Manufacturing of Pharmaceutical Proteins

Dr. Stefan Behme is the department head of Strategic Sourcing Finished Products, Contract Manufacturing at Bayer Healthcare, Berlin. Before that he worked with biotech operations of Bayer, taking care for external manufacturing cooperations for biotechnological production. Stefan started his industrial career with Bayer in the engineering department, managing healthcare investment projects in Germany and the US. From 2006 through 2010 Stefan worked as lecturer at the Universitys of Dortmund (Germany) and Berlin teaching GMP aspects of biopharmaceutical manufacturing and production processes in life sciences. In 2009 he published the book "Manufacturing of Pharmaceutical Proteins - from Technology to Economy". Stefan received his Master's degree in chemical engineering and worked after that as assistant teacher in the field of macromolecular thermodynamics at the Technical University of Berlin where he also earned his PhD degree.

Preface XIX Preface to First Edition XXI List of Abbreviations XXIII Part I: Introduction 1 1 Biopharmaceutical Production: Value Creation, Product Types, and Biological Basics Introduction 3 1.1 Role of Production in Pharmaceutical Biotechnology 3 1.1.1 Relationship Between Production and Development 6 1.1.2 Relationship Between Production and Marketing 8 1.2 Product Groups 10 1.2.1 Vaccines 11 1.2.2 Pharmaceuticals from Blood and Organs 11 1.2.3 Recombinant Therapeutic Proteins 13 1.2.4 Cell and Gene Therapeutics 13 1.2.5 Antibiotics 16 1.3 Basics of Biology 16 1.3.1 Cells and Microorganisms 17 1.3.2 The Four Molecular Building Blocks of Biochemistry 25 Part II: Technology 33 2 Manufacturing Process 35 2.1 Role of the Manufacturing Process in Biotechnology 35 2.2 Process Schematic and Evaluation 37 2.2.1 Drug Substance Manufacturing 38 2.2.2 Drug Product Manufacturing 40 2.2.3 Key Factors for Process Evaluation 41 2.3 Cell Bank 43 2.3.1 Expression Systems 43 2.3.2 Microbial Systems 44 2.3.3 Manufacturing and Storage of the Cell Bank 46 2.4 Fermentation 48 2.4.1 Basic Principles 48 2.4.2 Technologies and Equipment 56 2.4.3 Raw Materials and Processing Aids 61 2.4.4 Overview of Fermentation 63 2.5 Purification 64 2.5.1 Basic Principles 65 2.5.2 Technologies for Cell Separation and Product Isolation 73 2.5.3 Technologies for Final Purification 80 2.5.4 Raw Materials and Processing Aids 91 2.5.5 Overview of Purification 94 2.6 Formulation and Filling 96 2.6.1 Basic Principles 96 2.6.2 Freeze-Drying 98 2.7 Labeling and Packaging 99 3 Analytics 103 3.1 Role of Analytics in Biotechnology 103 3.2 Product Analytics 105 3.2.1 Identity 107 3.2.2 Content 107 3.2.3 Purity 109 3.2.4 Activity 109 3.2.5 Appearance 112 3.2.6 Stability 112 3.2.7 Quality Criteria of Analytical Methods 114 3.2.8 Analytical Methods 115 3.3 Process Analytics 132 3.3.1 Fermentation 132 3.3.2 Purification 133 3.3.3 Formulation and Packaging 134 3.4 Environmental Monitoring 135 3.5 Raw Material Testing 137 3.6 Product Comparability 137 Part III: Pharmacy 141 4 Pharmacology and Drug Safety 143 4.1 Action of Drugs in Humans 144 4.1.1 Pharmacokinetics 145 4.1.2 Pharmacodynamics 149 4.2 Routes and Forms of Administration 152 4.3 Drug Study 153 4.3.1 Pre-Clinical Study 155 4.3.2 Clinical Study 157 4.4 Path of the Drug from the Manufacturer to Patients 162 4.5 Drug Safety 164 4.5.1 Causes and Classification of Side-Effects 165 4.5.2 Methods for Supervising Drug Safety (Pharmacovigilance) 167 4.5.3 Measures upon Incidence of Adverse Reactions 168 Part IV: Quality Assurance 171 5 Fundamentals of Quality Assurance 173 5.1 Basic Principles 173 5.2 Benefit of Quality Assurance Activities 174 5.3 Quality Management According to ISO 9000 176 5.3.1 Fields of Activity 176 5.4 Structure of Quality Management Systems 178 5.5 Quality Management System Components in the Pharmaceutical Area 180 5.5.1 Documentation 180 5.5.2 Failure Prevention and Correction 181 5.5.3 Responsibility of Management and Training of Personnel 185 5.5.4 Audits 186 5.5.5 External Suppliers 187 5.5.6 Contract Review 188 5.6 Quality Assurance in Development 189 6 Quality Assurance in Manufacturing 191 6.1 GMP 191 6.1.1 Personnel 196 6.1.2 Premises and Equipment 198 6.1.3 Equipment Qualification 203 6.1.4 Process Validation 206 6.1.5 Computer Validation 208 6.1.6 Documentation 209 6.2 Operative Workflows under GMP Conditions 210 6.2.1 Product Release and Deviation Management 211 6.2.2 Changes in the Manufacturing Process 213 6.3 Production of Investigational Drugs 216 Appendix A Case Study Part 4:Warning Letters