Principles and Practices of Lyophilization in Product Development and Manufacturing

Preface
Contents
Overview of Freeze Drying
1 Why Freeze Drying?
2 Equipment
2.1 Chamber
2.2 Condenser
2.3 Vacuum System
2.3.1 Chamber Pressure Control
2.4 Control System
3 Formulation
4 Process
4.1 Freezing
4.1.1 Physics of the Freezing and Crystallization Process (Adapted from Book Chapter in ``Development of Biopharmaceutical Dru...
4.1.2 Impact of Freezing Process on Protein Solutions and Modes of Denaturation
4.1.3 Freezing Rate
4.1.4 Annealing
4.1.5 Effect of Thermocouples on Freezing Rates
4.2 Primary Drying
4.3 Secondary Drying
4.4 Process Control
4.4.1 Chamber Pressure Control and Monitoring
4.4.2 Condenser Pressure Control and Monitoring
4.4.3 Determination of the End Point of Primary Drying
5 Stability
References
Characterization and Determination of Freeze-Drying Properties of Frozen Formulations: Case Studies
1 Introduction
2 Definition of Freeze-Drying Properties
2.1 Collapse Temperature
2.2 Eutectic Melting Temperature (Te)
3 Characterization Techniques
3.1 Differential Scanning Calorimetry (DSC)
3.1.1 Method Design Considerations
3.2 Freeze Drying Microscopy (FDM)
3.2.1 Equipment and Experimental Procedure
3.2.2 Applications of Freeze-Drying Microscopy
3.2.2.1 Crystalline Systems
3.2.2.2 Case Studies
3.2.2.3 Crystalline Systems
3.3 Estimation of Tg´
References
Beyond pH: Acid/Base Relationships in Frozen and Freeze-Dried Pharmaceuticals
1 Introduction
2 Hammett Acidity Function and pHeq
3 Factors Which Impact Apparent Solid-State Acidity in Lyophiles
4 Correlations Between Solid-State Acidity and Stability of Freeze-Dried Formulations
5 Freezing Fundamentals: Quasi-Liquid Layer, Freeze-Concentration, Polarity, and the Workman-Reynolds Potential
6 Conclusions
References
Concepts and Strategies in the Design of Formulations for Freeze Drying
1 Introduction
2 Requirements and Expectations of a Lyophilized Product
3 Pre-formulation
3.1 Forced Degradation/Stress Studies
3.2 Chemical Instability
3.3 Physical Instability
3.3.1 Colloidal Instability
3.3.2 Conformational Instability
4 Formulation Development
4.1 Rational Design of the Formulation
4.2 Strategies to Mitigate Liabilities and Protein Aggregation
5 Stability Testing
5.1 Kinetics of Degradation in the Amorphous Solid State
5.2 Selection of Accelerated Testing Conditions, Temperature, and Time
References
Formulation Design for Freeze-Drying: Case Studies of Stabilization of Proteins
1 Excipient Selection
1.1 Role of Excipients
1.1.1 Protein Stabilization
1.1.2 Manufacturability
1.1.3 Tolerability
1.1.4 Drug Administration
1.2 Examples of Commercial Lyophilized Drug Products
2 In-Process and Storage Stability of Proteins: Stabilization During Freezing, Drying, and Storage
2.1 Theoretical Considerations
2.2 Practical Considerations
2.3 Excipient Properties and their Relevance for the Lyophilization Process
2.3.1 Analysis of Excipient Properties
2.3.2 The Link Between Excipient Properties and Lyophilization Process Parameters
2.3.2.1 Freezing
2.3.2.2 Annealing Prior to Primary Drying
2.3.2.3 Primary Drying
2.3.2.4 Secondary Drying
2.4 General Formulation ``Rules´´ for Freeze Drying
2.5 Solid State Dynamics
3 Product Quality Attributes
3.1 Residual Moisture
3.1.1 Impact of Water on Protein Stability
3.1.2 Water Content in Relation to Process Performance
3.2 Specific Surface Area
3.3 Cake Appearance
3.4 Reconstitution Time
4 Conclusions
References
Challenges and Considerations in the Development of a High Protein Concentration Lyophilized Drug Product
1 Introduction
2 Characteristics of High Protein Concentration Lyophilized Drug Product
2.1 Physical Appearance and Cake Structure
2.2 Prolonged Reconstitution Time
2.3 High Viscosity
2.4 Longer Primary Drying Time
2.5 Osmolality
