Continuous Manufacturing of Pharmaceuticals

 
 
Wiley (Verlag)
  • erschienen am 14. Juli 2017
  • |
  • 632 Seiten
 
E-Book | ePUB mit Adobe-DRM | Systemvoraussetzungen
978-1-119-00135-5 (ISBN)
 
A comprehensive look at existing technologies and processes for continuous manufacturing of pharmaceuticals
As rising costs outpace new drug development, the pharmaceutical industry has come under intense pressure to improve the efficiency of its manufacturing processes. Continuous process manufacturing provides a proven solution. Among its many benefits are: minimized waste, energy consumption, and raw material use; the accelerated introduction of new drugs; the use of smaller production facilities with lower building and capital costs; the ability to monitor drug quality on a continuous basis; and enhanced process reliability and flexibility. Continuous Manufacturing of Pharmaceuticals prepares professionals to take advantage of that exciting new approach to improving drug manufacturing efficiency.
This book covers key aspects of the continuous manufacturing of pharmaceuticals. The first part provides an overview of key chemical engineering principles and the current regulatory environment. The second covers existing technologies for manufacturing both small-molecule-based products and protein/peptide products. The following section is devoted to process analytical tools for continuously operating manufacturing environments. The final two sections treat the integration of several individual parts of processing into fully operating continuous process systems and summarize state-of-art approaches for innovative new manufacturing principles.
* Brings together the essential know-how for anyone working in drug manufacturing, as well as chemical, food, and pharmaceutical scientists working on continuous processing
* Covers chemical engineering principles, regulatory aspects, primary and secondary manufacturing, process analytical technology and quality-by-design
* Contains contributions from researchers in leading pharmaceutical companies, the FDA, and academic institutions
* Offers an extremely well-informed look at the most promising future approaches to continuous manufacturing of innovative pharmaceutical products
Timely, comprehensive, and authoritative, Continuous Manufacturing of Pharmaceuticals is an important professional resource for researchers in industry and academe working in the fields of pharmaceuticals development and manufacturing.
1. Auflage
  • Englisch
  • Newark
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  • Großbritannien
John Wiley & Sons
  • 32,07 MB
978-1-119-00135-5 (9781119001355)
weitere Ausgaben werden ermittelt
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.
  • Cover
  • Title Page
  • Copyright
  • Contents
  • About the Editors
  • List of Contributors
  • Series Preface
  • Preface
  • Chapter 1 Continuous Manufacturing: Definitions and Engineering Principles
  • 1.1 Introduction
  • 1.1.1 Definition of Continuous Manufacturing
  • 1.1.2 Continuous Manufacturing in the Pharmaceutical Industry
  • 1.1.3 Our View of Continuous Manufacturing
  • 1.1.4 Regulatory Environment
  • 1.2 Advantages of Continuous Manufacturing
