行業(yè)指南：藥品檢測(cè)結(jié)果OOS調(diào)查指南

1、DoCGuidanceforIndustryInvestigatingOutofSpecification(OOS)TestResultsforPharmaceuticalProduction行業(yè)指南：藥品檢驗(yàn)結(jié)果ooS勺調(diào)查DRAFTGUIDANCE指南草案U.S.DepartmentofHealthandHumanServicesFoodandDrugAdministrationCenterforDrugEvaluationandResearch(CDER)September1998CP#D0CDOCTABLEOFCONTENTS錄INTRODUCTION序1BACKGROUND.背景1I

2、DENTIFYINGANDASSESSINGOOSTESTRESULTSOOS檢驗(yàn)結(jié)果的判斷和評(píng)估.2ResponsibilityoftheAnalyst檢驗(yàn)員的責(zé)TOC o 1-5 h z任2ResponsibilitiesoftheSupervisor主管的責(zé)任3INVESTIGATINGOOSTESTRESULTSOOS檢驗(yàn)結(jié)果的調(diào)查一般調(diào)查原那實(shí)驗(yàn)室的調(diào)查階調(diào)查結(jié)果的解GeneralInvestigationalPrinciples.么5LaboratoryPhaseofanInvestigation.段6CONCLUDINGTHEINVESTIGATION.調(diào)查結(jié)10A.Interp

3、retationofInvestigationResults.10B.Reporting.11ThisguidancehasbeenpreparedbytheOfficeofpliance/DivisionofManufacturingandProductQuality,CenterforDrugEvaluationandResearch(CDER)attheFoodandDrugAdministration.ThisguidancedocumentrepresentstheAgencyscurrentthinkingonevaluatingOOStestresults.Itdoesnotcr

4、eateorconferanyrightsfororonanypersonanddoesnotoperatetobindFDAorthepublic.Analternativeapproachmaybeusedifsuchapproachsatisfiestherequirementsoftheapplicablestatute,regulations,orboth.本指南由FDA勺CDE的達(dá)標(biāo)辦公室/制造、產(chǎn)品、質(zhì)量分部起草，本指南說(shuō)明了機(jī)構(gòu)關(guān)于評(píng)估00檢驗(yàn)結(jié)果的現(xiàn)行的想法。它不會(huì)創(chuàng)造或贈(zèng)與任何人任何權(quán)力，也不會(huì)約束FDA或公眾。如果其他可選擇的相接近勺指南能滿足適用勺法令和法規(guī)勺要求，也可

5、以使用。GUIDANCEF0RINDUST1RYInvestigating0utofSpecification(00S)TestResultsforPharmaceuticalProduction行業(yè)指南：藥品檢驗(yàn)結(jié)果00的調(diào)查INTR0DUCTI0N序言ThisguidanceforindustryprovidestheAgencyscurrentthinkingonhowtoevaluatesuspect,oroutofspecification(00S),testresults.Forpurposesofthisdocument,theterm00Sresultsincludesalls

6、uspectresultsthatfalloutsidethespecificationsoracceptancecriteriaestablishedinnewdrugapplications,officialpendia,orbythemanufacturer.本行業(yè)指南反響了FDA關(guān)于如何評(píng)估懷疑的或00檢驗(yàn)結(jié)果的現(xiàn)行想法，本指南的目的，00S吉果包括超出了新藥申請(qǐng)材料、法定標(biāo)準(zhǔn)、生產(chǎn)商建立的可承受標(biāo)準(zhǔn)或規(guī)格的所有可疑的結(jié)果。Thisguidanceappliestolaboratorytestingduringthemanufactureofactivepharmaceuticalin

7、gredients,excipients,andotherponentsandthetestingoffinishedproductstotheextentthatcurrentgoodmanufacturingpractices(CGMP)regulationsapply(21CFRparts210and211).Specifically,theguidancediscusseshowtoinvestigatesuspect,orOOStestresults,includingtheresponsibilitiesoflaboratorypersonnel,thelaboratoryphas

8、eoftheinvestigation,additionaltestingthatmaybenecessary,whentoexpandtheinvestigationoutsidethelaboratory,andthefinalevaluationofalltestresults.本指南適用于API、賦形劑和其它組分生產(chǎn)的實(shí)驗(yàn)室檢驗(yàn)和CGM法規(guī)應(yīng)用的成品檢驗(yàn)。特別的，指南討論了如何調(diào)查可疑的或00檢驗(yàn)結(jié)果，包括了實(shí)驗(yàn)室人員的責(zé)任、實(shí)驗(yàn)室階段調(diào)查、必須的額外試驗(yàn)，何時(shí)進(jìn)展實(shí)驗(yàn)室X圍外的調(diào)查和對(duì)所有檢驗(yàn)結(jié)果的最終評(píng)估。BACKGR0UND背景FDAconsiderstheintegrityof

