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Preface Chapter 1 Biopharmaceuticals, an introductory overview 1.1 Introduction to pharmaceutical products 1.2 Genetic engineering and the advent of biopharmaceuticals 1.2.1 Manufacture of recombinant therapeutic proteins 1.3 Biopharmaceuticals: current status and future prospects 1.3.1 Monoclonal antibodies 1.3.2 Nucleic acid and engineered cell-based products 1.3.3 Biosimilars 1.3.4 Market value 1.3.5 Future prospects Sources of additional information Some journal articles Chapter 2 Biopharmaceuticals: Discovery, Development and Regulation 2.1 Introduction 2.2 Discovery of biopharmaceuticals 2.3 The impact of 'omics' and related technologies upon drug discovery 2.3.1 Genomics 2.3.2 Proteomics 2.3.3. Bioinformatics 2.3.4 Omics influence upon target or drug discovery 2.4 Lead discovery 2.5 Pharmacogenetics 2.6 The influence of artificial intelligence upon drug discovery 2.7 Lead characterization, CMC development and QbD 2.8 Delivery of biopharmaceuticals 2.8.1 Oral delivery systems 2.8.2 Pulmonary delivery 2.8.3 Nasal, transmucosal and transdermal delivery systems 2.9 Preclinical studies 2.10 Pharmacokinetics and pharmacodynamics 2.10.1 Protein pharmacokinetics 2.10.2 Tailoring of pharmacokinetic profile 2.10.3 Protein mode of action and pharmacodynamics 2.11 Toxicity studies 2.11.1 Reproductive toxicity and teratogenicity 2.11.2 Mutagenicity, carcinogenicity and other tests 2.12 Clinical trials 2.12.1 Clinical trial design 2.12.2 Trial size design and study population 2.13 The role and remit of regulatory authorities 2.14 The Food and Drug Administration (FDA) 2.15 European pharmaceutical law 2.15.1 National regulatory authorities and the EMA 2.15.2 Drug approval pathways in the EU 2.16 Pharmacovigilance 2.17 World harmonization of drug regulations and the ICH 2.18 The naming of biopharmaceuticals 2.19 Patenting 2.19.1 What is a patent and what is patentable? 2.19.2 Patenting in biotechnology 2.20 Biosimilar regulation Sources of additional information Some journal articles Chapter 3 Good Manufacturing Practice 3.1 Introduction 3.2 Guides to Good Manufacturing Practice (GMP) 3.3 Pharmacopoeia 3.4 The manufacturing facility 3.4.1. Clean rooms 3.4.2. Product flow through the facility 3.4.3 Cleaning, decontamination and sanitation. 3.4.4 Water for (bio)pharmaceutical processing. 3.4.5 Generation of purified water and WFI 3.4.6 Distribution system for WFI 3.5 Documentation 3.5.1 Standard Operating Procedures 3.5.2 Specifications 3.5.3. Manufacturing formulae, processing and packaging instructions. 3.5.4 Records 3.6 Validation 3.7 Further reading: Chapter 4 Protein structure 4.1 Introduction 4.2 Primary Structure 4.2.1 The peptide bond 4.2.2 Amino acid sequence determination 4.3 Higher level structure 4.3.1. Secondary structure 4.3.2. Tertiary structure 4.3.3. Experimental determination of a protein's three-dimensional structure 4.4 Protein folding and stability 4.5 Protein structure prediction 4.6 Protein post translational modification 4.6.1. Glycosylation 4.6.2 Carboxylation and Hydroxylation 4.6.3 Sulfation and amidation Further reading Chapter 5 Production of therapeutic proteins by recombinant means 5.1 Introduction 5.2 Nucleic acids; structure and function 5.2.1 Genome and gene organization 5.2.2 Nucleic acid purification and quantification 5.3 The principles of genetic engineering 5.3.1 Identification and isolation of the target DNA sequence 5.3.2 Cloning the target sequence 5.3.3. Expression vectors 5.3.4 Engineering of recombinant host cells 5.4 Cell types in which recombinant therapeutic proteins are produced 5.4.1 E coli as a source of recombinant, therapeutic proteins 5.4.2 Expression of recombinant proteins in animal cell culture systems 5.4.3 Yeast-based expression 5.4.4 Insect cell-based systems 5.4.5 Transgenic animals 5.4.6 Plant-based expression systems 5.5 Engineered therapeutic proteins 5.5.1 Engineering via altering amino acid sequence. 5.5.2 Engineering via chemical modification 5.5.3 Engineering of producer cell lines Further reading Chapter 6 Therapeutic protein manufacture: upstream processing 6.1 Introduction 6.2 Cell banking systems 6.3 Bioreactors 6.3.1 Stirred tank bioreactors 6.3.2 Bioreactor operation: batch v feed batch v continuous 6.3.3 Single use (disposable) bioreactors. 