Continuous Manufacturing of Pharmaceuticals

Editors Peter Kleinebudde is Professor for Pharmaceutical Technology at Heinrich-Heine-University Duesseldorf, Germany, and Vice-Dean of the Faculty of Mathematics and Natural Sciences. His main research area is development, production and characterization of solid dosage forms. Johannes Khinast is Professor of Chemical and Pharmaceutical Engineering and Head of the Institute of Process and Particle Engineering at the Graz University of Technology, Austria. Jukka Rantanen is Professor of Pharmaceutical Technology and Engineering at the Department of Pharmacy, University of Copenhagen, Denmark.

• About the Editors xviiList of Contributors xixSeries Preface xxvPreface xxvii1 Continuous Manufacturing: Definitions and Engineering Principles 1Johannes Khinast and Massimo Bresciani1.1 Introduction 11.1.1 Definition of Continuous Manufacturing 11.1.2 Continuous Manufacturing in the Pharmaceutical Industry 21.1.3 Our View of Continuous Manufacturing 31.1.4 Regulatory Environment 81.2 Advantages of Continuous Manufacturing 81.2.1 Flexibility 81.2.2 Effect on the Supply Chain 81.2.3 Agility and Reduced Scale-up Efforts 91.2.4 Real-Time Quality Assurance and Better Engineered Systems 91.2.5 Decentralized Manufacturing 101.2.6 Individualized Manufacturing 101.2.7 Reduced Floor Space and Investment Costs 101.2.8 More Efficient Chemistries 101.2.9 Societal Benefits 111.3 Engineering Principles of Continuous Manufacturing 111.3.1 Pharmaceutical Unit Operations 111.3.2 Fundamentals of Process Modeling 151.3.3 Balance Equations for Mass, Species, Energy and Momentum 161.3.4 Residence Time Distribution 201.3.5 Classical Reactor Types as a Basis for Process Understanding 211.3.6 Process Control, Modeling and PAT 241.3.7 Scale-Up 261.3.8 Dimensioning 271.4 Conclusion 28References 302 Process Simulation and Control for Continuous Pharmaceutical Manufacturing of Solid Drug Products 33Marianthi Ierapetritou, M. Sebastian Escotet-Espinoza and Ravendra Singh2.1 Introduction 332.1.1 Scope and Motivation 332.1.2 Process Simulation 342.1.3 Process Control 362.2 Pharmaceutical Solid Dosage Manufacturing Processes 382.2.1 Overview 382.2.2 Continuous Manufacturing Processes 382.2.3 Continuous Process Equipment 392.3 Mathematical Modeling Approaches 442.3.1 First Principle “Mechanistic” Models 442.3.2 Multi-dimensional Population Balance Models 442.3.3 Engineering or Phenomenological Models 462.3.4 Empirical and Reduced Order Models 472.4 Unit Operations Models 482.4.1 Feeders 482.4.2 Blenders (Mixers) 562.4.3 Tablet Press 632.4.4 Roller Compactor 672.4.5 Wet Granulation 712.4.6 Drying 752.4.7 Milling/Co-milling 762.4.8 Flowsheet Modeling 772.5 Process Control of Continuous Solid-based Drug Manufacturing 812.5.1 Process Control Basics 832.5.2 Control Design of Continuous Pharmaceutical Manufacturing Process 842.6 Summary 93Acknowledgments 94References 943 Regulatory and Quality Considerations for Continuous Manufacturing 107Gretchen 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 Zezza3.1 Introduction 1083.2 Current Regulatory Environment 1083.3 Existing Relevant Regulations, Guidelines, and Standards Supporting Continuous Manufacturing 1083.3.1 ICH Guidelines 1083.3.2 United States Food and Drug Administration Guidances 1093.3.3 US FDA Guidance on Process Validation 1093.3.4 American Society for Testing and Materials Standards 1093.3.5 European Union Guidelines 1103.4 Regulatory Considerations 1103.4.1 Development Considerations