9、laboratorytestinganddocumentationrecordstobeoffundamentalimportanceduringdrugmanufacturing.Laboratorytesting,whichisrequiredbytheCGMPregulations(211.165),isnecessarytoconfirmthatponents,containersandclosures,inprocessmaterials,andfinishedproductsconformtospecifications,includingstability.TestingSpec

10、ificationsmustbescientificallysoundandappropriate(21CFR211.160(b),andtestproceduresmustbevalidatedastotheiraccuracy,reliability,andsuitabilityunderactualconditionsofuse(21CFR211.194(a)(2).ForproductsthatarethesubjectsofNDAs,ANDAs,orINDs,specificationsarecontainedintheapplication.Specificationsfornon

11、-applicationproductsmaybefoundinofficialpendia,orestablishedbythemanufacturer.FDA認(rèn)為在藥品生產(chǎn)中實(shí)驗(yàn)室檢驗(yàn)和文件記錄的完整性是根本重要的。CGM要求的實(shí)驗(yàn)室檢驗(yàn)，必須確定成分、容器和封口材料、生產(chǎn)用輔料、成品符合標(biāo)準(zhǔn)要求，包括穩(wěn)定性。檢驗(yàn)標(biāo)準(zhǔn)必須是科學(xué)正確和適當(dāng)?shù)?CFR211.160(b)，檢驗(yàn)方法必須驗(yàn)證現(xiàn)行使用條件下的正確性、線性和適應(yīng)性(21CFR211.194(a)，如果是用于NDAs,ANDAs,或INDs申請(qǐng)的產(chǎn)品，申請(qǐng)材料中應(yīng)包括標(biāo)準(zhǔn)。如果是非申請(qǐng)產(chǎn)品的質(zhì)量標(biāo)準(zhǔn)，可以在法定標(biāo)準(zhǔn)中找到或由企業(yè)自已建

12、立。Althoughthesubjectofthisdocumentis00Sresults,muchoftheguidancemaybeusefulforexaminingresultsthatareoutoftrend.alsosupportsanalyticalandprocessvalidationefforts.GeneralCGMPregulationscoveringlaboratoryoperationscanbefoundinpart211,subpartsI(LaboratoryControls)andJ(RecordsandReports).Theseregulation

13、sprovidefortheestablishmentofscientificallysoundandappropriatespecifications,standards,andtestproceduresthataredesignedtoensurethatponentsandcontainersofdrugproductsconformtotheestablishedstandards.Section211.165(f)oftheCGMPregulationsspecifiesthatproductsthatfailtomeetestablishedstandardsandotherre

14、levantqualitycontrolcriteriawillberejected.盡管本指南的目的是00結(jié)果，其中許多局部對(duì)于調(diào)查超岀趨勢(shì)以外的結(jié)果也是有用的，對(duì)分析和工藝驗(yàn)證也有用。有關(guān)實(shí)驗(yàn)室操作一般性CGM法規(guī)可以在211局部，分目I(實(shí)驗(yàn)室控制)和分目J(報(bào)告和記錄)找到。這些法規(guī)規(guī)定了科學(xué)正確和適當(dāng)?shù)挠糜诒ＷC制劑的成分和容器符合建立標(biāo)準(zhǔn)的規(guī)格、標(biāo)準(zhǔn)和檢驗(yàn)方法的建立。CGM的211.165(f)章節(jié)規(guī)定不符合既定標(biāo)準(zhǔn)和其它相關(guān)質(zhì)量控制標(biāo)準(zhǔn)的產(chǎn)品不得放行。IDENTIFYINGANDASSESSING00STESTRESULTS00S檢驗(yàn)結(jié)果的判斷和評(píng)估FDAregulationsre

15、quirethataninvestigationbeconductedwheneveran00Stestresultisobtained.Thepurposeoftheinvestigationistodeterminethecauseofthe00S.Evenifabatchisrejectedbasedonan00Sresult,theinvestigationisnecessarytodetermineiftheresultisassociatedwithotherbatchesofthesamedrugproductorotherproducts.Batchrejectiondoesn