6.4 Microbial cell fermentation 6.5 Mammalian cell culture 6.5.1 Cell culture media 6.5.2 Adherent versus non-adherent cells 6.5.3 Bioprocess scale culture of adherent and non-adherent cells. Additional reading Chapter 7 Therapeutic protein manufacture: downstream processing 7.1 Initial product recovery 7.1.1 Centrifugation 7.1.2 Filtration 7.1.3 Cell disruption 7.2.4 Removal of nucleic acid 7.2 Initial product concentration 7.2.1 Ultrafiltration 7.2.2 Diafiltration 7.3 Chromatographic purification 7.3.1 Engineering proteins for purification 7.3.3 Size exclusion chromatography (Gel filtration) 7.3.3 Ion exchange chromatography 7.3.4 Hydrophobic interaction chromatography 7.3.5 Affinity chromatography 7.3.6 Chromatography on hydroxyapatite 7.3.7 Chromatofocusing 7.3.8 Multimodal chromatography 7.3.9 Flow through chromatography 7.3.10 HPLC of proteins 7.4 Viral clearance 7.5 Some influences which can alter the biological activity of proteins 7.5.1 Proteolytic degradation and alteration of sugar side chains. 7.5.2 Protein deamidation 7.5.3 Oxidation and disulphide exchange 7.6 Final product formulation 7.6.1 Excipients used in final product formulations 7.7 Sterilization and final product fill 7.7.1 Freeze drying 7.7.2 Labelling and packing 7.8 Trends in downstream processing Further reading Chapter 8 Product analysis 8.1 Introduction and regulatory context 8.2 Potency determination 8.3 Protein content 8.4 Purity determination and API characterization 8.5 Key analytical methodologies 8.5.1 High-performance liquid chromatography (HPLC) 8.5.2 Mass spectrometry 8.6 Product purity determination 8.7 API characterization 8.7.1 Compositional analysis 8.7.2. Peptide mapping 8.7.3. Partial sequencing 8.7.4. Detection of aggregates and chemically modified variants 8.7.5. PTM analysis. 8.7.6. Analysis of higher order structure. 8.8 Non-protein impurity characterization: DNA 8.9 Contaminant testing 8.9.1 Microbial contaminants, including mycoplasma 8.9.2 Viral contaminants 8.9.3 Endotoxin and other pyrogenic contaminants. 8.10 Additional tests Further reading Chapter 9 Antibodies 9.1.1 Antibody structure and function 9.1.2 Antibody structure 9.1.2 Antigen, epitopes and polyclonal antibodies 9.1.3 Antibody-antigen binding 9.1.4 Antibody function 9.1.3 Polyclonal antibody preparations used therapeutically 9.1.4 Hybridoma technology and first generation monoclonal antibodies 9.1.5 Limitations of hybridoma-derived mAbs 9.4 Chimeric and humanized antibodies 9.5 Fully human mAbs 9.6 Routine manufacture of mAbs 9.7 mAb therapeutic applications in overview 9.8 mAb therapeutics treating inflammation 9.9 mAbs therapeutic treating cancer 9.9.1 Antibodies targeting immune checkpoint inhibitors 9.9.2 Additional antibodies that inactivate molecules or pathways important in fueling cancer cell growth and division 9.9.3 Antibodies triggering cancer cell destruction 9.10 Some additional therapeutic mAbs 9.11 Additional engineered antibody formats 9.11.1 mAb fragments 9.11.2 Bispecific antibodies 9.11.3 Antibody drug conjugates 9.11.4 Glycoengineered mAbs 9.11.5 mAbs generated by multiple engineering 9.11.6 Antibody-based fusion products 9.12 The mAb market and the advent of mAb biosimilars Further reading Chapter 10 Vaccines 10.1 Introduction 10.2 Traditional vaccine preparations 10.2.1 Attenuated, dead or inactivated bacteria 10.2.2 Attenuated and inactivated viral vaccines 10.2.3 Toxoids and antigen-based vaccines 10.3 The impact of recombinant DNA technology on vaccines 10.3.1 Recombinant subunit vaccines 10.3.2 Vaccine vectors 10.3.3 mRNA vaccines 10.4 Adjuvant technology 10.4.1 Adjuvant mode of action 10.4.2 Mineral-based adjuvants 10.4.3 Emulsion-based adjuvants Further information & reading: Chapter 11 The cytokines - the interferon family 11.1 Introduction to the cytokines 11.1.1 Cytokine receptors 11.1.2 Cytokines as biopharmaceuticals 11.2 The Interferons 11.2.1 The biochemistry of Interferon-* 9.2.2 Interferon-* 11.2.3 Interferon-* 11.2.4 Interferon signal transduction 11.2.5 The