合成原料药dmf起草大纲

使用说明1、本大纲是为了帮助我公司客户把握DMF的整体内容而准备的，由于DMF内容繁多，从整体上了解和组成部分，对于理解FDADMF的要求和意图非常有必要；2、根据FDA的要求，凡是本大纲提到的内容，原料药制造商均3、本大纲的内容和相关要求能够确保客户目前的运作达到FDAcGMPDMF的过程，也使客户按照FDA的要求进行整改和提高FDA未来的现场检查打下的与此大纲配套的相关DFM指导性文件，包括《FDA药物主文件指《药物申办中方面通用技术文件格式与内容要求》5、凡是本大纲中提到的技术性具体内容要求，如杂质、稳定性、验证等具体技术要求，请参照本公司专有的A相关技术标准文件，验证指南》等；《合成原料药DMF起草大纲一、公司和生产场地1、第一类的DMF文件建议由位于之外的人提供，以帮助FDA对他们的生产设施进行现场检查。DMF文件应描述生产场地、设备能力、生产流程图等。ATypeIDMFis mendedfora outsideoftheUnitedStatestoassistFDAinconductingonsiteinspectionsoftheirmanufacturingfacilities.TheDMFshoulddescribethemanufacturingsite,equipmentcapabilities,andoperational2、第一类的DMF文件对国内设施通常不需要，除非该设施没有登记并定期接受检查。ATypeIDMFisnormallynotneededtodescribedomesticfacilities,exceptinspecialcases,suchaswhena isnotregisteredandnotroutinely图。提供该场地的鸟瞰图和平面图。Thedescriptionofthesiteshouldincludeacreage,actualsiteaddress,andamapshowingitslocationwithrespecttothenearestcity.Anaerialphotographandadiagramofthesitemaybehelpful.别新或独特的设备。Adiagramofmajorproductionandprocessingareasishelpfulforunderstandingtheoperationallayout.Majorequipmentshouldbedescribedintermsofcapabilities,application,andlocation.Makeandmodelwouldnotnormallybeneededunlesstheequipmentisneworunique.5制、质量保证岗位，Adiagramofmajorcorporateorganizationalelements,withkeymanufacturing,qualitycontrol,andqualityassurancepositionshighlighted,atboththemanufacturingsiteandcorporateheadquarters,isalsohelpful.二、原料药的物理和化学特1、特性相关要求对原料药的物理和化学特征做出详细描述该要求可以通过提供下述信息来满足：名称（通用名、化学名、编码等）、化学服务(CAS)编码、溶性的或非水溶性的）、分配系数、溶液pH值、解离常数、或沸点、折射方法”和有关描述蛋白质特性的专论。Theregulationsrequireafulldescriptionofthephysicalandchemicalcharacteristicsofthedrugsubstance.Thisrequirementmaybesatisfiedbythesubmissionofinformationsuchasthefollowing:name(genericname,chemicalname,codenumber);Chemical sService(CAS)numberifavailable;description(e.g.,appearance,color,physicalstate);molecularformulaandmolecularweight;structuralformula(includingionicstateifapplicable);stereochemistry(identifyingchiralcenters,cis-transisomerism,etc.);enantiomerorsolid-stateformratios(e.g.,forracemates,andfordefinedadmixturesofisomersorenantiomersorsolid-stateforms);solubilityprofile(aqueousandnonaqueousasapplicable);partitioncoefficients;solutionpH;dissociationconstant(s);meltingorboilingpoint;refractiveindex;specificgravity.Fordrugsubstancesthatareproteins,seethe"CRCHandbookofBiochemistryandMolecularBiology,""MethodsinEnzymology,"andrelatedmonographsforhowproteinpropertiesmaybedescribed.艺的复杂性的增加。Theitemsabovearenotnecessaryorappropriateforallsubmissions.Additionalinformationmayberequired,particularlyasthestateoftheartprogresses.2、结构（应当基于一个合适的物理和化学检测结果这包括以下内容元素分析质谱分析(S)核磁(N)紫外(U)和红外(I)（X（（功能团分析，衍生作用，络合形式等）Theelucidationofstructure(e.g.,thedataanditsinterpretation)shouldbebasedonappropriatephysicalandchemicaltestresults.Thesemayincludethefollowing: ysis;massspectrometry(MS);nuclearmagneticresonance(NMR),ultraviolet(UV),andinfrared(IR)spectroscopy;molecularweightdetermination;stereochemistryandconfigurationalorconformationalysis(e.g.,opticalandgeometricisomers);X-ray ysis;degradativeysis(e.g.,aminoacidsequencingand/or ysis);chromatographicprofile;othertests(e.g.,functionalgroup ysis,derivatization,complex,arenecessaryorappropriateinallcases,andthelistingshouldnotbeconsideredlimiting(i.e.,moreysismayberequiredasthestateoftheartprogressesandthenatureofthenewdrugsubstancedemands).TheactualdataandthedetailsofitsinterpretationshouldbecedinthesectionforReferenceStandard(seeII.F.2,and三、相关要求对原料药的稳定性做全面的描述。