Freeze-drying

430 Pages·2018·57.601 MB·English

by  Georg-Wilhelm Oetjen, Peter Haseley

Freeze-Drying

Freeze-Drying
Third, Completely Revised and Enlarged Edition
Peter Haseley and Georg-Wilhelm Oetjen
Authors AllbookspublishedbyWiley-VCHarecarefully
produced.Nevertheless,authors,editors,and
PeterHaseley
publisherdonotwarranttheinformation
Alfons-Auer-Str.8e
containedinthesebooks,includingthisbook,tobe
93053Regensburg
freeoferrors.Readersareadvisedtokeepinmind
Germany
thatstatements,data,illustrations,procedural
Georg-WilhelmOetjen∗ detailsorotheritemsmayinadvertentlybe
Lübeck inaccurate.
Germany
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Thecoverphotographshowsa
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productionfreeze-dryingplantwith
BritishLibrary.
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2018Wiley-VCHVerlagGmbH&Co.KGaA,
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PrintISBN:978-3-527-34306-5
ePDFISBN:978-3-527-80891-5
ePubISBN:978-3-527-80893-9
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v
Contents
PrefacetoThirdEditionandAcknowledgment ix
PrefacetotheSecondEdition xi
1 FoundationsandProcessEngineering 1
1.1 Freezing 2
1.1.1 AmountofHeat,HeatConductivity,HeatTransfer,
andCoolingRate 3
1.1.2 StructureofIce,Solutions,andDispersions 14
1.1.3 InfluenceofExcipients 22
1.1.4 FreezingofCellsandBacteria 32
1.1.5 MethodsofStructureAnalysis 34
1.1.5.1 MeasurementsofElectricalResistance(ER) 34
1.1.5.2 DifferentialThermalAnalysis(DTA) 45
1.1.5.3 Cryomicroscopy 51
1.1.5.4 Freeze-DryMicroscopy 59
1.1.5.5 DifferentialScanningCalorimetry(DSC) 60
1.1.5.6 NuclearMagneticResonance 68
1.1.5.7 ThermomechanicalAnalysis(TMA) 74
1.1.5.8 DielectricAnalysis(DEA) 76
1.1.5.9 XRPDDiffractometer–RamanSpectroscopy 77
1.1.6 ChangesofStructureinFreezingorFrozenProducts 78
1.2 Drying 79
1.2.1 MainDrying(SublimationDrying) 82
1.2.2 SecondaryDrying(DesorptionDrying) 101
1.2.3 TemperatureandPressureMeasurement 113
1.2.3.1 WirelessTemperatureMeasurement 135
1.2.4 WaterVaporTransportduringDrying 136
1.2.4.1 EndpointDeterminationofMainandSecondaryDrying 144
1.2.5 CollapseandRecrystallization 145
1.2.6 DryingProcesseswithoutVacuum 148
1.2.7 MicrowaveFreeze-Drying 149
1.2.8 SprayFreeze-Drying 150
1.3 Storage 150
1.3.1 MeasurementoftheResidualMoistureContent(RM) 151
vi Contents
1.3.1.1 GravimetricMethod 151
1.3.1.2 KarlFischer(KF)Method 151
1.3.1.3 Thermogravimetry(TG,TG/MS) 153
1.3.1.4 InfraredSpectroscopy 154
1.3.2 InfluenceofVialStoppersontheResidualMoisture
Content 156
1.3.3 QualitiesoftheDrySubstancesandTheirChanges 162
References 165
2 InstallationandEquipmentTechnique 177
2.1 FreezingInstallation 177
2.1.1 CoolingbyLiquids:Shell-FreezingandSpin-Freezing 177
2.1.2 CooledSurfaces 178
2.1.3 ProductintheFlowofColdAir,Foaming,andFreezingofExtracts
andPulps 179
2.1.4 DropletFreezinginColdLiquids 181
2.1.5 FreezingbyEvaporationofProductWater 184
2.1.6 Nucleation-on-DemandTechnology–ControLyoTM 184
2.2 ComponentsofaFreeze-DryingPlant 185
2.2.1 InstallationsforFlasksandManifolds 185
2.2.2 DryingChambersandFormsofTrays 186
2.2.3 ShelvesandTheirCoolingandHeating 192
2.2.4 WaterVaporCondensers 192
2.2.5 RefrigeratingSystemsandRefrigerants 201
2.2.6 VacuumPumps 215
2.2.7 InletVentingFilters 221
2.2.8 VacuumMeasuringSystems 224
2.2.9 LeakRateDetection 229
2.2.10 ProcessControlSystems 232
2.2.11 Problems,Failures,andDeviations 235
2.3 InstallationsUpto10kgIceCapacity 238