3 Stability Considerations for the Development of High Protein Concentration Lyophilized Drug Products
3.1 Protein Cold Denaturation
3.2 Freezing Stress
3.2.1 Freeze-Concentration
3.2.2 Ice-Water Interface
3.2.3 pH Change
3.3 Phase Separation
3.4 Dehydration Stress
4 Stability Strategy to Minimize Protein Degradation During Lyophilization Process and Shelf Life Storage
4.1 Buffer Species, Surfactants, and Viscosity Reducer Selection
4.2 Stabilizers Selection
4.3 Stability Strategy for a High Concentration Lyophilized Protein Drug Product Stable for Room Temperature Storage
4.4 Coformulation of High Concentration Lyophilized Protein Drug Product
5 Formulation and Process Strategy to Minimize the Reconstitution Time
5.1 Increase Cake Wettability and Crystallinity
5.2 Controlled Nucleation
6 Lyophilization Cycle Development for High Protein Concentration Drug Product
6.1 Freezing
6.2 Primary Drying
6.3 Secondary Drying
6.4 Lyophilization Cycle Scale-Up Considerations
7 Summary
References
Freeze-Drying of Thermosensible Pharmaceuticals with Organic Co-solvent + Water Formulations
1 Introduction
2 Preparation of Solution
3 Freezing Parameters
3.1 Nucleation Temperature
3.2 Solvent Crystals Morphology
4 Thermodynamical Properties
4.1 Phase Diagram
4.2 Equilibrium Vapour Pressures
4.3 Sublimation Enthalpies
5 Sublimation Kinetics
6 Residual TBA and Water Contents
7 Annealing Treatment
8 Design Space for Freeze-Drying of an Ibuprofen Formulation
8.1 Overall Heat Transfer Characterization
8.2 Mass Transfer Resistance of the Dried Layer
8.3 Determination of Sublimation Rates of Real Ibuprofen Formulation
8.4 Mean Product Temperature
8.5 Limits of Critical Quality Attributes
8.6 Reconstitution Properties
9 Conclusions
References
Primary Container Closure System Selection for Lyophilized Drug Products
1 Introduction
2 Primary Containers
2.1 Overall Considerations
2.2 Heat Transfer (Glass Vials)
2.3 Glass Versus Polymer
2.3.1 Heat Transfer
2.3.2 Breakage
2.3.2.1 Lyophilization
2.3.2.2 Storage at Low Temperatures
2.3.3 Delamination and Chemical Durability
2.3.4 Other Important Practical Consideration
2.4 Extractables and Leachables
2.5 Fogging
2.6 Coated Vials
3 Elastomeric Closures
3.1 Closure Geometry
3.1.1 Flange Thickness and Flange Design
3.1.2 Penetration Thickness
3.1.3 Plug Design
3.1.4 Standardization of Lyophilization Stoppers Geometry
3.2 Moisture Absorption/Desorption and Permeability Behavior
3.3 Fluoropolymer Coatings
4 Container Closure Fit and Integrity
4.1 Strategies and Methods for Assessing Component Fit
4.1.1 Visualization Techniques
4.1.2 Interference Fit Calculation: Assessment of the Plug Seal
4.1.3 Dimensional Stack-Up Analysis: Assessment of Flange Seal and Skirt Length
4.1.4 Container Closure Integrity and Seal Quality Test Methods
4.1.4.1 Helium Leakage
4.1.4.2 Laser-Based Headspace Analysis
4.1.4.3 Residual Seal Force
4.2 Common Causes of Loss of Vacuum and/or CCI: Raised Stoppers and Dried Product
5 Future Trends
5.1 Dual-Chamber Containers
5.2 Nested Vial Configurations and Press-Fit Caps
6 Conclusion
References
Vial Breakage During Lyophilization
1 Introduction
2 Use of Strain Gauges to Understand Vial Breakage
3 Parameters That Affect Vial Breakage
3.1 Vial Handling, Washing, Depyrogenation, and Other Handling in a Production Setting
3.2 Product Fill Volume
3.2.1 Interior Vial Coating
3.3 The ``Break-Free´´ or ``Plugging-Off´´ Event During Freezing
3.4 Warming of the Frozen Plug
3.5 Crystallizing Solutes
4 Conclusions and Recommendations
References
The Nucleation of Ice
1 Introduction
2 Definitions and the Formation of Ice
3 Ice Nucleation in Conventional Lyophilizers
3.1 The Effect of Cooling Rate on the Degree of Supercooling
3.2 The Effect of Vial Size and Fill Volume on the Degree of Supercooling
