合成原料藥dmf起草大綱

使用說明1、本大綱是為了幫助我公司客戶把握DMF的整體內容而準備的，由于DMF內容繁多，從整體上了解和組成部分，對于理解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容，原料藥制造商均3、本大綱的內容和相關要求能夠確保客戶目前的運作達到FDAcGMPDMF的過程，也使客戶按照FDA的要求進行整改和提高FDA未來的現(xiàn)場檢查打下的與此大綱配套的相關DFM指導性文件，包括《FDA藥物主文件指《藥物申辦中方面通用技術文件格式與內容要求》5、凡是本大綱中提到的技術性具體內容要求，如雜質、穩(wěn)定性、驗證等具體技術要求，請參照本公司專有的A相關技術標準文件，驗證指南》等；《合成原料藥DMF起草大綱一、公司和生產場地1、第一類的DMF文件建議由位于之外的人提供，以幫助FDA對他們的生產設施進行現(xiàn)場檢查。DMF文件應描述生產場地、設備能力、生產流程圖等。ATypeIDMFis mendedfora outsideoftheUnitedStatestoassistFDAinconductingonsiteinspectionsoftheirmanufacturingfacilities.TheDMFshoulddescribethemanufacturingsite,equipmentcapabilities,andoperational2、第一類的DMF文件對國內設施通常不需要，除非該設施沒有登記并定期接受檢查。ATypeIDMFisnormallynotneededtodescribedomesticfacilities,exceptinspecialcases,suchaswhena isnotregisteredandnotroutinely圖。提供該場地的鳥瞰圖和平面圖。Thedescriptionofthesiteshouldincludeacreage,actualsiteaddress,andamapshowingitslocationwithrespecttothenearestcity.Anaerialphotographandadiagramofthesitemaybehelpful.別新或獨特的設備。Adiagramofmajorproductionandprocessingareasishelpfulforunderstandingtheoperationallayout.Majorequipmentshouldbedescribedintermsofcapabilities,application,andlocation.Makeandmodelwouldnotnormallybeneededunlesstheequipmentisneworunique.5制、質量保證崗位，Adiagramofmajorcorporateorganizationalelements,withkeymanufacturing,qualitycontrol,andqualityassurancepositionshighlighted,atboththemanufacturingsiteandcorporateheadquarters,isalsohelpful.二、原料藥的物理和化學特1、特性相關要求對原料藥的物理和化學特征做出詳細描述該要求可以通過提供下述信息來滿足：名稱（通用名、化學名、編碼等）、化學服務(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、折射方法”和有關描述蛋白質特性的專論。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.藝的復雜性的增加。Theitemsabovearenotnecessaryorappropriateforallsubmissions.Additionalinformationmayberequired,particularlyasthestateoftheartprogresses.2、結構（應當基于一個合適的物理和化學檢測結果這包括以下內容元素分析質譜分析(S)核磁(N)紫外(U)和紅外(I)（X（（功能團分析，衍生作用，絡合形式等）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、相關要求對原料藥的穩(wěn)定性做全面的描述。具體要求，參見“關于提交人類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（物的異構體）被混入原料藥時，應提供純度如包括雜質的定量與定性色譜測的分析方法。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、詳細的合成信包括整個合成過程的流程圖以及每一合成步驟的說明）。Anapplicantshouldprovidecompleteinformationonthesynthesis,fromstartingmaterial(s)tothebulknewdrugsubstance.Thedescriptionshouldcontainadiagrticflowchartofthewholesynthesisandawrittenstatementforeachstepofthesynthesis.合成流程圖FlowchartoftheTheflowcharttypicallyshouldcontainthe反應物和產品的化學結構（如：起始原料、，以及引入到結構中的分子）Chemicalstructuresofreactants(i.e.,startingmaterialsandintermediates,andalsomoleculesincorporatedintothestructure)and)立體化學結構，如果有立體化學構Stereochemicalconfigurations,where（未分離的或已分離的）Intermediateseitherinsituor溶媒、催化劑和試劑Solventscatalystsand反應所產生的產品與副產品混合比率(如：兩個或異構體)應該顯示在流程圖 示出來（參見：第II.D.2.c.II.F.3.）Aratioormixtureofproductse.gtwoormoreisomers)producedbyareactionshouldbeshownintheflowchart.Significantsideproductsandimpurities,particularlythosethatinterferewiththeyticalproceduresoraretoxic,shouldbeillustratedseparay(seesectionsII.D.2.c.and合成描述Descriptionofthe每一個合成步驟的描述以及更詳細的最后加工步驟的描述應該包括以下內容Thewrittenstatementforeachstepofthesynthesis,withgreaterdetailincludedtowardthefinalstepsoftheprocess,shouldincludethe用于反應的典型設備Typicalequipmentusedforthe反應物（本步驟所使用的起始原料或，包括化學名稱和數(shù)量）Reactantsstartingmaterialorintermediateusedinthestep,withchemicalnamesand溶媒、催化劑和試劑（注明化學名稱和數(shù)量）Solventscatalystsandreagents(chemicalnamesandamounts);反應條件（溫度，pH值，時間，壓力等）ConditionstemperaturepH,time,pressure,etc.);反應完成的檢測，如果有的話。