  • 1.2.1 Flexibility
  • 1.2.2 Effect on the Supply Chain
  • 1.2.3 Agility and Reduced Scale-up Efforts
  • 1.2.4 Real-Time Quality Assurance and Better Engineered Systems
  • 1.2.5 Decentralized Manufacturing
  • 1.2.6 Individualized Manufacturing
  • 1.2.7 Reduced Floor Space and Investment Costs
  • 1.2.8 More Efficient Chemistries
  • 1.2.9 Societal Benefits
  • 1.3 Engineering Principles of Continuous Manufacturing
  • 1.3.1 Pharmaceutical Unit Operations
  • 1.3.2 Fundamentals of Process Modeling
  • 1.3.3 Balance Equations for Mass, Species, Energy and Momentum
  • 1.3.4 Residence Time Distribution
  • 1.3.5 Classical Reactor Types as a Basis for Process Understanding
  • 1.3.6 Process Control, Modeling and PAT
  • 1.3.7 Scale-Up
  • 1.3.8 Dimensioning
  • 1.4 Conclusion
  • References
  • Chapter 2 Process Simulation and Control for Continuous Pharmaceutical Manufacturing of Solid Drug Products
  • 2.1 Introduction
  • 2.1.1 Scope and Motivation
  • 2.1.2 Process Simulation
  • 2.1.3 Process Control
  • 2.2 Pharmaceutical Solid Dosage Manufacturing Processes
  • 2.2.1 Overview
  • 2.2.2 Continuous Manufacturing Processes
  • 2.2.3 Continuous Process Equipment
  • 2.3 Mathematical Modeling Approaches
  • 2.3.1 First Principle "Mechanistic" Models
  • 2.3.2 Multi-dimensional Population Balance Models
  • 2.3.3 Engineering or Phenomenological Models
  • 2.3.4 Empirical and Reduced Order Models
  • 2.4 Unit Operations Models
  • 2.4.1 Feeders
  • 2.4.2 Blenders (Mixers)
  • 2.4.3 Tablet Press
  • 2.4.4 Roller Compactor
  • 2.4.5 Wet Granulation
  • 2.4.6 Drying
  • 2.4.7 Milling/Co-milling
  • 2.4.8 Flowsheet Modeling
  • 2.5 Process Control of Continuous Solid-based Drug Manufacturing
  • 2.5.1 Process Control Basics
  • 2.5.2 Control Design of Continuous Pharmaceutical Manufacturing Process
  • 2.6 Summary
  • Acknowledgments
  • References
  • Chapter 3 Regulatory and Quality Considerations for Continuous Manufacturing
  • 3.1 Introduction
  • 3.2 Current Regulatory Environment
  • 3.3 Existing Relevant Regulations, Guidelines, and Standards Supporting Continuous Manufacturing
  • 3.3.1 ICH Guidelines
  • 3.3.2 United States Food and Drug Administration Guidances
  • 3.3.3 US FDA Guidance on Process Validation
  • 3.3.4 American Society for Testing and Materials Standards
  • 3.3.5 European Union Guidelines
  • 3.4 Regulatory Considerations
  • 3.4.1 Development Considerations for Continuous Manufacturing
  • 3.4.2 Special Considerations for Control Strategy in Continuous Manufacturing
  • 3.4.3 Stability Considerations for Continuous Manufacturing
  • 3.5 Quality/GMP Considerations
  • 3.5.1 Pharmaceutical Quality Systems
  • 3.5.2 Batch Release
  • 3.5.3 Startup and Shutdown Procedures
  • 3.5.4 State of Control: Product Collection and In-process Sampling
  • 3.5.5 Process Validation and CPV
  • 3.5.6 Material Traceability in Continuous Manufacturing
  • 3.5.7 Handling of Raw Material and In-process Material
  • 3.5.8 Detection and Treatment for Non-conformity
  • 3.5.9 Personnel Procedures and Training
  • 3.5.10 Material Carry-over
  • 3.5.11 Material Diversion
  • 3.5.12 Production Floor Product Monitoring
  • 3.5.13 Raw Material Variability
