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<p>Contents</p> <p>Preface to Third Edition and Acknowledgment ix</p> <p>Preface to the Second Edition xi</p> <p><b>1 Foundations and Process Engineering 1</b></p> <p>1.1 Freezing 2</p> <p>1.1.1 Amount of Heat, Heat Conductivity, Heat Transfer, and Cooling Rate 3</p> <p>1.1.2 Structure of Ice, Solutions, and Dispersions 14</p> <p>1.1.3 Influence of Excipients 22</p> <p>1.1.4 Freezing of Cells and Bacteria 32</p> <p>1.1.5 Methods of Structure Analysis 34</p> <p>1.1.5.1 Measurements of Electrical Resistance (ER) 34</p> <p>1.1.5.2 Differential Thermal Analysis (DTA) 45</p> <p>1.1.5.3 Cryomicroscopy 51</p> <p>1.1.5.4 Freeze-Dry Microscopy 59</p> <p>1.1.5.5 Differential Scanning Calorimetry (DSC) 60</p> <p>1.1.5.6 Nuclear Magnetic Resonance 68</p> <p>1.1.5.7 Thermomechanical Analysis (TMA) 74</p> <p>1.1.5.8 Dielectric Analysis (DEA) 76</p> <p>1.1.5.9 XRPD Diffractometer–Raman Spectroscopy 77</p> <p>1.1.6 Changes of Structure in Freezing or Frozen Products 78</p> <p>1.2 Drying 79</p> <p>1.2.1 Main Drying (Sublimation Drying) 82</p> <p>1.2.2 Secondary Drying (Desorption Drying) 101</p> <p>1.2.3 Temperature and Pressure Measurement 113</p> <p>1.2.3.1 Wireless Temperature Measurement 135</p> <p>1.2.4 Water Vapor Transport during Drying 136</p> <p>1.2.4.1 Endpoint Determination of Main and Secondary Drying 144</p> <p>1.2.5 Collapse and Recrystallization 145</p> <p>1.2.6 Drying Processes without Vacuum 148</p> <p>1.2.7 Microwave Freeze-Drying 149</p> <p>1.2.8 Spray Freeze-Drying 150</p> <p>1.3 Storage 150</p> <p>1.3.1 Measurement of the Residual Moisture Content (RM) 151</p> <p>1.3.1.1 Gravimetric Method 151</p> <p>1.3.1.2 Karl Fischer (KF) Method 151</p> <p>1.3.1.3 Thermogravimetry (TG, TG/MS) 153</p> <p>1.3.1.4 Infrared Spectroscopy 154</p> <p>1.3.2 Influence of Vial Stoppers on the Residual Moisture Content 156</p> <p>1.3.3 Qualities of the Dry Substances and Their Changes 162</p> <p>References 165</p> <p><b>2 Installation and Equipment Technique 177</b></p> <p>2.1 Freezing Installation 177</p> <p>2.1.1 Cooling by Liquids: Shell-Freezing and Spin-Freezing 177</p> <p>2.1.2 Cooled Surfaces 178</p> <p>2.1.3 Product in the Flow of Cold Air, Foaming, and Freezing of Extracts and Pulps 179</p> <p>2.1.4 Droplet Freezing in Cold Liquids 181</p> <p>2.1.5 Freezing by Evaporation of Product Water 184</p> <p>2.1.6 Nucleation-on-Demand Technology – ControLyoTM 184</p> <p>2.2 Components of a Freeze-Drying Plant 185</p> <p>2.2.1 Installations for Flasks and Manifolds 185</p> <p>2.2.2 Drying Chambers and Forms of Trays 186</p> <p>2.2.3 Shelves and Their Cooling and Heating 192</p> <p>2.2.4 Water Vapor Condensers 192</p> <p>2.2.5 Refrigerating Systems and Refrigerants 201</p> <p>2.2.6 Vacuum Pumps 215</p> <p>2.2.7 Inlet Venting Filters 221</p> <p>2.2.8 Vacuum Measuring Systems 224</p> <p>2.2.9 Leak Rate Detection 229</p> <p>2.2.10 Process Control Systems 232</p> <p>2.2.11 Problems, Failures, and Deviations 235</p> <p>2.3 Installations Up to 10 kg Ice Capacity 238</p> <p>2.3.1 Universal Laboratory Plants 238</p> <p>2.3.2 Pilot Plants 240</p> <p>2.3.3 Manipulators and Stoppering Systems for Vials 244</p> <p>2.3.4 Cleaning Installations, Sterilization by Steam, and Vaporized Hydrogen Peroxide (VHP®) 248</p> <p>2.4 Production Plants 264</p> <p>2.4.1 Loading and Unloading Systems 269</p> <p>2.4.2 What Is an Isolator? 