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GUIDETOINSPECTIONSOFLYOPHILIZATIONOFPARENTERALSNote:ThisdocumentisreferencematerialforinvestigatorsandotherFDApersonnel.ThedocumentdoesnotbindFDA,anddoesnoconferanyrights,privileges,benefits,orimmunitiesfororonanyperson(s).INTRODUCTIONLyophilizationorfreezedryingisaprocessinwhichwaterisremovedfromaproductafteritisfrozenandplacedunderavacuum,allowingtheicetochangedirectlyfromsolidtovaporwithoutpassingthroughaliquidphase.Theprocessconsistsofthreeseparate,unique,andinterdependentprocesses;freezing,primarydrying(sublimation),andsecondarydrying(desorption).Theadvantagesoflyophilizationinclude:Easeofprocessingaliquid,whichsimplifiesaseptichandlingEnhancedstabilityofadrypowderRemovalofwaterwithoutexcessiveheatingoftheproductEnhancedproductstabilityinadrystateRapidandeasydissolutionofreconstitutedproductDisadvantagesoflyophilizationinclude:IncreasedhandlingandprocessingtimeNeedforsterilediluentuponreconstitutionCostandcomplexityofequipmentThelyophilizationprocessgenerallyincludesthefollowingsteps:·Dissolvingthedrugandexcipientsinasuitablesolvent,generallywaterforinjection(WFI).·Sterilizingthebulksolutionbypassingitthrougha0.22micronbacteria-retentivefilter.·Fillingintoindividualsterilecontainersandpartiallystopperingthecontainersunderasepticconditions.·Transportingthepartiallystopperedcontainerstothelyophilizerandloadingintothechamberunderasepticconditions.·Freezingthesolutionbyplacingthepartiallystopperedcontainersoncooledshelvesinafreeze-dryingchamberorpre-freezinginanotherchamber.·Applyingavacuumtothechamberandheatingtheshelvesinordertoevaporatethewaterfromthefrozenstate.·Completestopperingofthevialsusuallybyhydraulicorscrewrodstopperingmechanismsinstalledinthelyophilizers.Therearemanynewparenteralproducts,includinganti-infectives,biotechnologyderivedproducts,andin-vitrodiagnosticswhicharemanufacturedaslyophilizedproducts.Additionally,inspectionshavedisclosedpotency,sterilityandstabilityproblemsassociatedwiththemanufactureandcontroloflyophilizedproducts.Inordertoprovideguidanceandinformationtoinvestigators,someindustryproceduresanddeficienciesassociatedwithlyophilizedproductsareidentifiedinthisInspectionGuide.18/18 Itisrecognizedthatthereiscomplextechnologyassociatedwiththemanufactureandcontrolofalyophilizedpharmaceuticaldosageform.Someoftheimportantaspectsoftheseoperationsinclude:theformulationofsolutions;fillingofvialsandvalidationofthefillingoperation;sterilizationandengineeringaspectsofthelyophilizer;scale-upandvalidationofthelyophilizationcycle;andtestingoftheendproduct.Thisdiscussionwilladdresssomeoftheproblemsassociatedwiththemanufactureandcontrolofalyophilizeddosageform.PRODUCTTYPE/FORMULATIONProductsaremanufacturedinthelyophilizedformduetotheirinstabilitywheninsolution.Manyoftheantibiotics,suchassomeofthesemi-syntheticpenicillins,cephalosporins,andalsosomeofthesaltsoferythromycin,doxycyclineandchloramphenicolaremadebythelyophilizationprocess.Becausetheyareantibiotics,lowbioburdenoftheseformulationswouldbeexpectedatthetimeofbatching.However,someoftheotherdosageformsthatarelyophilized,suchashydrocortisonesodiumsuccinate,methylprednisolonesodiumsuccinateandmanyofthebiotechnologyderivedproducts,havenoantibacterialeffectwheninsolution.Forthesetypesofproducts,bioburdenshouldbeminimalandthebioburdenshouldbedeterminedpriortosterilizationofthesebulksolutionspriortofilling.Obviously,thebatchingorcompoundingofthesebulksolutionsshouldbecontrolledinordertopreventanypotentialincreaseinmicrobiologicallevelsthatmayoccuruptothetimethatthebulksolutionsarefiltered(sterilized).Theconcernwithanymicrobiologicallevelisthepossibleincreaseinendotoxinsthatmaydevelop.Goodpracticeforthecompoundingoflyophilizedproductswouldalsoincludebatchinginacontrolledenvironmentandinsealedtanks,particularlyifthesolutionistobeheldforanylengthoftimepriortosterilization.Insomecases,manufacturershaveperformedbioburdentestingonbulksolutionsafterprefiltrationandpriortofinalfiltration.Whilethetestingofsuchsolutionsmaybemeaningfulindeterminingthebioburdenforsterilization,itdoesnotprovideanyinformationregardingthepotentialformationorpresenceofendotoxins.Whilethetestingof0.1mlsamplesbyLALmethodsofbulksolutionforendotoxinsisofvalue,testingofatleast100mlsizesamplespriortoprefiltration,particularlyforthepresenceofgramnegativeorganisms,wouldbeofgreatervalueinevaluatingtheprocess.Forexample,thepresenceofPseudomonassp.inthebioburdenofabulksolutionhasbeenidentifiedasanobjectionablecondition.FILLINGThefillingofvialsthataretobelyophilizedhassomeproblemsthataresomewhatunique.Thestopperisplacedontopofthevialandisultimatelyseatedinthelyophilizer.Asaresultthecontentsofthevialaresubjecttocontaminationuntiltheyareactuallysealed.Validationoffillingoperationsshouldincludemediafillsandthesamplingofcriticalsurfacesandairduringactivefilling(dynamicconditions).Becauseoftheactiveinvolvementofpeopleinfillingandasepticmanipulations,anenvironmentalprogramshouldalsoincludeanevaluationofmicrobiologicallevelsonpeopleworkinginasepticprocessingareas.Onemethodofevaluationofthetraining18/18 