Drying technologies are an indispensable production step in the pharmaceutical industry and the knowledge of drying technologies and applications is absolutely essential for current drug product development. This book focuses on the application of various drying technologies to the processing of pharmaceuticals and biologicals. It offers a complete overview of innovative as well as standard drying technologies, and addresses the issues of why drying is required and what the critical considerations are for implementing this process operation during drug product development.
Drying Technologies for Biotechnology and Pharmaceutical Applications discusses the state-of-the-art of established drying technologies like freeze- and spray- drying and highlights limitations that need to be overcome to achieve the future state of pharmaceutical manufacturing. The book also describes promising next generation drying technologies, which are currently used in fields outside of pharmaceuticals, and how they can be implemented and adapted for future use in the pharmaceutical industry. In addition, it deals with the generation of synergistic effects (e.g. by applying process analytical technology) and provides an outlook toward future developments.
-Presents a full technical overview of well established standard drying methods alongside various other drying technologies, possible improvements, limitations, synergies, and future directions
-Outlines different drying technologies from an application-oriented point of view and with consideration of real world challenges in the field of drug product development
-Edited by renowned experts from the pharmaceutical industry and assembled by leading experts from industry and academia
Drying Technologies for Biotechnology and Pharmaceutical Applications is an important book for pharma engineers, process engineers, chemical engineers, and others who work in related industries.
Table of Contents
1 Introduction 1
Alex Langford, Satoshi Ohtake, David Lechuga-Ballesteros, and Ken-ichi Izutsu
Acknowledgement 5
References 6
2 A Concise History of Drying 9
Sakamon Devahastin and Maturada Jinorose
2.1 Introduction 9
2.2 History of Drying of Pharmaceutical Products 11
2.3 History of Selected Drying Technologies 13
2.3.1 Freeze Drying 13
2.3.2 Spray Drying 15
2.3.3 Fluidized-Bed Drying 16
2.3.4 Supercritical Drying 16
2.4 Concluding Remarks 18
Acknowledgments 18
References 18
Part I Drug Product Development 23
3 Importance of Drying in Small Molecule Drug Product Development 25
Paroma Chakravarty and Karthik Nagapudi
3.1 Introduction 25
3.2 Drying Materials and Dryer Types 33
3.3 Directly Heated (Convective) Dryers 36
3.3.1 Tray Drying 36
3.3.1.1 Description 36
3.3.1.2 Utility 36
3.3.1.3 Drawbacks and Challenges 37
3.3.2 Fluidized-Bed Drying 39
3.3.2.1 Description 39
3.3.2.2 Determination of End Point of Drying 41
3.3.2.3 Advantages, Utility, and Drawbacks 42
3.3.3 Spray Drying 43
3.3.3.1 Description 43
3.3.3.2 Role in Formulation Development 44
3.4 Indirectly Heated (Conductive) Dryers 56
3.4.1 Rotary Drying 56
3.4.1.1 Description 56
3.4.1.2 Advantages and Drawbacks 57
3.4.2 Freeze Drying 57
3.4.2.1 Description 57
3.4.2.2 Advantages and Drawbacks 58
3.4.2.3 Role in Small Molecule Formulation Development 58
3.5 Emerging Drying Technologies 62
3.5.1 Supercritical Fluid (SCF) Drying 62
3.5.1.1 Description 62
3.5.1.2 Advantages and Drawbacks 62
3.5.1.3 Pharmaceutical Applications 63
3.5.2 Microwave Drying 67
3.5.2.1 Pharmaceutical Applications 68
3.6 Summary 74
References 74
4 Drying for Stabilization of Protein Formulations 91
Jacqueline Horn, Hanns-Christian Mahler, and Wolfgang Friess
4.1 Protein Stability 91
4.1.1 Physical Instability of Proteins 92
