FDA无菌原料药制造商检查指南.docx

FDA无菌原料药制造商检查指南.docx

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FDA无菌原料药制造商检查指南

GUIDETOINSPECTIONSOFSTERILEDRUGSUBSTANCEMANUFACTURERS

Note:

ThisdocumentisreferencematerialforinvestigatorsandotherFDApersonnel.ThedocumentdoesnotbindFDA,anddoesnoconferanyrights,privileges,benefits,orimmunitiesfororonanyperson（s）.

Oneofthemoredifficultprocessestoinspectandonewhichhaspresentedconsiderableproblemsovertheyearsisthatofthemanufactureofsterilebulkdrugsubstances.Withinthepastseveralyears,therehavebeenanumberofbatchesofsterilebulkdrugsubstancesfromdifferentmanufacturerswhichexhibitedmicrobiologicalcontamination.Onemanufacturerhadapproximately100batchescontaminatedina6monthtimeperiod.Anotherhadapproximately25batchescontaminatedinasimilarperiod.Othermanufacturershavehadrecallsduetothelackofassuranceofsterility.AlthoughtheInspectionGuideforBulkDrugSubstancesprovidessomedirectionfortheinspectionofthesterilebulkdrugsubstance,itdoesnotprovidethedetaileddirectionneeded.

I.INTRODUCTION

Inthemanufactureofthesterilebulkpowders,itisimportanttorecognizethatthereisnofurtherprocessingofthefinishedsterilebulkpowdertoremovecontaminantsorimpuritiessuchasparticulates,endotoxinsanddegradants.

Aswithotherinspections,anyrejectedbatches,alongwiththevariousreasonsforrejection,shouldbeidentifiedearlyintheinspectiontoprovidedirectionfortheinvestigator.Forexample,listsofbatchesrejectedand/orretestedoveraperiodoftimeshouldbeobtainedfromthemanufacturertoprovidedirectionforcoveragetobegiventospecificprocessesorsystems.Becausesomeoftheactualsterilebulkoperationsmaynotbeseen,andbecauseofthecomplexityoftheprocess,itisparticularlyimportanttoreviewreportsandsummaries,suchasvalidationstudies,rejectlists,EnvironmentalMonitoringSummaryReports,QAInvestigationLogs,etc.ThesesystemsandothersarediscussedintheBasicInspectionGuide.Thisisparticularlyimportantfortheforeignsterilebulkdrugsubstancemanufacturerwheretimeislimited.

Inthepreparationforasterilebulkdrugsubstanceinspection,aflowchartwiththemajorprocessingstepsshouldbeobtained.Generally,themanufactureofasterilebulksubstanceusuallyincludesthefollowingsteps:

1.Conversionofthenon-steriledrugsubstancetothesterileformbydissolvinginasolvent,sterilizationofthesolutionbyfiltrationandcollectioninasterilizedreactor（crystallizer）.

2.Asepticprecipitationorcrystallizationofthesteriledrugsubstanceinthesterilereactor.

3.Asepticisolationofthesterilesubstancebycentrifugationorfiltration.

4.Asepticdrying,millingandblendingofthesterilesubstance.

5.Asepticsamplingandpackagingthedrugsubstance.

Theseoperationsshouldbeperformedinclosedsystems,withminimaloperatorhandling.Anyasepticoperationsperformedbyanoperator（s）otherthaninaclosedsystemshouldbeidentifiedandcarefullyreviewed.

II.COMPONENTS

Inadditiontotheimpurityconcernsforthemanufactureofbulkdrugsubstances,thereisaconcernwithendotoxinsinthemanufactureofthesterilebulkdrugsubstances.Thevalidationreport,whichdemonstratestheremoval,ifpresent,ofendotoxinstoacceptablelevels,shouldbereviewed.Somemanufacturershavecommentedthatsinceanorganicsolventistypicallyusedfortheconversionofthenon-sterilebulkdrugsubstancetothesterilebulkdrugsubstance,thatendotoxinswillbereducedatthisstage.Aswithanyoperation,thismayormaynotbecorrect.Forexample,inaninspectionofamanufacturerwhoconductedextensivestudiesoftheconversion（crystallization）ofthenon-sterilesubstancetothesteriledrugsubstance,theyfoundnochangefromtheinitialendotoxinlevel.Organicsolventswereusedinthisconversion.Thus,itisimportanttoreviewandassessthisaspectofthevalidationreport.

Inthevalidationofthisconversion（non-steriletosterile）fromanendotoxinperspective,challengestudiescanbecarriedoutonalaboratoryorpilotscaletodeterminetheefficiencyofthestep.Onceitisestablishedthattheprocesswillresultinacceptableendotoxinlevels,somemonitoringoftheproductionbatcheswouldbeappropriate.Aswithanyvalidationprocess,thepurposeandefficiencyofeachstepshouldbeevaluated.Forexample,iftheconversion（crystallization）fromthenon-steriletothesterilesubstanceistoreduceendotoxinsbyonelog,thendatashouldsupportthisstep.

