合成原料藥dmf起草大綱

使用說(shuō)明1、本大綱是為了幫助我公司客戶把握DMF的整體內(nèi)容而準(zhǔn)備的，由于DMF內(nèi)容繁多，從整體上了解和組成部分，對(duì)于理解FDADMF的要求和意圖非常有必要；2、根據(jù)FDA的要求，凡是本大綱提到的內(nèi)容，原料藥制造商均3、本大綱的內(nèi)容和相關(guān)要求能夠確保客戶目前的運(yùn)作達(dá)到FDAcGMPDMF的過(guò)程，也使客戶按照FDA的要求進(jìn)行整改和提高FDA未來(lái)的現(xiàn)場(chǎng)檢查打下的與此大綱配套的相關(guān)DFM指導(dǎo)性文件，包括《FDA藥物主文件指《藥物申辦中方面通用技術(shù)文件格式與內(nèi)容要求》5、凡是本大綱中提到的技術(shù)性具體內(nèi)容要求，如雜質(zhì)、穩(wěn)定性、驗(yàn)證等具體技術(shù)要求，請(qǐng)參照本公司專(zhuān)有的A相關(guān)技術(shù)標(biāo)準(zhǔn)文件，驗(yàn)證指南》等；《合成原料藥DMF起草大綱一、公司和生產(chǎn)場(chǎng)地1、第一類(lèi)的DMF文件建議由位于之外的人提供，以幫助FDA對(duì)他們的生產(chǎn)設(shè)施進(jìn)行現(xiàn)場(chǎng)檢查。DMF文件應(yīng)描述生產(chǎn)場(chǎng)地、設(shè)備能力、生產(chǎn)流程圖等。ATypeIDMFis mendedfora outsideoftheUnitedStatestoassistFDAinconductingonsiteinspectionsoftheirmanufacturingfacilities.TheDMFshoulddescribethemanufacturingsite,equipmentcapabilities,andoperational2、第一類(lèi)的DMF文件對(duì)國(guó)內(nèi)設(shè)施通常不需要，除非該設(shè)施沒(méi)有登記并定期接受檢查。ATypeIDMFisnormallynotneededtodescribedomesticfacilities,exceptinspecialcases,suchaswhena isnotregisteredandnotroutinely圖。提供該場(chǎng)地的鳥(niǎo)瞰圖和平面圖。Thedescriptionofthesiteshouldincludeacreage,actualsiteaddress,andamapshowingitslocationwithrespecttothenearestcity.Anaerialphotographandadiagramofthesitemaybehelpful.別新或獨(dú)特的設(shè)備。Adiagramofmajorproductionandprocessingareasishelpfulforunderstandingtheoperationallayout.Majorequipmentshouldbedescribedintermsofcapabilities,application,andlocation.Makeandmodelwouldnotnormallybeneededunlesstheequipmentisneworunique.5制、質(zhì)量保證崗位，Adiagramofmajorcorporateorganizationalelements,withkeymanufacturing,qualitycontrol,andqualityassurancepositionshighlighted,atboththemanufacturingsiteandcorporateheadquarters,isalsohelpful.二、原料藥的物理和化學(xué)特1、特性相關(guān)要求對(duì)原料藥的物理和化學(xué)特征做出詳細(xì)描述該要求可以通過(guò)提供下述信息來(lái)滿足：名稱（通用名、化學(xué)名、編碼等）、化學(xué)服務(wù)(CAS)編碼、溶性的或非水溶性的）、分配系數(shù)、溶液pH值、解離常數(shù)、或沸點(diǎn)、折射方法”和有關(guān)描述蛋白質(zhì)特性的專(zhuān)論。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.藝的復(fù)雜性的增加。Theitemsabovearenotnecessaryorappropriateforallsubmissions.Additionalinformationmayberequired,particularlyasthestateoftheartprogresses.2、結(jié)構(gòu)（應(yīng)當(dāng)基于一個(gè)合適的物理和化學(xué)檢測(cè)結(jié)果這包括以下內(nèi)容元素分析質(zhì)譜分析(S)核磁(N)紫外(U)和紅外(I)（X（（功能團(tuán)分析，衍生作用，絡(luò)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、相關(guān)要求對(duì)原料藥的穩(wěn)定性做全面的描述。具體要求，參見(jiàn)“關(guān)于提交人類(lèi)用藥品和生物制品穩(wěn)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（物的異構(gòu)體）被混入原料藥時(shí)，應(yīng)提供純度如包括雜質(zhì)的定量與定性色譜測(cè)的分析方法。