FDA對藥物雜質(zhì)的控制要求Dr.GeorgeMa馬小波博士Toronto,CANADA多倫多市，加拿大國家食品藥品監(jiān)督管理局培訓(xùn)中心高級(jí)培訓(xùn)班

“美國仿制藥申報(bào)最新要求和案例分析”FDA對藥物雜質(zhì)的控制要求Dr.GeorgeMa國家食1FDA對藥物雜質(zhì)的控制要求：Contents目錄原料藥與成品藥中的有機(jī)雜質(zhì)有機(jī)雜質(zhì)來源和控制有機(jī)雜質(zhì)控制限度的論證案例分析：雜質(zhì)控制限度的設(shè)置和論證練習(xí)-雜質(zhì)控制限度的設(shè)置和論證原料藥與成品藥中的殘留溶劑殘留溶劑的指導(dǎo)原則和控制限額的建立案例分析：如何建立殘留溶劑控制限額具有基因毒性雜質(zhì)的控制練習(xí)-殘留溶劑控制限額的建立和論證FDA對藥物雜質(zhì)的控制要求：Contents目錄原料藥與成2DrugProductionandQualityControl

SynthesisofAPIDrugProductionandQualityCo3FDA對藥物雜質(zhì)的控制要求

原料藥與成品藥中的有機(jī)雜質(zhì)1999年11月，F(xiàn)DA-“仿制藥申請的原料藥雜質(zhì)研究指導(dǎo)原則”，“仿制藥申請的制劑雜質(zhì)研究指導(dǎo)原則”。2003年，ICH修訂的Q3A(R)“新原料藥雜質(zhì)研究指導(dǎo)原則”，“新制劑的雜質(zhì)研究指導(dǎo)原則”（簡稱Q3B(R))。雜質(zhì)分類有機(jī)雜質(zhì)合成雜質(zhì)(SyntheticImpurity)或工藝雜質(zhì)(ProcessImpurity)：一般來自生產(chǎn)過程中殘留的原料、中間體、試劑、配體和催化劑以及反應(yīng)副產(chǎn)物。只與原料藥的生產(chǎn)過程有關(guān)，在原料藥和制劑的儲(chǔ)存中一般不可能增長。通過對合成路線的分析可以確定某一雜質(zhì)是否為合成雜質(zhì)。

降解產(chǎn)物(DegradationProduct):來源于原料藥通過各種不同的化學(xué)反應(yīng)途徑的降解，一般需要結(jié)合對合成路線的分析和試驗(yàn)研究的結(jié)果，以確定某一雜質(zhì)是否為降解產(chǎn)物。

有的有機(jī)雜質(zhì)既是合成雜質(zhì)，又是降解產(chǎn)物。無機(jī)雜質(zhì)：來自生產(chǎn)過程所用的試劑（如氯化物）、配體和催化劑（如鈀，鉑等），包括重金屬或其它金屬殘留，以及無機(jī)鹽（例如，助濾劑、活性炭等）。它們通常是已知和確定的。殘留溶劑：生產(chǎn)過程中使用后未完全除去的溶劑（如甲醇、甲苯、四氫呋喃等），殘留的可揮發(fā)性試劑（如三乙胺等）和反應(yīng)中生成的可揮發(fā)產(chǎn)物。FDA對藥物雜質(zhì)的控制要求

原料4有機(jī)雜質(zhì)來源有機(jī)雜質(zhì)來源5常見的降解反應(yīng)常見的降解反應(yīng)6常見的降解反應(yīng)常見的降解反應(yīng)7確定降解產(chǎn)物-強(qiáng)制降解研究

（ForcedDegradationStudy)StressType強(qiáng)制降解類型CommonStress常用強(qiáng)制降解CommonForcedDegradationConditions常見強(qiáng)制降解條件SolutionStress溶液降解Acid酸0.1NHCl,室溫-100℃，4小時(shí)Base堿0.1NNaOH，室溫-100℃，4小時(shí)H2O2雙氧水1-3%H2O2，室溫，4小時(shí)Heat加熱H2O，100℃，4小時(shí)UV&VisuableLight紫外光和可見光（300-800nm）15小時(shí)（相當(dāng)于波長范圍為300-800nm,約2.0百萬勒克斯時(shí)Stress固態(tài)降解Thermal加熱60℃，14天Heat/humidity加熱/濕度40℃/75%RH，14天UV&VisuableLight紫外光和可見光（300-800nm）15小時(shí)（相當(dāng)于波長范圍為300-800nm,約2.0百萬勒克斯時(shí)強(qiáng)制降解試驗(yàn)：將原料藥或制劑置于比通常儲(chǔ)存條件劇烈得多的試驗(yàn)條件下進(jìn)行穩(wěn)定性考察的一系列試驗(yàn)。目的：了解該藥品的穩(wěn)定性及其降解途徑與降解產(chǎn)物。在一定程度上對有關(guān)物質(zhì)分析方法的專屬性進(jìn)行驗(yàn)證。實(shí)際操作：試劑的濃度、反應(yīng)的溫度和時(shí)間等都應(yīng)根據(jù)具體情況作調(diào)整。強(qiáng)制降解程度：根據(jù)經(jīng)驗(yàn)一般認(rèn)為，控制適當(dāng)?shù)膹?qiáng)制降解條件，從而達(dá)到大約10%的原料藥降解是比較合適的。常見的強(qiáng)制降解具體試驗(yàn)項(xiàng)目與試驗(yàn)條件確定降解產(chǎn)物-強(qiáng)制降解研究

