Lyophilization - Introduction and Basic Principles
(Third Printing)
By
Thomas A. Jennings, Ph.D.
Chapter 1 Introduction
Chapter 2 Product Formulation
Chapter 3 Importance of the Process Water
Chapter 4 Phase Changes
Chapter 5 Thermal Properties of Formulations
Chapter 6 Thermal Analytical Methods
Chapter 7 Freezing Process
Chapter 8 Primary Drying Process
Chapter 9 Secondary Drying Process
Chapter 10 Product Properties
Chapter 11 Vacuum Technology
Chapter 12 Container-Closure System
Chapter 13 Effect of Vacuum Freeze-Dryers - Present and Future
I. HISTORICAL REVIEW
II. EVOLUTION OF PROCESS AND EQUIPMENT
III. DEFINITION OF LYOPHILIZATION
IV. GENERAL DESCRIPTION OF THE PROCESS
A. Formulation
B. Freezing
C. Primary Drying
D. Secondary Drying
E. Container-Closure System
F. Freeze-Drying Equipment
1. FREEZE-DRYING CHAMBER
2. CONDENSER CHAMBER
3. VACUUM PUMPING SYSTEM
V. PROPERTIES OF LYOPHILIZED MATERIALS
A. Stability
1. LONG TERM OR REAL TIME STABILITY TESTING
2. ACCELERATED STABILITY TESTING
B. Cosmetic Properties
C. Moisture
D. Reconstitution
VI. APPLICATIONS
A. Healthcare Industry
B. Veterinary
C. Food
D. Other Applications
REFERENCES
I. INTRODUCTION
II. ACTIVE INGREDIENT
A. Synthetic
1. CIS PLATIN
2. SODIUM SALT OF [2,3-DICHLORO-4 (METHYLENEBUTYRYL) ACETIC ACID
B. Nature Derived
1.VACCINES
2. PROTEINS
C. Physical State
1. SOLVENT SYSTEM
2. HUMIDIFICATION
3. THERMAL TREATMENT
III. OTHER CONSTITUENTS
A. Buffers
1. LAW OF MASS ACTION
2. DEFINITION OF pH
3. BUFFER SOLUTION
B. Bulking Compounds
1. MANNITOL
2. POLYVINYLPYRROLIDONE (PVP)
3. OTHER BULKING AGENTS
C. Stabilizing Agents
1. LAW OF MASS ACTION
2. EXCIPIENT INDUCED CRYSTALLIZATION OF THE ACTIVE INGREDIENT
D. Cryoprotectants
E. Lyoprotectant
IV. SOLVENTS
A. Nature of Water
1. SOLUBILITY MECHANISM
2. SOLVATION
B. Other Solvent Systems
1. CRYSTALLIZATION OF THE ACTIVE INGREDIENT
2. STABILITY OF THE ACTIVE INGREDIENT
V. PHYSICAL CHARACTERISTICS
A. Colligative Properties
1. FREEZING POINT DEPRESSION
2. OSMOLARITY
B. Concentration Properties
1.OPTICAL
C. Particulate Matter
1. VISIBLE PARTICLES AND MEANS FOR THEIR DETECTION
2. SUBVISIBLE PARTICLES AND MEANS FOR THEIR DETECTION
3. AIR BUBBLES AND IMMISCIBLE LIQUID DROPLET
4. HANDLING AND STORAGE
5. VARIOUS SOURCES OF PARTICULAR MATTER IN A FORMULATION
VI. THERMAL PROPERTIES
A. Function of the Thermal Properties
B. Effect on the Cost of Manufacturing
C. Impact On The Freeze-Dryer
SYMBOLS
REFERENCES
Chapter 3 Importance of the Process Water
I. ROLE OF THE PROCESS WATER IN LYOPHILIZATION
A. Introduction
B. Purity
1. TOTAL SOLIDS
2. CHEMICAL TESTS
3. CONDUCTIVITY
4. pH MEASUREMENTS
5. ORGANIC COMPOUNDS
6. MICROBIAL AND ENDOTOXIN LEVELS
II. HYDROGEN BONDING
A. Formation
B. Impact of Excipients or Impurities
III. DEGREE OF SUPERCOOLING
A. Heterogeneous Nucleation
B. Homogenous Nucleation
C. Rate of Ice Growth
D. Effect on Cake Structure
1. CAKE STRUCTURE WITHOUT EXCIPIENT INTERACTION
2. CAKE STRUCTURE WITH EXCIPIENT INTERACTION.
IV. STRUCTURE OF ICE
A. Polymorphic Forms Of Ice
B. Hexagonal Structure Of Ice Ih
C. Affect of Solutes
1. CLATHRATES OR GAS HYDRATES
2. AMORPHOUS FROZEN WATER
V. ELECTRICAL CONDUCTIVITY OF ICE
A. Disordered Surface Region
B. Conductivity of Ice
1.INTRINSIC CONDUCTIVITY OF ICE.