具体要求，参见“关于提交人类用药品和生物制品稳定性文件的指南”。Theregulationsrequireafulldescriptionofthestabilityofthedrugsubstance.Seethe"GuidelineforSubmitting fortheStabilityofHumanDrugsandBiologics"forassistanceinfulfillingthis1、起始材料的控制程序Controlproceduresforstarting要。Startingmaterialsshouldbelisted.Acceptancespecificationsandtestsdefiningidentity,quality,andpurityshouldbeprovided.Theyticaltestmethodsshouldbebrieflydescribed.Thesourceofthestartingmaterialneednotbeidentified,butmaybe（物的异构体）被混入原料药时，应提供纯度如包括杂质的定量与定性色谱测的分析方法。Aspecificidentitytestshouldbeperformed,aswellasanassay,withlimitsforimpurities.Inthosecaseswhereimpurities(e.g.,positionalisomersofaromaticcompounds)couldbecarriedthroughtothedrugsubstance,apurityprofile chromatographywith impurities).Assurancesorstatementsofqualityfromtherareacceptablefortheprofile,providedthatthemanufacturerestablishesthereliabilityofther'sysesthroughvalidation,initiallyandatappropriateintervals.Thesestatementsfromrsshouldincludespecificationsandresultsandshouldindicatethetype（2、试剂、溶媒和辅料控制Reagentssolventsandauxiliarymaterials（Thesechemicalsshouldalsobelisted.Thespecificationsandtestmethodsforeachsuchmaterialshouldbestated,and/orastatementofqualityprovided.Theapplicantshoulddescribethespecificidentitytestperformedunlessomittingsuchatesthasbeenotherwisejustified,e.g.,becauseofhazard).Theextentofadditionaltestingperformed–whetherbytherorbytheapplicant--shouldbebasedontheroleofthechemicalinthesynthesis.Forexample:abase(e.g.,sodiumhydroxide)usedtoneutralizeexcessacidinasyntheticreactionmixturewouldnotnormallyrequireextensivepuritytesting;incontrast,anopticallyactiveorganicacidusedinaresolutionstepe.goneof icacid)wouldrequiresuchadditional3、详细的合成信包括整个合成过程的流程图以及每一合成步骤的说明）。Anapplicantshouldprovidecompleteinformationonthesynthesis,fromstartingmaterial(s)tothebulknewdrugsubstance.Thedescriptionshouldcontainadiagrticflowchartofthewholesynthesisandawrittenstatementforeachstepofthesynthesis.合成流程图FlowchartoftheTheflowcharttypicallyshouldcontainthe反应物和产品的化学结构（如：起始原料、，以及引入到结构中的分子）Chemicalstructuresofreactants(i.e.,startingmaterialsandintermediates,andalsomoleculesincorporatedintothestructure)and)立体化学结构，如果有立体化学构Stereochemicalconfigurations,where（未分离的或已分离的）Intermediateseitherinsituor溶媒、催化剂和试剂Solventscatalystsand反应所产生的产品与副产品混合比率(如：两个或异构体)应该显示在流程图 示出来（参见：第II.D.2.c.II.F.3.）Aratioormixtureofproductse.gtwoormoreisomers)producedbyareactionshouldbeshownintheflowchart.Significantsideproductsandimpurities,particularlythosethatinterferewiththeyticalproceduresoraretoxic,shouldbeillustratedseparay(seesectionsII.D.2.c.and合成描述Descriptionofthe每一个合成步骤的描述以及更详细的最后加工步骤的描述应该包括以下内容Thewrittenstatementforeachstepofthesynthesis,withgreaterdetailincludedtowardthefinalstepsoftheprocess,shouldincludethe用于反应的典型设备Typicalequipmentusedforthe反应物（本步骤所使用的起始原料或，包括化学名称和数量）Reactantsstartingmaterialorintermediateusedinthestep,withchemicalnamesand溶媒、催化剂和试剂（注明化学名称和数量）Solventscatalystsandreagents(chemicalnamesandamounts);反应条件（温度，pH值，时间，压力等）ConditionstemperaturepH,time,pressure,etc.);反应完成的检测，如果有的话。