Biopharmaceuticals Biochemistry and Biotechnology

by Walsh, Gary

• ISBN13: 9780470843277
• ISBN10: 0470843276
• Edition: 2nd
• Format: Paperback
• Copyright: 2003-08-29
• Publisher: Wiley-Blackwell

Summary

The latest edition of this highly acclaimed textbook, provides a comprehensive and up-to-date overview of the science and medical applications of biopharmaceutical products. Biopharmaceuticals refers to pharmaceutical substances derived from biological sources, and increasingly, it is synonymous with 'newer' pharmaceutical substances derived from genetic engineering or hybridoma technology. This superbly written review of the important areas of investigation in the field, covers drug production, plus the biochemical and molecular mechanisms of action together with the biotechnology of major biopharmaceutical types on the market or currently under development. There is also additional material reflecting both the technical advances in the area and detailed information on key topics such as the influence of genomics on drug discovery.

Author Biography

Gary Walsh is a senior lecturer in industrial biochemistry at the University of Limerick, Ireland. He combines industrial experience within the pharmaceutical industry with an extensive teaching and academic research background in pharmaceutical biotechnology. He has published half a dozen highly acclaimed books on various aspects of protein biotechnology. He is on the editorial board of several biopharmaceutical journals and is closely affiliated with the European Association of Pharma Biotechnology, serving as its scientific secretary.