  • 3.5.14 Cleaning Validation
  • 3.5.15 Equipment Failure
  • 3.6 Quality Considerations for Bridging Existing Batch Manufacturing to Continuous Manufacturing
  • 3.6.1 Physicochemical Equivalence Considerations
  • 3.6.2 Bioequivalence Considerations
  • 3.7 Glossary and Definitions
  • 3.7.1 Batch Definition
  • 3.7.2 21CFR 210.3
  • 3.7.3 CFR 211
  • 3.7.4 ICH Q7
  • 3.7.5 ICH Q10
  • 3.8 General Regulatory References
  • 3.8.1 cGMP Guidance
  • Chapter 4 Continuous Manufacturing of Active Pharmaceutical Ingredients via Flow Technology
  • 4.1 Introduction
  • 4.2 Micro Flow Technology
  • 4.2.1 Micromixing
  • 4.2.2 Flow Reactors
  • 4.2.3 Reaction Activation Tools
  • 4.2.4 Downstream Processing
  • 4.2.5 Process Analytical Technology and Automation
  • 4.3 Multi-step Synthesis of Active Pharmaceutical Ingredients in Micro Flow
  • 4.3.1 Aliskiren
  • 4.3.2 Artemisinin
  • 4.3.3 Ibuprofen
  • 4.3.4 Gleevec
  • 4.3.5 Nabumetone
  • 4.3.6 Quinolone Derivative as a Potent 5HT1B Antagonist
  • 4.3.7 Rufinamide
  • 4.3.8 Thioquinazolinone
  • 4.4 Larger-scale Syntheses
  • 4.4.1 Hydroxypyrrolotriazine (Bristol-Myers-Squibb)
  • 4.4.2 2,2-Dimethylchromenes (Bristol-Myers-Squibb)
  • 4.4.3 Fused-Bycyclic Isoxazolidines (Eli Lilly and Company)
  • 4.4.4 7-Ethyltryptophol on the Way to Etodolac
  • 4.4.5 6-Hydroxybuspirone (Bristol-Myers-Squibb)
  • 4.5 Current Industrial Applications
  • 4.6 Conclusion and Outlook
  • References
  • Chapter 5 Continuous Crystallisation
  • 5.1 Introduction
  • 5.2 Principles of Crystallisation
  • 5.2.1 Supersaturation
  • 5.2.2 Nucleation and Growth
  • 5.2.3 Conservation Equations
  • 5.3 Crystallisation Process Development
  • 5.4 Continuous Crystallisers and Applications
  • 5.4.1 Mixed Suspension Mixed Product Removal
  • 5.4.2 MSMPR Cascade
  • 5.4.3 Plug Flow Reactors
  • 5.4.4 Impinging Jet
  • 5.4.5 Microfluidics
  • 5.5 Process Monitoring, Analysis and Control
  • 5.5.1 Process Monitoring and Analysis
  • 5.5.2 Crystallisation Control Strategies
  • 5.6 Particle Characterisation
  • 5.7 Concluding Remarks
  • References
  • Chapter 6 Continuous Fermentation for Biopharmaceuticals?
  • 6.1 Introduction
  • 6.1.1 Definition of Fermentation
  • 6.1.2 Production of Biopharmaceuticals
  • 6.1.3 Structure of Chapter
  • 6.2 Operation of Fermentation Systems
  • 6.2.1 Comparison of Different Cultivation Systems
  • 6.2.2 Monitoring of Continuous Fermentation Processes
  • 6.2.3 Control of Continuous Fermentation Processes
  • 6.3 Continuous Fermentation Examples
  • 6.3.1 Continuous Ethanol Fermentation
  • 6.3.2 Continuous Lactic Acid Fermentation
  • 6.3.3 Single Cell Protein Production
  • 6.4 Discussion
  • 6.5 Conclusions
  • References
  • Chapter 7 Integrated Continuous Manufacturing of Biopharmaceuticals
  • 7.1 Background
  • 7.1.1 Current Status of Manufacturing of Biopharmaceuticals
  • 7.1.2 Challenges to Developing Continuous Processes
  • 7.1.3 Rationale for Continuous Biomanufacturing
  • 7.2 Continuous Upstream Processing
  • 7.2.1 Cell Lines and Cell Line Stability
  • 7.2.2 Perfusion Reactor
  • 7.2.3 Cell Retention Devices
  • 7.2.4 Chemostat and Turbidostat
  • 7.2.5 Overview of Products Produced by Continuous Upstream Processing
