SUPAC-IR指导原则：速释口服固体制剂：放大生产和批准后变更

GuidanceforIndustryImmediateReleaseSolidOralDosageFormsScale-UpandPostapprovalChanges:Chemistry,Manufacturing,andControls,InVitroDissolutionTesting,andInVivoBioequivalenceDocumentationSUPAC-IR指导原则：速释口服固体制剂放大生产和批准后变更：化学、生产和控制，体外溶出试验、体内生物等效性文件CenterforDrugEvaluationandResearch(CDER)November1995CMC5药品 评价 LEC评价法下载LEC评价法下载评价量规免费下载学院评价表文档下载学院评价表文档下载 与研究中心1995年11月CMC5TABLEOFCONTENTS目录I.PURPOSEOFGUIDANCE（本指导原则的目的）......................................1II.DEFINITIONOFTERMS（术语定义）...............................................3III.COMPONENTSANDCOMPOSITION（辅料成分或组成的变更）..........................6IV.SITECHANGES（地点变更）......................................................13V.CHANGESINBATCHSIZE(SCALE-UP/SCALE-DOWN)（批量大小（放大/缩小）的变更）......16VI.MANUFACTURING（生产变更）...................................................18VII.INVITRODISSOLUTION（体外溶出试验）..........................................23VIII.INVIVOBIOEQUIVALENCESTUDIES（体内生物等效性）.............................23IX.REFERENCES（参考文献）......................................................25APPENDIXA:NARROWTHERAPEUTICRANGEDRUGS（附录A：治疗窗狭窄药物）.........A-1GUIDANCEFORINDUSTRY1IMMEDIATERELEASESOLIDORALDOSAGEFORMSSCALE-UPANDPOSTAPPROVALCHANGES:CHEMISTRY,MANUFACTURING,ANDCONTROLS,INVITRODISSOLUTIONTESTING,ANDINVIVOBIOEQUIVALENCEDOCUMENTATION速释口服固体制剂放大生产和批准后变更：化学、生产和控制，体外溶出试验、体内生物等效性文件I.PURPOSEOFGUIDANCE（本指导原则的目的）Thisguidanceprovidesrecommendationstosponsorsofnewdrugapplications(NDA's),abbreviatednewdrugapplications(ANDA's),andabbreviatedantibioticapplications(AADA's)whointend,duringthepostapprovalperiod,tochange:1)thecomponentsorcomposition;2)thesiteofmanufacture;3)thescale-up/scale-downofmanufacture;and/or4)themanufacturing(processandequipment)ofanimmediatereleaseoralformulation.本指导原则所提供的的建议适用于新药申请（NDA's）、仿制药申请（ANDA's）和抗生素仿制药申请（AANA’S）的企业的批准后变更，内容包括：1）成分或组分的变更；2）生产地点的变更；3）放大/缩小生产规模的变更；和/或4）生产过程（工艺和设备）的变更Thisguidanceistheresultof:1)aworkshoponthescale-upofimmediatereleasedrugproductsconductedbytheAmericanAssociationofPharmaceuticalScientistsinconjunctionwiththeUnitedStatesPharmacopoeialConventionandtheFoodandDrugAdministration(FDA);2)researchconductedbytheUniversityofMarylandatBaltimoreonthechemistry,manufacturingandcontrolsofimmediatereleasedrugproductsundertheFDA/UniversityofMarylandManufacturingResearchContract;3)thedrugcategorizationresearchconductedattheUniversityofMichiganandtheUniversityofUppsalaonthepermeabilityofdrugsubstances;and4)theScale-UpandPostApprovalChanges(SUPAC)TaskForcewhichwasestablishedbytheCenterforDrugEvaluationandResearch(CDER)Chemistry,ManufacturingandControlsCoordinatingCommitteetodevelopguidanceonscale-upandotherpostapprovalchanges.