for Continuous Manufacturing 1113.4.2 Special Considerations for Control Strategy in Continuous Manufacturing 1123.4.3 Stability Considerations for Continuous Manufacturing 1143.5 Quality/GMP Considerations 1153.5.1 Pharmaceutical Quality Systems 1153.5.2 Batch Release 1153.5.3 Startup and Shutdown Procedures 1163.5.4 State of Control: Product Collection and In-process Sampling 1173.5.5 Process Validation and CPV 1173.5.6 Material Traceability in Continuous Manufacturing 1193.5.7 Handling of Raw Material and In-process Material 1193.5.8 Detection and Treatment for Non-conformity 1193.5.9 Personnel Procedures and Training 1203.5.10 Material Carry-over 1203.5.11 Material Diversion 1203.5.12 Production Floor Product Monitoring 1213.5.13 Raw Material Variability 1213.5.14 Cleaning Validation 1213.5.15 Equipment Failure 1223.6 Quality Considerations for Bridging Existing Batch Manufacturing to Continuous Manufacturing 1223.6.1 Physicochemical Equivalence Considerations 1233.6.2 Bioequivalence Considerations 1233.7 Glossary and Definitions 1233.7.1 Batch Definition 1233.7.2 21cfr 210.3 1243.7.3 Cfr 211 1243.7.4 Ich Q 7 1243.7.5 Ich Q 10 1243.8 General Regulatory References 1243.8.1 cGMP Guidance 1254 Continuous Manufacturing of Active Pharmaceutical Ingredients via Flow Technology 127Svetlana Borukhova and Volker Hessel4.1 Introduction 1274.2 Micro Flow Technology 1284.2.1 Micromixing 1294.2.2 Flow Reactors 1304.2.3 Reaction Activation Tools 1304.2.4 Downstream Processing 1394.2.5 Process Analytical Technology and Automation 1424.3 Multi-step Synthesis of Active Pharmaceutical Ingredients in Micro Flow 1504.3.1 Aliskiren 1514.3.2 Artemisinin 1514.3.3 Ibuprofen 1534.3.4 Gleevec 1544.3.5 Nabumetone 1554.3.6 Quinolone Derivative as a Potent 5HT 1B Antagonist 1554.3.7 Rufinamide 1554.3.8 Thioquinazolinone 1564.4 Larger-scale Syntheses 1564.4.1 Hydroxypyrrolotriazine (Bristol–Myers–Squibb) 1564.4.2 2,2-Dimethylchromenes (Bristol–Myers–Squibb) 1564.4.3 Fused-Bycyclic Isoxazolidines (Eli Lilly and Company) 1584.4.4 7-Ethyltryptophol on the Way to Etodolac 1584.4.5 6-Hydroxybuspirone (Bristol-Myers-Squibb) 1594.5 Current Industrial Applications 1604.6 Conclusion and Outlook 161References 1625 Continuous Crystallisation 169Cameron Brown, Thomas McGlone and Alastair Florence5.1 Introduction 1695.2 Principles of Crystallisation 1735.2.1 Supersaturation 1735.2.2 Nucleation and Growth 1765.2.3 Conservation Equations 1805.3 Crystallisation Process Development 1805.4 Continuous Crystallisers and Applications 1855.4.1 Mixed Suspension Mixed Product Removal 1865.4.2 MSMPR Cascade 1935.4.3 Plug Flow Reactors 1985.4.4 Impinging Jet 2065.4.5 Microfluidics 2075.5 Process Monitoring, Analysis and Control 2075.5.1 Process Monitoring and Analysis 2075.5.2 Crystallisation Control Strategies 2115.6 Particle Characterisation 2135.7 Concluding Remarks 215References 2176 Continuous Fermentation for Biopharmaceuticals? 227L. Mears, H. Feldman, F.C. Falco, C. Bach, M. Wu, A. Nørregaard and K.V. Gernaey6.1 Introduction 2276.1.1 Definition of Fermentation 2276.1.2 Production of Biopharmaceuticals 2286.1.3 Structure of Chapter 2286.2 Operation of Fermentation Systems 2296.2.1 Comparison of Different Cultivation Systems 2296.2.2 Monitoring of Continuous Fermentation Processes 2326.2.3 Control of Continuous Fermentation Processes 2346.3 Continuous Fermentation Examples 2386.3.1 Continuous Ethanol Fermentation 2386.3.2 Continuous Lactic Acid Fermentation 2396.3.3 Single Cell Protein Production 