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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. Sales of monoclonal antibody products have grown from approximately $50 billion in 2010 to almost $90 billion in 2015, an approximately 1.8‑fold increase and represent approximately 58% of biopharmaceutical sales.  As more and more exciting monoclonal antibody products for treatment of cancer, autoimmune diseases, cardiovascular disease, and others are introduced, sales from new products approved in the coming years will drive the world-wide sales of monoclonal antibody products to approximately $110 billion by 2018 and nearly $150 billion by 2021.

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 2017, to provide a roadmap for the development of a monoclonal antibody product from initial discovery through the filing of an Investigational New Drug Application (IND) or Investigational Medicinal Product Dossier (IMPD) or equivalent for first in human clinical trials. The primary focus of the report remains on the technical, regulatory, and management issues related to process development, manufacturing, quality control, and analysis of full-length single specificity monoclonal antibody products produced in mammalian cell culture. New to the Second Edition are an in-depth look at Quality by Design (QbD) for monoclonal antibodies in an all new chapter, an entirely new perspective on cell line development and engineering, a fresh look at process validation in line with current regulatory thinking, and updates aligning the content with today’s philosophies and practices throughout.

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.    


CHAPTER 1: The Therapeutic Monoclonal Antibody Market
CHAPTER 2: Overview of Chemistry, Manufacturing, and Control Activities for Monoclonal Antibody Product Development
CHAPTER 3: Quality by Design
CHAPTER 4: Analytical Development
CHAPTER 5: Cell Line Development and Engineering
CHAPTER 6: Cell Culture Development and Scale-up
CHAPTER 7: Purification Development
CHAPTER 8: Formulation Development and Stability
CHAPTER 9: Drug Product Manufacturing
CHAPTER 10: Comparability
CHAPTER 11: Process Validation
CHAPTER 12: Manufacturing Strategies
Tables and Figures - The Development of Therapeutic Monoclonal Antibody Products
Table 1.
Applications of Therapeutic Monoclonal Antibody Products
Table 1.
2015 Sales of the Top Ten Selling Biopharmaceutical Products
Table 1.
Commercially Marketed Therapeutic Monoclonal Antibody Products
Table 1.
Patent Expiration Dates for Key Monoclonal Antibody Products
Table 2.
Estimated CMC-Related Costs for Monoclonal Antibody Development
Table 3.
ICH Guidelines Related to Quality by Design
Table 3.
Control Strategy Elements
Table 4.
ICH Guidance Documents Covering the Testing
and Characterization of Monoclonal Antibody Products
Table 4.
Minimum AMV Characteristics from ICH Q2(R1)
Table 4.
Some Methods Used for Identity Testing of Monoclonal Antibody Products
Table 4.
Some Methods Used for Determination of Purity and
Product-Related Impurities of Monoclonal Antibody Products
Table 4.
Some Methods Used for Measurement of Some Process Related Impurities
Table 4.
Some Methods Used for Safety Testing of Monoclonal Antibody Products
Table 4.
Methods Used for Potency Testing of Monoclonal Antibody Products
Table 4.
Methods Used for Testing General Attributes of
Monoclonal Antibody Drug Substance and Drug Product
Table 4.
Analytical Methods Used to Characterize Monoclonal Antibody Drugs
Table 4.
Common Release Tests for Monoclonal Drug Substance and Drug Product
Table 4.
An Example of QC Release Methods and Specifications
for a Monoclonal Antibody Product in Early Clinical Development
Table 5.
CHO Species Used in Monoclonal Antibody Production
Table 5.
Commercially Available Expression Systems
Table 5.
Expression Vector Construction
Table 5.
Transfection and Selection
Table 5.
Single Cell Cloning
Table 5.
Testing of Mammalian Cell Banks
Table 7.
Parameters to be Considered in Chromatography Step Development
Table 7.
Comparison of High Throughput Methods
for the Development of Chromatographic Separations
Table 7.
Guidelines for Linear Scale-up of Chromatography
Table 8.
Formulation Details for Currently Marketed Therapeutic Monoclonal Antibody Products
Table 8.
Potential Degradation Pathways of Monoclonal Antibody
Products and Analytical Methods to Detect Them
Table 8.
Example of a Forced Degradation Matrix for a Monoclonal Antibody Product
Table 8.
Typical Analytical Methods Used in Monoclonal Antibody Stability Studies
Table 8.
Commonly Used Buffers in Monoclonal Antibody Formulations
Table 8.
Example of Design of Experiments Study Investigating
Four or Five Components of a Potential Monoclonal Antibody Product Formulation
Table 8.
Typical Stability Study Design for a Monoclonal Antibody Drug Substance
to Support Early Stage Clinical Development
Table 8.
Typical Stability Study Design for a Monoclonal Antibody Drug Product to Support Early Stage Clinical Development
Table 9.
Improvements in Rubber Stopper Formulations
Table 9.
Typical Monoclonal Antibody Drug Product Specifications
Table 10.
Regulatory Submissions Worldwide Supporting Process Changes
Table 10.
Risk Assessment and Comparability Requirements in Early Development
Table 10.
Typical Monoclonal Antibody Product Release Tests Used in Comparability Protocols
Table 10.
Characterization Tests used in Monoclonal Antibody Product Comparability Protocols
Table 11.
Typical Stage 1 Process Design Activities
Table 11.
Typical Stage 2 Process Qualification Activities
Table 11.
Potential Cell Culture Critical Process Parameters
Table 11.
Sample VMP Table of Contents
Table 12.
Typical Contents of a Request for Proposal for CMO Services
Table 12.
Operating Costs for Stainless Steel and Single-Use Facilities
   
