FDA警告信：驗(yàn)證失敗,部分批次能否放行

FDA警告信：驗(yàn)證失敗，部分批次能否放行?11月24日，F(xiàn)DA公布一封針對美國企業(yè)(AuroLifePharma,LLC,總部位于印度)的警告信。主要的缺陷項(xiàng)涉及OOS調(diào)查不充分、廠房維護(hù)不利、設(shè)施設(shè)備的清潔問題和針對工藝變更的驗(yàn)證不足。為縮短工藝時間，該公司對三種片劑產(chǎn)品的生產(chǎn)工藝進(jìn)行了變更，并執(zhí)行了工藝性能確認(rèn)(PPQ)。驗(yàn)證時，由于出現(xiàn)了均勻性不合格的問題，該公司拒放了某些批次，但放行了其余批次。FDA認(rèn)為，公司沒有數(shù)據(jù)來說明新工藝處于受控狀態(tài)，因此對那些放行批次提出了質(zhì)疑。為此，在483表格的回復(fù)中，該公司決定召回使用新工藝生產(chǎn)的所有PPQ批次，但FDA認(rèn)為公司的答復(fù)是不充分的，因?yàn)楣咎岢龅尿?yàn)證策略存在問題，需要提供有關(guān)驗(yàn)證計(jì)劃的詳細(xì)摘要及相關(guān)程序。警告信CMS#607087清潔問題3.Yourfirmfailedtoestablishandfollowwrittenproceduresforcleaningandmaintenanceofequipment(21CFR211.67(b)).3.你們公司未建立并遵循適當(dāng)?shù)臅娉绦?，來清潔和維護(hù)設(shè)備 (21CFR211.67(b))。Duringtheinspection,ourinvestigatorsobservedsurfacescoveredinpowderthroughoutyourfacilityincludingAPIsamplingrooms,rawmaterialdispensingrooms,commonproductioncorridorareas,granulationrooms,andcompressionrooms.在檢查過程中，我們的調(diào)查員觀察到整個設(shè)施表面都被粉末覆蓋，包括API取樣室、原料稱量間、公共生產(chǎn)通道區(qū)域、造粒間和壓縮空氣室。Forexample,ina(b)(4)granulationroomdocumentedas-cl“anedrweobservedapowderresiduecoatingthesurfaceofthe(b)(4)panel,theflooroftheroom,andthecontrolpanelofa(b)(4).例如，在記錄為“主要”清潔的XX造粒間中，我們觀察到粉末殘留物覆蓋了XX面板的表面，房間的地板和XX控制面板。Thevisiblepowderobservedinnumerousareasofyourfacilitycouldleadtocross-contaminationofyourfinisheddrugproducts.Notably,thehazardposedbythisdeviationisheightenedbecauseyoumanufacturehighpotencydrugproducts.在工廠的許多區(qū)域觀察到可見粉末，可能會導(dǎo)致成品制劑的交叉污染。值得注意的是，由于你們生產(chǎn)高活性的藥品，這種偏差帶來的危險會加增。Inyourresponse,youstatedyouwillreviseyourcleaningproceduresandtrainyourpersonnel.Yourresponsefailedtoaddresstherootcauseofinadequatepowdercontrolinyourfacilityandproposeadequatecorrections.在答復(fù)中，你們表示將修改清潔程序，并培訓(xùn)人員。你們的答復(fù)未能解決你們設(shè)施中粉末控制不足的根本原因，也沒有提出了適當(dāng)?shù)募m正措施。Inyourresponsetothisletter,provide:針對此信，請?zhí)峁篩ourCAPAplantoensurethatyouhaveeffectivepowdercontrol(e.g.,exhaust)systemsinyourfacility.你們的CAPA計(jì)劃，確保你們的設(shè)施中具有有效的粉末控制(例如，排風(fēng))系統(tǒng)。Acomprehensive,independentretrospectiveassessmentofyourcleaningeffectivenesstoevaluatethescopeofcross-contaminationhazards.Includetheidentityofresidues,othermanufacturingequipmentthatmayhavebeenimproperlycleaned,andanassessmentwhethercross-contaminatedproductsmayhavebeenreleasedfordistribution.Theassessmentshouldidentifyanyinadequaciesinfacilitydesign,cleaningprocedures,orcleaningpractices.Itshouldencompasseachproductionroomandpieceofmanufacturingequipmentusedtomanufacturemorethanoneproduct.