Pharmaceutical Biotechnology: Drug Discovery and Clinical Applications -- Contents -- Preface to the 2nd Edition -- List of Contributors -- Part One: Concepts and Methods for Recombinant Drug Production -- 1: Pharmaceutical Biotechnology and Industrial Applications - Learning Lessons from Molecular Biology -- 1.1 Introduction -- 1.2 Research Developments -- 1.2.1 Protein Engineering -- 1.2.2 Muteins -- 1.2.3 Post-translational Engineering -- 1.2.4 Synthetic Biology -- 1.3 Production Hosts and Upstream/Downstream Processing -- 1.4 Future Outlook -- References -- Weblinks -- 2: Prokaryotic Cells in Biotech Production -- 2.1 Introduction -- 2.2 Production of Natural Products by Microorganisms -- 2.2.1 Production of Libraries of Natural Products -- 2.2.2 Production of Natural Products by Cloning and Expression of Biosynthetic Gene Clusters -- 2.2.3 Culture Manipulation to Wake Up Silent Gene Clusters -- 2.2.4 Genomic Driven Approaches to Wake Up Silent Gene Clusters -- 2.2.5 E. coli, an Interesting Host Also for Natural Product Synthesis -- 2.2.5.1 Production of Polyketides in E. coli -- 2.2.5.2 Metabolic Engineering of E. coli for Isoprenoid Biosynthesis -- 2.2.6 Global-Scale Strategies for Strains Improvement -- 2.2.6.1 System Biology, System Biotechnology, and "Omic" Approaches -- 2.2.6.2 Synthetic Biology Tools -- 2.2.6.3 Whole Genome Engineering Approaches -- 2.3 Prokaryotes as Producers of Recombinant Therapeutic Proteins -- 2.3.1 Prokaryotic Expression Systems -- 2.3.1.1 Host Strains -- 2.3.1.2 Expression Vectors -- 2.3.2 Production Steps -- 2.3.3 Products -- 2.3.3.1 Somatropin (Somatotropin, STH, Human Growth Hormone, hGH) -- 2.3.3.2 Human Insulin -- References -- 3: Mammalian Cells in Biotech Production -- 3.1 Introduction -- 3.2 Process Concepts and Cells -- 3.3 CHO-Derived Production Cell Lines.

3.4 Rapid Generation of High-Producing Cell Lines -- 3.5 Silencing - Stability of Expression -- 3.6 High-Throughput Bioprocess Development -- 3.7 Disposable Bioreactors -- 3.8 Transient Gene Expression (TGE) -- 3.9 Conclusions -- References -- 4: Biopharmaceuticals from Plants -- 4.1 Introduction -- 4.2 Basics in Plant Biotechnology -- 4.3 Plant Cell Cultures as Production System for Human Glucocerebrosidase -- 4.4 Insulin from Safflower - A Unique Purification Scheme -- 4.5 Fast and Scalable Transient Tobacco-Based Expression Systems -- 4.6 Conclusion -- References -- 5: Production of Biopharmaceuticals in Transgenic Animals -- 5.1 Introduction -- 5.2 Sites of Production -- 5.2.1 Milk -- 5.2.2 Urine -- 5.2.3 Seminal Fluid -- 5.2.4 Blood -- 5.2.5 Bird Eggs -- 5.3 Transgenic Constructs -- 5.3.1 Organ Specific Expression Vectors -- 5.3.2 Inducible Expression -- 5.3.3 Non-integrating Vectors -- 5.4 Methods for the Production of Transgenic Animals -- 5.4.1 Pronuclear DNA Microinjection -- 5.4.1.1 Collection of Fertilized Eggs -- 5.4.1.2 Preparation of DNA -- 5.4.1.3 Injection of DNA -- 5.4.1.4 Transfer and Gestation in Recipients -- 5.4.1.5 Identification of Founders and Subsequent Breeding -- 5.4.2 Viral Mediated Gene Transfer -- 5.4.3 Sperm-Mediated Gene Transfer -- 5.4.4 Transposon-Mediated Gene Transfer -- 5.4.5 Pluripotent Stem Cells -- 5.4.5.1 Embryonic Stem Cells -- 5.4.5.2 Embryonic Germ Cells -- 5.4.5.3 Induced Pluripotent Stem Cells (iPS Cells) -- 5.4.6 Spermatogonial Stem Cells -- 5.4.7 Somatic Cell Nuclear Transfer -- 5.4.8 Highly Specific DNA Endonucleases -- 5.5 Analysis of Transgenic Animals -- 5.5.1 Analysis of Integrated Transgenes -- 5.5.2 Transgene Expression Profile -- 5.5.3 Collection, Processing, and Protein Purification -- 5.6 Quality and Safety of the Product -- 5.7 Conclusions and Outlook -- References.