Testsforcompletionofreaction,if分离的程序Workupandisolation原料药和的纯化过程，如果有。Purificationproceduresfordrugsubstanceandforintermediates,ifemployed;收率范围（初品和/或精品的重量和百分比）Yieldrangescrudeand/orpurified;weightandpercent).料药提纯的内容)。Thefinalstepofthesynthesisandtheisolationofthecrudenewdrugsubstance,aswellasitspurification,shouldbeprovidedinfulldetail.(SeesectionII.D.2.cbelowregardingpurificationofthedrugsubstance.)除了提供合成的描述，还包括经过确认的操作参数范围（参见第II节-E工艺控制）IV节[CGMP])以及预期收率，递交者同时要提供实际操作的的拷贝，它应该包括更详细的内容。Besidesprovidingawrittendescriptionofthesynthesiswhichincludesverifiedrangesfortheoperatingparameters(refertosectionII-E[ProcessControls]andsectionIV[CGMP])andfortheexpectedyield,theapplicantshouldprovideawrittenexampleofactualpractice,clearlyidentifiedasanexampleforthereviewer'sinformation.Thisexampleshouldnotbemerelyacopyofbatchrecordsbutshouldcontainmoredetail.（Anyalternatemethodorpermissiblevariationthatmaybeemployed(e.g.,alternatestartingmaterials,reactants,solvents,conditions,catalysts,isolation,and/orpurificationprocedures)shouldbereported.yticaldataforthematerialproducedbyeachvariantsyntheticmethodshouldbeprovided.原料药的纯化Purificationofthedrug括以下内容：Thedescriptionofthepurificationofthecrudenewdrugsubstanceanditsisolationfromthefinalreactionstepmixtureshouldbegivenindetail,andshould原料药的收率范围Theyieldrangesofthecrude任何用于判断原料产品纯度的检验。（参见下面第6条）Anytestsperformedonthecrudeproducttodetermineitspurityseeitem6,below);回收。Adetaileddescriptionoftheisolationandpurificationprocedurese.g.,forrecrystallization:thesolventused,thetyofsolventinrelationtotheamountofcrudeproduct,whetheritisfilteredwhilehot,whetheradecolorizingagentisused,therateofcoolingandthefinaltemperature,theuseorre-useofanymotherliquors,andifsecondcropsareobtained);purificationproceduresseethelastparagraphofsectionII.D.2.bseealsosectionII.G.);提纯产品的收率范围（重量和百分比）Theyieldrangeweightandpercent)ofthepurifiedproduct;证明提纯过程增加纯度的有关，例如色析法的前后对比Evidencedemonstratingthatthepurificationprocedureimprovesthepurity,suchasbefore-and-afterchromatographicillustrations.当提纯工艺被验证后，只需提供最初产品批次的检验相关信息。Thistestingandinformationmaybenecessaryonlyoninitialproductionbatchesoncethepurificationprocesshasbeenverifiedorvalidated.合成的变化ChangesintheDMF的补充来提交。为改变新药物递交(NDA)中已经包括有关溶媒的改变。ProposedchangesinthesynthesisshouldbesubmittedtotheapplicationasasupplementforanapprovedNDAorasanamendmenttoanIND,aDMF,orapendingNDA.Anapprovedsupplementisrequired21CFR314.70(b)(1)(iv)]tochangethemethodofsynthesisapprovedintheNDAforthedrugsubstance,includingachangeinsolvents.容不同时应该提供每一合成路线的比较分析数（如完整的纯度数据。下面讨论有关变化旨在重新定义起始原料的情况。