（ForcedDegradat8確定降解產(chǎn)物-原料藥和制劑的穩(wěn)定性試驗(yàn)長期（25℃±2℃、相對濕度60%±5%、至少12個(gè)月）穩(wěn)定性試驗(yàn)加速（40℃±2℃、相對濕度75%±5%、至少6個(gè)月）穩(wěn)定性試驗(yàn)分析研究收集到的穩(wěn)定性測試數(shù)據(jù)（StabilityData）也是確定降解產(chǎn)物的重要依據(jù)之一。一般測定不同時(shí)間樣品的HPLC圖譜并進(jìn)行比較分析，并與長期保留制劑樣品的測定結(jié)果進(jìn)行比較。在強(qiáng)制降解試驗(yàn)研究過程中注意觀察樣品外觀性狀、原料藥含量等變化，并與雜質(zhì)檢查結(jié)果相互印證。原料藥和雜質(zhì)的分離和檢測：將可能的中間體和副產(chǎn)物作為雜質(zhì)進(jìn)行柱效、流動(dòng)相及流動(dòng)相比例、波長和分離度等方法學(xué)的研究。待方法建立成熟后，根據(jù)中間體和副產(chǎn)物的安全性和獲得雜質(zhì)標(biāo)樣的難易程度，決定是否定為已知雜質(zhì)。如果雜質(zhì)標(biāo)樣難以得到，且比較安全，可考慮采用雜質(zhì)校正因子加上相對保留時(shí)間的方法，或采用雜質(zhì)相對保留時(shí)間加上自身對照的方法，對該雜質(zhì)進(jìn)行定量分析。如果得不到該雜質(zhì)樣品作為標(biāo)樣，對于有紫外吸收的樣品可以用二極管陣列檢測器，考察未精制的粗品，并對比已精制過的樣品，確定粗品種各成分的分離度和樣品中可能雜質(zhì)的檢測波長。方法確立后，可采用自身對照方法或面積歸一化法控制雜質(zhì)。確定降解產(chǎn)物-原料藥和制劑的穩(wěn)定性試驗(yàn)長期（25℃±2℃9原料藥與成品藥中的有機(jī)雜質(zhì)藥品中有機(jī)雜質(zhì)的分類有機(jī)雜質(zhì)特定雜質(zhì)（SpecifiedImpurities)：特定雜質(zhì)是指在質(zhì)量標(biāo)準(zhǔn)中分別規(guī)定了明確的限度，并單獨(dú)進(jìn)行控制的雜質(zhì)。特定雜質(zhì)包括化學(xué)結(jié)構(gòu)已知的雜質(zhì)（SpecifiedIdentifiedImpurity)和化學(xué)結(jié)構(gòu)未知（SpecifiedUnidentifiedImpurity）的雜質(zhì)。美國藥典通常采用代號(hào)來指認(rèn)特定雜質(zhì)，如相關(guān)化合物A（RelatedCompoundA）等。非特定雜質(zhì)（UnspecifiedImpurities）：在標(biāo)準(zhǔn)中未單獨(dú)列出，而僅采用一個(gè)通用的限度進(jìn)行控制的一系列雜質(zhì)。其結(jié)構(gòu)未知，在藥品中出現(xiàn)的種類與幾率并不固定。一般采用合適的定性分析指標(biāo)加以指認(rèn)，如相對保留時(shí)間為3.5的雜質(zhì)。有機(jī)雜質(zhì)檢測確定原料藥和制劑中潛在的合成雜質(zhì)和降解產(chǎn)物，需要應(yīng)用專業(yè)的有機(jī)化學(xué)知識(shí)對有關(guān)合成化學(xué)反應(yīng)和條件、原料藥化學(xué)結(jié)構(gòu)、理化性質(zhì)、穩(wěn)定性等進(jìn)行全面的科學(xué)分析和論證，并且比較實(shí)驗(yàn)室對樣品的常規(guī)分析和強(qiáng)制降解（ForcedDegradationStudy），以及穩(wěn)定性研究的結(jié)果。原料藥與成品藥中的有機(jī)雜質(zhì)藥品中有機(jī)雜質(zhì)的分類10Impurities:Origination&Identification

ClassificationofimpuritiesSyntheticImpurities(Residualsubstancesinthesynthesis)StartingmaterialBy-productsIntermediatesDegradationduringsynthesisReagents,ligandsandcatalystsDegradationProductsHydrolysisOxidationEsterificationEliminationofwater,HCl,etc.DehydrogenationResidualSolvents/OVI’sSolvents/reagentsusedinthereactions,purificationprocessorformedduringreactionMeOH,EtOH,IPA,THF,Dichloromethane,Acetone,Triethylamine,etc.ImpurityResources-API&DrugProductManufacturingProcessesImpurities:Origination&Iden11Impurities:Origination&Identification