ofoperatorsworkinginasepticprocessingfacilitiesincludesthesurfacemonitoringofglovesand/orgownsonadailybasis.Manufacturersareactivelysamplingthesurfacesofpersonnelworkinginasepticprocessingareas.AreferencewhichprovidesforthistypeofmonitoringistheUSPXXIIdiscussionoftheInterpretationofSterilityTestResults.Itstatesundertheheadingof"InterpretationofQualityControlTests"thatreviewconsiderationshouldbepaidtoenvironmentalcontroldata,including...microbialmonitoring,recordsofoperators,gowns,gloves,andgarbingpractices.Inthosesituationsinwhichmanufacturershavefailedtoperformsometypeofpersonnelmonitoring,ormonitoringhasshownunacceptablelevelsofcontamination,regulatorysituationshaveresulted.Typically,vialstobelyophilizedarepartiallystopperedbymachine.However,somefillinglineshavebeennotedwhichutilizeanoperatortoplaceeachstopperontopofthevialbyhand.Atthistime,itwouldseemthatitwouldbedifficultforamanufacturertojustifyahand-stopperingoperation,evenifsterileforcepsareemployed,inanytypeofoperationotherthanfillingaclinicalbatchorverysmallnumberofunits.Significantregulatorysituationshaveresultedwhensomemanufacturershavehand-stopperedvials.Again,theconcernistheimmediateavenueofcontaminationofferedbytheoperator.Itiswellrecognizedthatpeoplearethemajorsourceofcontaminationinanasepticprocessingfillingoperation.Thelongerapersonworksinanasepticoperation,themoremicroorganismswillbeshedandthegreatertheprobabilityofcontamination.Oncefilledandpartiallystoppered,vialsaretransportedandloadedintothelyophilizer.Thetransferandhandling,suchasloadingofthelyophilizer,shouldtakeplaceunderprimarybarriers,suchasthelaminarflowhoodsunderwhichthevialswerefilled.Validationofthishandlingshouldalsoincludetheusemediafills.Regardingthefillingofsterilemedia,therearesomemanufacturerswhocarryoutapartiallyophilizationcycleandfreezethemedia.Whilethiscouldseemtogreatermimictheprocess,thefreezingofmediacouldreducemicrobiallevelsofsomecontaminants.Sincethepurposeofthemediafillistoevaluateandjustifytheasepticcapabilitiesoftheprocess,thepeopleandthesystem,thepossiblereductionofmicrobiologicallevelsafterasepticmanipulationbyfreezingwouldnotbewarranted.Thepurposeofamediafillisnottodeterminethelethalityoffreezinganditseffectonanymicrobialcontaminantsthatmightbepresent.Inanefforttoidentifytheparticularsectionsoffillingandasepticmanipulationthatmightintroducecontamination,severalmanufacturershaveresortedtoexpandedmediafills.Thatis,theyhavefilledapproximately9000vialsduringamediafillandsegmentedthefillintothreestages.Onestagehasincludedfillingof3000vialsandstopperingonline;anotherstageincludedfilling3000vials,transportationtothelyophilizerandthenstoppering;athirdstageincludedthefillingof3000vials,loadinginthelyophilizer,andexposuretoaportionofthenitrogenflushandthenstoppering.Sincelyophilizersterilizationandsterilizationofthenitrogensystemusedtobackfillrequireseparatevalidation,mediafillsshouldprimarilyvalidatethefilling,transportationandloadingasepticoperations.18/18 Thequestionofthenumberofunitsneededformediafillswhenthecapacityoftheprocessislessthan3000unitsisfrequentlyasked,particularlyforclinicalproducts.Again,thepurposeofthemediafillistoassurethatproductcanbeasepticallyprocessedwithoutcontaminationunderoperatingconditions.Itwouldseem,therefore,thatthemaximumnumberofunitsofmediafilledbeequivalenttothemaximumbatchsizeifitislessthan3000units.Afterfilling,dosageunitsaretransportedtothelyophilizerbymetaltrays.Usually,thebottomofthetraysareremovedafterthedosageunitsareloadedintothelyophilizer.Thus,thedosageunitsliedirectlyonthelyophilizershelf.Therehavebeensomesituationsinwhichmanufacturershaveloadedthedosageunitsonmetaltrayswhichwerenotremoved.Unfortunately,atonemanufacturer,thetrayswarpedwhichcausedamoistureprobleminsomedosageunitsinabatch.Inthetransportofvialstothelyophilizer,sincetheyarenotsealed,thereisconcernforthepotentialforcontamination.Duringinspectionsandinthereviewofnewfacilities,thefailuretoprovidelaminarflowcoverageoraprimarybarrierforthetransportandloadingareasofalyophilizerhasbeenregardedasanobjectionablecondition.Onemanufacturerasameansofcorrectiondevelopedalaminarflowcarttotransportthevialsfromthefillinglinetothelyophilizer.Othermanufacturersbuildingnewfacilitieshavelocatedthefillinglineclosetothelyophilizerandhaveprovidedaprimarybarrierextendingfromthefillinglinetothelyophilizer.Inordertocorrectthistypeofproblem,anothermanufacturerinstalledaverticallaminarflowhoodbetweenthefillinglineandlyophilizer.Initially,highvelocitieswithinadequatereturncausedacontaminationprobleminamediafill.Itwasspeculatedthatnewaircurrentsresultedinreboundcontaminationoffthefloor.Fortunately,mediafillsandsmokestudiesprovidedenoughmeaningfulinformationthattheproblemcouldbecorrectedpriortothemanufactureofproduct.Typically,thelyophilizationprocessincludesthestopperingofvialsinthechamber.Anothermajorconcernwiththefillingoperationisassuranceoffillvolumes.Obviously,alowfillwouldrepresentasubpotencyinthevial.Unlikeapowderorliquidfill,alowfillwouldnotbereadilyapparentafterlyophilizationparticularlyforabiopharmaceuticaldrugproductwheretheactiveingredientmaybeonlyamilligram.Becauseoftheclinicalsignificance,sub-potencyinavialpotentiallycanbeaveryserioussituation.Forexample,intheinspectionofalyophilizationfillingoperation,itwasnotedthatthefirmwashavingafillingproblem.Thegateonthefillinglinewasnotcoordinatedwiththefillingsyringes,andsplashingandpartialfillingwasoccurring.Itwasalsoobservedthatsomeofthepartiallyfilledvialswereloadedintothelyophilizer.Thisresultedinrejectionofthebatch.Onoccasion,ithasbeenseenthatproductionoperatorsmonitoringfillvolumesrecordthesefillvolumesonlyafteradjustmentsaremade.Therefore,goodpracticeandagoodqualityassuranceprogramwouldincludethefrequentmonitoringofthevolumeoffill,suchasevery15minutes.Goodpracticewouldalsoincludeprovisionsfortheisolationofparticularsectionsoffillingoperationswhenloworhighfillsareencountered.18/18 