Whentherouteofsynthesisischanged(i.e.,reactionsand/orintermediatesaredifferentfromthoseapprovedintheNDA),comparativeyticaldata(i.e.,acompletepurityprofile)forthedrugsubstancemadebyeachrouteshouldbeprovided.Aspecialcase,wheretheproposedchangeistoredefinethestartingmaterial,isdiscussedbelow.的变化；参见II.GWhenthereisachangeinthesolventusedforthefinalcrystallizationofthenewdrugsubstance,thenewdrugsubstanceshouldbeexaminedforchangesincrystallineformand/orsolvation;refertosectionII.G.Thenewdrugsubstancemustmeetitsoriginalspecificationsforcrystallineformand/orsolvation.该改变可以产生同等质量和纯度的产品（化合物或）的，但无需考虑形态学问题。Solventchangesforotherreactionstepsorpurificationsalsorequireasupplementalapplication.Theapplicationshouldcontainevidencethatthechangeaffordsmaterial(compoundorintermediate)ofequivalentqualityandpurity,butmorphologyneednotbeconsidered.如果递交者想缩短新药递交(NA)中批准的合成方法或者通过重新定义起始原料时，则需要提交一个补充文件(21FR314.0(b)(1)。该起始原料是一种可商业获得的用于合成的化合物该化合物必须是新药递交（批准，而且，必须满足起始材料b"和c"标准要求。Anpprovdupplemntisrquird(21FR314.70b)(1)fnpplintwntstohortentheyntheispprovdintheNAordvlopanwyntheticmethodbyrdfiningthetartingmatrial,inordrtomployaompoundlatrintheyntheisthaths ommriallyvilble.ThisompoundmuthvebnnintrmediteinthepprovdNAynthei,ndmutmetboththeb"nd"ritriafortartingmatrial.beusedatleasttwofullstepsbeforethenewdrugsubstanceifpossible(i.e.,itshouldbepriortothefinalintermediate).Additionalinformationonthecharacterizationandpurityprofileofthestartingmaterialmaybeneeded,dependingontheadequacyoftheliturereferencescited(copiesshouldbeprovided).对于学术期所的化合物，详尽的材料就够了（如：有关杂质检验的额外信息）。在有关专利中所规定的化合物，需要提供其完整的特性和纯度。Forcompoundscitedinjournalarticlesanelaborationofthepublishedmaterial(i.e.,additionalinformationabouttestingforimpurities)maysuffice.Forcompoundsdescribedinpatentsbothcompletecharacterizationandafullpurityprofilewillusuallybeneeded.yticaltestproceduresusedtoqualifyeachnewsource/rofthenewstartingmaterialshouldbedescribed.Ageneraltestingprotocolmaybesuitable.验性规模（如:要大于规模）。Theapplicantshoulddemonstratebydirectcomparison(i.e.,bothbyysesandbyausetest)thatthecompoundisequivalenttothematerialusedtomakethenewdrugsubstanceemployedintheclinicaltrials,andthattheacceptancetestsandspecificationsforthecompoundareadequate.Theusetestshouldbeatleastonapilotscale(i.e.,largerthanbenchscale).和用于检测一个新的参考标准品的相同。Acommitmenttosubmitresultsfromthoroughexaminationofthefirstthreefull-scalebatchesmadewiththematerialshouldbeprovided.Theexaminationshouldbesimilarinscopeandextenttothetestinginvolvedinqualifyinganewreferencestandard.对于依据21CFR314.70(c)(3)所做的改变类型，只要有对合成过程的changesofthetypepermittedby21CFR314.70(c)(3),anadequatesynthesisdescriptiononfilewouldfacilitateaconclusionthatchangesinsiteofmanufactureofthenewdrugsubstancedonotrequirepriorFDAapprovalforimplementation.4标准品Reference原始递交的申报文件应该包括任何所使用的参照标准品的过程的描述，包括对提纯步骤的描述，参见II.F.3.Theoriginalapplicationshouldincludeafulldescriptionofthepreparationofanyreferencestandardsubstanceused,includingthedescriptionofthepurificationsteps.SeealsosectionII.F.3.II.D.4.五、1、和生产过程的控制IntermediatesandIn-process，相关要求在合成过程中选择一些中间环节实施控（检测项目与参数要求以保证合成和提纯工序顺利进行检测后的适合于以后的加工。