Aspecificidentitytestshouldbeperformed,aswellasanassay,withlimitsforimpurities.Inthosecaseswhereimpurities(e.g.,positionalisomersofaromaticcompounds)couldbecarriedthroughtothedrugsubstance,apurityprofile chromatographywith impurities).Assurancesorstatementsofqualityfromtherareacceptablefortheprofile,providedthatthemanufacturerestablishesthereliabilityofther'sysesthroughvalidation,initiallyandatappropriateintervals.Thesestatementsfromrsshouldincludespecificationsandresultsandshouldindicatethetype（2、試劑、溶媒和輔料控制Reagentssolventsandauxiliarymaterials（Thesechemicalsshouldalsobelisted.Thespecificationsandtestmethodsforeachsuchmaterialshouldbestated,and/orastatementofqualityprovided.Theapplicantshoulddescribethespecificidentitytestperformedunlessomittingsuchatesthasbeenotherwisejustified,e.g.,becauseofhazard).Theextentofadditionaltestingperformed–whetherbytherorbytheapplicant--shouldbebasedontheroleofthechemicalinthesynthesis.Forexample:abase(e.g.,sodiumhydroxide)usedtoneutralizeexcessacidinasyntheticreactionmixturewouldnotnormallyrequireextensivepuritytesting;incontrast,anopticallyactiveorganicacidusedinaresolutionstepe.goneof icacid)wouldrequiresuchadditional3、詳細(xì)的合成信包括整個(gè)合成過(guò)程的流程圖以及每一合成步驟的說(shuō)明）。Anapplicantshouldprovidecompleteinformationonthesynthesis,fromstartingmaterial(s)tothebulknewdrugsubstance.Thedescriptionshouldcontainadiagrticflowchartofthewholesynthesisandawrittenstatementforeachstepofthesynthesis.合成流程圖FlowchartoftheTheflowcharttypicallyshouldcontainthe反應(yīng)物和產(chǎn)品的化學(xué)結(jié)構(gòu)（如：起始原料、，以及引入到結(jié)構(gòu)中的分子）Chemicalstructuresofreactants(i.e.,startingmaterialsandintermediates,andalsomoleculesincorporatedintothestructure)and)立體化學(xué)結(jié)構(gòu)，如果有立體化學(xué)構(gòu)Stereochemicalconfigurations,where（未分離的或已分離的）Intermediateseitherinsituor溶媒、催化劑和試劑Solventscatalystsand反應(yīng)所產(chǎn)生的產(chǎn)品與副產(chǎn)品混合比率(如：兩個(gè)或異構(gòu)體)應(yīng)該顯示在流程圖 示出來(lái)（參見(jiàn)：第II.D.2.c.II.F.3.）Aratioormixtureofproductse.gtwoormoreisomers)producedbyareactionshouldbeshownintheflowchart.Significantsideproductsandimpurities,particularlythosethatinterferewiththeyticalproceduresoraretoxic,shouldbeillustratedseparay(seesectionsII.D.2.c.and合成描述Descriptionofthe每一個(gè)合成步驟的描述以及更詳細(xì)的最后加工步驟的描述應(yīng)該包括以下內(nèi)容Thewrittenstatementforeachstepofthesynthesis,withgreaterdetailincludedtowardthefinalstepsoftheprocess,shouldincludethe用于反應(yīng)的典型設(shè)備Typicalequipmentusedforthe反應(yīng)物（本步驟所使用的起始原料或，包括化學(xué)名稱和數(shù)量）Reactantsstartingmaterialorintermediateusedinthestep,withchemicalnamesand溶媒、催化劑和試劑（注明化學(xué)名稱和數(shù)量）Solventscatalystsandreagents(chemicalnamesandamounts);反應(yīng)條件（溫度，pH值，時(shí)間，壓力等）ConditionstemperaturepH,time,pressure,etc.);反應(yīng)完成的檢測(cè)，如果有的話。Testsforcompletionofreaction,if分離的程序Workupandisolation原料藥和的純化過(guò)程，如果有。Purificationproceduresfordrugsubstanceandforintermediates,ifemployed;收率范圍（初品和/或精品的重量和百分比）Yieldrangescrudeand/orpurified;weightandpercent).料藥提純的內(nèi)容)。