ListsofImpuritiesinICHOrganicimpuritiesEachidentifiedspecifiedimpurityEachunidentifiedspecifiedimpurityAnyunspecifiedimpuritywithanacceptancecriterionofnotmorethan(≤)thefigureintheidentificationthresholdinAttachment1,ICHQ3A(R)TotalimpuritiesResidualsolventsInorganicimpuritiesImpurities:Origination&Iden12有機(jī)雜質(zhì)控制限度設(shè)置美國藥典雜質(zhì)：在美國藥典正文（monograph）中列為特定雜質(zhì)（SpecifiedImpurities）的雜質(zhì)，其控制限度應(yīng)設(shè)置不高于美國藥典的限度。非美國藥典雜質(zhì)：如果美國藥典正文沒有對該雜質(zhì)設(shè)置控制限度，或者美國藥典沒有改藥物的正文，則根據(jù)ICH的雜質(zhì)指導(dǎo)原則Q3A(R)和Q3B(R)，同時(shí)也參考其它藥典，如歐洲藥典（EP）和英國藥典（BP）來設(shè)置該雜質(zhì)的控制限度。就ICH的雜質(zhì)指導(dǎo)原則來說，如果該雜質(zhì)在實(shí)驗(yàn)測試中的實(shí)際觀測水平高于ICH的鑒定限，則必須確定為特定雜質(zhì)，其控制限度必須設(shè)置為不高于ICH的論證限（QualificationThreshold）。非特定雜質(zhì)：在藥品中出現(xiàn)的種類與幾率并不固定。因此，在藥品的臨床前與臨床研究中，很難對這些雜質(zhì)的安全性進(jìn)行評(píng)估。為將這些雜質(zhì)可能帶來的安全性隱患降至最小，ICH的雜質(zhì)指導(dǎo)原則Q3A(R)和Q3B(R)對其限度用鑒定限（IdentificationThreshold）做了明確的規(guī)定，要求在原料藥標(biāo)準(zhǔn)中任何單個(gè)非特定雜質(zhì)的限度不得超過鑒定限。在仿制藥或改劑型藥品以及藥品上市后變更原料藥生產(chǎn)商等研究中，即使出現(xiàn)了新的雜質(zhì)，只要新雜質(zhì)的含量低于表中的鑒定限，就可以認(rèn)定這些新雜質(zhì)的安全性。有機(jī)雜質(zhì)控制限度設(shè)置美國藥典雜質(zhì)：在美國藥典正文（monog13有機(jī)雜質(zhì)控制限度設(shè)置FindouttheMaximumDailyDose(MMD,每日最大劑量)fromPDR,CPS,etc.UseMDDtocalculatetheICHThresholdsReportingThreshold(RT)IdentificationThreshold(IT)QualificationThreshold(QT)每日最大劑量1報(bào)告限(ReportingThreshold)2,3鑒定限（IdentificationThreshold)3論證限(QualificationThreshold)3≤2g/day0.05%每日攝入量0.10%或1.0毫克（取低值）每日攝入量0.15%或1.0毫克（取低值）≥2g/day0.03%0.05%0.05%1

每日原料藥的服用量。

2

更高的報(bào)告限必須提供充足的理由。

3

如果雜質(zhì)的毒性特別高則適合于更低的報(bào)告限。

有機(jī)雜質(zhì)控制限度設(shè)置FindouttheMaximum14ControlofImpurities:Compendia&ICH

EstablishingAcceptanceCriteriaforImpuritiesAcceptancecriteria(limits)forimpuritiesshouldbesetnohigherthanthelevelthathasbeenqualified.Inestablishingimpuritylimits,thefirstcriticalconsiderationiswhetheranimpurityisspecifiedintheUSP.IfthereisamonographintheUSPthatincludesalimitforanidentifiedspecifiedimpurity,thelimitsshouldbesetnohigherthantheofficialcompendiallimit.IfqualifiedbyanFDA-approvedhumandrugproduct,thelimitsmustbeconsistentwiththelevelobservedintheapprovedhumandrugproduct.Inothercircumstances(e.g.metabolites),thelimitsmayneedtobesettighterthanthequalifiedleveltoassuredrugsubstancequality.IftheleveloftheimpurityisabovethelevelspecifiedintheUSP,qualificationisnecessary.Then,ifappropriatequalificationhasbeenachieved,anapplicantmaywishtopetitiontheUSPforrevisionoftheimpurity’slimits.ControlofImpurities:Compend15ControlofImpurities:Compendia&ICH

ICHQ3A(R)andQ3B(R).ScopeDoesnotapplytonewdrugsubstances(Q3A(R)

)orproducts(Q3B(R))usedduringtheclinicalresearchstagesofdevelopment.Bothdonotcover:Biological/biotechniologicalproductsFermentationproductsPeptidesSemi-syntheticproductsOligonucleotidesHerbalproductsRadiopharmaceuticalsCrudeproductsofanimalPlantoriginQ3B(R)doesnotcover:ExtraneouscontaminantsthatshouldnotoccurinnewdrugproductsandareaddressedasGMPissues.PolymorphicformsEnantiomericimpuritiesControlofImpurities:Compend16制劑的雜質(zhì)限度

Q3B(R2).ICHThresholdforDegradationProductsinNewDrugProducts每日原料藥最大劑量*報(bào)告限（ReportingThreshold)鑒定限（IdentificationThreshold)論證限(QualificationThreshold)≤1g0.1%N/AN/A>1g0.05%N/AN/A<1mgN/A1.0%or5ugTDIN/A1mg~10mgN/A0.5%or20ugTDIN/A>10mg~2gN/A0.2%or2mgTDIN/A<10mgN/AN/A1.0%or50ugTDI10mg~100mgN/AN/A0.5%or200ugTDI>100mg~2gN/AN/A0.2%or3mgTDI>2gN/A0.10%0.15%*取低值，按百分含量或每日總攝入量（TDI）計(jì)。制劑的雜質(zhì)限度

Q3B(R2).ICHThreshold17有機(jī)雜質(zhì)控制限度論證雜質(zhì)控制限度論證：對一定限度的雜質(zhì)的生物安全性進(jìn)行研究和評(píng)估，建立雜質(zhì)的可接受限度并提供包括安全性考慮在內(nèi)的依據(jù)。如果雜質(zhì)在樣品測試中的實(shí)際觀察值較高，而需要設(shè)置一個(gè)高于美國藥典或ICH論證限（QualificationThreshold）的控制限度時(shí)，則必須提供一個(gè)充分合理的論證來說明所設(shè)的控制限度是合理的。有時(shí)將雜質(zhì)水平降低至美國藥典或ICH論證限以下是最為簡單的雜質(zhì)控制方法。對雜質(zhì)控制限度的論證如果被FDA接受，申請人還可以向美國藥典提出修改該雜質(zhì)限度的申請（Petition）。有機(jī)雜質(zhì)控制限度論證雜質(zhì)控制限度論證：對一定限度的雜質(zhì)的生物18