Table of Contents

Preface	xvii
Chapter 1 Pharmaceuticals, biologics and biopharmaceuticals	1	(42)
Introduction to pharmaceutical products	1	(1)
Biopharmaceuticals and pharmaceutical biotechnology	1	(2)
History of the pharmaceutical industry	3	(2)
The age of biopharmaceuticals	5	(3)
Biopharmaceuticals: current status and future prospects	8	(4)
Traditional pharmaceuticals of biological origin	12	(27)
Pharmaceuticals of animal origin	13	(14)
The sex hormones	14	(5)
The androgens	14	(1)
Oestrogens	15	(2)
Progesterone and progestogens	17	(2)
Corticosteroids	19	(2)
Catecholamines	21	(2)
Prostaglandins	23	(4)
Pharmaceutical substances of plant origin	27	(6)
Alkaloids	28	(2)
Atropine and scopalamine	28	(1)
Morphine and cocaine	29	(1)
Additional plant alkaloids	30	(1)
Ergot alkaloids	30	(1)
Flavonoids, xanthines and terpenoids	30	(3)
Cardiac glycosides and coumarins	33	(1)
Aspirin	33	(1)
Pharmaceutical substances of microbial origin	33	(11)
The macrolides and ansamycins	38	(1)
Peptide and other antibiotics	39	(1)
Conclusion	39	(1)
Further reading	40	(3)
Chapter 2 The drug development process	43	(50)
Drug discovery	44	(13)
The impact of genomics and related technologies upon drug discovery	45	(7)
Gene chips	47	(2)
Proteomics	49	(1)
Structural genomics	50	(1)
Pharmacogenetics	51	(1)
Plants as a source of drugs	52	(1)
Microbial drugs	53	(1)
Rational drug design	54	(2)
Combinatorial approaches to drug discovery	56	(1)
Initial product characterization	57	(1)
Patenting	57	(9)
What is a patent and what is patentable?	57	(5)
Patent types	62	(1)
The patent application	63	(1)
Patenting in biotechnology	64	(2)
Delivery of biopharmaceuticals	66	(3)
Oral delivery systems	66	(1)
Pulmonary delivery	67	(1)
Nasal, transmucosal and transdermal delivery systems	68	(1)
Pre-clinical trials	69	(4)
Pharmacokinetics and pharmacodynamics	69	(2)
Toxicity studies	71	(1)
Reproductive toxicity and teratogenicity	71	(1)
Mutagenicity, carcinogenicity and other tests	72	(1)
Clinical trials	73	(5)
Clinical trial design	75	(1)
Trial size and study population	75	(1)
Randomized control studies	76	(1)
Additional trial designs	76	(2)
The role and remit of regulatory authorities	78	(11)
The Food and Drug Administration	78	(6)
The investigational new drug application	80	(2)
The new drug application	82	(2)
European regulations	84	(4)
National regulatory authorities	84	(1)
The EMEA and the new EU drug approval systems	85	(1)
The centralized procedure	86	(2)
Mutual recognition	88	(1)
Drug registration in Japan	88	(1)
World harmonization of drug approvals	89	(1)
Conclusion	89	(1)
Further reading	89	(4)
Chapter 3 The drug manufacturing process	93	(96)
International pharmacopoeia	93	(1)
Martindale, the Extra Pharmacopoeia	94	(1)
Guides to good manufacturing practice	94	(3)
The manufacturing facility	97	(15)
Clean rooms	98	(3)
Cleaning, decontamination and sanitation (CDS)	101	(1)
CDS of the general manufacturing area	102	(1)
CDS of process equipment	102	(2)
Water for biopharmaceutical processing	104	(1)
Generation of purified water and water for injections (WFI)	105	(2)
Distribution system for WFI	107	(2)
Documentation	109	(1)
Specifications	110	(1)
Manufacturing formulae, processing and packaging instructions	110	(1)
Records	111	(1)
Generation of manufacturing records	111	(1)
Sources of biopharmaceuticals	112	(12)
E. coli as a source of recombinant, therapeutic proteins	112	(4)
Expression of recombinant proteins in animal cell culture systems	116	(1)
Additional production systems: yeasts	116	(1)
Fungal production systems	117	(1)
Transgenic animals	118	(4)
Transgenic plants	122	(1)
Insect cell-based systems	123	(1)
Production of final product	124	(35)
Cell banking systems	127	(1)
Upstream processing	128	(1)
Microbial cell fermentation	129	(4)
Mammalian cell culture systems	133	(1)
Downstream processing	134	(6)
Final product formulation	140	(2)
Some influences that can alter the biological activity of proteins	142	(1)
Proteolytic degradation	143	(1)
Protein deamidation	144	(1)
Oxidation and disulphide exchange	145	(2)
Alteration of glycoprotein glycosylation patterns	147	(3)
Stabilizing excipients used in final product formulations	150	(3)
Final product fill	153	(2)
Freeze-drying	155	(3)
Labelling and packing	158	(1)
Analysis of the final product	159	(26)
Protein-based contaminants	159	(1)
Removal of altered forms of the protein of interest from the product stream	160	(1)
Product potency	161	(2)
Determination of protein concentration	163	(1)
Detection of protein-based product impurities	164	(2)
Capillary electrophoresis	166	(1)
High-pressure liquid chromatography (HPLC)	167	(1)
Mass spectrometry	168	(1)
Immunological approaches to detection of contaminants	168	(1)