4 Controlled Ice Nucleation
4.1 Controlled Ice Nucleation Using a Reduced Pressure Ice Fog
4.2 Controlled Nucleation Using Rapid Depressurization
4.3 The Effect of Controlled Ice Nucleation on Process Time and Product Appearance
5 Summary
References
Stresses, Stabilization, and Recent Insights in Freezing of Biologics
1 Stresses During Freezing
1.1 Current Understanding of Freezing-Induced Stresses
1.2 Recent Insights in Freezing-Induced Stresses
1.2.1 Dissolved Gas
1.2.2 Mechanical Stress
2 Novel Modalities
2.1 Vaccines
2.2 DNA/RNA
2.3 Gene Therapy
2.4 Cells
3 Advances in Modeling Approaches
3.1 Practical Consideration for Frozen Products
4 Concluding Remarks
References
Lyophilization Process Understanding and Scaleup Using Ab Initio Vial Heat Transfer Modeling
1 Introduction
2 Materials and Methods
2.1 Theoretical Analysis of Heat Transfer to Product in Vials During Lyophilization
2.1.1 Definition of the Heat Transfer Coefficient, Kv
2.1.2 Phenomenological Parameters
2.1.3 Ab Initio Parameters and Their Dependence on the Equipment/Product/Process
2.2 Experimental Setup for Full-Shelf Gravimetric Measurements of Kv for Various Vials and Lyophilizers
2.3 Determining Ab Initio Kv Parameters for Various Vials and Lyophilizer Combinations
2.3.1 Shelf Heat Transfer Coefficient, Ks
2.3.2 Emissivity of the Shelf
2.3.3 Other Ab Initio Parameters - Kcs, kcs, Acs, es, ev, and lbot
2.4 Lyophilization Cycle Scaleup Using Ab Initio Vial Heat Transfer Modeling
2.4.1 Definition of a ``Design Condition/Case/Criteria (DC)´´
2.4.2 Placement Test of Data Sufficiency for Heat Transfer Analysis of a ``Target Design Condition´´
3 Results and Discussions
3.1 Experimental Results of Center Vial Kv for Different Lyophilizers and Vial Size
3.2 Example Case Studies to Scaleup Kv from a ``Known´´ to a ``Target´´ Design Condition (Lab-->Pilot) Using Ab Initio Paramet...
3.3 Discussion on the Uncertainty in the Estimated Kv
3.3.1 The Effect of Ks
3.3.2 Compilation of Literature Ab Initio Parameters for Kv
4 Conclusions
References
Secondary Drying: Challenges and Considerations
1 Introduction
2 Modeling of Secondary Drying
2.1 Desorption Kinetics Model
2.2 Heat Transfer Model
2.2.1 Empirical/Simplified Models
2.2.2 Theoretical Models
2.2.2.1 High Fidelity Model: Full 3D Simulation
2.2.2.2 Intermediate Fidelity Model: 1D Averaged Equations
2.2.2.3 Low Fidelity Model: 0D Lumped Capacitance Model
3 Characterization of Secondary Drying Process and the Lyophilized Cake
3.1 Temperature Measurement
3.2 Heat Flux Measurement
3.3 Moisture Content
3.3.1 Pressure Rise Test (PRT)
3.3.2 Tunable Diode Laser Absorption Spectroscopy
3.4 Properties of Lyophilized Cake
3.4.1 Structure of the Lyophilized Cake
3.4.2 Glass Transition Temperature and Collapse Temperature
4 Critical Process Variables During Secondary Drying
4.1 General Operational Conditions
4.2 Effect of Temperature
4.3 Effect of the Vial
4.4 Effect of Specific Surface Area
4.5 Effect of Excipients
4.6 Process Parameters Not Affecting Secondary Drying
5 Challenges in Secondary Drying
5.1 Moisture vs. Stability
5.2 Uncertainties in Heat Transfer Coefficient
5.3 Inefficient Heat Transfer
5.4 Defects in Dried Cake
5.5 Scaleup
5.6 Temperature and Moisture Uniformity
6 Concluding Remarks
References
Design and Process Considerations in Spray Freeze Drying
1 Introduction
1.1 Challenges for Traditional Freeze Drying
1.2 Desirable Attributes for an Improved Process
1.3 Spray Freeze Drying Developments
1.4 General Product and Process Considerations Related to Lyophilized Bulkware
2 Spray Freeze Drying
2.1 General Design Features and Process Characteristics
2.1.1 Spray Freezing
2.1.2 Rotary Freeze Drying
2.1.3 Equipment Configuration Options
2.2 Spray Freezing: Specific Design and Process Considerations in Spray Freezing
