Satoshi Ohtake, PhD, is the Senior Principal Scientist in Pharmaceutical Research & Development, BioTherapeutics Pharmaceutical Sciences at Pfizer in St. Louis (USA), and a member of the Scientific Advisory Committee for the Journal of Pharmaceutical Sciences. Ken-ichi Izutsu, PhD, is a Section Chief Research Scientist at the National Institute of Health Sciences (Japan), and External Scientific Advisor of the Pharmaceuticals and Medical Devices Agency (Japan). David Lechuga-Ballesteros, PhD, is a Principal Scientist at Pearl Therapeutics (USA), and serves as a member of the Editorial Advisory Board of the Journal of Pharmaceutical Sciences.

• 1 Introduction 1Alex Langford, Satoshi Ohtake, David Lechuga-Ballesteros, and Ken-ichi IzutsuAcknowledgement 5References 62 A Concise History of Drying 9Sakamon Devahastin and Maturada Jinorose2.1 Introduction 92.2 History of Drying of Pharmaceutical Products 112.3 History of Selected Drying Technologies 132.3.1 Freeze Drying 132.3.2 Spray Drying 152.3.3 Fluidized-Bed Drying 162.3.4 Supercritical Drying 162.4 Concluding Remarks 18Acknowledgments 18References 18Part I Drug Product Development 233 Importance of Drying in Small Molecule Drug Product Development 25Paroma Chakravarty and Karthik Nagapudi3.1 Introduction 253.2 Drying Materials and Dryer Types 333.3 Directly Heated (Convective) Dryers 363.3.1 Tray Drying 363.3.1.1 Description 363.3.1.2 Utility 363.3.1.3 Drawbacks and Challenges 373.3.2 Fluidized-Bed Drying 393.3.2.1 Description 393.3.2.2 Determination of End Point of Drying 413.3.2.3 Advantages, Utility, and Drawbacks 423.3.3 Spray Drying 433.3.3.1 Description 433.3.3.2 Role in Formulation Development 443.4 Indirectly Heated (Conductive) Dryers 563.4.1 Rotary Drying 563.4.1.1 Description 563.4.1.2 Advantages and Drawbacks 573.4.2 Freeze Drying 573.4.2.1 Description 573.4.2.2 Advantages and Drawbacks 583.4.2.3 Role in Small Molecule Formulation Development 583.5 Emerging Drying Technologies 623.5.1 Supercritical Fluid (SCF) Drying 623.5.1.1 Description 623.5.1.2 Advantages and Drawbacks 623.5.1.3 Pharmaceutical Applications 633.5.2 Microwave Drying 673.5.2.1 Pharmaceutical Applications 683.6 Summary 74References 744 Drying for Stabilization of Protein Formulations 91Jacqueline Horn, Hanns-Christian Mahler, and Wolfgang Friess4.1 Protein Stability 914.1.1 Physical Instability of Proteins 924.1.2 Chemical Instability of Proteins 924.1.2.1 Disulfide Bond Formation 924.1.2.2 Deamidation 934.1.2.3 Oxidation 944.1.2.4 Glycation 944.1.3 Analysis of Protein Stability 944.1.3.1 Particle Analysis in Protein Formulations 954.1.3.2 Other Purity Tests for Proteins 954.1.3.3 Analysis of Higher-Order Structure 964.2 Protein Stability in the Dried State 964.2.1 Theoretical Considerations 964.2.1.1 Water Replacement Hypothesis 964.2.1.2 Glass Dynamics Hypothesis and Vitrification 974.2.2 Analysis of the Dried State 974.2.2.1 Investigation of Endo- and Exothermic Processes: Glass Transition and Crystallization 974.2.2.2 Sample Morphology: Crystalline or Amorphous Matrix? 984.2.2.3 Residual Moisture 984.2.3 Excipients Used to Stabilize Proteins in the Dried State 994.2.3.1 Sugars 994.2.3.2 Polyols 1004.2.3.3 Polymers 1014.2.3.4 Amino Acids 1024.2.3.5 Additional Excipients: Metal Ions/HP-β-CD/Surfactants/Buffers 1024.3 How Does the Process Influence Protein Stability? 