Biopharmaceuticals

Gary Walsh is Chair of Industrial Biotechnology at the University of Limerick, Ireland. He has direct industrial experience within the pharmaceutical and diagnostic industries, as well as extensive teaching and research interests in the pharmaceutical and biotechnology arena.

• Preface xiv1 Biopharmaceuticals, an Introductory Overview 11.1 Introduction to Pharmaceutical Products 11.2 Genetic Engineering and the Advent of Biopharmaceuticals 71.3 Biopharmaceuticals: Current Status and Future Prospects 12Sources of Additional Information 20Some Journal Articles 212 Biopharmaceuticals: Discovery, Development, and Regulation 232.1 Introduction 232.2 Discovery of Biopharmaceuticals 242.3 The Impact of “Omics” and Related Technologies Upon Drug Discovery 262.4 Lead Discovery 342.5 Pharmacogenetics 342.6 The Influence of Artificial Intelligence Upon Drug Discovery 352.7 Lead Characterization, CMC Development, and QbD 362.8 Delivery of Biopharmaceuticals 392.9 Preclinical Studies 432.10 Pharmacokinetics and Pharmacodynamics 432.11 Toxicity Studies 502.12 Clinical Trials 532.13 The Role and Remit of Regulatory Authorities 572.14 The Food and Drug Administration (FDA) 582.15 European Pharmaceutical Law 612.16 Pharmacovigilance 652.17 World Harmonization of Drug Regulations and the ICH 662.18 The Naming of Biopharmaceuticals 672.19 Patenting 682.20 Biosimilar Regulation 69Sources of Additional Information 73Some Journal Articles 733 Good Manufacturing Practice 753.1 Introduction 753.2 Guides to Good Manufacturing Practice (GMP) 753.3 Pharmacopoeia 773.4 The Manufacturing Facility 783.5 Documentation 933.6 Validation 95Further Reading 974 Protein Structure 994.1 Introduction 994.2 Primary Structure 994.3 Higher-Level Structure 1064.4 Protein Folding and Stability 1114.5 Protein Structure Prediction 1134.6 Protein Post-translational Modification 115Further Reading 1235 Production of Therapeutic Proteins by Recombinant Means 1255.1 Introduction 1255.2 Nucleic Acids: Structure and Function 1255.3 The Principles of Genetic Engineering 1335.4 Cell Types in Which Recombinant Therapeutic Proteins Are Produced 1475.5 Engineered Therapeutic Proteins 159Further Reading 1646 Therapeutic Protein Manufacture: Upstream Processing 1656.1 Introduction 1656.2 Cell Banking Systems 1666.3 Bioreactors 1686.4 Microbial Cell Fermentation 1746.5 Mammalian Cell Culture 176Further Reading 1807 Therapeutic Protein Manufacture: Downstream Processing 1817.1 Initial Product Recovery 1817.2 Initial Product Concentration 1877.3 Chromatographic Purification 1907.4 Viral Clearance 2127.5 Some Influences Which can Alter the Biological Activity of Proteins 2137.6 Final Product Formulation 2177.7 Sterilization and Final Product Fill 2197.8 Trends in Downstream Processing 224Further Reading 2258 Product Analysis 2278.1 Introduction and Regulatory Context 2278.2 Potency Determination 2298.3 Protein Content 2328.4 Purity Determination and API Characterization 2338.5 Key Analytical Methodologies 2358.6 Product Purity Determination 2388.7 API Characterization 2408.8 Non- protein Impurity Characterization: DNA 2478.9 Contaminant Testing 2488.10 Additional Tests 255Further Reading 2559 Antibodies 2579.1 Antibody Structure and Function 2579.2 Polyclonal Antibody Preparations Used Therapeutically 2629.3 Hybridoma Technology and First- generation Monoclonal Antibodies 2659.4 Chimeric and Humanized Antibodies 2689.5 Fully Human mAbs 2719.6 Routine Manufacture of mAbs 2749.7 mAb Therapeutic Applications in Overview 2759.8 mAb Therapeutics Treating Inflammation 2759.9 mAbs Therapeutic Treating Cancer 2779.10 Some Additional Therapeutic mAbs 2839.11 Additional Engineered Antibody Formats 2869.12 The mAb Market and the Advent of mAb Biosimilars 302Further Reading 30510 Vaccines 30710.1 Introduction 30710.2 Traditional Vaccine Preparations 30910.3 The Impact of Recombinant DNA Technology on Vaccines 31310.4 Adjuvant Technology 332Further Reading 33511 The Cytokines – The Interferon Family 33711.1 Introduction to the Cytokines 33711.2 The Interferons 34411.3 Interferon Biotechnology 356Further Reading 36312 The Cytokines – Interleukins and Tumor Necrosis Factor 36512.1 Introduction to the Interleukins 36512.2 Interleukin- 2 36712.3 IL- 2 Biotechnology 37012.4 Interleukin 11 37312.5 Inhibition of Interleukin Activity 37412.6 Tumor Necrosis Factor 379Further Reading 38913 Growth Factors 39113.1 Introduction 39113.2 Hematopoietic Growth Factors 39113.3 Granulocyte Colony- Stimulating Factor (G- CSF) 39413.4 Macrophage colony- stimulating factor (M- CSF) 39513.5 Granulocyte Macrophage Colony- Stimulating Factor (GM- CSF) 39513.6 Clinical Application of CSFs 39613.7 Erythropoietin 40013.8 Therapeutic Applications of EPO 40213.9 Thrombopoietin 40413.10 Insulin- Like Growth Factors 40713.11 Neurotrophic Factors 40813.12 Fibroblast Growth Factors 41013.13 Platelet- Derived Growth Factor 41113.14 Bone Morphogenetic Proteins 41213.15 Inhibition of Growth Factor Activity 413Further Reading 41914 Hormones 42114.1 Introduction 42114.2 Insulin 42114.3 The Insulin Molecule 42314.4 The Insulin Receptor and Signal Transduction 42414.5 Insulin Manufacture by Traditional Means 42614.6 Production of Human Insulin by Recombinant DNA Technology 42714.7 Formulation of Insulin Products 42814.8 Engineered Insulins 43014.9 Glucagon- Like Peptide- 1 (GLP- 1)- Related Products 43414.10 GLP- 1 Receptor Agonists 43614.11 Human Growth Hormone 44014.12 The Gonadotrophins 44414.13 Medical Applications of Gonadotrophins 45114.14 Additional Recombinant Hormones Now Approved 455Further Reading 45815 Recombinant Blood Products and Therapeutic Enzymes 45915.1 Introduction 45915.2 Hemostasis 45915.3 The Coagulation Pathway 45915.4 Clotting Disorders 46315.5 Factor VIII and Hemophilia A 46415.6 Additional Recombinant Blood Factors 47015.7 Anticoagulants 47315.8 Thrombolytic Agents 47515.9 Enzymes of Therapeutic Value 480Further Reading 49216 Nucleic- Acid- Based Products 49316.1 Introduction 49316.2 Classical Gene Therapy 49416.3 Basic Approach to Gene Delivery 49516.4 Vectors Used in Gene Therapy 49916.5 Manufacture of Viral Vectors 51016.6 CAR- T- Based Gene Therapy 51816.7 Non- viral Vectors 52216.8 The Impact of CRISPR Technology on Gene Therapy 52416.9 Antisense Technology, Including siRNA 527Further Reading 533Index 535