FDA對(duì)藥物雜質(zhì)的控制要求

1、FDA對(duì)藥物雜質(zhì)的控制要求Dr.George MaToronto, CANADA多倫多市，加拿大“美國(guó)仿制藥申報(bào)最新要求和案例分析”1FDA對(duì)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(lái)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2Drug Production and Quality Control Synthesis of API3FDA對(duì)藥物雜質(zhì)的控制要求

2、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(qǐng)的原料藥雜質(zhì)研究指導(dǎo)原則”，“仿制藥申請(qǐng)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(jiǎn)稱Q3B(R)。雜質(zhì)分類有機(jī)雜質(zhì)合成雜質(zhì)(Synthetic Impurity)或工藝雜質(zhì)(Process Impurity)：一般來(lái)自生產(chǎn)過(guò)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(guò)程有關(guān)，在原料藥和制劑的儲(chǔ)存中一般不可能增長(zhǎng)。通過(guò)對(duì)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(Degradation Product):來(lái)

3、源于原料藥通過(guò)各種不同的化學(xué)反應(yīng)途徑的降解，一般需要結(jié)合對(duì)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(wú)機(jī)雜質(zhì)：來(lái)自生產(chǎn)過(guò)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(wú)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(guò)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。4有機(jī)雜質(zhì)來(lái)源5常見(jiàn)的降解反應(yīng)6常見(jiàn)的降解反應(yīng)7確定降解產(chǎn)物-強(qiáng)制降解研究（Forced Degradation Study)Stress Typ

4、e強(qiáng)制降解類型Common Stress 常用強(qiáng)制降解Common Forced Degradation Conditions 常見(jiàn)強(qiáng)制降解條件Solution Stress溶液降解Acid 酸0.1N HCl , 室溫-100，4小時(shí)Base 堿0.1N NaOH，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 & Visuable Light 紫外光和可見(jiàn)光（300-800nm）15小時(shí)（相當(dāng)于波長(zhǎng)范圍為300-800nm,約2.0百萬(wàn)勒克斯時(shí)Stress固態(tài)降解Thermal 加熱 60 ，14天Heat/humidity

5、 加熱/濕度40 /75%RH，14天UV & Visuable Light 紫外光和可見(jiàn)光（300-800nm）15小時(shí)（相當(dāng)于波長(zhǎng)范圍為300-800nm,約2.0百萬(wàn)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(duì)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(jiàn)的強(qiáng)制降解具體試驗(yàn)項(xiàng)目與試驗(yàn)條件8確定降解產(chǎn)物-原料藥和制劑的

6、穩(wěn)定性試驗(yàn)長(zhǎng)期（25 2 、相對(duì)濕度60% 5%、至少12個(gè)月）穩(wěn)定性試驗(yàn)加速（ 40 2 、相對(duì)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(cè)試數(shù)據(jù)（Stability Data）也是確定降解產(chǎn)物的重要依據(jù)之一。一般測(cè)定不同時(shí)間樣品的HPLC圖譜并進(jìn)行比較分析，并與長(zhǎng)期保留制劑樣品的測(cè)定結(jié)果進(jìn)行比較。在強(qiáng)制降解試驗(yàn)研究過(guò)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(cè)：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(zhǎng)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

7、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(duì)保留時(shí)間的方法，或采用雜質(zhì)相對(duì)保留時(shí)間加上自身對(duì)照的方法，對(duì)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(duì)于有紫外吸收的樣品可以用二極管陣列檢測(cè)器，考察未精制的粗品，并對(duì)比已精制過(guò)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(cè)波長(zhǎng)。方法確立后，可采用自身對(duì)照方法或面積歸一化法控制雜質(zhì)。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)（Specified Impurities)：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)（Spec

8、ified Identified Impurity) 和化學(xué)結(jié)構(gòu)未知（Specified Unidentified Impurity）的雜質(zhì)。美國(guó)藥典通常采用代號(hào)來(lái)指認(rèn)特定雜質(zhì)，如相關(guān)化合物A（Related Compound A）等。非特定雜質(zhì)（ Unspecified Impurities ）：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(duì)保留時(shí)間為3.5的雜質(zhì)。有機(jī)雜質(zhì)檢測(cè)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(duì)有關(guān)合成化學(xué)反應(yīng)和條件、原料藥化學(xué)結(jié)構(gòu)、