Thefinalstepofthesynthesisandtheisolationofthecrudenewdrugsubstance,aswellasitspurification,shouldbeprovidedinfulldetail.(SeesectionII.D.2.cbelowregardingpurificationofthedrugsubstance.)除了提供合成的描述，還包括經(jīng)過(guò)確認(rèn)的操作參數(shù)范圍（參見(jiàn)第II節(jié)-E工藝控制）IV節(jié)[CGMP])以及預(yù)期收率，遞交者同時(shí)要提供實(shí)際操作的的拷貝，它應(yīng)該包括更詳細(xì)的內(nèi)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.原料藥的純化Purificationofthedrug括以下內(nèi)容：Thedescriptionofthepurificationofthecrudenewdrugsubstanceanditsisolationfromthefinalreactionstepmixtureshouldbegivenindetail,andshould原料藥的收率范圍Theyieldrangesofthecrude任何用于判斷原料產(chǎn)品純度的檢驗(yàn)。（參見(jiàn)下面第6條）Anytestsperformedonthecrudeproducttodetermineitspurityseeitem6,below);回收。Adetaileddescriptionoftheisolationandpurificationprocedurese.g.,forrecrystallization:thesolventused,thetyofsolventinrelationtotheamountofcrudeproduct,whetheritisfilteredwhilehot,whetheradecolorizingagentisused,therateofcoolingandthefinaltemperature,theuseorre-useofanymotherliquors,andifsecondcropsareobtained);purificationproceduresseethelastparagraphofsectionII.D.2.bseealsosectionII.G.);提純產(chǎn)品的收率范圍（重量和百分比）Theyieldrangeweightandpercent)ofthepurifiedproduct;證明提純過(guò)程增加純度的有關(guān)，例如色析法的前后對(duì)比Evidencedemonstratingthatthepurificationprocedureimprovesthepurity,suchasbefore-and-afterchromatographicillustrations.當(dāng)提純工藝被驗(yàn)證后，只需提供最初產(chǎn)品批次的檢驗(yàn)相關(guān)信息。Thistestingandinformationmaybenecessaryonlyoninitialproductionbatchesoncethepurificationprocesshasbeenverifiedorvalidated.合成的變化ChangesintheDMF的補(bǔ)充來(lái)提交。為改變新藥物遞交(NDA)中已經(jīng)包括有關(guān)溶媒的改變。ProposedchangesinthesynthesisshouldbesubmittedtotheapplicationasasupplementforanapprovedNDAorasanamendmenttoanIND,aDMF,orapendingNDA.Anapprovedsupplementisrequired21CFR314.70(b)(1)(iv)]tochangethemethodofsynthesisapprovedintheNDAforthedrugsubstance,includingachangeinsolvents.容不同時(shí)應(yīng)該提供每一合成路線的比較分析數(shù)（如完整的純度數(shù)據(jù)。下面討論有關(guān)變化旨在重新定義起始原料的情況。Whentherouteofsynthesisischanged(i.e.,reactionsand/orintermediatesaredifferentfromthoseapprovedintheNDA),comparativeyticaldata(i.e.,acompletepurityprofile)forthedrugsubstancemadebyeachrouteshouldbeprovided.Aspecialcase,wheretheproposedchangeistoredefinethestartingmaterial,isdiscussedbelow.的變化；參見(jiàn)II.GWhenthereisachangeinthesolventusedforthefinalcrystallizationofthenewdrugsubstance,thenewdrugsubstanceshouldbeexaminedforchangesincrystallineformand/orsolvation;refertosectionII.G.Thenewdrugsubstancemustmeetitsoriginalspecificationsforcrystallineformand/orsolvation.該改變可以產(chǎn)生同等質(zhì)量和純度的產(chǎn)品（化合物或）的，但無(wú)需考慮形態(tài)學(xué)問(wèn)題。Solventchangesforotherreactionstepsorpurificationsalsorequireasupplementalapplication.Theapplicationshouldcontainevidencethatthechangeaffordsmaterial(compoundorintermediate)ofequivalentqualityandpurity,butmorphologyneednotbeconsidered.