Testsforcompletionofreaction,if分離的程序Workupandisolation原料藥和的純化過程，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).料藥提純的內容)。Thefinalstepofthesynthesisandtheisolationofthecrudenewdrugsubstance,aswellasitspurification,shouldbeprovidedinfulldetail.(SeesectionII.D.2.cbelowregardingpurificationofthedrugsubstance.)除了提供合成的描述，還包括經過確認的操作參數(shù)范圍（參見第II節(jié)-E工藝控制）IV節(jié)[CGMP])以及預期收率，遞交者同時要提供實際操作的的拷貝，它應該包括更詳細的內容。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括以下內容：Thedescriptionofthepurificationofthecrudenewdrugsubstanceanditsisolationfromthefinalreactionstepmixtureshouldbegivenindetail,andshould原料藥的收率范圍Theyieldrangesofthecrude任何用于判斷原料產品純度的檢驗。（參見下面第6條）Anytestsperformedonthecrudeproducttodetermineitspurityseeitem6,below);回收。Adetaileddescriptionoftheisolationandpurificationprocedurese.g.,forrecrystallization:thesolventused,thetyofsolventinrelationtotheamountofcrudeproduct,whetheritisfilteredwhilehot,whetheradecolorizingagentisused,therateofcoolingandthefinaltemperature,theuseorre-useofanymotherliquors,andifsecondcropsareobtained);purificationproceduresseethelastparagraphofsectionII.D.2.bseealsosectionII.G.);提純產品的收率范圍（重量和百分比）Theyieldrangeweightandpercent)ofthepurifiedproduct;證明提純過程增加純度的有關，例如色析法的前后對比Evidencedemonstratingthatthepurificationprocedureimprovesthepurity,suchasbefore-and-afterchromatographicillustrations.當提純工藝被驗證后，只需提供最初產品批次的檢驗相關信息。Thistestingandinformationmaybenecessaryonlyoninitialproductionbatchesoncethepurificationprocesshasbeenverifiedorvalidated.合成的變化ChangesintheDMF的補充來提交。為改變新藥物遞交(NDA)中已經包括有關溶媒的改變。ProposedchangesinthesynthesisshouldbesubmittedtotheapplicationasasupplementforanapprovedNDAorasanamendmenttoanIND,aDMF,orapendingNDA.Anapprovedsupplementisrequired21CFR314.70(b)(1)(iv)]tochangethemethodofsynthesisapprovedintheNDAforthedrugsubstance,includingachangeinsolvents.容不同時應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II.GWhenthereisachangeinthesolventusedforthefinalcrystallizationofthenewdrugsubstance,thenewdrugsubstanceshouldbeexaminedforchangesincrystallineformand/orsolvation;refertosectionII.G.Thenewdrugsubstancemustmeetitsoriginalspecificationsforcrystallineformand/orsolvation.該改變可以產生同等質量和純度的產品（化合物或）的，但無需考慮形態(tài)學問題。Solventchangesforotherreactionstepsorpurificationsalsorequireasupplementalapplication.Theapplicationshouldcontainevidencethatthechangeaffordsmaterial(compoundorintermediate)ofequivalentqualityandpurity,butmorphologyneednotbeconsidered.如果遞交者想縮短新藥遞交(NA)中批準的合成方法或者通過重新定義起始原料時，則需要提交一個補充文件(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，而且，必須滿足起始材料b"和c"標準要求。Anpprovdupplemntisrquird(21FR314.70b)(1)fnpplintwntstohortentheyntheispprovdintheNAordvlopanwyntheticmethodbyrdfiningthetartingmatrial,inordrtomployaompoundlatrintheyntheisthaths ommriallyvilble.ThisompoundmuthvebnnintrmediteinthepprovdNAynthei,ndmutmetboththeb"nd"ritriafortartingmatrial.beusedatleasttwofullstepsbeforethenewdrugsubstanceifpossible(i.e.,itshouldbepriortothefinalintermediate).Additionalinformationonthecharacterizationandpurityprofileofthestartingmaterialmaybeneeded,dependingontheadequacyoftheliturereferencescited(copiesshouldbeprovided).