Lyophilization : introduction and basic principles / Thomas A. Jennings.

CONTENIDO
Preface vii
1. Introduction 1
Historical Review 1
Evolution of Process and Equipment 3
Definition of Lyophilization 4
General Description of the Process 4
Formulation 4
Freezing 5
Primary Drying 6
Secondary Drying 6
Container-Closure System 6
Freeze-Drying Equipment 6
The Freeze-Drying Chamber
The Condenser Chamber
The Vacuum Pumping System
Properties of Lyophilized Materials 8
Stability 8
Long-Term or Real-Time Stability Testing
ccelerated Stability Testing
Cosmetic Properties 9
Moisture 10
Free Water
Bound Water
Reconstitution 11
Applications 11
Healthcare Industry 11
Veterinary 12
Food 12
Other Applications 12
References 13
2. Product Formulation 15
Introduction 15
Active Constituent 16
Synthetic 16
Cisplatin
Acetic Acid
Nature Derived 17
Vaccines
Proteins
Physical State 18
Solvent System
Humidification
Thermal Treatment
Other Constituents Buffers 20
Law of Mass Action
Definition of pH
Buffer Solution
Bulking Compounds 29
Mannitol
Polyvinyl Pyrrolidone
Other Bulking Agents
Stabilizing Agents 33
Law of Mass Action
Excipient Induced Crystallization of the Active Constituent
Cryoprotectants 35
Lyoprotectants 36
Solvents Nature of Water 38
Solubility and Solvation Properties of Water 39
Solubility Mechanism
Salvation
Other Solvent Systems 41
Crystallization of the Active Constituent
Stability of the Active Constituent
Physical Characteristics 42
Colligative Properties 42
Freezing-Point Depression
Osmolarity
Concentration Properties 44
Optical
Particulate Malter 48
Visible Particles and Means for Their Detection
Subvisible Particles and Means for Their Detection
Various Saurces of Extrinsic Particulate Matter in a Formulation
Thermal Properties 52
The Function of Thermal Properties 52
Effect on the Cost of Manufacturing 53
Impact on the Freeze-Dryer 53
3. The Importance of Process Water 59
Role of Process Water in Lyophilization 59
Introduction 59
Purity 59
Total Solids
Inorganic Compounds
Conductivity
pH Measurements
Organic Compounds
Microbial and Endotoxin Levels
Hydrogen Bonding Formation 62
Impact of Excípients or Impurities 63
Degree of Supercooling 64
Heterogeneous Nucleation 64
Homogeneous Nucleation 65
Rate of Ice Growth 67
Effect on Cake Structure 67
Cake Structure Without Excipient Interaction
Cake Structurc with Excipient Interaction
Structure of Ice 71
Polymorphic Forms of Ice 72
Hexagonal Structure of Ih 73
Affect of Solutes 74
Clathrates or Gas Hydrates
Amorphous Frozen Water
Electrical Conductivity of Ice Disordered Surface Region 77
Conductivity of Ice 78
Intrinsic Conductivity of Ice
Surface Conductivity of Ice
Summary 79
4. Phase Changes 83
Importance of Phase Changes 83
Homogeneous and Heterogeneous Systems 84
Homogeneous System 84
Heterogeneous System 84
Constituents and Components Constituent 85
Component 85
Intensive State Variables
Equilibrium Between Phases 86
Degrees of Freedom 87
Phase Rule 87
Claperyon-Clausis Equation 88
Glassy States 89
Formulation 90
Latent Heat of Melting 91
Glass Transition and Collapse Temperatures 91
5. The Thermal Properties of Formulations 93
Need for Identifying Thermal Properties 93
Reproducibility of the Formulation 93
Rationale for the Freezing and Primary Drying Processes 94
Ice-Like Water Clusters 94
Degree of Supercooling 95
Equilibrium Freezing Temperature 95
The Water System 95
Formulation 96
Degree of Crystallization 97
Eutectic Temperature 99
Definitions 100
Gibb's Phase Rule
Freezing-Point Depression
Frequency of Eutectic Points in Formulations 101
