PREFACE
1. Freeze-drying of parenteral drug products â" An Introduction
1.1 Introduction
1.2 Freeze-drying â" An overview
1.3 Product formulation
1.3.1 Understanding the drug substance
1.3.2 Excipients in freeze-dried drug product development
1.4 Freeze-dryer components
1.4.1 The vacuum system
1.4.2 The condenser
1.5 Standard process instrumentation
1.5.1 Product probes
1.5.2 Pressure gauges
1.6 Operational parameters
1.7 Process parameters
1.8 Designing the freezing stage
1.8.1 Cooling ramp and process of ice formation
1.8.2 Critical temperatures
1.8.3 Set shelf temperature
1.8.4 Holding period
1.8.5 Annealing
1.9 Designing the primary drying stage
1.9.1 Ice sublimation process
1.10 Designing the secondary drying stage
1.11 Process modelling and Process Analytical Technologies
1.12 Optical and spectroscopic PAT tools
2. Standard PAT instrumentation: Temperature sensors
2.1 Introduction
2.2 Resistance temperature detector (RTD)
2.3 Thermocouples
2.3.1 Thermocouple calibration
2.3.2 Thermocouple guides
2.4 Summary comparison between RTDs and TCs
2.5 American wire gauge
2.6 Wireless temperature sensors
2.7 Temperature measurements - Best practice
2.8 Disadvantages and drawbacks of product probes
2.9 Calibration methods
2.10 Applications of temperature sensors in freeze-drying
2.11 Limitations of product temperature sensors
2.12 Future outlook
3. Standard PAT instrumentation: Pressure gauges and vapour pressure sensors
3.1 Gas pressure
3.2 Units of gas pressure
3.3 Measurement of pressure
3.4 Overview
3.4.1 Capacitive pressure measurement
3.4.2 Capacitive pressure sensor
3.4.3 Capacitive vacuum sensor
3.4.4 Pirani vacuum sensor
3.5 Calibrating pressure sensors
3.6 Pressure voltage relationships
3.7 Pressure control techniques
3.8 Instrumental configuration
3.9 Pressure control for ice nucleation
3.10 Comparative pressure measurement
3.11 Water vapour pressure
3.11.1 Dynamic equilibria
3.11.2 Escape tendency (fugacity) and evaporation
3.11.3 Dalton's Law of partial pressures
3.11.4 Dew/Frost point
3.11.5 Partial pressure and relative humidity (RH)
3.11.6 Vapour pressure and temperature
3.11.7 The Clapeyron equation
3.11.8 Clausius-Clapeyron equation
3.12 Application of the Clausius-Clapeyron in freeze-drying
3.12.1 Empirical relationships
3.13 Colligative properties
3.13.1 Lowering of vapour pressure
3.14 Measurement of water vapour pressure
3.14.1 Chilled Mirror Hygrometer (CMH)
3.14.2 Dew Point Sensors (DPS)
3.14.3 Spectroscopic Hygrometers (SH)
3.15 Calibration of water vapour measurements
3.15.1 Mixed flow water vapour calibration systems
3.15.2 Pressure and temperature based water vapour calibration systems
3.16 Conclusion
4. Wireless sensor networks for lyophilization
4.1 Introduction
4.1.1 Overview of Wireless Sensor Applications
4.1.2 General Overview of Wireless Sensor Platforms
4.1.3 Conventional Lyophilization Process Monitoring
4.2 Existing Wireless Sensors of Lyophilization
4.2.1 Wireless Temperature Sensors
4.2.2 Wireless Pressure Sensors
4.2.3 Wireless Vial Strain Sensors
4.2.4 Wireless Sensor for Rapid Depressurization Controlled Ice-Nucleation (RD-CIN)
4.3 Prospective Wireless Sensor Concepts for Freeze-Drying
4.3.1 Existing Wireless Sensors with Unrealized Implementations
4.3.2 Optical Sensors
4.4 Conclusion
5. Monitoring methods based on the measure of the sublimation flow: Pressure Rise Test and other direct technologies
5.1 Introduction
5.2 Classic pressure rise methods for monitoring
5.2.1 Manometric Temperature Measurement
5.2.2 Pressure Rise Analysis
5.2.3 Dynamic Parameters Estimation
5.2.4 Analysis and comparison of MTM, PRA and DPE algorithms
5.2.5 Simplified DPE method for short PRT duration
5.3 Improvements and modifications of the DPE algorithm
5.3.1 Development of a modified DPE algorithm for heterogeneous batches