2.2.1 Introductory Remarks
2.2.2 Spray Freezing Equipment Design, Process, and Product Parameters
2.2.2.1 Tower
2.2.2.2 Spraying
2.2.3 Scale-up in Spray Freezing
2.3 Dynamic Rotary Bulk Freeze Drying
2.3.1 General Equipment Design, Process, and Product Parameters
2.3.2 Specific Aspects of Rotary Freeze Drying: Similarities and Differences When Comparing to Shelf Freeze Drying
2.3.2.1 Tg´
2.3.2.2 Pressure
2.3.2.3 Shelf and Drum Surface Temperature
2.3.2.4 IR-Power in Rotary Freeze Drying
2.3.2.5 Drum Rotation Speed in Rotary Freeze Drying
2.3.2.6 End Point Detection (By Comparative Pressure Measurement or Pressure Rise)
2.3.2.7 Formulation Aspects
2.3.2.8 Flow Properties of Spray Frozen Bulk in Dynamic Freeze Drying
Presence of Ice
Electrostatic Phenomena in Dynamic Bulk Freeze Drying
Formulation Aspects Relevant for Electrostatics
2.3.3 Annealing
2.3.3.1 Targets for Annealing
2.3.3.2 Annealing Procedure
2.3.3.3 Relevance of Annealing in Pharmaceutical Applications
2.3.3.4 Relevance of Annealing in Dynamic Spray Freeze Drying
2.3.3.5 Annealing Procedure in Dynamic Spray Freeze Drying
2.3.3.6 Further Annealing Effects in Dynamic Bulk Freeze Drying
2.3.4 Scale-up in Rotary Freeze Drying
2.3.4.1 Comparison of Conventional and Rotary Freeze Drying Scale-up
2.3.4.2 Changing Product Load in the Same Equipment
2.3.4.3 Changing Product Load Utilizing Different Equipment Sizes
3 Continuous Processing in Spray Freeze Drying: Aspects to Consider
4 Industrial Application of Spray Freeze Drying: Integration of Steps to an Aseptic Process Line
5 Summary
References
LyoPRONTO: Deterministic and Probabilistic Modeling - Tutorial and Case Study
1 Introduction
2 Numerical Modeling
2.1 Freezing Calculator
2.2 Primary Drying Calculator
2.3 Design Space Generator
2.4 Optimizer
3 Experimental Methodology
4 Case Study and Tutorial
4.1 Step-by-Step Tutorial
4.1.1 Freezing Calculator
4.1.2 Primary Drying Calculator: Deterministic Approach
4.1.3 Design Space Generator
4.1.4 Optimizer
4.2 Monte-Carlo-Based Probabilistic Approach and Comparison with Deterministic Methodology
4.2.1 Monte-Carlo Simulation Methodology and Input Parameters´ Variation
4.2.2 Probabilistic Approach: Case Study
5 Experimental Validation
5.1 Primary Drying Calculator: Probabilistic Approach
6 Conclusion
References
Utilizing Solid-State NMR Spectroscopy to Assess Properties of Lyophilized Formulations
1 Introduction
2 Analytical Challenges for Lyophilized Formulations
3 Basics of Solid-State NMR Spectroscopy
3.1 Relaxation
4 Characterization of Lyophilized Formulations by SSNMR
4.1 Identification of Formulation Components
4.2 Ionization Changes
4.3 Homogeneity of Formulation Components
4.4 Case Study: Phase Separation in Bovine Serum Albumin (BSA) and Lysozyme-Containing Formulations
4.5 Mobility
5 Comparison with Other Analytical Techniques
6 Conclusion
References
Design of Moisture Specification Studies for Lyophilized Product
1 Introduction
2 Stopper Moisture Studies
2.1 Stoppers Equilibrium Moisture Studies
2.2 Sterilization and Drying Studies
3 Lyophilized Product Moisture Studies
3.1 Moisture Equilibration
3.2 Sample Preparation
3.3 Moisture Analysis by Karl Fischer
4 Specifications
References
Laser-Based Headspace Moisture Analysis for Rapid Nondestructive Moisture Determination of Lyophilized Products
1 Introduction
1.1 Importance of Residual Moisture Content Determination
1.2 Traditional Methods to Determine Residual Moisture
1.3 The Need for a Better Residual Moisture Determination Method
2 Laser-Based Headspace Moisture Analysis
3 Case Study: Correlation of Headspace Moisture to Total Moisture Content
4 Case Study: Headspace Moisture as a Tool for Freeze-Drying Cycle Optimization
4.1 Conclusions
5 Case Study: Headspace Moisture as a Tool for Lyo Shelf Moisture Mapping