  • 7.3 Continuous Downstream Processing
  • 7.3.1 Overview of Unit Operations
  • 7.3.2 Continuous Centrifuges
  • 7.3.3 Continuous Filtration
  • 7.3.4 Continuous Chromatography
  • 7.3.5 Continuous Precipitation
  • 7.3.6 Continuous Formulation
  • 7.4 Process Integration and Single Use Technology
  • 7.4.1 Disposable Bioreactors
  • 7.4.2 Disposable Unit Operations in Downstream Processing
  • 7.4.3 Full Process Train
  • 7.5 Process Monitoring and Control
  • 7.6 Process Economics of Continuous Manufacturing
  • 7.7 Conclusions
  • Acknowledgments
  • References
  • Chapter 8 Twin-screw Granulation Process Development: Present Approaches, Understanding and Needs
  • 8.1 Introduction
  • 8.2 Continuous Wet-granulation using a TSG
  • 8.3 Components of High Shear Wet Granulation in a TSG
  • 8.4 Material Transport and Mixing in a TSG
  • 8.4.1 Granulation Time in a TSG
  • 8.4.2 Mixing in a TSG
  • 8.5 Granule Size Evolution During Twin-screw Granulation
  • 8.5.1 Granule Size and Shape Dynamics in a TSG
  • 8.5.2 Link Between RTD, Liquid Distribution and GSD in a TSG
  • 8.6 Model-based Analysis of Twin-screw Granulation
  • 8.6.1 Modelling RTD in a TSG
  • 8.6.2 Tracking GSD in a TSG using PBM
  • 8.7 Towards Generic Twin-screw Granulation Knowledge
  • 8.7.1 Regime Map Approach
  • 8.7.2 Particle-scale Simulation using DEM
  • 8.8 Strengths and Limitations of the Current Approaches in TSG Studies
  • 8.9 Glossary
  • References
  • Chapter 9 Continuous Line Roller Compaction
  • 9.1 Roller Compaction
  • 9.2 Main Components of a Roller Compactor
  • 9.3 Theory of Powder Densification in Roller Compaction
  • 9.4 Johanson Model
  • 9.5 Modified Johanson Model
  • 9.6 Experimental Observations of Pressure Distribution from Instrumented Roller Compactors
  • 9.7 Off-line Characterization of Ribbon Quality
  • 9.8 In-line Monitoring of Roller Compaction Process
  • 9.9 Formulative Aspects of Roller Compaction
  • 9.10 Roller Compaction as a Unit Operation in Continuous Manufacturing
  • 9.11 Process Control of Continuous Roller Compaction
  • 9.12 Conclusions
  • References
  • Chapter 10 Continuous Melt Extrusion and Direct Pelletization
  • 10.1 Introduction
  • 10.2 The Extruder
  • 10.3 Feeding
  • 10.3.1 Solid Feeding
  • 10.3.2 LIW Screw Feeders
  • 10.4 Twin-screw Extrusion
  • 10.4.1 Counter-rotating Twin-screw Extruder
  • 10.4.2 Co-rotating Twin-screw Extruder
  • 10.5 Operation Point
  • 10.6 Downstream Processing
  • 10.6.1 Direct Shaping of Final Product
  • 10.6.2 Intermediate Products
  • 10.7 Continuous Manufacturing with HME
  • 10.7.1 Process Understanding
  • 10.7.2 Control Strategy
  • 10.7.3 State of Control
  • 10.7.4 Diversion of Material
  • 10.8 PAT for HME
  • 10.8.1 Near-infrared Spectroscopy
  • 10.8.2 Raman Spectroscopy
  • 10.8.3 Chemical Imaging
  • 10.8.4 Particle Size Analysis
  • 10.8.5 Optical Coherence Tomography
  • 10.8.6 Data Processing
  • 10.9 Process Integration into Computerized Systems
  • 10.9.1 IT Structure of Supervisory Control Systems
  • 10.9.2 Real-time Release Testing
  • 10.10 Conclusion
  • References
  • Chapter 11 Continuous Processing in the Pharmaceutical Industry: Status and Perspective