如果遞交者想縮短新藥遞交(NA)中批準(zhǔn)的合成方法或者通過(guò)重新定義起始原料時(shí)，則需要提交一個(gè)補(bǔ)充文件(21FR314.0(b)(1)。該起始原料是一種可商業(yè)獲得的用于合成的化合物該化合物必須是新藥遞交（批準(zhǔn)，而且，必須滿足起始材料b"和c"標(biāo)準(zhǔn)要求。Anpprovdupplemntisrquird(21FR314.70b)(1)fnpplintwntstohortentheyntheispprovdintheNAordvlopanwyntheticmethodbyrdfiningthetartingmatrial,inordrtomployaompoundlatrintheyntheisthaths ommriallyvilble.ThisompoundmuthvebnnintrmediteinthepprovdNAynthei,ndmutmetboththeb"nd"ritriafortartingmatrial.beusedatleasttwofullstepsbeforethenewdrugsubstanceifpossible(i.e.,itshouldbepriortothefinalintermediate).Additionalinformationonthecharacterizationandpurityprofileofthestartingmaterialmaybeneeded,dependingontheadequacyoftheliturereferencescited(copiesshouldbeprovided).對(duì)于學(xué)術(shù)期所的化合物，詳盡的材料就夠了（如：有關(guān)雜質(zhì)檢驗(yàn)的額外信息）。在有關(guān)專(zhuān)利中所規(guī)定的化合物，需要提供其完整的特性和純度。Forcompoundscitedinjournalarticlesanelaborationofthepublishedmaterial(i.e.,additionalinformationabouttestingforimpurities)maysuffice.Forcompoundsdescribedinpatentsbothcompletecharacterizationandafullpurityprofilewillusuallybeneeded.yticaltestproceduresusedtoqualifyeachnewsource/rofthenewstartingmaterialshouldbedescribed.Ageneraltestingprotocolmaybesuitable.驗(yàn)性規(guī)模（如:要大于規(guī)模）。Theapplicantshoulddemonstratebydirectcomparison(i.e.,bothbyysesandbyausetest)thatthecompoundisequivalenttothematerialusedtomakethenewdrugsubstanceemployedintheclinicaltrials,andthattheacceptancetestsandspecificationsforthecompoundareadequate.Theusetestshouldbeatleastonapilotscale(i.e.,largerthanbenchscale).和用于檢測(cè)一個(gè)新的參考標(biāo)準(zhǔn)品的相同。Acommitmenttosubmitresultsfromthoroughexaminationofthefirstthreefull-scalebatchesmadewiththematerialshouldbeprovided.Theexaminationshouldbesimilarinscopeandextenttothetestinginvolvedinqualifyinganewreferencestandard.對(duì)于依據(jù)21CFR314.70(c)(3)所做的改變類(lèi)型，只要有對(duì)合成過(guò)程的changesofthetypepermittedby21CFR314.70(c)(3),anadequatesynthesisdescriptiononfilewouldfacilitateaconclusionthatchangesinsiteofmanufactureofthenewdrugsubstancedonotrequirepriorFDAapprovalforimplementation.4標(biāo)準(zhǔn)品Reference原始遞交的申報(bào)文件應(yīng)該包括任何所使用的參照標(biāo)準(zhǔn)品的過(guò)程的描述，包括對(duì)提純步驟的描述，參見(jiàn)II.F.3.Theoriginalapplicationshouldincludeafulldescriptionofthepreparationofanyreferencestandardsubstanceused,includingthedescriptionofthepurificationsteps.SeealsosectionII.F.3.II.D.4.五、1、和生產(chǎn)過(guò)程的控制IntermediatesandIn-process，相關(guān)要求在合成過(guò)程中選擇一些中間環(huán)節(jié)實(shí)施控（檢測(cè)項(xiàng)目與參數(shù)要求以保證合成和提純工序順利進(jìn)行檢測(cè)后的適合于以后的加工。申請(qǐng)者可以根據(jù)對(duì)整個(gè)合成工藝的開(kāi)發(fā)和確認(rèn)的經(jīng)驗(yàn)自行確定對(duì)那些或加行了檢驗(yàn)（至少是對(duì)反應(yīng)的內(nèi)容），每一個(gè)至少都進(jìn)行與純度有關(guān)參數(shù)的測(cè)定，包括純度的估計(jì)。