About the Editors xvii List of Contributors xix Series Preface xxv Preface xxvii 1 Continuous Manufacturing: Definitions and Engineering Principles 1 Johannes Khinast and Massimo Bresciani 1.1 Introduction 1 1.1.1 Definition of Continuous Manufacturing 1 1.1.2 Continuous Manufacturing in the Pharmaceutical Industry 2 1.1.3 Our View of Continuous Manufacturing 3 1.

1.4 Regulatory Environment 8 1.2 Advantages of Continuous Manufacturing 8 1.2.1 Flexibility 8 1.2.2 Effect on the Supply Chain 8 1.2.

3 Agility and Reduced Scale-up Efforts 9 1.2.4 Real-Time Quality Assurance and Better Engineered Systems 9 1.2.5 Decentralized Manufacturing 10 1.2.6 Individualized Manufacturing 10 1.2.

7 Reduced Floor Space and Investment Costs 10 1.2.8 More Efficient Chemistries 10 1.2.9 Societal Benefits 11 1.3 Engineering Principles of Continuous Manufacturing 11 1.3.1 Pharmaceutical Unit Operations 11 1.

3.2 Fundamentals of Process Modeling 15 1.3.3 Balance Equations for Mass, Species, Energy and Momentum 16 1.3.4 Residence Time Distribution 20 1.3.5 Classical Reactor Types as a Basis for Process Understanding 21 1.

3.6 Process Control, Modeling and PAT 24 1.3.7 Scale-Up 26 1.3.8 Dimensioning 27 1.4 Conclusion 28 References 30 2 Process Simulation and Control for Continuous Pharmaceutical Manufacturing of Solid Drug Products 33 Marianthi Ierapetritou, M. Sebastian Escotet-Espinoza and Ravendra Singh 2.

1 Introduction 33 2.1.1 Scope and Motivation 33 2.1.2 Process Simulation 34 2.1.3 Process Control 36 2.2 Pharmaceutical Solid Dosage Manufacturing Processes 38 2.

2.1 Overview 38 2.2.2 Continuous Manufacturing Processes 38 2.2.3 Continuous Process Equipment 39 2.3 Mathematical Modeling Approaches 44 2.3.

1 First Principle "Mechanistic" Models 44 2.3.2 Multi-dimensional Population Balance Models 44 2.3.3 Engineering or Phenomenological Models 46 2.3.4 Empirical and Reduced Order Models 47 2.4 Unit Operations Models 48 2.

4.1 Feeders 48 2.4.2 Blenders (Mixers) 56 2.4.3 Tablet Press 63 2.4.4 Roller Compactor 67 2.

4.5 Wet Granulation 71 2.4.6 Drying 75 2.4.7 Milling/Co-milling 76 2.4.8 Flowsheet Modeling 77 2.

5 Process Control of Continuous Solid-based Drug Manufacturing 81 2.5.1 Process Control Basics 83 2.5.2 Control Design of Continuous Pharmaceutical Manufacturing Process 84 2.6 Summary 93 Acknowledgments 94 References 94 3 Regulatory and Quality Considerations for Continuous Manufacturing 107 Gretchen Allison, Yanxi Tan Cain, Charles Cooney, Tom Garcia, Tara Gooen Bizjak, Oyvind Holte, Nirdosh Jagota, Bekki Komas, Evdokia Korakianiti, Dora Kourti, Rapti Madurawe, Elaine Morefield, Frank Montgomery, Moheb Nasr, William Randolph, Jean-Louis Robert, Dave Rudd and Diane Zezza 3.1 Introduction 108 3.2 Current Regulatory Environment 108 3.

3 Existing Relevant Regulations, Guidelines, and Standards Supporting Continuous Manufacturing 108 3.3.1 ICH Guidelines 108 3.3.2 United States Food and Drug Administration Guidances 109 3.3.3 US FDA Guidance on Process Validation 109 3.3.

4 American Society for Testing and Materials Standards 109 3.3.5 European Union Guidelines 110 3.4 Regulatory Considerations 110 3.4.1 Development Considerations for Continuous Manufacturing 111 3.4.2 Special Considerations for Control Strategy in Continuous Manufacturing 112 3.

4.3 Stability Considerations for Continuous Manufacturing 114 3.5 Quality/GMP Considerations 115 3.5.1 Pharmaceutical Quality Systems 115 3.5.2 Batch Release 115 3.5.

3 Startup and Shutdown Procedures 116 3.5.4 State of Control: Product Collection and In-process Sampling 117 3.5.5 Process Validation and CPV 117 3.5.6 Material Traceability in Continuous Manufacturing 119 3.5.

7 Handling of Raw Material and In-process Material 119 3.5.8 Detection and Treatment for Non-conformity 119 3.5.9 Personnel Procedures and Training 120 3.5.10 Material Carry-over 120 3.5.

11 Material Diversion 120 3.5.12 Production Floor Product Monitoring 121 3.5.13 Raw Material Variability 121 3.5.14 Cleaning Validation 121 3.5.

15 Equipment Failure 122 3.6 Quality Considerations for Bridging Existing Batch Manufacturing to Continuous Manufacturing 122 3.6.1 Physicochemical Equivalence Considerations 123 3.6.2 Bioequivalence Considerations 123 3.7 Glossary and Definitions 123 3.7.

