Handbook of Biological Therapeutic Proteins: Regulatory, Manufacturing, Testing, and Patent Issues, 2nd Edition

Since 1972, which marks the invention of recombinant engineering, more than 500 therapeutic proteins have been approved for clinical use. Today, biological drugs constitute almost 70% of all new drugs and have a biological origin. The first edition of this book dealt with biosimilars, and this edition (i.e., the second edition) focuses on new drugs, yet limits to therapeutic proteins. Newer technologies for drug development represent the updated topics in the book and include repurposing, AI-driven identification of newer designs, novel expression systems, manufacturing using these systems, rapidly changing regulatory pathways, and legal hurdles. This edition discusses how to identify, develop, manufacture, and take multibillion dollar products to market within the shortest possible time.Features:Complete and thorough coverage of the regulatory and technological challenges of developing generic therapeutic proteinsComprehensive analysis, discovery to market, newer technologies, regulatory planning and intellectual propertyâ••related hurdles are included, and this information is not found elsewhereExpanded volume that must be in the hands of every company interested in biological drugs, including mRNA-based biopharmaceutical companies that quickly enter into the marketDiscusses how to identify, develop, manufacture, and take multibillion dollar products to market within the shortest possible timeRenowned author and entrepreneur in the field of drug discovery and production Cover Half Title Title Page Copyright Page Table of Contents Preface Author Biography Introduction By Professor Francisco Baralle 1 Overview of the Development of Biosimilar Biopharmaceuticals 1.1 Introduction 1.2 Biosimilarity 1.3 Terminology 2 Regulatory Requirements for a Proposed Biosimilar Product 2.1 Qualification of a Product AS A Proposed Biosimilar 2.1.1 Qualified Reference Product 2.1.2 Mechanism of Action 2.1.3 Route of Administration 2.1.4 Dosage Form 2.1.5 Strength 2.1.6 Formulation 2.1.7 Drug Delivery Device 2.1.8 Current Good Manufacturing Practice Compliance 2.1.9 Extrapolation and Substitution 2.1.10 Study Waivers 2.1.11 Public Domain Knowledge 2.1.12 Reference Product 2.1.12.1 Reference Standard 2.2 Analytical Considerations 2.2.1 Physicochemical Properties 2.2.2 Nonclinical Testing 2.2.2.1 Immunochemical Properties 2.2.3 Purity and Impurity Profiles 2.2.4 Quantity 2.2.5 Specifications 2.2.6 Test Procedures 2.2.7 Function-Based Tests 2.2.8 Number of Batches 2.2.9 Data Evaluation 2.2.10 Expression System 2.2.11 Post-Translational Modifications 2.2.12 Quality Aspects 2.2.13 Release Specification 2.2.14 Formulation 2.2.15 Stability 2.2.16 Process Qualification 2.3 Animal Toxicology 2.4 Clinical Pharmacology 2.5 Clinical Immunogenicity 2.5.1 Pharmacodynamic Studies 2.5.1.1 Clinical Immunogenicity 2.5.2 Clinical Efficacy in Patients 2.5.3 Clinical Safety 2.6 Extrapolation 2.6.1 Pharmacovigilance 2.7 Interchangeability and Substitution 2.7.1 Miscellaneous 2.7.1.1 Naming 2.7.1.2 Label 2.7.1.3 Substitution 2.7.1.4 Pediatrics 2.7.1.5 Human Factors Studies 2.7.2 Risk Management 2.8 Documentation 3 Development of a Master Plan for the Biosimilar 3.1 Choice of The Product 3.1.1 Competition 3.1.2 Cost of Goods 