2.SURFACE CONDUCTIVITY OF ICE
VI. SUMMARY
SYMBOLS
REFERENCES
I. IMPORTANCE OF PHASE CHANGES
II. HOMOGENEOUS AND HETEROGENEOUS SYSTEMS
A. Homogeneous System
B. Heterogeneous System
III. CONSTITUENTS AND COMPONENTS
A. Constituent
B. Component
IV. INTENSIVE STATE VARIABLES
A. Equilibrium between Phases
B. Degrees of Freedom
C. Phase Rule
V. CLAPERYON-CLAUSIS EQUATION
VI. GLASSY STATES
A. Formulation
B. Latent Heat of Melting
C. Glass Transition and Collapse Temperatures
SYMBOLS
REFERENCES
Chapter 5 Thermal Properties of Formulations
I. NEED FOR IDENTIFYING THERMAL PROPERTIES
A. Reproducibility of the Formulation
B. Rational for the Freezing and Primary Drying Processes
II. ICE-LIKE WATER CLUSTERS
III. DEGREE OF SUPERCOOLING
IV. EQUILIBRIUM FREEZING TEMPERATURE
A. The Water System
B. Formulation
V. DEGREE OF CRYSTALLIZATION
VI. EUTECTIC TEMPERATURE
A. Definition
1. FIRST DEFINITION
2. SECOND DEFINITION
B. Frequency of Eutectic Points in Formulations
VII. COLLAPSE TEMPERATURE
VIII. INTERSTITIAL MELTING TEMPERATURE
IX. ICE MELTING TEMPERATURE
X. METASTABLE STATES
XI. ACTIVATION ENERGY
SYMBOLS
REFERENCES
Chapter 6 Thermal Analytical Methods
I. INTRODUCTION
II. THERMAL ANALYSIS
A. Description of the Apparatus
B. Analytical Method
1. CONTAINER
2. CERTIFICATION OF THE THERMOCOUPLES
3. FILL-VOLUME
4. SET-UP OF THE APPARATUS
5. COOLING
6. WARMING
C. Interpretation of the Data
1. COOLING DATA
2. WARMING DATA
D. Summary and Comments
1. APPARATUS
2. ANALYTICAL METHOD
3. THERMAL CHARACTERISTICS
III. DIFFERENTIAL THERMAL ANALYSIS (DTA)
A. Description of the Apparatus
B. Analytical Method
C. Interpretation of the Data
1. SODIUM CHLORIDE SOLUTION
2. EARL'S SOLUTION WITH GLUCOSE AND GLYCINE (Er.G.g).
D. Summary and Comments
1. APPARATUS
2. ANALYTICAL METHOD
3. THERMAL CHARACTERISTICS
4. LIMITATIONS
IV. DIFFERENTIAL SCANNING CALORIMETRY (DSC)
A. Description of the Apparatus
1. HEAT FLUX DESIGN
2. NULL-BALANCE SYSTEM
3. GENERAL CHARACTERISTICS OF DSC SYSTEMS
B. Analytical Method
1. CALIBRATION AND CERTIFICATION
2. PREPARATION OF THE SAMPLE AND REFERENCE
3. FREEZING OF THE SAMPLE
4. WARMING TEMPERATURE SCANNING RATE
C. Interpretation of the Data
1. COOLING THERMOGRAM
2. WARMING THERMOGRAM
D. Summary and Comments
1. APPARATUS
2. ANALYTICAL METHOD
3. THERMAL CHARACTERISTIC
V. FREEZING MICROSCOPE
A. Description of the Apparatus and Analytical Method
1. PHOTOMICROGRAPHY AND CINEMICROGRAPHY
2. FREEZE-DRYING MICROSCOPE
B. Interpretation of the Observations
1. FREEZING PROCESS
2. FREEZE-DRYING DURING WARMING
C. Summary and Comments
1. ADVANTAGES OF THE FREEZE-DRYING MICROSCOPE
2. LIMITATIONS OF THE FREEZE-DRYING MICROSCOPE
VI. ELECTRICAL RESISTANCE
A. Introduction
1. OHMS LAW
2. RELATIONSHIP BETWEEN RESISTANCE AND RESISTIVITY