1034.3.1 Process of Freeze Drying 1034.3.1.1 Freezing 1034.3.1.2 Drying 1054.3.1.3 Typical Defects in Lyophilized Products Beyond Protein Stability 1064.3.2 Process of Spray Drying 1064.3.2.1 Protein Stability During Droplet Formation 1064.3.2.2 Protein Stability During the Drying Phase 1074.4 Summary 107References 1075 Vaccines and Microorganisms 121Akhilesh Bhambhani and Valentyn Antochshuk5.1 Introduction 1215.2 Vaccine Drug Product Development 1225.2.1 Early Development to Phase I 1225.2.1.1 Developability 1225.2.1.2 Pre-formulation 1245.2.1.3 Formulation Development 1275.2.2 Late-Stage Development (Phase II and Beyond) 1295.2.2.1 Scale-Up Considerations and Case Studies 1305.3 Spray Drying: An Alternate to Lyophilization 1325.4 Summary and Path Forward 133References 134Part II Common Drying Technologies 1376 Advances in Freeze Drying of Biologics and Future Challenges and Opportunities 139Bakul Bhatnagar and Serguei Tchessalov6.1 Introduction 1396.2 Where AreWe Now? 1396.3 Current State 1406.3.1 Rational Formulation Design: Keeping It Simple 1406.3.2 Process Design and Monitoring 1436.3.2.1 Freezing 1436.3.2.2 Product Temperature Measurement 1456.3.2.3 Pressure Rise Test/Manometric Temperature Measurement 1466.3.2.4 SMART Freeze-DryerTM Technology 1466.3.2.5 Application of Pirani Gauge for the Control of Primary Drying 1476.3.2.6 Application of Mass Spectroscopy for Process Control 1486.3.2.7 Heat Flux Sensors as PAT Tools 1486.3.2.8 Pressure Decrease Method 1496.3.2.9 Tunable Diode Laser Absorption Spectroscopy (TDLAS) 1496.3.2.10 Emerging Analytical Tools for Process Monitoring and Control 1496.3.2.11 Modeling of Freeze-Drying Process 1506.3.3 Tools to Monitor Dried Products 1506.3.3.1 Structure of the Biologic 1506.3.3.2 Characterizing Matrix Contributions to Stability 1516.3.3.3 Looking Beyond the Biologic and the Formulation Matrix 1526.4 Current Challenges 1536.4.1 Understanding Protein Degradation in the Frozen State and Dried States 1536.4.2 Process Inefficiency 1546.5 Vision for the Future 1556.5.1 Advances in Container-Closure Systems 1556.5.2 Dryer Design 1566.5.2.1 Laboratory-Scale Dryers 1566.5.2.2 Commercial-Scale Freeze Dryers 1576.5.3 Redefining Product Appearance/Elegance 1606.5.4 “Intelligent” Formulation and Process Design 1606.5.5 How Could Alternate Drying Technologies and Freeze Drying Coexist? 1616.5.5.1 Alternatives to the Current Batch-Based Vial Drying 1616.6 Summary 162Acknowledgments 162Tributes 163References 1647 Spray Drying 179Reinhard Vehring, Herm Snyder, and David Lechuga-Ballesteros7.1 Background 1797.1.1 Spray-Drying Fundamentals 1807.1.2 Feedstock Preparation 1807.1.3 Spray-Drying Equipment 1817.1.4 Atomization 1837.1.4.1 Twin-Fluid or Gas (Air)-Assisted Atomizer 1847.1.4.2 Pressure or Hydraulic Nozzle 1857.1.4.3 Rotary Atomizer 1867.1.5 Drying Chamber 1877.1.6 Particle Collection 1897.2 Particle Engineering 1897.2.1 Particle Formation: Evaporation Stage 1917.2.2 Particle Formation: Solidification Stage 1937.2.3 Particle Formation: Solidification Stage for Crystallizing Excipients 1947.2.4 Particle Formation: Deformation Stage 1977.2.5 Particle Formation: Equilibration Phase 1987.3 Current Status 2007.4 Future Direction: Aseptic Spray Drying 2057.4.1 Initial System Sterilization of Product Contact Surfaces 2077.4.2 Maintaining