本指导原则是以下工作的成果：1）在美国药学科学家协会与美国药典委员会和FDA的指导下，进行速释药品放大生产的车间；2）在位于巴尔的摩的马里兰大学指导下，并在FDA/马里兰大学生产研究合同下的速释药品的化学、生产和控制的研究；3）在密歇根大学和乌普萨拉大学指导下的药品分类学研究中关于药物渗透性的研究；4）由药品评价和研究中心（CDER）化学、生产和控制协调委员会成立的放大生产和批准后变更（SUPAC）特别小组，来制定关于放大生产和其它的批准后变更的指导原则。Theguidancedefines:1)levelsofchange;2)recommendedchemistry,manufacturing,andcontrolstestsforeachlevelofchange;3)invitrodissolutiontestsand/orinvivobioequivalencetestsforeachlevelofchange;and4)documentationthatshouldsupportthechange.Forthosechangesfiledina“changesbeingeffectedsupplement”[21CFR314.70(c)],theFDAmay,afterareviewofthesupplementalinformation,decidethatthechangesarenotapprovable.ThisguidancethussetsforthapplicationinformationthatshouldbeprovidedtoCDERtoassurecontinuingproductqualityandperformancecharacteristicsofanimmediatereleasesolidoraldoseformulationforspecifiedpostapprovalchanges.Thisguidancedoesnotcommentonorotherwiseaffectcompliance/inspectiondocumentationthathasbeendefinedbyCDER’sOfficeofComplianceorFDA’sOfficeofRegulatoryAffairs.Thisguidancedoesnotaffectanypostapprovalchangesotherthantheonesspecified.Forchangesnotaddressedinthisguidance,orformultiplechangessubmittedatonetimeoroverashortperiodoftime,orwherethenumberofbatchesneededforstabilitytestingisnotspecified,sponsorsshouldcontacttheappropriateCDERreviewdivisionorconsultotherCDERguidances/guidelinestoobtaininformationabouttestsandapplicationdocumentation.本指导原则规定了以下内容：1）变更的类别；2）针对每一类变更建议进行的药物化学、药品生产以及生产和质量控制（CMC）研究内容；3）针对每一类变更建议进行的体外溶出试验和/或体内生物等效性试验；和4）变更用的支持性文件资料。对于那些在“起补充作用的变更”文件，FDA在对补充资料进行审查后，可以决定是否允许这些变更。本指导原则给出了需递交给药品评价和研究中心（CDER）的申请信息，以确保速释口服固体制剂在发生规定的变更后继续保持其质量和性能特点。本指导原则不评论也不更改由CDER法律管理办公室或FDA法规事务办公室颁布的法规/检查文件。本指导原则不涉及除了本文提到的变更情形外的其他情形的批准后变更。对于那些本指导原则未涉及的变更，以及同时或短时间内申请多个变更，或需进行稳定性实验的批次数量未规定的，申请人应与CDER相关审评部门沟通，或者参考CDER其他的指导原则/指南以获得有关研究和申报资料的信息。21CFR314.70(a)providesthatapplicantsmaymakechangestoanapprovedapplicationinaccordancewithaguideline,notice,orregulationpublishedintheFEDERALREGISTERthatprovidesforalessburdensomenotificationofthechange(forexample,bynotificationatthetimeasupplementissubmittedorinthenextannualreport).Thisguidancepermitslessburdensomenoticeofcertainpostapprovalchangeswithinthemeaningof§314.70(a).FDA的法规（21CFR314.70(a)）规定申请人可以根据发 表 关于同志近三年现实表现材料材料类招标技术评分表图表与交易pdf视力表打印pdf用图表说话 pdf 在联邦登记（FederalRegister）上的指导原则、通知或条例的规定，对所批准的申请内容实施变更，如此可以减轻繁重的变更通告量（举例而言，可以在递交补充申请时或在下一年年报中予以通告）。