  • 11.1 Industry Drivers for Continuous Processing: Competitive Advantages
  • 11.2 Continuous Manufacturing in Bioprocessing
  • 11.2.1 Continuous Bioprocessing Enablers and Guidance
  • 11.2.2 Process Technologies
  • 11.2.3 Examples of Continuous Manufacturing
  • 11.2.4 Economic and Design Implications
  • 11.3 Continuous Manufacturing for Oral Solid Dosage Forms
  • 11.3.1 Industry Approaches to the Implementation of CM
  • 11.3.2 Typical Installation Layouts
  • 11.3.3 Economic Justification and Business Excellence
  • 11.4 The Pharmaceutical Supply Chain of the Future
  • 11.4.1 Portable, Continuous, Miniature and Modular
  • 11.4.2 The PCMM Concept
  • 11.4.3 Discussion
  • 11.5 Conclusion
  • Acknowledgments
  • References
  • Chapter 12 Design of an Integrated Continuous Manufacturing System
  • 12.1 Introduction
  • 12.2 Step 1: Rough Conceptual Design
  • 12.2.1 Type of Product
  • 12.2.2 Type of Manufacturing Route - Direct Compaction, Wet Granulation or Dry Granulation
  • 12.2.3 Flexible or Dedicated
  • 12.2.4 Feeding Multiple Ingredients, Including Pre-blends
  • 12.2.5 Strategy for Sensing and Control
  • 12.2.6 Regulatory Strategy
  • 12.3 Step 2: Material Property Screening
  • 12.4 Step 3: Characterizing Unit Operation Using Actual Process Materials
  • 12.4.1 Loss in Weight Feeders
  • 12.4.2 Continuous Blenders
  • 12.5 Step 4: Develop and Calibrate Unit Operation Models Including Process Materials
  • 12.5.1 Application of the Model Development Algorithm in Pharmaceutical Problems
  • 12.5.2 Recommendations for Developing a Unit Operation Model that Incorporates the Effects of Material Properties
  • 12.6 Step 5: Develop an Integrated Model of an Open Loop System
  • 12.6.1 Model Integration Basics
  • 12.6.2 General Algorithm for Building an Integrated Model
  • 12.7 Step 6: Examine Open Loop Performance of the Process
  • 12.8 Step 7: Develop/Fine Tune PAT Methods for Appropriate Unit Operations
  • 12.9 Step 8: Implement Open Loop Kit with PAT and IPCs Enabled
  • 12.10 Step 9: Design of the Control Architecture
  • 12.11 Step 10: Develop Integrated Model of Closed Loop System
  • 12.12 Step 11: Implementation and Verification of the Control Framework
  • 12.13 Step 12: Characterize and Verify Closed Performance
  • 12.14 Conclusions
  • References
  • Chapter 13 End to End Continuous Manufacturing: Integration of Unit Operations
  • 13.1 Introduction
  • 13.2 Process Description
  • 13.2.1 Specific Benefits Obtained as a Result of CM
  • 13.3 System Dynamics
  • 13.3.1 Model-based Design and Control are the Governing Concepts in CM
  • 13.3.2 The Absence of True Steady-state Operation and the Implications for Product Quality Control
  • 13.3.3 Plant-wide Control for CM: Disentanglement of Times Scales and Control Objectives
  • 13.3.4 Residence Time Distribution of a CM Process: Impact of Recycling
  • 13.3.5 Disturbances, Nonlinearities, and Delays: Implications for Control
  • 13.3.6 Startup and Shutdown Procedures
  • 13.3.7 Buffering
  • 13.4 Process Monitoring and Control
  • 13.4.1 PAT Use in the Integrated Continuous Manufacturing Process
  • 13.4.2 Soft Sensors and Prediction of Future Performance
