Freeze-Drying

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. 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.

• ContentsPreface to Third Edition and Acknowledgment ixPreface to the Second Edition xi1 Foundations and Process Engineering 11.1 Freezing 21.1.1 Amount of Heat, Heat Conductivity, Heat Transfer, and Cooling Rate 31.1.2 Structure of Ice, Solutions, and Dispersions 141.1.3 Influence of Excipients 221.1.4 Freezing of Cells and Bacteria 321.1.5 Methods of Structure Analysis 341.1.5.1 Measurements of Electrical Resistance (ER) 341.1.5.2 Differential Thermal Analysis (DTA) 451.1.5.3 Cryomicroscopy 511.1.5.4 Freeze-Dry Microscopy 591.1.5.5 Differential Scanning Calorimetry (DSC) 601.1.5.6 Nuclear Magnetic Resonance 681.1.5.7 Thermomechanical Analysis (TMA) 741.1.5.8 Dielectric Analysis (DEA) 761.1.5.9 XRPD Diffractometer–Raman Spectroscopy 771.1.6 Changes of Structure in Freezing or Frozen Products 781.2 Drying 791.2.1 Main Drying (Sublimation Drying) 821.2.2 Secondary Drying (Desorption Drying) 1011.2.3 Temperature and Pressure Measurement 1131.2.3.1 Wireless Temperature Measurement 1351.2.4 Water Vapor Transport during Drying 1361.2.4.1 Endpoint Determination of Main and Secondary Drying 1441.2.5 Collapse and Recrystallization 1451.2.6 Drying Processes without Vacuum 1481.2.7 Microwave Freeze-Drying 1491.2.8 Spray Freeze-Drying 1501.3 Storage 1501.3.1 Measurement of the Residual Moisture Content (RM) 1511.3.1.1 Gravimetric Method 1511.3.1.2 Karl Fischer (KF) Method 1511.3.1.3 Thermogravimetry (TG, TG/MS) 1531.3.1.4 Infrared Spectroscopy 1541.3.2 Influence of Vial Stoppers on the Residual Moisture Content 1561.3.3 Qualities of the Dry Substances and Their Changes 162References 1652 Installation and Equipment Technique 1772.1 Freezing Installation 1772.1.1 Cooling by Liquids: Shell-Freezing and Spin-Freezing 1772.1.2 Cooled Surfaces 1782.1.3 Product in the Flow of Cold Air, Foaming, and Freezing of Extracts and Pulps 1792.1.4 Droplet Freezing in Cold Liquids 1812.1.5 Freezing by Evaporation of Product Water 1842.1.6 Nucleation-on-Demand Technology – ControLyoTM 1842.2 Components of a Freeze-Drying Plant 1852.2.1 Installations for Flasks and Manifolds 1852.2.2 Drying Chambers and Forms of Trays 1862.2.3 Shelves and Their Cooling and Heating 1922.2.4 Water Vapor Condensers 1922.2.5 Refrigerating Systems and Refrigerants 2012.2.6 Vacuum Pumps 2152.2.7 Inlet Venting Filters 2212.2.8 Vacuum Measuring Systems 2242.2.9 Leak Rate Detection 2292.2.10 Process Control Systems 2322.2.11 Problems, Failures, and Deviations 2352.3 Installations Up to 10 kg Ice Capacity 2382.3.1 Universal Laboratory Plants 2382.3.2 Pilot Plants 2402.3.3 Manipulators and Stoppering Systems for Vials 2442.3.4 Cleaning Installations, Sterilization by Steam, and Vaporized Hydrogen Peroxide (VHP®) 2482.4 Production Plants 2642.4.1 Loading and Unloading Systems 2692.4.2 What Is an Isolator? 2742.4.3 Isolators: Validation of Decontamination Processes 2802.5 Production Plants for Food 2832.5.1 Discontinuous Plants 2832.5.2 Continuous Plants with Tray Transport 2842.5.3 Continuous Plants with Product Transport by Wipers or by Vibration 2852.6 Process Automation 2872.6.1 Prerequisites for Process and Related Plant Automation 2872.6.2 Control of the Process and Related Plant Data by Thermodynamic Data Measured during the Process: Thermodynamic Lyophilization Control (TLC) 2892.6.2.1 Control of the Process without Temperature Sensors in the Product 2892.6.2.2 Measurement of the Ice Temperature at the Sublimation Front and the Desorption Rate as Process Guides 2922.6.2.3 Measurement of the Residual Moisture Content (RM) during the Process 3022.6.2.4 The Transfer of a Freeze-Drying Process from a Pilot to a Production Plant 3042.6.2.5 Summary of Prerequisites, Limits, and Suggestions for Automated Thermodynamic Lyophilization Control 308References 309Further Reading 3103 Pharmaceutical, Biological, and Medical Products 3133.1 Proteins and Hormones 3133.2 Viruses, Vaccines, Bacteria, and Yeasts 3303.3 Antibiotics, Cytostatics, Ibuprofen 3413.4 Liposomes and Nanoparticles 3423.5 Antibody 3503.6 Transplants, Collagen 3513.7 Freeze-Drying Subject Terms – Overview and Summary 358References 3604 Metal Oxides, Ceramic Powders 367References 3725 Trouble Shooting 3755.1 Prolonged Evacuation Time 3755.2 Sublimation Front Temperature Too High 3765.3 Sublimation Front Temperature Irregular 3765.4 Slow Pressure Increase in the Chamber during Main Drying 3765.5 Stoppers ›Pop Out‹ or Slide into the Vials 3775.6 Traces of Highly Volatile Solvents (Acetone, Ethanol) 3775.7 Different Structures of the Dried Product in the Center and Border of a Shelf 3786 Regulatory Issues 379Qualification and Validation of Processes and Installations 3796.1 PAT (Practical Analytical Technology) 3856.2 Quality of the Product 3886.3 Description of the Process Developed for Manufacturing of the Product 3896.4 Description of Production Installations and Their Handling 3916.5 Equipment Performance Tests 3926.6 Quality of Installation to Document the Ability of Equipment to Operate Processes (Described in Section 6.3) 3956.7 Documentation of the Quality of the Products Manufactured (in Comparison with Section 6.2) 396References 396Appendix: Abbreviations, Symbols, and Unit of Measure 399Index 405