制訂和論證雜質(zhì)合理限度的決策樹制訂和論證雜質(zhì)合理限度的決策樹19有機(jī)雜質(zhì)控制限度的論證方法對比分析法：仿制藥申請中原料藥的雜質(zhì)可以采用相同的已驗(yàn)證的分析方法（如HPLC法），與FDA已批準(zhǔn)的同品種人用制劑（ReferenceListedDrug,簡稱RLD，參照藥品）進(jìn)行對比研究。如果無法獲得參照藥品，也可對含有相同原料藥，以及相同給藥途徑和特征的不同藥物制劑（如片劑對膠囊）的雜質(zhì)含量進(jìn)行研究。如果仿制藥申請?jiān)纤幹幸谚b別雜質(zhì)的水平與相應(yīng)已獲準(zhǔn)上市人用藥物的雜質(zhì)水平相當(dāng)，則可以認(rèn)為該雜質(zhì)得到了合理控制。科學(xué)文獻(xiàn)和主要代謝物法：如果科學(xué)文獻(xiàn)已經(jīng)證明某一水平的雜質(zhì)在安全性方面沒有問題，那么根據(jù)這一水平建立的該雜質(zhì)的限度就無需進(jìn)一步論證。此外，如果科學(xué)文獻(xiàn)證明某雜質(zhì)本身也是原料藥在體內(nèi)代謝的主要代謝物，其安全性是顯而易見的，因而即使對該雜質(zhì)設(shè)置高于ICH論證限的控制限度，通常可以也認(rèn)為該雜質(zhì)已得到合理控制。遺傳毒性研究法：由于遺傳毒性試驗(yàn)費(fèi)時(shí)間且成本高昂，此法一般是在前兩種都無法對雜質(zhì)合理研究論證的情況下才采取的方法。這項(xiàng)研究可以采用含該雜質(zhì)的制劑或原料藥直接進(jìn)行研究，但實(shí)際上采用已分離的雜質(zhì)進(jìn)行研究可能更為恰當(dāng)。有機(jī)雜質(zhì)控制限度的論證方法對比分析法：仿制藥申請中原料藥的雜20有機(jī)雜質(zhì)控制限度的論證方法雜質(zhì)的合理控制應(yīng)基于多種因素，包括患者人群、日劑量、給藥途徑以及給藥周期。雜質(zhì)合理控制的最基本原則就是考慮其安全因素。根據(jù)ICH的雜質(zhì)指導(dǎo)原則Q3A(R)和Q3B(R)。當(dāng)滿足下述一個(gè)或多個(gè)條件時(shí)，可以認(rèn)為該雜質(zhì)的控制限度是合理的：當(dāng)雜質(zhì)實(shí)際觀察水平以及控制限度未超出FDA已經(jīng)批準(zhǔn)的人用制劑雜質(zhì)實(shí)際觀察水平；當(dāng)雜質(zhì)本身是原料藥在動(dòng)物和/或人體內(nèi)重要的代謝產(chǎn)物時(shí)；當(dāng)雜質(zhì)實(shí)際觀察水平以及控制限度有充分合理的科學(xué)文獻(xiàn)支持時(shí)；當(dāng)雜質(zhì)實(shí)際觀察水平以及控制限度未超過通過體外遺傳毒性比較研究得出的正確評(píng)估限度時(shí)。有機(jī)雜質(zhì)控制限度的論證方法雜質(zhì)的合理控制應(yīng)基于多種因素，包括21有機(jī)雜質(zhì)控制限度的論證方法當(dāng)雜質(zhì)本身是原料藥在動(dòng)物和/或人體內(nèi)重要的代謝產(chǎn)物時(shí)如果有可靠文獻(xiàn)報(bào)道該雜質(zhì)系人體代謝產(chǎn)物，其限度的確定并不需要從安全性方面進(jìn)行論證。限度設(shè)定時(shí)主要考慮批分析數(shù)據(jù)、穩(wěn)定性研究數(shù)據(jù)。具體限度的確定因藥物而異，但應(yīng)能保證批間藥品質(zhì)量的一致性，且得到批分析數(shù)據(jù)、穩(wěn)定性數(shù)據(jù)的支持。Example:SimvastatinEPImpA,DegradationProduct:Proposedtoincreasethelimitfrom0.5%to1.0%.Rationale:TheFDAguidelineforANDAs:Significantmetabolitesdonotneedfurtherqualification.ThemetabolicprofilesofSimvastatininhumananddogplasmashowedthatSimvastatinEPImpAisoneofthemajormetabolites.有機(jī)雜質(zhì)控制限度的論證方法當(dāng)雜質(zhì)本身是原料藥在動(dòng)物和/或人體22ImpurityLimitEstablishment:Examples

SimvastatinTabletsUSP.LimitsforSVRCAandSVRCBSimvastatin(Zocor):Alipid-loweringdrugapprovedbyFDAinDec.1991.Itreducescholesterolbyinhibitinganenzymeintheliver(HMG-CoAreductase)requiredfortheproductionofcholesterol.OtherstatinsincludeLovastatin(Mevacor),atorvastatin(Lipitor),fluvastatin(Lescol),androsuvastatin(Crestor).SVRCAandSVRCBwerecontrolledatNMT0.5%and0.1%,respectivelybefore.However,theresultsformthelongtermstabilitytestexceededthelimits.SVRCB,DegradationProduct:Proposedtoincreasethelimitfrom0.1%to0.2%.Rationale:TheICHguidelineQ3B(R):QTfordegradationproductscanbe0.5%or200mgTDI,whicheverislower,forthedrugwithMDDof10-100mg.MDDforSimvastatinis80mg.QTcanbe0.25%.ImpurityLimitEstablishment:23ImpurityLimitEstablishment:Examples

