Process Analytical Technology for Pharmaceutical Freeze-Drying

Geoff Smith is Professor of Pharmaceutical Process Analytical Technology at the Leicester School of Pharmacy, De Montfort University, UK, and developer of through-vial impedance spectroscopy (TVIS).Davide Fissore is Full Professor at Politecnico di Torino, Italy, member of the International Society for Lyophilization and Freeze-Drying, and member of the Editorial Advisory Board of the Journal of Pharmaceutical Sciences.

• Preface xv1 Freeze-Drying of Parenteral Drug Products and Vaccines 1Geoff Smith1.1 Introduction 11.2 Freeze-Drying—An Overview 21.3 Product Formulation 51.4 Freeze Dryer Components 61.5 Standard Process Instrumentation 111.6 Operational Parameters 121.7 Process Parameters 131.8 Designing the Freezing Stage 141.9 Designing the Primary Drying Stage 201.10 Designing the Secondary Drying Stage 271.11 Process Modeling and Process Analytical Technologies 281.12 Optical and Spectroscopic PAT Tools 332 Standard PAT Instrumentation: Temperature Sensors 45Geoff Smith2.1 Introduction 452.2 Resistance Temperature Detector (RTD) 462.3 Thermocouples 522.4 Summary Comparison Between RTDs and TCs 572.5 American Wire Gauge 582.6 Wireless Temperature Sensors 592.7 Temperature Measurements – Best Practice 612.8 Disadvantages and Drawbacks of Product Probes 622.9 Calibration Methods 622.10 Applications of Temperature Sensors in Freeze-Drying 632.11 Limitations of Product Temperature Sensors 642.12 Future Outlook 643 Standard PAT Instrumentation: Pressure Gauges and Vapor Pressure Sensors 69Geoff Smith, Georg Frinke, Robin Farley, and Ahmet Orun3.1 Gas Pressure 693.2 Units of Gas Pressure 703.3 Measurement of Pressure 713.4 Overview of Pressure Sensor Types 723.5 Calibrating Pressure Sensors 793.6 Pressure Voltage Relationships 823.7 Pressure Control Techniques 843.8 Instrumental Configuration 843.9 Pressure Control for Ice Nucleation 853.10 Comparative Pressure Measurement 863.11 Water Vapor Pressure 863.12 Dynamic Equilibria 883.13 Application of the Clausius–Clapeyron in FD 943.14 Colligative Properties 993.15 Measurement of Water Vapor Pressure 1023.16 Calibration of Water Vapor Measurements 1093.17 Conclusion 1114 Wireless Sensor Networks for Lyophilization 119Jesus Meza-Galvan, Andrew Strongrich, Ahmad Darwish, Dimitrios Peroulis, and Alina Alexeenko4.1 Introduction 1194.2 Existing Wireless Sensors of Lyophilization 1244.3 Prospective Wireless Sensor Concepts for Freeze-Drying 1384.4 Conclusion 1415 Monitoring Methods Based on the Measure of the Sublimation Flow: Pressure Rise Test and Other Direct Technologies 145Antonello Barresi, Roberto Pisano, and Davide Fissore5.1 Introduction 1455.2 Classic Pressure Rise Methods for Monitoring 146viii Contents5.3 Improvements and Modifications of the DPE Algorithm 1615.4 Methods Based on Direct Sublimation Flow Measurements 1725.5 Estimation of End of Primary Drying 1755.6 Estimation of Residual Moisture Content 1775.7 Use of PRT for Process Control and Optimization 1796 Spectroscopic-Based PAT in Freeze-Drying 193Ambra Massei, Nunzia Falco, and Davide Fissore6.1 The Emerging Role of Spectroscopic Techniques in Biopharmaceuticals 1936.2 Data Analysis: How to Interpret Spectra? 2006.3 Applications of NIR and Raman Spectroscopy 2086.4 Conclusions 2177 An Introduction to Through-Vial Impedance Spectroscopy (TVIS) 223Geoff Smith7.1 Introduction 2237.2 Description of the Current TVIS System 2277.3 TVIS – Principles of Operation 2427.4 An Impedance Model for the TVIS Vial 2437.5 Applications to Freeze-Drying 2447.6 TVIS Development History 2518 An Application for Through-Vial Impedance Spectroscopy (TVIS) in Modeling of the Ice Sublimation Process 261Geoff Smith8.1 Introduction 2618.2 Measured Parameters 2628.3 Predicted Parameters 2638.4 Challenges with Drying Rate Determinations 265x Contents8.5 An Alternative Approach 2678.6 The Sensing "Point" for TVIS-Based Temperature Measurements 2688.7 Experimental System for Temperature Calibration 2708.8 Temperature Calibration of log FPEAK 2728.9 Prediction of the TFPEAK Values in Primary Drying 2768.10 Temperature Compensation of C"PEAK 2778.11 C(circumflex)"PEAK and Drying Rate Predictions 2798.12 Critical Dimensions of the Frozen Solution 2848.13 Adjusting for Ice Mass Loss due to Sublimation 2898.14 Temperature Predictions at the Ice Base and the Ice Interface 2898.15 Determining Ice Vapor Pressure 2908.16 Determination of the Dry-Layer Resistance 2918.17 Determination of the Heat Transfer Coefficient (Kv) 2949 Multiplexing PAT for Qualitative Ice Sublimation Monitoring in Primary Drying 309Geoff Smith, Paul Matejtschuk, Pathum Wijesekara, and Kiran Malik9.1 Introduction 3099.2 Through-Vial Impedance Spectroscopy (TVIS) 3259.3 Multiplexing TVIS with Pirani Gauge Measurements 3319.4 Conclusion 34010 Freeze-Drying Monitoring and Control Using Thermal Imaging 345Paola Casucci, Thomas De Beer, and Davide Fissore10.1 Fundamentals of Infrared Radiation and Thermal Imaging 34510.2 Application of IR Thermal Imaging to Monitor a Continuous Freeze-Drying Process 34910.3 Application of IR Thermal Imaging to Monitor a Batch Freeze-Drying Process 35910.4 Benefits and Critical Issues 36411 Emerging Technologies in Pharmaceutical Freeze-Drying 371Fiora Artusio, Antonello A. Barresi, and Roberto Pisano11.1 Introduction 37111.2 Hybrid-Drying: Potential Role of Ultrasound and Infrared Heating in Lyophilization 37211.3 Microwave-Assisted Freeze-Drying 37511.4 Thin-Film Freeze-Drying 38511.5 Continuous Freeze-Drying 38511.6 Continuous Freeze-Drying Technologies for Particle-Based Products 38811.7 Foam Drying 39211.8 Nonstandard Containers for Freeze-Drying 39811.9 Freeze-Drying of Oral Solids 40311.10 Application of AI and Digital Twins in Freeze-Drying 40512 Innovations in Control of Freezing in Pharmaceutical Processes 425Antonello A. Barresi12.1 Introduction 42512.2 Ultrasound-Induced Ice Nucleation 425Contents xiii12.3 Vacuum-Induced Surface Freezing 42812.4 Other Controlled Nucleation Techniques 43112.5 Industrial Implementation of Controlled Nucleation Technologies 43312.6 Comparison of Performances of Different Controlled Nucleation Technologies 43612.7 Future Research Directions and Challenges 438List of Acronyms 439References 440Index 447