TY - BOOK AU - Jennings,Thomas A. TI - Lyophilization : : introduction and basic principles / SN - 1574910817 PY - 2002/// CY - Boca Raton : PB - CRC Press, KW - LIOFILIZACION KW - SECADO KW - CONGELACION KW - PROCESOS DE INGENIERIA QUIMICA KW - LYOPHILIZATION KW - DRYING KW - FREEZE KW - SECADO POR CONGELACION N1 - 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 ER -