BupropionERTablets:JustificationforIncreasingLimitsThelimitforRCm-chlorobenzoicacidinBupropionHydrochlorideERTabletsisproposedtoincreasefrom0.3%to0.5%.Rationale:Bupropionisextensivelymetabolizedinhumans,ratsanddogs.Metabolismstudiesinhumanindicatedthatbupropionwasmetabolizedtom-chlorohippuricacid,erythro-aminoalcohol(EB),threo-aminoalcohol(TB),hydroxymetabolite(HB)(references1-3).Itwasobviousthatm-chlorohippuricacid,whichisexcretedasthemajorurinarymetabolite,wasresultedfromoxidationofthebupropionsidechaintogivem-chlorobenzoicacidfollowedbyconjugationwithglycine.OtheraminoalcoholmetabolitessuchasEB,TBandHBareformedfromhydroxylationnofthetert-butylgroupofbupropionand/orreductionoftheintactparentaminoketone.Thismetabolismpathwayhasbeenconfirmedbythefactthatthemetabolisminratsanddogsgavepredominantlym-chlorohippuricacidandm-chlorobenzoicacidasthemetabolites,whichareformedfromsidechainoxidativecleavage.TheFDAguidelineforimpuritiesforANDAs(SeeGuidanceforIndustry.ANDAs:ImpuritiesinDrugSubstances)indicatesthattheimpuritiesthataresignificantmetabolitesdonotneedfurtherqualification.Itisconsideredreasonabletoincreasethetestlimitfrom0.3%to0.5%forBPRC2(m-chlorobenzoicacid).ImpurityLimitEstablishment:24ImpurityLimitEstablishment:Examples

SyntheticImpurities:NoNeedtoMonitor/ReportinDPSpecificationsResponseformFDAonthistypeofquestion:Syntheticimpuritiesneednotbereportedormonitoredforreleaseand/orstabilitytestingofthedrugproduct.Thus,nodrugproductlimitsfordrugsubstanceprocessimpuritiesneedbeincludedinthedrugtestingprotocol.Rationale:Syntheticimpuritiesaregeneratedduringthemanufacturingprocessofthedrugsubstance.Theyarecontrolledinthedrugsubstancespecification.Theyarenotexpectedtoincreaseduringtheproductionandstorageofthedrugproduct.ImpurityLimitEstablishment:25ImpurityLimitEstablishment:Examples

Semi-SyntheticorSyntheticChemical?“WhyistheFDAaskingustoqualifyanimpurityobservedinthissemi-syntheticdrugsubstance?Aren’tsemi-syntheticsexcludedfromtherecommendations?”Rationale:Itdependsonhowfarthedrugsubstanceisfromthenaturallyderivedsourcematerial.Ingeneral,drugsubstancesseparatedfromthesourcematerialbyoneortwochemicalmanipulationsarestillexcludedfromtherecommendations.However,theAgencybelievesthatthosedrugsubstancesseparatedfromthesourcematerialbyseveralsyntheticstepsresultinginmultipleisolatedandpurifiedintermediatesresembletraditionalchemicalsmorethantheyresembleclassicalsemi-syntheticmoieties.Hence,thenewrecommendationswouldapplytosuchdrugsubstances.ImpurityLimitEstablishment:26ImpurityLimitEstablishment:Examples

Clyndamycin.Semi-syntheticorSyntheticChemical?ImpurityLimitEstablishment:27案例分析：有機(jī)雜質(zhì)控制限度設(shè)置和論證