9、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(duì)樣品的常規(guī)分析和強(qiáng)制降解（Forced Degradation Study），以及穩(wěn)定性研究的結(jié)果。10Impurities: Origination & Identification Classification of impuritiesSynthetic Impurities (Residual substances in the synthesis) Starting material By-products Intermediates Degradation during synthesis Reagents, ligand

10、s and catalystsDegradation ProductsHydrolysisOxidationEsterificationElimination of water, HCl, etc.DehydrogenationResidual Solvents/OVIs Solvents/reagents used in the reactions, purification process or formed during reactionMeOH, EtOH, IPA, THF, Dichloromethane, Acetone, Triethylamine, etc.Impurity

11、Resources-API & Drug Product Manufacturing Processes11Impurities: Origination & Identification Lists of Impurities in ICHOrganic impuritiesEach identified specified impurityEach unidentified specified impurityAny unspecified impurity with an acceptance criterion of not more than () the figure in the

12、 identification threshold in Attachment 1, ICH Q3A(R)Total impuritiesResidual solventsInorganic impurities12有機(jī)雜質(zhì)控制限度設(shè)置美國(guó)藥典雜質(zhì)：在美國(guó)藥典正文（monograph）中列為特定雜質(zhì)（Specified Impurities）的雜質(zhì)，其控制限度應(yīng)設(shè)置不高于美國(guó)藥典的限度。非美國(guó)藥典雜質(zhì)：如果美國(guó)藥典正文沒(méi)有對(duì)該雜質(zhì)設(shè)置控制限度，或者美國(guó)藥典沒(méi)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(guó)藥典（BP）來(lái)設(shè)置該雜質(zhì)

13、的控制限度。就ICH的雜質(zhì)指導(dǎo)原則來(lái)說(shuō)，如果該雜質(zhì)在實(shí)驗(yàn)測(cè)試中的實(shí)際觀測(cè)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（Qualification Threshold）。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(duì)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(lái)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(duì)其限度用鑒定限（Identification Threshold）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(guò)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)

14、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。13有機(jī)雜質(zhì)控制限度設(shè)置Find out the Maximum Daily Dose (MMD,每日最大劑量) from PDR, CPS, etc.Use MDD to calculate the ICH ThresholdsReporting Threshold (RT)Identification Threshold (IT)Qualification Threshold (QT)每日最大劑量1報(bào)告限(Reporting Threshold) 2,3鑒定限（Identification Th

15、reshold) 3論證限(Qualification Threshold) 3 2 g/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） 2 g/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。14Control of Impurities: Compendia & ICH Establishing Acceptance Criteria for ImpuritiesAcceptance criteria (limits) for impuriti

16、es should be set no higher than the level that has been qualified.In establishing impurity limits, the first critical consideration is whether an impurity is specified in the USP.If there is a monograph in the USP that includes a limit for an identified specified impurity, the limits should be set n

17、o higher than the official compendial limit.If qualified by an FDA-approved human drug product, the limits must be consistent with the level observed in the approved human drug product.In other circumstances (e.g. metabolites), the limits may need to be set tighter than the qualified level to assure

18、 drug substance quality. If the level of the impurity is above the level specified in the USP, qualification is necessary. Then, if appropriate qualification has been achieved, an applicant may wish to petition the USP for revision of the impuritys limits.15Control of Impurities: Compendia & ICH ICH

19、 Q3A(R) and Q3B(R). ScopeDoes not apply to new drug substances (Q3A(R) ) or products (Q3B(R) used during the clinical research stages of development. Both do not cover: Biological/ biotechniological products Fermentation products Peptides Semi-synthetic products Oligonucleotides Herbal products Radi