3.1.3 Manufacturing Plan and Facility 3.1.4 Expression System 3.1.5 Batch Size 3.1.6 Residual Uncertainty 3.1.7 Clinical Safety and Efficacy 3.2 Historical Data On Regulatory Compliance 3.3 Planning for Manufacturing 4 Trends in the Manufacturing of Recombinant Proteins 4.1 Background 4.2 Process Optimization 4.2.1 Cell Line Development 4.2.2 Cell Culture Media 4.2.3 High–Cell Density Cryopreservation 4.2.4 Cell Culture Operations 4.2.5 Bioreactor Cycle 4.3 Single-Use Technology 4.3.1 Containers and Mixing Systems 4.3.2 Drums, Containers, and Tank Liners 4.3.2.1 Two-Dimensional Bags 4.3.2.2 Three-Dimensional Bags 4.3.3 Advantages of Single-Use Technology 4.3.4 Single-Use Bioreactors 4.3.5 Other Components 4.3.5.1 Optical Sensors 4.3.5.2 Biomass Sensors 4.3.5.3 Electrochemical Sensors 4.3.5.4 Pressure Sensors 4.3.5.5 Sampling Systems 4.3.5.6 Connectors 4.3.5.7 Tubing 4.3.5.8 Pumps 4.3.5.9 Tube Welder and Sealers 4.3.6 Sampling 4.3.7 Downstream Processing 4.3.7.1 Cell Harvest 4.3.7.2 Purification 4.3.7.3 Virus Removal 4.4 Filtration: Ultrafiltration/Diafiltration and Tangential Flow Filtration 4.4.1 General Filtration Applications 4.4.2 Fill-Finish Operations 4.4.3 Safety 4.4.4 Polymers and Additives 4.4.5 Material Selection 4.4.6 Testing 4.4.6.1 Regulatory Standards 4.5 Online Monitoring 4.6 Continuous Manufacturing 4.6.1 Continuous Chromatography Systems 4.6.1.1 Straight-Through Processing 4.6.1.2 Periodic Countercurrent Chromatography 4.6.1.3 Simulated Moving Bed Chromatography 4.7 Continuous Manufacturing 4.8 Summary Notes 5 Analytical Assessment of a Biosimilar 5.1 Introduction 5.2 Testing Plan 5.3 Sources of Variation 5.3.1 Expression System 5.3.2 Manufacturing Process 5.3.3 Structural Attributes 5.3.4 Functional Attributes 5.3.5 Physicochemical Properties 5.3.5.1 Aggregates 5.3.5.2 Impurities 5.3.5.3 Host Cell Protein and Residual DNA 5.3.6 Lot-To-Lot Variability 5.3.7 Product- Or Process-Related Substances 5.3.8 Method Sensitivity 5.3.9 Comparative Testing 5.3.10 Side-By-Side Testing 5.3.11 Heterogeneity 5.3.12 Structure Confirmation 5.3.13 Acceptance Criteria 5.3.14 Orthogonal Testing 5.3.15 Accountability of Lots 5.3.16 Critical Quality Attributes 5.3.17 Reference Standard 5.4 Finished Drug Product 5.4.1 Excipients 5.4.2 Stability 5.4.3 International Council for Harmonisation 5.4.4 Examples of Testing Methods 5.4.5 Risk Assessment 5.4.6 Statistical Considerations 5.4.7 Quantitative and Qualitative Data Analyses 5.4.7.1 Risk Ranking 5.4.7.2 Assay Variability 5.4.8 Functional Assessments 5.4.9 Orthogonal Studies 5.4.9.1 Lots Tested 5.5 In Vivo Assessment 5.5.1 Determination of the needs for in vivo studies 5.5.2 In Vivo Animal Studies 5.5.3 Animal Pharmacokinetics and Pharmacodynamics Measures 5.5.4 Animal Immunogenicity Testing 6 Clinical Pharmacology Assessment of a Proposed Biosimilar 6.1 Introduction 6.1.1 Scope of Studies 6.1.2 Study Plan 6.1.2.1 Healthy Subjects Versus Patients 6.1.2.2 Study Size 6.1.2.3 Study Design 6.1.2.4 Crossover Design 6.1.2.5 Parallel Design 6.1.2.6 Multiple Studies Combined 6.1.2.7 Unified Study 6.1.2.8 Study Materials 6.1.2.9 Dose Selection 6.1.2.10 Route of Administration 6.1.3 Pharmacokinetic Parameters 6.1.3.1 New Approach to Pharmacokinetics Analysis 6.1.3.2 Pharmacokinetic/Pharmacodynamic Waivers 6.1.3.3 Route of Administration 6.1.3.4 Pharmacodynamics