Sinceendotoxinsmaynotbeuniformlydistributed,itisalsoimportanttomonitorthebioburdenofthenon-sterilesubstance（s）beingsterilized.Forexample,gramnegativecontaminatsinanon-sterilebulkdrugsubstancepriortosterilizationareofconcern,particularlyifthesterilization（filtration）andcrystallizationstepsdonotreducetheendotoxinstoacceptablelevels.Therefore,microbiological,aswellasendotoxindataonthecriticalcomponentsandoperationalstepsshouldbereviewed.

III.FACILITY

FacilitydesignfortheasepticprocessingofsterilebulkdrugsubstancesshouldhavethesamedesignfeaturesasanSVPasepticprocessingfacility.Thesewouldincludetemperature,humidityandpressurecontrol.Becausesterilebulkasepticfacilitiesareusuallylarger,problemswithpressuredifferentialsandsanitizationhavebeenencountered.Forexample,amanufacturerwasfoundtohavethegowningareaundergreaterpressurethantheadjacentasepticareas.Theneedtoremovesolventvaporsmayalsoimpactonareapressurization.

Unnecessaryequipmentand/orequipmentthatcannotbeadequatelysanitized,suchaswoodenskidsandforklifttrucks,shouldbeidentified.Inquireaboutthemovementoflargequantitiesofsteriledrugsubstanceandthelocationofpass-throughareasbetweenthesterilecoreandnon-sterileareas.Observetheseareas,reviewenvironmentalmonitoringresultsandsanitizationprocedures.

TheCGMPRegulationsprohibittheuseofasbestosfiltersinthefinalfiltrationofsolutions.Atpresent,itwouldbedifficultforamanufacturertojustifytheuseofasbestosfiltersforfiltrationofairorsolutions.Inquireabouttheuseofasbestosfilters.

Facilitiesusedforthechargeoradditionofnon-sterilecomponents,suchasthenon-steriledrugsubstance,shouldbesimilartothoseusedforthecompoundingofparenteralsolutionspriortosterilization.Theconcernissolubleextraneouscontaminants,includingendotoxins,thatmaybecarriedthroughtheprocess.Observethisareaandreviewtheenvironmentalcontrolsandspecificationstodeterminetheviableandnon-viableparticulatelevelsallowedinthisarea.

IV.PROCESSING

Sterilepowdersareusuallyproducedbydissolvingthenon-sterilesubstanceorreactantsinanorganicsolventandthenfilteringthesolutionthroughasterilizingfilter.Afterfiltration,thesterilebulkmaterialisseparatedfromthesolventbycrystallizationorprecipitation.Othermethodsincludedissolutioninanaqueoussolution,filtrationsterilizationandseparationbycrystallization/filtration.Aqueoussolutionscanalsobesterilefilteredandspraydriedorlyophilized.

Inthehandlingofaqueoussolutions,priortosolventevaporation（eitherbyspraydryingorlyophilization）,checktheadequacyofthesystemandcontrolstominimizeendotoxincontamination.Insomeinstances,pipingsystemsforaqueoussolutionshavebeenshowntobethesourceofendotoxincontaminationinsterilepowders.Thereshouldbeaprintavailableofthepipingsystem.Tracetheactualpiping,compareitwiththeprintandassurethatthereareno"deadlegs"inthesystem.

Thevalidationdataforthefiltration（sterilization）processshouldalsobereviewed.Determinethefirm'scriteriaforselectionofthefilterandthefrequencyofchangingfilters.Determineifthefirmknowsthebioburdenandexaminetheirproceduresforintegritytestingfilters.

Filtersmightnotbechangedaftereachbatchissterilized.Determineifthereisdatatojustifytheintegrityofthefiltersforthetimeperiodsutilizedandthat"growthrough"hasnotoccurred.

Inthespraydryingofsterilepowders,therearesomeconcerns.Theseincludethesterilizationofthespraydryer,thesourceofairanditsquality,thechambertemperaturesandtheparticleresidenceorcontacttime.Insomecases,charringandproductdegradationhavebeenfoundforsmallportionsofabatch.

Withregardtobulklyophilization,concernsincludeairclassificationandasepticbarriersforloadingandunloadingtheunit,partialmeltback,unevenfreezingandheattransferthroughoutthepowderbed,andtheadditionalasepticmanipulationsrequiredtobreakupthelargecake.Forbulklyophilization,unlikeothersterilebulkoperations,mediachallengescanbeperformed.Atthispointintime,withtoday'sleveloftechnology,itwouldseemthatitwouldbedifficulttojustifythebulklyophilizationofsterilepowders（fromamicrobiologicalaspect）.RefertotheGuidefortheInspectionofaLyophilizationProcessforadditionaldirectionregardingthisprocess.

Seektodeterminethenumberandfrequencyofprocesschangesmadetoaspecificprocessorstep.Thiscanbeanindicatorofaproblemexperiencedinanumberofbatches.Anumberofchangesinashortperiodoftimecanbeanindicatorthatthefirmisexperiencingproblems.ReviewtheProcessChangeSOPandthelogforprocesschanges,includingthereasonforsuchchanges.

V.EQUIPMENT

Equipmentusedintheprocessingofsterilebulkdrugsubstancesshouldbesterileandcapableofbeingsterilized.Thisincludesthecrystallizer,centrifugeanddryer.Thesanitization,ratherthansterilizationofthisequipment,isunacce