对于符合§314.70(a)的某些批准后变更，本指导原则允许减少通告量。Forpostapprovalchangesforimmediatereleasedosageformsthataffectcomponentsandcomposition,scale-up,sitechange,andmanufacturingprocessorequipmentchanges,thisguidancesupersedestherecommendationsinsection4.GoftheOfficeofGenericDrugsPolicyandProcedureGuide22-90(September11,1990).Forallotherdosageformsandchanges,thisguidancedoesnotaffecttherecommendationsinGuide22-90.当速释制剂的批准后变更涉及成份和组成、生产规模放大、生产地点变化和生产工艺或设备改变时，本指导原则将代替仿制药办公室（OGD）制定的PolicyandProcedureGuide22-90（September11,1990）章节4.G中提供的建议。但对于所有其他的剂型和变更，本指导原则不适用，仍应遵循Guide22-90中的建议。II.DEFINITIONOFTERMS术语的定义A.Batch批Aspecificquantityofadrugorothermaterialproducedaccordingtoasinglemanufacturingorderduringthesamecycleofmanufactureandintendedtohaveuniformcharacterandquality,withinspecifiedlimits[21CFR210.3(b)(2)].在同一个生产周期中，按照相同的生产规程制备的特定数量的药品或其它物料，并意图使其性质和质量在规定的限度内具有一致性。B.ContiguousCampus毗邻区域Continuousorunbrokensiteorasetofbuildingsinadjacentcityblocks.连续的或未被隔断的地区，或者在毗邻街区内的一组建筑物。C.DissolutionTesting溶出试验CaseA:DissolutionofQ=85%in15minutesin900milliliters(mL)of0.1Nhydrochloride(HCl),usingtheUnitedStatesPharmacopeia(USP)<711>Apparatus1at100revolutionsperminute(rpm)orApparatus2at50rpm.情况A：采用美国药典（USP）<711>装置1，转速为100rpm（转/分），或采用装置2，转速为50rpm，溶出介质为900mL0.1N的HCl，药品15min内溶出限度达到85%。CaseB:Multi-pointdissolutionprofileintheapplication/compendialmediumat15,30,45,60,and120minutesoruntilanasymptoteisreachedfortheproposedandcurrentlyacceptedformulation.情况B：对变更后的产品和现行产品绘制多点溶出曲线，采用申报资料/药典的规定的溶出介质，取样点为15，30，45，60和120min或至达到稳态。CaseC:Multi-pointdissolutionprofilesperformedinwater,0.1NHCl,andUSPbuffermediaatpH4.5,6.5,and7.5(fiveseparateprofiles)fortheproposedandcurrentlyacceptedformulations.Adequatesamplingshouldbeperformedat15,30,45,60,and120minutesuntileither90%ofdrugfromthedrugproductisdissolvedoranasymptoteisreached.Asurfactantmaybeusedwithappropriatejustification.情况C：对变更后的产品和现行产品绘制多点溶出曲线，应选取水、0.1N的HCl，以及美国药典规定的3种pH分别为4.5，6.5和7.5的缓冲介质为溶出介质（5条独立的溶出曲线）。应采用充足的样品进行溶出度试验，取样点应选择15，30，45，60和120分钟直至药物累计溶出度达到90%或至稳态。在有恰当理由的情况下可使用表面活性剂。D.DrugProduct药品Adrugproductisafinisheddosageform(e.g.,tablet,capsule,orsolution)thatcontainsadrugsubstance,generally,butnotnecessarily,inassociationwithoneormoreotheringredients[21CFR314.3(b)].Asolidoraldosageformincludestablets,chewabletablets,capsules,andsoftgelatincapsules.药品是指已完工的剂型（比如片剂、胶囊或溶液），含有药物，一般还含有（但非必需）与其相关的一种或几种其它配料[21CFR314.3(b)]。固体口服剂型包括片剂、咀嚼片、胶囊和软胶囊。