3. CONDUCTION MECHANISM
4. PARKER EFFECT
B. Description of the Apparatus
1. MULTI-ELECTRODE SYSTEM
2. DUAL ELECTRODE SYSTEM
3. VERTICAL RESISTIVITY CELL
C. Analytical Methods
1. MULTI-ELECTRODE SYSTEM
2. DUAL ELECTRODE SYSTEM
3. VERTICAL RESISTIVITY CELL
D. Interpretation of the Data
1. MULTI-ELECTRODE SYSTEM
2. DUAL ELECTRODE SYSTEM
3. VERTICAL RESISTIVITY CELL
E. Summary and Comments
VII. DIELECTRIC ANALYSIS (DEA)
A. Introduction
B. Description of the Apparatus
C. Analytical Method
1. PREPARATION OF THE SAMPLE
2. TEST METHOD
D. Interpretation of the Data
1. WATER
2. RELAXATION TIME
3. DCC AND TOF METHODS
E. Summary and Comments
1. THEORETICAL BASIS FOR DEA MEASUREMENTS
2. APPARATUS
3. ANALYTICAL METHOD
E. INTERPRETATION OF THE DATA
VIII. D2 AND DTA ANALYTICAL SYSTEM
A. Introduction
1. D2 ANALYSIS
B. Description of the Apparatus
1. TEST CONTAINERS, SENSORS AND RESISTANCE CELLS
2. DATA COLLECTION AND COMPUTER SYSTEM
C. Analytical Method
1. RUN IDENTIFICATION
2. CALIBRATION
3. SETUP OF THE ANALYSIS
4. COOLING ANALYSIS
4. WARMING ANALYSIS
5. PRINTOUT OF DATA
D. Interpretation of the Data
1. COOLING
2. WARMING
E. Summary and Comments
1. APPARATUS
3. INTERPRETATION OF THE DATA
LIST OF SYMBOLS
REFERENCES
I. INTRODUCTION
II. FORMATION OF THE FROZEN MATRIX
A. Formation of Ice Crystals
B. Mushy System
C. Interstitial Region
1. GLASSY STATE
2. CRYSTALLINE AND GLASSY STATES
3. CRYSTALLINE STATE
D. Frozen Matrix
III. IMPACT OF THE FILL-VOLUME
A. Heat Transfer Rate
B. Heat Transfer During Freezing
IV. FREEZING FUNCTIONS AND METHODS
A. Introduction
B. Formulation #1
C. Formulation #2
D. Formulation #3
E. Other Freezing Methods
1. IMMERSION FREEZING
2. SNAP FREEZING
SYMBOLS
REFERENCES
Chapter 8 Primary Drying Process
I. INTRODUCTION
A. Function of Primary Drying Process
B. Perception of the Process
II. SUBLIMATION PROCESS
A. General Assumptions
1. MATRIX TEMPERATURE
2. DISORDERED ICE LAYER
3. FREQUENCY DISTRIBUTION OF ENERGY
B. Sublimation of Ice
1. SUBLIMATION MODEL BY N. MAENO AND H. NISHIMURA
2. SUBLIMATION MODEL BY PIKAL, SHAH, SENIOR AND LANG
3. RATE OF SUBLIMATION BY LIVESEY AND ROWE
4.SUBLIMATION MODEL BY DUSHMAN
5. EFFECT OF CHAMBER PRESSURE AND SHELF-SURFACE TEMPERATURE
C. Effect of Container Configuration
1. HEAT TRANSFER RATE
2. HEAT TRANSFER BETWEEN THE SHELF-SURFACE AND A TRAY
3. HEAT TRANSFER BETWEEN THE SHELF-SURFACE AND A VIAL
D. Primary Drying of a Formulation
1. CONFIGURATION OF THE FROZEN MATRIX
2. THE EFFECT THAT THE INTERSTITIAL REGION ON THE PRIMARY DRYING PROCESS.
III. KEY PROCESS PARAMETERS
A. General Relationship between Pc, Tp, Ts
1. PRIMARY DRYING INDEPENDENT OF THE BATCH SIZE
2. SIZE AND MAKE OF THE FREEZE-DRYER
B. Chamber Pressure
