chromatography 181(18)
Pete Gagnon
8.1 Introduction
181(1)
8.2 A Brief History
182(1)
8.3 Prerequisites for Industrial Implementation
183(2)
8.4 Mechanisms, Screening, and Method Development
185(7)
8.5 Capture Applications
192(1)
8.6 Polishing Applications
193(1)
8.7 Sequential Capture/Polishing Applications
193(1)
8.8 Future Prospects
193(1)
Acknowledgments
194(1)
References
194(5)
9 Advances in Technology and Process Development for Industrial-Scale Monoclonal Antibody Purification 199(16)
Nuno Fontes
Robert Van Reis
9.1 Introduction
199(1)
9.2 Affinity Purification Platform
200(1)
9.2.1 Overview
200(1)
9.2.2 Standard Purification Sequence
200(1)
9.2.3 Challenges and Opportunities
200(1)
9.3 Advances in the Purification of mAbs by CEX Chromatography
201(8)
9.3.1 Overview
201(1)
9.3.2 High-Capacity CEX
202(1)
9.3.3 An Exclusion Mechanism in IEX Chromatography
203(2)
9.3.4 Factors Affecting the Critical Conductivity
205(1)
9.3.5 Advances in mAb CEX Process Development
206(3)
9.4 High-Performance Tangential Flow Filtration
209(2)
9.4.1 Overview
209(1)
9.4.2 Advances in HPTFF
210(1)
9.5 A New Nonaffinity Platform
211(2)
References
213(2)
10 Alternatives to Packed-Bed Chromatography for Antibody Extraction and Purification 215(18)
Jorg Thommes
Richard M. Twyman
Uwe Gottschalk
10.1 Introduction
215(1)
10.2 Increasing the Selectivity of Harvest Procedures: Flocculation and Filter Aids
216(2)
10.2.1 Flocculation
216(1)
10.2.2 Filter Aids
217(1)
10.3 Solutions for Antibody Extraction, Concentration, and Purification
218(2)
10.3.1 Extraction and Concentration by Precipitation
218(1)
10.3.2 Extraction and Concentration by Liquid-Phase Partitioning
219(1)
10.3.3 Concentration by Evaporation
220(1)
10.4 Antibody Purification and Formulation Without Chromatography
220(3)
10.4.1 Crystallization
220(2)
10.4.2 Controlled Freeze-Thaw
222(1)
10.4.3 Lyophilization
222(1)
10.5 Membrane Adsorbers
223(2)
10.6 Conclusions
225(1)
References
226(7)
11 Process-Scale Precipitation of Impurities in Mammalian Cell Culture Broth 233(14)
Judy Glynn
11.1 Introduction
233(2)
11.2 Precipitation of DNA and Protein-Other Applications
235(1)
11.3 A Comprehensive Evaluation of Precipitants for the Removal of Impurities
236(5)
11.3.1 Protocol
236(1)
11.3.2 Ammonium Sulfate Precipitation
237(1)
11.3.3 Polymer Precipitation
237(1)
11.3.4 Precipitation with Ionic Liquids
238(1)
11.3.5 Precipitation with Cationic Detergents
239(1)
11.3.6 Ethacridine Precipitation
239(1)
11.3.7 Caprylic Acid Precipitation
240(1)
11.4 Industrial-Scale Precipitation
241(2)
11.5 Cost of Goods Comparison
243(1)
11.6 Summary
244(1)
Acknowledgments
244(1)
References
244(3)
12 Charged Ultrafiltration and Microfiltration Membranes for Antibody Purification 247(22)
Mark R. Etzel
Abhiram Arunkumar
12.1 Introduction
247(1)
12.2 Charged UF Membranes
248(1)
12.3 Concentration Polarization and Permeate Flux
248(1)
12.4 Stagnant Film Model
249(1)
12.5 Sieving Coefficient
250(1)
12.6 Mass Transfer Coefficient
251(1)
12.7 Mass Balance Models
251(2)
12.8 Scale-Up Strategies and the Constant Wall Concentration (Cw) Approach
253(2)
12.9 Membrane Cascades
255(1)
12.10 Protein Fractionation Using Charged UF Membranes
256(1)
12.11 Case Study
257(2)
12.11.1 Methods
257(1)
12.11.2 Results
257(2)
12.11.3 Discussion
259(1)
12.12 Charged MF Membranes
259(1)