1 Batch Definition 123 3.7.2 21cfr 210.3 124 3.7.3 Cfr 211 124 3.7.4 Ich Q 7 124 3.

7.5 Ich Q 10 124 3.8 General Regulatory References 124 3.8.1 cGMP Guidance 125 4 Continuous Manufacturing of Active Pharmaceutical Ingredients via Flow Technology 127 Svetlana Borukhova and Volker Hessel 4.1 Introduction 127 4.2 Micro Flow Technology 128 4.2.

1 Micromixing 129 4.2.2 Flow Reactors 130 4.2.3 Reaction Activation Tools 130 4.2.4 Downstream Processing 139 4.2.

5 Process Analytical Technology and Automation 142 4.3 Multi-step Synthesis of Active Pharmaceutical Ingredients in Micro Flow 150 4.3.1 Aliskiren 151 4.3.2 Artemisinin 151 4.3.3 Ibuprofen 153 4.

3.4 Gleevec 154 4.3.5 Nabumetone 155 4.3.6 Quinolone Derivative as a Potent 5HT 1B Antagonist 155 4.3.7 Rufinamide 155 4.

3.8 Thioquinazolinone 156 4.4 Larger-scale Syntheses 156 4.4.1 Hydroxypyrrolotriazine (Bristol-Myers-Squibb) 156 4.4.2 2,2-Dimethylchromenes (Bristol-Myers-Squibb) 156 4.4.

3 Fused-Bycyclic Isoxazolidines (Eli Lilly and Company) 158 4.4.4 7-Ethyltryptophol on the Way to Etodolac 158 4.4.5 6-Hydroxybuspirone (Bristol-Myers-Squibb) 159 4.5 Current Industrial Applications 160 4.6 Conclusion and Outlook 161 References 162 5 Continuous Crystallisation 169 Cameron Brown, Thomas McGlone and Alastair Florence 5.1 Introduction 169 5.

2 Principles of Crystallisation 173 5.2.1 Supersaturation 173 5.2.2 Nucleation and Growth 176 5.2.3 Conservation Equations 180 5.3 Crystallisation Process Development 180 5.

4 Continuous Crystallisers and Applications 185 5.4.1 Mixed Suspension Mixed Product Removal 186 5.4.2 MSMPR Cascade 193 5.4.3 Plug Flow Reactors 198 5.4.

4 Impinging Jet 206 5.4.5 Microfluidics 207 5.5 Process Monitoring, Analysis and Control 207 5.5.1 Process Monitoring and Analysis 207 5.5.2 Crystallisation Control Strategies 211 5.

6 Particle Characterisation 213 5.7 Concluding Remarks 215 References 217 6 Continuous Fermentation for Biopharmaceuticals? 227 L. Mears, H. Feldman, F.C. Falco, C. Bach, M. Wu, A.

Nørregaard and K.V. Gernaey 6.1 Introduction 227 6.1.1 Definition of Fermentation 227 6.1.2 Production of Biopharmaceuticals 228 6.

1.3 Structure of Chapter 228 6.2 Operation of Fermentation Systems 229 6.2.1 Comparison of Different Cultivation Systems 229 6.2.2 Monitoring of Continuous Fermentation Processes 232 6.2.

3 Control of Continuous Fermentation Processes 234 6.3 Continuous Fermentation Examples 238 6.3.1 Continuous Ethanol Fermentation 238 6.3.2 Continuous Lactic Acid Fermentation 239 6.3.3 Single Cell Protein Production 240 6.

4 Discussion 241 6.5 Conclusions 243 References 244 7 Integrated Continuous Manufacturing of Biopharmaceuticals 247 Alois Jungbauer and Nikolaus Hammerschmidt 7.1 Background 247 7.1.1 Current Status of Manufacturing of Biopharmaceuticals 247 7.1.2 Challenges to Developing Continuous Processes 249 7.1.

3 Rationale for Continuous Biomanufacturing 250 7.2 Continuous Upstream Processing 251 7.2.1 Cell Lines and Cell Line Stability 251 7.2.2 Perfusion Reactor 252 7.2.3 Cell Retention Devices 252 7.

2.4 Chemostat and Turbidostat 254 7.2.5 Overview of Products Produced by Continuous Upstream Processing 254 7.3 Continuous Downstream Processing 257 7.3.1 Overview of Unit Operations 257 7.3.

2 Continuous Centrifuges 257 7.3.4 Continuous Chromatography 260 7.3.5 Continuous Precipitation 263 7.3.6 Continuous Formulation 266 7.4 Process Integration and Single Use Technology 266 7.

4.1 Disposable Bioreactors 268 7.4.2 Disposable Unit Operations in Downstream Processing 268 7.4.3 Full Process Train 270 7.5 Process Monitoring and Control 270 7.6 Process Economics of Continuous Manufacturing 274 7.

7 Conclusions 275 Acknowledgments 276 References 276 8 Twin-screw Granulation Process Development: Present Approaches, Understanding and Needs 283 A. Kumar, K.V. Gernaey, I. Nopens and T. De Beer 8.1 Introduction 283 8.2 Continuous Wet-granulation using a TSG 284 8.

3 Components of High Shear Wet Granulation in a TSG 287 8.4 Material Transport and Mixing in a TSG 287 8.4.1 Granulation Time in a TSG 288 8.4.2 Mixing in a TSG 291 8.5 Granule Size Evolution During Twin-screw Granulation 294 8.5.

1 Granule Size and Shape Dynamics in a TSG 295 8.5.2 Link Between RTD, Liquid Distribution and GSD in a TSG.