隨著合成經(jīng)驗(yàn)的積累，應(yīng)選擇關(guān)鍵的反應(yīng)步驟和進(jìn)行。在遞交新藥申請(qǐng)(NDA)時(shí)，生產(chǎn)過(guò)程的控制點(diǎn)應(yīng)該已經(jīng)選定，相關(guān)控制參數(shù)和檢驗(yàn)方法也已確立，以滿足法律的要求。Theregulationsrequirethatcontrols(specificationsandtests)beemployedatselectedintermediatestagesofthesyntheticprocesstoassurethatthesyntheticandpurificationproceduresareoperatingproperlyandthattheintermediatetestedissuitableforsubsequentprocessing.Thechoiceofwhichintermediate(s)orstepsintheprocesstotest,andthekindoftestingrequired,aretheresponsibilityoftheapplicantbasedonhisexperienceduringthedevelopmentandverificationofthetotalsyntheticprocess.Inearlydevelopmentwork,everystepwouldusuallyhavebeenexaminedatleastforextentofreaction)andeveryintermediateatleastpartiallycharacterizedwithsomeestimateofpurityAsexperienceisgainedwiththesynthesisthecriticalreactionstepsandintermediatestobemonitoredareselected.AtthetimeofNDAsubmission,in-processcontrolpointsshouldhavebeenselectedandappropriatespecificationsandtestsestablishedtomeettherequirementsoftheregulations.，和的根據(jù)。應(yīng)當(dāng)證明控制參數(shù)和檢測(cè)方法對(duì)合成過(guò)程的控制是充分的。應(yīng)當(dāng)依據(jù)相關(guān)控制點(diǎn)（控制參數(shù)和檢測(cè)方法）來(lái)提供控制參數(shù)范圍的描程的控制程序。該控制程序的改變需要額外的驗(yàn)證（參見(jiàn)：IV）。Thiswholeoperationispartoftheprocessvalidationofthesynthesis.Thebasisforselectingcontrolpointsandintermediatesshouldbeexined,andtheadequacyofthespecificationsandteststocontrolthesyntheticprocessdemonstrated.Therangesfortheoperatingparametersinthewrittendescriptionofthesynthesisshouldbechoseninlightofthecontrols(specificationsandtests).Generally,broadoperatingrangeswillrequirestrictercontrols.(SeealsosectionII.E.b.(recoveryandrework)below.)WithadditionalexperiencesubsequenttoNDAapproval,thechoiceandnatureofin-processcontrolproceduresmayrequiremodification.Changesinin-processcontrolprocedureswillrequireadditionalvalidation(seesectionIV).Controlsmaybedesigned證明已獲得了想要生產(chǎn)的產(chǎn)品demonstratethatthedesiredproducthasbeen確定關(guān)鍵的物理特征（如：、旋光度等）determineakeyphysicalproperty(e.g.,meltingpoint,opticalrotation,etc.);確定的純度和雜質(zhì)determinepurity/impurityofthe確定收率是限定在通常的操作范圍之內(nèi)determinethattheyieldiswithinthenormaloperatingrange.在某些情況下，對(duì)的控制是不可行的（如：它們處于溶液狀態(tài)或直接加工成下一個(gè)化合物）?？赡埽瑱z測(cè)也可僅限于對(duì)合成過(guò)程的（如：反應(yīng)是否完成）。Insomecasesnocontrolsfortheintermediatemaybefeasible(e.g.,wheretheyareheldinsolution,oraredirectlyprocessedtothenextcompound).Whenappropriate,testingmayconsistonlyofatestdesignedtomonitortheprogressofthesynthesis(i.e.,reactioncompletion).列過(guò)程控制的要求為減少最終的大規(guī)模清除從第一個(gè)到原料藥本身,中間體的純度應(yīng)該逐漸提高。