  • 13.5 Outlook: Opportunities for Novel Unit Operations and System Configurations
  • 13.6 Summary and Closing Thoughts
  • References
  • Chapter 14 Methodology for Economic and Technical Comparison of Continuous and Batch Processes to Enhance Early Stage Decision-making
  • 14.1 Introduction
  • 14.2 Technical-Economic Evaluation Methodology
  • 14.2.1 Definition of the System Boundaries and Performance Targets
  • 14.2.2 Modeling of the Process Chains
  • 14.2.3 Performing Technical Feasibility and Risk Assessment
  • 14.2.4 Evaluation of the Process Options
  • 14.2.5 Calculation of Process Costs, Cost Comparison and Interpretation
  • 14.2.6 Technology-Economic Profiling and Interpretation of Results
  • 14.2.7 Performing Scenario, Sensitivity and Uncertainty Analysis
  • 14.3 Conclusion
  • References
  • Chapter 15 Drivers for a Change - Manufacturing of Future Medicines for Personalized Drug Therapies
  • 15.1 Introduction
  • 15.2 Personalized Medicine
  • 15.2.1 Therapy Based on Individualized Needs for Different Patient Groups
  • 15.2.2 Point of Care Diagnostics
  • 15.3 Flexible Dosing with Innovative Products
  • 15.4 Future Health Care Scenario
  • 15.4.1 Enabling Manufacturing Technologies and Materials Science
  • 15.4.2 The Regulatory Environment
  • 15.4.3 Supply Chain
  • References
  • Chapter 16 Perspectives of Printing Technologies in Continuous Drug Manufacturing
  • 16.1 Introduction
  • 16.1.1 Printing Technologies - Enablers of Continuous Drug Manufacturing Approaches
  • 16.2 Inkjet (Microdrop Generation Techniques)
  • 16.2.1 Inkjet - Technical Description
  • 16.2.2 Ink Development and Printability
  • 16.2.3 Pharmaceutical Applications of Inkjet Printing
  • 16.3 Flexographic Printing
  • 16.3.1 Flexography - Technique Description
  • 16.3.2 Pharmaceutical Applications of Flexographic Printing
  • 16.4 Formulation Approaches for Inkjet and Flexography
  • 16.5 Process Control and Process Analytical Technology for Continuous Printing Applications
  • 16.6 From Laboratory-scale Printing Towards an Industrial Scale
  • 16.7 Three-dimensional Printing/Additive Manufacturing
  • 16.7.1 From Prototyping to Large-scale Manufacturing
  • 16.7.2 Fused Deposition Modeling or Fused Filament Fabrication
  • 16.7.3 Feedstock Material for FDM Printing
  • 16.7.4 3D Printing Techniques used in the Biomedical and Pharmaceutical Area
  • References
  • Chapter 17 Development of Liquid Dispensing Technology for the Manufacture of Low Dose Drug Products
  • 17.1 Introduction
  • 17.2 Background
  • 17.3 Goals for the LDT Program
  • 17.4 Overview of LDT
  • 17.4.1 Formulation Overview
  • 17.4.2 LDT Platforms
  • 17.5 LDT Machine Design Details
  • 17.5.1 Commercial Line Operation
  • 17.5.2 Liquid Dispensing Cell
  • 17.5.3 Solvent Evaporation
  • 17.5.4 Inspection Systems on the Commercial Machine for Critical Quality Attributes
  • 17.5.5 Pad Printing Cell
  • 17.6 Scale-independence of the LDT Technology
  • 17.7 Real-time Release Potential
  • 17.8 Occupational Health, Environmental and Cleaning Considerations
  • 17.8.1 Occupational Health
  • 17.8.2 Environmental Controls/Cleaning
  • 17.9 Conclusion
  • Acknowledgments
  • References
  • Index
  • EULA

