治療用モノクロナール抗体製品の開発

モノクロナール抗体製品の売上は、2010年の約500億米ドルから2015年の約900億米ドルへ、およそ1.8倍の増加を示し、バイオ医薬品売上の約58%を構成しました。世界におけるモノクロナール抗体製品の売上は、癌の治療、自己免疫疾患、および心血管疾患などへの採用に加え、今後数年で認可が見込まれる新製品の売上に促進され、2018年までに1,100億米ドル、2021年までに1,500億米ドルへ拡大すると予測されています。

当レポートでは、世界における治療用モノクロナール抗体製品市場について調査し、市場の概要、開発・製造・品質管理などに関連した技術・規制・マネジメントの課題について分析しています。

第1章　治療用モノクロナール抗体市場

第2章　モノクロナール抗体製品開発の化学、製造、および管理活動の概要

第3章　品質：設計別

第4章　解析的展開

第5章　細胞株開発・エンジニアリング

第6章　細胞培養開発・スケールアップ

第7章　精製開発

第8章　処方開発・安定性

第9章　医薬品製造

第10章　比較可能性

第11章　プロセス評価

第12章　製造戦略

図表

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.

About the Author(s):

Howard L. Levine, Ph.D., President and CEO of BioProcess Technology Consultants, Inc. (BPTC), is a pioneer and thought leader in the biopharmaceutical industry with extensive strategic and operational experience in biopharmaceutical product development and commercialization. In his more than 35 years in the biopharmaceutical industry Dr. Levine has assisted numerous companies in developing biological products, provided strategic input in the development of new manufacturing technologies, and participated in the successful commercialization of several of these products. Prior to founding BioProcess Technology Consultants in 1994, Dr. Levine was Vice President of Manufacturing Operations at Repligen Corporation and previously held positions of increasing responsibility in process development and manufacturing at Genentech, Amgen, and Xoma.

Brendan R. Cooney, Associate Consultant of BioProcess Technology Consultants, Inc., has over eight years of experience as a technical and science writer in the pharmaceutical industry and academia. He has been involved in developing and writing document guidance systems and internal documentation systems for both research and commercial applications. Prior to working for BioProcess Technology Consultants, Brendan founded and ran CBRC Consulting, which provided technical writing consulting services to biotech companies including Shire HGT and Histogenics Corporation. He was awarded a B.A., magna cum laude, from Northeastern University in Boston, Massachusetts.

Table of Contents

List of Tables

List of Figures

Foreword

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

List of Tables

• Table 1.1: Applications of Therapeutic Monoclonal Antibody Products
• Table 1.2: 2015 Sales of the Top Ten Selling Biopharmaceutical Products
• Table 1.3: Commercially Marketed Therapeutic Monoclonal Antibody Products
• Table 1.4: Patent Expiration Dates for Key Monoclonal Antibody Products
• Table 2.1: Estimated CMC-Related Costs for Monoclonal Antibody Development
• Table 3.1: ICH Guidelines Related to Quality by Design
• Table 3.2: Control Strategy Elements
• Table 4.1: ICH Guidance Documents Covering the Testing and Characterization of Monoclonal Antibody Products
• Table 4.2: Minimum AMV Characteristics from ICH Q2(R1)
• Table 4.3: Some Methods Used for Identity Testing of Monoclonal Antibody Products
• Table 4.4: Some Methods Used for Determination of Purity and Product-Related Impurities of Monoclonal Antibody Products
• Table 4.5: Some Methods Used for Measurement of Some Process Related Impurities
• Table 4.6: Some Methods Used for Safety Testing of Monoclonal Antibody Products
• Table 4.7: Methods Used for Potency Testing of Monoclonal Antibody Products
• Table 4.8: Methods Used for Testing General Attributes of Monoclonal Antibody Drug Substance and Drug Product
• Table 4.9: Analytical Methods Used to Characterize Monoclonal Antibody Drugs
• Table 4.10: Common Release Tests for Monoclonal Drug Substance and Drug Product
• Table 4.11: An Example of QC Release Methods and Specifications for a Monoclonal Antibody Product in Early Clinical Development
• Table 5.1: CHO Species Used in Monoclonal Antibody Production
• Table 5.2: Commercially Available Expression Systems
• Table 5.3: Expression Vector Construction
• Table 5.4: Transfection and Selection
• Table 5.5: Single Cell Cloning
• Table 5.6: Testing of Mammalian Cell Banks
• Table 7.1: Parameters to be Considered in Chromatography Step Development
• Table 7.2: Comparison of High Throughput Methods for the Development of Chromatographic Separations
• Table 7.3: Guidelines for Linear Scale-up of Chromatography
• Table 8.1: Formulation Details for Currently Marketed Therapeutic Monoclonal Antibody Products
• Table 8.2: Potential Degradation Pathways of Monoclonal Antibody Products and Analytical Methods to Detect Them
• Table 8.3: Example of a Forced Degradation Matrix for a Monoclonal Antibody Product
• Table 8.4: Typical Analytical Methods Used in Monoclonal Antibody Stability Studies
• Table 8.5: Commonly Used Buffers in Monoclonal Antibody Formulations
• Table 8.6: Example of Design of Experiments Study Investigating Four or Five Components of a Potential Monoclonal Antibody Product Formulation
• Table 8.7: Typical Stability Study Design for a Monoclonal Antibody Drug Substance to Support Early Stage Clinical Development
• Table 8.8: Typical Stability Study Design for a Monoclonal Antibody Drug Product to Support Early Stage Clinical Development
• Table 9.1: Improvements in Rubber Stopper Formulations
• Table 9.2: Typical Monoclonal Antibody Drug Product Specifications
• Table 10.1: Regulatory Submissions Worldwide Supporting Process Changes
• Table 10.2: Risk Assessment and Comparability Requirements in Early Development
• Table 10.3: Typical Monoclonal Antibody Product Release Tests Used in Comparability Protocols
• Table 10.4: Characterization Tests used in Monoclonal Antibody Product Comparability Protocols
• Table 11.1: Typical Stage 1 Process Design Activities
• Table 11.2: Typical Stage 2 Process Qualification Activities
• Table 11.3: Potential Cell Culture Critical Process Parameters
• Table 11.4: Sample VMP Table of Contents
• Table 12.1: Typical Contents of a Request for Proposal for CMO Services
• Table 12.2: Operating Costs for Stainless Steel and Single-Use Facilities