a Sterile Environment over the Course of the Spray-Dried Batch 2087.4.3 Aseptic Extraction and Handling the Dried Powder Product from the Dryer System 208References 209Part III Next Generation Drying Technologies 2178 Spray Freeze Drying 219Bernhard Luy and Howard Stamato8.1 Introduction 2198.2 Background 2208.2.1 Shelf Freeze Drying 2208.2.2 Spray Freeze Drying 2218.2.2.1 Single Dose vs. Bulk Manufacturing 2218.2.2.2 Process Considerations 2228.2.3 Spray-Freeze-Drying Developments 2248.3 Spray Freezing and Dynamic Freeze Drying 2258.3.1 Spray Freezing 2258.3.2 Dynamic Freeze Drying 2298.3.2.1 Rotary Freeze-Drying Technology 2298.3.2.2 Process Considerations 2308.3.3 Industrial Application: Integration of Process Steps to a Process Line 2318.3.4 Product Innovation Potential 2338.3.5 Bulkware Innovation Potential: Supply Chain Flexibility 2358.4 Conclusion 235References 2369 Microwave Drying of Pharmaceuticals 239Tim Durance, Reihaneh Noorbakhsh, Gary Sandberg, and Natalia Sáenz-Garza9.1 Fundamentals of Microwave Heating and Drying 2399.1.1 Theory of Microwave Heating and Drying 2399.1.2 Ionic Conduction 2409.1.3 Dipolar Rotation/Vibration 2409.1.4 Microwave Application at Low Pressures 2419.2 Equipment Used for Microwave Freeze Drying 2429.2.1 Microwave Generators 2429.2.2 Chambers 2429.2.3 Vacuum Systems 2439.2.4 Safety and Microwave Leakage Control 2459.3 Formulation Characterization 2469.3.1 Dielectric Properties, Microwave Absorption, and Depth of Penetration 2469.3.2 Glass Transition Temperature and Collapse 2489.3.3 Excipients for Microwave Freeze Drying of Pharmaceutical Products 2489.4 Dehydration Process Using Microwave Freeze Drying 2499.4.1 Primary Drying 2499.4.2 Secondary Drying 2509.4.3 Control of Drying 2519.5 Advantages and Challenges of Pharmaceutical Microwave Freeze Drying 2519.5.1 Advantages 2519.5.2 Challenges 2519.6 Some of the Published Patents for Application of Microwave Freeze Drying 252References 25310 Foam Drying 257Phillip M. Lovalenti and Vu Truong-Le10.1 Introduction 25710.1.1 Challenges in Developing Stable Dosage Forms for Biopharmaceuticals 25810.1.2 Chapter Overview 25810.2 Comparison of Drying Methods 25810.2.1 Brief Description of Established Pharmaceutical Drying Methods 25810.2.1.1 Freeze Drying 25910.2.1.2 Spray Drying 25910.2.1.3 Vacuum Foam Drying 25910.2.1.4 Other Drying Methods 26010.2.2 Advantages of Foam Drying over Other Methods 26110.3 Foam Drying: Historical Perspective 26210.3.1 Foam Drying in the Food Industry 26210.3.2 Foam Drying in the Pharmaceutical Industry 26310.4 The Foam-Drying Process 26310.4.1 Detailed Thermal Cycle and Equipment Parameters 26310.4.2 Wet Blend Requirements 26510.4.3 Variants of the Foam-Drying Process 26610.4.3.1 Annear 26610.4.3.2 Roser and Gribbon 26610.4.3.3 Bronshtein (PFF) 26610.4.3.4 Truong (FFD) 26810.4.3.5 Truong (CFD) 26810.4.3.6 Bronshtein (PBV) 26810.4.4 Challenges to Commercialization 26910.4.4.1 Process Stresses 26910.4.4.2 Scalability and Process Robustness 26910.4.4.3 Drug Delivery Requirements 27010.4.4.4 Barriers to Change in the Pharmaceutical Industry 27010.5 Application of Foam Drying to Biostabilization 27010.5.1 Formulation Considerations 27110.5.1.1 Moisture Content 27110.5.1.2 Buffers and pH 27110.5.1.3 Glass Formers 27110.5.1.4 Foaming Agents 27210.5.1.5 Polymers 27210.5.1.6 