274</p> <p>2.4.3 Isolators: Validation of Decontamination Processes 280</p> <p>2.5 Production Plants for Food 283</p> <p>2.5.1 Discontinuous Plants 283</p> <p>2.5.2 Continuous Plants with Tray Transport 284</p> <p>2.5.3 Continuous Plants with Product Transport by Wipers or by Vibration 285</p> <p>2.6 Process Automation 287</p> <p>2.6.1 Prerequisites for Process and Related Plant Automation 287</p> <p>2.6.2 Control of the Process and Related Plant Data by Thermodynamic Data Measured during the Process: Thermodynamic Lyophilization Control (TLC) 289</p> <p>2.6.2.1 Control of the Process without Temperature Sensors in the Product 289</p> <p>2.6.2.2 Measurement of the Ice Temperature at the Sublimation Front and the Desorption Rate as Process Guides 292</p> <p>2.6.2.3 Measurement of the Residual Moisture Content (RM) during the Process 302</p> <p>2.6.2.4 The Transfer of a Freeze-Drying Process from a Pilot to a Production Plant 304</p> <p>2.6.2.5 Summary of Prerequisites, Limits, and Suggestions for Automated Thermodynamic Lyophilization Control 308</p> <p>References 309</p> <p>Further Reading 310</p> <p><b>3 Pharmaceutical, Biological, and Medical Products 313</b></p> <p>3.1 Proteins and Hormones 313</p> <p>3.2 Viruses, Vaccines, Bacteria, and Yeasts 330</p> <p>3.3 Antibiotics, Cytostatics, Ibuprofen 341</p> <p>3.4 Liposomes and Nanoparticles 342</p> <p>3.5 Antibody 350</p> <p>3.6 Transplants, Collagen 351</p> <p>3.7 Freeze-Drying Subject Terms – Overview and Summary 358</p> <p>References 360</p> <p><b>4 Metal Oxides, Ceramic Powders 367</b></p> <p>References 372</p> <p><b>5 Trouble Shooting 375</b></p> <p>5.1 Prolonged Evacuation Time 375</p> <p>5.2 Sublimation Front Temperature Too High 376</p> <p>5.3 Sublimation Front Temperature Irregular 376</p> <p>5.4 Slow Pressure Increase in the Chamber during Main Drying 376</p> <p>5.5 Stoppers ›Pop Out‹ or Slide into the Vials 377</p> <p>5.6 Traces of Highly Volatile Solvents (Acetone, Ethanol) 377</p> <p>5.7 Different Structures of the Dried Product in the Center and Border of a Shelf 378</p> <p><b>6 Regulatory Issues 379</b></p> <p>Qualification and Validation of Processes and Installations 379</p> <p>6.1 PAT (Practical Analytical Technology) 385</p> <p>6.2 Quality of the Product 388</p> <p>6.3 Description of the Process Developed for Manufacturing of the Product 389</p> <p>6.4 Description of Production Installations and Their Handling 391</p> <p>6.5 Equipment Performance Tests 392</p> <p>6.6 Quality of Installation to Document the Ability of Equipment to Operate Processes (Described in Section 6.3) 395</p> <p>6.7 Documentation of the Quality of the Products Manufactured (in Comparison with Section 6.2) 396</p> <p>References 396</p> <p>Appendix: Abbreviations, Symbols, and Unit of Measure 399</p> <p>Index 405</p> <p> </p>

Dipl. Ing. Peter Haseley is an independent consultant for lyophilization technology incl. process and cycle development with an expertise in freeze-drying of ODT (oral fast dissolving tablets), the development and design study for an semi-continuous working lyophilization plants, the transfer of Freeze-Drying cycles from an Usifroid plant to a Telstar plant, cycle development and process optimization and the standardization of projects for costs reduction and fast track component production. <br> He worked already together with Dr. Georg-Wilhelm Oetjen (who passed away 2015) on the second edition of ?Freeze-Drying? and has now taken over the authorship for the third edition.<br>

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