Preface ........................................................ IX
Preface to the First Edition ................................... XI
1. Foundations and Process Engineering .......................... 1
1.1. Freezing ................................................ 2
1.1.1. Amount of Heat, Heat Conductivity, Heat
Transfer and Cooling Rate
1.1.2. Structure of Ice, Solutions and Dispersions ..... 13
1.1.3. Influence of Excipients ......................... 21
1.1.4. Freezing of Cells and Bacteria .................. 30
1.1.5. Methods of Structure Analysis ................... 32
1.1.5.1. Measurements of Electrical
Resistance (ER) ........................ 32
1.1.5.2. Differential Thermal Analysis (DTA) .... 43
1.1.5.3. Cryomicroscopy ......................... 49
1.1.5.4. Differential Scanning Calorimetry
(DSC) .................................. 57
1.1.5.5. Nuclear Magnetic Resonance ............. 65
1.1.5.6. Thermomechanical Analysis (TMA) ........ 70
1.1.5.7. Dielectric Analysis (DEA) .............. 73
1.1.5.8. X-ray Diffractometry-Raman
Spectroscopy ........................... 74
1.1.6. Changes of Structure in Freezing or Frozen
Products ........................................ 74
1.2. Drying ................................................. 76
1.2.1. Main Drying (Sublimation Drying) ................ 77
1.2.2. Secondary Drying (Desorption Drying) ............ 96
1.2.3. Temperature and Pressure Measurement ........... 105
1.2.4. Water Vapor Transport During Drying ............ 127
1.2.5. Collapse and Recrystallization ................. 134
1.2.6. Drying Processes Without Vacuum ................ 139
1.3. Storage ............................................... 140
1.3.1. Measurement of the Residual Moisture
Content (RM) ................................... 141
1.3.1.1. Gravimetric Method .................... 141
1.3.1.2. Karl Fischer (KF) Method .............. 141
1.3.1.3. Thermogravimetry (TG, TG/MS) .......... 142
1.3.1.4. Infrared Spectroscopy ................. 144
1.3.2. Influence of Vial Stoppers on the Residual
Moisture Content ............................... 148
1.3.3. Qualities of the Dry Substances and Their
Changes ........................................ 151
1.4. References for Chapter 1 .............................. 254
2. Installation and Equipment Technique ....................... 165
2.1. Freezing Installation ................................. 165
2.1.1. Cooling by Liquids: Shell-freezing and Spin-
freezing ....................................... 165
2.1.2. Cooled Surfaces ................................ 166
2.1.3. Product in the Flow of Cold Air, Foaming
and Freezing of Extracts and Pulps ............. 167
2.1.4. Droplet Freezing in Cold Liquids ............... 170
2.1.5. Freezing by Evaporation of Product Water ....... 173
2.2. Components of a Freeze-drying Plant ................... 173
2.2.1. Installations for Flasks and Manifolds ......... 173
2.2.2. Drying Chambers and Forms of Trays ............. 174
Trays for Special Applications ................. 181
2.2.3. Shelves and their Cooling and Heating .......... 181
2.2.4. Water Vapor Condensers ......................... 182
2.2.5. Refrigerating Systems and Refrigerants ......... 190
2.2.6. Vacuum Pumps ................................... 205
2.2.7. Inlet Venting Filters .......................... 211
2.2.8. Vacuum Measuring Systems ....................... 216
2.2.9. Leak Rate Detection ............................ 219
2.2.10.Process Control Systems ........................ 222
2.2.11.Problems, Failures and Deviations .............. 225
2.3. Installations up to 10 kg Ice Capacity ................ 229
2.3.1. Universal Laboratory Plants .................... 229
2.3.2. Pilot Plants ................................... 230
2.3.3. Manipulators and Stoppering Systems for
Vials .......................................... 235
2.3.4. Cleaning Installations, Sterilization by
Steam and Vaporized Hydrogen Peroxide (VHP®) ... 238
2.4. Production Plants ..................................... 253
2.4.1. Loading and Unloading Systems .................. 258
2.5. Production Plants for Food ............................ 264
2.5.1. Discontinuous Plants ........................... 264
2.5.2. Continuous Plants with Tray Transport .......... 265
2.5.3. Continuous Plants with Product Transport by
Wipers or by Vibration ......................... 267
2.6. Process Automation .................................... 268
2.6.1. Prerequisites for Process and Related Plant
Automation ..................................... 270
2.6.2. Control of the Process and Related Plant
Data by Thermodynamic Data Measured During
the Process: Thermodynamic Lyophilization
Control (TLC) .................................. 273
2.6.2.1. Control of the Process Without
Temperature Sensors in the Product .... 273
2.6.2.2. Measurement of the Ice Temperature
at the Sublimation Front and the
Desorption Rate as Process Guides ..... 274
2.6.2.3. Measurement of the Residual
Moisture Content (RM) During the
Process ............................... 284
2.6.2.4. The Transfer of a Freeze-drying
Process from a Pilot to a Production
Plant ................................. 287
2.6.2.5. Summary of Prerequisites, Limits
and Suggestions for Automated
Thermodynamic Lyophilization
Control ............................... 291
2.7. References for Chapter 2 .............................. 291
3. Pharmaceutical, Biological and Medical Products ............ 295
3.1. Proteins and Hormones ................................. 295
3.2. Viruses, Vaccines, Bacteria and Yeasts ................ 313
3.3. Antibiotics, Cytostatics, Ibuprofen ................... 324
3.4. Liposomes and Nanoparticles ........................... 325
3.5. Transplants, Collagen ................................. 333
3.6. References for Chapter 3 .............................. 340
4. Food and Luxury Food ....................................... 345
4.1. Vegetables, Potatoes, Fruits and Juices ............... 349
4.2. Coffee ................................................ 352
4.3. Eggs, Rice ............................................ 355
4.4. References for Chapter 4 .............................. 355
5. Metal Oxides, Ceramic Powders .............................. 359
5.1. References for Chapter 5 .............................. 364
6. Trouble Shooting and Regulatory Issues ..................... 367
6.1. Trouble Shooting ...................................... 367
6.1.1. Prolonged Evacuation Time ...................... 367
6.1.2. Sublimation Front Temperature Too High ......... 368
6.1.3. Sublimation Front Temperature Irregular ........ 368
6.1.4. Slow Pressure Increase in the Chamber During
Main Drying .................................... 368
6.1.5. Stoppers >Pop Out< or Slide Into the Vials ..... 369
6.1.6. Traces of Highly Volatile Solvents (Acetone,
Ethanol) ....................................... 369
6.1.7. Different Structure of the Dried Product in
the Center and Border of a Shelf ............... 370
6.2. Qualification and Validation of Processes and
Installations ......................................... 371
6.2.1. Quality of the Product ......................... 376
6.2.2. Description of the Process Developed for
Manufacturing of the Product ................... 377
6.2.3. Description of Production Installations and
Their Handling ................................. 379
6.2.4. Equipment Performance Tests .................... 381
6.2.5. Quality of Installation to Document the
Ability of Equipment to Operate Processes
(Described in Section 6.2.2) ................... 382
6.2.6. Documentation of the Quality of the Products
Manufactured (in Comparison with 6.2.1) ........ 384
6.3. References for Chapter 6 .............................. 384
Appendix, abbreviations, symbols , and unit of measure ........ 385
Index ......................................................... 389
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