12.13 Virus Clearance
260(1)
12.14 Salt Tolerance
261(3)
12.15 Conclusions
264(1)
Acknowledgments
264(1)
References
264(5)
13 Disposable Prepacked-Bed Chromatography for Downstream Purification: Form, Fit, Function, and Industry Adoption 269(34)
Stephen K. Tingley
13.1 Introduction
269(2)
13.2 Development-Scale Prepacked Column Applications
271(4)
13.2.1 Resin and Condition Scouting
271(1)
13.2.2 Process Development
271(2)
13.2.3 Process Optimization and Troubleshooting
273(1)
13.2.4 Virus Titer Reduction Validation
273(2)
13.3 Process-Scale Prepacked Column Applications
275(3)
13.3.1 Overview
275(1)
13.3.2 Prepacked Columns-Form
275(2)
13.3.3 Prepacked Columns-Design Considerations
277(1)
13.3.4 Prepacked Columns-Function
277(1)
13.4 Basic Technical Datasets
278(7)
13.4.1 Scale-Up and Basic Chromatography
278(1)
13.4.2 Column Cycling
278(2)
13.4.3 Column Cleanability
280(1)
13.4.4 Shelf Life
281(1)
13.4.5 Extractables and Leachables
282(1)
13.4.6 Shipping and Handling
283(2)
13.5 Independent Industry Assessments of "Fit for Purpose"
285(1)
13.6 Case Study 1: Cation-Exchange Polishing Chromatography
285(2)
13.7 Case Study 2: Prepacked Columns for Pilot-/Large-Scale Bioprocessing
287(5)
13.8 Prepacked Columns-Fit
292(3)
13.8.1 Manufacturing Operations for Toxic Products
292(1)
13.8.2 Single-Use/Disposable Facilities
292(1)
13.8.3 Clinical Manufacturing Operations
293(1)
13.8.4 Contract Manufacturing
293(1)
13.8.5 Distributed Commercial Manufacturing
294(1)
13.9 The Economics of Prepacked Column Technologies
295(2)
13.10 The Implementation of Disposable Prepacked Columns
297(3)
13.10.1 Cross-Functional Alignment
297(1)
13.10.2 Project and Process Fit
297(1)
13.10.3 Risk Analysis and Risk Mitigation
297(1)
13.10.4 Enabling Future Processes
298(1)
13.10.5 Technological Pros and Cons
299(1)
13.11 Conclusions
300(1)
References
301(2)
14 Integrated Polishing Steps for Monoclonal Antibody Purification 303(22)
Sanchayita Ghose
Mi Jin
Jia Liu
John Hickey
Steven Lee
14.1 Introduction
303(1)
14.2 Polishing Steps for Antibody Purification
304(12)
14.2.1 Ion-Exchange Chromatography
304(4)
14.2.1.1 AEX Chromatography
304(1)
14.2.1.2 CEX Chromatography
305(3)
14.2.2 Hydrophobic Interaction Chromatography
308(4)
14.2.3 HA Chromatography
312(1)
14.2.4 Mixed-Mode and Other Modes of Chromatography
313(3)
14.2.5 Dedicated Virus Removal Steps
316(1)
14.3 Integration of Polishing Steps
316(4)
14.3.1 Case Study I: Selection and Placement of Polishing Steps
316(2)
14.3.2 Case Study II: Selecting an Operational Mode and the Influence of the Upstream Polishing Step
318(2)
14.4 Conclusions
320(1)
Acknowledgment
320(1)
References
320(5)
15 Orthogonal Virus Clearance Applications in Monoclonal Antibody Production 325(18)
Joe X. Zhou
15.1 Introduction
325(1)
15.2 Model Viruses and Virus Assays
326(2)
15.3 Virus Clearance Strategies at Different Development Stages
328(1)
15.4 Orthogonal Virus Clearance During mAb Production
328(10)
15.4.1 Capture, Low-pH Virus Inactivation, and Polishing
328(1)
15.4.2 Disposable Systems
329(16)
15.4.2.1 Depth Filtration
329(1)
15.4.2.2 Q Membrane Chromatography
330(3)
15.4.2.3 Virus Clearance Using 20-nm Filters
333(5)
15.5 Conclusions and Future Perspectives
338(1)
Acknowledgments
339(1)
References
339(4)
16 Development of a Platform Process for the Purification of Therapeutic Monoclonal Antibodies 343(22)