E.DrugSubstance原料药Anactiveingredientthatisintendedtofurnishpharmacologicalactivityorotherdirecteffectinthediagnosis,cure,mitigation,treatment,orpreventionofadisease,ortoaffectthestructureofanyfunctionofthehumanbody,butdoesnotincludeintermediatesusedinthesynthesisofsuchingredient[21CFR314.3(b)].在疾病的诊断，治疗，症状缓解，处理或疾病的预防中发挥药理活性或其他直接作用，或者能影响人体的功能或结构的一种活性成分，不包括其制备过程中产生的中间体[21CFR314.3(b)]。F.Equipment设备Automatedornon-automated,mechanicalornon-mechanicalequipmentusedtoproducethedrugproduct,includingequipmentusedtopackagethedrugproduct.用于生产药物制剂的自动化或非自动化、机械式或非机械式的设备，包括包装设备。G.Formulation处方Alistingoftheingredientsandcompositionofthedosageform.制剂中的一系列的配料和组分。H.Justification合理性证明Reportscontainingscientificdataandexpertprofessionaljudgmenttosubstantiatedecisions.用以证明决策合理的报告，其内容由科学数据和专家的专业评判组成。I.NewDrugSubstance新原料药Anysubstancethat,whenusedinthemanufacture,processing,orpackingofadrug,causesthatdrugtobeanewdrug,butdoesnotincludeintermediatesusedinthesynthesisofsuchsubstance[21CFR310.3(g)].在药品生产、加工或包装过程中用到的使药品成为一种新药的物质。但不包括其合成中产生的中间体。J.OperatingPrinciple工作原理Rulesorconceptsgoverningtheoperationofthesystem.用于指导系统运行的规则或理念。K.PilotScale中试规模Themanufactureofeitherdrugsubstanceordrugproductbyaprocedurefullyrepresentativeofandsimulatingthatusedforfullmanufacturingscale.Forsolidoraldosageformsthisisgenerallytakentobe,ataminimum,one-tenththatoffullproduction,or100,000tabletsorcapsules,whicheverislarger(seetheFEDERALREGISTERofThursday,September22,1994,59FR48754-59).按照可完全代表和模拟全规模生产的过程生产的原料药或制剂。对于口服固体制剂，中试规模一般至少是生产规模的十分之一或者100，000片或胶囊，取其中值较大者（见联邦公报1994年9月22日）。L.Process工艺Aseriesofoperationsand/oractionsusedtoproduceadesiredresult.为产生期望的结果而进行的一系列的操作和/行动。M.Ranges范围Theextenttowhichorthelimitsbetweenwhichacceptablevariationexists.可接受的变化程度或范围N.Same相同Agreeinginkind,amount;unchangedincharacterorcondition.种类和数量上的一致性；性质或状态不变。O.Scale-up放大Theprocessofincreasingthebatchsize.批量放大的过程。P.Scale-down缩小Theprocessofdecreasingthebatchsize.批量缩小的过程。Q.Similar相似Havingagenerallikeness.具有总体上的相似性。R.Significantbodyofinformation大量信息Asignificantbodyofinformationonthestabilityofthedrugproductislikelytoexistafterfiveyearsofcommercialexperiencefornewmolecularentities,orthreeyearsofcommercialexperiencefornewdosageforms.对于新分子实体而言，制剂稳定性方面的大量信息可能会在上市后五年得到；对于新剂型而言，则可能为上市后三年。S.Validation验证Establishingthroughdocumentedevidenceahighdegreeofassurancethataspecificprocesswillconsistentlyproduceaproductthatmeetsitspredeterminedspecificationsandqualityattributes.Avalidatedmanufacturingprocessisonethathasbeenproventodowhatitpurportsorisrepresentedtodo.Theproofofvalidationisobtainedthroughcollectionandevaluationofdata,preferablybeginningfromtheprocessdevelopmentphaseandcontinuingthroughtheproductionphase.Validationnecessarilyincludesprocessqualification(thequalificationofmaterials,equipment,systems,buildings,andpersonnel),butitalsoincludesthecontroloftheentireprocessesforrepeatedbatchesorruns.