Preface xv
1 Freeze-Drying of Parenteral Drug Products and Vaccines 1
Geoff Smith
1.1 Introduction 1
1.2 Freeze-Dryingâ"An Overview 2
1.3 Product Formulation 5
1.4 Freeze Dryer Components 6
1.5 Standard Process Instrumentation 11
1.6 Operational Parameters 12
1.7 Process Parameters 13
1.8 Designing the Freezing Stage 14
1.9 Designing the Primary Drying Stage 20
1.10 Designing the Secondary Drying Stage 27
1.11 Process Modeling and Process Analytical Technologies 28
1.12 Optical and Spectroscopic PAT Tools 33
2 Standard PAT Instrumentation: Temperature Sensors 45
Geoff Smith
2.1 Introduction 45
2.2 Resistance Temperature Detector (RTD) 46
2.3 Thermocouples 52
2.4 Summary Comparison Between RTDs and TCs 57
2.5 American Wire Gauge 58
2.6 Wireless Temperature Sensors 59
2.7 Temperature Measurements â" Best Practice 61
2.8 Disadvantages and Drawbacks of Product Probes 62
2.9 Calibration Methods 62
2.10 Applications of Temperature Sensors in Freeze-Drying 63
2.11 Limitations of Product Temperature Sensors 64
2.12 Future Outlook 64
3 Standard PAT Instrumentation: Pressure Gauges and Vapor Pressure Sensors 69
Geoff Smith, Georg Frinke, Robin Farley, and Ahmet Orun
3.1 Gas Pressure 69
3.2 Units of Gas Pressure 70
3.3 Measurement of Pressure 71
3.4 Overview of Pressure Sensor Types 72
3.5 Calibrating Pressure Sensors 79
3.6 Pressure Voltage Relationships 82
3.7 Pressure Control Techniques 84
3.8 Instrumental Configuration 84
3.9 Pressure Control for Ice Nucleation 85
3.10 Comparative Pressure Measurement 86
3.11 Water Vapor Pressure 86
3.12 Dynamic Equilibria 88
3.13 Application of the Clausiusâ"Clapeyron in FD 94
3.14 Colligative Properties 99
3.15 Measurement of Water Vapor Pressure 102
3.16 Calibration of Water Vapor Measurements 109
3.17 Conclusion 111
4 Wireless Sensor Networks for Lyophilization 119
Jesus Meza-Galvan, Andrew Strongrich, Ahmad Darwish, Dimitrios Peroulis, and Alina Alexeenko
4.1 Introduction 119
4.2 Existing Wireless Sensors of Lyophilization 124
4.3 Prospective Wireless Sensor Concepts for Freeze-Drying 138
4.4 Conclusion 141
5 Monitoring Methods Based on the Measure of the Sublimation Flow: Pressure Rise Test and Other Direct Technologies 145
Antonello Barresi, Roberto Pisano, and Davide Fissore
5.1 Introduction 145
5.2 Classic Pressure Rise Methods for Monitoring 146viii Contents
5.3 Improvements and Modifications of the DPE Algorithm 161
5.4 Methods Based on Direct Sublimation Flow Measurements 172
5.5 Estimation of End of Primary Drying 175
5.6 Estimation of Residual Moisture Content 177
5.7 Use of PRT for Process Control and Optimization 179
6 Spectroscopic-Based PAT in Freeze-Drying 193
Ambra Massei, Nunzia Falco, and Davide Fissore
6.1 The Emerging Role of Spectroscopic Techniques in Biopharmaceuticals 193
6.2 Data Analysis: How to Interpret Spectra? 200
6.3 Applications of NIR and Raman Spectroscopy 208
6.4 Conclusions 217
7 An Introduction to Through-Vial Impedance Spectroscopy (TVIS) 223
Geoff Smith
7.1 Introduction 223
7.2 Description of the Current TVIS System 227
7.3 TVIS â" Principles of Operation 242
7.4 An Impedance Model for the TVIS Vial 243
7.5 Applications to Freeze-Drying 244
7.6 TVIS Development History 251
8 An Application for Through-Vial Impedance Spectroscopy (TVIS) in Modeling of the Ice Sublimation Process 261
Geoff Smith
8.1 Introduction 261
8.2 Measured Parameters 262
8.3 Predicted Parameters 263
8.4 Challenges with Drying Rate Determinations 265x Contents
8.5 An Alternative Approach 267
8.6 The Sensing "Point" for TVIS-Based Temperature Measurements 268
8.7 Experimental System for Temperature Calibration 270
8.8 Temperature Calibration of log FPEAK 272
8.9 Prediction of the TFPEAK Values in Primary Drying 276
8.10 Temperature Compensation of C"PEAK 277
8.11 C(circumflex)"PEAK and Drying Rate Predictions 279
8.12 Critical Dimensions of the Frozen Solution 284
8.13 Adjusting for Ice Mass Loss due to Sublimation 289
8.14 Temperature Predictions at the Ice Base and the Ice Interface 289
8.15 Determining Ice Vapor Pressure 290
8.16 Determination of the Dry-Layer Resistance 291
8.17 Determination of the Heat Transfer Coefficient (Kv) 294
9 Multiplexing PAT for Qualitative Ice Sublimation Monitoring in Primary Drying 309
Geoff Smith, Paul Matejtschuk, Pathum Wijesekara, and Kiran Malik
9.1 Introduction 309
9.2 Through-Vial Impedance Spectroscopy (TVIS) 325
9.3 Multiplexing TVIS with Pirani Gauge Measurements 331
9.4 Conclusion 340
10 Freeze-Drying Monitoring and Control Using Thermal Imaging 345
Paola Casucci, Thomas De Beer, and Davide Fissore
10.1 Fundamentals of Infrared Radiation and Thermal Imaging 345
10.2 Application of IR Thermal Imaging to Monitor a Continuous Freeze-Drying Process 349
10.3 Application of IR Thermal Imaging to Monitor a Batch Freeze-Drying Process 359
10.4 Benefits and Critical Issues 364
11 Emerging Technologies in Pharmaceutical Freeze-Drying 371
Fiora Artusio, Antonello A. Barresi, and Roberto Pisano
11.1 Introduction 371
11.2 Hybrid-Drying: Potential Role of Ultrasound and Infrared Heating in Lyophilization 372
11.3 Microwave-Assisted Freeze-Drying 375
11.4 Thin-Film Freeze-Drying 385
11.5 Continuous Freeze-Drying 385
11.6 Continuous Freeze-Drying Technologies for Particle-Based Products 388
11.7 Foam Drying 392
11.8 Nonstandard Containers for Freeze-Drying 398
11.9 Freeze-Drying of Oral Solids 403
11.10 Application of AI and Digital Twins in Freeze-Drying 405
12 Innovations in Control of Freezing in Pharmaceutical Processes 425
Antonello A. Barresi
12.1 Introduction 425
12.2 Ultrasound-Induced Ice Nucleation 425Contents xiii
12.3 Vacuum-Induced Surface Freezing 428
12.4 Other Controlled Nucleation Techniques 431
12.5 Industrial Implementation of Controlled Nucleation Technologies 433
12.6 Comparison of Performances of Different Controlled Nucleation Technologies 436
12.7 Future Research Directions and Challenges 438
List of Acronyms 439
References 440
Index 447