Collapse Temperature 102
Interstitial Melting Temperature 103
Ice Melting Temperature 103
Metastable States 103
Activation Energy 104
6. Thermal Analytical Methods 109
Introduction 109
Thermal Analysis 109
Description of the Apparatus 110
Analytical Method 111
Container
Certification of the Thermocouples
Fill Volume
Setup of the Apparatus
Cooling
Warming
Interpretation of the Data 112
Cooling Data
Warming Data
Apparatus
Analytical Method
Thermal Characteristics
Differential Thermal Analysis 115
Description of the Apparatus 116
Analytical Method 116
Interpretation of the Data 116
Sodium Chloride Solution
Earl's Solution with Glucose and Glycine
Apparatus
Analytical Method
Thermal Characteristics
Limitations
Differential Scanning Calorimetry 121
Description of the Apparatus 121
Heat Flux Design
Null-Balance System
General Characteristics of DSC Systems
Analytical Method 124
Calibration and Certification
Preparation of the Sample and Reference
Freezing of the Sample
Warming Temperature Scanning Rate
Interpretation of the Data 125
Cooling Thermogram
Warming Thermogram
Summary and Comments 129
Apparatus
Analytical Method
Thermal Characteristics
Freezing Microscope 132
Description of the Apparatus and Analytical Method 132
Photomicrography and Cinemicrography
Freeze-Drying Microscope
Interpretation of the Observations 134
Freezing Process
Freeze-Drying During Warming
Summary and Comments 136
Advantages of the Freeze-Drying Microscope
Limitations of the Freeze-Drying Microscope
Electrical Resistance 138
Ohm's Law
Relationship Between Resistance and Resistivity
Conduction Mechanism
Parker Effect
Description of the Apparatus 142
Multielectrode System
Dual Electrode System
Vertical Resistivity Cell
Analytical Methods 146
Multielectrode System
Dual Electrode System
Vertical Resistivity Cell
Interpretation of the Data 147
Multielectrode System
Dual Electrode System
Vertical Resistivity Cell
Summary and Comments 151
Dielectric Analysis Introduction 153
Description of the Apparatus 155
Analytical Method 156
Preparation of the Sample
Test Method
Interpretation of the Data 156
Water
Relaxation Time
DCC and TOF Methods
Theoretical Basis for DEA Measurements
Apparatus
Analytical Method
Interpretation of the Data
D2 and DTA Analytical System 162
D2 Analysis
Description of the Apparatus 165
Test Containers, Sensors, and Resistance Cells
Data Collection and Computer System
Analytical Method 166
Run Identification
Calibration
Setup of the Analysis
Cooling Analysis
Warming Analysis
Printout of Data
Interpretation of the Data 170
Cooling
Warming
Apparatus
Appendix A: Data for Thermal Properties of a 0.9 percent NaCl Solution During Cooling and Warming 193
Appendix B: Data for a D2 and DTA Analysis of a 0.9 (wt/v) NaCl Solution 203
Appendix C: Data for 3 (wt/v) and 0.9 NaCl (wt/v) Solution 227
Appendix D: Data for a D2 and DTA Analysis of a 3 Lactose Solution 252
7. The Freezing Process 261
Introduction 261
Formation of the Frozen Matrix 262
Formation of Ice Crystals 262
Mushy System 262
Interstitial Region 263
Glassy State
Crystalline and Glassy States
Crystalline State
Frozen Matrix 266
Impact of the Fill Volume 267
Heat-Transfer Rate 267
Heat Transfer During Freezing 268
Freezing Functions and Methods 270
Other Freezing Methods 276
Immersion Freezing
Snap Freezing
8. The Primary Drying Process 261
Introduction 283
The Function of the Primary Drying Process 283
The Perception of the Primary Drying Process 283
The Sublimation Process 284
General Assumptions 284
Matrix Temperature
Disordered Ice Layer
