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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,sitechang