Continuous Pharmaceutical Processing and Process Analytical Technology

Cover
Half Title
Series Page
Title Page
Copyright Page
Dedication
Table of Contents
Preface
Editor Biographies
Contributors
Part I: Design and Control: Continuous Manufacturing of Small Molecule Drug Substances and Products
	Chapter 1: A Survey of Continuous API Syntheses: Insights at the Interface of Chemistry and Chemical Engineering
		1.1 Introduction
		1.2 Reaction Types That Lend Themselves for Continuous Processing
			1.2.1 Highly Energetic Reactions
			1.2.2 Diazomethane
			1.2.3 Nitration Reactions
			1.2.4 Oxidations
			1.2.5 Azides
			1.2.6 Organometallic Reactions
				1.2.6.1 Fluconazole
				1.2.6.2 Goniothalamin
		1.3 Continuous Catalytic Reactions
			1.3.1 Catalytic Hydrogenation Reactions
				1.3.1.1 Thebaine (Hydrocodone)
				1.3.1.2 Mepivacaine
				1.3.1.3 API 1 (JAK2 Kinase Inhibitor by AstraZeneca) – Augustine Method
				1.3.1.4 N-4-Nitrophenyl Nicotinamide
				1.3.1.5 Linezolid (Zyvox)
			1.3.2 Cross-Coupling Reactions
				1.3.2.1 Suzuki-Miyaura Cross-Coupling
			1.3.3 Photochemical Organic Syntheses
				1.3.3.1 Practical Flow Reactor Designs for Continuous Organic Photochemistry
				1.3.3.2 Photochemical Flow Synthesis of Artemisinin
				1.3.3.3 Photocatalysts as Alternatives to Precious Metal Catalysts
			1.3.4 (R) and (S) Rolipram Paper
		1.4 Total Syntheses of API
			1.4.1 Significant Jump from Batch to Flow
				1.4.1.1 Dolutegravir
				1.4.1.2 Noroxymorphone
				1.4.1.3 Ciprofloxacin
			1.4.2 Greenness, Safety, PMI in Continuous Flow Processes
				1.4.2.1 Nevirapine
				1.4.2.2 1 H -4-Substituted Imidazoles
				1.4.2.3 Daclatasvir
				1.4.2.4 Iloperidone
			1.4.3 Overcoming Challenges in Chemistry and Reaction Engineering with Flow
				1.4.3.1 Ibuprofen
				1.4.3.2 Benadryl
				1.4.3.3 4,5-Disubstituted Oxazoles
				1.4.3.4 Efavirenz
				1.4.3.5 Hydroxychloroquine
				1.4.3.6 Drug-Like Pyrrolidines Library
				1.4.3.7 Endoperoxide OZ439
				1.4.3.8 KRAIC: Continuous Crystallization
				1.4.3.9 AI Cloud-Based Server Designed Routes to Three APIs
				1.4.3.10 Aliskiren: Continuous Preparation from Reagent to Finished Drug Tablet
				1.4.3.11 Real-Time Monitoring of Continuous API Manufacturing with Cutting Edge PAT
		1.5 Conclusion
		References
	Chapter 2: Development of Continuous Pharmaceutical Crystallization
		2.1 Introduction: Background and Driving Forces
		2.2 Basic Kinetics and Thermodynamic Principles in Crystallization
			2.2.1 Solubility and Supersaturation
			2.2.2 Nucleation and Growth
			2.2.3 Mass and Population Balance Equation
		2.3 Development and Application of Continuous Crystallizers
			2.3.1 Single Stage and Cascades of Mixed Suspension Mixed Product Removal
			2.3.2 Continuous Tubular Crystallizers
		2.4 Monitoring and Controlling Continuous Pharmaceutical Crystallization via Process Analytical Technology
			2.4.1 Process Monitoring and Analysis
			2.4.2 Advances Crystallization Control Approaches
				2.4.2.1 Model-Based Control Strategies
				2.4.2.2 Classical Feedback Loop Control Strategies
			2.4.3 Obstacles in the Scale-Up to Industrial Scale
		2.5 Conclusion
		Note
		References
	Chapter 3: Residence Time Distribution in Continuous Manufacturing
		3.1 Importance of RTD in CM
		3.2 Determination of the RTD
		3.3 RTD Modelling
		3.4 Importance of Tracer Selection in RTD Experimental Approach
		3.5 Importance of a Proper Statistical Methodology to Compare RTD Profiles
		3.6 Model-Dependent Approach
