性試驗問答〔中英文〕GuidanceforIndustry行業(yè)指南ANDAs:StabilityTestingofDrugSubstancesandProductsQuestionsandAnswersANDA：原料藥和制劑穩(wěn)定性試驗問答DRAFTGUIDANCE指南草案Thisguidancedocumentisbeingdistributedforcommentpurposesonly.本指南文件公布僅供爭論。Commentsandsuggestionsregardingthisdraftdocumentshouldbesubmittedwithin60daysofpublicationintheFederalRegisterofthenoticeannouncingtheavailabilityofthedraftguidance.Submitelectroniccommentsto“:///“://.SubmitwrittencommentstotheDivisionofDocketsManagement(HFA-305),FoodandDrugAdministration,5630FishersLane,rm.1061,Rockville,MD20852.AllcommentsshouldbeidentifiedwiththedocketnumberlistedinthenoticeofavailabilitythatpublishesintheFederalRegister.Forquestionsregardingthisdraftdocumentcontact(CDER)RadhikaRajagopalan240-276-8546.U.S.DepartmentofHealthandHumanServicesFoodandDrugAdministrationCenterCenterforDrugEvaluationandResearch(CDER)August2023GenericsGuidanceGuidanceforIndustryANDAs:StabilityTestingofDrugSubstancesandProductsQuestionsandAnswersANDA：原料藥和制劑穩(wěn)定性試驗問答Additionalcopiesareavailablefrom:OfficeofCommunicationsDivisionofDrugInformation,WO51,Room2201CenterforDrugEvaluationandResearchFoodandDrugAdministration10903NewHampshireAve.,SilverSpring,MD20993Phone:301-796-3400;Fax:301-847-8714“mailto:druginfo@“druginfo@“:///Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm“:///Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htmU.S.DepartmentofHealthandHumanServicesFoodandDrugAdministrationCenterforDrugEvaluationandResearch(CDER)August2023GenericsContainsNonbindingRecommendationsDraft—NotforImplementationTABLETABLEOFCONTENTSI.INTRODUCTION介紹II.QUESTIONSANDANSWERS問與答A.General一般問題B.DrugMasterFile藥物主文件.C.DrugProductManufacturingandPackaging藥品生產(chǎn)和包裝D.AmendmentstoPendingANDAApplicationANDA申請的增補E.StabilityStudies穩(wěn)定性試驗.GuidanceforIndustry[1]ANDAs:StabilityTestingofDrugSubstancesandProductsQuestionsandAnswersANDA ：原料藥和制劑穩(wěn)定性試驗問答Thisdraftguidance,whenfinalized,willrepresenttheFoodandDrugAdministration’s(FDA’s)currentthinkingonthistopic.ItdoesnotcreateorconferanyrightsfororonanypersonanddoesnotoperatetobindFDAorthepublic.Youcanuseanalternativeapproachiftheapproachsatisfiestherequirementsoftheapplicablestatutesandregulations.Ifyouwanttodiscussanalternativeapproach,contacttheFDAstaffresponsibleforimplementingthisguidance.IfyoucannotidentifytheappropriateFDAstaff,calltheappropriatenumberlistedonthetitleofthisguidance.FDA目前對這一專題的態(tài)度。它并未建FDA或公眾有任何綁定。你可以使用任何FDA可以撥打本指南首頁所列的相應(yīng)的號。INTRODUCTION介紹ThisdraftguidanceprovidesanswerstoquestionsfromthepubliccommentswereceivedonthedraftguidanceforindustryonANDAs:StabilityTestingofDrugSubstancesandProducts(stabilityguidance)thatpublishedonSeptember25,2023.ThefinalguidanceforindustryofthesametitlepublishedonJune20,2023.Generalissues;drugmasterfiles(DMFs);drugproductmanufacturingandpackaging;andstabilitystudiesarediscussedinthisguidanceandareintendedtoclarifythestabilitytestingdatarecommendationsforabbreviatednewdrugapplications(ANDAs).Inthisdocument,thetermsdrugsubstanceandactivepharmaceuticalingredient(API)areusedinterchangeably.2023925日公布的行業(yè)指南草案〔ANDA：原料藥和制劑穩(wěn)定性試驗〔穩(wěn)定性指南〕〕起草中收到的公眾問題的答復匯總。