1. EFFECT OF LACK OF PRESSURE CONTROL HAS ON THE PRIMARY DRYING
2. IMPACT OF THE NATURE OF THE PRESSURE GAUGE
3. GAUGE LOCATION AND DESIGN FEATURES OF THE DRYER
C. Shelf Temperature
1. FLUID-SHELF TEMPERATURE
2. INLET AND OUTLET FLUID TEMPERATURES
3. SHELF-SURFACE TEMPERATURE
D. Product Temperature
1. IMPORTANCE OF MONITORING Tp
2. INDIRECT DETERMINATION OF Tp
3. MANOMETRIC MEASUREMENTS OF TP
E. Condenser Temperature
1. HIGH Tc VALUES
2. LOW OPERATING Pc VALUES
3. DESIGN AND CONSTRUCTION OF THE CONDENSER
IV. EXAMPLES OF PRIMARY DRYING PROCESSES
A. Formulation #1
1. DETERMINATION OF THE OPERATING PARAMETERS
2. PRIMARY DRYING PROCESS FOR FORMULATION #1
B. Formulation #2
1. DETERMINATION OF THE OPERATING PARAMETERS
2. PRIMARY DRYING PROCESS FOR FORMULATION #2
C. Formulation #3
1. DETERMINATION OF THE OPERATING PARAMETERS
2. PRIMARY DRYING PROCESS FOR FORMULATION #3
D. Commentary
V. PROCESS MONITORING TECHNIQUES
A. Pressure Rise Test
B. Comparative Pressure Measurement
C. Dielectric Moisture Sensor
D. Windmill Device
E. Commentary
VI. CALORIMETRIC MEASUREMENT TECHNIQUE
A. Introduction
B. Method For Making Calorimetric Measurements
1. DETERMINATION OF Q
2. DETERMINATION OF Hm.t
C. Determination of Co
1. PREPARATION OF THE SENSOR VIAL
2. MEASUREMENT METHOD
3. DETERMINATION OF Co VALUE
D. Measurement of Qm and Hm during Primary Drying
E. Applications of the Frequency Distribution of Co
1. SENSORS FOR CALORIMETRIC MEASUREMENTS
2. USE OF THE STANDARD DEVIATION
F. Commentary
SYMBOLS
REFERENCES
Chapter 9 Secondary Drying Process
I. INTRODUCTION
II. ROLE IN THE DRYING PROCESS
A. Historical Background
B General Description of Secondary Drying
III. CRITERIA FOR SELECTING SECONDARY DRYING PARAMETERS
A. Residual Moisture and Stability
1. RESIDUAL MOISTURE
2. BOUND WATER
B. Absorption, Adsorption and Desorption of Gases
1. ABSORPTION
2. ADSORPTION
3. DESORPTION
C. Model for Secondary Drying
1. MODEL
2. EXAMPLES OF ADSORPTION OR DESORPTION ISOTHERMS OF LYOPHILIZED PRODUCTS
D. Secondary Drying Parameters
1. STANDARD OPERATING SECONDARY DRYING PARAMETERS
2. CALORIMETRIC MONITORING OF THE SECONDARY DRYING
IV. PROCESS MONITORING TECHNIQUES
A. Pressure Rise Test
1. DESCRIPTION OF THE TEST METHOD
2. COMMENTARY
B. Comparative Pressure Sensors
1. DESCRIPTION OF THE METHOD
2. COMMENTARY
C. Humidity Sensor
1. DESCRIPTION OF THE METHOD.
2. COMMENTARY
D. Residual Gas Analyzer
1. DESCRIPTION OF THE ANALYTICAL METHOD
2. COMMENTARY
E. Purge Method
F Calorimetric Measurements
1. RESULTS OF CALORIMETRIC MEASUREMENTS DURING SECONDARY DRYING
2. COMMENTARY
V. EXAMPLES OF THE SECONDARY DRYING PROCESS
A. Formulation #1
1. SELECTION OF THE OPERATING PARAMETERS
2. SECONDARY DRYING FOR FORMULATION #1
