The Development of Therapeutic Monoclonal Antibody Products
The Development of Therapeutic Monoclonal Antibody Products
As the pharmaceutical market in the United States and the rest of the world continues to expand, biopharmaceutical products have taken on increasing importance in the treatment of disease. From 2005 through 2015, the global pharmaceutical market has grown from approximately $6.5 billion to nearly $11 billion, driven in large part by the introduction of more and more monoclonal antibody products. Sales of this segment of the pharmaceutical market have grown at a compound annual growth rate of approximately 10% for the last 10 years making biologics approximately nearly 15% of the total pharmaceutical market. As more and more exciting monoclonal antibody products for treatment of cancer, autoimmune diseases, cardiovascular disease, and others are introduced, the growth of monoclonal antibodies is predicted to continue with expectations that sales of these products expected to reach almost $250 million by 2020.
When The Development of Therapeutic Monoclonal Antibodies was originally released in 2010, it quickly became an indispensable tool for those involved in the development or financing of monoclonal antibodies. It served as a guide to the complex technical, regulatory, and strategic Chemistry, Manufacturing, and Controls (CMC) activities necessary to successfully advance new monoclonal antibody products to clinical trials and the market as quickly as possible. This Second Edition has been fully revised and updated for 2016, with the addition of new content addressing advancements in Quality by Design (QbD), analytical development, and process validation, and more. Since publication of the First Edition of this book, regulatory agencies in the US, Europe, and the rest of the world have updated or issued all of the major guidances and regulations related to biopharmaceutical products. This new Second Edition includes a discussion of these new guidance documents from FDA, EMA, and ICH.
The Second Edition takes an updated look at, and provides recommendations for, all aspects of CMC necessary for the development of monoclonal antibody products from discovery through First In-Human Trials. The regulatory framework in which developers of monoclonal antibodies must operate is complex and constantly evolving. This report provides an overview of the most up to date regulatory thinking and the course that it may take going forward.
The Development of Therapeutic Monoclonal Antibodies Second Edition goes beyond other reports by incorporating the latest technical developments and integrating strategic and regulatory considerations with these technical requirements. This report will serve as a guide to product development companies, service providers, investors, and analyst as they work their way through the complex and rapidly evolving world of therapeutic monoclonal antibodies.
As the pharmaceutical market in the United States and the rest of the world continues to expand, biopharmaceutical products have taken on increasing importance in the treatment of disease. From 2005 through 2015, the global pharmaceutical market has grown from approximately $6.5 billion to nearly $11 billion, driven in large part by the introduction of more and more monoclonal antibody products. Sales of this segment of the pharmaceutical market have grown at a compound annual growth rate of approximately 10% for the last 10 years making biologics approximately nearly 15% of the total pharmaceutical market. As more and more exciting monoclonal antibody products for treatment of cancer, autoimmune diseases, cardiovascular disease, and others are introduced, the growth of monoclonal antibodies is predicted to continue with expectations that sales of these products expected to reach almost $250 million by 2020.
When The Development of Therapeutic Monoclonal Antibodies was originally released in 2010, it quickly became an indispensable tool for those involved in the development or financing of monoclonal antibodies. It served as a guide to the complex technical, regulatory, and strategic Chemistry, Manufacturing, and Controls (CMC) activities necessary to successfully advance new monoclonal antibody products to clinical trials and the market as quickly as possible. This Second Edition has been fully revised and updated for 2016, with the addition of new content addressing advancements in Quality by Design (QbD), analytical development, and process validation, and more. Since publication of the First Edition of this book, regulatory agencies in the US, Europe, and the rest of the world have updated or issued all of the major guidances and regulations related to biopharmaceutical products. This new Second Edition includes a discussion of these new guidance documents from FDA, EMA, and ICH.
The Second Edition takes an updated look at, and provides recommendations for, all aspects of CMC necessary for the development of monoclonal antibody products from discovery through First In-Human Trials. The regulatory framework in which developers of monoclonal antibodies must operate is complex and constantly evolving. This report provides an overview of the most up to date regulatory thinking and the course that it may take going forward.