5.3.2 Improving robustness: the DPE+ algorithm
5.3.3 Use of DPE algorithm in presence of co-solvents
5.3.4 Use of DPE for monitoring lyophilization in tray and with radiating energy: the DPE++ algorithm
5.3.5 Influence of pressure sensor dynamics in monitoring large batches: the DPE3+ algorithm
5.4 Methods based on direct sublimation flow measurements
5.4.1 TDLAS
5.4.2 Other approaches: PDT and valveless systems
5.4.2.1 Pressure Decrease Test (PDT)
5.4.2.2 Valveless Monitoring System (VMS)
5.5 Estimation of end of primary drying
5.6 Estimation of residual moisture content
5.7 Use of PRT for process control and optimization
6. Spectroscopic-based PAT in freeze-drying
6.1 The emerging role of spectroscopic techniques in biopharmaceuticals
6.1.1 Fundamentals of NIR theory
6.1.2 NIR spectroscopy in pharmaceutical field
6.1.3 Fundamentals of Raman theory
6.1.4 Raman spectroscopy in pharmaceutical field
6.2 Data analysis: how to interpret spectra?
6.2.1 Pre-processing techniques
6.2.2 Exploratory data analysis: Principal Component Analysis (PCA)
6.2.3 Regression Modelling
6.2.3.1 Partial Least Squares Regression: Theory
6.2.3.2 Artificial Neural Network: Theory
6.2.4 Classification modelling
6.2.4.1 Partial Least Squares Discriminant Analysis: Theory
6.2.5 Performance evaluation
6.3 Applications of NIR and Raman spectroscopy
6.3.1 At-line NIR spectroscopy application
6.3.2 In-line NIR spectroscopy application
6.3.3 At-line Raman spectroscopy application
6.3.4 In-line Raman spectroscopy application
6.4 Conclusions
7. An introduction to Through-Vial Impedance Spectroscopy (TVIS)
7.1 Introduction
7.2 Description of the current TVIS system
7.2.1 TVIS electrode system
7.2.2 Fill volume considerations
7.2.3 Non-invasive temperature measurement
7.2.4 Cabling and connectors
7.2.5 Junction box
7.2.6 Feed-through plate - Electrical connections
7.2.7 External ports on a freeze-dryer
7.2.8 TVIS feed-though adapters for different freeze-dryers
7.3 TVIS - Principles of operation
7.4 An impedance model for the TVIS vial
7.5 Applications to freeze-drying
7.5.1 The ice formation process
7.5.2 Glass transitions and phase behaviour (devitrification)
7.5.3 Annealing
7.5.4 Glass wall effects
7.5.5 Extraction of critical process parameters
7.5.6 Secondary drying
7.6 TVIS development history
ANNEX 1 Fundamentals of impedance spectroscopy
Resistance vs conductance and impedance vs admittance
Capacitive reactance: The electrical impedance of a capacitor
Complex capacitance
8. An application for Through-Vial Impedance Spectroscopy (TVIS) in modelling of the ice sublimation process
8.1 Introduction
8.2 Measured parameters
8.3 Predicted parameters
8.4 Challenges with drying rate determination
8.5 An alternative approach
8.6 The sensing 'point' for TVIS based temperature measurements
8.7 Experimental system for temperature calibration
8.8 Temperature calibration of log FPEAK
8.9 Prediction of the TFPEAK values in primary drying
8.10 Temperature compensation of CPEAK''
8.11 CPEAK'' 'and drying rate predictions
8.12 Critical dimensions of the frozen solution
8.12.1 Characteristic features of the TVIS vial
8.12.2 Definition of the geometries
8.12.3 Determination of the height of the frozen solution
8.13 Adjusting for ice mass loss due to sublimation
8.13.1 Temperature predictions at the ice interface and ice base
8.14 Determination of the temperature at the base of the ice
8.14.1 Fourier's Law for heat transfer
8.15 Determination of the temperature at the ice interface
8.16 Determining ice vapor pressure
8.16.1 Empirical equation for ice vapor pressure
8.16.2 Correction for unfrozen water content
8.17 Determination of the dry layer resistance
8.18 Determination of the heat transfer coefficient (Kv)
ANNEX 1 Equivalent circuit modelling
ANNEX 2 Height of the liquid meniscus
ANNEX 3 Transition from a planar ice interface