對于學術期所的化合物，詳盡的材料就夠了（如：有關雜質檢驗的額外信息）。在有關專利中所規(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).和用于檢測一個新的參考標準品的相同。Acommitmenttosubmitresultsfromthoroughexaminationofthefirstthreefull-scalebatchesmadewiththematerialshouldbeprovided.Theexaminationshouldbesimilarinscopeandextenttothetestinginvolvedinqualifyinganewreferencestandard.對于依據(jù)21CFR314.70(c)(3)所做的改變類型，只要有對合成過程的changesofthetypepermittedby21CFR314.70(c)(3),anadequatesynthesisdescriptiononfilewouldfacilitateaconclusionthatchangesinsiteofmanufactureofthenewdrugsubstancedonotrequirepriorFDAapprovalforimplementation.4標準品Reference原始遞交的申報文件應該包括任何所使用的參照標準品的過程的描述，包括對提純步驟的描述，參見II.F.3.Theoriginalapplicationshouldincludeafulldescriptionofthepreparationofanyreferencestandardsubstanceused,includingthedescriptionofthepurificationsteps.SeealsosectionII.F.3.II.D.4.五、1、和生產過程的控制IntermediatesandIn-process，相關要求在合成過程中選擇一些中間環(huán)節(jié)實施控（檢測項目與參數(shù)要求以保證合成和提純工序順利進行檢測后的適合于以后的加工。申請者可以根據(jù)對整個合成工藝的開發(fā)和確認的經驗自行確定對那些或加行了檢驗（至少是對反應的內容），每一個至少都進行與純度有關參數(shù)的測定，包括純度的估計。隨著合成經驗的積累，應選擇關鍵的反應步驟和進行。在遞交新藥申請(NDA)時，生產過程的控制點應該已經選定，相關控制參數(shù)和檢驗方法也已確立，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)。應當證明控制參數(shù)和檢測方法對合成過程的控制是充分的。應當依據(jù)相關控制點（控制參數(shù)和檢測方法）來提供控制參數(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證（參見：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的產品demonstratethatthedesiredproducthasbeen確定關鍵的物理特征（如：、旋光度等）determineakeyphysicalproperty(e.g.,meltingpoint,opticalrotation,etc.);確定的純度和雜質determinepurity/impurityofthe確定收率是限定在通常的操作范圍之內determinethattheyieldiswithinthenormaloperatingrange.在某些情況下，對的控制是不可行的（如：它們處于溶液狀態(tài)或直接加工成下一個化合物）?？赡埽瑱z測也可僅限于對合成過程的（如：反應是否完成）。Insomecasesnocontrolsfortheintermediatemaybefeasible(e.g.,wheretheyareheldinsolution,oraredirectlyprocessedtothenextcompound).Whenappropriate,testingmayconsistonlyofatestdesignedtomonitortheprogressofthesynthesis(i.e.,reactioncompletion).列過程控制的要求為減少最終的大規(guī)模清除從第一個到原料藥本身,中間體的純度應該逐漸提高。Someoralloftheabovekindsofprocesscontrolsshouldbemetateachpointselectedforin-processcontroltesting.Pivotal,key,andfinalintermediatesseeGlossary,andbelow)wouldordinarilyrequireatleastthein-processcontrolslistedaboveToeliminatetheneedforheroicfinalcleanupsitisexpectedthatthedegreeofpurityofintermediateswillincreaseprogressively,fromthefirstintermediateontothedrugsubstanceitself.2、關鍵（見術語表）Pivotalintermediate(s)(See應該用足夠的細節(jié)（如詳細描述其特征）描述任何關鍵，并作為控制參商或合成發(fā)生改變時，要做以上檢查。當關鍵接近成為最終時，對其進行的檢測程度和純度要求也應該增加Anypivotalintermediateshouldbedescribedinadequatedetail(i.e.,bewellcharacterized)andbesubjecttorigorousexaminationproceduresaspartofthespecificationsandtests,includingthoroughchromatographicexaminationsoastoavoidoverlookingimpuritiesarisingfromalternativesyntheses.Suchrigorousexaminationneednotberoutinebutmaybeneededinspecialcircumstancessuchaswhentherorsynthesisischanged.Thedegreeoftestingandthelevelofpurityrequiredforapivotalintermediateshouldincreaseasitspositioninthesynthesisschemeapproachesthefinalintermediate.3、（參見術語表）Keyintermediate(s)(Seespecificationsshouldbeadequatetoassurethatthemoleculararchitecturenecessaryforthefinalproduct,aswellastherequisitedegreeofpurity,havebeenattained.Testproceduresshouldthusshowthatthedesiredtransformation(suchasintroductionofchirality,orastereospecificreaction)hasoccurredinthemannerexpectedandwithinthenormalyieldrangeexpected,andshowbytativedetermination(s)thatundesiredmaterials(e.g.,isomers,by-products,startingmaterials)arewithinestablishedlimits.4、最終（參見術語表）Finalintermediate(see關于最終的規(guī)格和檢驗應該與原料藥的規(guī)格和檢驗同樣廣泛和嚴格因為這是最終反應前的最后純度和雜質的機會。Specificationsandtestsforfinalintermediateshouldbenearlyasextensiveandstringentasthoseforthenewdrugsubstanceitself,becausethisisthelastopportunitytomonitorpurityandimpuritiesbeforethefinalreaction.5、返工對不符合加工規(guī)格要求的，可以按照新藥申請(NDA)中所描述的提純方受最后加工操作與檢驗。Intermediateswhichdonotmeetin-processspecificationsmaybefurtherpurifiedusingthesamepurificationproceduredescribedintheNDA.Whenanalternatepurificationprocedureisused,therecoveredmaterialshouldbesubjectedtothesamefinalprocessingoperationandthesametestingasforthefirst（如：偏離或較小的背離），應當采用什么樣的程序，來使該批或原料應該按使用分析標準參照品是否合格的程序來進行檢驗。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，當雜質含量積累時，它并（GP第IV節(jié)和“關于大宗藥用化學物制造的現(xiàn)場檢查指南”）。Inprossontrolprodurshouldbetblihdndderibedforthehndlingofmothrliquorsndrovryofondropswhnthisisdon;etionII..3..hilethereueofmothrliquorsndrovryfondropsmaybeommon/normalprtiendisptablefromaGPviepoint,itisnotnsarilyptablei.whnimpritylevlsbuildup),ndxteniverylingfmotrliqursrrptedrovriesofdditionalropsisdiourgdrfrtotionVGPndtheGuidlinefrInptionofulkPhrmautilhmilnufctur"inthisrgrd.)母液的回收程序應該包括在批產品生產中新藥申請(NDA)中應規(guī)定對不符次再結晶來完成。不需要額外的分析檢驗。Therecoveryproceduresshouldbeincludedinbatchproductionrecords.ProvisionshouldbemadeintheNDAforthetypicalandusualreprocessprocedurefordrugsubstancewhichfailstomeetspecifications,usuallybyoneormoreadditionalrecrystallizationsfromthefinalsolvent.Extraordinaryyticalexaminationisnotrequiredinthiscase.不符合既定標準的單一批產品可以通過適當?shù)某绦騺砑兓缓蟀凑招滤幧暾?)AinglebtchfdrugubtanewhihfilstometpifictionsmaybepurfiedbynpproriaterodurendthenprodbythemefinalpurifictionproduredribedintheNA,providedthtthepurityoftherprodmatrialbingotrtedinthefinalpurfictiontepissgoodsthenormaldrugubtanetthistageofroing.由客戶退回的產品）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行的混批是不能接受的。Suchreworkeddrugsubstancebatchesshouldbesubjectedtoadditional yticalexamination,asindicatedabove(i.e.,fordrugsubstanceresultingfromminordeviationsofprocessconditions).Thereworkoperation,andthereasonforit,shouldbeed.Theblendingofbatchesorlotsforthepurposeofsalvagingunsatisfactorybatches,withoutsubsequentadditionalpurificationbyanappropriateprocedureandprocessingbythefinalpurificationstepdescribedintheNDA,isnotpermittedundercurrentguidelines.“化學原料藥生產現(xiàn)場檢查指南”。IfnotpartoftheoriginalNDA,asupplementshouldbesubmittedtotheNDAwhenastandard(validated)reprocessingprocedureforunsatisfactorybulkdrugsubstanceistoberoutinelyemployed;refertotheGuidetoInspectionofBulkPharmaceuticalChemicalManufacturing."“關于提交制劑產品生產和控制文件的指南”。這樣的操作需要提供補充資料。Whendrugsubstanceistoberecoveredfromdosageforms,referenceshouldalsobemadetothe"GuidelineforSubmittingationfortheManufactureofandControlsforDrugProducts."Thistypeofoperationwillrequirea六、息，以定義這些控制參數(shù)和檢驗方法。