Yuling Li
Min Zhu
Haibin Lu
Justin R. Weaver
16.1 Introduction
343(2)
16.2 Chromatography Steps in the Platform Process
345(7)
16.2.1 Capture Step: General Considerations
345(3)
16.2.1.1 Protein A Affinity Chromatography
346(1)
16.2.1.2 CEX Chromatography
347(1)
16.2.1.3 Mixed-Mode Chromatography
347(1)
16.2.1.4 Overview of Capture Resin Platforms
348(1)
16.2.2 Intermediate/Polishing Steps
348(4)
16.2.2.1 CEX Chromatography
348(1)
16.2.2.2 AEX Chromatography
349(1)
16.2.2.3 Mixed-Mode and HIC
349(2)
16.2.2.4 Selection of Polishing Resins
351(1)
16.3 Virus Inactivation
352(1)
16.4 UF/DF Platform Considerations
352(2)
16.4.1 Optimization
353(1)
16.4.2 Challenges and Facility Fit
354(1)
16.4.3 Application Examples
354(1)
16.5 Platform Development: Virus Filtration and Bulk Fill
354(2)
16.5.1 Virus Filtration in Platform Processes
355(1)
16.5.2 Filtration in Platform Processes
355(1)
16.6 Addressing Future Challenges in Downstream Processing
356(1)
16.7 Representative Platform Processes
356(3)
16.7.1 Example 1: Three-Column Process Including Protein A
356(2)
16.7.2 Example 2: Three-Column Process Without Protein A
358(1)
16.7.3 Example 3: Streamlined Processes with One or Two Columns
359(1)
16.8 Developing a Virus Clearance Database Using a Platform Process
359(2)
16.9 Summary
361(1)
References
361(4)
17 The Evolution of Platform Technologies for the Downstream Processing of Antibodies 365(26)
Lee Allen
17.1 Introduction
365(1)
17.2 The Definition of a Platform Purification Process
366(1)
17.3 The Dominant Process Design
367(5)
17.3.1 Convergence on a Dominant Design
367(1)
17.3.2 Evolutionary Pressure on Purification Platforms
368(4)
17.4 The Evolution of Unit Operations
372(10)
17.4.1 Incremental Improvements in Capture Technology
372(5)
17.4.1.1 The Development of Protein A Affinity Chromatography
374(1)
17.4.1.2 Incremental Improvements in Protein A Affinity Chromatography
375(2)
17.4.2 Incremental Improvements in Polishing Technology
377(4)
17.4.2.1 AEX Chromatography
377(1)
17.4.2.2 Aggregate Reduction Steps
378(3)
17.4.3 Incremental Improvements in Virus Clearance
381(14)
17.4.3.1 Virus Inactivation
381(1)
17.4.3.2 Virus Removal by Filtration
381(1)
17.5 Adapting the Platform Process for Product-Specific Issues
382(1)
17.6 Future Perspectives-Future Evolutionary Pathways
382(1)
17.7 Concluding Remarks
383(1)
Acknowledgments
384(1)
References
384(7)
18 Countercurrent Chromatography for the Purification of Monoclonal Antibodies, Bispecific Antibodies, and Antibody-Drug Conjugates 391(18)
Thomas Muller-Spath
Massimo Morbidelli
18.1 Introduction
391(1)
18.2 Chromatography to Reduce Product Heterogeneity
392(2)
18.3 Definition of Performance Parameters
394(1)
18.4 Gradient Chromatography for Biomolecules
394(1)
18.5 Continuous and Countercurrent Chromatography
395(2)
18.5.1 Overview
395(1)
18.5.2 The Simulated Moving Bed Process
396(1)
18.5.3 Advantages and Disadvantages of Batch and SMB Chromatography
396(1)
18.6 Multicolumn Countercurrent Solvent Gradient Purification
397(6)
18.6.1 MCSGP Process Principle and Design
398(1)
18.6.2 MCSGP for the Capture of Antibodies from Clarified Cell Culture Supernatants
399(1)
18.6.3 MCSGP for the Separation of mAb Variants
400(2)
18.6.4 MCSGP for the Purification of bsAbs
402(1)
18.6.5 MCSGP for the Purification of ADCs