ANNEX 4 Methods for the determination of the height of the apex of the domed base on the inside of the vial
ANNEX 5 Onset of sublimation
9. Freeze-drying monitoring and control using thermal imaging
9.1 Fundamentals of infrared radiation and thermal imaging
9.1.1 Basic principles
9.1.2 The infrared spectrum
9.1.3 Temperature measurement through thermal imaging
9.1.4 Components and optical materials of infrared cameras
9.2 Application of IR thermal imaging to monitor a continuous freeze-drying process
9.2.1 Temperature, end of primary drying and product resistance monitoring
9.2.2 Thermal imaging application on spin freezing
9.2.3 Implementation of a PAT-based in-line control system
9.3 Application of IR thermal imaging to monitor a batch freeze-drying process
9.3.1 Image acquisition
9.3.2 Primary drying monitoring in a batch process using IR thermal imaging
9.3.3 Freezing monitoring in a batch process using IR thermal imaging
9.3.4 Process control using IR thermal imaging
9.4 Benefits and critical issues
10. Multiplexing PAT for qualitative ice sublimation monitoring in primary drying
10.1 Introduction
10.2 Direct single-vial methods
10.3 In-direct single-vial methods
10.4 End of primary drying â" Batch methods
10.5 Primary drying â" Is not just sublimation
10.6 Through-Vial Impedance Spectroscopy (TVIS)
10.7 Different characteristic shapes
10.8 Numerical prediction of TVIS primary drying end point
10.9 Multiplexing TVIS with Pirani gauge measurements
10.10 Does the front TVIS vial predict the batch end point?
10.11 Where is the true sublimation end point on the Pirani curve?
10.12 Real time monitoring and early estimates of the primary drying end point
10.13 Statistical significance
10.14 Qualification of the batch ice sublimation end point from the Pirani profile
10.15 Conclusion
11. Emerging technologies in pharmaceutical freeze-drying
11.1 Introduction
11.2 Hybrid-drying: potential role of ultrasound and infrared heating in lyophilization
11.2.1 Ultrasound-Assisted Drying
11.2.2 Infra-Red Assisted Freeze-Drying
11.3 Microwave-assisted freeze-drying
11.3.1 Principles of microwave technology in drying
11.3.2 Current applications, benefits and limitations of microwave-assisted freeze-drying
11.3.3 Modelling microwave-assisted freeze drying
11.4 Thin-Film Freeze-Drying
11.5 Continuous Freeze-Drying
11.6 Continuous Freeze-Drying Technologies for Particle-Based Products
11.7 Foam drying
11.7.1 Applications of foam drying in pharmaceuticals
11.7.2 Advantages of foam drying
11.7.3 Disadvantages and challenges
11.7.4 Key considerations
11.8 Non-Standard Containers for Freeze-Drying
11.8.1 Types of containers beyond the traditional glass vial
11.8.2 Interactions between container and dosage form
11.8.3 Container closure integrity
11.9 Freeze-Drying of Oral Solids
11.9.1 Considerations for oral solids formulation
11.9.2 Considerations for oral solids freeze-drying
11.9.3 Case studies of ODTs produced via freeze-drying
11.10 Application of AI and Digital Twins in Freeze-Drying
11.10.1 Use of ML for formulation design
11.10.2 Role of ML in freeze-drying process monitoring, control, and optimization
11.10.3 Use of ML for freeze-dried product characterization
11.10.4 Current state of the implementation of AI/ML technologies within pharmaceutical process models and regulatory considerations
12. Innovations in control of freezing in pharmaceutical processes
12.1 Introduction
12.2 Ultrasound-Induced Ice Nucleation (UIIN)
12.3 Vacuum Induced Surface Freezing (VISF)
12.4 Other controlled nucleation techniques
12.5 Industrial implementation of controlled nucleation technologies
12.6 Comparison of performances of different controlled nucleation technologies
12.7 Future research directions and challenges
Index
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