Someoralloftheabovekindsofprocesscontrolsshouldbemetateachpointselectedforin-processcontroltesting.Pivotal,key,andfinalintermediatesseeGlossary,andbelow)wouldordinarilyrequireatleastthein-processcontrolslistedaboveToeliminatetheneedforheroicfinalcleanupsitisexpectedthatthedegreeofpurityofintermediateswillincreaseprogressively,fromthefirstintermediateontothedrugsubstanceitself.2、關(guān)鍵（見(jiàn)術(shù)語(yǔ)表）Pivotalintermediate(s)(See應(yīng)該用足夠的細(xì)節(jié)（如詳細(xì)描述其特征）描述任何關(guān)鍵，并作為控制參商或合成發(fā)生改變時(shí)，要做以上檢查。當(dāng)關(guān)鍵接近成為最終時(shí)，對(duì)其進(jìn)行的檢測(cè)程度和純度要求也應(yīng)該增加Anypivotalintermediateshouldbedescribedinadequatedetail(i.e.,bewellcharacterized)andbesubjecttorigorousexaminationproceduresaspartofthespecificationsandtests,includingthoroughchromatographicexaminationsoastoavoidoverlookingimpuritiesarisingfromalternativesyntheses.Suchrigorousexaminationneednotberoutinebutmaybeneededinspecialcircumstancessuchaswhentherorsynthesisischanged.Thedegreeoftestingandthelevelofpurityrequiredforapivotalintermediateshouldincreaseasitspositioninthesynthesisschemeapproachesthefinalintermediate.3、（參見(jiàn)術(shù)語(yǔ)表）Keyintermediate(s)(Seespecificationsshouldbeadequatetoassurethatthemoleculararchitecturenecessaryforthefinalproduct,aswellastherequisitedegreeofpurity,havebeenattained.Testproceduresshouldthusshowthatthedesiredtransformation(suchasintroductionofchirality,orastereospecificreaction)hasoccurredinthemannerexpectedandwithinthenormalyieldrangeexpected,andshowbytativedetermination(s)thatundesiredmaterials(e.g.,isomers,by-products,startingmaterials)arewithinestablishedlimits.4、最終（參見(jiàn)術(shù)語(yǔ)表）Finalintermediate(see關(guān)于最終的規(guī)格和檢驗(yàn)應(yīng)該與原料藥的規(guī)格和檢驗(yàn)同樣廣泛和嚴(yán)格因?yàn)檫@是最終反應(yīng)前的最后純度和雜質(zhì)的機(jī)會(huì)。Specificationsandtestsforfinalintermediateshouldbenearlyasextensiveandstringentasthoseforthenewdrugsubstanceitself,becausethisisthelastopportunitytomonitorpurityandimpuritiesbeforethefinalreaction.5、返工對(duì)不符合加工規(guī)格要求的，可以按照新藥申請(qǐng)(NDA)中所描述的提純方受最后加工操作與檢驗(yàn)。Intermediateswhichdonotmeetin-processspecificationsmaybefurtherpurifiedusingthesamepurificationproceduredescribedintheNDA.Whenanalternatepurificationprocedureisused,therecoveredmaterialshouldbesubjectedtothesamefinalprocessingoperationandthesametestingasforthefirst（如：偏離或較小的背離），應(yīng)當(dāng)采用什么樣的程序，來(lái)使該批或原料應(yīng)該按使用分析標(biāo)準(zhǔn)參照品是否合格的程序來(lái)進(jìn)行檢驗(yàn)。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，當(dāng)雜質(zhì)含量積累時(shí)，它并（GP第IV節(jié)和“關(guān)于大宗藥用化學(xué)物制造的現(xiàn)場(chǎng)檢查指南”）。Inprossontrolprodurshouldbetblihdndderibedforthehndlingofmothrliquorsndrovryofondropswhnthisisdon;etionII..3..hilethereueofmothrliquorsndrovryfondropsmaybeommon/normalprtiendisptablefromaGPviepoint,itisnotnsarilyptablei.whnimpritylevlsbuildup),ndxteniverylingfmotrliqursrrptedrovriesofdditionalropsisdiourgdrfrtotionVGPndtheGuidlinefrInptionofulkPhrmautilhmilnufctur"inthisrgrd.)