Frequency Distribution of Energy
The Sublimation of Ice 286
Sublimation Model by Maeno and Nishimura
Sublimation Model by Pikal, Shah, Senior, and Lang
Rate of Sublimation by Livesey and Rowe
Sublimation Model by Dushman
Effects of Chamber Pressure and Shelf-Surface Temperature
Effect of Container Configuration 292
Heat-Transfer Rate
Heat Transfer Between the Shelf Surface and a Tray
Heat Transfer Between the Shelf Surface and a Vial
Primary Drying of a Formulation 306
Configuration of the Frozen Matrix
The Effect of the Interstitial Region on the Primary Drying Process
Key Process Parameters 313
General Relationship Between Pc Tp and Ts 313
Primary Drying Independent of the Batch Size
Size and Manufacturer of the Freeze-Dryer
Chamber Pressure 314
Effect of Lack of Pressure Control on Primary Drying
Impact of the Nature of the Pressure Gauge
Gauge Location and Design Features of the Dryer
Shelf Temperature 319
Fluid-Shelf Temperature
Inlet and Outlet Fluid Temperatures
ShelfSurface Temperature
Product Temperature 322
The Importance of Monitoring Tp
Indirect Determination of Tp
Manometric Measurements of Tp
Condenser Temperature 330
High Tc Values
Low Operating Pc Values
Design and Construction of the Condenser
Examples of Primary Drying Processes 331
Formulation #1 332
Determination of the Operating Parameters
Primary Drying Process for Formulation #1
Formulation #2 334
Determination of the Operating Parameters
Primary Drying Process for Formulation #2
Formulation #3 335
Determination of the Operating Parameters
Primary Drying Process for Formulation #3
Summary 338
Process Monitoring Techniques 339
Pressure Rise Test 339
Comparative Pressure Measurement 339
Dielectric Moisture Sensor 340
Windmill Device 342
Summary 342
Calorimetric Measurement Techniques 343
Introduction 343
Method for Making Calorimetric Measurements 343
Determination of Qm
Determination of Hm,t
Determination of Co 345
Preparation of the Sensor Vial
Measurement Method
Determination of Co Value
Measurement of Qm and Hm During Primary Drying 346
Applications of the Frequency Distribution of Co 348
Sensors for Calorimetric Measurements
Standard Deviation
9. Secondary Drying Processes 355
Role of the Drying Process 355
Historical Background 355
General Description of Secondary Drying 356
Criteria for Selecting Secondary Drying Parameters 356
Residual Moisture and Stability 357
Residual Moisture
Bound Water
Absorption, Adsorption, and Desorption of Gases 359
Absorption
Adsorption
Desorption
Model for Secondary Drying 363
Model
Examples of Adsorption or Desorption Isotherms of Lyophilized Products
Secondary Drying Parameters 368
Standard Operating Secondary Drying Parameters
Calorimetric Monitoring of Secondary Drying
Process Monitoring Techniques 372
Pressure Rise Test 372
Description of the Test Method
Comparative Pressure Sensors 373
Description of the Method
Humidity Sensor 375
Description of The Method
Residual Gas Analysis 375
Description of the Analytical Method
Purge Method 376
Calorimetric Measurements 377
Results of Calorimetric Measurements During Secondary Drying
Examples of the Secondary Drying Process 379
Formulation #1 380
Selection of the Operating Parameters
Secondary Drying for Formulation #1
Determination of Completion of Secondary Drying
Stoppering of the Vials
Formulation #2 383
Selection of the Operating Parameters
Secondary Drying for Formulation #2
Determination of Completion of Secondary Drying
Formulation #3 386
Selection of the Operating Parameters
Secondary Drying for Formulation #3