2406.4 Discussion 2416.5 Conclusions 243References 2447 Integrated Continuous Manufacturing of Biopharmaceuticals 247Alois Jungbauer and Nikolaus Hammerschmidt7.1 Background 2477.1.1 Current Status of Manufacturing of Biopharmaceuticals 2477.1.2 Challenges to Developing Continuous Processes 2497.1.3 Rationale for Continuous Biomanufacturing 2507.2 Continuous Upstream Processing 2517.2.1 Cell Lines and Cell Line Stability 2517.2.2 Perfusion Reactor 2527.2.3 Cell Retention Devices 2527.2.4 Chemostat and Turbidostat 2547.2.5 Overview of Products Produced by Continuous Upstream Processing 2547.3 Continuous Downstream Processing 2577.3.1 Overview of Unit Operations 2577.3.2 Continuous Centrifuges 2577.3.4 Continuous Chromatography 2607.3.5 Continuous Precipitation 2637.3.6 Continuous Formulation 2667.4 Process Integration and Single Use Technology 2667.4.1 Disposable Bioreactors 2687.4.2 Disposable Unit Operations in Downstream Processing 2687.4.3 Full Process Train 2707.5 Process Monitoring and Control 2707.6 Process Economics of Continuous Manufacturing 2747.7 Conclusions 275Acknowledgments 276References 2768 Twin-screw Granulation Process Development: Present Approaches, Understanding and Needs 283A. Kumar, K.V. Gernaey, I. Nopens and T. De Beer8.1 Introduction 2838.2 Continuous Wet-granulation using a TSG 2848.3 Components of High Shear Wet Granulation in a TSG 2878.4 Material Transport and Mixing in a TSG 2878.4.1 Granulation Time in a TSG 2888.4.2 Mixing in a TSG 2918.5 Granule Size Evolution During Twin-screw Granulation 2948.5.1 Granule Size and Shape Dynamics in a TSG 2958.5.2 Link Between RTD, Liquid Distribution and GSD in a TSG 2958.6 Model-based Analysis of Twin-screw Granulation 2988.6.1 Modelling RTD in a TSG 2988.6.2 Tracking GSD in a TSG using PBM 3008.7 Towards Generic Twin-screw Granulation Knowledge 3028.7.1 Regime Map Approach 3038.7.2 Particle-scale Simulation using DEM 3058.8 Strengths and Limitations of the Current Approaches in TSG Studies 3078.9 Glossary 308References 3099 Continuous Line Roller Compaction 313Ossi Korhonen9.1 Roller Compaction 3139.2 Main Components of a Roller Compactor 3139.3 Theory of Powder Densification in Roller Compaction 3159.4 Johanson Model 3179.5 Modified Johanson Model 3199.6 Experimental Observations of Pressure Distribution from Instrumented Roller Compactors 3229.7 Off-line Characterization of Ribbon Quality 3249.8 In-line Monitoring of Roller Compaction Process 3269.9 Formulative Aspects of Roller Compaction 3289.10 Roller Compaction as a Unit Operation in Continuous Manufacturing 3309.11 Process Control of Continuous Roller Compaction 3329.12 Conclusions 333References 33410 Continuous Melt Extrusion and Direct Pelletization 337Stephan Laske, Theresa Hörmann, Andreas Witschnigg, Gerold Koscher, Patrick Wahl, Wen Kai Hsiao and Johannes Khinast10.1 Introduction 33710.2 The Extruder 33810.3 Feeding 34110.3.1 Solid Feeding 34110.3.2 LIW Screw Feeders 34210.4 Twin-screw Extrusion 34510.4.1 Counter-rotating Twin-screw Extruder 34610.4.2 Co-rotating Twin-screw Extruder 34710.5 Operation Point 34710.6 Downstream Processing 34910.6.1 Direct Shaping of Final Product 35010.6.2 Intermediate Products 35210.7 Continuous Manufacturing with HME 35610.7.1 Process Understanding 35610.7.2 Control Strategy 35610.7.3 State of Control 35710.7.4 Diversion of Material 35710.8 PAT for HME 36010.8.1 Near-infrared Spectroscopy 36010.8.2 Raman Spectroscopy 36010.8.3 Chemical Imaging 36110.8.4 Particle Size Analysis 