List of Figures

• Figure 1.1: Antibody Structure
• Figure 1.2: IgG Oligosaccharide Structure
• Figure 1.3: Annual Approvals of Monoclonal Antibody Products
• Figure 1.4: Sales of Biopharmaceutical Products by Product Type and Class
• Figure 1.5: Sales Growth for Commercial Monoclonal Antibody Products
• Figure 2.1: Typical CMC Timeline for Monoclonal Antibody Development
• Figure 3.1: The Quality by Design Approach
• Figure 3.2: CQA Risk Assessment
• Figure 3.3: Prior Knowledge Elements
• Figure 3.4: Example of a Design Space
• Figure 3.5: Specifications Settings
• Figure 3.6: Relationship of Process Characterization Studies to Design Space
• Figure 3.7: Development of a Process Control Strategy
• Figure 4.1: Analytical Methods Lifecycle
• Figure 4.2: Method Validation Readiness Flow Path
• Figure 5.1: Representative Cell Line Development Workflow
• Figure 7.1: Typical Unit Operations Used in Monoclonal Antibody Purification
• Figure 7.2: Basic Elements of a Platform Purification Processes
• Figure 7.3: Effect of Processing Time on Membrane Area for a UF/DF Process
• Figure 7.4: Principle of Linear Scale-up of a Chromatography Column
• Figure 8.1: Structure of a Monoclonal Antibody
• Figure 8.2: Mechanism of Methionine Oxidation
• Figure 8.3: Mechanism of Deamidation of Asparagine Residues
• Figure 8.4: Disulfide Rearrangement
• Figure 8.5: Mechanism of β-Elimination and Rearrangement or Hydrolysis
• Figure 8.6: Hydrolysis of Asp-Gly Peptide Bonds
• Figure 8.7: Aggregation Pathways for Monoclonal Antibody Products
• Figure 8.8: Liquid and Lyophilized Formulations for Currently Marketed Therapeutic Monoclonal Antibody Products
• Figure 9.1: Steps in the Manufacture of a Monoclonal Antibody Drug Product
• Figure 10.1: Typical Stability Study Design for a Monoclonal Antibody Drug Product to Support Early Stage Clinical Development
• Figure 10.2: Comparability Decision Tree
• Figure 11.1: Overall Sequence of Process Validation Activities
• Figure 11.2: Overview of Quality Risk Management
• Figure 11.3: An example of an Ishikawa or Fishbone Diagram
• Figure 11.4: Unit Operation-based Approach to Risk Assessment
• Figure 11.5: Relationship between the Phases of Product Development and the Process Validation Lifecycle
• Figure 11.6: Risk Assessment for Classifying Process Parameter Criticality
• Figure 11.7: Defining Operating Parameter Ranges
• Figure 12.1: Manufacturing Strategy Considerations
• Figure 12.2: Pilot Plant for Production of Monoclonal Antibody Bulk Drug Substance
• Figure 12.4: Cost Breakdown for a Simple Monoclonal Antibody Pilot Plant
• Figure 12.4: Monoclonal Antibody Pilot Plant Construction Timeline