3. DETERMINATION OF COMPLETION OF SECONDARY DRYING
4. STOPPERING OF THE VIALS
5. COMMENTARY
B. Formulation #2
1. SELECTION OF THE OPERATING PARAMETERS
2. SECONDARY DRYING FOR FORMULATION #2
3. DETERMINATION OF COMPLETION OF SECONDARY DRYING
C. Formulation #3
1. SELECTION OF THE OPERATING PARAMETERS
2. SECONDARY DRYING FOR FORMULATION #3
3. DETERMINATION OF COMPLETION OF SECONDARY DRYING
SYMBOLS
REFERENCES
I. INTRODUCTION
A. Need For Evaluation
B. General Overview of the Chapter
1. GENERAL PHYSICAL PROPERTIES OF THE CAKE
2. MOISTURE
3. RECONSTITUTION
4. STABILITY
II. PHYSICAL PROPERTIES
A. Effects of the Formulation
1. TRANSITION TEMPERATURE
2. CAKE VOLUME
3. COLOR
4. TEXTURE
5. CAKE DENSITY
6. SHRINKAGE OR COLLAPSE
7. PORES
8. CRYSTALLIZATION
9. STRUCTURE
10. CAKE STRENGTH
11. FRACTURABILITY
12. VIAL BREAKAGE
B. Effects of the Lyophilization Parameters
1. POTENCY
2. MATRIX STRUCTURE
3. BILAYER STRUCTURE
4. FROTH OR FOAM
5. CAKE STRENGTH
6. CRUST OR GLAZE
7. COLLAPSE
8. MELTBACK
9. PUFFING
10. BROWNING
11. EFFECTS OF STORAGE
III. MOISTURE
A. Residual and Bound Water
1. RESIDUAL MOISTURE
2. DEPENDENCE ON SURFACE AREA
3. CHANGE IN THE RESIDUAL MOISTURE CONTENT
4. BOUND WATER
B. Analytical Methods
1. GRAVIMETRIC ANALYSIS OF BULK MATERIALS
2. GRAVIMETRIC ANALYSIS OF LYOPHILIZED PRODUCTS
3. THERMOGRAVIMETRIC
4. KARL FISCHER METHOD
5. COULOMETRIC KARL FISCHER
6. COMPARATIVE STUDY OF GRAVIMETRIC, THERMOGRAVIMETRIC MOISTURE ANALYSIS AND KARL FISCHER MOISTURE ANALYSIS
7. WATER PRESSURE DETERMINATION
8. HIGH VACUUM MOISTURE DETERMINATION
IV. RECONSTITUTION
A. Diluent
1. PROPERTIES OF THE DILUENT
B. Reconstitution Time
1. SURFACE AREA AND PHYSICAL PROPERTIES
2. METHODS FOR RECONSTITUTION
3. RELATIONSHIP WITH LYOPHILIZATION PROCESS
4. EFFECT OF STORAGE
B. Specifications - Particular Matter
1. USP LIMITS FOR PARTICULAR MATTER FOR INJECTABLE
2. SOURCES OF SUB-VISIBLE PARTICLES
3. METHOD OF MEASUREMENT
C. Additional Tests of the Reconstituted Formulation
1. COLLIGATIVE PROPERTIES
2. CONCENTRATION PROPERTIES
V. PRODUCT STABILITY
A. Introduction
1. REAL TIME STABILITY
2. ACCELERATED DETERMINATION OF STABILITY
B. Key Product Properties Affecting Stability
1. STRUCTURE
2. MOISTURE
3. CONTAINER SYSTEM
C. Review of Statistical Methods and Control Charts
1. FREQUENCY DISTRIBUTION
2. ARITHMETIC MEAN
3. STANDARD DEVIATION
D. Real Time Stability Studies
1. MOISTURE CONTENT
2. PRODUCT STABILITY
E. Accelerated Studies
1. ARRHENIUS RATE EXPRESSION
2. DESCRIPTION OF THE METHOD
3. GENERAL REACTION EXPRESSION
4. RESULTS OF ARRHENIUS ACCELERATED STUDIES
SYMBOLS
REFERENCES
I. INTRODUCTION
A. Need to Understand Vacuum Technology
B. Objectives of the Chapter
1. KINETIC THEORY OF GASES
2. PRESSURE AND ITS MEASUREMENT
3. MEAN FREE PATH