4.1.2 Chemical Instability of Proteins 92
4.1.2.1 Disulfide Bond Formation 92
4.1.2.2 Deamidation 93
4.1.2.3 Oxidation 94
4.1.2.4 Glycation 94
4.1.3 Analysis of Protein Stability 94
4.1.3.1 Particle Analysis in Protein Formulations 95
4.1.3.2 Other Purity Tests for Proteins 95
4.1.3.3 Analysis of Higher-Order Structure 96
4.2 Protein Stability in the Dried State 96
4.2.1 Theoretical Considerations 96
4.2.1.1 Water Replacement Hypothesis 96
4.2.1.2 Glass Dynamics Hypothesis and Vitrification 97
4.2.2 Analysis of the Dried State 97
4.2.2.1 Investigation of Endo- and Exothermic Processes: Glass Transition and Crystallization 97
4.2.2.2 Sample Morphology: Crystalline or Amorphous Matrix? 98
4.2.2.3 Residual Moisture 98
4.2.3 Excipients Used to Stabilize Proteins in the Dried State 99
4.2.3.1 Sugars 99
4.2.3.2 Polyols 100
4.2.3.3 Polymers 101
4.2.3.4 Amino Acids 102
4.2.3.5 Additional Excipients: Metal Ions/HP-β-CD/Surfactants/Buffers 102
4.3 How Does the Process Influence Protein Stability? 103
4.3.1 Process of Freeze Drying 103
4.3.1.1 Freezing 103
4.3.1.2 Drying 105
4.3.1.3 Typical Defects in Lyophilized Products Beyond Protein Stability 106
4.3.2 Process of Spray Drying 106
4.3.2.1 Protein Stability During Droplet Formation 106
4.3.2.2 Protein Stability During the Drying Phase 107
4.4 Summary 107
References 107
5 Vaccines and Microorganisms 121
Akhilesh Bhambhani and Valentyn Antochshuk
5.1 Introduction 121
5.2 Vaccine Drug Product Development 122
5.2.1 Early Development to Phase I 122
5.2.1.1 Developability 122
5.2.1.2 Pre-formulation 124
5.2.1.3 Formulation Development 127
5.2.2 Late-Stage Development (Phase II and Beyond) 129
5.2.2.1 Scale-Up Considerations and Case Studies 130
5.3 Spray Drying: An Alternate to Lyophilization 132
5.4 Summary and Path Forward 133
References 134
Part II Common Drying Technologies 137
6 Advances in Freeze Drying of Biologics and Future Challenges and Opportunities 139
Bakul Bhatnagar and Serguei Tchessalov
6.1 Introduction 139
6.2 Where AreWe Now? 139
6.3 Current State 140
6.3.1 Rational Formulation Design: Keeping It Simple 140
6.3.2 Process Design and Monitoring 143
6.3.2.1 Freezing 143
6.3.2.2 Product Temperature Measurement 145
6.3.2.3 Pressure Rise Test/Manometric Temperature Measurement 146
6.3.2.4 SMART Freeze-DryerTM Technology 146
6.3.2.5 Application of Pirani Gauge for the Control of Primary Drying 147
6.3.2.6 Application of Mass Spectroscopy for Process Control 148
6.3.2.7 Heat Flux Sensors as PAT Tools 148
6.3.2.8 Pressure Decrease Method 149
6.3.2.9 Tunable Diode Laser Absorption Spectroscopy (TDLAS) 149
6.3.2.10 Emerging Analytical Tools for Process Monitoring and Control 149
6.3.2.11 Modeling of Freeze-Drying Process 150
6.3.3 Tools to Monitor Dried Products 150
6.3.3.1 Structure of the Biologic 150
6.3.3.2 Characterizing Matrix Contributions to Stability 151
6.3.3.3 Looking Beyond the Biologic and the Formulation Matrix 152
6.4 Current Challenges 153
6.4.1 Understanding Protein Degradation in the Frozen State and Dried States 153
6.4.2 Process Inefficiency 154
6.5 Vision for the Future 155
6.5.1 Advances in Container-Closure Systems 155
6.5.2 Dryer Design 156
6.5.2.1 Laboratory-Scale Dryers 156
6.5.2.2 Commercial-Scale Freeze Dryers 157
6.5.3 Redefining Product Appearance/Elegance 160
6.5.4 “Intelligent” Formulation and Process Design 160
6.5.5 How Could Alternate Drying Technologies and Freeze Drying Coexist? 161
6.5.5.1 Alternatives to the Current Batch-Based Vial Drying 161
6.6 Summary 162
Acknowledgments 162
Tributes 163
References 164
7 Spray Drying 179
Reinhard Vehring, Herm Snyder, and David Lechuga-Ballesteros
7.1 Background 179
7.1.1 Spray-Drying Fundamentals 180
7.1.2 Feedstock Preparation 180
7.1.3 Spray-Drying Equipment 181
