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| Preface | |
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| Pharmaceuticals, biologics and biopharmaceuticals | |
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| Introduction to pharmaceutical products | |
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| Biopharmaceuticals and pharmaceutical biotechnology | |
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| History of the pharmaceutical industry | |
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| The age of biopharmaceuticals | |
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| Biopharmaceuticals: current status and future prospects | |
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| Traditional pharmaceuticals of biological origin | |
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| Pharmaceuticals of animal origin | |
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| The sex hormones | |
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| The androgens | |
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| Oestrogens | |
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| Progesterone and progestogens | |
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| Corticosteroids | |
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| Catecholamines | |
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| Prostaglandins | |
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| Pharmaceutical substances of plant origin | |
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| Alkaloids | |
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| Atropine and scopalamine | |
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| Morphine and cocaine | |
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| Additional plant alkaloids | |
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| Ergot alkaloids | |
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| Flavonoids, xanthines and terpenoids | |
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| Cardiac glycosides and coumarins | |
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| Aspirin | |
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| Pharmaceutical substances of microbial origin | |
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| The macrolides and ansamycins | |
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| Peptide and other antibiotics | |
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| Conclusion | |
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| Further reading | |
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| The drug development process | |
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| Drug discovery | |
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| The impact of genomics and related technologies upon drug discovery | |
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| Gene chips | |
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| Proteomics | |
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| Structural genomics | |
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| Pharmacogenetics | |
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| Plants as a source of drugs | |
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| Microbial drugs | |
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| Rational drug design | |
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| Combinatorial approaches to drug discovery | |
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| Initial product characterization | |
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| Patenting | |
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| What is a patent and what is patentable? | |
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| Patent types | |
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| The patent application | |
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| Patenting in biotechnology | |
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| Delivery of biopharmaceuticals | |
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| Oral delivery systems | |
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| Pulmonary delivery | |
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| Nasal, transmucosal and transdermal delivery systems | |
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| Pre-clinical trials | |
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| Pharmacokinetics and pharmacodynamics | |
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| Toxicity studies | |
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| Reproductive toxicity and teratogenicity | |
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| Mutagenicity, carcinogenicity and other tests | |
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| Clinical trials | |
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| Clinical trial design | |
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| Trial size and study population | |
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| Randomized control studies | |
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| Additional trial designs | |
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| The role and remit of regulatory authorities | |
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| The Food and Drug Administration | |
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| The investigational new drug application | |
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| The new drug application | |
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| European regulations | |
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| National regulatory authorities | |
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| The EMEA and the new EU drug approval systems | |
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| The centralized procedure | |
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| Mutual recognition | |
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| Drug registration in Japan | |
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| World harmonization of drug approvals | |
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| Conclusion | |
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| Further reading | |
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| The drug manufacturing process | |
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| International pharmacopoeia | |
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| Martindale, the Extra Pharmacopoeia | |
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| Guides to good manufacturing practice | |
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| The manufacturing facility | |
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| Clean rooms | |
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| Cleaning, decontamination and sanitation (CDS) | |
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| CDS of the general manufacturing area | |
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| CDS of process equipment | |
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| Water for biopharmaceutical processing | |
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| Generation of purified water and water for injections (WFI) | |
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| Distribution system for WFI | |
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| Documentation | |
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| Specifications | |
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| Manufacturing formulae, processing and packaging instructions | |
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| Records | |
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| Generation of manufacturing records | |
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| Sources of biopharmaceuticals | |
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| E. coli as a source of recombinant, therapeutic proteins | |
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| Expression of recombinant proteins in animal cell culture systems | |
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| Additional production systems: yeasts | |
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| Fungal production systems | |
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| Transgenic animals | |
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| Transgenic plants | |
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| Insect cell-based systems | |
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| Production of final product | |
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| Cell banking systems | |
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| Upstream processing | |
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| Microbial cell fermentation | |
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| Mammalian cell culture systems | |
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| Downstream processing | |
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| Final product formulation | |
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| Some influences that can alter the biological activity of proteins | |
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| Proteolytic degradation | |
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| Protein deamidation | |
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| Oxidation and disulphide exchange | |
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| Alteration of glycoprotein glycosylation patterns | |
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| Stabilizing excipients used in final product formulations | |
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| Final product fill | |
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| Freeze-drying | |
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| Labelling and packing | |
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| Analysis of the final product | |
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| Protein-based contaminants | |
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| Removal of altered forms of the protein of interest from the product stream | |
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| Product potency | |
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| Determination of protein concentration | |
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| Detection of protein-based product impurities | |
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| Capillary electrophoresis | |
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| High-pressure liquid chromatography (HPLC) | |
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| Mass spectrometry | |
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| Immunological approaches to detection of contaminants | |