該指南終稿在2023620日出版。在本指南中，爭論了一般問題、DMF問題、藥品生產(chǎn)ANDA穩(wěn)定性試驗數(shù)據(jù)的一些意見。在本文件中，“藥用物質(zhì)”和“活性藥用物質(zhì)成份”交互使用。thisguidance,donotestablishlegallyenforceableresponsibilities.Instead,guidancesdescribetheAgency’scurrentthinkingonatopicandshouldbeviewedonlyasrecommendations,unlessspecificregulatoryorstatutoryrequirementsarecited.TheuseofthewordshouldinAgencyguidancesmeansthatsomethingissuggestedorrecommended,butnotrequired.FDA的指南文件，包括本指南，并未建立法定的強制責任。指南中只是描述了“應(yīng)當〔should〕”一詞表示這是建議或推舉，而非必需。General一般Q1:Whatisthescopeofandimplementationdateforthestabilityguidance?穩(wěn)定性指南的范圍和實施日期？穩(wěn)定性指南的范圍和實施日期？A1:A1:ThestabilityguidancecoversallnewANDAsundertheFederalFood,Drug,andCosmeticAct,section505(j),andDMFs(TypeIIfordrugsubstancesthatsupporttheANDAs).Itdoesnotapplytopostapprovalchanges.ThefinalguidanceavailabilitywillbeannouncedintheFederalRegister.TheimplementationdateisJune20,2023.ANDA申請，和DMF申請〔支持ANDA的二類藥用物質(zhì)〕。不適用于上市后變更。最終指南將在聯(lián)邦注冊上公布。實施日期2023年6月20日。Q2:HowwillthisguidanceaffectthePresident’sEmergencyPlanforAIDSRelief(PEPFAR)andpositronemissiontomography(PET)ANDAs?〔PEPFA〔有何影響？A2:Forchemistry,manufacturing,andcontrols(CMC)information,PEPFARANDAsshouldfollowtheguidanceforindustryonFixedDoseCombinations,Co-PackagedDrugProducts,andSingle-EntityVersionsofPreviouslyApprovedAntiretroviralsfortheTreatmentofHIV[1].學體的規(guī)定。ForForPETANDAs,theAgencyrecommendsaminimumofthreebatchesatorneartheupperendoftheproposedradio-concentration.Ifdifferentsynthesizers(methodsofsynthesis)areused,threebatchesfromeachmethodofsynthesisatorneartheupperendoftheproposedradio-concentrationarerecommended.Batchesdonothavetobemadeinthesamefacility.Fortheadditionalmanufacturingfacilities,applicantsshouldprovidestabilitydataonatleastonebatchfromeachfacility,althoughbracketingapproachescouldbesubmittedforreview.Foradditionalinformation,theAgencyhaspublishedaguidanceforindustryonFDAOversightofPETProducts,QuestionsandAnswers.對于PET的ANDA，當局建議至少三個最高或接近最高輻射強度批次。如〔合成方法〕，建議每個合成方式三個最高或信息，當局已出版行業(yè)指南“FDA對PET產(chǎn)品的監(jiān)管：問答”。Q3(i):Q3(i):CananANDAbesubmittedwith6monthsofacceleratedstabilityand6monthsoflong-termstabilitydata?ANDA提交時可否只包括6個月的加速試驗和6個月長期穩(wěn)定性試驗數(shù)據(jù)？A3(i):Yes.StabilitydataexpectationatthetimeofANDAsubmissionis6monthsofacceleratedand6monthsoflong-termdata.However,if6monthsaccelerateddatashowsignificantchange[2]orfailureofanyattribute,6monthsofintermediatedataarealsorecommendedatthetimeofsubmission.6666個月的中間條件數(shù)據(jù)。Q3(ii):Q3(ii):Whendointermediatestabilitystudiesneedtobeinitiatedintheeventoffailureatacceleratedcondition?假設(shè)加速條件失敗，什么時候開頭中間條件穩(wěn)定性試驗？A3(ii):Werecommendstartingintermediatestability,accelerated,andlong-termstudiesatthesametimesothedataareavailableatthetimeofsubmission,ifneeded.時就能獲得全部需要的數(shù)據(jù)。Q3(iii):Ifoneamongthethreebatchesinacceleratedconditionsshowasignificantchange,whatshouldbedone?假設(shè)三批加速試驗中有一批表現(xiàn)出顯著性變更，應(yīng)當怎么辦？A3(iii):Intheeventaccelerateddatashowsignificantchangeorfailureofanyattributeinoneormorebatches,intermediatedataisrecommendedforallthreebatches.3批的中間條件的數(shù)據(jù)。