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Pharmaceuticals and Healthcare » Biotechnology » Biotechnology

The Development of Therapeutic Monoclonal Antibody Products

  • ID:RM003415
  • Published: August-2017
  • Pages:306
  • IPR
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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 anShow More

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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


List Of Tables

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

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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