403(1)
18.7 Scalability of Multicolumn Countercurrent Chromatography
403(1)
18.8 Online Process Monitoring for Multicolumn Countercurrent Chromatography
404(1)
18.9 Outlook
405(1)
References
405(4)
19 The Evolution of Continuous Chromatography: From Bulk Chemicals to Biopharma 409(22)
Marc Bisschops
19.1 Introduction
409(1)
19.2 Continuous Chromatography in Traditional Process Industries
410(3)
19.2.1 Continuous IEX
410(1)
19.2.2 SMB Technology
411(2)
19.3 Continuous Chromatography in the Biopharmaceutical Industry
413(7)
19.3.1 Continuous Multicolumn Chromatography Systems
414(3)
19.3.2 Continuous Multicolumn Capture Chromatography
417(1)
19.3.3 Number of Columns
418(2)
19.3.4 Beyond Affinity Capture Chromatography
420(1)
19.4 Advantages of Continuous Chromatography
420(2)
19.5 Implementation Aspects of Continuous Chromatography
422(2)
19.5.1 Single-Use Bioprocessing
422(1)
19.5.2 Integrated Continuous Bioprocessing
422(2)
19.6 Regulatory Aspects
424(2)
19.7 Conclusions
426(1)
References
427(4)
20 Accelerated Seamless Antibody Purification: Simplicity is Key 431(14)
Benoit Mothes
20.1 Introduction
431(1)
20.2 Accelerated Seamless Antibody Purification
432(5)
20.2.1 Concept of the ASAP Process
432(1)
20.2.2 ASAP Process Development
433(5)
20.2.2.1 Buffer Solutions
433(1)
20.2.2.2 The Protein A Step
434(1)
20.2.2.3 The Mixed-Mode Step
434(2)
20.2.2.4 The AEX Step
436(1)
20.2.2.5 Summary of ASAP Process Performance
436(1)
20.2.2.6 ASAP Process Robustness
436(1)
20.3 Advantages of the ASAP Process
437(1)
20.4 Scaling Up the ASAP Process
438(2)
20.4.1 Laboratory Scale-Up
438(2)
20.4.2 Pilot-Scale ASAP in a cGMP Environment
440(1)
20.5 New Perspectives
440(2)
20.5.1 Purification Skid
440(1)
20.5.2 Process Analytical Technology
441(1)
20.5.3 Membrane Adsorbers
441(1)
20.6 Conclusion
442(1)
Acknowledgments
442(1)
Suggested Reading
443(2)
21 Process Economic Drivers in Industrial Monoclonal Antibody Manufacture 445(22)
Suzanne S. Farid
21.1 Introduction
445(1)
21.2 Challenges When Striving for the Cost-Effective Manufacture of mAbs
446(2)
21.2.1 Constraints
446(1)
21.2.2 Uncertainties
447(1)
21.3 Cost Definitions and Benchmark Values
448(2)
21.3.1 Capital Investment
448(1)
21.3.2 Cost of Goods per Gram
449(1)
21.4 Economies of Scale
450(3)
21.5 Overall Process Economic Drivers
453(4)
21.5.1 Titer
453(1)
21.5.2 Overall DSP Yield
454(1)
21.5.3 Batch Duration
455(1)
21.5.4 Batch Success Rate
455(1)
21.5.5 Logistics
456(1)
21.6 DSP Drivers At High Titers
457(2)
21.6.1 Material Reuse and Lifetime
458(1)
21.6.2 Buffer/WFI Demands
458(1)
21.6.3 Chromatography Capacity
459(1)
21.7 Process Economic Trade-Offs for Downstream Process Bottlenecks
459(2)
21.7.1 Chromatography Resin Dynamic Binding Capacity
460(1)
21.7.2 Chromatography Flow Rates
460(1)
21.7.3 Chromatography Resin Cycle Limits
460(1)
21.7.4 Platform Processes
460(1)
21.7.5 Alternatives to Chromatography
461(1)
21.8 Summary and Outlook
461(1)
References
462(5)
22 Design and Optimization of Manufacturing 467(28)
Andrew Sinclair
22.1 Introduction
467(1)
22.2 Process Design and Optimization
468(2)
22.3 Modeling Approaches
470(11)
22.3.1 Process Models for mAb Manufacturing: Understanding Economics
470(6)
22.3.1.1 Basic Accounting Principles
471(1)
22.3.1.2 Project Appraisal
472(1)
22.3.1.3 Cost of Goods Modeling
