FDA无菌原料药制造商检查指南Word文档下载推荐.docx
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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