Determination of Completion of Secondary Drying
10. Product Properties 393
Need for Evaluation of the Lyophilized Product 393
General Overview of the Chapter 393
General Physical Properties of the Cake
Moisture
Reconstitution
Stability
Physical Properties 395
Effects of the Formulation 395
Transition Temperature
Cake Volume
Color
Texture
Cake Density
Shrinkage or Collapse
Pores
Crystallization
Structure
Cake Strength
Fractureability
Vial Breakage
Effects of the Lyophilization Parameters 405
Potency
Matrix Structure
Bilayer Structure
Froth or Foam
Cake Strength
Crust or Glaze
Collapse
Meltback
Puffing
Browning
Effects of Storage
Moisture Residual and Bound Water 410
Residual Moisture and Free Water
Dependence on Surface Area
Change in the Residual Moisture Content
Bound Water
Analytical Methods 412
Gravimetric Analysis of Bulk Materials
Gravimetric Analysis of Lyophilized Products
Thermogravimetric Analysis
Karl Fischer Method
Coulometric Karl Fischer Analysis
Comparative Study of Gravimetric, Thermogravimetric, and Karl Fischer Moisture Analyses
Water Pressure Determination
High Vacuum Moisture Determination
Reconstitution 426
The Diluent 426
pH of the Diluent
Temperature
Particulate Matter
Diluent Formulation
Reconstitution Time 427
Surface Area and Physical Properties
Methods for Reconstitution
Relationship of Lyophilization Process and Reconstitution
Effect of Storage
Specifications for Particulate Matter 429
USP Limits for Particulate Matter for Injectable Solutions
Sources of Subvisible Particles
Measurement of Particulate Matter
Additional Tests of the Reconstituted Formulation 431
Colligative Properties
Concentration Properties
Product Stability 432
Real-Time Stability 432
Accelerated Determination of Stability 432
Key Product Properties Affecting Stability 432
Structure
Moisture
Container System
Review of Statistical Methods and Control Charts 434
Frequency Distribution
Arithmetic Mean
Standard Deviation
Real-Time Stability Studies 438
Moisture Content
Product Stability
Accelerated Studies 443
Arrhenius Rate Equation
Description of the Method
General Reaction Expression
Results of Arrhenius Accelerated Studies
11. Vacuum Technology 457
The Need to Understand Vacuum Technology 457
Objectives of the Chapter 458
Kinetic Theory of Gases 459
Postulates 459
Gas Pressure 459
Units of Pressure
Partial and Vapor Pressures
Mean Free Path 463
Gas Flow 465
General Gas Flow Expression
Viscous Flow
Molecular Flow
Effect of Bends on Gas Conduction
Vapor Throughout 467
Gas Thermal Conductivity 470
Pressure Gauges 470
U Tube 470
McLeod Gauge 472
Fundamental Principles of The McLeod Gauge
Operation of The McLeod Gauge
Thermal Conductivity Gauges 474
Fundamental Principles of a Thermal Conductivity Gauge
Operation of the Thermocouple Gauge
Operating of a Pirani Gauge
Capacitance Manometer Gauge 478
Construction of the Capacitance Manometer Gauge
Operation of the Capacitance Manometer Gauge
Zeroing of the Gauge
Residual Gas Analysis RGA 480
Overall Instrument
Quadrupole Mass Spectrometer
Ion Formation and Fragmentation Patterns
Procedure for Determining the Partial Pressure of a Gas
Vacuum Leaks 487
Real Leaks 487
Straight Leak Path
Serpentine Leak Path
Malecular Flow Leak Paths
Virtual Leaks 490
12. Container-Closure System 495
Introduction 495
The Closure 496
Closure Composition and Formation 496
Polymer Component
Reinforcing Agent
Other Constituents
Formation of the Closure
Physical Properties 498
Modulus
Compression Set
Durometer Hardness
Glass Transition Temperature
Vapor Transport Properties