卡托普利（Captopril)原料藥的合成路線案例分析：有機(jī)雜質(zhì)控制限度設(shè)置和論證

卡托普利（28卡托普利（Captopril）有機(jī)雜質(zhì)控制限度的設(shè)置卡托普利（Captopril）有機(jī)雜質(zhì)控制限度的設(shè)置29卡托普利（Captopril）有機(jī)雜質(zhì)控制限度的設(shè)置美國藥典和歐洲藥典都發(fā)表了有關(guān)卡托普利原料藥的正文。根據(jù)美國藥典正文，Captoprildisulphide雜質(zhì)控制限度不超過1.0%，而其它單一雜質(zhì)不超過0.2%，總雜質(zhì)不超過0.5%。歐洲藥典正文把雜質(zhì)A,B,C,D,E和F作為特定雜質(zhì)控制在不超過0.15%（其中例外的是雜質(zhì)A控制在≤1.0%，雜質(zhì)F控制在≤0.2%），非特定雜質(zhì)控制在不超過0.10%，總雜質(zhì)不超過1.2%。如果原料藥生命符合美國或歐洲藥典標(biāo)準(zhǔn)，通常必須符合該藥典正文的每一項(xiàng)要求。然而，對于與合成路線毫無關(guān)系的藥典雜質(zhì)，在實(shí)驗(yàn)測試結(jié)果顯示“NoneDetected未檢出”的基礎(chǔ)上，可以從合成路線和化學(xué)反應(yīng)機(jī)理的角度進(jìn)行論證，提供足夠理由說明在原料藥標(biāo)準(zhǔn)中可以不設(shè)限度進(jìn)行常規(guī)控制。下面以聲明符合美國藥典標(biāo)準(zhǔn)的卡托普利為例來說明如何提供適當(dāng)?shù)睦碛蓪λ付ǖ臉?biāo)準(zhǔn)進(jìn)行論證。從化學(xué)反應(yīng)機(jī)理的角度考慮，雜質(zhì)B和D產(chǎn)生于含溴的原料，與康樂化學(xué)公司的合成路線無關(guān)。標(biāo)準(zhǔn)規(guī)格中勿需設(shè)定限度來控制雜質(zhì)B和D。卡托普利的最高劑量為450毫克/日。根據(jù)ICH指導(dǎo)文件Q3A(R)，原料藥的報(bào)告限（ReportingThreshold)為0.05%，鑒定限（IdentificationThreshold）為0.10%，論證限(QualificationThreshold)為0.15%。原料藥中的控制限度設(shè)置如下：已知雜質(zhì)C和E中單一已知雜質(zhì)不超過0.1%，雜質(zhì)A不超過0.5%，雜質(zhì)F不超過0.2%，單一未知雜質(zhì)不超過0.10%，總雜質(zhì)不超過0.5%。此雜質(zhì)控制限度符合或緊于美國藥典要求，也與ICH和原料藥廠家的要求一致。卡托普利（Captopril）有機(jī)雜質(zhì)控制限度的設(shè)置美國藥典30練習(xí)-雜質(zhì)控制限度的設(shè)置和論證MichelleisworkinginagenericpharmaceuticalcompanytodevelopadrugproductcalledOMEforulcerdisease.SheadoptstheEuropeanPharmacopoeiaHPLCmethodtoanalyzethedrugsubstanceandobservedknownEPimpuritiesA(0.25),B(0.46%)andC(0.20%),andanunknownimpurity1(0.18%).ThemaximumdailydoseforOMEis120mg.ItisreportedthatimpurityBisadegradationproductandmetabolite,impuritiesAisalsoadegradationproduct,whileimpurityCisasyntheticimpurity.Table1.ICHThresholdsforImpuritiesinNewDrugSubstancesMaximumDailyDose-1ReportingThreshold2,3IdentificationThreshold3QualificationThreshold3≤2g/day0.05%0.10%or1.0mgperdayintake(whicheverislower)0.15%or1.0mgperdayintake(whicheverislower)＞2g/day0.03%0.05%0.05%1Theamountofdrugsubstanceadministeredperday.2Higherreportingthresholdsshouldbesignificantlyjustified.3Lowerthresholdscanbeappropriateiftheimpurityisunusuallytoxic.練習(xí)-雜質(zhì)控制限度的設(shè)置和論證Michelleiswor31練習(xí)-雜質(zhì)控制限度的設(shè)置和論證ActiveingredientmaximumdailydoseReportingThresholdsIdentificationThreshold*QualificationThreshold*≤1g0.1%N/AN/A>1g0.05%N/AN/A<1mgN/A1.0%or5μgTDIN/A1mg~10mgN/A0.5%or20μgTDIN/A>10mg~2gN/A0.2%or2mgTDIN/A<10mgN/AN/A1.0%or50μgTDI10mg~100mgN/AN/A0.5%or200μgTDI>100mg~2gN/AN/A0.2%or3mgTDI>2gN/A0.10%0.15%Table2.ICHThresholdsforDegradationProductsinNewDrugProducts*Takethelowerfigure,%ortotaldailyintake(TDI)練習(xí)-雜質(zhì)控制限度的設(shè)置和論證Activeingredie32練習(xí)-雜質(zhì)控制限度的設(shè)置和論證UsetheaboveTables1and2asreferencesandotherknowledgeyoulearnedfromthiscoursetoestablishappropriatecontrollinglimitsandfillintoTable3forImpuritiesA,BandCforbothdrugsubstanceanddrugproductifnecessary.ItisnotrequiredtoestablishalimittocontrolimpurityCfordrugproduct.However,theHPLCmethodfordegradationproductsshouldbecapableofdetectingandseparatingimpurityCfromotherimpurities.Why?WhycanalimitforadegradationproductbeconsideredqualifiedevenitexceedstheICHlimit?ReportingThreshold(%)ImpurityA(%)ImpurityB(%)ImpurityC(%)UnknownImpurity1(%)ICHlimitsforDrugsubstanceRecommendedLimitsforDrugSubstanceICHlimitsforDrugProductRecommendedLimitsforDrugProduct練習(xí)-雜質(zhì)控制限度的設(shè)置和論證UsetheaboveT33FDA對藥物雜質(zhì)的控制要求

原料藥與成品藥中的殘留溶劑1997年，ICH制訂了“Q3C雜質(zhì)：殘留溶劑的指導(dǎo)原則”。美國藥典（USP）2008年修正了第<467>節(jié)，重新命名為殘留溶劑（Residualsolvents）。ICH將藥品生產(chǎn)及純化過程中常用的69種有機(jī)溶劑按照對人體和環(huán)境的危害程度分為4類。第1類溶劑：指已知或極可能對人體致癌和對環(huán)境有害的溶劑，在藥品制造過程中必須避免使用。其殘留量必須嚴(yán)格控制在規(guī)定的范圍內(nèi)。第2類溶劑：指無基因毒性但有動(dòng)物致癌性的溶劑，可以選擇適當(dāng)?shù)姆椒ú⒔⒁欢ǖ南薅冗M(jìn)行控制。第3類溶劑：指對人體低毒的溶劑，可用于生產(chǎn)過程中。其殘留溶劑的量如果不高于0.5%則無需論證。未分類溶劑：指目前沒有足夠毒性資料的溶劑，如異丙醚（Isopropylether）。由于無響應(yīng)的“允許日接觸量”（PDE）資料，生產(chǎn)廠商在使用時(shí)必須提供這些溶劑在制劑中的殘留水平，以及對產(chǎn)品安全影響的論證報(bào)告，或者根據(jù)FDA在2008年12月出版的控制基因毒性和致癌性以及任何可疑但未知具體毒理的雜質(zhì)的指導(dǎo)原則（草案），控制這類殘留溶劑日接觸量不超過1.5微克。FDA對藥物雜質(zhì)的控制要求