5.1 Conclusions
6 Case Study: Lyo Shelf Moisture Mapping to Demonstrate Freeze-Dryer Equivalence
6.1 Conclusions
7 Headspace Moisture Determination as a Water Activity Measurement
7.1 Thermodynamic Activity of Water
7.2 Moisture Sorption Isotherms
7.3 Product Decay Rate
8 Case Study: Correlation of Product Stability to Water Vapor Partial Pressure
8.1 Pharmaceutical Formulation
8.2 Sample Preparation and Storage
8.3 Results and Discussion
8.4 Conclusions
9 Chapter Summary
References
Application of PAT in Real-Time Monitoring and Controlling of Lyophilization Process
1 Introduction
2 PAT for Freeze-Drying Process Monitoring and Control
2.1 Dependent Variables/Critical Process Parameters of Freeze-Drying
2.2 Product Temperature
2.3 Product Resistance
2.4 Sublimation Rate
2.5 Nucleation Temperature
2.6 End Point Determination of Primary Drying Phase
2.7 End Point Determination of Secondary Drying Phase
3 PAT for Freeze-Drying Process Monitoring and Control
4 Single Vial Methods
4.1 Thermocouples and RTDs
4.2 TEMPRIS
4.3 Near Infrared Spectroscopy (NIR)
4.4 Microbalance Technique
5 Batch PAT Methods
5.1 Pressure Measurements: Capacitance Manometer and Pirani Gauge
5.2 Dew-Point Monitor
5.3 Manometric Temperature Measurement (MTM)
5.4 Thermodynamic Lyophilization Control (TLC)
5.4.1 Gas Plasma Spectroscopy (Lyotrack)
5.4.2 Residual Gas Analyzer Mass Spectrometer (LYOPLUS)
5.5 Tunable Diode Laser Absorption Spectroscopy
5.6 TDLAS Measurements of Vapor Mass Flow
5.7 Instrument Requirements
5.8 Sensor Validation
5.9 Sensor Applications
5.10 Lyophilizer OQ
5.11 Determination of Primary and Secondary Drying Endpoints
5.12 Determination of Vial Heat Transfer Coefficients and Product Temperature
5.13 Determination of Product Resistance
6 TDLAS Summary
References
Process Analytical Technology (PAT) for Lyophilization Process Monitoring and End Point Detection
1 Introduction
2 Product Temperature Measurement
2.1 Resistance Temperature Detector
2.2 Thermocouple
2.3 Wireless Temperature Sensor
2.4 Manometric Temperature Measurement (MTM)
3 Pressure Measurement
3.1 Pirani Gauge
3.2 Capacitance Manometer
4 Heat and Mass Transfer during Primary Drying and Secondary Drying
4.1 Primary Drying Heat Transfer and Vial Heat Transfer Coefficient
4.2 Mass Transfer Determination
4.2.1 Mass Loss by Gravimetric Measurement
4.2.2 Manometric Temperature Measurement (MTM)
4.2.3 TDLAS
5 Cycle Endpoint Detection
5.1 Limitations of Product Temperature Measurement
5.2 Alternatives to Product Temperature Measurement
5.2.1 Comparative Pressure Measurement (Pirani vs CM)
5.2.2 Electronic Hygrometer
5.2.3 Residual Gas Analysis
5.2.4 Pressure Rise Test (PRT)
5.2.5 Manometric Temperature Measurement (MTM)
5.2.6 TDLAS
6 Summary and Future Trend
Bibliography
Advances in Process Analytical Technology: A Small-Scale Freeze-Dryer for Process Analysis, Optimization, and Transfer
1 Introduction
2 Development of the MicroFD
3 Lyophilization Design Space
4 Vial Thermal Conductivity (Kv)
5 Product Cake Resistance (Rp)
6 PAT Technologies
6.1 AccuFlux Heat Flux Sensor
7 AutoDry Product Temperature Control
8 End of Primary Drying: Pirani Versus Capacitance Manometer Pressure Differential
9 FreezeBooster Controlled Nucleation
9.1 Freezing Process PAT
10 Nucleation (Intra-vial)
11 Nucleation (Inter-vial)
11.1 Freezing of Freeze Concentrate
11.2 Measurement and Control of Freezing Heat Flow Post-controlled Nucleation
12 Freezing Events
12.1 The Effect of Freezing and Heat Flow Control on Primary Drying
12.2 Summary of Experiments on the Different Freezing Methods on Primary Drying Times
13 Developing Transferrable Protocols
14 Summary
References
Overview of Heat and Mass Transfer Modeling in Lyophilization to Create Design Spaces and Improve Process Analytical Technolog...