通过文件证明的方式，高度确保某一具体生产工艺能始终如一地生产出符合预设 标准 excel标准偏差excel标准偏差函数exl标准差函数国标检验抽样标准表免费下载红头文件格式标准下载 和品质的产品。生产工艺经过验证指其生产的产品被证明与其所声称的一致。验证通过积累和评价数据来进行，这一过程最好从工艺开发就开始，并一直贯穿于实际生产。验证必然包括工艺确认（原材料确认、设备确认、系统确认、车间确认和人员确认），除此之外还应包括对整个工艺过程的控制以保证批次间具有重现性。III.COMPONENTSANDCOMPOSITION辅料的种类和组成的变更Thissectionoftheguidancefocusesonchangesinexcipientsinthedrugproduct.Changesintheamountofdrugsubstancearenotaddressedbythisguidance.ChangesincomponentsorcompositionthathavetheeffectofaddinganewexcipientordeletinganexcipientaredefinedatLevel3(definedbelow),exceptasdescribedbelow.本章重点讨论药品辅料的变更。而原料药含量的变更不在本指导原则的讨论范围。对于辅料种类和组成的变更，涉及增加或减少辅料种类的变更被归入下述的第3类变更，其他的类型如下所述。A.Level1Changes1类变更1.DefinitionofLevel定义Level1changesarethosethatareunlikelytohaveanydetectableimpactonformulationqualityandperformance.1类变更是指不会对制剂质量和性能产生可查知的影响的变更。Examples:例如：a.Deletionorpartialdeletionofaningredientintendedtoaffectthecolororflavorofthedrugproduct;orchangeintheingredientoftheprintinginktoanotherapprovedingredient.去除或部分去除会影响药品颜色或味道的成分；或者将印字油墨的成分改为另外一种已批准的成分。b.Changesinexcipients,expressedaspercentage(w/w)oftotalformulation,lessthanorequaltothefollowingpercentranges:辅料的变更，以其在处方中的百分比（w/w）表示，应小于或等于下表中的百分比范围：EXCIPIENT辅料PERCENTEXCIPIENT(w/w)OUTOFTOTALTARGETDOSAGEFORMWEIGHT辅料与整个片剂重量的百分比（w/w）Filler填充剂±5Disintegrant崩解剂Starch淀粉±3Other其他±1Binder粘合剂±0.5Lubricant润滑剂Calcium(Ca)orMagnesium(Mg)Stearate硬脂酸钙或硬脂酸镁±0.25Other其他±1Glidant助流剂Talc滑石粉±1Other其他±0.1FilmCoat薄膜衣±1Thesepercentagesarebasedontheassumptionthatthedrugsubstanceintheproductisformulatedto100%oflabel/potency.Thetotaladditiveeffectofallexcipientchangesshouldnotbemorethan5%.(Example:InaproductconsistingofactiveingredientA,lactose,microcrystallinecelluloseandmagnesiumstearate,thelactoseandmicrocrystallinecelluloseshouldnotvarybymorethananabsolutetotalof5%(e.g.lactoseincreases2.5%andmicrocrystallinecellulosedecreasesby2.5%)relativetothetargetdosageformweightifitistostaywithintheLevel1range).该百分比是假设产品中的原料药按标签/效价的100%投料，所有辅料的变更累计应不大于5%。（例如：一个产品的处方包括活性成分A、乳糖、微晶纤维素和硬脂酸镁，那么乳糖和微晶纤维素变更的绝对总量不应超过5%（例如乳糖增加2.5%同时微晶纤维素减少2.5%））Thecomponents(activeandexcipients)intheformulationshouldhavenumericaltargetswhichrepresentthenominalcompositionofthedrugproductonwhichanyfuturechangesinthecompositionoftheproductaretobebased.AllowablechangesinthecompositionshouldbebasedontheapprovedtargetcompositionandnotonpreviousLevel1changesinthecomposition.