Theregulationsrequirespecificationsandyticalmethods(i.e.,releasecontrolsforthenewdrugsubstance)tohelpassurethattheproperidentity,strength,quality,andpurityofthedrugsubstancehavebeenattainedandareconsistentfrombatchtobatch.Thefollowinginformationshouldbesubmittedtodefinethesespecificationsandtestmethods:1的依據(jù)；抽樣應該滿足相關統(tǒng)計學的考慮。SamplingrequirementsarecoveredbyCGMPregulations(seesectionIV).Thesamplingnshouldbedescribed,givingthebasisforthen;itshouldsatisfyappropriatestatisticalconsiderations.2、放行控制Release對放行中可能使用的規(guī)格和檢驗標準，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)和質譜測定法(MS)）Specificidentitytest(s)(i.e.,infrared(IR),nuclearmagneticresonance(NMR),andmassspectrometry(MS)).種色析法的相對保留時間[R[f]或T[R]值]，將被認為是確認性的而不是專屬性別。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:該方法能夠檢測雜質與溶解雜質（如：方法的靈敏性和專屬性）Abilitythemethodtodetectandresolveimpurities(i.e.,thesensitivityandspecificityofthe定量和線性tation,andlinearityof雜質特性（如：起始原料、、降解物）natureoftheimpurity(e.g.,startingmaterial,intermediate,degradationproduct);分類([如：還未被從化學上確定的])laifiction(.g.,majrorminotoxi,kownorunknown[i..,notythmillyidentifiedrhrteriz]);雜質的分離純化與結構證明（如：鑒別和特征），需要時與樣品進行比較isolation,purification,andproofofstructure(i.e.,identificationandcharacterization),includingthepreparationofauthenticspecimensforcomparisonwhenneeded.驗是充分的，并已做了合理的努力來鑒別和描述它們的特征）。Thesectiononimpuritiesintheapplicationshoulddemonstratethatalltheabovepointshavebeenconsideredi.ethattheexaminationofthenewdrugsubstanceforimpuritieshasbeenadequate,andthatreasonableeffortshavebeenmadetofullyidentifyand/orcharacterizethem).測方法，參照II.F.3.節(jié)（參照標準）。Structuresofknownimpurities,andvalidationoftheyticalmethods,shouldbeprovided(followingtheSpecificationsandTests)andbereferencedinsectionII.F.3.(ReferenceStandard).Allmajorimpuritiesshouldbeindividuallylimited.Theumamountperunitdoesofeveryindividualimpurityshouldbeprovided.Ifthereisinformationontoxicityorinformationontoxiclimitsthathavebeensetfortheseimpurities,thisinformationshouldbeprovided.所有雜質（單個與總雜質，并包括那些未知的）。Asummarytabulationoftheresultsfromtheyticalexaminationofindividualbatchesofthedrugsubstanceusedinanimalandclinicaltesting,listingallimpuritiesindividuallyaswellastotal,andincludingthosewhichareunidentified),shouldbeprovided.含量測定用同樣的方法測量原料藥和雜質（如：HPLC法）。由于需要一個專屬的鑒別檢Theassayforthedrugsubstanceshouldbespecificifpossiblesinceitcanthenbeusedforstability-indicatingpurposes.Itmaybepracticaltomeasurethedrugsubstanceandimpuritiesbythesameprocedure(e.g.,highpressureliquidchromatography(HPLC)).Sinceaspecificidentitytestisrequired,assayspecificityisnotessentialwhenimpuritieswhichmightinterferearecontrolled(andlimited)bysuitable(e.g.,chromatographic)methods;inthesecircumstancesnon-specificassaymethods,suchasapotentiometrictitration,maybeemployed.新原料藥DNA的制定一個含量的范圍和雜質的限度，應該基于實際的生產結（如：通過對單批產品的分析）。最好是按照實際條件下的化合物的穩(wěn)定性，制定再檢測日期。TheassaylimitsestablishedintheNDAforthenewdrugsubstance,aswellasthelimitsforimpurities,shouldbebasedonactualmanufacturingresults(i.e.,from ysesofindividualbatches).Aretestdate,basedonthestabilityofthecompoundunderactualstorageconditions,isdesirable.Microencapsulatedcompoundsshouldal