1 Introduction
2 Heat and Mass Transfer Modeling for Process Development
2.1 Vial Heat and Mass Transfer Studied by Quasi-Steady One-Dimensional Modeling
2.2 Equipment Capability of Lyophilizers Studied by Quasi-Steady 3-D CFD Modeling of Choked Flow Conditions
2.3 Creation of the Design Spaces of Various Types
3 Heat and Mass Transfer Modeling for Process Monitoring and Optimization
3.1 Experimental Data of Chamber and Condenser Pressures, Pch and Pcd
3.2 Sublimation Flow Rate Studied by Quasi-Steady 3D CFD Modeling of Subsonic Non-choked Flow Conditions
3.3 Model-Based Process Monitoring Using the Chamber to Condenser Pressures Drops
4 Summary
References
Application of QbD Elements in the Development and Manufacturing of a Lyophilized Product
1 Introduction
2 Target Product Profile (TPP)
3 Formulation Development and Selection
4 Use of Prior Knowledge
4.1 Justification for Lyophilized Dosage Form: Why Lyophilization?
4.2 Preformulation Studies/Preliminary Work/Formulation Screening
5 Lyophilization Process Development
5.1 Justification of Commercial Manufacturing Lyophilization Cycle
6 Risk Assessment
6.1 Risk Assessment (Formulation)
6.2 Risk Assessment (Lyophilization)
7 Design of Experiments (DOE)
7.1 Combined Approach
7.1.1 Initial Screening Studies
7.1.2 Optimization Phase
7.1.3 Data Analysis to Build Response Surface Model (RSM) for Each Response
7.1.4 Identify Design Space Boundaries
7.2 Individual Approach: Formulation
7.2.1 pH Characterization Studies
7.2.2 Protein Concentration Characterization Studies
7.2.3 Characterization Mannitol and Sucrose
7.2.4 Effect of Critical Formulation Parameters on the Freeze-Drying Properties of the Formulation
7.2.5 Characterization of Polysorbate 20 Concentration
7.3 Individual Approach: Lyophilization
7.3.1 Robustness Studies and Construction of a Design Space
7.3.2 Design of Experiments (DOE)
7.3.2.1 Prior Knowledge on Freezing Ramp Rates
7.3.2.2 Annealing Temperature
7.3.2.3 Primary Drying
References
Characterization of Freeze Dryers
1 Introduction
2 Critical Characteristics of Freeze Dryer
2.1 Shelf Temperature Mapping and Ramp Rates
2.2 Pressure Control
2.3 Condenser Capacity
2.4 Vacuum Integrity Testing
2.4.1 Measurement Techniques
2.5 Characterization with Thermal Load
2.5.1 Upfront Manufacturability Assessment
2.5.2 Optimization of Process Conditions
2.5.2.1 Sublimation Tests
2.5.2.2 Experimental Methodology (Vial Kv Measurement Methodology)
Vials Loading and Product Probe Placement
2.5.2.3 Measurement of Heat Transfer Coefficient
2.5.2.4 Actual Shelf Surface Temperature
2.5.2.5 Minimum Controllable Chamber Pressure as a Function of Sublimation Rate (Experimental)
Methodology
Calculation of Minimum Controllable Pressure as a Function of Sublimation Rate (Pmin Test)
Estimation of Maximum Sublimation Rate
2.5.2.6 Minimum Controllable Chamber Pressure as a Function of Sublimation Rate (Computational Modelling)
2.5.2.7 Manufacturing Environment (Nucleation Temperature)
3 Engineering Run
References
Principles and Practice of Lyophilization Process and Product Development: Scale-Up and Technology Transfer
1 Introduction
2 Lyophilization Process Overview
3 Considerations for Scale-Up and Technology Transfer
3.1 Freezing (Ice-Nucleation) Differences
3.2 Heat and Mass Transfer Differences Due to Equipment Design Differences
3.2.1 Mass Transfer Differences
3.2.2 Heat Transfer Differences