		3.7 Model-Independent Approach
		3.8 Discussion
		Note
		References
	Chapter 4: Powder Electrostatics in Continuous Pharmaceutical Manufacturing
		4.1 Introduction
		4.2 Charging Mechanisms
			4.2.1 Material Categorization: Conductors, Semi-Conductors, and Insulators
			4.2.2 Charging Mechanisms in Pharmaceutical Applications
				4.2.2.1 Electron Transfer
				4.2.2.2 Ion Transfer
				4.2.2.3 Material Transfer
		4.3 Principal Factors Impacting Powder Electrostatics
			4.3.1 Tribocharging Dependence on Material-Related Factors
				4.3.1.1 Work Function
				4.3.1.2 Surface Chemistry
				4.3.1.3 Powder Crystallinity
				4.3.1.4 Particle Size and Particle Size Distribution
				4.3.1.5 Particle Shape
				4.3.1.6 Surface Roughness
				4.3.1.7 Mechanical Properties
				4.3.1.8 Hygroscopicity
				4.3.1.9 Formulation
			4.3.2 Impact of Process-Related Factors on Tribocharging
				4.3.2.1 Unit Operation
				4.3.2.2 Equipment Surface and Design
				4.3.2.3 Process Parameters
					4.3.2.3.1 Number, Time, and Energy of Contact
					4.3.2.3.2 Shear and Normal Forces
					4.3.2.3.3 Environmental Conditions
		4.4 Principles and Techniques for Charge Measurement
			4.4.1 Static Measurement Methods
				4.4.1.1 Faraday Cup
				4.4.1.2 Induction Probe
				4.4.1.3 Other Static Measurement Techniques
			4.4.2 Dynamic Measurement Methods
				4.4.2.1 Ring-Shaped Electrostatic Inductive Sensor
				4.4.2.2 High-Speed Videography Combined with Acoustic Levitation
				4.4.2.3 Electrical Single Particle Aerodynamic Relaxation Time
				4.4.2.4 Phase Doppler Particle Analyzer
				4.4.2.5 Charge Spectrometer
				4.4.2.6 Other Dynamic Measurement Techniques
			4.4.3 Atomic Force Microscopy Measurement Method
			4.4.4 Advancement in Process Analytical Technology for Direct and Indirect In-Process Measurement of Powder Charging
			4.4.5 Best Measurement Practices
		4.5 Modeling Approaches of Powder Tribocharging
			4.5.1 Molecular Modeling and Simulation
			4.5.2 Discrete Element Method Models
			4.5.3 Discrete Element Method and Computational Fluid Dynamics
			4.5.4 Statistical Modeling and Machine Learning
		4.6 Strategies for the Control and Mitigation of Powder Tribocharging during (Continuous) Pharmaceutical Operations
			4.6.1 Particle/Formulation Engineering
				4.6.1.1 Surface Functionalization
				4.6.1.2 Doping
				4.6.1.3 Surface Coating
				4.6.1.4 Modifications to Material and Particle Properties
				4.6.1.5 Addition of Antistatic Additives or Fines
			4.6.2 Optimization of Process Space
				4.6.2.1 Equipment Design and Process Parameters
				4.6.2.2 Grounding
				4.6.2.3 Auxiliary Equipment for In-Process Charge Mitigation
				4.6.2.4 Environmental Conditions
		4.7 Current Gaps and Future Perspectives
		Acknowledgments
		References
	Chapter 5: Continuous Impregnation Processes
		5.1 Introduction
		5.2 Impregnation Onto Porous Carriers
		5.3 Materials Selection
			5.3.1 Carrier Properties
			5.3.2 API Properties and Solvent Selection
		5.4 Continuous Impregnation
			5.4.1 Requirements of Continuous Processing and Online Testing Equipment
				5.4.1.1 A Suitable Gravimetric Feeder for the Carrier: The K-Tron KT20
				5.4.1.2 A Useful Continuous Contactor: The Glatt Continuous Powder Mixer
				5.4.1.3 An Efficient ONLINE Monitoring Tool: The Matrix NIR Spectrometer
		5.5 Chapter Summary
		References
	Chapter 6: Leveraging a Mini-Batchwise Continuous Direct Compression (CDC) Approach to Optimize Efficiency in Process Development, On-Demand Manufacturing, and Continuous Process Verification (CPV)