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| Amino acid analysis | |
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| Peptide mapping | |
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| N-terminal sequencing | |
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| Analysis of secondary and tertiary structure | |
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| Endotoxin and other pyrogenic contaminants | |
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| Endotoxin, the molecule | |
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| Pyrogen detection | |
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| DNA | |
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| Microbial and viral contaminants | |
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| Viral assays | |
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| Miscellaneous contaminants | |
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| Validation studies | |
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| Further reading | |
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| The cytokines--the interferon family | |
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| Cytokines | |
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| Cytokine receptors | |
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| Cytokines as biopharmaceuticals | |
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| The interferons | |
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| The biochemistry of interferon-[alpha] | |
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| Interferon-[beta] | |
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| Interferon-[gamma] | |
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| Interferon signal transduction | |
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| The interferon receptors | |
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| The JAK-STAT pathway | |
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| The interferon JAK-STAT pathway | |
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| The biological effects of interferons | |
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| The eIF-2[alpha] protein kinase system | |
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| Interferon biotechnology | |
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| Production and medical uses of IFN-[alpha] | |
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| Medical uses of IFN-[beta] | |
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| Medical applications of IFN-[gamma] | |
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| Interferon toxicity | |
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| Additional interferons | |
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| Conclusion | |
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| Further reading | |
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| Cytokines: interleukins and tumour necrosis factor | |
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| Interleukin-2 (IL-2) | |
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| IL-2 production | |
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| IL-2 and cancer treatment | |
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| IL-2 and infectious diseases | |
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| Safety issues | |
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| Inhibition of IL-2 activity | |
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| Interleukin-1 (IL-1) | |
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| The biological activities of IL-1 | |
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| IL-1 biotechnology | |
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| Interleukin-3: biochemistry and biotechnology | |
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| Interleukin-4 | |
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| Interleukin-6 | |
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| Interleukin-11 | |
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| Interleukin-5 | |
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| Interleukin-12 | |
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| Tumour necrosis factors (TNFs) | |
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| TNF biochemistry | |
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| Biological activities of TNF-[alpha] | |
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| Immunity and inflammation | |
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| TNF receptors | |
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| TNF: therapeutic aspects | |
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| Further reading | |
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| Haemopoietic growth factors | |
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| The interleukins as haemopoietic growth factors | |
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| Granulocyte colony stimulating factor (G-CSF) | |
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| Macrophage colony-stimulating factor (M-CSF) | |
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| Granulocyte-macrophage colony stimulating factor (GM-CSF) | |
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| Clinical application of CSFs | |
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| Leukaemia inhibitory factor (LIF) | |
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| Erythropoietin (EPO) | |
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| The EPO receptor and signal transduction | |
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| Regulation of EPO production | |
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| Therapeutic applications of EPO | |
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| Chronic disease and cancer chemotherapy | |
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| Additional non-renal applications | |
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| Tolerability | |
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| Thrombopoietin | |
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| Further reading | |
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| Growth factors | |
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| Growth factors and wound healing | |
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| Insulin-like growth factors (IGFs) | |
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| IGF biochemistry | |
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| IGF receptors | |
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| IGF-binding proteins | |
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| Biological effects | |
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| IGF and fetal development | |
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| IGFs and growth | |
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| Renal and reproductive effects | |
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| Neuronal and other effects | |
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| Epidermal growth factor (EGF) | |
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| The EGF receptor | |
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| Platelet-derived growth factor (PDGF) | |
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| The PDGF receptor and signal transduction | |
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| PDGF and wound healing | |
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| Fibroblast growth factors (FGFs) | |
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| Transforming growth factors (TGFs) | |
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| TGF-[alpha] | |
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| TGF-[beta] | |
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| Neurotrophic factors | |
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| The neurotrophins | |
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| Neurotrophin receptors | |
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| The neurotrophin low-affinity receptor | |
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| Ciliary neurotrophic factor and glial cell line-derived neurotrophic factor | |
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| Neurotrophic factors and neurodegenerative disease | |
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| Amyotrophic lateral sclerosis (ALS) and peripheral neuropathy | |
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| Neurotrophic factors and neurodegenerative diseases of the brain | |
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| Further reading | |
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| Hormones of therapeutic interest | |
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| Insulin | |
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| Diabetes mellitus | |
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| The insulin molecule | |
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| The insulin receptor and signal transduction | |
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| Insulin production | |
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| Enzymatic conversion of porcine insulin | |
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| Production of human insulin by recombinant DNA technology | |
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| Formulation of insulin products | |
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| Engineered insulins | |
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| Additional means of insulin administration | |
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| Treating diabetics with insulin-producing cells | |
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| Glucagon | |
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| Human growth hormone (hGH) | |
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| Growth hormone releasing factor (GHRF) and inhibitory factor (GHRIF) | |
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| The GH receptor | |
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| Biological effects of GH | |
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| Therapeutic uses of GH | |
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| Recombinant hGH (rhGH) and pituitary dwarfism | |
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| Idiopathic short stature and Turner's syndrome | |
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| Metabolic effects of hGH | |
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| GH, lactation and ovulation | |
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| The gonadotrophins | |
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| Follicle stimulating hormone (FSH), luteinizing hormone (LH) and human chorionic gonadotrophin (hCG) | |