应明确处方中各组分（包括活性成分和辅料）的具体比例（目标比例），该目标比例代表药品的公称成分，后续的任何产品成分的变更都是基于该目标比例。在评价药品成分变更能否被接受时，应以最初批准时的目标比例作为比较对象，而不是以前述的发生过1类变更后的处方比例作为比较对象。2.TestDocumentation试验资料a.ChemistryDocumentation化学资料Application/compendialreleaserequirementsandstabilitytesting.Stabilitytesting:onebatchonlong-termstabilitydatareportedinannualreport.申报资料/药典要求的资料和在年报中提供的稳定性试验资料。稳定性试验资料：在年报中提交一批长期稳定性数据b.DissolutionDocumentation溶出研究资料Nonebeyondapplication/compendialrequirements.申报资料/药典要求的资料，不需其他资料。c.InVivoBioequivalenceDocumentation体内生物等效性资料None.不需要3.FilingDocumentation归档文件Annualreport(allinformationincludinglong-termstabilitydata).年报（记录所有信息，包括长期稳定性数据）B.Level2Changes2类变更1.DefinitionofLevel定义2类变更是指对产品质量和性能可能产生显著影响的变更。Level2changesarethosethatcouldhaveasignificantimpactonformulationqualityandperformance.TestsandfilingdocumentationforaLevel2changevarydependingonthreefactors:therapeuticrange,solubility,andpermeability.Therapeuticrangeisdefinedaseithernarrowornon-narrow.AlistofnarrowtherapeuticrangedrugsisprovidedinAppendixA.Drugsolubilityanddrugpermeabilityaredefinedaseitherloworhigh.Solubilityiscalculatedbasedontheminimumconcentrationofdrug,milligram/milliliter(mg/mL),inthelargestdosagestrength,determinedinthephysiologicalpHrange(pH1to8)andtemperature(37+0.5oC).Highsolubilitydrugsarethosewithadose/solubilityvolumeoflessthanorequalto250mL.(Example:CompoundAhasasitslowestsolubilityat37+0.5C,1.0mg/mLatpH7,andisavailablein100mg,200mgand400mgstrengths.Thisdrugwouldbeconsideredalowsolubilitydrugasitsdose/solubilityvolumeisgreaterthan250mL(400mg/1.0mg/mL=400mL).Permeability(Pe,centimeterpersecond)isedefinedastheeffectivehumanjejunalwallpermeabilityofadrugandincludesanapparentresistancetomasstransporttotheintestinalmembrane.Highpermeabilitydrugsaregenerallythosewithanextentofabsorptiongreaterthan90%intheabsenceofdocumentedinstabilityinthegastrointestinaltract,orthosewhosepermeabilityattributeshavebeendeterminedexperimentally).2类变更的试验和归档文件的改变取决于3种因素：治疗范围，溶解性和渗透性。治疗范围被定义为治疗范围狭窄或非狭窄两类。治疗范围狭窄药物的列表见附录A。药物的溶解性和渗透性均被定义为低或高两类。溶解性是根据药物的最大应用剂量在生理pH范围（pH1-8）和生理温度（37+0.5℃）条件下，计算得出的药物的最低浓度（mg/mL）。高溶解性药物是指溶解单位剂量药物体积小于等于250ml的药物。（例如化合物A，在37+0.5C,pH7条件下的最低溶解度为1.0mg/mL，且其可应用的剂量为100mg，200mg和400mg。那么认为该药物为低溶解性药物，因为其剂量/溶解度的值大于250mL（400mg/1.0mg=400mL））。渗透性（P，度每秒）定义为药物对正常人空肠壁的渗透性，包括对物质转运到肠膜的表观阻力。高渗透性药物一般是指吸收度超过90%且无此药物在胃肠道不稳定的记录，或者渗透性已通过实验确定的药物）。Examples例如：a.Changeinthetechnicalgradeofanexcipient.(Example:AvicelPH102vs.AvicelPH200.)