interferon receptors 11.2.6 The JAK-STAT pathway 11.2.7 The interferon JAK-STAT pathway 11.2.8 The biological effects of interferons 11.2.9 The eIF - 2* protein kinase system 11.3 Interferon biotechnology 11.3.1 Medical uses of IFN-ß 11.3.2 Medical applications of IFN-? Further reading Chapter 12 The cytokines - Interleukins and Tumour Necrosis Factor 12.1 Introduction to the interleukins 12.2 Interleukin-2 12.3 IL-2 biotechnology 12.4 Interleukin 11 12.5 Inhibition of interleukin activity 12.6 Tumour Necrosis Factor 12.6.1 TNF biochemistry 12.6.2 Biological activities of TNF 12.6.3 Tumour necrosis factor receptors 12.6.4 TNF as a therapeutic agent 12.6.5 Inhibition of TNF activity Further reading Chapter 13 Growth Factors 13.1 Introduction 13.2 Haematopoietic growth factors 13.2.1 The interleukins as haemopoietic growth factors 13.3 Granulocyte colony stimulating factor (G-CSF) 13.4 Macrophage colony-stimulating factor (M-CSF) 13.5 Granulocyte macrophage colony-stimulating factor (GM-CSF) 13.6 Clinical application of CSFs 13.7 Erythropoietin 13.8 Therapeutic applications of EPO 13.9 Thrombopoietin 13.10 Insulin-like growth factors 13.10.1 IGF biological effects 13.11 Neurotrophic factors 13.12 Fibroblast growth factors 13.13 Platelet-derived growth factor 13.14 Bone morphogenetic proteins 13.15 Inhibition of growth factor activity 13.15.1 Inhibition of VEGF activity 13.15.2 Inhibition of HER2-related signaling Further reading Chapter 14 Hormones 14.1 Introduction 14.2 Insulin 14.2.1 Type 1 diabetes 14.2.2 Type 2 diabetes 14.3 The Insulin Molecule 14.4 The Insulin Receptor and signal transduction 14.5 Insulin manufacture by traditional means 14.6 Production of human insulin by recombinant DNA technology 14.7 Formulation of insulin products 14.8 Engineered insulins 14.8.1 Fast-acting insulins 14.8.2 Long-acting insulins 14.9 Glucagon-like peptide-1 (GLP-1) related products 14.10 GLP-1 receptor agonists 14.10.1 GLP-1 receptor agonists; further uses 14.11 Human Growth Hormone 14.11.1 The GH receptor 14.11.2 Biological effects of GH 14.11.3 Therapeutic uses of GH 14.12 The Gonadotrophins 14.12.1 FSH, LH and hCG 14.12.2 The inhibins and activins 14.13 Medical applications of gonadotrophins 14.13.1 Sources and medical uses of FSH, LH and hCG 14.13.2 Recombinant Gonadotrophins 14.14 Additional recombinant hormones now approved Further reading Chapter 15 Recombinant blood products and therapeutic enzymes 15.1 Introduction 15.2 Haemostasis 15.3 The coagulation pathway 15.3.1 Terminal steps of coagulation pathway 15.4 Clotting disorders 15.5 Factor VIII and hemophilia A 15.5.1 Production of factor VIII 15.6 Additional recombinant blood factors 15.7 Anticoagulants 15.7.1 Antithrombin 15.8 Thrombolytic agents 15.8.1 Tissue plasminogen activator 15.8.2 Streptokinase 15.8.3 Urokinase 15.9 Enzymes of therapeutic value 15.9.1 Asparaginase 15.9.2 DNase 15.9.3 Enzymes used to treat genetic diseases. 15.9.4 Glucocerebrosidase 15.9.5 ?-Galactosidase 15.9.6 Debriding agents 15.9.7 Digestive aids Further reading Chapter 16 Nucleic acid based products 16.1 Introduction 16.2 Classical Gene Therapy 16.3 Basic approach to gene delivery 16.3.1 Ex vivo versus in vivo targeted gene delivery 16.4 Vectors used in gene therapy 16.4.1 Retroviral vectors 16.4.2 Adenoviral -based vectors 16.4.3 Adeno-associated virus-based vectors 16.4.4 Herpes simplex viral vectors 16.5 Manufacture of viral vectors 16.5.1 Initial production of plasmids 16.5.2 Vector producer cell culture and subsequent plasmid transfection 16.5.3 Vector recovery, purification and formulation 16.5.4 Lentiviral vector downstream processing 16.5.5 AAV vector downstream processing 16.5.6 Variant approaches to viral vector production 16.6 CAR-T based gene therapy 16.6 Non-viral vectors 16.7 The impact of CRISPR technology on gene therapy 16.8 Antisense technology, including siRNA 16.8.1 Antisense oligonucleotides (ASOs) and their mode of action 16.8.2 Uses, advantages and disadvantages of ASOs 16.8.3 Oligonucleotide pharmacokinetics and delivery 16.8.4 ASO manufacture 16.8.5 siRNA-based antisense products Further reading Index

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