Q4:Canstabilitybracketingand/ormatrixingbeusedtodeterminetheconfigurationstobeplacedonstabilityforanoriginalANDAwithoutpriorapprovalfromtheOfficeofGenericDrugs(OGD)?假設(shè)沒有獲得官方通用藥〔假設(shè)沒有獲得官方通用藥〔OGD〕預批準，穩(wěn)定性試驗是否可以承受分類試驗和/或正交試驗來選擇ANDA初始提交中的參數(shù)？A4:Yes.YoushouldfollowtheInternationalConferenceonHarmonisation(ICH)guidanceforindustryonQ1DBracketingandMatrixingDesignsforStabilityTestingofNewDrugSubstancesandProductsanditsexampletables.可以。你可以依據(jù)ICH行業(yè)指南Q1D“原料藥和制劑穩(wěn)定性試驗分類和”及其樣表的要求進展設(shè)計。Q5(i):IfanapplicationthatqualifiesfortheGenericDrugUserFeeAct(GDUFA)10-monthreviewisfiledwith6monthsofacceleratedand6monthsoflong-termdata,andtherearenoblockingpatentsorexclusivities,will24monthsofexpirationdatingbegranted?6個月的加速和長期穩(wěn)定性試驗數(shù)據(jù)，并且沒有相關(guān)專利阻礙，也沒有行24個月的有效期嗎？Q5(ii):Duringthereviewcycle,willtheapplicationneedtobeupdatedwith12monthsoflong-termdata?在審計過程中，是否需要提交12個月長期穩(wěn)定性更數(shù)據(jù)？A5(i,ii):FDAwillgrantaproposedexpiryperiodoftwotimestheavailablelong-termdataatthetimeofapproval(upto24months)followingtheICHQ1EEvaluationofStabilityData(ICHQ1E)guidance,providedthesubmitteddataaresatisfactory,anddataevaluationisprovidedinaccordancewithICHQ1E.Pleaserefertothedecisiontree(AppendixA)inICHQ1E.TheANDAshouldbeupdatedwith12monthsoflong-termdata.FDAICHQ1E評價要求，假設(shè)提交的數(shù)據(jù)符合要ICHQ1E的要求，有效期長度為批準時長期穩(wěn)定性〔24個月ICHQ1E〔ANDA12個月的長期穩(wěn)定性試驗數(shù)據(jù)。Q6:CanonlytwolotsoffinishedproductatpilotscalebatchsizeeverbesufficienttosupportthestabilityofanANDAforsimpledosageforms?ANDA單劑型穩(wěn)定性試驗要求？A6:No.Youshouldfollowtherecommendationsinthestabilityguidancewherethreepilotscalebatchesortwopilotscalebatchesandonesmallscalebatcharerecommended.Thisappliestoalldosageforms.32批中試批量加一批中試放大批量。該要求適用于全部劑型。Q7:Howistheproposedexpirationdatesupposedtobecalculated?Will6monthsofaccelerateddataequal24monthsatlong-term?應(yīng)如何計算建議效期？624個月的長期試驗嗎？A7:ICHQ1Eprincipleswillhelpinthecalculationofexpirationdating.DatafromthethreeANDAsubmissionbatches(i.e.,6months),accelerateddatameetingallcriteria(withoutsignificantchangeperICHQ1A(R2)),and12monthslong-termdatawithoutvariabilitywillnotneedstatisticalevaluation.StabilitydatafromthreeANDAsubmissionbatchesat12monthslong-termarerecommendedfor24-monthextrapolation.ICHQ1E原則可以幫助計算有效期。三批ANDA申報批次〔6個月〕穩(wěn)定性數(shù)據(jù)，加速數(shù)據(jù)符合全部標準〔ICHQ1A(R2)無顯著變更〕，12ANDA申報批次1224個月有效期。Ifthereisasignificantchangeintheaccelerateddata,ICHQ1E,AppendixA,providesmoredetailregardingwhenintermediateconditionstabilitydataarerecommended.假設(shè)加速數(shù)據(jù)有顯著性變更，ICHQ1EA，供給了建議什么時候承受中間條件數(shù)據(jù)的具體說明。Q8:For6monthsaccelerateddata,will24weeksbethetimeframerequiredbecause12weeksisacceptedasequivalentto3months?6123個月，所以需要24周的時間框架？A8:No.TheICHstabilityguidanceshaveindicatedtimerecommendationonlyintermsofmonths.不需要。ICH穩(wěn)定性指南已經(jīng)指出時間推舉僅用月計。Q9:WhenapatentisduetoshortlyexpireandtherearenoapprovedANDAs,canwefilewith3monthsstabilitydatawithacommitmenttosupply6monthsdatawhenavailable?ANDA3個月穩(wěn)定性試驗數(shù)據(jù)，并承諾在獲得6個月數(shù)據(jù)時即進展補充？A9:No.ICHstabilityguidancesshouldbefollowedregardlessofpatentstatus;6monthsofaccelerateddataarerecommendedatthetimeoffilingtheANDA.ICHANDA時，6個月加速穩(wěn)定性數(shù)據(jù)。