16、otnegatetheneedtoperformtheinvestigation.Theregulationsrequirethatawrittenrecordoftheinvestigationbemadeincludingtheconclusionsoftheinvestigationandfollow-up(211.192).FDA法規(guī)要求當(dāng)00S僉驗(yàn)結(jié)果岀現(xiàn)時(shí)應(yīng)該進(jìn)展調(diào)查，調(diào)查的目的是確定引起00S勺原因。即使因00結(jié)果判斷了不合格批，仍必須進(jìn)展調(diào)查以確定該結(jié)果是否影響到同種產(chǎn)品其它批號(hào)或其它產(chǎn)品。法規(guī)要求對(duì)調(diào)查包括調(diào)查結(jié)論和隨后采取的措施進(jìn)展記錄(211.192)。Tobemeani

17、ngful,theinvestigationshouldbethorough,timely,unbiased,well-documented,andscientificallydefensible.Thefirstphaseofsuchaninvestigationshouldincludeaninitialassessmentoftheaccuracyofthelaboratorysdata,beforetestsolutionsarediscarded,wheneverpossible.Thisway,hypothesesregardinglaboratoryerrororinstrume

18、ntmalfunctionsmaybetestedusingthesametestsolutions.Ifthisinitialassessmentindicatesthatnoerrorsweremadeintheanalyticalprocessusedtoarriveatthedata,apletefailureinvestigationshouldfollow.更有意義的，調(diào)查必須是完全的，與時(shí)的，不帶有任何偏見(jiàn)的，記錄是完整的和經(jīng)得起科學(xué)推敲的。調(diào)查的最初階段應(yīng)該在試驗(yàn)溶液丟棄前，對(duì)實(shí)驗(yàn)室數(shù)據(jù)正確性進(jìn)展最初評(píng)估，這樣，假定認(rèn)為是實(shí)驗(yàn)室錯(cuò)誤或儀器故障，可以用原溶液測(cè)定。如果最初的評(píng)估評(píng)

19、估顯示在得到該數(shù)據(jù)的分析過(guò)程中沒(méi)有發(fā)生錯(cuò)誤，必須立即開(kāi)展一個(gè)完全的不合風(fēng)格查。A.ResponsibilityoftheAnalyst檢驗(yàn)員的責(zé)任Thefirstresponsibilityforachievingaccuratelaboratorytestingresultslieswiththeanalystwhoisperformingthetest.TheanalystshouldbeawareofpotentialproblemsthatcouldoccurduringthetestingprocessandshouldwatchforproblemsthatcouldcreateO

20、OSresults.從事測(cè)試的檢驗(yàn)員的首要責(zé)任是取得正確實(shí)驗(yàn)室檢驗(yàn)結(jié)果。檢驗(yàn)員應(yīng)該意識(shí)到在實(shí)驗(yàn)過(guò)程中可能發(fā)生的潛在的問(wèn)題和應(yīng)該注意可能產(chǎn)生00結(jié)果的問(wèn)題。InaccordancewiththeCGMPregulations(211.160(b)(4),theanalystshouldensurethatonlythoseinstrumentsmeetingestablishedspecificationsareusedandthatallinstrumentsareproperlycalibrated.Certainanalyticalmethodshavesystemsuitabilityr

21、equirements,andsystemsnotmeetingsuchrequirementsshouldnotbeused.Forexample,inchromatographicsystems,referencestandardsolutionsmaybeinjectedatintervalsthroughoutchromatographicrunstomeasuredrift,noise,andrepeatability.Ifreferencestandardresponsesindicatethatthesystemisnotfunctioningproperly,allofthed

22、atacollectedduringthesuspecttimeperiodshouldbeproperlyidentifiedandshouldnotbeused.Thecauseofthemalfunctionshouldbeidentifiedandcorrectedbeforeadecisionismadewhethertouseanydatapriortothesuspectperiod.依據(jù)CGMP(211.160(b)(4)，檢驗(yàn)員應(yīng)該保證只有符合既定標(biāo)準(zhǔn)的儀器才能使用和所有的儀器都經(jīng)過(guò)的校正。某些分析方法有系統(tǒng)適應(yīng)性要求，不符合要求的系統(tǒng)不能使用。例如：在色譜系統(tǒng)中，在進(jìn)展色譜

23、檢測(cè)期間內(nèi)間隔一段時(shí)間進(jìn)樣對(duì)照品溶液去測(cè)定漂移、噪聲和重復(fù)性。如果對(duì)照品響應(yīng)值顯示該系統(tǒng)功能不正常，在可疑的時(shí)間內(nèi)收集的所有數(shù)據(jù)應(yīng)該被適當(dāng)標(biāo)識(shí)并不能使用。在決定是否使用可疑期間之前的數(shù)據(jù)前，應(yīng)鑒別故障的原因并予以糾正。Beforediscardingtestpreparationsorstandardpreparations,analystsshouldcheckthedataforpliancewithspecifications.Whenunexpectedresultsareobtainedandnoobviousexplanationexists,testpreparationssho