3.3 Measurement Differences
4 Considerations for Successful Technology Transfer from Lab-Scale to Pilot-Scale to Commercial
4.1 Process Design Considerations for Scale-Up and Technology Transfer
4.1.1 Equipment Factors Affecting Scale-Up Process
4.1.1.1 Condenser Design Differences
4.1.1.2 Temperature Uniformity of Condenser Coil
4.1.1.3 Cooling Rate Uniformity
4.1.1.4 Shelf Temperature Uniformity
4.1.2 Equipment Capability Testing for Scale-Up Transfer
4.1.2.1 Minimum Controllable Chamber Pressure Test
4.1.2.2 Maximum Sublimation Rate Test
4.2 PPQ Strategies with Process Verification and Sampling Plan
4.2.1 Assessment for Homogeneity
4.3 Continuous Process Verification
4.4 Drug Product Quality Attributes (for Lyo Product)
5 Process Analytical Technology (PAT) and Next-Generation Advancements
6 Summary
References
Lyophilization Validation: Process Design and Modeling
1 Introduction
2 Lyophilization Process Validation
2.1 Stage 1: Process Design
2.2 Stage 2: Process Qualification
2.3 Stage 3: Continued Process Verification
3 Stage 1: Process Design
3.1 Generation and Use of Design Space
3.1.1 Introduction to the Driving Forces and Resistances During Primary Drying
3.1.2 Equations for the First Principles of Heat and Mass Transfer
3.1.3 Determination of Primary Drying Conditions and Construction of Design Space
3.2 Engineering/Development Runs at Commercial Scale
4 Power of Simple Modeling for Process Optimization and Scale-Up
4.1 Development and Optimization of a Lyophilization Process
4.2 Scale-Up and Transfer
4.2.1 Class 100/Particle-Free Environment (Tn)
4.2.2 Equipment Capability (Minimum Controllable Chamber Pressure as a Function of Sublimation Rate)
4.2.3 Heat Transfer Coefficient (Kv)
5 Case Studies
5.1 Construction of Design Space
5.2 Effect of Batch Sizes (Product Load), Fill Volume, and Dose Strength
5.3 Controlled Ice Nucleation Technology (CIN) and Its Effect on Product Resistance
6 Summary
References
Lyophilization Validation: Process Qualification and Continued Process Verification
1 Introduction
2 Lyophilization Process Validation
2.1 Stage 1: Process Design
2.2 Stage 2: Process Qualification
2.2.1 Qualification of the Lyophilization Equipment
2.2.2 Lyophilization Process Performance Qualification
2.3 Stage 3: Continued Process Verification
3 Current Practices in Lyophilization Process Validation
4 Stage 2: Process Performance Qualification
4.1 PPQ Protocol
4.1.1 Batch Size
4.1.2 Number of PPQ Lots
4.1.3 Potential CPPs to Be Monitored
4.1.4 Potential CQAs to Be Tested
5 Stage 3: Continued Process Verification
5.1 Use of Run or Control Chart
5.2 Selection of CQAs and CPPs to Use in the Plot
5.2.1 Lyophilized Products in Vials
5.3 Options for Plotting Variations in Control Chart
5.3.1 Sample
5.4 Options for Plotting Data in Run Chart
5.4.1 Sample
6 Special Cases of Lyophilization Process Validation
6.1 Validation Approaches to Freeze-Drying of Pharmaceuticals in Alternative Containers
6.1.1 Emerging and Existing Container Closure Systems
6.1.1.1 Dual Chamber Vials
6.1.1.2 Dual Chamber Syringes and Cartridges
6.1.1.3 Trays
6.1.2 Specifics of Heat and Mass Transfer in Dual Chamber Devices
6.1.3 Specifics of Heat and Mass Transfer in Tray Drying
6.1.4 Validation Approaches for Dual Chamber Devices and Tray Drying
7 Case Studies
7.1 Monoclonal Antibody Case: Fill Volumes and Equipment Validation Strategy