6: Translation of New Technologies in Biomedicines: Shaping the Road from Basic Research to Drug Development and Clinical Application - and Back Again -- 6.1 Drug Discovery and Development -- 6.2 The Nature of Models and the Need for Them -- 6.3 New Technologies Toolbox -- 6.3.1 Use of Existing Knowledge -- 6.3.2 In Chemico and Other Physicochemical Approaches -- 6.3.3 In Silico Methods -- 6.3.3.1 In Silico Methods and Drug Discovery -- 6.3.3.2 In Silico Methods and Toxicology -- 6.3.4 In Vitro Systems -- 6.3.4.1 Cell Fractions -- 6.3.4.2 Cell Monolayer or Supension Cultures -- 6.3.4.3 Co-cultures, Organotypic Cultures, and Reconstituted Tissue Constructs -- 6.3.4.4 Tissue Engineering -- 6.3.4.5 Stem Cells -- 6.3.4.6 Examples of Some Specific In Vitro Systems -- 6.3.4.7 Dynamic Bioreactors -- 6.3.4.8 Multi-organ Systems -- 6.3.4.9 Challenge of Cells, Organs, and Organisms on a Chip -- 6.3.4.10 In Vitro Assays -- 6.3.4.11 Coordinated Approach with In Vitro Models: the Vitrocellomics Project -- 6.3.5 High-Throughput Screening -- 6.3.6 High-Content Screening -- 6.3.7 Omics Approaches -- 6.3.7.1 Variety of Omics -- 6.3.7.2 Application of the Omics -- 6.3.7.3 Handling Information Produced by the Omics -- 6.3.8 Systems Modeling and Simulation -- 6.3.8.1 Pharmacokinetic Modeling -- 6.3.8.2 Virtual Tissue Modeling -- 6.3.8.3 Virtual Patient Populations -- 6.3.9 Biomarkers -- 6.3.10 Clinical Imaging -- 6.3.11 Bioinformatics -- 6.4 Strategic Use of the New Technology Tools -- 6.4.1 The Tools -- 6.4.2 The Strategies -- 6.4.3 Systems Biology -- 6.4.4 Involving the Patient -- 6.5 Translation as a Two-Way Process -- 6.6 Concluding Comment -- References -- Part Two: Bringing the Drug into Action - From Downstreaming to Approval -- 7: Overview and Classification of Approved Recombinant Drugs -- 7.1 Introduction.