		6.1 Introduction
			6.1.1 Definitions
			6.1.2 Background and Driving Forces
				6.1.2.1 Historical Challenges
				6.1.2.2 The Emergence of QbD and PAT
				6.1.2.3 CM as a Third Wave of the FDA 21st-Century Quality Initiative
				6.1.2.4 Recent Filings
				6.1.2.5 Benefits Analysis at Roche
			6.1.3 Direct Compression
			6.1.4 Description of the Different Scales of Production
				6.1.4.1 Mass CDC
				6.1.4.2 Macro CDC
				6.1.4.3 Mini-Batch CDC
				6.1.4.4 Inflexion Point between Continuous and Mini-Batch Operations (Strengths/Weaknesses of Both)
		6.2 Technology Aspects of Mini-Batch
			6.2.1 Modes of Operation of Feeders When Running Mini-Batch
				6.2.1.1 Top-Up
				6.2.1.2 Feeding
				6.2.1.3 Sequential
			6.2.2 Description of Types of MBB
				6.2.2.1 Horizontal Paddle Mixers
				6.2.2.2 Ribbon
				6.2.2.3 Vertical
				6.2.2.4 Blending Modes: Thrusting vs. Turbulent vs. Intensify Mixer
			6.2.3 Commercial Manufacturing
				6.2.3.1 Batch Size
				6.2.3.2 Justifying Post Approval Changes in Batch Size
				6.2.3.3 Tech Transfer between ‘Mirror’ Equipment/Sites
				6.2.3.4 Possibilities for Distributed Manufacturing
		6.3 Safe, Compliant Operations
			6.3.1 Control Strategy
				6.3.1.1 Complexity Pyramid
					6.3.1.1.1 Recipe Control – Level 3
					6.3.1.1.2 Pharmaceutical Control – Level 2
					6.3.1.1.3 Engineering Control – Level 1
			6.3.2 Application of PAT
				6.3.2.1 Blend Assay
				6.3.2.2 Determining Blend Uniformity
					6.3.2.2.1 At-Line/Off-Line Analysis
					6.3.2.2.2 Soft-Sensor/Process Models
					6.3.2.2.3 Online Spectroscopy
					6.3.2.2.4 BA/BU at Point of Compression
				6.3.2.3 Tablet Weight, Tablet Assay, and Content Uniformity
			6.3.3 Impact of Material Transfers
				6.3.3.1 Segregation
				6.3.3.2 Intermixing
				6.3.3.3 Impact of Passage Through the Tablet Press
				6.3.3.4 Control Strategy Consideration
			6.3.4 Mini-Batch CDC Validation Approaches
				6.3.4.1 Process Performance Qualification
					6.3.4.1.1 Understanding Start-Up, Run, Pause, and Shut-Down States
				6.3.4.2 Process Monitoring
					6.3.4.2.1 Ongoing Process Trending
		6.4 Mini-Batch CDC Technology: Formulation Composition and Development Consideration
		6.5 Conclusion
		References
	Chapter 7: Predictive In-Vitro Dissolution for Real-Time Release Test (RTRT) for Continuous Manufacturing Process on Drug Product
		7.1 Introduction
		7.2 Model Development
			7.2.1 Reference Dissolution Method Development
			7.2.2 Model Calibration
				7.2.2.1 Independent Data
				7.2.2.2 Dependent Data
		7.3 Model Validation
		7.4 Lifecycle Management
		7.5 Janssen’s Case Study – A Statistical Approach to the Development of a Real-Time Release Testing Surrogate Model for Dissolution [ 43 ]
			7.5.1 Introduction
			7.5.2 The Three-Step Surrogate Model Development Paradigm
				7.5.2.1 Step 1: Experimental Design
				7.5.2.2 Defining the Multivariate Response – The Three-Parameter Weibull Function
				7.5.2.3 Step 2: Development of the Process Model
				7.5.2.4 Step 3: Surrogate Model
			7.5.3 Case Study
				7.5.3.1 Step 1: Weibull Fit by Tablet
				7.5.3.2 Step 2: Building the Process Model
				7.5.3.3 Step 3: Building the Surrogate Model
				7.5.3.4 Model Fit Assessment
				7.5.3.5 Bayesian Model Assessment for Accuracy and Precision
			7.5.4 Surrogate Model Validation
			7.5.5 Summary
		Appendix 1 Raw Data Listing arranged by Experimental Run (Exptal Run).