4. GAS FLOW
5. VAPOR THROUGHPUT OF A SYSTEM
6. REAL LEAKS
7. VIRTUAL LEAKS
II. KINETIC THEORY OF GASES
A. Postulates
1. FIRST POSTULATE
2. SECOND POSTULATE
B. Gas Pressure
1. UNITS OF PRESSURE
2. PARTIAL AND VAPOR PRESSURES
C. Mean Free Path
D. Gas Flow
1. GENERAL GAS FLOW EXPRESSION
2. VISCOUS FLOW
3. MOLECULAR FLOW
4. EFFECTIVE OF BENDS ON THE GAS CONDUCTION
E. Vapor Throughput
1. CONDUCTANCE LIMITED
2. EFFECT ON THROUGHPUT (Qt )
F. Gas Conductivity
III. PRESSURE GAUGES
A. U Tube
B. McLeod Gauge
1. FUNDAMENTAL PRINCIPLES OF A MCLEOD GAUGE
2. OPERATION OF THE MCLEOD GAUGE
C. Thermoconductivity Gauges
1. FUNDAMENTAL PRINCIPLES OF A THERMAL CONDUCTIVITY GAUGE
2. OPERATION OF THE THERMOCOUPLE GAUGE
3. OPERATION OF A PIRANI GAUGE
D. Capacitance Manometer Gauge
1. CONSTRUCTION OF THE CAPACITANCE MANOMETER GAUGE
2. OPERATION OF THE CAPACITANCE MANOMETER GAUGE
3. ZEROING OF THE GAUGE
E Residual Gas Analyzer (RGA)
1. OVERALL INSTRUMENT
2. QUADRUPLE MASS SPECTROMETER
3. ION FORMATION AND FRAGMENTATION PATTERNS
4. PROCEDURE FOR DETERMINING THE PARTIAL PRESSURE OF A GAS
IV. VACUUM LEAKS
A. Real Leaks
1. STRAIGHT LEAK PATH
2. SERPENTINE LEAK PATH
3. MOLECULAR FLOW LEAK PATHS
B. Virtual Leaks
V SUMMARY
SYMBOLS
REFERENCES
Chapter 12 Container-Closure System
I. INTRODUCTION
II. CLOSURE
A. Closure Composition and Formation
1. POLYMER COMPONENT
2. REINFORCING AGENT
3. OTHER CONSTITUENTS
4. FORMATION OF THE CLOSURE
B. Physical Properties
1. MODULUS
2. COMPRESSION SET
3. DUROMETER HARDNESS
4. GLASS TRANSITION TEMPERATURE
5. MASS TRANSPORT PROPERTIES
C. Diffusion and Permeation
1. DIFFUSION
2. PERMEATION
D. Outgassing
1. OUTGASSING OR GAS PERMEATION
2. OUTGASSING OF WATER VAPOR
3. MEANS FOR DETERMINING THE OUTGASSING OF WATER VAPOR
4. FREQUENCY DISTRIBUTION FOR THE OUTGASSING OF WATER VAPOR
5. OUTGASSING OF OTHER GAS SPECIES FROM CLOSURES
E. Coring
1. CONDITIONS FOR CORING OF CLOSURES
2. CORE TESTING OF THE CLOSURE
F. Siliconized of Closures
III CONTAINER
A. Introduction
B. Historical
C. Dissolution and Leaching of Glass
1. DISSOLUTION
2. LEACHING
3. GLASS TYPES
4. CLEANING OF THE VIALS
D. Physical Properties of Vials
1. EFFECT OF VIAL CONFIGURATION
2. MOLDED AND TUBING VIALS
3. GLASS AMPOULES
IV. CONTAINER-CLOSURE SYSTEM
A. Description of the Sealing System
1. CRIMPING OPERATION
2. CONTAINER-CLOSURE SEAL
B. Measurement of Compressive Forces
1. TWIST METHOD
2. SEAL FORCE MONITOR
3. WEST SEAL TESTER
4. CONSTANT RATE OF STRAIN TESTING
5. ON-LINE TESTING
V. CONTAINER-CLOSURE LEAKS
A. Bubble Test
1. STANDARD METHOD
2. VACUUM BUBBLE TEST
B. Pressure Rise
C. Color Dye Test
D. Helium Leak Testing
1. VERIFICATION OF THE HELIUM LEAK TEST FOR A CONTAINER-CLOSURE
2. DETERMINATION OF THE LEAK RATE FOR UN-CRIMP CLOSURE