原料藥34ICHQ3CandUSPGeneralChapter<467>“…residualsolventsinpharmaceuticalsaredefinedasorganicvolatilechemicalsthatareusedorproducedinthemanufacturingofdrugsubstanceorexcipient,orinthepreparationofdrugproducts.”[Note:“residualsolvents”referstotheamountnotremovedduringthepurificationoftheproduct]ICHQ3CandUSPGeneralChapte35USP:ResidualSolventsGeneralNoticesStatement:Allarticlesaresubjecttobetestedforresidualsolvents(Delayedimplementation)MonographChanges<467>Residualsolvents:meetstherequirementsaddedinallmonograph(DelayedImplementation)RevisedretractedUSP:ResidualSolventsGeneral36ResidualSolvents<467>:MainPointsDrivingforce:Safetyofthepatient;recommendeduseoflesstoxicsolventsTestingistobeperformedonlyforsolvents“l(fā)ikelytobepresent”UsedorproducedinthefinalmanufacturingstepUsedinpreviousstepsandnotremovedbyavalidatedprocedureThelimitsforacceptableconcentrationslistedintheChapterarefordrugproducts,notforitscomponentsResidualSolvents<467>:MainP37ResidualSolvents<467>:MainPointsTheconcentrationinthedrugproductmaybeCalculatedfromtheconcentrationsofcomponentsDeterminedexperimentally;mandatoryifSolventsareusedinitsmanufactureCumulativecalculationexceedslimitsManufacturesofdrugproductsmayrelyondataprovidedbythesuppliersofcomponentsProvidesunambiguousidentificationandqualificationmethodIncludesoptionstoallowuseofmaterialsthatexceedthelimitsestablishedResidualSolvents<467>:MainP38ResidualSolvents<467>:MainPoints,Continued…“Theproceduresdescribedinthisgeneralchapteraretobeappliedwhereverpossible.Otherwise,manufacturesmayselectthemostappropriatevalidatedanalyticalprocedureforaparticularapplication.”(ICHandEPtakesimilarapproach,see<1225>ValidationofCompendialProceduresSubmissionofalternativemethodsisnotrequired.ResidualSolvents<467>:MainP39ScopeICH“…Theguidedoesnotapplytoexistingmarketedproducts.”USP(andEP)“Thisgeneralchapterappliestoexistingdrugsubstances,excipientsandmedicalproductswhetherornottheyarethesubjectofamonographofthePharmacopeia”.ScopeICH“…Theguidedoesnot40Risk-basedclassificationofsolventsClass1-Unacceptabletoxicities;shouldbeavoided,unlesstheirusecanbestronglyjustifiedinarisk-basedassessment.Class2-Lessseveretoxicities;shouldbelimited.Class3-Lesstoxic;shouldbeusedwherepractical.

[Note:Othersolventsmaybeusedbutonlyafterapprovalfromaregulatoryagency.]Risk-basedclassificationofs41SupplierUSP<467>LimitsinexcipientsforeachexcipientLimitsarenotspecificationsforeachexcipientSomeexcipientsusedasdrugproductsManufacturerofdrugproducthastocalculate,baseduponPDEandlimit.USPwithdrew<467>requirementinexcipientmonographsArequirementislistedinGeneralNotices;noneedforunnecessarytesting.SupplierUSP<467>Limitsinex42SupplierGenerally,Class1Solventssuchasbenzenearenolongerbeingusedinproducingexcipients.ManyproducedwithClass2or3.Eliminatingorloweringsolventlevelsmaychangequalityandperformanceforcertainfunctions.Takeadvantageofcalculationoption.SupplierGenerally,Class1Sol43SupplierManufacturersofpharmaceuticalproductsneedcertaininformationaboutthecontentsofresidualsolventsindrugsubstancesorexcipientsinordertomeetthecriteriaofthisgeneralchapter.OnlyClass3solventsarelikelytobepresent.Lossondryingislessthan0.5%.OnlyClass2solventsX,Y,…arelikelytobepresent.AllarebelowtheOption1limit.(HerethesupplierwouldnametheClass2solventsrepresentedbyX,Y,…)OnlyClass2solventsX,Y,…andClass3solventsarelikelytobepresent.ResidualClass2solventsarebellowtheOption1limitandresidualClass3solventsarebelow0.5%.SupplierManufacturersofpharm44SupplierNeedinformationexchangebetweenuserandsupplier.Howeverthereareconfidentialityconcerns.Trustneededbetweentwoparties.Asupplierauditmaybeneeded,GMPconcernforregulatorydepartmentandFDA.NotjustrelyonCofA.SupplierNeedinformationexcha45EstablishingExposureLimits

(Appendix3intheGeneralChapter)PermittedDailyExposure(PDE)derivedfromtheNo-observed-effectlevel(NOEL)inanimalstudies.ForClass1solvents,exposurelimitsaredeterminedusingalargesafetyfactor(10,000to100,000)ForClass2solvents,PDEwascalculatedfromNOEL,weightadjustmentsandcorrectionfactors(e.g.extrapolatingbetweenspeciesandaccountingforvariabilitybetweenindividuals)EstablishingExposureLimits