473(3)
22.3.2 Process Schedule Visualization for mAb Manufacturing
476(5)
22.3.2.1 Process/Facility Schedule
478(1)
22.3.2.2 Data Requirements
479(1)
22.3.2.3 Bioprocess Models in Relation to ANSI/ISA-88
480(1)
22.4 Process Modeling in Practice
481(10)
22.4.1 Manufacturing Strategies
481(4)
22.4.1.1 Pooling Strategies for Multiple Single-Use Bioreactors
482(1)
22.4.1.2 Measuring the Overall Impact of Novel Single-Use Platforms
482(3)
22.4.2 The Potential of Continuous Downstream Processing Operations
485(1)
22.4.3 Manufacturing Technologies-Single-Use Systems
485(6)
22.4.3.1 Impact on Product and Solution Handling
487(3)
22.4.3.2 Membrane Adsorbers
490(1)
22.5 Impact of the Process on the Facility
491(1)
22.5.1 The Management of Multiproduct Manufacturing
491(1)
Acknowledgments
492(1)
References
492(3)
23 Smart Design for an Efficient Facility With a Validated Disposable System 495(20)
Joe X. Zhou
Jason Li
Michael Cui
Haojun Chen
23.1 Design and Optimization of a Manufacturing Facility
495(12)
23.1.1 Introduction
495(1)
23.1.2 Considerations for the Design and Construction of a New Facility
496(1)
23.1.3 Adapting to a New mAb Production Platform
496(4)
23.1.4 Process Modeling
500(1)
23.1.5 New Facility Project Management
501(3)
23.1.6 Site Selection and Master Planning
504(3)
23.2 Validation of a Disposable System
507(5)
23.2.1 Introduction
507(1)
23.2.2 Regulatory Requirements for Process Validation
508(1)
23.2.3 General Considerations for the Validation of Disposable Systems
509(1)
23.2.4 Implementation of Disposable Systems Validation
510(2)
23.3 Conclusion
512(1)
Acknowledgments
512(1)
References
512(3)
24 High-Throughput Screening and Modeling Technologies for Process Development in Antibody Purification 515(22)
Tobias Hahn
Thiemo Huuk
Jurgen Hubbuch
24.1 Introduction
515(1)
24.2 Adsorption Isotherms
516(3)
24.2.1 Example 1: Langmuir Isotherm
516(1)
24.2.2 Example 2: Steric Mass Action Isotherm
517(1)
24.2.3 Adsorption Kinetics
518(1)
24.3 Batch Chromatography
519(5)
24.3.1 Design Space Exploration
521(3)
24.3.2 Mechanistic Data Analysis
524(1)
24.4 Column Chromatography
524(8)
24.4.1 Comparability of HTCC and Benchtop Systems
525(1)
24.4.2 Mechanistic Modeling
526(13)
24.4.2.1 Solution of the Model Equation
527(1)
24.4.2.2 Model Calibration
527(2)
24.4.2.3 Example: Modeling a mAb Polishing Step
529(3)
References
532(5)
25 Downstream Processing of Monoclonal Antibody Fragments 537(22)
Mariangela Spitali
25.1 Introduction
537(1)
25.2 Production of Antibody Fragments for Therapeutic Use
538(1)
25.3 Downstream Processing
539(13)
25.3.1 Primary Recovery
539(3)
25.3.2 Capture
542(6)
25.3.3 Expanded Bed Adsorption Chromatography
548(2)
25.3.4 Further Purification and Polishing
550(9)
25.3.4.1 Intermediate Purification
550(1)
25.3.4.2 Polishing
551(1)
25.4 Improving the Pharmacological Characteristics of Antibody Fragments
552(1)
25.5 Conclusions
553(2)
Acknowledgments
555(1)
References
555(4)
26 Downstream Processing of Fc Fusion Proteins, Bispecific Antibodies, and Antibody-Drug Conjugates 559(36)
Abhinav A. Shukla
Carnley L. Norman
26.1 Introduction
559(3)
26.1.1 Fragment Crystallizable Fusion Proteins
559(2)
26.1.2 Bispecific Antibodies
561(1)
26.1.3 Antibody-Drug Conjugates
562(1)
26.2 Biochemical Properties
562(14)
26.2.1 Fc Fusion Proteins
562(7)
26.2.2 Bispecific Antibodies
569(3)
26.2.2.1 IgG-Like bsAbs
569(3)
26.2.2.2 bsAb Fragments
572(1)
26.2.3 Antibody-Drug Conjugates
572(4)
26.3 Purification From Mammalian Expression Systems
576(9)
26.3.1 Platform Approaches for Downstream Purification
576(2)
26.3.2 Fc Fusion Proteins: Capture, Virus Inactivation, and Polishing
578(3)
26.3.3 bsAbs: Molecule Design and Purification
581(1)
26.3.4 ADCs: Additional Steps
582(14)
26.3.4.1 Lysine Conjugation
584(1)
26.3.4.2 Cysteine Conjugation
584(1)
26.3.4.3 Manufacturing Challenges
585(1)
26.4 Purification From Microbial Production Systems
585(2)
26.5 Future Innovations
587(2)
Acknowledgment
589(1)
References
589(6)
27 Manufacturing Concepts for Antibody-Drug Conjugates 595(20)
Thomas Rohrer
27.1 Introduction
595(1)
27.2 Targeting Components
596(4)
27.2.1 Targeting Components for Random Conjugation
596(2)
27.2.2 Targeting Components for Site-Specific Conjugation
598(2)
27.3 Cytotoxic Drugs
600(2)
27.4 Chemically Labile Linkers
602(1)
27.5 General Process Overview
602(2)
27.6 Facility Design and Supporting Technology
604(3)
27.7 Single-Use Equipment
607(1)
27.8 Manufacturing ADCs
608(1)
27.9 Analytical Support for ADC Manufacturing
609(2)
27.9.1 Drug-to-Antibody Ratio and Distribution
609(1)
27.9.2 Size-Variant Analysis
610(1)
27.9.3 Unconjugated Drug in the Drug Substance and Product
611(1)
27.10 Raw Materials Supply Chain
611(1)
27.11 Conclusion
611(2)
Acknowledgments
613(1)
References
613(2)
28 Purification of IgM and IgA 615(16)
Charlotte Cabanne
Xavier Santarelli
28.1 Introduction
615(1)
28.2 Purification of IgM
616(5)
28.2.1 IgM Structure and Properties
616(1)
28.2.2 IgM Purification Technologies
616(1)
28.2.3 Affinity and Pseudoaffinity Matrices
617(4)
28.2.3.1 Protein L
617(1)
28.2.3.2 Mannose-Binding Protein
617(1)
28.2.3.3 Thiophilic Matrices
618(1)
28.2.3.4 Immobilized Metal Affinity Chromatography
618(1)
28.2.3.5 Hydroxyapatite
619(1)
28.2.3.6 Protein A Mimetic TG 19318
619(1)
28.2.3.7 VHH Camelid Ligand
619(1)
28.2.3.8 Hexamer Peptide Ligands HWRGWV, HYFKFD, and HFRRHL
620(1)
28.2.3.9 Capto™ Core 700
620(1)
28.3 Purification of IgA
621(2)
28.3.1 IgA Structure and Properties
621(1)
28.3.2 Affinity and Pseudoaffinity Matrices
621(11)
28.3.2.1 Protein L, Thiophilic Matrices, and IMAC
621(1)
28.3.2.2 Hydroxyapatite
621(1)
28.3.2.3 Jacalin Matrix
622(1)
28.3.2.4 Protein A Mimetic TG 19318
622(1)
28.3.2.5 Streptococcal IgA-Binding Peptide
622(1)
28.3.2.6 ZIgA Ligand
622(1)
28.3.2.7 Hexameric Peptide Ligand HWRGWV
622(1)
28.3.2.8 VHH Camelid Ligand
622(1)
28.4 Conclusion
623(1)
Acknowledgments
623(1)
References
623(8)
29 Purification of Monoclonal Antibodies From Plants 631(24)
Zivko L Nikolov
Jeffrey T. Regan
Lynn F. Dickey
Susan L. Woodard
29.1 Introduction
631(1)
29.2 Antibody Production in Plants
632(4)
29.2.1 Subcellular Localization and Glycosylation
632(3)
29.2.2 Other Factors Affecting mAb Accumulation
635(1)
29.3 Downstream Processing of Antibodies Produced in Plants
636(5)
29.3.1 Tissue Disintegration
638(1)
29.3.2 Solids Separation and Clarification
639(1)
29.3.3 Pretreatment of Clarified Extracts
640(1)
29.4 Purification of Plant-Derived Antibodies Using Protein A Resins
641(1)
29.5 Purification of Plant-Derived Antibodies Using Non-Protein A Media
642(1)
29.6 Polishing Steps
643(2)
29.7 Conclusions
645(1)
Acknowledgment
645(1)