Q10:Howlongdothethreepilotscalebatches,submittedasapartofanANDA,needtobestoredbeforedestruction?假設(shè)ANDA申報批次是三批中試放大批，是否需要存貯直至銷毀？A10:Samplestoragetimesarediscussedin21CFR320.38and21CFR320.63forbioequivalence-study-sampleswhenthepilotscalebatchisusedinthebioequivalencestudyorstudies.Inaddition,theguidanceforindustryonHandlingandRetentionofBAandBETestingSamplsaybehelpful.Ingeneral,ANDAsubmissionbatchsamplesshouldbestoredfor1yearafterapprovaloftheANDA,andsamplesofthedrugproductusedforbioequivalencestudiesshouldbestoredfollowingrequirementslistedintheCFRcitationsandrecommendationsintheguidancelistedabove.21CFR320.3821CFR320.63對于承受中試批準進展生物等效性爭論“BABE試驗樣品的處理和保存”ANDA申報批次樣品ANDA1CFR中列出的要求以及上述指南中的推舉。ThisguidancehasbeenpreparedbytheOfficeofGenericDrugs,OfficeofPharmaceuticalScienceintheCenterforDrugEvaluationandResearch(CDER)attheFoodandDrugAdministration.Weupdateguidancesperiodically.Tomakesureyouhavethemostrecentversionofaguidance,checktheFDADrugsguidanceWebat“:///Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.ht“:///Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.我們會周期更指南。為保證你所獲得的是最版本，請核對FDA官網(wǎng)。SeetheInternationalConferenceonHarmonisation(ICH)guidancetoindustryonQ1A(R2)StabilityTestingofNewDrugSubstancesandProducts,section.參見ICH行業(yè)指南Q1A(R2)原料藥和制劑穩(wěn)定性試驗指南，第局部。DefinedinICHQ1A(R2)Glossary.Ibid.Fornasalaerosols(meter-doseinhalers)andnasalsprays(meter-dosespraypumps),youshouldsubmitthreedifferentlotsofdrugsubstance.SeetheguidanceforindustryonResidualDruginTransdermalandRelatedDrugDeliverySystems.SeetheCDERDataStandardsManual,“:///Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirem“:///Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirements/ElectronicSubmissions/DataStandardsManualmonographs/default.htm.Thisrecommendationalsoappliestonasalspray,inhalationsolution,suspension,aerosols,andliposomaldrugproducts.DrugMasterFile藥物主文件Q1:PleaseclarifytheeffectofthestabilityguidanceonDrugMasterFile(DMF)holders.DMF持有人的影響Q1(i):Arestabilitydatafromthreecurrentgoodmanufacturingpractice(CGMP)batchesrequiredtobefiledintheDMFtosupporttheAPIretestdate?DMF里的三批穩(wěn)定性數(shù)據(jù)是否需要在GMP狀態(tài)下生產(chǎn)？A1(i):ICHQ1A(R2)recommendsthreeprimarybatches[1](atleastofthepilotscale[2]size)forthedrugsubstancefiledintheDMF.ThesebatchesshouldbemadeunderCurrentGoodManufacturingPractices(CGMP).Thestabilityguidancerecommendsaminimumof6monthsofacceleratedand6monthsoflong-termdataforthepilotscalebatchestobesubmittedinitially.Additionallong-termdataforallthreebatches,asthedatabecomesavailablethroughtheproposedretestperiod,shouldbesubmittedasanamendment.ICHQ1A(R2)〔至少為中試批量DMF申報。這些批次應(yīng)在CGMP的條件下生產(chǎn)。穩(wěn)定性試驗指南推舉在初始申報中包括663批長期增補中提交。Q1(ii):Howmanymonthsoflong-termandaccelerateddataarerequiredwhena“CompletenessAssessment”isperformedontheDMF?Also,whatshouldtheDMFstabilitysectioncontainforthesame?DMF進展“完整性評估”時，需要多少個月的長期和加速穩(wěn)定性試驗數(shù)據(jù)？DMF穩(wěn)定性局部應(yīng)包括哪些內(nèi)容？