Therearesomeatypicalfillingoperationswhichhavenotbeendiscussed.Forexample,therehavealsobeensomesituationsinwhichlyophilizationisperformedontraysofsolutionratherthaninvials.Basedonthecurrenttechnologyavailable,itwouldseemthatforasterileproduct,itwouldbedifficulttojustifythisprocedure.Thedualchambervialalsopresentsadditionalrequirementsforasepticmanipulations.Mediafillsshouldincludethefillingofmediainbothchambers.Also,thediluentinthesevialsshouldcontainapreservative.(Withoutapreservative,thefillingofdiluentwouldbeanalogoustothefillingofmedia.Insuchcases,a0%levelofcontaminationwouldbeexpected.)LYOPHILIZATIONCYCLEANDCONTROLSAftersterilizationofthelyophilizerandasepticloading,theinitialstepisfreezingthesolution.Insomecycles,theshelvesareatthetemperatureneededforfreezing,whileforothercycles,theproductisloadedandthentheshelvesaretakentothefreezingtemperaturenecessaryforproductfreeze.Inthosecyclesinwhichtheshelvesareprecooledpriortoloading,thereisconcernforanyiceformationonshelvespriortoloading.Iceonshelvespriortoloadingcancausepartialorcompletestopperingofvialspriortolyophilizationoftheproduct.Arecentfieldcomplaintofaproductinsolutionandnotlyophilizedwasattributedtopreliminarystopperingofafewvialspriortoexposuretothelyophilizationcycle.Unfortunately,thefirm's100%vialinspectionfailedtoidentifythedefectivevial.Typically,theproductisfrozenatatemperaturewellbelowtheeutecticpoint.Thescale-upandchangeoflyophilizationcycles,includingthefreezingprocedures,havepresentedsomeproblems.Studieshaveshowntherateandmanneroffreezingmayaffectthequalityofthelyophilizedproduct.Forexample,slowfreezingleadstotheformationoflargericecrystals.Thisresultsinrelativelylargevoids,whichaidintheescapeofwatervaporduringsublimation.Ontheotherhand,slowfreezingcanincreaseconcentrationshiftsofcomponents.Also,therateandmanneroffreezinghasbeenshowntohaveanaffectonthephysicalform(polymorph)ofthedrugsubstance.Itisdesirableafterfreezingandduringprimarydryingtoholdthedryingtemperature(intheproduct)atleast4-5obelowtheeutecticpoint.Obviously,themanufacturershouldknowtheeutecticpointandhavethenecessaryinstrumentationtoassuretheuniformityofproducttemperatures.Thelyophilizershouldalsohavethenecessaryinstrumentationtocontrolandrecordthekeyprocessparameters.Theseinclude:shelftemperature,producttemperature,condensertemperature,chamberpressureandcondenserpressure.Themanufacturingdirectionsshouldprovidefortime,temperatureandpressurelimitsnecessaryforalyophilizationcycleforaproduct.Themonitoringofproducttemperatureisparticularlyimportantforthosecyclesforwhichthereareatypicaloperatingprocedures,suchaspowerfailuresorequipmentbreakdown.Electromechanicalcontrolofalyophilizationcyclehasutilizedcam-typerecorder-controllers.However,newerunitsprovideformicrocomputercontrolofthefreezedryingprocess.Averybasicrequirementforacomputercontrolledprocessisaflowchartorlogic.Typically,operatorinvolvementinacomputercontrolled18/18 lyophilizationcycleprimarilyoccursatthebeginning.Itconsistsofloadingthechamber,insertingtemperatureprobesinproductvials,andenteringcycleparameterssuchasshelftemperatureforfreezing,productfreezetemperature,freezingsoaktime,primarydryingshelftemperatureandcabinetpressure,producttemperatureforestablishmentoffillvacuum,secondarydryingshelftemperature,andsecondarydryingtime.Insomecases,manufacturershavehadtocontinuouslymakeadjustmentsincyclesastheywerebeingrun.Inthesesituations,thelyophilizationprocesswasfoundtobenon-validated.Validationofthesoftwareprogramofalyophilizerfollowsthesamecriteriaasthatforotherprocesses.Basicconcernsincludesoftwaredevelopment,modificationsandsecurity.TheGuidetoInspectionofComputerizedSystemsinDrugProcessingcontainsadiscussiononpotentialproblemareasrelatingtocomputersystems.AGuidetotheInspectionofSoftwareDevelopmentActivitiesisareferencethatprovidesamoredetailedreviewofsoftwarerequirements.Leakageintoalyophilizermayoriginatefromvarioussources.Asinanyvacuumchamber,leakagecanoccurfromtheatmosphereintothevesselitself.Othersourcesaremediaemployedwithinthesystemtoperformthelyophilizingtask.Thesewouldbethethermalfluidcirculatedthroughtheshelvesforproductheatingandcooling,therefrigerantemployedinsidethevaporcondensercoolingsurfaceandoilvaporsthatmaymigratebackfromthevacuumpumpingsystem.Anyone,oracombinationofall,cancontributetotheleakageofgasesandvaporsintothesystem.Itisnecessarytomonitortheleakrateperiodicallytomaintaintheintegrityofthesystem.Itisalsonecessary,shouldtheleakrateexceedspecifiedlimits,todeterminetheactualleaksiteforpurposesofrepair.Thus,itwouldbebeneficialtoperformaleaktestatsometimeaftersterilization,possiblyatthebeginningofthecycleorpriortostoppering.Thetimeandfrequencyforperformingtheleaktestwillvaryandwilldependonthedatadevelopedduringthecyclevalidation.Thepressurerisefoundacceptableatvalidationshouldbeusedtodeterminetheacceptablepressureriseduringproduction.Alimitandwhatactionistobetakenifexcessiveleakageisfoundshouldbeaddressedinsometypeofoperatingdocument.Inordertominimizeoilvapormigration,somelyophilizersaredesignedwithatortuouspathbetweenthevacuumpumpandchamber.Forexample,onefabricatorinstalledanoiltrapinthelinebetweenthevacuumpumpandchamberinalyophilizerwithaninternalcondenser.Leakagecanalsobeidentifiedbysamplingsurfacesinthechamberafterlyophilizationforcontaminants.Onecouldconcludethatifcontaminationisfoundonachambersurfaceafterlyophilization,thendosageunitsinthechambercouldalsobecontaminated.Itisagoodpracticeaspartofthevalidationofcleaningofthelyophilizationchambertosamplethesurfacesbothbeforeandaftercleaning.Becauseofthelengthycyclerunsandstrainonmachinery,itisnotunusualtoseeequipmentmalfunctionorfailduringalyophilizationcycle.Thereshouldbeprovisionsinplaceforthecorrectiveactiontobetakenwhentheseatypicalsituations18/18 occur.Inadditiontodocumentationofthemalfunction,thereshouldbeanevaluationofthepossibleeffectsontheproduct(e.g.,partialorcompletemeltback.Refertosubsequentdiscussion).Merelytestingsamplesafterthelyophilizationcycleisconcludedmaybeinsufficienttojustifythereleaseoftheremainingunits.Forexample,theleakageofchambershelffluidintothechamberorabreakinsterilitywouldbecauseforrejectionofthebatch.ThereviewofPreventiveMaintenanceLogs,aswellasQualityAssuranceAlertNotices,DiscrepancyReports,andInvestigationReportswillhelptoidentifyproblembatcheswhenthereareequipmentmalfunctionsorpowerfailures.Itisrecommendedthattheserecordsbereviewedearlyintheinspection.CYCLEVALIDATIONManymanufacturersfile(inapplications)theirnormallyophilizationcyclesandvalidatethelyophilizationprocessbasedonthesecycles.Unfortunately,suchdatawouldbeoflittlevaluetosubstantiateshorterorabnormalcycles.Insomecases,manufacturersareunawareoftheeutecticpoint.Itwouldbedifficultforamanufacturertoevaluatepartialorabnormalcycleswithoutknowingtheeutecticpointandthecycleparametersneededtofacilitateprimarydrying.Scale-upforthelyophilizedproductrequiresaknowledgeofthemanyvariablesthatmayhaveaneffectontheproduct.Someofthevariableswouldincludefreezingrateandtemperaturerampingrate.Aswiththescale-upofotherdrugproducts,thereshouldbeadevelopmentreportthatdiscussestheprocessandlogicforthecycle.Probablymoresothananyotherproduct,scale-upofthelyophilizationcycleisverydifficult.Therearesomemanufacturersthatmarketmultiplestrengths,vialsizesandhavedifferentbatchsizes.Itisconceivableandprobablethateachwillhaveitsowncycleparameters.Amanufacturerthathasonecycleformultiplestrengthsofthesameproductprobablyhasdoneapoorjobofdevelopingthecycleandprobablyhasnotadequatelyvalidatedtheirprocess.Investigatorsshouldreviewthereportsanddatathatsupportthefiledlyophilizationcycle.LYOPHILIZERSTERILIZATION/DESIGNThesterilizationofthelyophilizerisoneofthemorefrequentlyencounteredproblemsnotedduringinspections.Someoftheolderlyophilizerscannottoleratesteamunderpressure,andsterilizationismarginalatbest.Theselyophilizerscanonlyhavetheirinsidesurfaceswipedwithachemicalagentthatmaybeasterilantbutusuallyhasbeenfoundtobeasanitizingagent.Unfortunately,pipingsuchasthatfortheadministrationofinertgas(usuallynitrogen)andsterileairforbackfillorvacuumbreakisofteninaccessibletosuchsurface"sterilization"ortreatment.Itwouldseemverydifficultforamanufacturertobeabletodemonstratesatisfactoryvalidationofsterilizationofalyophilizerbychemical"treatment".Anothermethodofsterilizationthathasbeenpracticedistheuseofgaseousethyleneoxide.Aswithanyethyleneoxidetreatment,humidificationisnecessary.Providingamethodforintroducingthesterilemoisturewithuniformityhasbeenfoundtobedifficult.18/18 AmanufacturerhasbeenobservedemployingWaterForInjectionasafinalwashorrinseofthelyophilizer.Whilethechamberwaswet,itwasthenethyleneoxidegassterilized.Asdiscussedabove,thismaybesatisfactoryforthechamberbutinadequateforassociatedplumbing.Anotherproblemassociatedwithethyleneoxideistheresidue.Onemanufacturerhadacommonethyleneoxide/nitrogensupplylinetoanumberoflyophilizersconnectedinparalleltothesystem.Thus,therecouldbesomeethyleneoxideinthenitrogensupplylineduringthebackfillingstep.Obviously,thistypeofsystemisobjectionable.Agenerallyrecognizedacceptablemethodofsterilizingthelyophilizeristhroughtheuseofmoiststeamunderpressure.Sterilizationproceduresshouldparallelthatofanautoclave,andatypicalsystemshouldincludetwoindependenttemperaturesensingsystems.Onewouldbeusedtocontrolandrecordtemperaturesofthecycleaswithsterilizers,andtheotherwouldbeinthecoldspotofthechamber.Aswithautoclaves,lyophilizersshouldhavedrainswithatmosphericbreakstopreventbacksiphonage.Asdiscussed,thereshouldalsobeprovisionsforsterilizingtheinertgasorairandthesupplylines.Somemanufacturershavechosentolocatethesterilizingfiltersinaportofthechamber.Theportissteamsterilizedwhenthechamberissterilized,andthenthesterilizingfilter,previouslysterilized,isasepticallyconnectedtothechamber.Somemanufacturershavechosentosterilizethefilteranddownstreampipingtothechamberinplace.Typicalsterilization-in-placeoffiltersmayrequiresteamingofbothtoobtainsufficienttemperatures.Inthistypeofsystem,thereshouldbeprovisionsforremovingand/ordrainingcondensate.Thefailuretosterilizenitrogenandairfiltersandthepipingdownstreamleadingintothechamberhasbeenidentifiedasaproblemonanumberofinspections.Sincethesefiltersareusedtosterilizeinertgasand/orair,thereshouldbesomeassuranceoftheirintegrity.Someinspectionshavedisclosedalackofintegritytestingoftheinertgasand/orairfilter.Thequestionisfrequentlyaskedhowoftenshouldtheventfilterbetestedforintegrity?Aswithmanydecisionsmadebymanufacturers,thereisalevelofriskassociatedwiththeoperation,processorsystem,whichonlythemanufacturercandecide.Ifthesterilizingfilterisfoundtopasstheintegritytestafterseveralusesorbatches,thenonecouldclaimitsintegrityforthepreviousbatches.However,ifitisonlytestedafterseveralbatcheshavebeenprocessedandiffoundtofailtheintegritytest,thenonecouldquestionthesterilityofallofthepreviousbatchesprocessed.Inanefforttominimizethisrisk,somemanufacturershaveresortedtoredundantfiltration.Formostcycles,stopperingoccurswithinthelyophilizer.Typically,thelyophilizerhassometypeofrodorrods(ram)whichentertheimmediatechamberatthetimeofstoppering.Oncetherodentersthechamber,thereisthepotentialforcontaminationofthechamber.However,sincethevialsarestoppered,thereisnoavenueforcontaminationofthevialsinthechamberwhicharenowstoppered.Generally,lyophilizersshouldbesterilizedaftereachcyclebecauseofthepotentialforcontaminationoftheshelfsupportrods.Additionally,thephysicalactofremovingvialsandcleaningthechambercanincreaselevelsofcontamination.18/18 Insomeofthelargerunits,theshelvesarecollapsedaftersterilizationtofacilitateloading.Obviously,theportionsoftheramenteringthechambertocollapsetheshelvesentersfromanon-sterilearea.Attemptstominimizecontaminationhaveincludedwipingtheramwithasanitizingagentpriortoloading.Controlaspectshaveincludedtestingtheramformicrobiologicalcontamination,testingitforresiduesofhydraulicfluid,andtestingthefluidforitsbacteriostaticeffectiveness.Onelyophilizerfabricatorhasproposeddevelopingaflexible"skirt"tocovertheram.Inadditiontomicrobiologicalconcernswithhydraulicfluid,thereisalsotheconcernwithproductcontamination.Duringsteamsterilizationofthechamber,thereshouldbespacebetweenshelvesthatpermitpassageoffreeflowingsteam.Somemanufacturershaveplaced"spacers"betweenshelvestopreventtheirtotalcollapse.Othershaveresortedtoatwophasesterilizationofthechamber.Theinitialphaseprovidesforsterilizationoftheshelveswhentheyareseparated.Thesecondphaseprovidesforsterilizationofthechamberandpistonwiththeshelvescollapsed.Typically,biologicalindicatorsareusedinlyophilizerstovalidatethesteamsterilizationcycle.OnemanufacturerofaBiopharmaceuticalproductwasfoundtohaveapositivebiologicalindicatoraftersterilizationat121oCfor45minutes.Duringthechambersterilization,traysusedtotransportvialsfromthefillinglinetothechamberwerealsosterilized.Thetraysweresterilizedinaninvertedpositiononshelvesinthechamber.Itisbelievedthatthepositivebiologicalindicatoristheresultofpoorsteampenetrationunderthesetrays.Thesterilizationofcondensersisalsoamajorissuethatwarrantsdiscussion.Mostofthenewerunitsprovideforthecapabilityofsterilizationofthecondenseralongwiththechamber,evenifthecondenserisexternaltothechamber.Thisprovidesagreaterassuranceofsterility,particularlyinthosesituationsinwhichthereissomeequipmentmalfunctionandthevacuuminthechamberisdeeperthaninthecondenser.Malfunctionsthatcanoccur,whichwouldindicatethatsterilizationofthecondenseriswarranted,includevacuumpumpbreakdown,refrigerationsystemfailuresandthepotentialforcontaminationbythelargevalvebetweenthecondenserandchamber.Thisisparticularlytrueforthoseunitsthathaveseparatevacuumpumpsforboththecondenserandchamber.Whenthereareproblemswiththesystemsinthelyophilizer,contaminationcouldmigratefromthecondenserbacktothechamber.Itisrecognizedthatthecondenserisnotabletobesterilizedinmanyoftheolderunits,andthisrepresentsamajorproblem,particularlyinthosecyclesinwhichthereissomeequipmentand/oroperatorfailure.Asreferencedabove,leakageduringalyophilizationcyclecanoccur,andthedoorsealorgasketpresentsanavenueofentryforcontaminants.Forexample,inaninspection,itwasnotedthatduringsteamsterilizationofalyophilizer,steamwasleakingfromtheunit.Ifsteamcouldleakfromaunitduringsterilization,aircouldpossiblyenterthechamberduringlyophilization.Someofthenewerlyophilizershavedoubledoors-oneforloadingandtheotherforunloading.Thetypicalsingledoorlyophilizeropensinthecleanareaonly,and18/18 contaminationbetweenloadswouldbeminimal.Thiscleanarea,previouslydiscussed,representsacriticalprocessingareaforaproductmadebyasepticprocessing.Inmostunits,onlythepistonraising/loweringshelvesisthesourceofcontamination.Foradoubledoorsystemunloadingthelyophilizerinanon-sterileenvironment,otherproblemsmayoccur.Thenon-sterileenvironmentpresentsadirectavenueofcontaminationofthechamberwhenunloading,anddoorcontrolssimilartodoubledoorsterilizersshouldbeinplace.Obviously,thelyophilizerchamberistobesterilizedbetweenbatchesbecauseofthedirectmeansofcontamination.Aproblemwhichmaybesignificantisthatofleakagethroughthedoorseal.Forthesingledoorunit,leakagepriortostopperingaroundthedoorsealisnotamajorproblemfromasterilityconcern,becausesingledoorunitsonlyopenintosterileareas.However,leakagefromadoorgasketorsealfromanon-sterileareawouldpresentasignificantmicrobiologicalproblem.Inordertominimizethepotentialforcontamination,itisrecommendedthatthelyophilizersbeunloadedinacleanroomareatominimizecontamination.Forexample,inaninspectionofanewmanufacturingfacility,itwasnotedthattheunloadingareafordoubledoorunitswasacleanroom,withthecondenserlocatedbelowthechamberonalowerlevel.Aftersteamsterilization,thereisoftensomecondensateremainingonthefloorofthechamber.Somemanufacturersremovethiscondensatethroughthedrainlinewhilethechamberisstillpressurizedaftersterilization.Unfortunately,somemanufacturershaveallowedthechambertocometoandremainatatmosphericpressurewiththedrainlineopen.Thus,non-sterileaircouldcontaminatethechamberthroughthedrainline.Somemanufacturershaveattemptedtodrythechamberbyblowingsterilenitrogengasthroughthechamberatapressureaboveatmosphericpressure.Inaninspectionofabiopharmaceuticaldrugproduct,aPseudomonasproblemprobablyattributedtocondensateaftersterilizationwasnoted.Onaroutinesurfacesampletakenfromachambershelfaftersterilizationandprocessing,ahighcountofPseudomonassp.wasobtained.Aftersterilizationandcoolingwhenthechamberdoorwasopened,condensateroutinelyspilledontothefloorfromthedoor.AsurfacesampletakenfromthefloorbelowthedooralsorevealedPseudomonassp.contamination.Sincethecompanybelievedthecondensateremainedinthechamberaftersterilization,theyrepipedthechamberdrainandaddedalinetoawatersealvacuumpump.FINISHEDPRODUCTTESTINGFORLYOPHILIZEDPRODUCTSThereareseveralaspectsoffinishedproducttestingwhichareofconcerntothelyophilizeddosageform.Theseincludedoseuniformitytesting,moistureandstabilitytesting,andsterilitytesting.(a)DoseUniformityTheUSPincludestwotypesofdoseuniformitytesting:contentuniformityandweightvariation.Itstatesthatweightvariationmaybeappliedtosolids,withorwithoutaddedsubstances,thathavebeenpreparedfromtruesolutionsandfreeze-driedinfinalcontainers.However,whenotherexcipientsorotheradditivesarepresent,18/18 weightvariationmaybeapplied,providedthereiscorrelationwiththesampleweightandpotencyresults.Forexample,inthedeterminationofpotency,itissometimescommontoreconstituteandassaytheentirecontentsofavialwithoutknowingtheweightofthesample.Performingtheassayinthismannerwillprovideinformationonthelabelclaimofaproduct,butwithoutknowingthesampleweightwillprovidenoinformationaboutdoseuniformity.Oneshouldcorrelatethepotencyresultobtainedformtheassaywiththeweightofthesampletested.(b)StabilityTestingAnobviousconcernwiththelyophilizedproductistheamountofmoisturepresentinvials.Themanufacturer'sdatafortheestablishmentofmoisturespecificationsforbothproductreleaseandstabilityshouldbereviewed.Aswithotherdosageforms,theexpirationdateandmoisturelimitshouldbeestablishedbasedonworstcasedata.Thatis,amanufacturershouldhavedatathatdemonstratesadequatestabilityatthemoisturespecification.Aswithimmediatereleasepotencytesting,stabilitytestingshouldbeperformedonvialswithaknownweightofsample.Forexample,testingavial(sample)whichhadahigherfillweight(volume)thantheaveragefillvolumeofthebatchwouldprovideahigherpotencyresultsandnotrepresentthepotencyofthebatch.Also,theexpirationdateandstabilityshouldbebasedonthosebatcheswiththehighermoisturecontent.Suchdatashouldalsobeconsideredintheestablishmentofamoisturespecification.Forproductsshowingalossofpotencyduetoaging,therearegenerallytwopotencyspecifications.Thereisahigherlimitforthedosageformatthetimeofrelease.ThislimitisgenerallyhigherthantheofficialUSPorfiledspecificationwhichisofficialthroughouttheentireexpirationdateperiodofthedosageform.TheUSPpointsoutthatcompendialstandardsapplyatanytimeinthelifeofthearticle.Stabilitytestingshouldalsoincludeprovisionsfortheassayofagedsamplesandsubsequentreconstitutionoftheseagedsamplesforthemaximumamountoftimespecifiedinthelabeling.Onsomeoccasions,manufacturershaveestablishedexpirationdateswithoutperforminglabelclaimreconstitutionpotencyassaysatthevarioustestintervalsandparticularlytheexpirationdatetestinterval.Additionally,thisstabilitytestingofreconstitutedsolutionsshouldincludethemostconcentratedandtheleastconcentratedreconstitutedsolutions.Themostconcentratedreconstitutedsolutionwillusuallyexhibitdegradationatafasterratethanlessconcentratedsolutions.(c)SterilityTestingWithrespecttosterilitytestingoflyophilizedproducts,thereisconcernwiththesolutionusedtoreconstitutethelyophilizedproduct.AlthoughproductsmaybelabeledforreconstitutionwithBacteriostaticWaterForInjection,SterileWaterForInjection(WFI)shouldbeusedtoreconstituteproducts.BecauseofthepotentialtoxicitiesassociatedwithBacteriostaticWaterForInjection,manyhospitalsonlyutilizeWFI.BacteriostaticWaterForInjectionmaykillsomeofthevegetativecellsifpresentascontaminants,andthusmaskthetruelevelofcontaminationinthedosageform.18/18 