7.2 Classification of Recombinant Drugs from a Technical Point of View -- 7.3 Expression Systems -- 7.4 Proteins Derived from Modified Genes -- 7.5 Artificial Proteins -- 7.6 Post-expression Modifications of Recombinant Proteins -- 7.7 Biosimilars -- References -- 8: Downstream Processing -- 8.1 Introduction -- 8.2 General Principles of DSP -- 8.3 Clarification -- 8.3.1 Centrifugation -- 8.3.2 Filtration -- 8.3.3 Increasing the Efficiency of Clarification -- 8.4 Chromatography -- 8.4.1 Column Chromatography -- 8.4.2 Membrane Chromatography -- 8.4.3 Capture Chromatography -- 8.4.4 Polishing Chromatography -- 8.4.5 Continuous Chromatography -- 8.5 Ultrafiltration/Diafiltration, and Virus Filtration -- 8.5.1 Ultrafiltration/Diafiltration -- 8.5.2 Virus Filtration -- 8.6 Crystallization -- 8.7 Recent Developments in Downstream Processing -- References -- 9: Characterization of Recombinant Proteins -- 9.1 Introduction -- 9.2 Physical Chemical Characterization -- 9.2.1 Spectroscopic Methods -- 9.2.1.1 Ultraviolet Absorption Spectroscopy -- 9.2.1.2 Fluorescence Spectroscopy -- 9.2.1.3 Fourier Transform Infrared Spectroscopy -- 9.2.2 Chromatographic Methods -- 9.2.2.1 Size-Exclusion Chromatography -- 9.2.2.2 Reversed-Phase Chromatography -- 9.2.2.3 Hydrophilic Interaction Chromatography -- 9.2.2.4 Ion-Exchange Chromatography -- 9.2.3 Electrophoretic Methods -- 9.2.3.1 Gel Electrophoresis -- 9.2.3.2 Capillary Electrophoresis -- 9.2.4 Other Physical Chemical Methods -- 9.2.5 Mass Spectrometric Analysis of Biopharmaceutical Proteins -- 9.2.5.1 Operating Principle of Mass Spectrometers -- 9.2.5.2 Common Methods for MS Analysis of Biopharmaceuticals -- 9.3 Biological Characterization of Biopharmaceuticals In Vitro -- 9.3.1 Bioassays -- 9.3.1.1 Introduction -- 9.3.1.2 Defining Bioactivity -- 9.3.1.3 Binding Assays -- 9.3.1.4 Bead Array Technology.

9.3.1.5 Immunogenicity Testing -- 9.3.1.6 Cell-Based Assays (CBA) -- 9.3.1.7 Assay Qualification and Validation -- 9.3.1.8 Outlook -- Acknowledgments -- Legals -- References -- 10: Formulation Strategies for Recombinant Protein and Related Biotech Drugs -- 10.1 Introduction -- 10.2 Formulation and Stability of Protein Solutions -- 10.2.1 Dry Formulations -- 10.2.2 Modern Formulation Screening Strategies -- 10.2.3 Analytics -- 10.2.4 Formulation Development for the Market -- 10.2.5 Interface between Downstreaming and "Fill and Finish" -- 10.2.6 Highly Concentrated Protein Formulations -- 10.2.7 New Proteins and Related Formulation Aspects -- 10.2.8 Summary -- 10.3 Formulation of Vaccines -- 10.3.1 Analytics -- References -- 11: Drug Approval in the European Union and United States -- 11.1 Introduction -- 11.2 Regulation within the European Union -- 11.2.1 EU Regulatory Framework -- 11.2.2 EMA -- 11.2.3 New Drug Approval Routes -- 11.2.3.1 Centralized Procedure -- 11.3 Regulation in the United States of America -- 11.3.1 CDER and CBER -- 11.3.2 Approvals Procedure -- 11.4 International Regulatory Harmonization -- 11.5 Regulation of Biosimilars -- 12: Patents in the Pharmaceutical Biotechnology Industry: Legal and Ethical Issues -- 12.1 Introduction -- 12.2 Patent Law -- 12.2.1 What Is a Patent? -- 12.2.2 How Does One Obtain a Patent? -- 12.2.3 What Is the Proper Subject Matter for a Patent? -- 12.2.4 Types of Patents in Pharmaceutical Biotechnology -- 12.2.5 Patent Infringement -- 12.2.6 International Patent Law -- 12.3 Ethical and Policy Issues in Biotechnology Patents -- 12.3.1 No Patents on Nature -- 12.3.2 Threats to Human Dignity -- 12.3.3 Access to Technology -- 12.3.4 Benefit Sharing -- 12.4 Conclusion -- References -- 13: Biosimilar Drugs -- 13.1 Introduction -- 13.2 Recombinant Therapeutic Proteins -- 13.3 Definition of Biosimilars.

13.4 Regulatory Situation.