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| Pregnant mare serum gonadotrophin (PMSG) | |
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| The inhibins and activins | |
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| LHRH and regulation of gonadotrophin production | |
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| Medical and veterinary applications of gonadotrophins | |
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| Sources and medical uses of FSH, LH and hCG | |
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| Recombinant gonadotrophins | |
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| Veterinary uses of gonadotrophins | |
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| Gonadotrophin releasing hormone (GnRH) | |
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| Additional recombinant hormones now approved | |
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| Conclusions | |
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| Further reading | |
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| Blood products and therapeutic enzymes | |
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| Disease transmission | |
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| Whole blood | |
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| Platelets and red blood cells | |
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| Blood substitutes | |
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| Dextrans | |
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| Albumin | |
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| Gelatin | |
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| Oxygen-carrying blood substitutes | |
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| Haemostasis | |
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| The coagulation pathway | |
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| Terminal steps of coagulation pathway | |
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| Clotting disorders | |
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| Factor VIII and haemophilia | |
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| Production of factor VIII | |
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| Factors IX, VII[subscript a] and XIII | |
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| Anticoagulants | |
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| Heparin | |
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| Vitamin K antimetabolites | |
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| Hirudin | |
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| Antithrombin | |
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| Thrombolytic agents | |
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| Tissue plasminogen activator (tPA) | |
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| First-generation tPA | |
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| Engineered tPA | |
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| Streptokinase | |
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| Urokinase | |
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| Staphylokinase | |
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| [alpha subscript 1]-Antitrypsin | |
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| Enzymes of therapeutic value | |
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| Asparaginase | |
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| DNase | |
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| Glucocerebrosidase | |
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| [alpha]-Galactosidase and urate oxidase | |
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| Superoxide dismutase | |
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| Debriding agents | |
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| Digestive aids | |
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| Lactase | |
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| Further reading | |
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| Antibodies, vaccines and adjuvants | |
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| Polyclonal antibody preparations | |
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| Anti-D immunoglobulin | |
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| Normal immunoglobulins | |
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| Hepatitis B and tetanus immunoglobulin | |
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| Snake and spider antivenins | |
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| Monoclonal antibodies | |
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| Production of monoclonals via hybridoma technology | |
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| Antibody screening: phage display technology | |
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| Therapeutic application of monoclonal antibodies | |
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| Tumour immunology | |
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| Antibody-based strategies for tumour detection/destruction | |
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| Drug-based tumour immunotherapy | |
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| First-generation anti-tumour antibodies: clinical disappointment | |
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| Tumour-associated antigens | |
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| Antigenicity of murine monoclonals | |
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| Chimaeric and humanized antibodies | |
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| Antibody fragments | |
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| Additional therapeutic applications of monoclonal antibodies | |
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| Cardiovascular and related disease | |
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| Infectious diseases | |
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| Autoimmune disease | |
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| Transplantation | |
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| Vaccine technology | |
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| Traditional vaccine preparations | |
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| Attenuated, dead or inactivated bacteria | |
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| Attenuated and inactivated viral vaccines | |
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| Toxoids, antigen-based and other vaccine preparations | |
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| The impact of genetic engineering on vaccine technology | |
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| Peptide vaccines | |
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| Vaccine vectors | |
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| Development of an AIDS vaccine | |
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| Difficulties associated with vaccine development | |
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| AIDS vaccines in clinical trials | |
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| Cancer vaccines | |
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| Recombinant veterinary vaccines | |
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| Adjuvant technology | |
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| Adjuvant mode of action | |
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| Mineral-based adjuvants | |
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| Oil-based emulsion adjuvants | |
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| Bacteria/bacterial products as adjuvants | |
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| Additional adjuvants | |
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| Further reading | |
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| Nucleic acid therapeutics | |
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| Gene therapy | |
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| Basic approach to gene therapy | |
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| Some additional questions | |
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| Vectors used in gene therapy | |
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| Retroviral vectors | |
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| Additional viral-based vectors | |
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| Manufacture of viral vectors | |
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| Non-viral vectors | |
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| Manufacture of plasmid DNA | |
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| Gene therapy and genetic disease | |
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| Gene therapy and cancer | |
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| Gene therapy and AIDS | |
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| Gene-based vaccines | |
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| Gene therapy: some additional considerations | |
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| Anti-sense technology | |
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| Anti-sense oligonucleotides | |
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| Uses, advantages and disadvantages of 'oligos' | |
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| Delivery and cellular uptake of oligonucleotides | |
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| Manufacture of oligonucleotides | |
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| Vitravene, an approved antisense agent | |
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| Antigene sequences and ribozymes | |
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| Conclusion | |
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| Further reading | |
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| Biopharmaceuticals thus far approved in the USA or European Union | |
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| Some Internet addresses relevant to the biopharmaceutical sector | |
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| Two selected monographs reproduced from the European Pharmacopoeia with permission from the European Commission | |
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| Products of recombinant DNA technology | |
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| Interferon [alpha]-2 concentrated solution | |
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| Manufacture of biological medicinal products for human use. (Annex 2 from The Rules Governing Medicinal Products in the European Community, Vol. 4, Good Manufacturing Practice for Medicinal Products) | |
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| Index | |