24、uldberetainedandtheanalystshouldinformthesupervisor.Anassessmentoftheaccuracyoftheresultsshouldbestartedimmediately.在丟棄樣品制備液和標(biāo)準(zhǔn)制備液之前，檢驗(yàn)員應(yīng)該核查數(shù)據(jù)對(duì)標(biāo)準(zhǔn)的符合性。當(dāng)獲得意想不到的結(jié)果且沒(méi)有明顯的理由時(shí)，應(yīng)該保存樣品制備液且檢驗(yàn)員應(yīng)該通知主管。應(yīng)該立即開(kāi)始評(píng)估檢驗(yàn)結(jié)果的正確性。Iferrorsareobvious,suchasthespillingofasamplesolutionortheinpletetransferofasampleposite,thea

25、nalystshouldimmediatelydocumentwhathappened.Analystsshouldnotknowinglycontinueananalysistheyexpecttoinvalidateatalatertimeforanassignablecause(i.e.,analysesshouldnotbepletedforthesolepurposeofseeingwhatresultscanbeobtainedwhenobviouserrorsareknown).Thesesameresponsibilitiesextendtoanalystsatcontract

26、testinglaboratories.如果錯(cuò)誤是明顯的，如：樣品溶液有灑出或樣品成分的未完全轉(zhuǎn)移，檢驗(yàn)員應(yīng)該立即記錄所發(fā)生的情況。檢驗(yàn)員不應(yīng)該有意的繼續(xù)這無(wú)效的分析也就是，當(dāng)明顯的錯(cuò)誤發(fā)生了，不應(yīng)該帶著會(huì)得出什么結(jié)果的目的去完成分析。這些一樣的責(zé)任適用于合同實(shí)驗(yàn)室的檢驗(yàn)員。B.ResponsibilitiesoftheSupervisor主管的責(zé)任OnceanOOSresulthasbeenidentified,thesupervisorsassessmentshouldbeobjectiveandtimely.Thereshouldbenopreconceivedassumptionsas

27、tothecauseoftheOOSresult.Datashouldbeassessedpromptlytoascertainiftheresultsmaybeattributedtolaboratoryerror,orwhethertheresultscouldindicateproblemsinthemanufacturingprocess.Animmediateassessmentcouldincludere-examinationoftheactualsolutions,testunits,andglasswareusedintheoriginalmeasurementsandpre

28、parations,whichwouldallowmorecredibilitytobegiventolaboratoryerrortheories.一旦00結(jié)果被確定，主管應(yīng)該客觀的和與時(shí)的進(jìn)展評(píng)估。不應(yīng)該對(duì)00結(jié)果的原因進(jìn)展預(yù)想的假定。應(yīng)該迅速評(píng)估數(shù)據(jù)以確定結(jié)果是否屬于實(shí)驗(yàn)室錯(cuò)誤，或該結(jié)果是否顯示是生產(chǎn)過(guò)程的問(wèn)題。立即的評(píng)估應(yīng)該包括重新檢測(cè)原溶液、測(cè)試的單位、玻璃器具和溶液制備過(guò)程，這樣可以進(jìn)一步證實(shí)對(duì)00S結(jié)果屬于實(shí)驗(yàn)室錯(cuò)誤的假設(shè)。Thefollowingstepsshouldbetakenaspartofthesupervisorsassessment:下面是作為主管應(yīng)評(píng)估的局部步驟：

29、Discussthetestmethodwiththeanalyst;confirmanalystknowledgeofandperformanceofthecorrectprocedure.與檢驗(yàn)員討論檢測(cè)方法；確認(rèn)檢驗(yàn)員知道并執(zhí)行了正確的程序。Examinetherawdataobtainedintheanalysis,includingchromatogramsandspectra,andidentifyanomalousorsuspectinformation.檢查分析的原始數(shù)據(jù)，包括色譜和光譜，并識(shí)別出反常或可疑的信息。Confirmtheperformanceoftheinstru

30、ments.確認(rèn)儀器性能Determinethatappropriatereferencestandards,solvents,reagents,andothersolutionswereusedandthattheymeetqualitycontrolspecifications.確定使用了適宜的參照標(biāo)準(zhǔn)品、溶媒、試劑和其它溶液，并且它們符合質(zhì)量控制標(biāo)準(zhǔn)。Evaluatetheperformanceofthetestingmethodtoensurethatitisperformingaccordingtothestandardexpectedbasedonmethodvalidationd