20、opharmaceuticals Crude products of animal Plant originQ3B (R) does not cover:Extraneous contaminants that should not occur in new drug products and are addressed as GMP issues.Polymorphic formsEnantiomeric impurities16制劑的雜質(zhì)限度Q3B(R2). ICH Threshold for Degradation Products in New Drug Products每日原料藥最大

21、劑量 *報(bào)告限（Reporting Threshold)鑒定限（Identification Threshold)論證限(Qualification Threshold) 1g0.1%N/AN/A 1g0.05%N/AN/A 10mg 2gN/A0.2% or 2mg TDIN/A 100mg 2gN/AN/A0.2% or 3mg TDI 2gN/A0.10%0.15%*取低值，按百分含量或每日總攝入量（TDI）計(jì)。17有機(jī)雜質(zhì)控制限度論證雜質(zhì)控制限度論證：對(duì)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(cè)試中的實(shí)際觀察值較高，而

22、需要設(shè)置一個(gè)高于美國(guó)藥典或ICH論證限（ Qualification Threshold ）的控制限度時(shí)，則必須提供一個(gè)充分合理的論證來(lái)說(shuō)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(guó)藥典或ICH論證限以下是最為簡(jiǎn)單的雜質(zhì)控制方法。對(duì)雜質(zhì)控制限度的論證如果被FDA接受，申請(qǐng)人還可以向美國(guó)藥典提出修改該雜質(zhì)限度的申請(qǐng)（Petition）。18 制訂和論證雜質(zhì)合理限度的決策樹(shù)19有機(jī)雜質(zhì)控制限度的論證方法對(duì)比分析法：仿制藥申請(qǐng)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（Reference Listed Drug, 簡(jiǎn)稱RLD，參照藥品）進(jìn)行對(duì)比

23、研究。如果無(wú)法獲得參照藥品，也可對(duì)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(duì)膠囊）的雜質(zhì)含量進(jìn)行研究。如果仿制藥申請(qǐng)?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?？茖W(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(méi)有問(wèn)題，那么根據(jù)這一水平建立的該雜質(zhì)的限度就無(wú)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(jiàn)的，因而即使對(duì)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

24、兩種都無(wú)法對(duì)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)。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

25、時(shí)；當(dāng)雜質(zhì)實(shí)際觀察水平以及控制限度未超過(guò)通過(guò)體外遺傳毒性比較研究得出的正確評(píng)估限度時(shí)。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:Simvastatin EP Imp A, Degradation Product: Proposed to increase the limit from 0.5% to 1.0%.Ratio

26、nale: The FDA guideline for ANDAs: Significant metabolites do not need further qualification. The metabolic profiles of Simvastatin in human and dog plasma showed that Simvastatin EP Imp A is one of the major metabolites.22Impurity Limit Establishment: Examples Simvastatin Tablets USP. Limits for SV

27、 RCA and SV RCBSimvastatin (Zocor): A lipid-lowering drug approved by FDA in Dec.1991. It reduces cholesterol by inhibiting an enzyme in the liver (HMG-CoA reductase) required for the production of cholesterol. Other statins include Lovastatin (Mevacor), atorvastatin (Lipitor), fluvastatin (Lescol),

28、 and rosuvastatin (Crestor).SV RC A and SV RC B were controlled at NMT0.5% and 0.1%, respectively before. However, the results form the long term stability test exceeded the limits.SV RC B, Degradation Product: Proposed to increase the limit from 0.1% to 0.2%.Rationale:The ICH guideline Q3B(R): QT f

29、or degradation products can be 0.5% or 200mg TDI, whichever is lower, for the drug with MDD of 10-100mg.MDD for Simvastatin is 80mg. QT can be 0.25%. 23Impurity Limit Establishment: ExamplesBupropion ER Tablets: Justification for Increasing LimitsThe limit for RC m-chlorobenzoic acid in Bupropion Hy

30、drochloride ER Tablets is proposed to increase from 0.3% to 0.5%.Rationale:Bupropion is extensively metabolized in humans, rats and dogs. Metabolism studies in human indicated that bupropion was metabolized to m-chlorohippuric acid, erythro-amino alcohol (EB), threo-amino alcohol (TB), hydroxy metab