對清潔效果進(jìn)行全面、獨(dú)立的回顧性評估，以評估交叉污染危害的范圍。包括殘留物的識別，可能未正確清潔的其它生產(chǎn)設(shè)備，并評估放行分發(fā)的產(chǎn)品是否可能發(fā)生了交叉污染。評估應(yīng)確定設(shè)施設(shè)計(jì)、清潔程序或清潔實(shí)踐中的任何不足之處。這應(yīng)涵蓋每個用于多個產(chǎn)品生產(chǎn)的房間和設(shè)備。工藝變更驗(yàn)證不足.Yourfirmfailedtoestablishadequatewrittenproceduresforproductionandprocesscontroldesignedtoassurethatthedrugproductsyoumanufacturehavetheidentity,strength,quality,andpuritytheypurportorarerepresentedtopossess(21CFR211.100(a))..公司未建立用于生產(chǎn)和過程控制的書面程序，以確保你所生產(chǎn)的藥品具有其聲稱或代表擁有的鑒別、強(qiáng)度、質(zhì)量和純度(21CFR211.100(a))。Toreducethemanufacturingprocesstimeforthreestrengthsofacetaminophenandcodeinephosphatetablets,youimplementedamanufacturingprocesschange.Usingthisnewprocess,youmanufactured(b)(4)processperformancequalification(PPQ)batches.Yourejected(b)(4)batchesforuniformityfailures(e.g.,blend,contentuniformity)andreleasedtheremaining(b)(4)batches.為了減少三種對乙酰氨基酚和磷酸可待因片劑的生產(chǎn)工藝時間，你們實(shí)施了生產(chǎn)工藝變更。使用此新工藝，你們生產(chǎn)了XX個工藝性能確認(rèn)(PPQ)批次。由于均勻性失敗(例如，混合、含量均勻性)，你們拒放了XX個批次，但放行了其余XX個批次。Youdidnothavedatatosupportthatyourprocesswasinastateofcontrolpriortoreleasingthose(b)(4)batches.在放行那些XX批次之前，你們沒有數(shù)據(jù)來支持你們的工藝處于受控狀態(tài)。Yourevaluationoftheprocesschangeafterimplementationconcludedthatthenewprocessresultedinanon-uniformblend,yourpreviousmanufacturingprocesswasmoreconsistentandrobust,andtheremainingbatchesshouldbeheldpendingfurtherdiscussion.Eightmonthsafterthisinitialevaluationyoumadethedecisiontoreverttotheoldprocess.However,yourfirmdeterminedthatthequarantinedbatchescouldbedistributed.對于實(shí)施后的工藝變更，你們的評估得出結(jié)論，即：新工藝導(dǎo)致混合不均勻，你們以前的生產(chǎn)工藝更加一致且穩(wěn)定，剩余批次應(yīng)等待進(jìn)一步討論。在此初始評估的八個月后，你們決定恢復(fù)到舊工藝。但是，你們公司決定可以分發(fā)之前隔離的那些批次。Inyourresponse,youwrotethatyouwouldreviewtheselotsandrecallifnecessary.在答復(fù)中，你們寫道，你們將審查這些批次，并在必要時召回。Youalsowrotethatonlythefirst(b)(4)consecutive“successfullymanufactured”PPQvalidationbatchescanbeconsideredforreleaseintothemarketandthatanypriorfailedPPQbatchescanbeconsidered“(b)(4).”YouaddedifanyfailureisobservedinPPQbatches“withunassignablerootcausethenthefailedbatchandthebatchesmanufacturedpriortothefailedbatchshallnotbereleasedintothemarket.”Yourresponseisinadequate,becauseyourproposedvalidationstrategyfailstoensureallPPQbatchesareproperlyevaluatedwhendeterminingwhetherornotyourprocessisinaninitialstateofcontrol.