7.2 Impact of Lyophilization Chamber Loading Process on Product Appearance and Product Rejection Rates
7.3 Lyophilization Cycle for a Product in a Dual-Chamber Cartridge
8 Summary and Future Outlook
References
Homogeneity Assessment of Lyophilized Biological Drug Products During Process Performance Qualification
1 Introduction
2 Methodology
2.1 Experimental Design
2.2 Statistical Model
2.3 Equivalence Testing and the Homogeneity Acceptance Criterion (HAC)
3 Results and Discussion
3.1 Protocol Phase
3.2 Protocol Execution Phase
3.3 Report Phase
4 Summary
References
Informed Manufacturing Through the Use of Big Data Analytics for Freeze Drying Process and Equipment
1 Introduction
1.1 Continued Process Verification and Freeze Dryer System Monitoring
2 Components of a Lyophilizer
2.1 Chamber and Condenser
2.2 Refrigeration
2.3 Heat Transfer
2.4 Vacuum
2.5 Hydraulics
3 Maintenance Practices and Data Analytics
3.1 Preventive Maintenance Techniques and Challenges in Preventive Maintenance
3.2 Infrastructure and Need for Data Analytics
3.3 The Role of Process Monitoring and Process Control
3.4 Sensor Network to Support Data-Driven Manufacturing
4 Case Studies for Data Analytics on Production Freeze Dryers
4.1 Condenser Temperature Excursions
4.2 Vacuum Pump Performance
4.3 Equipment Utilization
4.4 Leak Rate Tests
4.5 Refrigeration System Performance
4.6 Pressure Fluctuations
4.7 Stage Identification
5 Conclusions
References
Multivariate Analysis for Process Understanding, Continuous Process Verification, and Condition Monitoring of Lyophilization P...
1 Introduction
2 Data Gathering, Storing, and Analysis Infrastructure
3 Multivariate Data Analysis Theory
3.1 Univariate vs. Multivariate Analysis
3.2 Principal Component Analysis
3.2.1 Latent Variables, Loadings, and Scores
3.2.2 PCA Model Tuning and Performance Indexes
3.2.3 Algorithms for Building PCA Models
3.3 Principal Component Regression (PCR)
3.4 Projection to Latent Structure Regression (PLSR)
3.4.1 Algorithms for Building PLS Models
3.5 Data Unfolding for Applying PCA/PLS on Process Trajectory Data
3.5.1 Batchwise Unfolding
3.5.2 Variable-Wise Unfolding
4 Continuous Process Verification
4.1 Example Using PLS for Lyophilization and Applying on CPV
5 Condition Monitoring of Lyophilization
6 Future Directions of MVDA
6.1 Deep Learning Techniques for Lyophilization Condition Monitoring
References
Lyophilized Drug Product Cake Appearance: What Is Acceptable?
1 Introduction
2 Current Status of Lyophilized Product Cake Appearance: General and Regulatory Expectations
3 Terminologies Used to Define Variations in Cake Appearance from Ideal Expectations of ``Uniform and Elegant´´
3.1 Nonconformity or Defect
3.2 Irregularities/Nonuniform Cake Appearance
3.3 Visual Attributes of Freeze-Dried Products
3.3.1 Collapsed Cake
3.3.2 Meltback
3.3.3 Product Ejection
3.3.4 Puffing
3.3.5 Lifted Cake
3.3.6 Cake Shrinkage and Cracked Cake
3.3.7 Dusting, Chipping, and Broken Cake
3.3.7.1 Fogging
3.3.8 Lyo Ring, Minor Splashing, and Major Splashing
3.3.9 Bubble or Foam Formation
3.3.10 Volcano
3.3.11 Cake Texture
3.3.12 Droplets and Product on Inside Walls of the Vial
4 Potential Clinical Relevance of Cake Appearance
4.1 What Cake Appearances Are Acceptable?
4.2 Additional Considerations for Accepting Variations in Cake Appearance - Example: Collapsed Cake
4.3 Summary
References
Index