申请者可以根据对整个合成工艺的开发和确认的经验自行确定对那些或加行了检验（至少是对反应的内容），每一个至少都进行与纯度有关参数的测定，包括纯度的估计。随着合成经验的积累，应选择关键的反应步骤和进行。在递交新药申请(NDA)时，生产过程的控制点应该已经选定，相关控制参数和检验方法也已确立，以满足法律的要求。Theregulationsrequirethatcontrols(specificationsandtests)beemployedatselectedintermediatestagesofthesyntheticprocesstoassurethatthesyntheticandpurificationproceduresareoperatingproperlyandthattheintermediatetestedissuitableforsubsequentprocessing.Thechoiceofwhichintermediate(s)orstepsintheprocesstotest,andthekindoftestingrequired,aretheresponsibilityoftheapplicantbasedonhisexperienceduringthedevelopmentandverificationofthetotalsyntheticprocess.Inearlydevelopmentwork,everystepwouldusuallyhavebeenexaminedatleastforextentofreaction)andeveryintermediateatleastpartiallycharacterizedwithsomeestimateofpurityAsexperienceisgainedwiththesynthesisthecriticalreactionstepsandintermediatestobemonitoredareselected.AtthetimeofNDAsubmission,in-processcontrolpointsshouldhavebeenselectedandappropriatespecificationsandtestsestablishedtomeettherequirementsoftheregulations.，和的根据。应当证明控制参数和检测方法对合成过程的控制是充分的。应当依据相关控制点（控制参数和检测方法）来提供控制参数范围的描程的控制程序。该控制程序的改变需要额外的验证（参见：IV）。Thiswholeoperationispartoftheprocessvalidationofthesynthesis.Thebasisforselectingcontrolpointsandintermediatesshouldbeexined,andtheadequacyofthespecificationsandteststocontrolthesyntheticprocessdemonstrated.Therangesfortheoperatingparametersinthewrittendescriptionofthesynthesisshouldbechoseninlightofthecontrols(specificationsandtests).Generally,broadoperatingrangeswillrequirestrictercontrols.(SeealsosectionII.E.b.(recoveryandrework)below.)WithadditionalexperiencesubsequenttoNDAapproval,thechoiceandnatureofin-processcontrolproceduresmayrequiremodification.Changesinin-processcontrolprocedureswillrequireadditionalvalidation(seesectionIV).Controlsmaybedesigned证明已获得了想要生产的产品demonstratethatthedesiredproducthasbeen确定关键的物理特征（如：、旋光度等）determineakeyphysicalproperty(e.g.,meltingpoint,opticalrotation,etc.);确定的纯度和杂质determinepurity/impurityofthe确定收率是限定在通常的操作范围之内determinethattheyieldiswithinthenormaloperatingrange.在某些情况下，对的控制是不可行的（如：它们处于溶液状态或直接加工成下一个化合物）。可能，检测也可仅限于对合成过程的（如：反应是否完成）。Insomecasesnocontrolsfortheintermediatemaybefeasible(e.g.,wheretheyareheldinsolution,oraredirectlyprocessedtothenextcompound).Whenappropriate,testingmayconsistonlyofatestdesignedtomonitortheprogressofthesynthesis(i.e.,reactioncompletion).列过程控制的要求为减少最终的大规模清除从第一个到原料药本身,中间体的纯度应该逐渐提高。Someoralloftheabovekindsofprocesscontrolsshouldbemetateachpointselectedforin-processcontroltesting.Pivotal,key,andfinalintermediatesseeGlossary,andbelow)wouldordinarilyrequireatleastthein-processcontrolslistedaboveToeliminatetheneedforheroicfinalcleanupsitisexpectedthatthedegreeofpurityofintermediateswillincreaseprogressively,fromthefirstintermediateontothedrugsubstanceitself.2、关键（见术语表）Pivotalintermediate(s)(See应该用足够的细节（如详细描述其特征）描述任何关键，并作为控制参商或合成发生改变时，要做以上检查。