2.3.1 UniversalLaboratoryPlants 238
2.3.2 PilotPlants 240
2.3.3 ManipulatorsandStopperingSystemsforVials 244
2.3.4 CleaningInstallations,SterilizationbySteam,andVaporized
HydrogenPeroxide(VHP®) 248
2.4 ProductionPlants 264
2.4.1 LoadingandUnloadingSystems 269
2.4.2 WhatIsanIsolator? 274
2.4.3 Isolators:ValidationofDecontaminationProcesses 280
2.5 ProductionPlantsforFood 283
2.5.1 DiscontinuousPlants 283
2.5.2 ContinuousPlantswithTrayTransport 284
2.5.3 ContinuousPlantswithProductTransportbyWipersorby
Vibration 285
2.6 ProcessAutomation 287
2.6.1 PrerequisitesforProcessandRelatedPlantAutomation 287
Contents vii
2.6.2 ControloftheProcessandRelatedPlantDatabyThermodynamic
DataMeasuredduringtheProcess:ThermodynamicLyophilization
Control(TLC) 289
2.6.2.1 ControloftheProcesswithoutTemperatureSensorsinthe
Product 289
2.6.2.2 MeasurementoftheIceTemperatureattheSublimationFrontandthe
DesorptionRateasProcessGuides 292
2.6.2.3 MeasurementoftheResidualMoistureContent(RM)duringthe
Process 302
2.6.2.4 TheTransferofaFreeze-DryingProcessfromaPilottoaProduction
Plant 304
2.6.2.5 SummaryofPrerequisites,Limits,andSuggestionsforAutomated
ThermodynamicLyophilizationControl 308
References 309
FurtherReading 310
3 Pharmaceutical,Biological,andMedicalProducts 313
3.1 ProteinsandHormones 313
3.2 Viruses,Vaccines,Bacteria,andYeasts 330
3.3 Antibiotics,Cytostatics,Ibuprofen 341
3.4 LiposomesandNanoparticles 342
3.5 Antibody 350
3.6 Transplants,Collagen 351
3.7 Freeze-DryingSubjectTerms–OverviewandSummary 358
References 360
4 MetalOxides,CeramicPowders 367
References 372
5 TroubleShooting 375
5.1 ProlongedEvacuationTime 375
5.2 SublimationFrontTemperatureTooHigh 376
5.3 SublimationFrontTemperatureIrregular 376
5.4 SlowPressureIncreaseintheChamberduringMainDrying 376
5.5 Stoppers›PopOut‹orSlideintotheVials 377
5.6 TracesofHighlyVolatileSolvents(Acetone,Ethanol) 377
5.7 DifferentStructuresoftheDriedProductintheCenterandBorderof
aShelf 378
6 RegulatoryIssues 379
QualificationandValidationofProcessesandInstallations 379
6.1 PAT(PracticalAnalyticalTechnology) 385
6.2 QualityoftheProduct 388
6.3 DescriptionoftheProcessDevelopedforManufacturingofthe
Product 389
6.4 DescriptionofProductionInstallationsandTheirHandling 391
6.5 EquipmentPerformanceTests 392
viii Contents
6.6 QualityofInstallationtoDocumenttheAbilityofEquipmentto
OperateProcesses(DescribedinSection6.3) 395
6.7 DocumentationoftheQualityoftheProductsManufactured
(inComparisonwithSection6.2) 396
References 396
Appendix:Abbreviations,Symbols,andUnitofMeasure 399
Index 405
ix
Preface to Third Edition and Acknowledgment
Thisthird,revisededitionIwouldliketodedicatetoDr.Georg-WilhelmOetjen,
who passed away in 2015. He introduced me to Freeze-Drying and essentially
influenced my professional career.
I would like to acknowledge my supporters who helped me to complete this
book.WithouttheircontinuedsupportandeffortIprobablywouldhavenotbeen
abletobringmyworktoasuccessfulcompletion.IwouldliketothankMr.Mars
Ho – CEO Austar Group, Hong Kong; Mr. Austin McDonald – CEO Sterile
Technology LLC, USA; Mr. Manfred Steiner – GEA Lyophil GmbH, Germany;
and Mr. Anton Mangold – CEO iQ-mobil solutions, Germany.
Without the professional support of Mrs. Regine Fisher, MD Semicom
Media & Communications, Germany, I would have had difficulties to finish
thebook.Shewasresponsibleforthetextfinalizationandproofreadingaswell
as for the editing and handling of images, tables, and graphics.
Peter Haseley
Dipl.-Ing.(FH)