Amino acid analysis	169	(1)
Peptide mapping	170	(1)
N-terminal sequencing	171	(2)
Analysis of secondary and tertiary structure	173	(1)
Endotoxin and other pyrogenic contaminants	173	(1)
Endotoxin, the molecule	174	(2)
Pyrogen detection	176	(3)
DNA	179	(1)
Microbial and viral contaminants	180	(1)
Viral assays	181	(1)
Miscellaneous contaminants	182	(1)
Validation studies	183	(2)
Further reading	185	(4)
Chapter 4 The cytokines - the interferon family	189	(34)
Cytokines	189	(7)
Cytokine receptors	194	(1)
Cytokines as biopharmaceuticals	195	(1)
The interferons	196	(23)
The biochemistry of interferon-α	197	(1)
Interferon-β	198	(1)
Interferon-γ	198	(1)
Interferon signal transduction	198	(1)
The interferon receptors	199	(1)
The JAK-STAT pathway	199	(3)
The interferon JAK-STAT pathway	202	(1)
The biological effects of interferons	203	(4)
The eIF-2α protein kinase system	207
Interferon biotechnology	201	(9)
Production and medical uses of IFN-α	210	(3)
Medical uses of IFN-α	213	(1)
Medical applications of IFN-γ	214	(2)
Interferon toxicity	216	(2)
Additional interferons	218	(1)
Conclusion	219	(1)
Further reading	219	(4)
Chapter 5 Cytokines: interleukins and tumour necrosis factor	223	(32)
Interleukin-2 (IL-2)	225	(7)
IL-2 production	228	(1)
IL-2 and cancer treatment	228	(2)
IL-2 and infectious diseases	230	(1)
Safety issues	231	(1)
Inhibition of IL-2 activity	231	(1)
Interleukin-1 (IL-1)	232	(3)
The biological activities of IL-1	233	(1)
IL-1 biotechnology	234	(1)
Interleukin-3: biochemistry and biotechnology	235	(1)
Interleukin-4	236	(2)
Interleukin-6	238	(2)
Interleukin-11	240	(1)
Interleukin-5	241	(3)
Interleukin-12	244	(2)
Tumour necrosis factors (TNFs)	246	(6)
TNF biochemistry	246	(1)
Biological activities of TNF-α	247	(1)
Immunity and inflammation	248	(1)
TNF receptors	249	(1)
TNF: therapeutic aspects	250	(2)
Further reading	252	(3)
Chapter 6 Haemopoietic growth factors	255	(22)
The interleukins as haemopoietic growth factors	257	(1)
Granulocyte colony stimulating factor (G-CSF)	258	(1)
Macrophage colony-stimulating factor (M-CSF)	259	(1)
Granulocyte-macrophage colony stimulating factor (GM-CSF)	259	(2)
Clinical application of CSFs	261	(2)
Leukaemia inhibitory factor (LIF)	263	(1)
Erythropoietin (EPO)	264	(9)
The EPO receptor and signal transduction	261	(6)
Regulation of EPO production	267	(1)
Therapeutic applications of EPO	268	(11)
Chronic disease and cancer chemotherapy	271	(1)
Additional non-renal applications	272	(1)
Tolerability	273	(1)
Thrombopoietin	273	(2)
Further reading	275	(2)
Chapter 7 Growth factors	277	(26)
Growth factors and wound healing	277	(2)
Insulin-like growth factors (IGFs)	279	(6)
IGF biochemistry	280	(1)
IGF receptors	280	(2)
IGF-binding proteins	282	(1)
Biological effects	282	(1)
IGF and fetal development	283	(1)
IGFs and growth	283	(1)
Renal and reproductive effects	284	(1)
Neuronal and other effects	285	(1)
Epidermal growth factor (EGF)	285	(2)
The EGF receptor	286	(1)
Platelet-derived growth factor (PDGF)	287	(2)
The PDGF receptor and signal transduction	288	(1)
PDGF and wound healing	289	(1)
Fibroblast growth factors (FGFs)	289	(1)
Transforming growth factors (TGFs)	290	(3)
TGF-α	290	(2)
TGF-β	292	(1)
Neurotrophic factors	293	(7)
The neurotrophies	294	(2)
Neurotrophin receptors	296	(1)
The neurotrophin low-affinity receptor	297	(1)
Ciliary neurotrophic factor and glial cell line-derived neurotrophic factor	297	(1)
Neurotrophic factors and neurodegenerative disease	298	(1)
Amyotrophic lateral sclerosis (ALS) and peripheral neuropathy	298	(1)
Neurotrophic factors and neurodegenerative diseases of the brain	298	(2)
Further reading	300	(3)
Chapter 8 Hormones of therapeutic interest	303	(48)
Insulin	303	(18)
Diabetes mellitus	304	(1)
The insulin molecule	304	(3)
The insulin receptor and signal transduction	307	(1)
Insulin production	307	(4)
Enzymatic conversion of porcine insulin	311	(1)
Production of human insulin by recombinant DNA technology	312	(2)
Formulation of insulin products	314	(3)
Engineered insulins	317	(3)
Additional means of insulin administration	320	(1)
Treating diabetics with insulin-producing cells	321	(1)
Glucagon	321	(3)
Human growth hormone (hGH)	324	(7)
Growth hormone releasing factor (GHRF) and inhibitory factor (GHRIF)	325	(1)
The GH receptor	325	(2)
Biological effects of GH	327	(1)
Therapeutic uses of GH	328	(1)
Recombinant hGH (rhGH) and pituitary dwarfism	328	(2)
Idiopathic short stature and Turner's syndrome	330	(1)
Metabolic effects of hGH	330	(1)
GH, lactation and ovulation	331	(1)
The gonadotrophins	331	(17)
Follicle stimulating hormone (FSH), luteinizing hormone (LH) and human chorionic gonadotrophin (hCG)	331	(4)