Parameters 6.2 Statistical Evaluation of Pharmacokinetics and Pharmacodynamics Results 6.2.1 Utility Tools 6.2.2 Assay Considerations 6.2.3 Specific Assays 6.2.3.1 Ligand Binding Assays 6.2.3.2 Concentration and Activity Assays 6.2.3.3 Pharmacodynamics Assays 6.2.4 Reserve Samples 6.2.5 Example Pharmacokinetics Studies 6.2.5.1 Adalimumab 6.2.5.2 Pegfilgrastim 6.2.5.3 Trastuzumab 6.2.5.4 Rituximab 7 Clinical Immunogenicity Assessment of the Biosimilar 7.1 Introduction 7.2 Focus On T-Cell Dependent Immunogenicity Assessment and Mitigation 7.2.1 Definitions: T-Cell–Dependent Immune Responses to Biotherapeutics 7.2.2 T-Cell–Independent Vs. T-Cell–Dependent Responses 7.2.3 Innate Immune Response 7.2.4 Drug Function as a Determinant of Immunogenicity 7.2.5 Drug Target and Immunogenicity: Checkpoint Inhibitors 7.2.6 Drug Target and Immunogenicity: Inhibition of Anti-Inflammatory Cytokines 7.2.7 Peptide Drugs 7.2.8 In Silico Screening 7.2.9 T-Cell Epitope Prediction 7.2.10 Screening for Selfness (Tolerogenic Potential) 7.2.11 Screening Against Relevant Peptide Libraries 7.2.12 Ranking Biologic Candidates By Immunogenic Potential 7.3 In Vitro Methods For Assessing Immunogenicity Risk 7.3.1 Human Leukocyte Antigen Binding Assay 7.3.2 Peripheral Blood Mononuclear Cell Assays 7.3.3 Dendritic Cell–T-Cell Assays 7.3.4 Flow Cytometry Analysis of T-Cell Phenotype 7.3.5 Major Histocompatibility Complex–Associated Peptide Proteomics Assays 7.4 Mitigation By Deimmunization and Tolerization 7.4.1 Deimmunization 7.4.2 Tolerization 7.4.3 Treatment-Induced Tolerance 7.4.4 Antidrug Antibody Assay Standardization 7.5 New Modalities and Immunogenicity Risk Assessment 7.5.1 Specific Cell Lines/Soluble T-Cell Receptors 7.5.2 Modeling 7.5.3 Immunogenicity-Focused Organizations 7.5.4 Regulatory Perspective On Immunogenicity 7.5.5 Integration of Risk Assessment Into the Preclinical Pipeline 7.6 Five-Year View 7.7 Immunogenicity Investigation 7.7.1 Assay 7.7.2 Sensitivity 7.7.3 Specificity 7.7.4 Selectivity 7.7.5 Precision 7.7.6 Reproducibility 7.7.7 Robustness and Sample Stability 7.7.8 Format 7.7.9 Reagents 7.7.10 Reporting Results 7.7.11 Lifecycle Management 7.7.12 Immunogenicity Testing Methods 7.7.12.1 Population 7.7.12.2 Side-By-Side Assessment 7.7.12.3 Endpoints 7.7.12.4 Sampling Schedule 7.7.12.5 Dependence On Pharmacokinetics 7.7.13 Safety and Efficacy Relationship 7.7.13.1 Management of Immunogenicity Testing 7.7.14 Example Studies 7.7.14.1 Infliximab 7.7.14.2 Etanercept 8 Clinical Efficacy Assessment of the Proposed Biosimilar 8.1 Residual Uncertainty 8.2 Waivers 8.3 Types of Study Design 8.3.1 Study Designs for Comparative Safety and Efficacy Testing 8.3.1.1 Traditional Comparative (Two-Sided) Study 8.3.1.2 Equivalence Testing 8.3.1.3 Noninferiority Testing 8.3.2 Justification of Extrapolation 8.3.3 Ethics and Practicality 8.4 Selection of Study Protocols 8.5 Study Design 8.5.1 Efficacy Endpoints 8.6 Clinical Safety 8.6.1 Study Population 8.6.2 Sample Size and Study Duration 8.6.2.1 Study Design and Analyses 8.6.3 Clinical Endpoints 8.6.4 Extrapolation of Clinical Data Across Indications 8.6.5 Extrapolation Across Indications 8.6.6 Additional Conditions of Use 9 Recombinant Manufacturing System for Biopharmaceuticals 9.1 Overview 9.2 Expression Systems 9.3 Bacterial Cells 9.4 Yeast 9.5 Mammalian Cells 9.5.1 Nonhuman