一种辅料技术等级的改变。（例如：AvicelPH102改为AvicelPH200.）b.Changesinexcipients,expressedaspercent(w/w)oftotalformulation,greaterthanthoselistedaboveforaLevel1changebutlessthanorequaltothefollowingpercentranges(whichrepresentatwofoldincreaseoverLevel1changes):辅料用量的改变，以处方总质量的百分比（w/w）计算，大于上述的1类变更，但小于或等于以下百分比范围（其代表超过1类变更2倍的增加）。EXCIPIENT辅料PERCENTEXCIPIENT(w/w)OUTOFTOTALTARGETDOSAGEFORMWEIGHT辅料与整个片剂重量的百分比（w/w）Filler填充剂±10Disintegrant崩解剂Starch淀粉±6Other其他±2Binder粘合剂±1Lubricant润滑剂Calcium(Ca)orMagnesium(Mg)Stearate硬脂酸钙或硬脂酸镁±0.5Other其他±2Glidant助流剂Talc滑石粉±2Other其他±0.2FilmCoat薄膜衣±2Thesepercentagesarebasedontheassumptionthatthedrugsubstanceinthedrugproductisformulatedto100%oflabel/potency.Thetotaladditiveeffectofallexcipientchangesshouldnotchangebymorethan10%该百分比是假设产品中的原料药按标签/效价的100%投料，所有辅料的变更累计应不大于10%。Thecomponents(activeandexcipients)intheformulationshouldhavenumericaltargetsthatrepresentthenominalcompositionoftheproductonwhichanyfuturechangesinthecompositionoftheproductaretobebased.AllowablechangesinthecompositionshouldbebasedontheapprovedtargetcompositionandnotonthecompositionbasedonpreviousLevel1orLevel2changes.应明确处方中各组分（包括活性成分和辅料）的具体比例（目标比例），该目标比例代表药品的公称成分，后续的任何产品成分的变更都是基于该目标比例。在评价药品成分变更能否被接受时，应以最初批准时的目标比例作为比较对象，而不是以前述的发生过1类或2类变更后的处方比例作为比较对象。2.TestDocumentation实验资料a.ChemistryDocumentation化学资料Application/compendialreleaserequirementsandbatchrecords.Stabilitytesting:1batchwith3monthsacceleratedstabilitydatainsupplementand1batchonlong-termstability.申报资料/药典要求的资料和批记录。稳定性试验资料：1批样品的3个月的加速稳定性试验数据（在补充申请中提供），以及1批样品的长期稳定性试验数据。b.DissolutionDocumentation溶出研究资料CaseA:HighPermeability,HighSolubilityDrugs情况A：高渗透性、高溶解性药物Dissolutionof85%in15minutesin900mLof0.1NHCl.Ifadrugproductfailstomeetthiscriterion,theapplicantshouldperformthetestsdescribedforCaseBorC(below).以900mL0.1N的HCl溶液为溶出介质，药物的溶出度可在15min内达到85%。如果药物未达到此标准，那么该药的申报应执行如情况B或C（下文）所述的试验。CaseB:LowPermeability,HighSolubilityDrugs情况B：低渗透性、高溶解性药物Multi-pointdissolutionprofileshouldbeperformedintheapplication/compendialmediumat15,30,45,60and120minutesoruntilanasymptoteisreached.Thedissolutionprofileoftheproposedandcurrentlyusedproductformulationsshouldbesimilar.多点溶出曲线的绘制，应选取申报资料/药典中规定的溶出介质，取样点应为15，30，45，60和120分钟或直至达到稳态。变更后的产品应与现行产品的溶出曲线相似。CaseC:HighPermeability,LowSolubilityDrugs情况C：高渗透性，低溶解性药物Multi-pointdissolutionprofilesshouldbeperformedinwater,0.1NHCl,andUSPbuffermediaatpH4.5,6.5,and7.5(fiveseparateprofiles)fortheproposedandcurrentlyacceptedformulations.Adequatesamplingshouldbeperformedat15,30,45,60,and120minutesuntileither90%ofdrugfromthedrugproductisdissolvedoranasymptoteisreached.Asurfactantmaybeused,butonlywithappropriatejustification.Thedissolutionprofileoftheproposedandcurrentlyusedproductformulationsshouldbesimilar.