FDA微生物化验室的检查指南英文稿

GUIDETOINSPECTIONSOFMICROBIOLOGICALPHARMACEUTICALQUALITYCONTROLLABORATORIESNote:ThisdocumentisreferencematerialforinvestigatorsandotherFDApersonnel.ThedocumentdoesnotbindFDA,anddoesnotconferanyrights,privileges,benefits,orimmunitiesfororonanyperson(s).I.INTRODUCTIONTheGuidetotheInspectionofPharmaceuticalQualityControlLaboratoriesprovidedverylimitedguidanceonthematterofinspectionofmicrobiologicallaboratories.Whilethatguideaddressesmanyoftheissuesassociatedwiththechemicalaspectoflaboratoryanalysisofpharmaceuticals,thisdocumentwillserveasaguidetotheinspectionofthemicrobiologyanalyticalprocess.Aswithanylaboratoryinspection,itisrecommendedthatananalyst(microbiologist)whoisfamiliarwiththetestsbeinginspectedparticipateintheseinspections.II.MICROBIOLOGICALTESTINGOFNON-STERILEPRODUCTSForavarietyofreasons,wehaveseenanumberofproblemsassociatedwiththemicrobiologicalcontaminationoftopicaldrugproducts,nasalsolutionsandinhalationproducts.TheUSPMicrobiologicalAttributesChapter1111provideslittlespecificguidanceotherthanThesignificanceofmicroorganismsinnon-sterilepharmaceuticalproductsshouldbeevaluatedintermsoftheuseoftheproduct,thenatureoftheproduct,andthepotentialhazardtotheuser.TheUSPrecommendsthatcertaincategoriesberoutinelytestedfortotalcountsandspecifiedindicatormicrobialcontaminants.Forexamplenaturalplant,animalandsomemineralproductsforSalmonella,oralliquidsforE.Coli,topicalsforP.aeruginosaandS.Aureus,andarticlesintendedforrectal,urethral,orvaginaladministrationforyeastsandmolds.Anumberofspecificmonographsalsoincludedefinitivemicrobiallimits.Asageneralguideforacceptablelevelsandtypesofmicrobiologicalcontaminationinproducts,Dr.DunniganoftheBureauofMedicineoftheFDAcommentedonthehealthhazard.In1970,hesaidthattopicalpreparationscontaminatedwithgramnegativeorganismsareaprobablemoderatetoserioushealthhazard.Throughtheliteratureandthroughourinvestigations,ithasbeenshownthatavarietyofinfectionshavebeentracedtothegramnegativecontaminationoftopicalproducts.TheclassicalexamplebeingthePseudomonascepaciacontaminationofPovidoneIodineproductsreportedbyahospitalinMassachusettsseveralyearsago.Therefore,eachcompanyisexpectedtodevelopmicrobialspecificationsfortheirnon-sterileproducts.Likewise,theUSPMicrobialLimitsChapter61providesmethodologyforselectedindicatororganisms,butnotallobjectionableorganisms.Forexample,itiswidelyrecognizedthatPseudomonascepaciaisobjectionableiffoundinatopicalproductornasalsolutioninhighnumbers;yet,therearenotestmethodsprovidedintheUSPthatwillenabletheidentificationofthepresenceofthismicroorganism.ArelevantexampleofthisproblemistherecallofMetaproterenolSulfateInhalationSolution.TheUSPXXIImonographrequiresnomicrobialtestingforthisproduct.TheagencyclassifiedthisasaClassIrecallbecausetheproductwascontaminatedwithPseudomonasgladioli/cepacia.Thehealthhazardevaluationcommentedthattheriskofpulmonaryinfectionisespeciallyseriousandpotentiallylife-threateningtopatientswithchronicobstructiveairwaydisease,cysticfibrosis,andimmuno-compromisedpatients.Additionally,theseorganismswouldnothavebeenidentifiedbytestingproceduresdelineatedinthegeneralMicrobialLimitssectionoftheCompendia.TheUSPcurrentlyprovidesforretestsintheMicrobialLimitssection61howeverthereisacurrentproposaltoremovetheretestprovision.Aswithanyothertest,theresultsofinitialtestshouldbereviewedandinvestigated.Microbiologicalcontaminationisnotevenlydispersedthroughoutalotorsampleofproductandfindingacontaminantinonesampleandnotinanotherdoesnotdiscountthefindingsoftheinitialsampleresults.Retestresultsshouldbereviewedandevaluated,andparticularemphasisshouldbeplacedonthelogicandrationaleforconductingtheretest.Inordertoisolatespecificmicrobialcontaminants,FDAlaboratories,aswellasmanyintheindustry,employsometypeofenrichmentmediacontaininginactivators,suchasTweenorlecithin.Thisisessentialtoinactivatepreservativesusuallypresentinthesetypesofproductandprovidesabettermediumfordamagedorslowgrowingcells.Othergrowthparametersincludealowertemperatureandlongerincubationtime(atleast5days)thatprovideabettersurvivalconditionfordamagedorslow-growingcells.Forexample,FDAlaboratoriesusethetestproceduresforcosmeticsintheBacteriologicalAnalyticalManual(BAM),6thEdition,toidentifycontaminationinnon-steriledrugproducts.Thistestingincludesanenrichmentofasampleinmodifiedletheenbroth.Afterincubation,furtheridentificationiscarriedoutonBloodAgarPlatesandMacConkeyAgarPlates.Isolatedcoloniesarethenidentified.ThisprocedureallowsFDAmicrobiologiststooptimizetherecoveryofallpotentialpathogensandtoquantitateandspeciateallrecoveredorganisms.AnotherimportantaspectofproceduresusedbyFDAanalystsistodeterminegrowthpromotioncharacteristicsforallofthemediaused.Theselectionoftheappropriateneutralizingagentsarelargelydependentuponthepreservativeandformulationoftheproductunderevaluation.Ifthereisgrowthintheenrichmentbroth,transfertomoreselectiveagarmediaorsuitableenrichmentagarmaybenecessaryforsubsequentidentification.MicrobiologicaltestingmayincludeanidentificationofcoloniesfoundduringtheTotalAerobicPlateCou