Plasticizers 27210.5.1.7 Proteins and Amino Acids 27210.5.2 Examples of Foam-Dried Biopharmaceuticals: Case Studies 27310.5.2.1 Protein: IgG1 Monoclonal Antibody 27310.5.2.2 Viral Vaccine: Influenza 27410.5.2.3 Bacterial Vaccine: Ty21a 27510.5.2.4 Human Cells: T Cells 27610.6 Physiochemical Characterization of the Foam-Dried Product 27710.6.1 Thermal Analysis and Protein Secondary Structure 27710.6.2 Specific Surface Area and Surface Composition Analysis 27810.6.3 Molecular Mobility and Amorphous Structure Analysis 27810.7 Conclusions and Future Prospects 279References 27911 Effects of Electric and Magnetic Field on Freezing 283Arun S. Mujumdar and Meng W.Woo11.1 Introduction 28311.2 The Different Stages and Parameters of Freezing 28411.3 Effect of Electric Field on Freezing 28511.3.1 Application to Water and Systems with Dissolved Solute 28511.3.2 Application to Solid Materials 28711.3.3 Application of AC Field to Freezing 28811.3.4 Important Additional Considerations 28911.4 Effect of Magnetic Field on Freezing 29011.4.1 Patent Claims and Studies on Magnetic Field Assisted Freezing 29011.4.2 Debate on the Possible Nonsignificant Effect of Magnetic Field to Freezing 29111.5 Possible Effect of Electric and Magnetic Field on the Sublimation Process 29411.6 Future Outlook for Pharmaceutical Application 296References 29612 Desired Attributes and Requirements for Implementation 303Howard Stamato and Jim Searles12.1 Introduction 30312.2 Measuring Dryness 30512.3 Process Considerations 30612.4 Product Considerations 30712.5 Scale-Up Considerations 30912.6 Implementation 309References 310Part IV Formulation Considerations for Solid Dosage Preparation 31513 The Roles of Acid–Base Relationships, Interfaces, and Molecular Mobility in Stabilization During Drying and in the Solid State 317Danforth P.Miller, Evgenyi Shalaev, and Jim Barnard13.1 Introduction 31713.2 Acid–Base Relationships and Change in Ionization During Freezing and Drying 31813.3 Role of Interfaces in Instability During Freeze Drying and Spray Drying 32313.4 Influence of Molecular Mobility on Physicochemical Stability 32513.5 Fast β-Relaxation in Practice 33213.6 Conclusions and Advice to the Formulator 336References 337Part V Implementation 34714 Challenges and Considerations for New Technology Implementation and Synergy with Development of Process Analytical Technologies (PAT) 349Howard Stamato and Jim SearlesReferences 353Part VI Future Perspectives 35515 Future Directions: Lyophilization Technology Roadmap to 2025 and Beyond 357Alina Alexeenko and Elizabeth Topp15.1 Introduction 35715.2 Overview of the Roadmapping Process 35815.2.1 Roadmap Framework and Development 35815.2.2 Roadmap Summary 36015.3 Trends and Drivers 36315.4 Lyophilized Products 36415.4.1 New and Improved Analytical Methods 36515.4.2 Improved Container/Closure Systems 36515.4.3 Adapt Lyophilization to New Product Types 36615.5 Process 36615.5.1 Process Monitoring Instrumentation 36615.5.2 Process Modeling and Simulation 36715.5.3 Process Control and Automation 36715.6 Equipment 36715.6.1 Equipment Harmonization and Scale-Up 36815.6.2 Improve Lyophilized Technologies and Equipment for Existing and New Products 36915.6.3 Disruptive Lyophilization/Drying Technologies and Equipment 36915.7 Regulatory Interface 37015.8 Workforce Development 371References 372Index 373