The Development of Therapeutic Monoclonal Antibodies Second Edition goes beyond other reports by incorporating the latest technical developments and integrating strategic and regulatory considerations with these technical requirements. This report will serve as a guide to product development companies, service providers, investors, and analyst as they work their way through the complex and rapidly evolving world of therapeutic monoclonal antibodies.
Table of Contents - The Development of Therapeutic Monoclonal Antibody Products
Table of Contents
List of Tables
iv
List of Figures
vi
Foreword
viii
CHAPTER 1: The Therapeutic Monoclonal Antibody Market
1
CHAPTER 2: Overview of Chemistry, Manufacturing, and Control Activities for Monoclonal Antibody Product Development
33
CHAPTER 3: Quality by Design
65
CHAPTER 4: Analytical Development
95
CHAPTER 5: Cell Line Development and Engineering
155
CHAPTER 6: Cell Culture Development and Scale-up
195
CHAPTER 7: Purification Development
241
CHAPTER 8: Formulation Development and Stability
313
CHAPTER 9: Drug Product Manufacturing
370
CHAPTER 10: Comparability
393
CHAPTER 11: Process Validation
423
CHAPTER 12: Manufacturing Strategies
473
Table of Contents
List of Tables
iv
List of Figures
vi
Foreword
viii
CHAPTER 1: The Therapeutic Monoclonal Antibody Market
1
CHAPTER 2: Overview of Chemistry, Manufacturing, and Control Activities for Monoclonal Antibody Product Development
33
CHAPTER 3: Quality by Design
65
CHAPTER 4: Analytical Development
95
CHAPTER 5: Cell Line Development and Engineering
155
CHAPTER 6: Cell Culture Development and Scale-up
195
CHAPTER 7: Purification Development
241
CHAPTER 8: Formulation Development and Stability
313
CHAPTER 9: Drug Product Manufacturing
370
CHAPTER 10: Comparability
393
CHAPTER 11: Process Validation
423
CHAPTER 12: Manufacturing Strategies
473
Tables and Figures - The Development of Therapeutic Monoclonal Antibody Products
Table of Contents
Table 1.1
Applications of Therapeutic Monoclonal Antibody Products
7
Table 1.2
2015 Sales of the Top Ten Selling Biopharmaceutical Products
9
Table 1.3
Commercially Marketed Therapeutic Monoclonal Antibody Products
11
Table 1.4
Patent Expiration Dates for Key Monoclonal Antibody Products
23
Table 2.1
Estimated CMC-Related Costs for Monoclonal Antibody Development
56
Table 3.1
ICH Guidelines Related to Quality by Design
66
Table 3.2
Control Strategy Elements
86
Table 4.1
ICH Guidance Documents Covering the Testing
and Characterization of Monoclonal Antibody Products
99
Table 4.2
Minimum AMV Characteristics from ICH Q2(R1)
107
Table 4.3
Some Methods Used for Identity Testing of Monoclonal Antibody Products
109
Table 4.4
Some Methods Used for Determination of Purity and
Product-Related Impurities of Monoclonal Antibody Products
113
Table 4.5
Some Methods Used for Measurement of Some Process Related Impurities
119
Table 4.6
Some Methods Used for Safety Testing of Monoclonal Antibody Products
121
Table 4.7
Methods Used for Potency Testing of Monoclonal Antibody Products
122
Table 4.8
Methods Used for Testing General Attributes of
Monoclonal Antibody Drug Substance and Drug Product
124
Table 4.9
Analytical Methods Used to Characterize Monoclonal Antibody Drugs
126
Table 4.10
Common Release Tests for Monoclonal Drug Substance and Drug Product
143
Table 4.11
An Example of QC Release Methods and Specifications
for a Monoclonal Antibody Product in Early Clinical Development
145
Table 5.1
CHO Species Used in Monoclonal Antibody Production
160
Table 5.2
Commercially Available Expression Systems
164
Table 5.3
Expression Vector Construction
168
Table 5.4
Transfection and Selection
170
Table 5.5
Single Cell Cloning
172
Table 5.6
Testing of Mammalian Cell Banks