当关键接近成为最终时，对其进行的检测程度和纯度要求也应该增加Anypivotalintermediateshouldbedescribedinadequatedetail(i.e.,bewellcharacterized)andbesubjecttorigorousexaminationproceduresaspartofthespecificationsandtests,includingthoroughchromatographicexaminationsoastoavoidoverlookingimpuritiesarisingfromalternativesyntheses.Suchrigorousexaminationneednotberoutinebutmaybeneededinspecialcircumstancessuchaswhentherorsynthesisischanged.Thedegreeoftestingandthelevelofpurityrequiredforapivotalintermediateshouldincreaseasitspositioninthesynthesisschemeapproachesthefinalintermediate.3、（参见术语表）Keyintermediate(s)(Seespecificationsshouldbeadequatetoassurethatthemoleculararchitecturenecessaryforthefinalproduct,aswellastherequisitedegreeofpurity,havebeenattained.Testproceduresshouldthusshowthatthedesiredtransformation(suchasintroductionofchirality,orastereospecificreaction)hasoccurredinthemannerexpectedandwithinthenormalyieldrangeexpected,andshowbytativedetermination(s)thatundesiredmaterials(e.g.,isomers,by-products,startingmaterials)arewithinestablishedlimits.4、最终（参见术语表）Finalintermediate(see关于最终的规格和检验应该与原料药的规格和检验同样广泛和严格因为这是最终反应前的最后纯度和杂质的机会。Specificationsandtestsforfinalintermediateshouldbenearlyasextensiveandstringentasthoseforthenewdrugsubstanceitself,becausethisisthelastopportunitytomonitorpurityandimpuritiesbeforethefinalreaction.5、返工对不符合加工规格要求的，可以按照新药申请(NDA)中所描述的提纯方受最后加工操作与检验。Intermediateswhichdonotmeetin-processspecificationsmaybefurtherpurifiedusingthesamepurificationproceduredescribedintheNDA.Whenanalternatepurificationprocedureisused,therecoveredmaterialshouldbesubjectedtothesamefinalprocessingoperationandthesametestingasforthefirst（如：偏离或较小的背离），应当采用什么样的程序，来使该批或原料应该按使用分析标准参照品是否合格的程序来进行检验。FDArecognizesthatoperatingconditions(suchastimeandtemperature)occasionallydeviatefromtheNDAdescription.Aprotocolshouldbeprovidedfortheprocedurewhichwillbeusedtoqualifythebatchofintermediateordrugsubstanceasmeetingspecificationswhenreactionconditionsoroperatingparametersfalloutsidethetypical/normalrange(i.e.,"excursions,"orminordeviations).Theprotocolshoulddescribetheadditionalyticaltestingwhichwillbeusedinqualificationofthebatch.Thetestingshouldbemoreextensivethanrequiredbyroutinespecificationsandtestsandmayinclude,asappropriate,theuseofnonregulatory yticalmethods.Forexample,batchesofnewdrugsubstanceinthiscategory(i.e,whenreactionconditionsareoutsidethenorm)shouldbeexaminedbydiscerning yticalproceduressuchasthoseusedforReferenceStandardqualification.II.D.3..GMP接受，当杂质含量积累时，它并（GP第IV节和“关于大宗药用化学物制造的现场检查指南”）。Inprossontrolprodurshouldbetblihdndderibedforthehndlingofmothrliquorsndrovryofondropswhnthisisdon;etionII..3..hilethereueofmothrliquorsndrovryfondropsmaybeommon/normalprtiendisptablefromaGPviepoint,itisnotnsarilyptablei.whnimpritylevlsbuildup),ndxteniverylingfmotrliqursrrptedrovriesofdditionalropsisdiourgdrfrtotionVGPndtheGuidlinefrInptionofulkPhrmautilhmilnufctur"inthisrgrd.)母液的回收程序应该包括在批产品生产中新药申请(NDA)中应规定对不符次再结晶来完成。不需要额外的分析检验。Therecoveryproceduresshouldbeincludedinbatchproductionrecords.ProvisionshouldbemadeintheNDAforthetypicalandusualreprocessprocedurefordrugsubstancewhichfailstomeetspecifications,usuallybyoneormoreadditionalrecrystallizationsfromthefinalsolvent.Extraordinaryyticalexaminationisnotrequiredinthiscase.