31、ata.評(píng)估檢驗(yàn)方法的執(zhí)行情況，以保證是按照標(biāo)準(zhǔn)執(zhí)行并有方法驗(yàn)證數(shù)據(jù)。Documentandpreserveevidenceofthisassessment.記錄并保存評(píng)估的證據(jù)。TheassignmentofacauseforOOSresultswillbegreatlyfacilitatediftheretainedsamplepreparationsareexaminedpromptly.Hypothesesregardingwhatmighthavehappened(e.g.dilutionerror,instrumentmalfunction)canbetested.Examinat

32、ionoftheretainedsolutionscanbeperformedaspartofthelaboratoryinvestigation.如果與時(shí)檢測(cè)了所保存的樣品制備液，會(huì)極大的促進(jìn)00S吉果原因確實(shí)定?？梢詫?duì)所發(fā)生的事情的假設(shè)如：稀釋錯(cuò)誤、儀器故障進(jìn)展檢測(cè)。對(duì)被留的溶液的檢驗(yàn)可以作為實(shí)驗(yàn)室調(diào)查的一局部。Examples:例如!Solutionscanbere-injectedaspartofaninvestigationwhereatransientequipmentmalfunctionissuspected.Thiscouldoccurifbubbleswereintrodu

33、cedduringaninjectiononachromatographicsystem,whichothertestsindicatedwasperformingproperly.Suchtheoriesaredifficulttoprove.However,areinjectioncanprovidestrongevidencethattheproblemshouldbeattributedtotheinstrument,ratherthanthesampleoritspreparation.如果懷疑設(shè)備瞬間的故障，那么調(diào)查可以重新進(jìn)樣該溶液。如果在色譜系統(tǒng)一次進(jìn)樣期間引入了氣泡，而其它的

34、試驗(yàn)進(jìn)展正常，這是可能發(fā)生的。這樣的推測(cè)很困難去證明。但是，重新進(jìn)樣能有力的證明問(wèn)題與儀器有關(guān)，而不是與樣品或樣品的準(zhǔn)備有關(guān)。!Forreleaseratetestingofcertainspecializeddosageforms,wherepossible,examinationofthedosageunittestedmightdeterminewhetheritwasdamagedinawaythataffecteditsperformance.SuchdamagewouldprovideevidencetoinvalidatetheOOStestresult,andaretestwo

35、uldbeindicated.對(duì)于某一特定制劑的放行檢驗(yàn)，如果可能，檢查一下被測(cè)的這份制劑可以確定是否在什么方面被損壞而影響了其性能。這樣的損壞能提供證據(jù)使00檢驗(yàn)結(jié)果無(wú)效，這樣就可以進(jìn)展重新檢驗(yàn)。!Furtherextractionofadosageunitcanbeperformedtodeterminewhetheritwasfullyextractedduringtheoriginalanalysis.Inpleteextractioncouldinvalidatethetestresultsandshouldleadtoquestionsregardingvalidationofth

36、etestmethod.對(duì)一份制劑做進(jìn)一步提取以確定在初次檢驗(yàn)期間是否被充分的提取了。不完全的提取能使檢驗(yàn)結(jié)果無(wú)效，將導(dǎo)致檢驗(yàn)方法驗(yàn)證的問(wèn)題。Itisimportantthateachstepintheinvestigationbefullydocumented.Thesupervisorshouldascertainnotonlythereliabilityoftheindividualvalueobtained,butalsothesignificancetheseOOSresultsrepresentintheoverallqualityassuranceprogram.在調(diào)查的每一步都

37、應(yīng)做充分的記錄，這是很重要的。主管不僅應(yīng)該確定獲得的個(gè)別值的可靠性，也應(yīng)該確定在整個(gè)質(zhì)量保證程序中說(shuō)明的00結(jié)果的重要性。Supervisorsshouldbeespeciallyalerttodevelopingtrends.主管應(yīng)該特別警惕開(kāi)展趨勢(shì)。Laboratoryerrorshouldberelativelyrare.Frequenterrorssuggestaproblemthatmightbeduetoinadequatetrainingofanalysts,poorlymaintainedorimproperlycalibratedequipment,orcarelesswor

38、k.Wheneverlaboratoryerrorisidentified,thefirmshoulddeterminethesourceofthaterrorandtakecorrectiveactiontoensurethatitdoesnotoccuragain.ToensurefullpliancewiththeCGMPregulations,themanufactureralsoshouldmaintainadequatedocumentationofthecorrectiveaction.Insummary,whenclearevidenceoflaboratoryerrorexi