Cell Lines 9.5.1.1 Chinese Hamster Ovary Cells 9.5.1.2 CHO Expression System 9.5.1.3 Myeloma Cells 9.5.1.4 Human Cells 9.6 Algae 9.7 Insect Cells 9.7.1 Insect Cell Expression Systems: SF9 and SF21 9.8 Comparative Analysis 10 Upstream Processes Involved in Protein Production 10.1 Overview 10.2 Culture Media 10.2.1 Culture Media for Microbial Cells 10.2.2 Cell Culture Media 10.2.2.1 Culture Media Preparation 10.2.2.2 Culture Media Optimization 10.3 Cell Culture Fermentation 10.4 Basic Concepts 10.4.1 Cell Growth 10.4.2 Cell Death 10.4.3 Metabolic Control 10.5 Culture Production Process 10.5.1 Seed Train 10.5.1.1 Vial Thaw 10.5.1.2 Fermenter Setup 10.5.1.3 Inoculation of Production Vessel and Sampling 10.5.1.4 Fed-Batch Process Outline 10.6 Cell Separation And Harvesting 10.6.1 Centrifugation 10.6.2 Depth Filtration 10.6.3 Ultrafiltration and Microfiltration Tangential Flow Filtration 10.6.3.1 Choosing the Appropriate Method 10.7 Analytical Tools 10.7.1 Cell Culture/Fermentation 10.7.2 Cell Harvest 10.8 Upstream Equipment 10.9 Media and Solution Preparation Systems 10.10 Bioreactor Systems 10.11 Bioreactor Types 10.11.1 Stirred Tank Bioreactor 10.11.2 Airlift Bioreactor 10.11.3 Packed Bed and Fluidized Bed Bioreactor 10.12 Modes of Operation 10.12.1 Batch Culture 10.12.2 Fed-Batch 10.12.3 Continuous Reactor Process 10.12.4 Perfusion 10.13 Key System Components of A Bioreactor 10.13.1 Agitation 10.13.2 Aeration 10.13.3 Temperature Control 10.13.4 PH Control 10.13.5 Foam Control 10.13.6 Controller System 10.14 Harvest and Clarification Systems 10.15 Ancillary and Peripheral Equipment 10.15.1 Sterilization 10.15.2 Cleaning-In-Place 10.15.3 Pumps, Valves, Tubes, and Pipes 10.16 Summary 11 Downstream Processes Involved in Protein Production 11.1 Overview 11.2 E. Coli System: Recovery and Purification 11.2.1 Cell Disruption 11.2.1.1 Physical Methods 11.2.1.2 Chemical Methods 11.3 Inclusion Body Recovery and Separation 11.3.1 Inclusion Body Solubilization 11.3.2 Inclusion Body Renaturation 11.3.2.1 Dilution 11.3.2.2 Dialysis 11.3.2.3 On-Column 11.3.2.4 Depth Filtration for the Clarification of Refolded Protein 11.4 Purification 11.5 Capturing 11.6 Intermediate Purification 11.6.1 Polishing 11.7 Mammalian System Purification 11.8 Capture–Protein-A Chromatography 11.9 Intermediate Purification and Final Polishing 11.10 Polishing 11.11 Viral Removal, Inactivation, and Filtration 11.11.1 PH Treatment 11.11.2 Virus Filtration 11.11.3 Other Methods 11.11.3.1 Chromatography 11.11.3.2 Detergent 11.11.3.3 Heat Treatment 11.11.3.4 Ultraviolet Irradiation 11.12 Virus Removal Validation 11.13 Product Concentration 11.14 Analytical Methods 11.15 Downstream Processing Equipment and System Components 11.16 Sensors, Probes, and Meters 11.16.1 Ultraviolet Monitoring 11.16.2 PH Monitoring 11.16.3 Conductivity Monitoring 11.16.4 Pressure Sensors 11.16.5 Temperature 11.16.6 Flow Meters 11.16.7 Air Sensors 11.17 Flow Path 11.18 Pumps 11.19 Valves 11.20 In-Line Filtration (Sterile Filtration And Particle Filtration) 11.21 Summary 12 Formulation of Biopharmaceuticals 12.1 Overview 12.2 Protein Structure 12.2.1 Basis 12.2.2 Physical Degradation 12.2.2.1 Structural Changes 12.2.2.2 Aggregation 12.2.3 Chemical Degradation 12.2.3.1 Deamidation 12.2.3.2 PH 12.2.3.3 Racemization and Isomerization 12.2.3.4 Temperature 12.2.3.5 Excipients 