多点溶出曲线的绘制，应选取水、0.1N的HCl，以及美国药典规定的3种pH分别为4.5，6.5和7.5的缓冲介质（5条独立的溶出曲线）。应采用充足的样品进行溶出度试验，取样点应选择15，30，45，60和120分钟直至药物累计溶出度达到90%或至稳态。可使用表面活性剂，但其使用只能在有恰当理由的情况下。变更后的产品应与现行产品的溶出曲线相似。c.InVivoBioequivalenceDocumentation体内生物等效性资料None:ifthesituationdoesnotmeetthedescriptioninCaseA,CaseBorCaseC,refertoLevel3changes.不需要：如果变更不满足情况A、B或情况C所描述的情形，请参考第3类变更。3.FilingDocumentation归档文件Priorapprovalsupplement(allinformationincludingacceleratedstabilitydata);annualreport(long-termstabilitydata).此前批准的补充文件（所有信息，包括加速稳定性试验数据）；年报（长期稳定性试验数据）C.Level3Changes3类变更1.DefinitionofLevel定义Level3changesarethosethatarelikelytohaveasignificantimpactonformulationqualityandperformance.3类变更是指可能对制剂质量和性能产生显著影响的变更。Testsandfilingdocumentationvarydependingonthefollowingthreefactors:therapeuticrange,solubility,andpermeability.试验和归档文件根据因三个因素而不同：治疗窗、溶解度、渗透性。Examples:例如a.AnyqualitativeandquantitativeexcipientchangestoanarrowtherapeuticdrugbeyondtherangesnotedinSectionIII.A.1.b.治疗窗狭窄药物处方中辅料的质和量的改变超出章节III.A.1.b.规定的范围。b.AllotherdrugsnotmeetingthedissolutioncriteriaunderSectionIII.B.2.b.其它所有未达到章节III.A.2.b.规定的溶出度标准的药品。c.Changesintheexcipientrangesoflowsolubility,lowpermeabilitydrugsbeyondthoselistedinSectionIII.A.1.b.低溶解性、低渗透性药物处方辅料的变更超出了章节III.A.1.b.规定的范围。d.ChangesintheexcipientrangesofalldrugsbeyondthoselistedinSectionIII.B.1.b.所有药物处方中辅料的变更超出了章节III.B.2.b规定的范围。2.TestDocumentation试验资料a.ChemistryDocumentation化学资料Application/compendialreleaserequirementsandbatchrecords.申报资料/药典要求的资料和批记录。Significantbodyofinformationavailable:（已积累大量信息的情况）Onebatchwiththreemonthsacceleratedstabilitydatareportedinsupplement;onebatchonlong-termstabilitydatareportedinannualreport.在补充申请资料中应提供一批3个月的加速稳定性试验数据；在年报中提供的一批长期稳定性试验数据。Significantbodyofinformationnotavailable:（未积累大量信息的情况）Uptothreebatcheswiththreemonthsacceleratedstabilitydatareportedinsupplement;onebatchonlong-termstabilitydatareportedinannualreport.在补充申请资料中应提供3批3个月的加速稳定性试验数据；在年报中提供一批的长期稳定性试验数据。b.DissolutionDocumentation溶出研究资料CaseBdissolutionprofileasdescribedinSectionIII.B.2.b.在章节III.B.2.b中规定的情况B的溶出曲线。c.InVivoBioequivalenceDocumentation体内生物等效性试验资料Fullbioequivalencestudy.Thebioequivalencestudymaybewaivedwithanacceptableinvivo/invitrocorrelationhasbeenverified.完整的生物等效性研究资料。当该药品被证明具有可接受的体内外相关性时，可以免除生物等效性研究。3.FilingDocumentation归档文件Priorapprovalsupplement(allinformationincludingacceleratedstabilitydata);annua