Diffusion and Permeation 501
Diffusion
Permeation
Outgassing 504
Outgassing or Gas Permeation
Outgassing of Water Vapor
Determining the Outgassing of Water Vapor
Frequency Distribution for the Outgassing of Water Vapor
Outgassing of Other Gas Species from Closures
Coring 514
Conditions for the Coring of Closures
Core Testing of the Closure
Siliconization of Closures 516
The Container 517
Historical 517
Dissolution and Leaching of Glass 517
Dissolution
Leaching
Glass Types
Cleaning of the Vials
The Physical Properties of Vials 519
Effect of Vial Configuration
Molded and Tubing Vials
Glass Ampollles
Container-Closure System 523
Description of the Sealing System 523
The Crimping Operation
Container-Closure Seal
Measurement of compressive Forces 525
Twist Method
Seal Force Monitor
West Seal Tester
Constant Rate of Strain Testing
On-Line Testing
Container-Closure Leaks 528
Bubble Test 529
Standard Method
Vacuum Bubble Test
Pressure Rise 531
Color Dye Test 533
Helium Leak Testing 533
Verification of the Helium Leak Test for a Container-Closure
Determination of the Leak Rate for an Uncrimped Closure
Leak Rate for a Crimped Container-Closure System
Glow Discharge Method 538
Nature of the Glow Discharge
Electro-Technic VC-105 Automatic Vacuum Tester
Effect of the Glow Discharge on the Properties of the Lyophilized Cake
Microbial Transport Tests 542
Microbial Ingress Test Method
Microbial Regress Test Method
Miscellaneous Tests 543
Vacuum/Pressure Decay
Carbon Dioxide Tracer Gas
Oxygen as a Tracer Gas
Ampoule Seal 544
Leak Testing of Ampoules 545
Water Bath
Dark Field Microscopy
13. Effect of Vacuum Freeze-Dryers-Present and Future 549
Introduction 549
Impact on the Lyophilization Process 549
Impact on the Lyophilized Product 550
Effect on the Container-Closure System 550
Safety Considerations 551
The Drying Chamber 551
Chamba Design or Configuration 551
Construction 553
Materials
Finish
Insulation
Leaks 555
Real Leaks
Virtual Leaks
Leak Testing 559
Dryer Preparation Leaks and the Nature of the Leak
Soap Solution
Acetone
Helium Leak Testing
Mass Spectrometer
Refrigerant Leak Detection
Fluorescence
Door 567
Design and Construction
Thermal Insulation
Gorilla Effect Shelves 571
Construction
Unusable and Usable Shelves
Spacing
Heat Transfer
Direct Expansion
Gas Conductance
Heat-Transfer Fluid
Shelf Temperature
Safe Environment 580
Particulate Matter 580
Swab Test
Filter Test
Counter
Vapor Deposits 582
Swab Test
Contact Angle
Cleaning 584
Manual
Clean-in-Place
Flooding
The Condenser 586
Condenser Configuration 587
Plates
Coils
Capacity 589
Condenser Temperatures 589
Internal Condenser 590
External Condenser 591
Isolation Valve 591
Valve Configuration
Gas Conductance
Vacuum System The Need for a Vacuum System 592
Foreline 593
Backstreaming of Oil Vapors 593
Methods for Determining Backstreaming
Means for Eliminating or Preventing Backstreaming
Gas Ballast 598
Instrumentation 600
Vacuum Gauges 600
Mercury McLeod Gauge
Pirani and Thermocouple Gauges
Capacitance Manometer Gauge
Process Control Systems 602
Automatic Resistivity Control System
Computer Control System
Temperature Control
Data Collection System
The Future of Lyophilization 606
New Objectives 607
Formulation 608
Thermal Properties
Cake Properties
Statistical Approach
The Scientific Forum
Batch Verses Continuous 610
The Batch System
The Continuous System
A Prototype of a Continuous Freeze-Dryer
A Comparison of a Conventional and a Continuous Dryer
A Comparison of Required Utilities
A Comparison of Production Parameters and Capacity