Aswithothersterileproducts,sterilitytestresultswhichshowcontaminationontheinitialtestshouldbeidentifiedandreviewed.FINISHEDPRODUCTINSPECTION-MELTBACKTheUSPpointsoutthatitisgoodpharmaceuticalpracticetoperform100%inspectionofparenteralproducts.Thisincludessterilelyophilizedpowders.Criticalaspectswouldincludethepresenceofcorrectvolumeofcakeandthecakeappearance.Withregardtocakeappearance,oneofthemajorconcernsismeltback.Meltbackisaformofcakecollapseandiscausedbythechangefromthesolidtoliquidstate.Thatis,thereisincompletesublimation(changefromthesolidtovaporstate)inthevial.Associatedwiththisproblemisachangeinthephysicalformofthedrugsubstanceand/orapocketofmoisture.Thesemayresultingreaterinstabilityandincreasedproductdegradation.Anotherproblemmaybepoorsolubility.Increasedtimeforreconstitutionattheuserstagemayresultinpartiallossofpotencyifthedrugisnotcompletelydissolved,sinceitiscommontousein-linefiltersduringadministrationtothepatient.Manufacturersshouldbeawareofthestabilityoflyophilizedproductswhichexhibitpartialorcompletemeltback.Literatureshowsthatforsomeproducts,suchasthecephalosporins,thatthecrystallineformismorestablethantheamorphousformoflyophilizedproduct.Theamorphousformmayexistinthe"meltback"portionofthecakewherethereisincompletesublimation.GLOSSARYATMOSPHERE,THEEARTHTheenvelopeofgasessurroundingtheearth,exertingundergravityapressureattheearth'ssurface,whichincludesbyvolume78%nitrogen,21%oxygen,smallquantitiesofhydrogen,carbondioxide,noblegases,watervapor,pollutantsanddust.ATMOSPHERICPRESSUREThepressureexertedattheearth'ssurfacebytheatmosphere.Forreferencepurposesastandardatmosphereisdefinedas760torrormillimetersofmercury,or760,000microns.BACKSTREAMINGAprocessthatoccursatlowchamberpressureswherehydrocarbonvaporsfromthevacuumsystemcanentertheproductchamber.BLANK-OFFPRESSUREThisistheultimatepressurethepumporsystemcanattain.BLOWER(seeMechanicalBoosterPump)Thispumpispositionedbetweenthemechanicalpumpandthechamber.Itoperatesbymeansoftwolobesturningatahighrateofspeed.Itisusedtoreducethechamberpressuretolessthan20microns.BREAKINGVACUUMAdmittingairoraselectedgastoanevacuatedchamber,whileisolatedfromavacuumpump,toraisethepressuretowards,orupto,atmospheric.CIRCULATIONPUMPApumpforconveyingtheheattransferfluid.18/18 CONDENSER(Coldtrap)Intermsofthelyophilizationprocess,thisisthevesselthatcollectsthemoistureonplatesandholdsitinthefrozenstate.Protectsthevacuumpumpfromwatervaporcontaminatingthevacuumpumpoil.CONDENSER/RECEIVERIntermsofrefrigeration,thisunitcondenses(changes)thehotrefrigerantgasintoaliquidandstoresitunderpressuretobereusedbythesystem.COOLINGTheloweringofthetemperatureinanypartofthetemperaturescale.CONAXCONNECTIONAdevicetopassthermocouplewiresthroughandmaintainavacuumtightvessel.CONTAMINATIONlnthevacuumsystem,theintroductionofwatervaporintotheoilinthevacuumpump,whichthencausesthepumptoloseitsabilitytoattainitsultimatepressure.DEFROSTINGTheremovaloficefromacondenserbymeltingormechanicalmeans.DEGREEOFCRYSTALLIZATIONTheratiooftheenergyreleasedduringthefreezingofasolutiontothatofanequalvolumeofwater.DEGREEOFSUPERCOOLINGThenumberofdegreesbelowtheequilibriumfreezingtemperaturewhereicefirststartstoform.DESICCANTAdryingagent.DRYFreefromliquid,and/ormoisture.DRYINGTheremovalofmoistureandotherliquidsbyevaporation.EQUILIBRIUMFREEZINGTEMPERATURESThetemperaturewhereicewillformintheabsenceofsupercooling.EUTECTICTEMPERATUREApointofaphasediagramwhereallphasesarepresentandthetemperatureandcompositionoftheliquidphasecannotbealteredwithoutoneofthephasesdisappearing.EXPANSIONTANKThistankislocatedinthecirculationsystemandisusedasaholdingandexpansiontankforthetransferliquid.FILTERORFILTER/DRIERTherearetwosystemsthathavetheirsystemsfilteredorfilter/dried.Theyarethecirculationandrefrigerationsystems.Inthenewerdryersthisfilterorfilter/dryeristhesame,andcanbereplacedwithanewcore.FREEWATERThefreewaterinaproductisthatwaterthatisabsorbedonthesurfacesoftheproductandmustberemovedtolimitfurtherbiologicalandchemicalreactions.18/18 FREEZINGThisistheabsenceofheat.Acontrolledchangeoftheproducttemperatureasafunctionoftime,duringthefreezingprocess,soastoensureacompletelyfrozenform.GASBALLASTUsedinthevacuumsystemonthevacuumpumptodecontaminatesmallamountsofmoistureinthevacuumpumpoil.GASBLEED(Vacuumcontrol)Tocontrolthepressureinthechamberduringthecycletohelpthedryingprocess.Infreeze-dryingthepurposeistoimproveheat-transfertotheproduct.HEATEXCHANGERThisexchangerislocatedinthecirculationandrefrigerationsystemsandtransferstheheatfromthecirculationsystemtotherefrigerationsystem.HEATTRANSFERFLUIDAliquidofsuitablevaporpressureandviscosityrangefortransferringheattoorfromacomponent,forexample,ashelforcondenserinafreeze-dryer.Thechoiceofsuchafluidmaydependonsafetyconsiderations.Diathermicfluid.HOTGASBYPASSThisisarefrigerationsystem.TocontrolthesuctionpressureoftheBIGFOUR(20-30Hp)compressorsduringtherefrigerationoperation.HOTGASDEFROSTThisisarefrigerationsystem.Todefrostthecondenserplatesafterthelyophilizationcycleiscomplete.ICEThesolid,crystallineformofwater.INERTGASAnygasofagroupincludinghelium,radonandnitrogen,formerlyconsideredchemicallyinactive.INTERSTAGEInatwostagecompressorsystem,thisisthecrossoverpipingontopofthecompressorthatconnectsthelowsidetothehighside.Onecouldalsothinkofitaslowside,intermediate,andhighside.INTERSTAGEPRESSUREREGULATINGVALVEThisvalvecontrolstheinterstagepressurefromexceeding80-90PSI.Thisvalveopenstosuctionastheinterstagepressurerisesabove80-90PSI.LEXSOLAheattransferfluid(highgradekerosene).LIQUIDSUB-COOLERHEATEXCHANGER(seeSub-cooledLiquid)Theliquidrefrigerantleavingthecondenser/receiveratcoolingwatertemperatureissub-cooledtoatemperatureof+15oF(-10oC)to-15oF(-25oC).LYOPHILIZATIONAprocessinwhichtheproductisfirstfrozenandthen,whilestillinthefrozenstate,themajorportionofthewaterandsolventsystemisreducedbysublimationand18/18 