36110.8.5 Optical Coherence Tomography 36110.8.6 Data Processing 36210.9 Process Integration into Computerized Systems 36210.9.1 IT Structure of Supervisory Control Systems 36410.9.2 Real-time Release Testing 36510.10 Conclusion 365References 36611 Continuous Processing in the Pharmaceutical Industry: Status and Perspective 369Richard Steiner and Maik Jornitz11.1 Industry Drivers for Continuous Processing: Competitive Advantages 36911.2 Continuous Manufacturing in Bioprocessing 37111.2.1 Continuous Bioprocessing Enablers and Guidance 37111.2.2 Process Technologies 37211.2.3 Examples of Continuous Manufacturing 37611.2.4 Economic and Design Implications 37711.3 Continuous Manufacturing for Oral Solid Dosage Forms 38111.3.1 Industry Approaches to the Implementation of cm 38111.3.2 Typical Installation Layouts 38311.3.3 Economic Justification and Business Excellence 38711.4 The Pharmaceutical Supply Chain of the Future 39511.4.1 Portable, Continuous, Miniature and Modular 39511.4.2 The PCMM Concept 39611.4.3 Discussion 39911.5 Conclusion 400Acknowledgments 401References 40112 Design of an Integrated Continuous Manufacturing System 405Sarang S. Oka, M. Sebastian Escotet-Espinoza, Ravendra Singh, James V. Scicolone, Douglas B. Hausner, Marianthi Ierapetritou and Fernando J. Muzzio12.1 Introduction 40512.2 Step 1: Rough Conceptual Design 40612.2.1 Type of Product 40612.2.2 Type of Manufacturing Route – Direct Compaction, Wet Granulation or Dry Granulation 40712.2.3 Flexible or Dedicated 40812.2.4 Feeding Multiple Ingredients, Including Pre-blends 40812.2.5 Strategy for Sensing and Control 40912.2.6 Regulatory Strategy 40912.3 Step 2: Material Property Screening 41012.4 Step 3: Characterizing Unit Operation Using Actual Process Materials 41212.4.1 Loss in Weight Feeders 41212.4.2 Continuous Blenders 41512.5 Step 4: Develop and Calibrate Unit Operation Models Including Process Materials 42212.5.1 Application of the Model Development Algorithm in Pharmaceutical Problems 42212.5.2 Recommendations for Developing a Unit Operation Model that Incorporates the Effects of Material Properties 42312.6 Step 5: Develop an Integrated Model of an Open Loop System 42412.6.1 Model Integration Basics 42512.6.2 General Algorithm for Building an Integrated Model 42512.7 Step 6: Examine Open Loop Performance of the Process 42712.8 Step 7: Develop/Fine Tune PAT Methods for Appropriate Unit Operations 42912.9 Step 8: Implement Open Loop Kit with PAT and IPCs Enabled 43012.10 Step 9: Design of the Control Architecture 43212.11 Step 10: Develop Integrated Model of Closed Loop System 43612.12 Step 11: Implementation and Verification of the Control Framework 43812.13 Step 12: Characterize and Verify Closed Performance 44012.14 Conclusions 442References 44313 End to End Continuous Manufacturing: Integration of Unit Operations 447R. Lakerveld, P. L. Heider, K. D. Jensen, R. D. Braatz, K. F. Jensen, A. S. Myerson, and B. L. Trout13.1 Introduction 44713.2 Process Description 44813.2.1 Specific Benefits Obtained as a Result of cm 45213.3 System Dynamics 45213.3.1 Model-based Design and Control are the Governing Concepts in cm 45213.3.2 The Absence of True Steady-state Operation and the Implications for Product Quality Control 45313.3.3 Plant-wide Control for CM: Disentanglement of Times Scales and Control Objectives 45513.3.4 Residence Time Distribution of a CM Process: Impact of Recycling 45613.3.5 Disturbances, Nonlinearities, and Delays: Implications for Control 46013.3.6 Startup and