A1(ii):TopasstheCompletenessAssessment(seethedraftguidanceforindustryonInitialCompletenessAssessmentsforTypeIIAPIDMFsunderGDU)F,ADMFsshouldhavethestabilityprotocol,commitments,anddatademonstratingthatstabilitystudieshavestarted.Theinitialandoneadditionaltimepointfortheacceleratedstudiesandlong-termstudiesaresufficient.TheDMFholdershouldamendtheDMFwithupdatedstabilitydatatoprepareforthefullscientificreview,iftheDMFdoesnotmeettherecommendationsrecommendationsunderA1(i)aboveatthetimeoftheCompletenessAssessment.要通過完整性評估〔見行業(yè)指南草案：對二類原料藥DMF依據(jù)GDUFA法案進行的初始完整性評估〕，DMF應(yīng)包括穩(wěn)定性試驗方案、承諾、數(shù)據(jù)證明穩(wěn)夠了。假設(shè)DMF在完整性評估時不符合A1(i)中的要求，DMF持有人應(yīng)提交更的穩(wěn)定性數(shù)據(jù)作為補充，為全面的科學性批閱作好預備。Q2:Q2:WillsubmissionstoDMFsbeacceptedbasedonstabilitydatafromproductionscalebatches?DMF申報能被承受嗎？A2:Yes.PerICHQ1A(R2),sectionII,A,8,StabilityCommitment(2.1.8),thesubmissionisappropriateifsatisfactorystabilitydatafromthreeproductionbatchesmadeunderCGMParefiledintheDMFwith6monthsofaccelerateddataandlong-termdatacoveringtheproposedretestperiod.ICHQ1A(R2)II局部，A，8，穩(wěn)定性承諾〔2.1.8〕，申報文件中假設(shè)是在GMP條件下三個大生產(chǎn)批次，具有6個月加速和長期穩(wěn)定性試驗數(shù)據(jù)，掩蓋建議的復驗期，是可以承受的。DefinedinICHQ1A(R2)Glossary.Ibid.DrugProductManufacturingandPackaging藥品生產(chǎn)和包裝Q1:Canthesplitbulksolutionfilledintodifferentfillvolumesbeconsidereddifferentbatches?將散裝溶液裝入不同分裝體積應(yīng)作為不同批號嗎？A1:No.Splitfillingonebatchofbulksolutionintodifferentfillvolumesizesdoesnotconstitutediscretebatches.不。分裝一個批號散裝溶液至不同分裝體積不構(gòu)成分批。Q2:Canyouclarifythepackagingrecommendationsforthesubmissionbatchesforblow-fill-sealcontainers?可否說明一下對吹瓶/灌裝/封口的包裝形式申報批有什么包裝方面的建議？A2:Blow-fill-sealcontainersarenotanexceptionfromregularpackagingandareusuallypackagedinsideasecondarycontaineroracarton.Thesecondarypackagingshouldbeincludedinallthreebatches.ICHQ1A(R2)addressessecondarypackagingusefulness(seesectionII,B,4,DrugProductContainerClosureSystem(2.2.4)).吹瓶/灌裝/三個批次均應(yīng)進展外包裝。ICHQ1A(R2)里說明白外包裝是有用的?！矃⒁奍I局部，B，4，藥品包裝〔2.2.4〕〕Q3:Shouldallthreebatchesbestoredinfinalproposedpackaging?全部三個批次均應(yīng)以完整的包裝形式存貯嗎？A3:Yes.Youshouldpackageallthreebatchesinthecontainerclosuresystemproposedformarketing.Q1A(R2)addressesthisquestion(seesectionII,B,4,DrugProductContainerClosureSystem(2.2.4)).Q1A(R2)中說明白該問題〔II局部，B，4，藥品包裝〔2.2.4〕〕。Q4:WhatistheAgency’spositiononusingdifferentlotsofAPIsand/orpackagingmaterials?HowmanyAPIlotsshouldbeusedinthemanufactureoffinishedproductlotsusedtosupporttheANDA?法規(guī)當局對于承受不同批次原料藥和/或包裝材料是什么態(tài)度？在藥品生產(chǎn)中可ANDA？A4:Aminimumoftwolotsofthedrugsubstance[1]shouldbeusedtopreparethethreeprimarybatchesofdrugproduct.Itisnotnecessarytousedifferentlotsofpackagingmaterial,exceptincaseswherethepackagingmaterialcouldaffectdrugproductperformanceand/ordelivery.23同批次的包裝材料，除非包裝材料可能會對藥品的性能和/或運輸產(chǎn)生影響。Q5:Shouldthesmallscalebatchesbepackagedwithcommercialequipment,orisitacceptabletopackageusingresearchequipmentorbyhand?包裝？A5:Smallscalebatchesshouldbepackagedwithcommercialequipment.Packagingsystemsusedshouldbethesameasorsimilartopackagingproposedforstorageandmarketdistribution.PleaserefertoICHQ1A(R2)sectionII,B,3,SelectionofBatches(2.2.3)andtheglossarydefinitionforprimarybatches.ICHQ1A(R2)II局部，B，3批次的選擇〔2.2.3〕和內(nèi)包裝的術(shù)語定義。Q6:Whatwilltherecommendationforsecondarypackagingbe?對外包裝有什么建議？