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Author:   Stefan Behme
Publisher:   Wiley-VCH Verlag GmbH
Imprint:   Blackwell Verlag GmbH
Edition:   2nd Edition
Dimensions:   Width: 18.00cm , Height: 2.80cm , Length: 25.10cm
Weight:   0.988kg
ISBN:  

9783527337668

ISBN 10:   3527337660
Pages:   456
Publication Date:   25 March 2015
Audience:   Professional and scholarly ,  Professional & Vocational
Replaced By:   9783527349470
Format:   Hardback
Publisher's Status:   Active
Availability:   To order  
Stock availability from the supplier is unknown. We will order it for you and ship this item to you once it is received by us.

Table of Contents

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 by FDA 219 Part V: Pharmaceutical Law 223 7 Pharmaceutical Law and Regulatory Authorities 225 7.1 Fields of Pharmaceutical Law 225 7.2 Bindingness of Regulations 226 7.3 Authorities, Institutions, and Their Regulations 228 7.3.1 FDA 228 7.3.2 EMA 231 7.3.3 German Authorities 233 7.3.4 Japanese Authorities 235 7.3.5 Authorities of Growth Markets 236 7.3.6 Other Important Institutions 237 7.4 Official Enforcement of Regulations 240 7.5 Drug Approval 242 Appendix B Case Study Part 5: Clinical Trials for Protein Products 245 B.1 Mabthera®/Rituxan® 245 B.2 Enbrel® 246 B.3 Remicade®Infliximab 247 B.4 Humira®40 mg 248 B.5 Lucentis® 249 B.6 Zaltrap® 249 Part VI: Production Facilities 251 8 Facility Design 253 8.1 Basic Principles 253 8.2 GMP-Compliant Plant Design 256 8.2.1 Production Flow Diagram 258 8.2.2 Conceptual Plant Layout 259 8.2.3 GMP Flow Analysis 263 8.2.4 Zoning Concept 266 8.3 Basic Concepts for Production Plants 270 8.3.1 Single- and Multiproduct Plants 271 8.3.2 Fractal and Integrated Configuration 274 8.3.3 Flexible and Fixed Piping 275 8.3.4 Steel Tanks and Disposable Equipment 277 8.4 Clean and Plant Utilities 278 8.4.1 Clean Utilities 278 8.4.2 Plant Utilities 285 8.4.3 Waste Management 288 8.5 Equipment Cleaning 289 8.6 Clean-Rooms 290 8.6.1 Separation of Zones by Clean-Room Design 291 8.6.2 Finishing of Floors,Walls, and Ceilings 293 8.6.3 HVAC Installations 294 8.6.4 Qualification 295 8.7 Automation 296 8.8 QC Laboratories 297 8.9 Location Factors 298 8.9.1 Cost 298 8.9.2 Personnel 299 8.9.3 Permitting 299 8.9.4 Synergies with Existing Facilities or Units 299 8.9.5 Logistics 299 8.9.6 Know-How and Intellectual Property Protection 300 8.9.7 Other Risks 300 8.9.8 Market Access 300 8.9.9 Language and Culture 300 9 Planning, Construction, and Commissioning of a Manufacturing Plant 301 9.1 Steps of the Engineering Project 301 9.1.1 Planning 302 9.1.2 Construction 303 9.1.3 Commissioning, Qualification, Validation 305 9.2 Project Schedules 308 9.3 Cost Estimates 309 9.4 Organization of an Engineering Project 311 9.4.1 Expert Groups Involved 311 9.4.2 Role and Selection of Contractors 311 9.4.3 Contracts and Scope Changes 312 9.5 Successful Execution of an Engineering Project 316 9.6 Legal Aspects of Facility Engineering 317 9.6.1 Health, Safety, and Environmental Law 318 9.6.2 Building Law 319 Part VII: Economy 321 10 Production Costs 323 10.1 Drug Life Cycle 323 10.2 Position of the Manufacturing Costs in the Overall Cost Framework 327 10.3 Basic Principles of Cost Calculation 329 10.3.1 Nominal Accounting – Actual Accounting 330 10.3.2 Cost Accounting – Profit and Loss Accounting 330 10.3.3 Direct Costs – Indirect Costs 330 10.3.4 Fixed Costs – Variable Costs 331 10.3.5 Relevant and Irrelevant Costs 333 10.3.6 Cost Type, Cost Center, and Cost Unit 333 10.4 Costs of Biotechnological Manufacturing Processes 334 10.4.1 Capital Costs 335 10.4.2 Operating Costs 337 10.5 Accounting Methods 338 10.5.1 Cost Accounting 347 10.5.2 Profit and Loss Accounting 350 11 Investments 353 11.1 Basic Principles 354 11.1.1 Investment Targets 354 11.1.2 Types of Investments 355 11.1.3 Decision Processes 357 11.2 Value–Benefit Analysis 361 11.3 Investment Appraisal 362 11.3.1 Static Methods 366 11.3.2 Dynamic Methods 367 11.4 Dynamic Payback Time 369 12 Production Concept 371 12.1 Capacity Planning 371 12.2 Dilemma of In-House Manufacturing 374 12.3 Aspects of Manufacturing Outsourcing 377 12.3.1 Types of Cooperation 378 12.3.2 Contractual Agreements 379 12.3.3 Technology Transfer 384 12.3.4 Time Schedules 386 12.4 Make-or-Buy Analysis 387 12.5 Process Optimization after Market Launch 389 12.6 Supply-Chain Management 391 12.6.1 Security of Supply 393 12.6.2 Performance Management 396 Appendix C Examples Part 7: Manufacturing Cost Calculation 399 C.1 Introduction 399 C.2 Basic Assumptions for Both Production Processes 399 C.3 Step 1: Production of Product 1 in Dedicated Facility 399 C.3.1 Cost Structure 400 C.3.2 Product Costs 401 C.3.3 Idle Costs 401 C.3.4 Unit Price Based on Facility Usage 401 C.4 Step 2: Addition of a Second Product 402 C.4.1 Costs of Products 403 C.4.2 Evaluation of Manufacturing Options 404 References 407 Further Reading 407 Biotechnology General 407 Fermentation 408 Purification 408 Aseptic Filling and Lyophilization 408 Bioanalytics 408 Regulatory 408 Pharmacy and Clinical Development 409 Quality and Validation 409 Good Manufacturing Practice 410 Facility Design 410 Clean Rooms 410 Project Management 410 Engineering 410 Economy 411 Weblinks 411 Index 413

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Author Information

"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."

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