不符合既定标准的单一批产品可以通过适当的程序来纯化，然后按照新药申请()AinglebtchfdrugubtanewhihfilstometpifictionsmaybepurfiedbynpproriaterodurendthenprodbythemefinalpurifictionproduredribedintheNA,providedthtthepurityoftherprodmatrialbingotrtedinthefinalpurfictiontepissgoodsthenormaldrugubtanetthistageofroing.由客户退回的产品）可以用同样的方法加工。Sometypesofbulkdrugsubstanceforsalvage(e.g.,accumulatedunusedyticalsamples,unusedportionsoflots,bulkreturnedfromcustomers)maybeprocessedinthisfashion.为使不合格的批可再利用而进行的混批是不能接受的。Suchreworkeddrugsubstancebatchesshouldbesubjectedtoadditional yticalexamination,asindicatedabove(i.e.,fordrugsubstanceresultingfromminordeviationsofprocessconditions).Thereworkoperation,andthereasonforit,shouldbeed.Theblendingofbatchesorlotsforthepurposeofsalvagingunsatisfactorybatches,withoutsubsequentadditionalpurificationbyanappropriateprocedureandprocessingbythefinalpurificationstepdescribedintheNDA,isnotpermittedundercurrentguidelines.“化学原料药生产现场检查指南”。IfnotpartoftheoriginalNDA,asupplementshouldbesubmittedtotheNDAwhenastandard(validated)reprocessingprocedureforunsatisfactorybulkdrugsubstanceistoberoutinelyemployed;refertotheGuidetoInspectionofBulkPharmaceuticalChemicalManufacturing."“关于提交制剂产品生产和控制文件的指南”。这样的操作需要提供补充资料。Whendrugsubstanceistoberecoveredfromdosageforms,referenceshouldalsobemadetothe"GuidelineforSubmittingationfortheManufactureofandControlsforDrugProducts."Thistypeofoperationwillrequirea六、息，以定义这些控制参数和检验方法。Theregulationsrequirespecificationsandyticalmethods(i.e.,releasecontrolsforthenewdrugsubstance)tohelpassurethattheproperidentity,strength,quality,andpurityofthedrugsubstancehavebeenattainedandareconsistentfrombatchtobatch.Thefollowinginformationshouldbesubmittedtodefinethesespecificationsandtestmethods:1的依据；抽样应该满足相关统计学的考虑。SamplingrequirementsarecoveredbyCGMPregulations(seesectionIV).Thesamplingnshouldbedescribed,givingthebasisforthen;itshouldsatisfyappropriatestatisticalconsiderations.2、放行控制Release对放行中可能使用的规格和检验标准，举例如下：Examplesofspecificationsandteststhatmaybeapplicableareasfollows:外观/描述物理特性（如：熔化范围、旋光率、折射率、晶形、粒度III部分。Physicalproperties(e.g.,meltingrange,specificrotation,refractiveindex,crystallineform,particlesize).Fordrugsubstanceswithchiralcentersorotherconfigurationalrequirements,thespecificationsandtestsshouldassurethatmaterial(whetherasingleenantiomerorisomer,aracemate,oraknownratioofisomers)withtherequisitepropertiesfortherapeuticactivityhasbeenproduced.SeesectionIIIinthisregard.statepropertiesseesectionII.Gofthenewdrugsubstancesuchaspolymorphismorparticlesize,areknowntoaffectphysiologicalorpharmacologicalactivity(i.e,bioavailabilityofthedrugproduct),thespecificationsandtestsshouldprovideappropriatelimitsfortheseproperties(whetherassingleformsorasadmixtures).鉴别检查（如：红外线(IR)、核磁的(NMR)和质谱测定法(MS)）Specificidentitytest(s)(i.e.,infrared(IR),nuclearmagneticresonance(NMR),andmassspectrometry(MS)).种色析法的相对保留时间[R[f]或T[R]值]，将被认为是确认性的而不是专属性别。