A6:WerecommendfollowingICHQ1A(R2)sectionII,B,4,DrugProductContainerClosureSystem(2.2.4).ICHII的要求。Q7:WhatQ7:Whataretherecommendationsforstabilitytestingofmodifiedreleaseproducts?對于緩釋產(chǎn)品的穩(wěn)定性試驗有什么建議？A7:FDArecommendsfollowingtheguidancefordataonthreebatchesperICHQ1A(R2).ICHstabilityguidancesdonotdistinguishamongdifferentdosageforms.FDAICHQ1A(R2)ICH穩(wěn)定性指南并未對不同劑型進展區(qū)分。Q8:Whataretherecommendationsforthesubmissionoforalsolutions,ophthalmicsolutions,oralandophthalmicsuspensions,transdermalpatches,ointments,creams,granulesforreconstitution,andparenterals?對于口服溶液、眼藥水、口服和眼用懸混劑、透皮貼劑、軟膏劑、擦劑、重塑顆粒劑和注射劑申報有什么建議？A8:OurrecommendationsfollowICHQ1A(R2),andwerecommendthreediscretebatchesand6monthsofacceleratedandlong-termdataatthetimeofsubmissionforalldosageforms.Also,refertootherquestionsandcorrespondinganswersthatspecificallydiscussotherdosageformsincludedinthisdocument.我們的建議是遵守ICHQ1A(R2)的其它問題和相關(guān)答復。Q9:Are6monthsofstabilitydatarequiredonallthreebatches,orwouldonebatchat6monthsandtwolotsat3monthsbeacceptable?6623個月數(shù)據(jù)呢？A9:FollowingICHstabilityguidances,6months(accelerated)stabilityisrecommendedonallthreesubmissionbatches.ICH6個月〔加速〕穩(wěn)定性試驗數(shù)據(jù)。Q10:ShouldtheexecutedbatchrecordsforthethreebatchesbeincludedintheANDAsubmission?三批生產(chǎn)填寫的批記錄是否需要包括在ANDA申報中？A10:Yes.是的Q11:DoesallrelevantCMCbatchinformationforthethreestabilitybatchesneedtobeincludedintheapplication(i.e.,excipientCertificateofAnalysis(COA))?是否全部與三個穩(wěn)定性試驗批次的相關(guān)CMC批次信息都需要包括在申報資料中〔即輔料檢驗報告〕？A11:Yes.WhenmorethanonelotofAPIorexcipientsisused,thecorrespondingsectioninModule3shouldcontainthatinformation.3信息。Q12:IfyouareanapplicantsubmittinganANDAwithtwoAPIsources,areyourequiredtoperformstabilityonthreebatchesofdrugproductforeachAPIsource?ANDA有兩個原料藥來源，是否需要對每個原料藥來源制成3批進展穩(wěn)定性試驗呢？A12:A12:IfyouproposetoaddasecondormorethantwosourcesofAPIforthesamedrugsubstance,werecommendyouprovidethefollowingCMCinformation:CMC信息Comparisonandjustificationofcomparability(bythefirm)ofthephysico-chemicalpropertiesandimpuritiesofthedrugsubstancefromeachsource.全部不同來源原料藥的理化特性和雜質(zhì)比較和判定AppropriatestabilitydataonthreebatchesofdrugproductqualifyingthefirstAPIsourceusedinthebioequivalence(BE)studiesasrecommendedbythestabilityguidance.在穩(wěn)定性試驗指南中，建議用于生物等效性〔BE〕爭論的第一個原料藥所生產(chǎn)3批藥品應(yīng)有適當?shù)姆€(wěn)定性數(shù)據(jù)。Asinglepilotscalebatchofthedrugproductbio-strength(s)manufacturedusingthesecondoreachoftheotherproposedAPIsource(s)usedtosupporttheANDAapplication,alongwithcomparativedissolutiondata.ANDA申報，以及比較性溶出度數(shù)據(jù)。Appropriatestabilitydata(acceleratedandlong-termfor6monthsatthetimeoffiling)onthestrength(s)manufacturedforeachAPIsource.Appropriatestabilitydatamayinsomecasesincludeintermediateconditionstabilitydata.每個原料藥來源生產(chǎn)的不同劑量下適當?shù)姆€(wěn)定性數(shù)據(jù)〔6個月數(shù)據(jù)Q13:Whatismeantby“small”scale?“Small”isnotadefinedwordinICHguidance.Whatarethepackagingexpectationsfromthesmallbatch,aswellasfromthetwopilotscalebatches?Traditionally,ANDAsaresubmittedwith100,000unitsforsolidoraldosageforms.Isthisstillapplicable?“小”ICH指南中“小”是沒有定義的。小批量的包裝期望是怎么樣的，是要求與兩個中試批準一樣嗎？