39、sts,laboratorytestingresultsshouldbeinvalidated.Whenevidenceoflaboratoryerrorremainsunclear,afailureinvestigationshouldbeconductedtodeterminewhatcausedtheunexpectedresults.Itshouldnotbeassumedthatfailingtestresultsareattributabletoanalyticalerrorwithoutperforminganddocumentinganinvestigation.Boththe

40、initiallaboratoryassessmentandthefollowingfailureinvestigationshouldbedocumentedfully.實(shí)驗(yàn)室錯(cuò)誤應(yīng)該是極少發(fā)生的。頻繁的錯(cuò)誤暗示一個(gè)問(wèn)題，那就是檢驗(yàn)員培訓(xùn)不充分，設(shè)備維護(hù)保養(yǎng)不善或沒(méi)有得到正確校正，或工作粗心。如果實(shí)驗(yàn)室錯(cuò)誤被確定了，企業(yè)應(yīng)該確定錯(cuò)誤的來(lái)源并采取糾正措施去保證錯(cuò)誤不再發(fā)生。為保證完全符合CGMP生產(chǎn)商應(yīng)該保持充分的糾正措施的記錄?？傊?，當(dāng)實(shí)驗(yàn)室錯(cuò)誤的證據(jù)已經(jīng)存在，實(shí)驗(yàn)室檢驗(yàn)結(jié)果應(yīng)該作廢。當(dāng)實(shí)驗(yàn)室錯(cuò)誤的證據(jù)仍然不清楚，應(yīng)該進(jìn)展不合格結(jié)果的調(diào)查以確定引起意外結(jié)果的原因。在沒(méi)有進(jìn)展調(diào)查與調(diào)查文件確定

41、之前不應(yīng)該假定失敗的檢驗(yàn)結(jié)果屬于檢驗(yàn)錯(cuò)誤。最初的實(shí)驗(yàn)室評(píng)估和下面的不合格結(jié)果的調(diào)查應(yīng)該被充分的記錄。INVESTIGATING00STESTRESULTS00S吉果調(diào)查Whentheinitialassessmentdoesnotdeterminethatlaboratoryerrorcausedthe00Sresultandtestingresultsappeartobeaccurate,afull-scalefailureinvestigationusingapredefinedprocedureshouldbeconducted.Theobjectiveofsuchaninvestiga

42、tionshouldbetoidentifythesourceofthe00Sresult.Varyingtestresultscouldindicateproblemsinthemanufacturingprocess,orresultfromsamplingproblems.Suchinvestigationspresentachallengebothtoemployeesandtomanagementandshouldbegiventhehighestpriority.如果最初的評(píng)估不能確定是實(shí)驗(yàn)室錯(cuò)誤造成了00結(jié)果且實(shí)驗(yàn)結(jié)果是正確的，應(yīng)按照預(yù)先確定的程序進(jìn)展全方位的不合風(fēng)格查。這樣調(diào)查

43、的目的是確定00結(jié)果的來(lái)源，變化的試驗(yàn)結(jié)果可能顯示是生產(chǎn)工藝的問(wèn)題或取樣問(wèn)題導(dǎo)致的結(jié)果。這樣的調(diào)查是對(duì)員工和管理者的挑戰(zhàn)應(yīng)給予極高度的重視。Theinvestigationshouldbeconductedbythequalitycontrolunitandshouldinvolveallotherdepartmentsthatcouldbeimplicated,includingmanufacturing,processdevelopment,maintenance,andengineering.0therpotentialproblemsshouldbeidentifiedandinves

44、tigated.調(diào)查應(yīng)該由質(zhì)量控制部門(mén)和所有其它相關(guān)的部門(mén)完成，包括生產(chǎn)部門(mén)，工藝研發(fā)部門(mén)，維護(hù)保養(yǎng)和工程部門(mén)。其它的潛在問(wèn)題也應(yīng)該被確定和調(diào)查。Therecordsanddocumentationofthemanufacturingprocessshouldbefullyinvestigatedtodeterminethepossiblecauseofthe00Sresults.應(yīng)該充分調(diào)查生產(chǎn)過(guò)程的記錄和文件以判斷引起00結(jié)果的可能原因。A.GeneralInvestigationalPrinciples一般調(diào)查原那么Afailureinvestigationshouldconsistof

45、atimely,thorough,andwell-documentedreview.一個(gè)不合格結(jié)果的調(diào)查在于與時(shí)，徹底，和完善的記錄審核。Thewrittenrecordshouldreflectthatthefollowinggeneralstepshavebeentaken.記錄應(yīng)該反映通常采取的以下步驟：Thereasonfortheinvestigationhasbeenclearlyidentified.調(diào)查的原因被清楚確實(shí)定。Themanufacturingprocesssequencesthatmayhavecausedtheproblemshouldbesummarized.對(duì)