Thespecificidentitytest(s)shouldbecapableofdistinguishingthenewdrugsubstancefromrelatedcompoundsIfonlyonespecificidentitytestisperformed,anIRspectrum(KBrpellet)ispreferred.Otheridentitytests(suchasUVspectra,orrelativemobility[R[f]orT[R]values]byvariouschromatographicmethods)areconsideredconfirmatoryratherthanspecific.ngadditional(confirmatory)testsisencouraged;however,fileandlimits(i.e.,teststodetect,identify,andtatethepresenceofstartingmaterialsandintermediates,by-products,degradationproducts,solvents,andotherimpurities,aswellas mendedlimitsforsuchimpurities).是什么化合物。Impuritiesshouldnotonlybedetectedandtated,butshouldalsobeidentifiedandcharacterizedwhenthisispossiblewithreasonableeffort.Duringthedevelopmentandvalidationofthe yticalmethodsthefollowingconcernsshouldbeaddressed:该方法能够检测杂质与溶解杂质（如：方法的灵敏性和专属性）Abilitythemethodtodetectandresolveimpurities(i.e.,thesensitivityandspecificityofthe定量和线性tation,andlinearityof杂质特性（如：起始原料、、降解物）natureoftheimpurity(e.g.,startingmaterial,intermediate,degradationproduct);分类([如：还未被从化学上确定的])laifiction(.g.,majrorminotoxi,kownorunknown[i..,notythmillyidentifiedrhrteriz]);杂质的分离纯化与结构证明（如：鉴别和特征），需要时与样品进行比较isolation,purification,andproofofstructure(i.e.,identificationandcharacterization),includingthepreparationofauthenticspecimensforcomparisonwhenneeded.验是充分的，并已做了合理的努力来鉴别和描述它们的特征）。Thesectiononimpuritiesintheapplicationshoulddemonstratethatalltheabovepointshavebeenconsideredi.ethattheexaminationofthenewdrugsubstanceforimpuritieshasbeenadequate,andthatreasonableeffortshavebeenmadetofullyidentifyand/orcharacterizethem).测方法，参照II.F.3.节（参照标准）。Structuresofknownimpurities,andvalidationoftheyticalmethods,shouldbeprovided(followingtheSpecificationsandTests)andbereferencedinsectionII.F.3.(ReferenceStandard).Allmajorimpuritiesshouldbeindividuallylimited.Theumamountperunitdoesofeveryindividualimpurityshouldbeprovided.Ifthereisinformationontoxicityorinformationontoxiclimitsthathavebeensetfortheseimpurities,thisinformationshouldbeprovided.所有杂质（单个与总杂质，并包括那些未知的）。Asummarytabulationoftheresultsfromtheyticalexaminationofindividualbatchesofthedrugsubstanceusedinanimalandclinicaltesting,listingallimpuritiesindividuallyaswellastotal,andincludingthosewhichareunidentified),shouldbeprovided.含量测定用同样的方法测量原料药和杂质（如：HPLC法）。由于需要一个专属的鉴别检Theassayforthedrugsubstanceshouldbespecificifpossiblesinceitcanthenbeusedforstability-indicatingpurposes.Itmaybepracticaltomeasurethedrugsubstanceandimpuritiesbythesameprocedure(e.g.,highpressureliquidchromatography(HPLC)).Sinceaspecificidentitytestisrequired,assayspecificityisnotessentialwhenimpuritieswhichmightinterferearecontrolled(andlimited)bysuitable(e.g.,chromatographic)methods;inthesecircumstancesnon-specificassaymethods,suchasapotentiometrictitration,maybeemployed.新原料药DNA的制定一个含量的范围和杂质的限度，应该基于实际的生产结（如：通过对单批产品的分析）。最好是按照实际条件下的化合物的稳定性，制定再检测日期。TheassaylimitsestablishedintheNDAforthenewdrugsubstance,aswellasthelimitsforimpurities,shouldbebasedonactualmanufacturingresults(i.e.,from ysesofindividualbatches).Aretestdate,basedonthestabilityofthecompoundunderactualstorageconditions,isdesirable.Microencapsulatedcompoundsshouldal