傳統(tǒng)意義上，ANDA固體口服制劑100，000個最小單位包裝，現(xiàn)在還適用嗎？A13:TheinterpretationofwhatconstitutesasmallscalebatchforthepurposeoffilingANDAsisfurtherelaboratedbelowforvariousdosageformsandtheirpackagingrecommendations.Unlessspecificallynotedbelow,oneprimarybatchshouldbefullypackaged.ANDA時所要求的小批量是什么，在下面對不同劑型及其包裝狀況進展了說明。假設(shè)以下未另加說明，則一個根本批的數(shù)據(jù)應(yīng)全部進展包裝。Oraldosageforms口服制劑Tablets/Capsules(e.g.,immediaterelease,extendedrelease,chewable,orallydisintegratinganddelayedreleasetabletsorcapsules):片劑、膠囊〔例如中間釋放、緩釋、咀嚼、口腔崩解、延時釋放片劑或膠囊〕Twoofthethreebatchesshouldbeofatleast10percentoftheproposedproductionbatchor100,000finisheddosageunits,whicheverisgreater(i.e.,pilotscalebatches).Thethirdbatchcanbesmallerthanthe10percentoftheproposedproductionbatch,butnotlessthan25percentofthepilotscalebatch.WerecommendstabilitydatabegeneratedforthethreeANDAsubmissionbatchesintheproposedmarketingcontainer.Aminimumof100,000unitsinallproposedpresentationsisrecommended.Representativesamplesfromallthreebatchesmustbepackagedinasufficientnumberofproposedmarketingpresentationstocomplywith21CFR211.166(a)(1-5)and211.166(b).10%100,000最小制劑單位，取其中較大者〔即中試批次〕。第三批可以比目標批量的10%小，但不能低于25%ANDA申報批100,000個最小制劑單位。三批申報批中211.166〔b〕的要求。Powders/Solutions/Suspensions:粉劑/溶液/混懸劑

1-5〕Twoofthethreebatchesshouldbeatleast10percentoftheproposedmaximumsizecommercialbatch.Thethirdbatchcanbesmallerthan10percentoftheproposedcommercialbatch,butnotlessthan25percentofthepilotscalebatch.Tocapturevariabilityintroducedbypackaging,theproductfromallthebatchesshouldbeusedinthepackagingprocess.Werecommendpackagingrepresentativesamplesfromallthreebatchesofasufficientnumberofproposedmarketingpresentationstocomplywith21CFR211.166(a)(1-5)and211.166(b).3210%3批可以小于提出的商業(yè)批量10%25%批量。為了覺察包裝引起的差異，全部21CFR211.166(a)(1-5)和211.166(b)3批中均按申請的上市包裝對足夠數(shù)據(jù)樣品進展包裝獲得代表性樣品。ParenteralsSolutions/PowdersforSolutions(lyophilizedcakes)/Suspensions/SterileTopicals(OphthalmicandOticdrugproducts):注射液/溶液用粉劑〔凍干粉〕/混懸劑/無菌局部〔眼用和耳用劑〕Twoofthethreebatchesshouldbeatleast10percentoftheproposedmaximumsizecommercialbatch(i.e.,pilotscalesize)or50L(perbatch),whicheverislarger.Thethirdbatchcanbesmallerthan10percentoftheproposedcommercialbatch,butnotlessthan25percentofthepilotscalebatch.Tocapturevariabilityintroducedbypackaging,theproductfromallthebatchesshouldbeusedinthepackagingprocess.Representativesamplesfromallthethreebatchesshouldbepackagedinasufficientnumberofproposedmarketingpresentationstocomplywith21CFR211.166(a)(1-5)and211.166(b).Werecommendmanufacturingallthebatchestomeetsterilityrequirements.3210%〔即中試批量50L〔每批3102521CFR211.166(a)(1-5)211.166(b)3批中均按準生產(chǎn)均滿足無菌要求。TransdermalPatches經(jīng)皮給藥貼劑Twoofthethreebatchsizesforeachstrengthshouldbeatleast10percentoftheproposedcommercialproductionbatchor25,000units(foreachstrength),whicheverisgreater.Thethirdbatchcanbesmallerthan10percentoftheproposedcommercialbatch,butnotlessthan60percentofthepilotscalebatch.Fortransdermalmatrixproducts,wheredifferentstrengthsareidentifiedbythetransdermalpatchsize(surfacearea),tocomplywiththethreebatchsizerecommendation,werecommendprovidingdataonpatchesmanufacturedusingthreedistinctmatrixlaminatesatthetimeofsubmission.