3. LEAK RATE FOR A CRIMPED CONTAINER-CLOSURE SYSTEM
E. Glow Discharge Method
1. NATURE OF THE GLOW DISCHARGE
2. ELECTRO-TECHNIC VC-105 AUTOMATIC VACUUM TESTER
3. EFFECT OF THE GLOW DISCHARGE ON THE PROPERTIES OF THE LYOPHILIZED CAKE
4. COMMENT
F. Microbial Transport Tests
1. MICROBIAL INGRESS TEST METHOD
2. MICROBIAL REGRESS TEST METHOD
G. Miscellaneous Tests
1. VACUUM/PRESSURE DECAY
2. CARBON DIOXIDE TRACER GAS
3. OXYGEN AS A TRACER GAS
VI. Ampoule Seal
A. Leak Testing of Ampoules
1. WATER BATH
2. DARK FIELD MICROSCOPY
SYMBOLS
REFERENCES
Chapter 13 Effect of Vacuum Freeze-Dryers - Present and Future
I. INTRODUCTION
A. Impact on the lyophilization Process
B. Impact on the Lyophilized Product
C. Effect on the Container-Closure System
D. Safety Considerations
II. DRYING CHAMBER
A. Chamber Design or Configuration
B. Construction
1. MATERIALS
2. FINISH
3. INSULATION
C. Leaks
1. REAL LEAKS
2. VIRTUAL LEAKS
D. Leak Testing
1. DRYER PREPARATION LEAK AND NATURE OF THE LEAK
2. SOAP SOLUTION
3. ACETONE
4. HELIUM LEAK TESTING
5. MASS SPECTROMETER
6. REFRIGERANT LEAK DETECTION
7. FLUORESCENCE
E. Door
1. DESIGN AND CONSTRUCTION
2. THERMAL INSULATION
3. GORILLA EFFECT
F. Shelves
1. CONSTRUCTION
2. UN-USABLE AND USABLE SHELVES
3. SPACING
4. HEAT TRANSFER
5. SHELF TEMPERATURE
III. ENVIRONMENT
A. Particulate Matter
1. SWAB TEST
2. FILTER TEST
3. COUNTER
B. Vapor Deposits
1. SWAB TEST
2. CONTACT ANGLE
C Cleaning
1. MANUAL
2. CLEAN IN PLACE (CIP)
3. FLOODING
IV. CONDENSER
A. Condenser Configuration
1. PLATES
2. COILS
B. Capacity
C. Condenser Temperatures.
D. Internal Condenser
E. External Condenser
F Isolation Valve
1. VALVE CONFIGURATION
2. GAS CONDUCTANCE
V. VACUUM SYSTEM
A. Need for Vacuum System
B. Foreline
C. Backstreaming of Oil Vapors
1. METHODS FOR DETERMINING BACKSTREAMING
2. MEANS FOR ELIMINATING OR PREVENTING BACKSTREAMING
D. Gas Ballast
VI. INSTRUMENTATION
A. Vacuum gauges
1. MERCURY MCLEOD GAUGE
2. PIRANI AND THERMOCOUPLE GAUGES
3. CAPACITANCE MANOMETER GAUGE
B. Process Control Systems
1. AUTOMATIC RESISTIVITY CONTROL SYSTEM
2. COMPUTER CONTROL SYSTEM
3. TEMPERATURE CONTROL
4. DATA COLLECTION SYSTEM
VII. FUTURE OF LYOPHILIZATION
A. New Objectives
B. Formulation
1.THERMAL PROPERTIES
2.CAKE PROPERTIES
3.STATISTICAL APPROACH
C. The Scientific Forum
D. Batch Verses Continuous
1. BATCH SYSTEM
2. CONTINUOUS SYSTEM
3. PROTOTYPE OF A CONTINUOUS FREEZE-DRYER
4. COMPARISON OF A CONVENTIONAL AND CONTINUOUS DRYER
D. Comparison of Require Utilities
E. Comparison of Production Parameters and Capacity
SYMBOLS
REFERENCES
INDEX
APPENDIXES
Please be advised that the above Table of Contents differs in format and content (an extra heading has been added) from that published in the book.