List of Figures
 
Figure 1.
Antibody Structure
Figure 1.
IgG Oligosaccharide Structure
Figure 1.
Annual Approvals of Monoclonal Antibody Products
Figure 1.
Sales of Biopharmaceutical Products by Product Type and Class
Figure 1.
Sales Growth for Commercial Monoclonal Antibody Products
Figure 2.
Typical CMC Timeline for Monoclonal Antibody Development
Figure 3.
The Quality by Design Approach
Figure 3.
CQA Risk Assessment
Figure 3.
Prior Knowledge Elements
Figure 3.
Example of a Design Space
Figure 3.
Specifications Settings
Figure 3.
Relationship of Process Characterization Studies to Design Space
Figure 3.
Development of a Process Control Strategy
Figure 4.
Analytical Methods Lifecycle
Figure 4.
Method Validation Readiness Flow Path
Figure 5.
Representative Cell Line Development Workflow
Figure 7.
Typical Unit Operations Used in Monoclonal Antibody Purification
Figure 7.
Basic Elements of a Platform Purification Processes
Figure 7.
Effect of Processing Time on Membrane Area for a UF/DF Process
Figure 7.
Principle of Linear Scale-up of a Chromatography Column
Figure 8.
Structure of a Monoclonal Antibody
Figure 8.
Mechanism of Methionine Oxidation
Figure 8.
Mechanism of Deamidation of Asparagine Residues
Figure 8.
Disulfide Rearrangement
Figure 8.
Mechanism of β-Elimination and Rearrangement or Hydrolysis
Figure 8.
Hydrolysis of Asp-Gly Peptide Bonds
Figure 8.
Aggregation Pathways for Monoclonal Antibody Products
Figure 8.
Liquid and Lyophilized Formulations for Currently Marketed Therapeutic Monoclonal Antibody Products
Figure 9.
Steps in the Manufacture of a Monoclonal Antibody Drug Product
Figure 10.
Typical Stability Study Design for a Monoclonal Antibody Drug Product to Support Early Stage Clinical Development
Figure 10.
Comparability Decision Tree
Figure 11.
Overall Sequence of Process Validation Activities
Figure 11.
Overview of Quality Risk Management
Figure 11.
An example of an Ishikawa or Fishbone Diagram
Figure 11.
Unit Operation-based Approach to Risk Assessment
Figure 11.
Relationship between the Phases of Product
Development and the Process Validation Lifecycle
Figure 11.
Risk Assessment for Classifying Process Parameter Criticality
Figure 11.
Defining Operating Parameter Ranges
Figure 12.
Manufacturing Strategy Considerations
Figure 12.
Pilot Plant for Production of Monoclonal Antibody Bulk Drug Substance
Figure 12.
Cost Breakdown for a Simple Monoclonal Antibody Pilot Plant
Figure 12.
Monoclonal Antibody Pilot Plant Construction Timeline

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