冻干制剂检查指南FDA.docx
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冻干制剂检查指南FDA.docx
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冻干制剂检查指南FDA
GUIDETOINSPECTIONSOFLYOPHILIZATIONOFPARENTERALS
Note:
ThisdocumentisreferencematerialforinvestigatorsandotherFDApersonnel.ThedocumentdoesnotbindFDA,anddoesnoconferanyrights,privileges,benefits,orimmunitiesfororonanyperson(s).
INTRODUCTION
Lyophilizationorfreezedryingisaprocessinwhichwaterisremovedfromaproductafteritisfrozenandplacedunderavacuum,allowingtheicetochangedirectlyfromsolidtovaporwithoutpassingthroughaliquidphase.Theprocessconsistsofthreeseparate,unique,andinterdependentprocesses;freezing,primarydrying(sublimation),andsecondarydrying(desorption).
Theadvantagesoflyophilizationinclude:
Easeofprocessingaliquid,whichsimplifiesaseptichandling
Enhancedstabilityofadrypowder
Removalofwaterwithoutexcessiveheatingoftheproduct
Enhancedproductstabilityinadrystate
Rapidandeasydissolutionofreconstitutedproduct
Disadvantagesoflyophilizationinclude:
Increasedhandlingandprocessingtime
Needforsterilediluentuponreconstitution
Costandcomplexityofequipment
Thelyophilizationprocessgenerallyincludesthefollowingsteps:
∙Dissolvingthedrugandexcipientsinasuitablesolvent,generallywaterforinjection(WFI).
∙Sterilizingthebulksolutionbypassingitthrougha0.22micronbacteria-retentivefilter.
∙Fillingintoindividualsterilecontainersandpartiallystopperingthecontainersunderasepticconditions.
∙Transportingthepartiallystopperedcontainerstothelyophilizerandloadingintothechamberunderasepticconditions.
∙Freezingthesolutionbyplacingthepartiallystopperedcontainersoncooledshelvesinafreeze-dryingchamberorpre-freezinginanotherchamber.
∙Applyingavacuumtothechamberandheatingtheshelvesinordertoevaporatethewaterfromthefrozenstate.
∙Completestopperingofthevialsusuallybyhydraulicorscrewrodstopperingmechanismsinstalledinthelyophilizers.
Therearemanynewparenteralproducts,includinganti-infectives,biotechnologyderivedproducts,andin-vitrodiagnosticswhicharemanufacturedaslyophilizedproducts.Additionally,inspectionshavedisclosedpotency,sterilityandstabilityproblemsassociatedwiththemanufactureandcontroloflyophilizedproducts.Inordertoprovideguidanceandinformationtoinvestigators,someindustryproceduresanddeficienciesassociatedwithlyophilizedproductsareidentifiedinthisInspectionGuide.
Itisrecognizedthatthereiscomplextechnologyassociatedwiththemanufactureandcontrolofalyophilizedpharmaceuticaldosageform.Someoftheimportantaspectsoftheseoperationsinclude:
theformulationofsolutions;fillingofvialsandvalidationofthefillingoperation;sterilizationandengineeringaspectsofthelyophilizer;scale-upandvalidationofthelyophilizationcycle;andtestingoftheendproduct.Thisdiscussionwilladdresssomeoftheproblemsassociatedwiththemanufactureandcontrolofalyophilizeddosageform.
PRODUCTTYPE/FORMULATION
Productsaremanufacturedinthelyophilizedformduetotheirinstabilitywheninsolution.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.
FILLING
Thefillingofvialsthataretobelyophilizedhassomeproblemsthataresomewhatunique.Thestopperisplacedontopofthevialandisultimatelyseatedinthelyophilizer.Asaresultthecontentsofthevialaresubjecttocontaminationuntiltheyareactuallysealed.
Validationoffillingoperationsshouldincludemediafillsandthesamplingofcriticalsurfacesandairduringactivefilling(dynamicconditions).
Becauseoftheactiveinvolvementofpeopleinfillingandasepticmanipulations,anenvironmentalprogramshouldalsoincludeanevaluationofmicrobiologicallevelsonpeopleworkinginasepticprocessingareas.Onemethodofevaluationofthetrainingofoperatorsworkinginasepticprocessingfacilitiesincludesthesurfacemonitoringofglovesand/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,transportationtothe
lyophilizerandthenstoppering;athirdstageincludedthefillingof3000vials,loadinginthelyophilizer,andexposuretoaportionofthenitrogenflushandthenstoppering.Sincelyophilizersterilizationandsterilizationofthenitrogensystemusedtobackfillrequireseparatevalidation,mediafillsshouldprimarilyvalidatethefilling,transportationandloadingasepticoperations.
Thequestionofthenumberofunitsneededformediafillswhenthecapacityoftheprocessislessthan3000unitsisfrequentlyasked,particularlyforclinicalproducts.Again,thepurposeofthemediafillistoassurethatproductcanbeasepticallyprocessedwithoutcontaminationunderoperatingconditions.Itwouldseem,therefore,thatthemaximumnumberofunitsofmediafilledbeequivalenttothemaximumbatchsizeifitislessthan3000units.
Afterfilling,dosageunitsaretransportedtothelyophilizerbymetaltrays.Usually,thebottomofthetraysareremovedafterthedosageunitsareloadedintot
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