7.1.4 Atomization 183
7.1.4.1 Twin-Fluid or Gas (Air)-Assisted Atomizer 184
7.1.4.2 Pressure or Hydraulic Nozzle 185
7.1.4.3 Rotary Atomizer 186
7.1.5 Drying Chamber 187
7.1.6 Particle Collection 189
7.2 Particle Engineering 189
7.2.1 Particle Formation: Evaporation Stage 191
7.2.2 Particle Formation: Solidification Stage 193
7.2.3 Particle Formation: Solidification Stage for Crystallizing Excipients 194
7.2.4 Particle Formation: Deformation Stage 197
7.2.5 Particle Formation: Equilibration Phase 198
7.3 Current Status 200
7.4 Future Direction: Aseptic Spray Drying 205
7.4.1 Initial System Sterilization of Product Contact Surfaces 207
7.4.2 Maintaining a Sterile Environment over the Course of the Spray-Dried Batch 208
7.4.3 Aseptic Extraction and Handling the Dried Powder Product from the Dryer System 208
References 209
Part III Next Generation Drying Technologies 217
8 Spray Freeze Drying 219
Bernhard Luy and Howard Stamato
8.1 Introduction 219
8.2 Background 220
8.2.1 Shelf Freeze Drying 220
8.2.2 Spray Freeze Drying 221
8.2.2.1 Single Dose vs. Bulk Manufacturing 221
8.2.2.2 Process Considerations 222
8.2.3 Spray-Freeze-Drying Developments 224
8.3 Spray Freezing and Dynamic Freeze Drying 225
8.3.1 Spray Freezing 225
8.3.2 Dynamic Freeze Drying 229
8.3.2.1 Rotary Freeze-Drying Technology 229
8.3.2.2 Process Considerations 230
8.3.3 Industrial Application: Integration of Process Steps to a Process Line 231
8.3.4 Product Innovation Potential 233
8.3.5 Bulkware Innovation Potential: Supply Chain Flexibility 235
8.4 Conclusion 235
References 236
9 Microwave Drying of Pharmaceuticals 239
Tim Durance, Reihaneh Noorbakhsh, Gary Sandberg, and Natalia Sáenz-Garza
9.1 Fundamentals of Microwave Heating and Drying 239
9.1.1 Theory of Microwave Heating and Drying 239
9.1.2 Ionic Conduction 240
9.1.3 Dipolar Rotation/Vibration 240
9.1.4 Microwave Application at Low Pressures 241
9.2 Equipment Used for Microwave Freeze Drying 242
9.2.1 Microwave Generators 242
9.2.2 Chambers 242
9.2.3 Vacuum Systems 243
9.2.4 Safety and Microwave Leakage Control 245
9.3 Formulation Characterization 246
9.3.1 Dielectric Properties, Microwave Absorption, and Depth of Penetration 246
9.3.2 Glass Transition Temperature and Collapse 248
9.3.3 Excipients for Microwave Freeze Drying of Pharmaceutical Products 248
9.4 Dehydration Process Using Microwave Freeze Drying 249
9.4.1 Primary Drying 249
9.4.2 Secondary Drying 250
9.4.3 Control of Drying 251
9.5 Advantages and Challenges of Pharmaceutical Microwave Freeze Drying 251
9.5.1 Advantages 251
9.5.2 Challenges 251
9.6 Some of the Published Patents for Application of Microwave Freeze Drying 252
References 253
10 Foam Drying 257
Phillip M. Lovalenti and Vu Truong-Le
10.1 Introduction 257
10.1.1 Challenges in Developing Stable Dosage Forms for Biopharmaceuticals 258
10.1.2 Chapter Overview 258
10.2 Comparison of Drying Methods 258
10.2.1 Brief Description of Established Pharmaceutical Drying Methods 258
10.2.1.1 Freeze Drying 259
10.2.1.2 Spray Drying 259
10.2.1.3 Vacuum Foam Drying 259
10.2.1.4 Other Drying Methods 260
10.2.2 Advantages of Foam Drying over Other Methods 261
10.3 Foam Drying: Historical Perspective 262
10.3.1 Foam Drying in the Food Industry 262
10.3.2 Foam Drying in the Pharmaceutical Industry 263
10.4 The Foam-Drying Process 263
10.4.1 Detailed Thermal Cycle and Equipment Parameters 263
10.4.2 Wet Blend Requirements 265
10.4.3 Variants of the Foam-Drying Process 266
10.4.3.1 Annear 266
10.4.3.2 Roser and Gribbon 266
10.4.3.3 Bronshtein (PFF) 266
10.4.3.4 Truong (FFD) 268
10.4.3.5 Truong (CFD) 268
10.4.3.6 Bronshtein (PBV) 268
10.4.4 Challenges to Commercialization 269
10.4.4.1 Process Stresses 269
10.4.4.2 Scalability and Process Robustness 269