184
Table 7.1
Parameters to be Considered in Chromatography Step Development
278
Table 7.2
Comparison of High Throughput Methods
for the Development of Chromatographic Separations
281
Table 7.3
Guidelines for Linear Scale-up of Chromatography
294
Table 8.1
Formulation Details for Currently Marketed Therapeutic Monoclonal Antibody Products
314
Table 8.2
Potential Degradation Pathways of Monoclonal Antibody
Products and Analytical Methods to Detect Them
322
Table 8.3
Example of a Forced Degradation Matrix for a Monoclonal Antibody Product
332
Table 8.4
Typical Analytical Methods Used in Monoclonal Antibody Stability Studies
333
Table 8.5
Commonly Used Buffers in Monoclonal Antibody Formulations
336
Table 8.6
Example of Design of Experiments Study Investigating
Four or Five Components of a Potential Monoclonal Antibody Product Formulation
343
Table 8.7
Typical Stability Study Design for a Monoclonal Antibody Drug Substance
to Support Early Stage Clinical Development
354
Table 8.8
Typical Stability Study Design for a Monoclonal Antibody Drug Product to Support Early Stage Clinical Development
359
Table 9.1
Improvements in Rubber Stopper Formulations
378
Table 9.2
Typical Monoclonal Antibody Drug Product Specifications
386
Table 10.1
Regulatory Submissions Worldwide Supporting Process Changes
399
Table 10.2
Risk Assessment and Comparability Requirements in Early Development
403
Table 10.3
Typical Monoclonal Antibody Product Release Tests Used in Comparability Protocols
408
Table 10.4
Characterization Tests used in Monoclonal Antibody Product Comparability Protocols
411
Table 11.1
Typical Stage 1 Process Design Activities
431
Table 11.2
Typical Stage 2 Process Qualification Activities
440
Table 11.3
Potential Cell Culture Critical Process Parameters
448
Table 11.4
Sample VMP Table of Contents
464
Table 12.1
Typical Contents of a Request for Proposal for CMO Services
485
Table 12.2
Operating Costs for Stainless Steel and Single-Use Facilities
492
List of Figures
Figure 1.1
Antibody Structure
2
Figure 1.2
IgG Oligosaccharide Structure
4
Figure 1.3
Annual Approvals of Monoclonal Antibody Products
10
Figure 1.4
Sales of Biopharmaceutical Products by Product Type and Class
17
Figure 1.5
Sales Growth for Commercial Monoclonal Antibody Products
19
Figure 2.1
Typical CMC Timeline for Monoclonal Antibody Development
54
Figure 3.1
The Quality by Design Approach
68
Figure 3.2
CQA Risk Assessment
72
Figure 3.3
Prior Knowledge Elements
73
Figure 3.4
Example of a Design Space
76
Figure 3.5
Specifications Settings
78
Figure 3.6
Relationship of Process Characterization Studies to Design Space
79
Figure 3.7
Development of a Process Control Strategy
84
Figure 4.1
Analytical Methods Lifecycle
101
Figure 4.2
Method Validation Readiness Flow Path
104
Figure 5.1
Representative Cell Line Development Workflow
169
Figure 7.1
Typical Unit Operations Used in Monoclonal Antibody Purification
252
Figure 7.2
Basic Elements of a Platform Purification Processes
274
Figure 7.3
Effect of Processing Time on Membrane Area for a UF/DF Process
292
Figure 7.4
Principle of Linear Scale-up of a Chromatography Column
293
Figure 8.1
Structure of a Monoclonal Antibody
320
Figure 8.2
Mechanism of Methionine Oxidation
323
Figure 8.3
Mechanism of Deamidation of Asparagine Residues
324
Figure 8.4
Disulfide Rearrangement
325
Figure 8.5
Mechanism of β-Elimination and Rearrangement or Hydrolysis
326
Figure 8.6
Hydrolysis of Asp-Gly Peptide Bonds
327
Figure 8.7
Aggregation Pathways for Monoclonal Antibody Products
329
Figure 8.8
Liquid and Lyophilized Formulations for Currently Marketed Therapeutic Monoclonal Antibody Products
344
Figure 9.1
Steps in the Manufacture of a Monoclonal Antibody Drug Product
371