(46LimitsofResidualSolventsClass1:concentrationlimits,inppm,areprovidedinaTable.Theyshouldnotbeexceededunlessotherwisestatedintheindividualmonograph.Class2:concentrationlimitsaretobecalculatedfromPDEwiththeformula:

concentration(ppm)=1000PDE/dose,wherePDEisinmg/dayanddoseising/day

Atableisprovided,tobeusedwhenthedailydoseis10gorless,orwhenthedailydoseisnotknownorfixed.Class3:PDEis50mg/day(“unlessotherwisestatedintheindividualmonograph”),correspondingtoaconcentrationof0.5%fordailydosesof10gorlessLimitsofResidualSolventsCla47LimitsofResidualSolvents:Class1Class1Residualsolvents(Table1):Shouldnotbeusedinthemanufacturingofdrugsubstances,excipientsordrugproductsbecauseofunacceptabletoxicitiesordeleteriousenvironmentaleffectsoftheresidualsolvents.However,ifthereuseisunavoidable,theirlevelsshouldberestrictedasshowninTable1.LimitsofResidualSolvents:C48Table1.Class1ResidualSolventsSolventConcentrationLimit(ppm)ConcernBenzene2CarcinogenCarbontetrachloride4ToxicandenvironmentalHazard1,2-Dichlorothane5Toxic1,1-Dichlorothane5Toxic1,1,1-Trichlorothane1500EnvironmentalHazardTable1.Class1ResidualSolv49LimitsofResidualSolvents:Class2Class2:26solventsClass2ResidualSolvents:shouldbelimitedindrugsubstances,excipientsordrugproductsbecauseoftheirinherenttoxicities.TheirlevelsshouldberestrictedasshowninTable2.Concentrationlimitsvarybetween50(Methylbutylketone)and3880(cyclohexane).WhenClass2residualsolventsareused(orproduced)inthemanufacturingorpurificationprocess,theyshouldbeidentifiedandquantified.LimitsofResidualSolvents:C50Table2.Class2ResidualSolventsSolventPDE(mg/day)ConcentrationLimit(ppm)Acetonitrile4.1410Chlorobenzene3.6360Chloroform0.660Cyclohexane38.838801,2-Dichloroethane18.718701,2-Dimethylacetamide10.91090N,N-Dimethylformamide8.88801,4-Dioxane3.83802-Ethoxyethanol1.6160Table2.Class2ResidualSolv51Table2.Class2ResidualSolventsContinued…SolventPDE(mg/day)ConcentrationLimit(ppm)Ethyleneglycol6.2620Formamide2.2220Hexane2.9290Methanol30.030002-Methoxyethanol0.550Methylbutylketone0.550Methycyclohexane11.81180Methylenechloride6.0600N-methylpyrrolidone5.3530Table2.Class2ResidualSolv52Table2.Class2ResidualSolventsContinued…SolventPDE(mg/day)ConcentrationLimit(ppm)1,2-Dimethoxyethane1.0100Nitromethane0.550Pyridine2.0200Sulfolane1.6160Tetrahydrofuran7.2720Tetralin1.0100Toluene8.9890Trichloroethylene0.880Xylenes21.72170Table2.Class2ResidualSolv53LimitsofResidualSolvents:Class3Class3:28solventsLesstoxicandoflowerrisktohumanhealthUnlessotherwisestatedintheindividualmonograph,PDEisNMT50mg/day,correspondingtoaconcentrationlimitof5000ppmfordailydosesnotgreaterthan10goftheproductIfthemonographallowsforaconcentrationresultinginmorethan50mg/day,Class3solventsmustbeidentifiedandquantified.LimitsofResidualSolvents:C54Table3.Class3ResidualSolventsAceticAcidEthylacetateMethyliobutylketoneAcetoneEthylether2-Methyl-1-propanolAnisoleEthylformatePentane1-ButanolFormicacid1-Pentanol2-ButanolHeptane1-PropanolButylacetateIsobutylacetate2--Propanoltert-ButylmethyletherIsopropylacetatePropylacetateCmeneMethylacetateDimethylsulfoxide3-Methyl-1-butanolEthanolMethylethylketoneTable3.Class3ResidualSolv55殘留溶劑控制限度的建立FDA要求所有在制造原料、輔料和產(chǎn)品時(shí)使用或產(chǎn)生的有機(jī)溶劑，其殘留量都必須予以檢測和控制。仿制藥生產(chǎn)商可選擇直接在產(chǎn)品中檢測，若產(chǎn)品制造過程中均未使用有機(jī)溶劑，亦可先檢測原料、輔料的有機(jī)溶劑殘留量，檢測結(jié)果若較規(guī)定值低，則產(chǎn)品無須進(jìn)行檢測，若較高，則必須檢測產(chǎn)品，以證實(shí)制造過程中有機(jī)溶劑的殘留是否已經(jīng)降到合格標(biāo)準(zhǔn)。若只有第3類的殘留溶劑，則可用USP<731>干燥減重的方式控制。殘留溶劑控制限度的建立FDA要求所有在制造原料、輔料和產(chǎn)品時(shí)56OptionsforDeterminingLevelsof

Class2ResidualSolventsOption1:Componentsofthedrugproduct(drugsubstancesandexcipients)meettheconcentrationlimitslistedinTable2,andthedailydosedoesnotexceed10g.在設(shè)定殘留溶劑時(shí)，首先采用第一選擇方法，即根據(jù)美國藥典<467>（或ICHQ3C）中標(biāo)1-3所列的限度來建立標(biāo)準(zhǔn)中的溶劑限度。第一選擇方法以每日用藥量10克為假設(shè)來計(jì)算“每日允許接觸量”（PDE），從而確定溶劑的限度。

MeOH第一選擇方法最高允許值

=1000微克/毫克×PDE（毫克/日）/最高日劑量（克/日）

=（1000×30）微克/（10×1000000）微克=3000ppmOptionsforDeterminingLevels57Option2forDeterminingLevelsof

Class2ResidualSolventsinDrugProductsOption2:Atleastoneofthecomponentsofthedrugproductexceedstheconcentrationlimits,orthedailydoseexceeds10g:thedailyexposuretoasolvent(calculatedasthesumofthecomponentscontributions)shouldbelessthanPDE.當(dāng)殘留溶劑含量超過美國藥典<467>第一選擇限度時(shí)可以采用第二選擇方法來建立殘留溶劑的