母液的回收程序應(yīng)該包括在批產(chǎn)品生產(chǎn)中新藥申請(qǐng)(NDA)中應(yīng)規(guī)定對(duì)不符次再結(jié)晶來(lái)完成。不需要額外的分析檢驗(yàn)。Therecoveryproceduresshouldbeincludedinbatchproductionrecords.ProvisionshouldbemadeintheNDAforthetypicalandusualreprocessprocedurefordrugsubstancewhichfailstomeetspecifications,usuallybyoneormoreadditionalrecrystallizationsfromthefinalsolvent.Extraordinaryyticalexaminationisnotrequiredinthiscase.不符合既定標(biāo)準(zhǔn)的單一批產(chǎn)品可以通過(guò)適當(dāng)?shù)某绦騺?lái)純化，然后按照新藥申請(qǐng)()AinglebtchfdrugubtanewhihfilstometpifictionsmaybepurfiedbynpproriaterodurendthenprodbythemefinalpurifictionproduredribedintheNA,providedthtthepurityoftherprodmatrialbingotrtedinthefinalpurfictiontepissgoodsthenormaldrugubtanetthistageofroing.由客戶退回的產(chǎn)品）可以用同樣的方法加工。Sometypesofbulkdrugsubstanceforsalvage(e.g.,accumulatedunusedyticalsamples,unusedportionsoflots,bulkreturnedfromcustomers)maybeprocessedinthisfashion.為使不合格的批可再利用而進(jìn)行的混批是不能接受的。Suchreworkeddrugsubstancebatchesshouldbesubjectedtoadditional yticalexamination,asindicatedabove(i.e.,fordrugsubstanceresultingfromminordeviationsofprocessconditions).Thereworkoperation,andthereasonforit,shouldbeed.Theblendingofbatchesorlotsforthepurposeofsalvagingunsatisfactorybatches,withoutsubsequentadditionalpurificationbyanappropriateprocedureandprocessingbythefinalpurificationstepdescribedintheNDA,isnotpermittedundercurrentguidelines.“化學(xué)原料藥生產(chǎn)現(xiàn)場(chǎng)檢查指南”。IfnotpartoftheoriginalNDA,asupplementshouldbesubmittedtotheNDAwhenastandard(validated)reprocessingprocedureforunsatisfactorybulkdrugsubstanceistoberoutinelyemployed;refertotheGuidetoInspectionofBulkPharmaceuticalChemicalManufacturing."“關(guān)于提交制劑產(chǎn)品生產(chǎn)和控制文件的指南”。這樣的操作需要提供補(bǔ)充資料。Whendrugsubstanceistoberecoveredfromdosageforms,referenceshouldalsobemadetothe"GuidelineforSubmittingationfortheManufactureofandControlsforDrugProducts."Thistypeofoperationwillrequirea六、息，以定義這些控制參數(shù)和檢驗(yàn)方法。Theregulationsrequirespecificationsandyticalmethods(i.e.,releasecontrolsforthenewdrugsubstance)tohelpassurethattheproperidentity,strength,quality,andpurityofthedrugsubstancehavebeenattainedandareconsistentfrombatchtobatch.Thefollowinginformationshouldbesubmittedtodefinethesespecificationsandtestmethods:1的依據(jù)；抽樣應(yīng)該滿足相關(guān)統(tǒng)計(jì)學(xué)的考慮。SamplingrequirementsarecoveredbyCGMPregulations(seesectionIV).Thesamplingnshouldbedescribed,givingthebasisforthen;itshouldsatisfyappropriatestatisticalconsiderations.2、放行控制Release對(duì)放行中可能使用的規(guī)格和檢驗(yàn)標(biāo)準(zhǔn)，舉例如下：Examplesofspecificationsandteststhatmaybeapplicableareasfollows:外觀/描述物理特性（如：熔化范圍、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).