你們還寫道，只有前XX個連續(xù)“成功生產(chǎn)”的PPQ驗(yàn)證批次才可以考慮投放市場，而任何先前失敗的PPQ批次都可以考慮為“XX”。你們補(bǔ)充道，如果在PPQ批次中發(fā)現(xiàn)任何失敗，“根本原因無法確定時，則該失敗批次和之前生產(chǎn)的批次將不會投放市場?！蹦銈兊拇饛?fù)不充分，因?yàn)樵诖_定你們的工藝是否處于初始控制狀態(tài)時，你們提出的驗(yàn)證策略無法確保正確評估所有PPQ批次。WeacknowledgeyouhaverecentlymadethedecisiontorecallthePPQbatchesmadeusingthenewprocess.你們最近決定召回使用新工藝生產(chǎn)的PPQ批次，對此我們已經(jīng)知曉。Processvalidationevaluatesthesoundnessofdesignandstateofcontrolofaprocessthroughoutitslifecycle.Eachsignificantstageofamanufacturingprocessmustbedesignedappropriatelyandensurethequalityofrawmaterialinputs,in-processmaterials,andfinisheddrugs.Failuretoconductthesestudiescanresultinproductqualityattributefailures.Processqualificationstudiesdeterminewhetheraninitialstateofcontrolhasbeenestablished.Successfulprocessqualificationstudiesarenecessarybeforecommercialdistribution.Thereafter,ongoingvigilantoversightofprocessperformanceandproductqualityisnecessarytoensureyoumaintainastablemanufacturingoperationthroughouttheproductlifecycle.工藝驗(yàn)證會評估整個工藝生命周期中設(shè)計(jì)的合理性和控制狀態(tài)。生產(chǎn)工藝中的每個重要階段都必須進(jìn)行適當(dāng)?shù)脑O(shè)計(jì)，并確保原材料輸入、在制品和成品制劑的質(zhì)量。未能進(jìn)行這些研究可能會導(dǎo)致產(chǎn)品質(zhì)量屬性失敗。工藝確認(rèn)研究確定是否已建立初始控制狀態(tài)。商業(yè)放行之前，必須進(jìn)行成功的工藝確認(rèn)研究。此后，有必要對工藝性能和產(chǎn)品質(zhì)量進(jìn)行持續(xù)的監(jiān)控，以確保你們在整個產(chǎn)品生命周期中保持穩(wěn)定的生產(chǎn)操作。SeeFDA,sguidancedocumentProcessValidation:GeneralPrinciplesandPracticesforgeneralprinciplesandapproachesthatFDAconsidersappropriateelementsofprocessvalidationat/media/71021/download.請參閱FDA的指南《工藝驗(yàn)證：一般原則和實(shí)踐》，就FDA考慮的工藝驗(yàn)證適當(dāng)要素，獲取一般原則和方法。Inresponsetothisletter,provide:針對此信，請?zhí)峁篈detailedsummaryofyourvalidationprogramforensuringastateofcontrolthroughouttheproductlifecycle,alongwithassociatedprocedures.Describeyourprogramforprocessperformancequalification,andongoingmonitoringofbothintra-batchandinter-batchvariationtoensureacontinuingstateofcontrol.有關(guān)驗(yàn)證計(jì)劃的詳細(xì)摘要(確保整個產(chǎn)品生命周期中的控制狀態(tài))，以及相關(guān)程序。描述你們的計(jì)劃，以進(jìn)行工藝性能確認(rèn)(PPQ)，并持續(xù)監(jiān)控批內(nèi)和批間變化，以確保持續(xù)的控制狀態(tài)。