12.2.3.6 Hydrolysis 12.2.3.7 Disulfide Bond 12.2.3.8 Glycation 12.2.3.9 Oxidation 12.3 Formulation Composition 12.3.1 Excipients and Properties 12.3.1.1 PH 12.3.1.2 Surface Tension 12.3.1.3 Tonicity 12.3.1.4 Protectants 12.3.1.5 Stabilizers 12.3.2 Liquid Formulations 12.3.3 Lyophilized Formulations 12.3.4 Higher-Concentration Formulations 12.3.5 Examples of Formulations 12.4 Routes of Administration 12.4.1 Intravenous Administration 12.4.2 Subcutaneous Administration 12.4.3 Oral Administration 12.4.4 Nasal/Pulmonary Administration 12.4.5 Transdermal Administration 12.4.6 Ocular Administration 12.4.7 Rectal Administration 12.5 Formulation Technologies 12.5.1 Hydrogels and In Situ Forming Gels 12.5.2 Nanoparticles 12.5.3 Liposomes 12.6 Summary Appendix: Physicochemical Properties of Proteins and Peptides Approved By the Food and Drug Administration 13 Quality and Compliance Systems 13.1 Compliance 13.1.1 Current Good Manufacturing Practice Compliance 13.1.1.1 Food and Drug Administration 13.1.2 European Directorate for the Quality of Medicines and Healthcare 13.1.3 World Health Organization 13.1.4 Harmonization 13.2 Quality System 13.2.1 Management Responsibilities 13.2.2 Providing Leadership 13.2.3 Organizational Structure 13.2.4 Building a Quality System 13.2.5 Establishing Policies, Objectives, and Plans 13.2.5.1 Review of the System 13.2.5.2 Change Control 13.2.5.3 Corrective and Preventive Action 13.2.5.4 Data Management 13.2.5.5 Resources 13.2.6 General Arrangements 13.2.7 Developing Personnel 13.2.8 Facilities and Equipment 13.2.9 Control Outsourced Operations 13.2.9.1 Manufacturing Operations 13.2.9.2 Design and Develop Product and Processes 13.2.9.3 Monitoring the Packaging and Labeling Processes 13.2.9.4 Examining Inputs 13.2.10 Perform and Monitor Operations 13.2.10.1 Address Nonconformities 13.2.10.2 Evaluation of Activities 13.2.11 Risk Assessment 13.2.11.1 Corrective Action 13.2.11.2 Promote Improvement 13.3 Validation Master Plan 13.3.1 Overview 13.3.2 Analytical Methods 13.3.3 Documentation 13.4 Good Laboratory Practices 13.4.1 Overview 13.4.2 Elements of Good Laboratory Practice 13.4.2.1 Quality Assurance: Establishing Confidence in Reported Data 13.4.2.2 Instrumentation Validation 13.4.2.3 Reagent and Materials Certification 13.4.2.4 Certification of Laboratory Facilities 13.4.2.5 Specimen and Sample Tracking 13.4.2.6 Documentation and Maintenance of Records 13.4.3 Electronic Data Handling 13.4.3.1 Overview 13.4.3.2 Code of Federal Regulations 21 Part 11: Electronic Records 13.4.4 Validation 13.4.5 Audit Trails 13.4.6 Record Retention 13.4.7 Data Errors 13.4.7.1 Absolute and Relative Errors 13.4.8 Systematic and Random Errors 13.4.9 Statistical Analysis 13.4.10 Conclusions 13.5 Quality Control 13.5.1 Overview 13.5.2 In-Process Control 13.5.3 Specifications 13.5.4 Regulatory Compliance 13.6 Summary 14 Intellectual Property Issues for Scientists 14.1 Overview 14.1.1 Guide 14.2 The Patent Dance 14.3 Patent Landscape 14.4 Patent Law Basics 14.4.2 United States Patent Elements 14.4.3 Types of Patents 14.4.4 Unpatentable Inventions 14.4.5 Software Patents 14.4.6 Medical Method Patents 14.4.7 Business Methods Patents 14.4.7.1 Utility Model in the European Union 14.4.8 Provisional Application 14.5 Comparison of Patent Laws 14.5.1 Jurisdiction 14.5.2 The Patent Cooperative Treaty 14.5.3 