Chapter 1
Continuous Manufacturing: Definitions and Engineering Principles


Johannes Khinast1,2 and Massimo Bresciani2

1Institute of Process and Particle Engineering, Graz University of Technology, Austria

2Research Center for Pharmaceutical Engineering, Graz, Austria

1.1 Introduction


1.1.1 Definition of Continuous Manufacturing


In chemical engineering, manufacturing processes can be categorized in different ways, one being the mode of operation with respect to the strategy of feeding and removing materials from a process unit. Specifically, one distinguishes between:

  • Batch manufacturing: All materials are charged before processing and are discharged at the end of processing (example: batch crystallization).
  • Semi-batch manufacturing: Some materials may be continuously added during processing and discharged at the end (example: air feed during batch fermentation).
  • Continuous manufacturing: Material is simultaneously charged and discharged from the process (example: flow-through reactor cell).
  • Quasi-continuous manufacturing: Material is treated in batches, yet removed in defined intervals (example: fluid-batch drying of intermediate batches).
  • Semi-continuous manufacturing: Like continuous manufacturing, but for a defined time period (example: continuous manufacturing on a campaign basis).

Thus, continuous manufacturing (CM) is a method of manufacturing products and processing materials without interruption and with constant material feed and removal. Also tableting, which actually is a batch operation on the scale of a single die, can be viewed as a continuous process. In contrast to batch manufacturing, in a continuous process materials remain constantly in motion, undergo chemical transformations, or are subject to mechanical or heat treatment. Continuous processing on a large scale generally means operating 24 h/day, 7 days/week (often called 24/7) with infrequent (weekly, monthly, semi-annual, or annual) planned maintenance shutdowns. However, continuous manufacturing can also be carried out on a campaign basis, that is, semi-continuous manufacturing of an intermediate chemical compound for a few weeks in a continuous plant.

The concept of continuous processing is not new. It has widely been used across the industry, including oil refining and the production of chemicals, fertilizers, paper, and foods. One of the earliest continuous processes relates to the paper industry (Fourdrinier paper machine, patented in 1799). Automotive manufacturing (at least the assembly part) can also be viewed as a continuous process. Here, the first assembly lines were installed at the beginning of the twentieth century by Olds (Oldsmobile) and, with more publicity, several years later by Ford (Ford model T).

1.1.2 Continuous Manufacturing in the Pharmaceutical Industry


Although not used on a broad basis, continuous manufacturing is not new to the pharmaceurical sector. Some pharmaceutical manufacturing processes (e.g., separations) have operated continuously for decades [1]. Furthermore, many pharmaceutical unit operations, such as plug-flow reactors, roller compaction, tablet compression, extrusion, and capsule filling, are inherently continuous process steps. Yet, since continuous quality assurance was not integrated in these processes in the past, they remain continuous processes operated in a batch way and will only become truly continuous when real-time quality assurance is fully implemented in the process control.The first publication by ICI, clearly outlining the advantages of continuous manufacturing (as they are cited today), dates back to 1984 [2].

On the academic side, continuous manufacturing of pharmaceuticals has been studied for more than two decades. In the early 1990s, Muzzio at Rutgers University launched the first research program for the continuous manufacturing of pharmaceuticals. In addition, Leuenberger (University of Basel) early on pointed out the advantages of continuous manufacturing in the pharmaceutical industry [3]. Since then, significant efforts have been made in this field, and several focused research programs are currently underway. For example, the Novartis-MIT center for continuous manufacturing (USA) focuses on primary active pharmaceutical ingredient (API) manufacturing and integrating drug synthesis into a continuous production line [4]. Continuous manufacturing and crystallisation (CMAC) at Strathclyde University (UK) investigates related topics that range from synthesis to crystallization. A series of white papers from the International Symposium on Continuous Manufacturing of Pharmaceuticals [5], organized jointly by MIT and CMAC, highlights the current view on CM. In the field of secondary manufacturing (drug product), together with its partners at Purdue University, NJIT, and University of Puerto Rico, Rutgers University developed a continuous manufacturing plant based on blending and direct compaction within their NSF-funded research center C-SOPS [6]. The Research Center for Pharmaceutical Engineering (RCPE) currently leads the European Consortium for Continuous Manufacturing, fearuring three continuous lines. Its partners are the groups of Ketolainen at University of Eastern Finland (roller-compaction based granulation), Remon and De Beer at Ghent University (wet granulation lines), Kleinebudde at Heinrich-Heine University (roller compaction), and Graz University of Technology (hot-melt extrusion and down-streaming).