References
645(10)
30 Very-Large-Scale Production of Monoclonal Antibodies in Plants 655(18)
Johannes F. Buyel
Richard M. Twyman
Rainer Fischer
30.1 Introduction
655(1)
30.2 Process Schemes for mAb Production in Plants
656(5)
30.2.1 Extraction
657(1)
30.2.2 Clarification
658(1)
30.2.3 Purification
659(2)
30.3 Scalable Process Models
661(2)
30.4 Process Adaptation for VLS Requirements
663(3)
30.5 Translation into VLS Applications
666(1)
References
667(6)
31 Trends in Formulation and Drug Delivery for Antibodies 673(26)
Hanns-Christian Mahler
Roman Mathas
31.1 Introduction
673(1)
31.2 Degradation Pathways
674(1)
31.3 Physical Instability
674(2)
31.3.1 Denaturation
674(1)
31.3.2 Aggregation/Precipitation
675(1)
31.3.3 Adsorption
676(1)
31.4 Chemical Instability
676(2)
31.4.1 Deamidation
677(1)
31.4.2 Asp Isomerization
677(1)
31.4.3 Oxidation
677(1)
31.4.4 Hydrolysis
678(1)
31.4.5 Glycation
678(1)
31.4.6 Disulfide and Nondisulfide Cross-linking
678(1)
31.5 How to Achieve Product Stability
678(1)
31.6 Developability: Molecule Selection and Elimination of Degradation Hotspots
679(1)
31.7 Stabilizing an Antibody in a Liquid Formulation
679(2)
31.8 Stabilizing an Antibody by Drying
681(1)
31.9 Choice of Adequate Primary Packaging
682(1)
31.10 Minimizing Stress During Drug Product Processing
683(2)
31.10.1 Freeze/Thaw
683(1)
31.10.2 Mixing
683(1)
31.10.3 Filling
684(1)
31.10.4 Filtration
684(1)
31.10.5 Shipping
684(1)
31.10.6 Environmental Impact
685(1)
31.11 Implementation of a Formulation Strategy
685(1)
31.12 Hot Topics
685(4)
31.12.1 Protein Aggregation and Protein Particles
685(1)
31.12.2 High-Concentration Antibody Formulations for Subcutaneous Administration
686(1)
31.12.3 Drug/Device Combination Products
687(1)
31.12.4 When Stabilizers Need a Stabilizer
688(1)
31.12.5 Protein Oxidation
689(1)
31.12.6 The Bioprocess May Affect Drug Product Stability
689(1)
31.13 Summary
689(1)
References
690(9)
32 Antibody Purification: Drivers of Change 699(18)
Narahari Pujar
Duncan Low
Rhona O'Leary
32.1 Introduction
699(2)
32.2 The Changing Regulatory Environment-Pharmaceutical Manufacturing for the 21st Century
701(6)
32.2.1 Using Design Space to Enable Change
704(2)
32.2.2 High-Throughput and Microscale Approaches to Process Development and Characterization
706(1)
32.3 Technology Drivers-Advances and Innovations
707(1)
32.3.1 Process Analytical Technology
707(1)
32.3.2 Process Control Technology
708(1)
32.4 Economic Drivers
708(3)
32.4.1 Cost of Goods
708(1)
32.4.2 Single-Use Disposable Components
709(1)
32.4.3 Globalization
710(1)
32.4.4 FOBs or Biosimilars
711(1)
32.5 Conclusions
711(1)
Acknowledgment
712(1)
References
713(4)
Index 717
Uwe Gottschalk, PhD,is Chief Technology Officer at Lonza Pharma/Biotech, Switzerland. Previously, he served as Group Vice President at Sartorius Stedim Biotech (2004-2014) and in various development and manufacturing capacities at Bayer Health Care (19912004). Dr. Gottschalk received a doctorate in chemistry from the University of Münster (Germany) for work on antibody-drug conjugates at the Cancer Research Campaign Laboratories in Nottingham (UK). He is Head Lecturer at the University of Duisburg-Essen, Germany, and has written extensively in the areas of industrial biotechnology and somatic gene therapy.
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