First-To-Invent Rule 14.5.4 First-To-File Rule 14.5.5 Best Mode Requirement 14.5.6 Patent Publication 14.5.7 Rights Conferred 14.5.8 Opposition After Grant 14.5.9 Inventive Step 14.5.10 Two-Part Claim 14.6 Patent Assignment 14.7 Patent Infringement 14.8 Biological Patents 14.8.1 Monoclonal Antibody Technology 14.8.2 Antisense Technology 14.8.3 Transgenic Plants 14.8.4 Exclusivities for Biological Products 14.8.5 Broad Coverage 14.9 Purple Book 14.10 Patent Term Extension 14.10.1 Patent Term Adjustment 14.10.1.1 Factors Affecting a Patent Term 14.10.1.2 Pharmaceutical Patent Variations 14.10.1.3 Annuity Fees and Term Computation 14.10.1.4 Information On Aspects of Patent Term 14.10.1.5 USPTO Web Sources 14.10.1.6 Other Web Registers 14.10.1.7 Commercial Online Files 14.10.2 Non-Patent Office Sources 14.11 Freedom-To-Operate Opinions 14.11.1 Submarine Patents 14.11.2 System Expression Patents 14.11.3 Process Patents of Originator 14.11.4 Third-Party Process Patents 14.11.5 Formulation Composition 14.11.6 Lifecycle Formulation Projections 14.11.7 Alternate Offering 14.11.8 Indications and Dosage 14.11.9 Delivery Devices 14.11.10 Developing Freedom to Operate 14.12 Conclusion Bibliography Index Since 1972, which marks the invention of recombinant engineering, more than 500 therapeutic proteins have been approved for clinical use. Today, biological drugs constitute almost 70% of all new drugs and have a biological origin. The first edition of this book dealt with biosimilars, and this edition (i.e., the second edition) focuses on new drugs, yet limits to therapeutic proteins. Newer technologies for drug development represent the updated topics in the book and include repur-posing, AI- driven identification of newer designs, novel expression systems, manufacturing using these systems, rapidly changing regulatory pathways, and legal hurdles. This edition discusses how to identify, develop, manufacture, and take multibillion dollar products to market within the shortest possible time. Features: Complete and thorough coverage of the regulatory and technological challenges of developing generic therapeutic proteins Comprehensive, discovery to market, newer technologies, regulatory planning and IP hurdles are included that are not found elsewhere Expanded volume that must be in the hands of every company interested in biological drugs, including the mRNA-based biopharmaceutical companies fast appearing on the market Discusses how to identify, develop, manufacture, and take multibillion dollar products to market in the shortest possible time Renowned author and entrepreneur in the field of drug discovery and production Since 1972 when recombinant engineering was invented, over 500 therapeutic proteins have been approved. Today, biological drugs constitute almost 70% of all new drugs and are of biological origin. The first edition of this book dealt with biosimilars, the second focuses on new drugs yet limits to therapeutic proteins. The newer technologies for development represent the updated topics in the book and include repurposing, AI-driven identification of newer designs, novel expression systems and manufacturing, fast changing regulatory pathways, and legal hurdles. Discusses how to identify, develop, manufacture and take multibillion dollar products to market in the shortest possible time. Features