		Appendix 2: Statistical Description of Surrogate Model Development Steps
		Appendix 3: Model Selection Process
		Appendix 4: Exploratory Model Listing for element b1
		Appendix 5: Final PROC MIXED Final Reduced Model Listing for b1
		Appendix 6: PROC BGLIMM Listing of Multivariate Bayesian Process Model
		Appendix 7: SAS PROC IML Code for Surrogate Predictions
		Appendix 8: Congruence Plots of Empirical Weibull Parameters with
Surrogate Model Predicted Weibull Parameters at Run Average Level
		Appendix 9: Plot of Empirical Profiles with Surrogate Model Predicted Profiles of
Run Averages at the 3 levels of Factor 4 by Experimental Run
		Appendix 10: SAS macro SIM 1
		References
Part II: Design and Control: Continuous Manufacturing of Large Molecule Drug Substances and Products
	Chapter 8: Continuous Manufacturing of Biologics Drug Products: Challenges of Implementing Innovation in cGMP
		8.1 Preface
		8.2 Introduction
		8.3 CM in Manufacturing of Biologics Drug Substance
		8.4 CM in Manufacturing of Biologics Drug Product
		8.5 Enablers and Challenges of CM (Innovation) Implementation in Biologics Drug Products
			8.5.1 Project Timeline vs. Innovation Timeline
			8.5.2 Dedication to Developing and Implementing CM
				8.5.2.1 Organizational Factors
				8.5.2.2 Cultural Factors
				8.5.2.3 Geographical Factors
				8.5.2.4 Financial Factors
			8.5.3 Scale Optimization and Agility
				8.5.3.1 Scale Compatibility between Unit Operations
				8.5.3.2 Real-time Response to Patient Demand
			8.5.4 Systems Integration: Software and Hardware
				8.5.4.1 Integration Between Raw Material Vendor and DP Manufacturer
				8.5.4.2 Integration between Equipment that Serve Sequential Unit Operations
		Acknowledgements
		References
	Chapter 9: Modernizing Manufacturing of Parenteral Products: From Batch to Continuous Lyophilization
		9.1 Introduction
		9.2 Pros and Cons of Batch Lyophilization
			9.2.1 Time Consumption
			9.2.2 Scale-Up Issues
			9.2.3 Impossible Quality Assurance
			9.2.4 Unpredictable Freezing
			9.2.5 Vial-to-Vial Heterogeneity during Drying
		9.3 Continuous Freeze-Drying as a Solution to the Batch Freeze-Drying Problems
			9.3.1 Time Consumption
			9.3.2 Scale-Up and Process Conditions Uniformity
			9.3.3 Quality Assurance and Process Analytical Technologies (PATs)
			9.3.4 Economic Impact
			9.3.5 Delocalization and Stockpiles
		9.4 The History of Continuous Lyophilization
		9.5 Freeze-Drying of Unit Doses
			9.5.1 Continuous Freeze-Drying of Unit Doses Based on the Concept of Spin/Shell Freezing and Vacuum Drying
			9.5.2 IR-Assisted Drying of Previously Spin-Frozen Samples
			9.5.3 Suspended-Vials Concept
			9.5.4 Freeze-Drying of Unconventional Containers – Zydis®, Example of the Semi-Continuous Lyophilization of Orally Disintegrating Tablets (ODT) from Catalent
		9.6 Freeze-Drying of Bulk Products
			9.6.1 Spray Freeze-Drying Overview
			9.6.2 Patented Concepts by Arsem, Bruttini, and Oyler
			9.6.3 LyoMotion System by Meridion
			9.6.4 Stirred Freeze-Drying by Hosokawa Micron
			9.6.5 Fine-Spray Freeze-Drying by ULVAC
			9.6.6 Rey’s Concept
			9.6.7 LYnfinity by IMA
		9.7 Conclusion
		References
Part III: Process Analytical Technologies
	Chapter 10: Near-infrared Spectroscopy as Process Analytical Technology in Continuous Solid Dosage Form Manufacturing
		10.1 Introduction
		10.2 Theory
			10.2.1 NIR Fundamentals
			10.2.2 Mainstream and Emerging Analyzer Technologies for Process Analytical Technology Applications
		10.3 NIRS as a PAT Tool for Process Monitoring and Control in Solid Dosage Form Manufacturing
			10.3.1 Quantitative Chemometric Model Development
			10.3.2 Blending
			10.3.3 Granulation
			10.3.4 Hot Melt Extrusion
			10.3.5 Tableting
			10.3.6 Coating
		10.4 Implementation of an In-Line NIR Spectrometer Inside the Tablet Press for Blend Uniformity and Tablet Content Uniformity Monitoring
		10.5 NIR as PAT for Advanced Process Control of Oral Solid Dosage Form Manufacturing
		10.6 Chemometric Model Maintenance
		10.7 Outlook
		References
	Chapter 11: The Role of Process Analytical Technology (PAT) in Biologics Development
		11.1 Introduction
			11.1.1 Significance of PAT for Biologics Development and Continuous Processes