46、可能引起問(wèn)題的生產(chǎn)工藝流程進(jìn)展了總結(jié)。Resultsofthedocumentationreviewshouldbeprovidedwiththeassignmentofactualorprobablecause.文件審核的結(jié)果提供了實(shí)際的或可能的原因。Areviewshouldbemadetodetermineiftheproblemhasoccurredpreviously.審核并判斷是否以前發(fā)生過(guò)這類問(wèn)題。Correctiveactionstakenshouldbedescribed.應(yīng)該描述采取的糾正措施Thegeneralreviewshouldincludealistofother

47、batchesandproductspossiblyaffectedandanyrequiredcorrectiveactionstakenincludinganymentsandsignaturesofappropriateproductionandqualitycontrolpersonnelregardinganymaterialthatmayhavebeenreprocessedafteradditionaltesting.一般性審核應(yīng)該包括可能受影響的其它批和產(chǎn)品的列表，任何必須的糾正行為包括對(duì)復(fù)檢后進(jìn)展返工的物料的適宜的生產(chǎn)和質(zhì)量控制人員的評(píng)論和簽名。B.LaboratoryPha

48、seofanInvestigation實(shí)驗(yàn)室階段的調(diào)查Anumberofpracticesareusedduringthelaboratoryphaseofaninvestigation.Theseinclude:(1)retestingaportionoftheoriginalsample,(2)testingaspecimenfromthecollectionofanewsamplefromthebatch,(3)resamplingtestingdata,and(4)usingoutliertesting.在實(shí)驗(yàn)室階段的一系列調(diào)查包括：1最初樣品一局部的再檢驗(yàn)，2從該批中重新取樣樣品的檢

49、驗(yàn)，3重新取樣的檢驗(yàn)數(shù)據(jù)，4逸出值的檢驗(yàn)1.Retesting重新檢驗(yàn)Partoftheinvestigationmayinvolveretestingofaportionoftheoriginalsample.Thesampleusedfortheretestingshouldbetakenfromthesamehomogeneousmaterialthatwasoriginallycollectedfromthelot,tested,andyieldedtheOOSresults.Foraliquid,itmaybefromtheoriginalunitliquidproductorpos

50、iteoftheliquidproduct;forasoliditmaybeanadditionalweighingfromthesamesamplepositethathadbeenpreparedbytheanalyst.調(diào)查局部工作包括最初檢驗(yàn)樣品的再檢驗(yàn)。用于再檢驗(yàn)的樣品應(yīng)該是最初收集檢驗(yàn)的、岀現(xiàn)00結(jié)果的樣品均質(zhì)物料的一局部。如果是液體，可以是液體成品的原始單位或液體成品的混合物。如果是固體，可以是檢驗(yàn)員制備的一樣混合物的額外的稱量。Situationswhereretestingisindicatedincludeinvestigatingtestinginstrumentmalf

51、unctionsortoidentifyapossiblesamplehandlingintegrityproblem,forexample,asuspecteddilutionerror.Generally,retestingisneitherspecifiednorprohibitedbyapprovedapplicationsorbythependia.Decisionstoretestshouldbebasedontheobjectivesofthetestingandsoundscientificjudgment.Retestingshouldbeperformedbyananaly

52、stotherthantheonewhoperformedtheoriginaltest.再檢驗(yàn)的情況標(biāo)明包括檢驗(yàn)儀器故障的調(diào)查或判斷樣品處理完整性。例如：一個(gè)可疑的溶解錯(cuò)誤。一般地，在批準(zhǔn)的申請(qǐng)中或藥典中既沒(méi)有限定也沒(méi)有禁止，應(yīng)該依據(jù)客觀的檢驗(yàn)和正確科學(xué)的判斷決定再檢驗(yàn)。再檢驗(yàn)應(yīng)該是另一檢驗(yàn)員完成而不是最初檢驗(yàn)人員。TheCGMPregulationsrequiretheestablishmentofspecifications,standards,samplingplans,testprocedures,andotherlaboratorycontrolmechanisms(211.160

53、).Theestablishmentofsuchcontrolmechanismsforexaminationofadditionalspecimens，formercialorregulatorypliancetestingmustbeinaccordancewithpredeterminedguidelinesorsamplingstrategies(USP23,GeneralNoticesandRequirements,p.9).CGM法規(guī)要求建立規(guī)格、標(biāo)準(zhǔn)、取樣計(jì)劃、檢驗(yàn)程序和其它的實(shí)驗(yàn)室控制機(jī)制(211.160)。符加樣品的檢驗(yàn)、商業(yè)或調(diào)整的依從性試驗(yàn)的控制機(jī)制的建立必須依據(jù)預(yù)先確定