Several system suppliers have developed GMP-certified continuous manufacturing lines. One approach to integrating multiple continuous unit operations into a continuous downstream line is the Consigma system by GEA. It is an integrated tableting line with continuous wet granulation via co-rotating twin-screw extrusion, semi-continuous drying in a segmented fluid bed and tableting with state of the art online monitoring systems [7]. Recently, GLATT introduced the "MODCOS" system, which is a continuous rotary chamber insert for converting Glatt's GPCG drying batch system into a continuous fluidized bed drying system. In combination with various associated continuous process equipment from other companies [e.g., feeders, process analytical technology (PAT), and continuous granulation systems] it makes an integrated continuous wet granulation line possible. Moreover, other advanced industrial systems are under development, such as the continuous manufacturing line(s) by Bohle for blending, dry and wet granulation, tableting, and coating. Bosch is another equipment company developing downstream continuous manufacturing systems in cooperation with RCPE. Continuus Pharmaceuticals, a spin-off from MIT is offering equipment for continuous synthesis and dosage-form manufacturing. Similarly, suppliers of continuous flow chemistry systems are increasingly active on the market (Thalesnano, Syrris, Ehrfeld, AM Technology, Uniqsis, Chemtrix, Future Chemistry, Vapourtec and others).

In addition, several pharmaceutical companies have started significant programs on continuous manufacturing, such as Novartis, Pfizer (recently in a joint effort with GEA), AstraZeneca, GSK, Bayer, UCB and many others. In fact, in 2015 the FDA approved a continuous manufacturing plant by Vertex in the USA (for Orkambi, a drug treating cystic fibrosis) and in 2016 a continuous line by Jannsen (for Darunavir, a drug for treating HIV infections) in Puerto Rico. At time of the writing of this book, also other approvals are in the pipeline, not only in the United States, but also in Europe and other regulatory regions.

1.1.3 Our View of Continuous Manufacturing


Traditional batch manufacturing follows a sequential approach. Before processing, the materials are introduced into a specific unit operation, then transformed into a processed intermediate product and finally discharged at the end of processing. After each production step the intermediate products are collected and analyzed, if required, and physically transported in various containers (IBCs) to the next process step. Typically, the intermediate and final products are extensively tested off-line in a quality assurance laboratory. Frequently, intermediates are shipped across the globe from one production site to the next one that has suitable equipment using cold-chain systems or freeze containers, which may lead to segregation or instability. Depending on the number and nature of the unit operations (typically 10-30), a batch manufacturing process on a commercial scale may last from several weeks to a year (or longer).

In contrast, it only takes a few hours or days to make the final product via a CM process that consists of the same unit operations as the batch process. Simultaneously introduced into and discharged from the process, the material is automatically transferred and monitored and controlled in-line along the manufacturing path. Based on the implemented control strategy, the process can be adjusted by means of in-process measurements. The quality is assured (QA) in real-time, and - in theory - real-time release is possible.

Figure 1.1 General overview of a CM process chain.

Pharmaceutical manufacturing is typically divided into primary and secondary. Primary manufacturing is the production of an API and excipient materials. Secondary manufacturing is the production of a final dosage form. In oral dosage form production, crystallization, filtration, washing, and drying steps are considered primary steps, and dry API is made at primary manufacturing plants. Lyophilization of proteins,...

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Das Dateiformat ePUB ist sehr gut für Romane und Sachbücher geeignet - also für "fließenden" Text ohne komplexes Layout. Bei E-Readern oder Smartphones passt sich der Zeilen- und Seitenumbruch automatisch den kleinen Displays an. Mit Adobe-DRM wird hier ein "harter" Kopierschutz verwendet. Wenn die notwendigen Voraussetzungen nicht vorliegen, können Sie das E-Book leider nicht öffnen. Daher müssen Sie bereits vor dem Download Ihre Lese-Hardware vorbereiten.

Bitte beachten Sie bei der Verwendung der Lese-Software Adobe Digital Editions: wir empfehlen Ihnen unbedingt nach Installation der Lese-Software diese mit Ihrer persönlichen Adobe-ID zu autorisieren!

Weitere Informationen finden Sie in unserer E-Book Hilfe.


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