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Preface xvii
Chapter 1 Pharmaceuticals, biologics and biopharmaceuticals 1 Introduction to pharmaceutical products 1 Biopharmaceuticals and pharmaceutical biotechnology 1 History of the pharmaceutical industry 3 The age of biopharmaceuticals 5 Biopharmaceuticals: current status and future prospects 8 Traditional pharmaceuticals of biological origin 12 Pharmaceuticals of animal origin 13 The sex hormones 14 The androgens 14 Oestrogens 15 Progesterone and progestogens 17 Corticosteroids 19 Catecholamines 21 Prostaglandins 23 Pharmaceutical substances of plant origin 27 Alkaloids 28 Atropine and scopalamine 28 Morphine and cocaine 29 Additional plant alkaloids 30 Ergot alkaloids 30 Flavonoids, xanthines and terpenoids 30 Cardiac glycosides and coumarins 33 Aspirin 33 Pharmaceutical substances of microbial origin 33 The macrolides and ansamycins 38 Peptide and other antibiotics 39 Conclusion 39 Further reading 40
Chapter 2 The drug development process 43 Drug discovery 44 The impact of genomics and related technologies upon drug discovery 45 Gene chips 47 Proteomics 49 Structural genomics 50 Pharmacogenetics 51 Plants as a source of drugs 52 Microbial drugs 53 Rational drug design 54 Combinatorial approaches to drug discovery 56 Initial product characterization 57 Patenting 57 What is a patent and what is patentable? 57 Patent types 62 The patent application 63 Patenting in biotechnology 64 Delivery of biopharmaceuticals 66 Oral delivery systems 66 Pulmonary delivery 67 Nasal, transmucosal and transdermal delivery systems 68 Pre-clinical trials 69 Pharmacokinetics and pharmacodynamics 69 Toxicity studies 71 Reproductive toxicity and teratogenicity 71 Mutagenicity, carcinogenicity and other tests 72 Clinical trials 73 Clinical trial design 75 Trial size and study population 75 Randomized control studies 76 Additional trial designs 76 The role and remit of regulatory authorities 78 The Food and Drug Administration 78 The investigational new drug application 80 The new drug application 82 European regulations 84 National regulatory authorities 84 The EMEA and the new EU drug approval systems 85 The centralized procedure 86 Mutual recognition 88 Drug registration in Japan 88 World harmonization of drug approvals 89 Conclusion 89 Further reading 89
Chapter 3 The drug manufacturing process 93 International pharmacopoeia 93 Martindale , the Extra Pharmacopoeia 94 Guides to good manufacturing practice 94 The manufacturing facility 97 Clean rooms 98 Cleaning, decontamination and sanitation (CDS) 101 CDS of the general manufacturing area 102 CDS of process equipment 102 Water for biopharmaceutical processing 104 Generation of purified water and water for injections (WFI) 105 Distribution system for WFI 107 Documentation 109 Specifications 110 Manufacturing formulae, processing and packaging instructions 110 Records 111 Generation of manufacturing records 111 Sources of biopharmaceuticals 112 E. coli as a source of recombinant, therapeutic proteins 112 Expression of recombinant proteins in animal cell culture systems 116 Additional production systems: yeasts 116 Fungal production systems 117 Transgenic animals 118 Transgenic plants 122 Insect cell-based systems 123 Production of final product 124 Cell banking systems 127 Upstream processing 128 Microbial cell fermentation 129 Mammalian cell culture systems 133 Downstream processing 134 Final product formulation 140 Some influences that can alter the biological activity of proteins 142 Proteolytic degradation 143 Protein deamidation 144 Oxidation and disulphide exchange 145 Alteration of glycoprotein glycosylation patterns 147 Stabilizing excipients used in final product formulations 150 Final product fill 153 Freeze-drying 155 Labelling and packing 158 Analysis of the final product 159 Protein-based contaminants 159 Removal of altered forms of the protein of interest from the product stream 160 Product potency 161 Determination of protein concentration 163 Detection of protein-based product impurities 164 Capillary electrophoresis 166 High-pressure liquid chromatography (HPLC) 167 Mass spectrometry 168 Immunological approaches to detection of contaminants 168 Amino acid analysis 169 Peptide mapping 170 N-terminal sequencing 171 Analysis of secondary and tertiary structure 173 Endotoxin and other pyrogenic contaminants 173 Endotoxin, the molecule 174 Pyrogen detection 176 Dna 179 Microbial and viral contaminants 180 Viral assays 181 Miscellaneous contaminants 182 Validation studies 183 Further reading 185