54、指南或取樣策略。Somefirmshaveusedastrategyofrepeatedtestinguntilapassingresultisobtained(testingintopliance),thendisregardingtheOOSresultswithoutscientificjustification.TestingintoplianceisobjectionableundertheCGMPs.ThenumberofreteststobeperformedonasampleshouldbespecifiedinadvancebythefirmintheSOP.許多企業(yè)使用重復(fù)

55、的檢驗(yàn)直到獲得滿意的結(jié)果的策略，然后沒(méi)有科學(xué)的理由就無(wú)視了00結(jié)果。重復(fù)的檢驗(yàn)直到獲得滿意的結(jié)果，CGM是不允許的。樣品的再檢驗(yàn)次數(shù)應(yīng)該在企業(yè)的SO中被預(yù)先限定。Thenumbermayvarydependinguponthevariabilityoftheparticulartestmethodemployed,butshouldbebasedonscientificallysound,supportableprinciples.Thenumbershouldnotbeadjusteddependingontheresultsobtained.Thefirmspredeterminedtes

56、tingproceduresshouldcontainapointatwhichthetestingendsandtheproductisevaluated.If,atthispoint,theresultsareunsatisfactory,thebatchissuspectandmustberejectedorheldpendingfurtherinvestigation(211.165(f).檢驗(yàn)次數(shù)可以根據(jù)使用的檢驗(yàn)方法的可變性決定，但必須依據(jù)科學(xué)正確和可支持的原那么。檢驗(yàn)次數(shù)不能依據(jù)結(jié)果進(jìn)展判斷。企業(yè)預(yù)先確定的檢驗(yàn)程序應(yīng)該包括何時(shí)檢驗(yàn)完畢和進(jìn)展產(chǎn)品評(píng)估。如果，就這一點(diǎn)，結(jié)果是不滿意的

57、，這批產(chǎn)品就是可疑的，必須批準(zhǔn)不合格或進(jìn)一步調(diào)查后再作決定(211.165(f).。Inthecaseofaclearlyidentifiedlaboratoryerror,theretestresultswouldsubstitutefortheoriginaltestresults.Theoriginalresultsshouldberetained,however,andanexplanationrecorded.Thisrecordshouldbeinitialedanddatedbytheinvolvedpersonsandincludeadiscussionoftheerroran

58、dsupervisoryments.在明確確定了實(shí)驗(yàn)室錯(cuò)誤的情況下，再檢驗(yàn)結(jié)果將取代最初檢驗(yàn)結(jié)果，應(yīng)該保存最初結(jié)果和一個(gè)解釋記錄，這個(gè)記錄應(yīng)該有相關(guān)人員人員的簽名、注上日期，并應(yīng)包括對(duì)錯(cuò)誤的討論、主管的注釋。Ifnolaboratoryorstatisticalerrorsareidentifiedinthefirsttest,thereisnoscientificbasisforinvalidatinginitial00Sresultsinfavorofpassingretestresults.Alltestresults,bothpassingandsuspect,shouldberepo

59、rtedandconsideredinbatchreleasedecisions.如果不能確定是首次的試驗(yàn)是實(shí)驗(yàn)室或統(tǒng)計(jì)錯(cuò)誤，就沒(méi)有為了讓產(chǎn)品通過(guò)復(fù)檢而廢除最初00結(jié)果的科學(xué)根底。所有檢驗(yàn)結(jié)果，不論是通過(guò)的和可疑的，都應(yīng)該報(bào)告并供批放行結(jié)論中考慮。Resampling再取樣DOCWhileretestingreferstoanalysisoftheoriginalsample,resamplinginvolvesanalyzingaspecimenfromthecollectionofanewsamplefromthebatch.Theestablishmentofcontrolmechani

60、smsforexaminationofadditionalspecimensformercialorregulatorypliancetestingshouldbeinaccordancewithpredeterminedproceduresandsamplingstrategies(211.165(c).涉與最初樣品分析的再檢驗(yàn)，再取樣包括從該批產(chǎn)品抽取新的樣品。應(yīng)該按照預(yù)先制定的程序和取樣策略來(lái)建立為符合商業(yè)或法規(guī)的試驗(yàn)的目的而對(duì)額外樣品進(jìn)展檢驗(yàn)的控制機(jī)制。Insomecases,whenalldatahavebeenexamined,itmaybeconcludedthattheorig