Shutdown Procedures 46413.3.7 Buffering 46513.4 Process Monitoring and Control 46813.4.1 PAT Use in the Integrated Continuous Manufacturing Process 46813.4.2 Soft Sensors and Prediction of Future Performance 46913.5 Outlook: Opportunities for Novel Unit Operations and System Configurations 47113.6 Summary and Closing Thoughts 477References 48014 Methodology for Economic and Technical Comparison of Continuous and Batch Processes to Enhance Early Stage Decision-making 485Isabella Aigner, Wen-Kai Hsiao, Diana Dujmovic, Sven Stegemann and Johannes Khinast14.1 Introduction 48514.2 Technical–Economic Evaluation Methodology 48614.2.1 Definition of the System Boundaries and Performance Targets 48814.2.2 Modeling of the Process Chains 48914.2.3 Performing Technical Feasibility and Risk Assessment 49014.2.4 Evaluation of the Process Options 49214.2.5 Calculation of Process Costs, Cost Comparison and Interpretation 49814.2.6 Technology–Economic Profiling and Interpretation of Results 49814.2.7 Performing Scenario, Sensitivity and Uncertainty Analysis 50214.3 Conclusion 502References 50415 Drivers for a Change – Manufacturing of Future Medicines for Personalized Drug Therapies 507Jukka Rantanen and Jörg Breitkreutz15.1 Introduction 50715.2 Personalized Medicine 50815.2.1 Therapy Based on Individualized Needs for Different Patient Groups 50815.2.2 Point of Care Diagnostics 50915.3 Flexible Dosing with Innovative Products 51015.4 Future Health Care Scenario 51315.4.1 Enabling Manufacturing Technologies and Materials Science 51315.4.2 The Regulatory Environment 51815.4.3 Supply Chain 520References 52116 Perspectives of Printing Technologies in Continuous Drug Manufacturing 525Niklas Sandler and Petri Ihalainen16.1 Introduction 52516.1.1 Printing Technologies – Enablers of Continuous Drug Manufacturing Approaches 52516.2 Inkjet (Microdrop Generation Techniques) 52716.2.1 Inkjet – Technical Description 52716.2.2 Ink Development and Printability 53116.2.3 Pharmaceutical Applications of Inkjet Printing 53316.3 Flexographic Printing 53516.3.1 Flexography – Technique Description 53516.3.2 Pharmaceutical Applications of Flexographic Printing 53716.4 Formulation Approaches for Inkjet and Flexography 53816.5 Process Control and Process Analytical Technology for Continuous Printing Applications 53916.6 From Laboratory-scale Printing Towards an Industrial Scale 54016.7 Three-dimensional Printing/Additive Manufacturing 54116.7.1 From Prototyping to Large-scale Manufacturing 54216.7.2 Fused Deposition Modeling or Fused Filament Fabrication 54316.7.3 Feedstock Material for FDM Printing 54416.7.4 3D Printing Techniques used in the Biomedical and Pharmaceutical Area 545References 54617 Development of Liquid Dispensing Technology for the Manufacture of Low Dose Drug Products 551Allan Clarke and Dave Doughty17.1 Introduction 55117.2 Background 55217.3 Goals for the LDT Program 55417.4 Overview of LDT 55517.4.1 Formulation Overview 55517.4.2 LDT Platforms 55717.5 LDT Machine Design Details 55917.5.1 Commercial Line Operation 55917.5.2 Liquid Dispensing Cell 56017.5.3 Solvent Evaporation 56317.5.4 Inspection Systems on the Commercial Machine for Critical Quality Attributes 56317.5.5 Pad Printing Cell 56517.6 Scale-independence of the LDT Technology 56617.7 Real-time Release Potential 56717.8 Occupational Health, Environmental and Cleaning Considerations 57017.8.1 Occupational Health 57017.8.2 Environmental Controls/Cleaning 57217.9 Conclusion 573Acknowledgments 574References 574Index 577