Chapter 4 The cytokines --the interferon family 189 Cytokines 189 Cytokine receptors 194 Cytokines as biopharmaceuticals 195 The interferons 196 The biochemistry of interferon-a 197 Interferon-b 198 Interferon-g 198 Interferon signal transduction 198 The interferon receptors 199 The JAK-STAT pathway 199 The interferon JAK-STAT pathway 202 The biological effects of interferons 203 The eIF-2a protein kinase system 207 Interferon biotechnology 207 Production and medical uses of IFN-a 210 Medical uses of IFN-b 213 Medical applications of IFN-g 214 Interferon toxicity 216 Additional interferons 218 Conclusion 219 Further reading 219
Chapter 5 Cytokines: interleukins and tumour necrosis factor 223 Interleukin-2 (IL-2) 225 IL-2 production 228 IL-2 and cancer treatment 228 IL-2 and infectious diseases 230 Safety issues 231 Inhibition of IL-2 activity 231 Interleukin-1 (IL-1) 232 The biological activities of IL- 1 233 IL-1 biotechnology 234 Interleukin-3: biochemistry and biotechnology 235 Interleukin- 4 236 Interleukin- 6 238 Interleukin- 11 240 Interleukin- 5 241 Interleukin- 12 244 Tumour necrosis factors (TNFs) 246 TNF biochemistry 246 Biological activities of TNF-a 247 Immunity and inflammation 248 TNF receptors 249 TNF: therapeutic aspects 250 Further reading 252
Chapter 6 Haemopoietic growth factors 255 The interleukins as haemopoietic growth factors 257 Granulocyte colony stimulating factor (G-CSF) 258 Macrophage colony-stimulating factor (M-CSF) 259 Granulocyte-macrophage colony stimulating factor (GM-CSF) 259 Clinical application of CSFs 261 Leukaemia inhibitory factor (LIF) 263 Erythropoietin (EPO) 264 The EPO receptor and signal transduction 267 Regulation of EPO production 267 Therapeutic applications of EPO 268 Chronic disease and cancer chemotherapy 271 Additional non-renal applications 272 Tolerability 273 Thrombopoietin 273 Further reading 275
Chapter 7 Growth factors 277 Growth factors and wound healing 277 Insulin-like growth factors (IGFs) 279 IGF biochemistry 280 IGF receptors 280 IGF-binding proteins 282 Biological effects 282 IGF and fetal development 283 IGFs and growth 283 Renal and reproductive effects 284 Neuronal and other effects 285 Epidermal growth factor (EGF) 285 The EGF receptor 286 Platelet-derived growth factor (PDGF) 287 The PDGF receptor and signal transduction 288 PDGF and wound healing 289 Fibroblast growth factors (FGFs) 289 Transforming growth factors (TGFs) 290 TGF-a 290 TGF-b 292 Neurotrophic factors 293 The neurotrophins 294 Neurotrophin receptors 296 The neurotrophin low-affinity receptor 297 Ciliary neurotrophic factor and glial cell line-derived neurotrophic factor 297 Neurotrophic factors and neurodegenerative disease 298 Amyotrophic lateral sclerosis (ALS) and peripheral neuropathy 298 Neurotrophic factors and neurodegenerative diseases of the brain 298 Further reading 300
Chapter 8 Hormones of therapeutic interest 303 Insulin 303 Diabetes mellitus 304 The insulin molecule 304 The insulin receptor and signal transduction 307 Insulin production 307 Enzymatic conversion of porcine insulin 311 Production of human insulin by recombinant DNA technology 312 Formulation of insulin products 314 Engineered insulins 317 Additional means of insulin administration 320 Treating diabetics with insulin-producing cells 321 Glucagon 321 Human growth hormone (hGH) 324 Growth hormone releasing factor (GHRF) and inhibitory factor (GHRIF) 325 The GH receptor 325 Biological effects of GH 327 Therapeutic uses of GH 328 Recombinant hGH (rhGH) and pituitary dwarfism 328 Idiopathic short stature and Turner''s syndrome 330 Metabolic effects of hGH 330 GH, lactation and ovulation 331