鑒別檢查（如：紅外線(IR)、核磁的(NMR)和質(zhì)譜測(cè)定法(MS)）Specificidentitytest(s)(i.e.,infrared(IR),nuclearmagneticresonance(NMR),andmassspectrometry(MS)).種色析法的相對(duì)保留時(shí)間[R[f]或T[R]值]，將被認(rèn)為是確認(rèn)性的而不是專(zhuān)屬性別。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:該方法能夠檢測(cè)雜質(zhì)與溶解雜質(zhì)（如：方法的靈敏性和專(zhuān)屬性）Abilitythemethodtodetectandresolveimpurities(i.e.,thesensitivityandspecificityofthe定量和線性tation,andlinearityof雜質(zhì)特性（如：起始原料、、降解物）natureoftheimpurity(e.g.,startingmaterial,intermediate,degradationproduct);分類(lèi)([如：還未被從化學(xué)上確定的])laifiction(.g.,majrorminotoxi,kownorunknown[i..,notythmillyidentifiedrhrteriz]);雜質(zhì)的分離純化與結(jié)構(gòu)證明（如：鑒別和特征），需要時(shí)與樣品進(jìn)行比較isolation,purification,andproofofstructure(i.e.,identificationandcharacterization),includingthepreparationofauthenticspecimensforcomparisonwhenneeded.驗(yàn)是充分的，并已做了合理的努力來(lái)鑒別和描述它們的特征）。Thesectiononimpuritiesintheapplicationshoulddemonstratethatalltheabovepointshavebeenconsideredi.ethattheexaminationofthenewdrugsubstanceforimpuritieshasbeenadequate,andthatreasonableeffortshavebeenmadetofullyidentifyand/orcharacterizethem).測(cè)方法，參照II.F.3.節(jié)（參照標(biāo)準(zhǔn)）。Structuresofknownimpurities,andvalidationoftheyticalmethods,shouldbeprovided(followingtheSpecificationsandTests)andbereferencedinsectionII.F.3.(ReferenceStandard).Allmajorimpuritiesshouldbeindividuallylimited.Theumamountperunitdoesofeveryindividualimpurityshouldbeprovided.Ifthereisinformationontoxicityorinformationontoxiclimitsthathavebeensetfortheseimpurities,thisinformationshouldbeprovided.所有雜質(zhì)（單個(gè)與總雜質(zhì)，并包括那些未知的）。Asummarytabulationoftheresultsfromtheyticalexaminationofindividualbatchesofthedrugsubstanceusedinanimalandclinicaltesting,listingallimpuritiesindividuallyaswellastotal,andincludingthosewhichareunidentified),shouldbeprovided.含量測(cè)定用同樣的方法測(cè)量原料藥和雜質(zhì)（如：HPLC法）。由于需要一個(gè)專(zhuān)屬的鑒別檢Theassayforthedrugsubstanceshouldbespecificifpossiblesinceitcanthenbeusedforstability-indicatingpurposes.Itmaybepracticaltomeasurethedrugsubstanceandimpuritiesbythesameprocedure(e.g.,highpressureliquidchromatography(HPLC)).Sinceaspecificidentitytestisrequired,assayspecificityisnotessentialwhenimpuritieswhichmightinterferearecontrolled(andlimited)bysuitable(e.g.,chromatographic)methods;inthesecircumstancesnon-specificassaymethods,suchasapotentiometrictitration,maybeemployed.新原料藥DNA的制定一個(gè)含量的范圍和雜質(zhì)的限度，應(yīng)該基于實(shí)際的生產(chǎn)結(jié)（如：通過(guò)對(duì)單批產(chǎn)品的分析）。最好是按照實(shí)際條件下的化合物的穩(wěn)定性，制定再檢測(cè)日期。TheassaylimitsestablishedintheNDAforthenewdrugsubstance,aswellasthelimitsforimpurities,shouldbebasedonactualmanufacturingresults(i.e.,from ysesofindividualbatches).Aretestdate,basedonthestabilityofthecompoundunderactualstorageconditions,isdesirable.Microencapsulatedcompoundsshouldal