Figure 10.1
Typical Stability Study Design for a Monoclonal Antibody Drug Product to Support Early Stage Clinical Development
396
Figure 10.2
Comparability Decision Tree
404
Figure 11.1
Overall Sequence of Process Validation Activities
426
Figure 11.2
Overview of Quality Risk Management
427
Figure 11.3
An example of an Ishikawa or Fishbone Diagram
430
Figure 11.4
Unit Operation-based Approach to Risk Assessment
435
Figure 11.5
Relationship between the Phases of Product
Development and the Process Validation Lifecycle
437
Figure 11.6
Risk Assessment for Classifying Process Parameter Criticality
444
Figure 11.7
Defining Operating Parameter Ranges
444
Figure 12.1
Manufacturing Strategy Considerations
475
Figure 12.2
Pilot Plant for Production of Monoclonal Antibody Bulk Drug Substance
489
Figure 12.4
Cost Breakdown for a Simple Monoclonal Antibody Pilot Plant
491
Figure 12.4
Monoclonal Antibody Pilot Plant Construction Timeline
493
Table of Contents
Table 1.1
Applications of Therapeutic Monoclonal Antibody Products
7
Table 1.2
2015 Sales of the Top Ten Selling Biopharmaceutical Products
9
Table 1.3
Commercially Marketed Therapeutic Monoclonal Antibody Products
11
Table 1.4
Patent Expiration Dates for Key Monoclonal Antibody Products
23
Table 2.1
Estimated CMC-Related Costs for Monoclonal Antibody Development
56
Table 3.1
ICH Guidelines Related to Quality by Design
66
Table 3.2
Control Strategy Elements
86
Table 4.1
ICH Guidance Documents Covering the Testing
and Characterization of Monoclonal Antibody Products
99
Table 4.2
Minimum AMV Characteristics from ICH Q2(R1)
107
Table 4.3
Some Methods Used for Identity Testing of Monoclonal Antibody Products
109
Table 4.4
Some Methods Used for Determination of Purity and
Product-Related Impurities of Monoclonal Antibody Products
113
Table 4.5
Some Methods Used for Measurement of Some Process Related Impurities
119
Table 4.6
Some Methods Used for Safety Testing of Monoclonal Antibody Products
121
Table 4.7
Methods Used for Potency Testing of Monoclonal Antibody Products
122
Table 4.8
Methods Used for Testing General Attributes of
Monoclonal Antibody Drug Substance and Drug Product
124
Table 4.9
Analytical Methods Used to Characterize Monoclonal Antibody Drugs
126
Table 4.10
Common Release Tests for Monoclonal Drug Substance and Drug Product
143
Table 4.11
An Example of QC Release Methods and Specifications
for a Monoclonal Antibody Product in Early Clinical Development
145
Table 5.1
CHO Species Used in Monoclonal Antibody Production
160
Table 5.2
Commercially Available Expression Systems
164
Table 5.3
Expression Vector Construction
168
Table 5.4
Transfection and Selection
170
Table 5.5
Single Cell Cloning
172
Table 5.6
Testing of Mammalian Cell Banks
184
Table 7.1
Parameters to be Considered in Chromatography Step Development
278
Table 7.2
Comparison of High Throughput Methods
for the Development of Chromatographic Separations
281
Table 7.3
Guidelines for Linear Scale-up of Chromatography
294
Table 8.1
Formulation Details for Currently Marketed Therapeutic Monoclonal Antibody Products
314
Table 8.2
Potential Degradation Pathways of Monoclonal Antibody
Products and Analytical Methods to Detect Them
322
Table 8.3
Example of a Forced Degradation Matrix for a Monoclonal Antibody Product
332
Table 8.4
Typical Analytical Methods Used in Monoclonal Antibody Stability Studies
333
Table 8.5
Commonly Used Buffers in Monoclonal Antibody Formulations
336
Table 8.6
Example of Design of Experiments Study Investigating
Four or Five Components of a Potential Monoclonal Antibody Product Formulation
343
Table 8.7
Typical Stability Study Design for a Monoclonal Antibody Drug Substance
to Support Early Stage Clinical Development
354
Table 8.8
Typical Stability Study Design for a Monoclonal Antibody Drug Product to Support Early Stage Clinical Development
359
Table 9.1
Improvements in Rubber Stopper Formulations
378
Table 9.2
Typical Monoclonal Antibody Drug Product Specifications
386
Table 10.1
Regulatory Submissions Worldwide Supporting Process Changes
399
Table 10.2
Risk Assessment and Comparability Requirements in Early Development
403
Table 10.3
Typical Monoclonal Antibody Product Release Tests Used in Comparability Protocols
408
Table 10.4
Characterization Tests used in Monoclonal Antibody Product Comparability Protocols
411
Table 11.1
Typical Stage 1 Process Design Activities
431
Table 11.2
Typical Stage 2 Process Qualification Activities
440
Table 11.3
Potential Cell Culture Critical Process Parameters
448
Table 11.4
Sample VMP Table of Contents
464
Table 12.1
Typical Contents of a Request for Proposal for CMO Services
485
Table 12.2
Operating Costs for Stainless Steel and Single-Use Facilities
492
List of Figures
Figure 1.1
Antibody Structure
2
Figure 1.2
IgG Oligosaccharide Structure
4
Figure 1.3
Annual Approvals of Monoclonal Antibody Products
10
Figure 1.4
Sales of Biopharmaceutical Products by Product Type and Class
17
Figure 1.5
Sales Growth for Commercial Monoclonal Antibody Products
19
Figure 2.1
Typical CMC Timeline for Monoclonal Antibody Development
54
Figure 3.1
The Quality by Design Approach
68
Figure 3.2
CQA Risk Assessment
72
Figure 3.3
Prior Knowledge Elements
73
Figure 3.4
Example of a Design Space
76
Figure 3.5
Specifications Settings
78
Figure 3.6
Relationship of Process Characterization Studies to Design Space
79
Figure 3.7
Development of a Process Control Strategy
84
Figure 4.1
Analytical Methods Lifecycle
101
Figure 4.2
Method Validation Readiness Flow Path
104
Figure 5.1
Representative Cell Line Development Workflow
169
Figure 7.1
Typical Unit Operations Used in Monoclonal Antibody Purification
252
Figure 7.2
Basic Elements of a Platform Purification Processes
274
Figure 7.3
Effect of Processing Time on Membrane Area for a UF/DF Process
292
Figure 7.4
Principle of Linear Scale-up of a Chromatography Column
293
Figure 8.1
Structure of a Monoclonal Antibody
320
Figure 8.2
Mechanism of Methionine Oxidation
323
Figure 8.3
Mechanism of Deamidation of Asparagine Residues
324
Figure 8.4
Disulfide Rearrangement
325
Figure 8.5
Mechanism of β-Elimination and Rearrangement or Hydrolysis
326
Figure 8.6
Hydrolysis of Asp-Gly Peptide Bonds
327
Figure 8.7
Aggregation Pathways for Monoclonal Antibody Products
329
Figure 8.8
Liquid and Lyophilized Formulations for Currently Marketed Therapeutic Monoclonal Antibody Products
344
Figure 9.1
Steps in the Manufacture of a Monoclonal Antibody Drug Product
371
Figure 10.1
Typical Stability Study Design for a Monoclonal Antibody Drug Product to Support Early Stage Clinical Development
396
Figure 10.2
Comparability Decision Tree
404
Figure 11.1
Overall Sequence of Process Validation Activities
426
Figure 11.2
Overview of Quality Risk Management
427
Figure 11.3
An example of an Ishikawa or Fishbone Diagram
430
Figure 11.4
Unit Operation-based Approach to Risk Assessment
435
Figure 11.5
Relationship between the Phases of Product
Development and the Process Validation Lifecycle
437
Figure 11.6
Risk Assessment for Classifying Process Parameter Criticality
444
Figure 11.7
Defining Operating Parameter Ranges
444
Figure 12.1
Manufacturing Strategy Considerations
475
Figure 12.2
Pilot Plant for Production of Monoclonal Antibody Bulk Drug Substance
489
Figure 12.4
Cost Breakdown for a Simple Monoclonal Antibody Pilot Plant
491
Figure 12.4
Monoclonal Antibody Pilot Plant Construction Timeline
493
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