10.4.4.3 Drug Delivery Requirements 270
10.4.4.4 Barriers to Change in the Pharmaceutical Industry 270
10.5 Application of Foam Drying to Biostabilization 270
10.5.1 Formulation Considerations 271
10.5.1.1 Moisture Content 271
10.5.1.2 Buffers and pH 271
10.5.1.3 Glass Formers 271
10.5.1.4 Foaming Agents 272
10.5.1.5 Polymers 272
10.5.1.6 Plasticizers 272
10.5.1.7 Proteins and Amino Acids 272
10.5.2 Examples of Foam-Dried Biopharmaceuticals: Case Studies 273
10.5.2.1 Protein: IgG1 Monoclonal Antibody 273
10.5.2.2 Viral Vaccine: Influenza 274
10.5.2.3 Bacterial Vaccine: Ty21a 275
10.5.2.4 Human Cells: T Cells 276
10.6 Physiochemical Characterization of the Foam-Dried Product 277
10.6.1 Thermal Analysis and Protein Secondary Structure 277
10.6.2 Specific Surface Area and Surface Composition Analysis 278
10.6.3 Molecular Mobility and Amorphous Structure Analysis 278
10.7 Conclusions and Future Prospects 279
References 279
11 Effects of Electric and Magnetic Field on Freezing 283
Arun S. Mujumdar and Meng W.Woo
11.1 Introduction 283
11.2 The Different Stages and Parameters of Freezing 284
11.3 Effect of Electric Field on Freezing 285
11.3.1 Application to Water and Systems with Dissolved Solute 285
11.3.2 Application to Solid Materials 287
11.3.3 Application of AC Field to Freezing 288
11.3.4 Important Additional Considerations 289
11.4 Effect of Magnetic Field on Freezing 290
11.4.1 Patent Claims and Studies on Magnetic Field Assisted Freezing 290
11.4.2 Debate on the Possible Nonsignificant Effect of Magnetic Field to Freezing 291
11.5 Possible Effect of Electric and Magnetic Field on the Sublimation Process 294
11.6 Future Outlook for Pharmaceutical Application 296
References 296
12 Desired Attributes and Requirements for Implementation 303
Howard Stamato and Jim Searles
12.1 Introduction 303
12.2 Measuring Dryness 305
12.3 Process Considerations 306
12.4 Product Considerations 307
12.5 Scale-Up Considerations 309
12.6 Implementation 309
References 310
Part IV Formulation Considerations for Solid Dosage Preparation 315
13 The Roles of Acid-Base Relationships, Interfaces, and Molecular Mobility in Stabilization During Drying and in the Solid State 317
Danforth P.Miller, Evgenyi Shalaev, and Jim Barnard
13.1 Introduction 317
13.2 Acid-Base Relationships and Change in Ionization During Freezing and Drying 318
13.3 Role of Interfaces in Instability During Freeze Drying and Spray Drying 323
13.4 Influence of Molecular Mobility on Physicochemical Stability 325
13.5 Fast β-Relaxation in Practice 332
13.6 Conclusions and Advice to the Formulator 336
References 337
Part V Implementation 347
14 Challenges and Considerations for New Technology Implementation and Synergy with Development of Process Analytical Technologies (PAT) 349
Howard Stamato and Jim Searles
References 353
Part VI Future Perspectives 355
15 Future Directions: Lyophilization Technology Roadmap to 2025 and Beyond 357
Alina Alexeenko and Elizabeth Topp
15.1 Introduction 357
15.2 Overview of the Roadmapping Process 358
15.2.1 Roadmap Framework and Development 358
15.2.2 Roadmap Summary 360
15.3 Trends and Drivers 363
15.4 Lyophilized Products 364
15.4.1 New and Improved Analytical Methods 365
15.4.2 Improved Container/Closure Systems 365
15.4.3 Adapt Lyophilization to New Product Types 366
15.5 Process 366
15.5.1 Process Monitoring Instrumentation 366
15.5.2 Process Modeling and Simulation 367
15.5.3 Process Control and Automation 367
15.6 Equipment 367
15.6.1 Equipment Harmonization and Scale-Up 368
15.6.2 Improve Lyophilized Technologies and Equipment for Existing and New Products 369
15.6.3 Disruptive Lyophilization/Drying Technologies and Equipment 369
15.7 Regulatory Interface 370
15.8 Workforce Development 371
References 372
Index 373