(Eachlaminatecanbecuttosupportmultiplestrengthsintheapplication,whereapplicable.)Werecommendyoucontacttheappropriatereviewdivisionifyouaremanufacturingtransdermalpatchesusingothertechnologies(e.g.,reservoir).[2]3210%23000個最小單位〔每個劑量〕，310%，60%尺寸〔外表積〕差異一樣，符合3個批量的推舉，我們建議在申報時供給承受3〔〕。假設(shè)你承受了其它技術(shù)〔例如膏藥〕來生產(chǎn)經(jīng)皮給藥貼劑，我們推舉你聯(lián)系適當?shù)膶徍瞬块T，Youshouldincludearepresentativesamplefromallthreebatchesusingdifferentcomponentsofbacking,adhesives,releaseliner,andothercriticalexcipientsusedinpackagingasufficientnumberofproposedmarketingpresentationstocomplywith21CFR211.166(a)(1-5)and211.166(b).3裝的關(guān)鍵輔料的代表性樣品，承受上市包裝獲得足夠數(shù)量的樣品，以滿足21CFR211.166(a)(1-5)211.166(b)的要求。Topicals局部用藥Creams/Lotions/Gels:膏劑/洗液/膠Fornonsterilesemi-soliddosageforms[3],thetwopilotscalebatchesshouldbeatleast100Kgor10percentoftheproductionbatch,whicheverislarger.Thethirdbatchcanbesmallerthan10percentoftheproposedcommercialbatch,butnotlessthan40percentofthepilotscalebatch.Werecommendpackagingrepresentativesamplesfromallthethreebatchesinasufficientnumberofproposedmarketingpresentationstocomplywith21CFR211.166(a)(1-5)and211.166(b).2100kg10%，310%40%。我們推舉全部321CFR211.166(a)(1-5)211.166(b)的要求。InhalationSolutions/NasalSprays(nasalnonmetereddoseatomizer):吸入溶液/鼻腔噴劑〔鼻腔非定量噴霧器〕Pleaserefertothefollowingguidancesforindustryforinformation:NasalSprayandInhalationSolution,Suspension,andSprayDrugProducts–Chemistry,Manufacturing,andControlsDocumentation,andBioavailabilityandBioequivalenceStudiesforNasalAerosolsandNasalSpraysforLocalAction.請參見以下行業(yè)指南：鼻腔噴霧劑和吸入溶液，混懸液，和噴霧藥品 化學，PleasecontactOGDtodiscussotherdosageformsand/orroutesofadministrationnotcoveredinthisdocument.如需爭論其它劑量形式和/或在本文件中未涵蓋的給藥方法，請聯(lián)系OGD。Q14:Isitacceptabletouseatechnicalgradeofthedrugsubstanceforthesmallscalebatchesoroneofthetwopilotscalebatchesoffinishedproduct?是否可以承受技術(shù)級的原料藥用于小批量或兩個中試批中的一批的藥品生產(chǎn)？A14:No.CGMPrequirementsforANDAsubmissionareexpectedforthedrugsubstanceanddrugproduct.Becausethedrugsubstancequalitycanaffectthedrugproductstability,thedrugsubstanceusedfortheANDAbatches(supportingtheapplication)shouldbeofthesamequalityintendedforthemarketproduct.Wewouldconsiderdatafromtheuseofadifferentgradedrugsubstanceforaproductassupportingdata.Thisdoesnotsatisfythesubmissionbatchrecommendations.不行以。ANDA申報要求原料藥和制劑均在CGMP狀態(tài)下生產(chǎn)。由于原料藥質(zhì)量可能會影響藥品穩(wěn)定性，用于ANDA〔支持申報應(yīng)具有上持性數(shù)據(jù)，但這并不符合申報批次的要求。Fornasalaerosols(meter-doseinhalers)andnasalsprays(meter-dosespraypumps),youshouldsubmitthreedifferentlotsofdrugsubstance.SeetheguidanceforindustryonResidualDruginTransdermalandRelatedDrugDeliverySystems.SeetheCDERDataStandardsManual,“:///Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirem“:///Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirements/ElectronicSubmissions/DataStandardsManualmonographs/default.htm.15:DothesmallscalebatchesneedtobemanufacturedinaccordancewithallCGMPregulations,orisitacceptabletomanufacturethesmallscalebatchesinaresearchsetting?小批是否需要依據(jù)全部CGMP法規(guī)要求進展生產(chǎn)，還是可以在小規(guī)模的研發(fā)設(shè)施中進展？A15:AllANDAsubmissionbatchesshouldbemadeunderCGMP.AND