Table Of Content

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 LibraryofCongressCardNo.:appliedfor Cover BritishLibraryCataloguing-in-PublicationDataA Thecoverphotographshowsa cataloguerecordforthisbookisavailablefromthe productionfreeze-dryingplantwith BritishLibrary. slotdoorforloadingandunloadingat thefrontandmainservicedooratthe Bibliographicinformationpublishedbythe righthandside. DeutscheNationalbibliothekTheDeutsche Nationalbibliothekliststhispublicationinthe (Photograph:AustarGroup,China) DeutscheNationalbibliografie;detailed bibliographicdataareavailableonthe Internetat<http://dnb.d-nb.de>. 2018Wiley-VCHVerlagGmbH&Co.KGaA, Boschstr.12,69469Weinheim,Germany Allrightsreserved(includingthoseoftranslation intootherlanguages).Nopartofthisbookmaybe reproducedinanyform–byphotoprinting, microfilm,oranyothermeans–nortransmittedor translatedintoamachinelanguagewithoutwritten permissionfromthepublishers.Registerednames, trademarks,etc.usedinthisbook,evenwhennot specificallymarkedassuch,arenottobe consideredunprotectedbylaw. PrintISBN:978-3-527-34306-5 ePDFISBN:978-3-527-80891-5 ePubISBN:978-3-527-80893-9 MobiISBN:978-3-527-80892-2 oBookISBN:978-3-527-80894-6 CoverDesignAdamDesign,Weinheim,Germany TypesettingThomsonDigital,Noida,India PrintingandBindingWeinheim Printedonacid-freepaper ∗deceased 10 9 8 7 6 5 4 3 2 1 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