			11.1.2 Key Elements of a Typical PAT Platform
				11.1.2.1 Analytical Sensor
				11.1.2.2 Automation
				11.1.2.3 Data Management and Visualization System
				11.1.2.4 Distribution Control System
		11.2 In-line Vibrational Spectroscopy and MVDA Tools
		11.3 On-line LC
		11.4 Other Sensors
		11.5 Conclusion
		References
	Chapter 12: Moving to Manufacturing: Lessons Learned in a Career in Process Analytical Technology
		Introduction – Always Encountering PAT
		PAT from Development to Manufacturing
		Raw Material Identification – An Ideal Starting Point for PAT Projects
		The Business Case for PAT
		Industry–University Collaboration in PAT
		PAT and Company Culture
		Further Analytical Challenges/Implementing in Manufacturing
		Sampling Considerations
		Concluding Remarks
		Acknowledgments
		References
Part IV: Modeling, Design Space, and Future Outlook
	Chapter 13: End-to-End Design Space for Continuous Manufacturing of Pharmaceuticals: Understanding Interactions Across Integrated Continuous Operations
		13.1 Introduction
		13.2 Continuous Manufacturing of Tablets
		13.3 Interactions Across Integrated Operations for Continuous Manufacturing of Tablets
			13.3.1 Potential Interaction Effects between Material Properties and Process Parameters
			13.3.2 Potential Interaction Effects among Process Parameters Across Integrated Operations
		13.4 Holistic Control Strategy Elements for Continuous Manufacturing
		13.5 End-to-End Design Space Considerations for Continuous Manufacturing
		13.6 End-to-End Continuous Manufacturing Connecting Drug Substance and Drug Product
		13.7 Conclusions
		References
	Chapter 14: Control Strategies in Continuous Direct Compression
		14.1 Introduction
		14.2 Formulation Considerations and Development of Continuous Direct Compression Process
			14.2.1 Feeding
			14.2.2 Continuous Blending
				14.2.2.1 Axial Mixing
				14.2.2.2 Cross-Sectional Mixing
		14.3 Process Control Strategies
			14.3.1 Control Strategies for Unit Operations
				14.3.1.1 Feeding
				14.3.1.2 Blending
				14.3.1.3 Tableting
			14.3.2 In-Process Methods for Monitoring Blend Concentration
				14.3.2.1 Spectroscopic Approach
					14.3.2.1.1 Development of Spectroscopic Blend Concentration Monitoring Method
					14.3.2.1.2 Challenges, Risks and Mitigation Strategies
				14.3.2.2 RTD Model-Based Approach
					14.3.2.2.1 Development of RTD Model for Blend Concentration Monitoring
					14.3.2.2.2 Challenges, Risks and Mitigation Strategies
				14.3.2.3 Hybrid Approach to In-Process Blend Concentration Monitoring
		14.4 Control of Materials Attributes of Input Materials
		14.5 Control of Critical Quality Attributes in CDC
			14.5.1 Tablet Content Uniformity and Potency
			14.5.2 Dissolution
		14.6 Conclusions
		Acknowledgments
		References
	Chapter 15: Framework for the Validation of Mechanistic and Hybrid Models as Process Analytical Tools in the Pharmaceutical Industry
		15.1 Introduction
			15.1.1 PAT Journey from Hard Sensors to Soft Sensors and Modeling
			15.1.2 The ASME Verification and Validation Approach
			15.1.3 Potential Interface of V&V40 with Pharmaceutical Guidelines
		15.2 Case-Study on the Use of ASME V&V40 on a Pharmaceutical Application
			15.2.1 Application Description
			15.2.2 Sources of Error and Uncertainty
			15.2.3 Applying ASME V&V20 to Assess Model Uncertainty
			15.2.4 Applying ASME V&V40 to Assess Model Credibility
		15.3 Conclusions and Recommendations
		References
	Chapter 16: Understanding the History of Continuous Manufacturing in Other Industries to Guide Future Development in Pharmaceuticals
		16.1 Introduction – What Is Continuous Manufacturing and Why Is It Used?
		16.2 A Very Early Example of Continuous Processing – Milling Grain in Pompeii 79 AD
		16.3 Moving From Single Unit Operation to Multiple Integrated Unit Operations
		16.4 Loss-in-Weight Feeder
		16.5 Integration of Automated Control Across Multiple Unit Operations with Multiple Sensors – Laundry Industry 2001
		16.6 Contemporary Pharmaceutical Applications of Continuous Manufacturing
		16.7 Challenges and Future Opportunities for Pharmaceutical Continuous Manufacturing
		16.8 Summary
		References
Index