Pregnant mare serum gonadotrophin (PMSG)	335	(2)
The inhibins and activins	337	(1)
LHRH and regulation of gonadotrophin production	338	(1)
Medical and veterinary applications of gonadotrophins	339	(1)
Sources and medical uses of FSH, LH and hCG	340	(2)
Recombinant gonadotrophins	342	(2)
Veterinary uses of gonadotrophins	344	(1)
Gonadotrophin releasing hormone (GnRH)	345	(1)
Additional recombinant hormones now approved	345	(3)
Conclusions	348	(1)
Further reading	348	(3)
Chapter 9 Blood products and therapeutic enzymes	351	(52)
Disease transmission	351	(2)
Whole blood	353	(1)
Platelets and red blood cells	353	(1)
Blood substitutes	353	(5)
Dextrans	354	(1)
Albumin	355	(2)
Gelatin	357	(1)
Oxygen-carrying blood substitutes	357	(1)
Haemostasis	358	(42)
The coagulation pathway	358	(3)
Terminal steps of coagulation pathway	361	(4)
Clotting disorders	365	(1)
Factor VIII and haemophilia	366	(5)
Production of factor VIII	368	(3)
Factors IX, Vila and XIII	371	(1)
Anticoagulants	372	(7)
Heparin	372	(3)
Vitamin K antimetabolites	375	(1)
Hirudin	375	(4)
Antithrombin	379	(1)
Thrombolytic agents	380	(9)
Tissue plasminogen activator (tPA)	381	(4)
First-generation tPA	383	(1)
Engineered tPA	383	(2)
Streptokinase	385	(1)
Urokinase	386	(1)
Staphylokinase	386	(2)
α1-Antitrypsin	388	(1)
Enzymes of therapeutic value	389	(14)
Asparaginase	390	(2)
DNase	392	(1)
Glucocerebrosidase	393	(2)
α Galactosidase and urate oxidase	395	(2)
Superoxide dismutase	397	(1)
Debriding agents	397	(1)
Digestive aids	398	(2)
Lactase	400	(1)
Further reading	400	(3)
Chapter 10 Antibodies, vaccines and adjuvants	403	(60)
Polyclonal antibody preparations	403	(6)
Anti-D immunoglobulin	406	(1)
Normal immunoglobulins	407	(1)
Hepatitis B and tetanus immunoglobulin	407	(1)
Snake and spider antivenins	408	(1)
Monoclonal antibodies	409	(26)
Production of monoclonals via hybridoma technology	411	(1)
Antibody screening: phage display technology	412	(2)
Therapeutic application of monoclonal antibodies	414	(1)
Tumour immunology	415	(13)
Antibody-based strategies for tumour detection/destruction	417	(7)
Drug-based tumour immunotherapy	424	(2)
First-generation anti-tumour antibodies: clinical disappointment	426	(1)
Tumour-associated antigens	426	(2)
Antigenicity of murine monoclonals	428	(1)
Chimaeric and humanized antibodies	429	(3)
Antibody fragments	432	(1)
Additional therapeutic applications of monoclonal antibodies	433	(2)
Cardiovascular and related disease	433	(1)
Infectious diseases	433	(1)
Autoimmune disease	434	(1)
Transplantation	434	(1)
Vaccine technology	435	(25)
Traditional vaccine preparations	436	(5)
Attenuated, dead or inactivated bacteria	438	(1)
Attenuated and inactivated viral vaccines	439	(1)
Toxoids, antigen-based and other vaccine preparations	440	(1)
The impact of genetic engineering on vaccine technology	441	(6)
Peptide vaccines	444	(1)
Vaccine vectors	445	(2)
Development of an AIDS vaccine	447	(3)
Difficulties associated with vaccine development	450	(1)
AIDS vaccines in clinical trials	450	(2)
Cancer vaccines	452	(1)
Recombinant veterinary vaccines	452	(1)
Adjuvant technology	453	(2)
Adjuvant mode of action	455	(8)
Mineral-based adjuvants	455	(1)
Oil-based emulsion adjuvants	455	(2)
Bacteria/bacterial products as adjuvants	457	(1)
Additional adjuvants	458	(2)
Further reading	460	(3)
Chapter 11 Nucleic acid therapeutics	463	(36)
Gene therapy	463	(25)
Basic approach to gene therapy	464	(3)
Some additional questions	467	(1)
Vectors used in gene therapy	468	(12)
Retroviral vectors	468	(4)
Additional viral-based vectors	472	(2)
Manufacture of viral vectors	474	(2)
Non-viral vectors	476	(4)
Manufacture of plasmid DNA	480	(2)
Gene therapy and genetic disease	482	(3)
Gene therapy and cancer	485	(1)
Gene therapy and AIDS	486	(2)
Gene-based vaccines	488	(1)
Gene therapy: some additional considerations	488	(1)
Anti-sense technology	488	(7)
Anti-sense oligonucleotides	490	(1)
Uses, advantages and disadvantages of 'oligos'	491	(2)
Delivery and cellular uptake of oligonucleotides	493	(1)
Manufacture of oligonucleotides	493	(1)
Vitravene, an approved antisense agent	494	(1)
Antigene sequences and ribozymes	494	(1)
Conclusion	495	(1)
Further reading	496	(3)
Appendix 1 Biopharmaceuticals thus far approved in the USA or European Union	499	(10)
Appendix 2 Some Internet addresses relevant to the biopharmaceutical sector	509	(6)
Appendix 3 Two selected monographs reproduced from the European Pharmacopoeia with permission from the European Commission:
I. Products of recombinant DNA technology	515	(5)
II. Interferon α-2 concentrated solution	520	(7)
Appendix 4 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)	527	(6)
Index	533