BIOPHARMACEUTICALSBIOCHEMISTRY AND BIOTECHNOLOGY
Second Edition
Gary Walsh
Industrial Biochemistry ProgrammeCES Department
University of Limerick, Ireland
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BIOPHARMACEUTICALSBIOCHEMISTRY AND BIOTECHNOLOGY
Second Edition
BIOPHARMACEUTICALSBIOCHEMISTRY AND BIOTECHNOLOGY
Second Edition
Gary Walsh
Industrial Biochemistry ProgrammeCES Department
University of Limerick, Ireland
First Edition 1998 u John Wiley & Sons, Ltd
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I dedicate this book to my beautiful son Shane, born during therevision of Chapter 6. I include his photograph in the hope that aHollywood producer, looking for a child film star, will spot it andimmediately offer to make us suitably rich. In the future, I also hopeto use it to embarrass him during his teenage years, by showing it to
all his cool, sophisticated friends.
Contents
Preface xvii
Chapter 1 Pharmaceuticals, biologics and biopharmaceuticals 1
Introduction to pharmaceutical products 1Biopharmaceuticals and pharmaceutical biotechnology 1History of the pharmaceutical industry 3The age of biopharmaceuticals 5Biopharmaceuticals: current status and future prospects 8Traditional pharmaceuticals of biological origin 12Pharmaceuticals of animal origin 13
The sex hormones 14The androgens 14Oestrogens 15Progesterone and progestogens 17
Corticosteroids 19Catecholamines 21Prostaglandins 23
Pharmaceutical substances of plant origin 27Alkaloids 28
Atropine and scopalamine 28Morphine and cocaine 29Additional plant alkaloids 30Ergot alkaloids 30
Flavonoids, xanthines and terpenoids 30Cardiac glycosides and coumarins 33Aspirin 33
Pharmaceutical substances of microbial origin 33The macrolides and ansamycins 38Peptide and other antibiotics 39
Conclusion 39Further reading 40
Chapter 2 The drug development process 43
Drug discovery 44The impact of genomics and related technologies upon drug discovery 45
Gene chips 47Proteomics 49Structural genomics 50Pharmacogenetics 51
Plants as a source of drugs 52Microbial drugs 53Rational drug design 54Combinatorial approaches to drug discovery 56Initial product characterization 57
Patenting 57What is a patent and what is patentable? 57Patent types 62The patent application 63Patenting in biotechnology 64
Delivery of biopharmaceuticals 66Oral delivery systems 66Pulmonary delivery 67Nasal, transmucosal and transdermal delivery systems 68
Pre-clinical trials 69Pharmacokinetics and pharmacodynamics 69Toxicity studies 71Reproductive toxicity and teratogenicity 71Mutagenicity, carcinogenicity and other tests 72
Clinical trials 73Clinical trial design 75Trial size and study population 75Randomized control studies 76Additional trial designs 76
The role and remit of regulatory authorities 78The Food and Drug Administration 78
The investigational new drug application 80The new drug application 82
European regulations 84National regulatory authorities 84The EMEA and the new EU drug approval systems 85The centralized procedure 86Mutual recognition 88
Drug registration in Japan 88World harmonization of drug approvals 89
Conclusion 89Further reading 89
Chapter 3 The drug manufacturing process 93
International pharmacopoeia 93Martindale, the Extra Pharmacopoeia 94
Guides to good manufacturing practice 94
viii CONTENTS
The manufacturing facility 97Clean rooms 98Cleaning, decontamination and sanitation (CDS) 101CDS of the general manufacturing area 102CDS of process equipment 102Water for biopharmaceutical processing 104Generation of purified water and water for injections (WFI) 105Distribution system for WFI 107Documentation 109Specifications 110Manufacturing formulae, processing and packaging instructions 110Records 111Generation of manufacturing records 111
Sources of biopharmaceuticals 112E. coli as a source of recombinant, therapeutic proteins 112Expression of recombinant proteins in animal cell culture systems 116Additional production systems: yeasts 116Fungal production systems 117Transgenic animals 118Transgenic plants 122Insect cell-based systems 123
Production of final product 124Cell banking systems 127Upstream processing 128Microbial cell fermentation 129Mammalian cell culture systems 133Downstream processing 134Final product formulation 140Some influences that can alter the biological activity of proteins 142Proteolytic degradation 143Protein deamidation 144Oxidation and disulphide exchange 145Alteration of glycoprotein glycosylation patterns 147Stabilizing excipients used in final product formulations 150Final product fill 153Freeze-drying 155Labelling and packing 158
Analysis of the final product 159Protein-based contaminants 159Removal of altered forms of the protein of interest from the product stream 160Product potency 161Determination of protein concentration 163Detection of protein-based product impurities 164Capillary electrophoresis 166High-pressure liquid chromatography (HPLC) 167Mass spectrometry 168Immunological approaches to detection of contaminants 168
CONTENTS ix
Amino acid analysis 169Peptide mapping 170N-terminal sequencing 171Analysis of secondary and tertiary structure 173Endotoxin and other pyrogenic contaminants 173Endotoxin, the molecule 174Pyrogen detection 176DNA 179Microbial and viral contaminants 180Viral assays 181Miscellaneous contaminants 182Validation studies 183
Further reading 185
Chapter 4 The cytokines the interferon family 189
Cytokines 189Cytokine receptors 194Cytokines as biopharmaceuticals 195
The interferons 196The biochemistry of interferon-a 197Interferon-b 198Interferon-g 198Interferon signal transduction 198The interferon receptors 199The JAKSTAT pathway 199The interferon JAKSTAT pathway 202The biological effects of interferons 203The eIF-2a protein kinase system 207Interferon biotechnology 207Production and medical uses of IFN-a 210Medical uses of IFN-b 213Medical applications of IFN-g 214Interferon toxicity 216Additional interferons 218
Conclusion 219Further reading 219
Chapter 5 Cytokines: interleukins and tumour necrosis factor 223
Interleukin-2 (IL-2) 225IL-2 production 228IL-2 and cancer treatment 228IL-2 and infectious diseases 230Safety issues 231Inhibition of IL-2 activity 231
x CONTENTS
Interleukin-1 (IL-1) 232The biological activities of IL-1 233IL-1 biotechnology 234
Interleukin-3: biochemistry and biotechnology 235Interleukin-4 236Interleukin-6 238Interleukin-11 240Interleukin-5 241Interleukin-12 244Tumour necrosis factors (TNFs) 246TNF biochemistry 246Biological activities of TNF-a 247Immunity and inflammation 248TNF receptors 249TNF: therapeutic aspects 250
Further reading 252
Chapter 6 Haemopoietic growth factors 255
The interleukins as haemopoietic growth factors 257Granulocyte colony stimulating factor (G-CSF) 258Macrophage colony-stimulating factor (M-CSF) 259Granulocyte-macrophage colony stimulating factor (GM-CSF) 259Clinical application of CSFs 261Leukaemia inhibitory factor (LIF) 263Erythropoietin (EPO) 264The EPO receptor and signal transduction 267Regulation of EPO production 267Therapeutic applications of EPO 26
