冻干制剂检查指南FDA.docx

冻干制剂检查指南FDA.docx

《冻干制剂检查指南FDA.docx》由会员分享，可在线阅读，更多相关《冻干制剂检查指南FDA.docx（25页珍藏版）》请在冰点文库上搜索。

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