AdeterminationofwhetherthePPQforeachofyourmarketeddrugproductswasproperlyexecutedandusedtheappropriatecriteria.#推薦使用CGMP顧問ConsultantrecommendedBaseduponthenatureoftheviolationsweidentifiedatyourfirm,westronglyrecommendengagingaconsultantqualifiedassetforthin21CFR211.34toassistyourfirminmeetingCGMPrequirements.根據(jù)我們發(fā)現(xiàn)的違規(guī)行為的性質(zhì)，我們強(qiáng)烈建議聘請符合21CFR211.34規(guī)定的合格顧問，來協(xié)助你們公司滿足CGMP要求。Youruseofaconsultantdoesnotrelieveyourfirm'sobligationtocomplywithCGMP.Yourfirm,sexecutivemanagementremainsresponsibleforresolvingalldeficienciesandsystemicflawstoensureongoingCGMPcompliance.你們聘用顧問并不能免除公司遵守CGMP的義務(wù)。你們公司的執(zhí)行管理層仍然負(fù)責(zé)解決所有缺陷和系統(tǒng)性缺陷，以確保持續(xù)符合CGMP。結(jié)論ConclusionTheviolationscitedinthisletterarenotintendedtobeanall-inclusivelistofviolationsthatexistatyourfacility.Youareresponsibleforinvestigatinganddeterminingthecausesoftheseviolationsandforpreventingtheirrecurrenceortheoccurrenceofotherviolations.本信函中引用的違規(guī)行為并非旨在列出與你們產(chǎn)品相關(guān)的所有違規(guī)行為。你們有責(zé)任調(diào)查和確定這些違規(guī)的原因，并防止其再次發(fā)生或發(fā)生其它違規(guī)情況。Ifyouareconsideringanactionthatislikelytoleadtoadisruptioninthesupplyofdrugsproducedatyourfacility,FDArequeststhatyoucontactCDER,sDrugShortagesStaffimmediately,atdrugshortages@,sothatFDAcanworkwithyouonthemosteffectivewaytobringyouroperationsintocompliancewiththelaw.ContactingtheDrugShortagesStaffalsoallowsyoutomeetanyobligationsyoumayhavetoreportdiscontinuancesorinterruptionsinyourdrugmanufactureunder21U.S.C.356C(b).ThisalsoallowsFDAtoconsider,assoonaspossible,whatactions,ifany,maybeneededtoavoidshortagesandprotectthehealthofpatientswhodependonyourproducts.如果你們正在考慮可能會導(dǎo)致你們的工廠生產(chǎn)的藥物供應(yīng)中斷的行動，則FDA要求你們立即聯(lián)系CDER的藥物短缺人員(drugshortages@)，以便FDA可以與你們以最有效的方式使你們的運(yùn)營符合法律規(guī)定。與藥品短缺人員聯(lián)系還可以使你們履行報告21USC356C(b)規(guī)定的藥品生產(chǎn)中斷或暫停的義務(wù)。這也使FDA可以盡快考慮可能需要采取什么措施，以避免短缺和保護(hù)依賴你們產(chǎn)品的患者的健康。Correcttheviolationscitedinthisletterpromptly.Failuretopromptlycorrecttheseviolationsmayresultinlegalactionwithoutfurthernoticeincluding,withoutlimitation,seizureandinjunction.UnresolvedviolationsinthiswarninglettermayalsopreventotherFederalagenciesfromawardingcontracts.及時糾正此信中引用的違規(guī)行為。不及時糾正這些違法行為，可能會導(dǎo)致采取法律行動(恕不另行通知)，包括但不限于：扣押和強(qiáng)制令。此警告信中未解決的違反行為也可能阻止其它聯(lián)邦機(jī)構(gòu)給予合同。FDAmayalsowithholdapprovalofre