desorptionsoastolimitbiologicalandchemicalreactionsatthedesignatedstoragetemperature,MAINVACUUMVALVE(seeVaporValve)Thisvalveisbetweenthechamberandexternalcondensertoisolatethetwovesselsaftertheprocessisfinished.Thisisthevalvethatprotectsthefinishedproduct.MATRIXAmatrix,intermsofthelyophilizationprocess,isasystemoficecrystalsandsolidsthatisdistributedthroughouttheproduct.MECHANICALBOOSTERPUMP(seeBlower)Arootspumpwithahighdisplacementforitssizebutalowcompressionratio.Whenbackedbyanoil-sealrotarypumpthecombinationisaneconomicalalternativetoatwo-stageoil-sealedrotarypump,withtheadvantageofobtainingahighvacuum.MECHANICALVACUUMPUMPThemechanicalpumpingsystemthatlowersthepressureinthechambertobelowatmosphericpressuresothatsublimationcanoccur.MELTINGTEMPERATURE(Melt-back)Thattemperaturewheremobilewaterfirstbecomesevidentinafrozensystem.MICRON(seeTorr)Aunitofpressureusedinthelyophilizationprocess.Onemicron=oneMtorror25,400microns=1"Hg.,or760,000microns=oneatmosphere.NONCONDENSABLESAmixtureofgasessuchasnitrogen,hydrogen,chlorine,andhydrocarbons.Theymaybedrawnintothesystemthroughleakswhenpartofthesystemisunderavacuum.Theirpresencereducestheoperatingefficiencyofthesystembyincreasingthecondensingpressure.NUCLEATIONTheformationoficecrystalsonforeignsurfacesorasaresultofthegrowthofwaterclusters.OIL-MISTFILTERInvacuumterminologyafilterattachedtothedischarge(exhaust)ofanoil-sealedrotarypumptoeliminatemostofthe"smoke"ofsuspendedfinedropletsofoilwhichwouldbedischargedintotheenvironment.OILSEALEDROTARYPUMPAstandardtypeofmechanicalvacuumpumpusedinfreeze-dryingwithahighcompressionratiobuthavingarelativelylowdisplacement(speed)foritssize.Atwo-stagepumpiseffectivelytwosuchpumpsinseriesandcanobtainanultimatevacuum.OILSEPARATORSeparatestheoilfromthecompressordischargegasandreturnstheoilthroughtheoilfloattrapandpipingtothecompressorcrankcase.REALLEAKArealleakisasourceofatmosphericgasesresultingfromapenetrationthroughthechamber.RECONSTITUTE18/18 Thedissolvingofthedriedproductintoasolventordiluent.RELIEFVALVEUsedforsafetypurposestopreventdamageincaseexcessivepressureisencountered.ROTARYVANEPUMPAmechanicalpumpingsystemwithslidingvanesasthemechanicalseal.Canbesingleortwostages.SHELFCOMPRESSOR(ControllingCompressor)Usedforcontrollingtheshelftemperature,eithercoolingorfromoverheating.SELFLIQUIDHEATEXCHANGERThetransferofheatfromtheshelffluidtotherefrigerationsystemthroughtubesintheexchangercausingcompressorsuctiongastowarm.SHELVESIntermsofthelyophilizationprocess,theyareaformofheatexchanger,withinthechamber,thathaveaserpentineliquidflowthroughthem,enteringonesideandflowingtotheotherside.Theyarelocatedinthecirculationsystem.SINGLESTAGECOMPRESSORThisisanormaltypecompressorusedinrefrigeration.Inthelyophilizationprocessitisusedtocontroltheshelftemperature,bothforcoolingandkeepingtheshelftemperaturefromoverheatingusingatemperaturecontroller.SILICONEOILAheattransferfluid.STERILIZATIONTheuseofsteamandpressuretokillanybacteriathatmaybeabletocontaminatethatenvironmentorvessel.SUBLIMATIONTheconversionofamaterialfromasolidphasedirectlytoavaporphase,withoutpassingthroughtheliquidphase.Thisisreferredtoastheprimarydryingstage.SUB-COOLEDLIQUID(SeeLiquidSub-coolerHeatExchanger)Theliquidrefrigerantiscooledthroughanexchangersothatitincreasestherefrigeratingeffectaswellasreducesthevolumeofgasflashedfromtheliquidrefrigerantinpassagethroughtheexpansionvalve.SUCTIONLINEACCUMULATORToprovideadequaterefrigerantliquidslugprotection(dropletsofliquidrefrigerant)fromreturningtothecompressor,andcausingdamagetothecompressor.TCETrichloroethylene-Aheattransferfluid.TEMPERATUREThedegreeofhotnessorcoldnessofabody.THERMOCOUPLEAmetal-to-metalcontactbetweentwodissimilarmetalsthatproducesasmallvoltageacrossthefreeendsofthewire.THERMOSTATICEXPANSIONVALVEAnautomaticvariabledevicecontrollingtheflowofliquidrefrigerant.18/18 TORR(SeeMicron)Aunitofmeasureequivalenttotheamountofpressurein1000microns.TWOSTAGECOMPRESSOR(seeInterstage)Thisisaspeciallybuiltcompressor.Itsfunctionistobeabletoattainlowtemperaturesbybeingabletooperateatlowpressures.Itistwocompressorsbuiltintoone.Alowstageconnectedinternallyandahighstageconnectedexternallywithpiping,calledinterstage.UNLOADINGVALVEThisvalveconnectstheinterstagewithsuctiontoequalizebothpressuresduringpump-down.VACUUMStrictlyspeaking,aspaceinwhichthetotalpressureislessthanatmospheric.VACUUMCONTROL(GasBleed)Toassistintherateofsublimation,bycontrollingthepressureinthelyophilizer.VACUUMPUMPAmechanicalwayofreducingthepressureinavesselbelowatmosphericpressuretowheresublimationcanoccur.Therearethreetypesofpumps,rotaryvane,rotarypistonandmechanicalbooster.VAPORBAFFLEAtargetshapedobjectplacedinthecondensertodirectvaporflowandtopromoteanevendistributionofcondensate.VACUUMVALVESThevacuumvalvesusedareofaballordisktypethatcansealwithoutleaking.ThebalItypesareusedforservicestothechamberandcondenser.Theyarealsousedfordrainsandisolationapplications.Thedisktypesareusedinthevacuumlinesystemandareconnectedtothevacuumpump,chamberandcondenser.VAPORVALVE(SeeMainVacuumValve)Thevacuumvalvebetweenthechamberandexternalcondenser.Whenthisvalveisclosedthechamberisisolatedfromtheexternalcondenser.Alsoknownasthemainvaporvalve.VIALAsmallglassbottlewithaflatbottom,shortneckandflatflangedesignedforstoppering.VIRTUALLEAKInthevacuumsystemavirtualleakisthepassageofgasintothechamberfromasourcethatislocatedinternallyinthechamber.Returnto:PageTop|InspectionStartMoreinInspectionGuides18/18 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