31、olite (HB) (references 1-3).It was obvious that m-chlorohippuric acid, which is excreted as the major urinary metabolite, was resulted from oxidation of the bupropion side chain to give m-chlorobenzoic acid followed by conjugation with glycine. Other aminoalcohol metabolites such as EB, TB and HB ar

32、e formed from hydroxylation nof the tert-butyl group of bupropion and /or reduction of the intact parent aminoketone. This metabolism pathway has been confirmed by the fact that the metabolism in rats and dogs gave predominantly m-chlorohippuric acid and m-chlorobenzoic acid as the metabolites, whic

33、h are formed from side chain oxidative cleavage.The FDA guideline for impurities for ANDAs (See Guidance for Industry. ANDAs: Impurities in Drug Substances) indicates that the impurities that are significant metabolites do not need further qualification.It is considered reasonable to increase the te

34、st limit from 0.3% to 0.5% for BP RC2 (m-chlorobenzoic acid ).24Impurity Limit Establishment: ExamplesSynthetic Impurities: No Need to Monitor/Report in DP SpecificationsResponse form FDA on this type of question: Synthetic impurities need not be reported or monitored for release and /or stability t

35、esting of the drug product. Thus, no drug product limits for drug substance process impurities need be included in the drug testing protocol.Rationale:Synthetic impurities are generated during the manufacturing process of the drug substance.They are controlled in the drug substance specification.The

36、y are not expected to increase during the production and storage of the drug product.25Impurity Limit Establishment: Examples Semi-Synthetic or Synthetic Chemical?“Why is the FDA asking us to qualify an impurity observed in this semi-synthetic drug substance? Arent semi-synthetics excluded from the

37、recommendations?”Rationale: It depends on how far the drug substance is from the naturally derived source material. In general, drug substances separated from the source material by one or two chemical manipulations are still excluded from the recommendations. However, the Agency believes that those

38、 drug substances separated from the source material by several synthetic steps resulting in multiple isolated and purified intermediates resemble traditional chemicals more than they resemble classical semi-synthetic moieties. Hence, the new recommendations would apply to such drug substances. 26Imp

39、urity Limit Establishment: Examples Clyndamycin. Semi-synthetic or Synthetic Chemical?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28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(guó)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(guó)藥典正文，Captopril disulphide 雜質(zhì)控制限度不超過(guò)1.0%，而其它單一雜質(zhì)不超過(guò)0.2%，總雜質(zhì)不超過(guò)0.5%。歐洲藥典正文把雜質(zhì)A,B,C,D,

40、E和F作為特定雜質(zhì)控制在不超過(guò)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(guò)0.10%，總雜質(zhì)不超過(guò)1.2%。如果原料藥生命符合美國(guó)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(duì)于與合成路線毫無(wú)關(guān)系的藥典雜質(zhì)，在實(shí)驗(yàn)測(cè)試結(jié)果顯示“None Detected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(shuō)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(guó)藥典標(biāo)準(zhǔn)的卡托普利為例來(lái)說(shuō)明如何提供適當(dāng)?shù)睦碛蓪?duì)所指定的標(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(lè)化學(xué)公司的合成路線

41、無(wú)關(guān)。標(biāo)準(zhǔn)規(guī)格中勿需設(shè)定限度來(lái)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（Reporting Threshold)為0.05%，鑒定限（Identification Threshold）為0.10%，論證限(Qualification Threshold) 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(guò)0.1%，雜質(zhì)A不超過(guò)0.5%，雜質(zhì)F不超過(guò)0.2%，單一未知雜質(zhì)不超過(guò)0.10%，總雜質(zhì)不超過(guò)0.5%。此雜質(zhì)控制限度符合或緊于美國(guó)藥典要求，也與ICH和原料藥廠家的要求一致。30練習(xí)-雜質(zhì)控制限度的設(shè)置和論

42、證Michelle is working in a generic pharmaceutical company to develop a drug product called OME for ulcer disease. She adopts the European Pharmacopoeia HPLC method to analyze the drug substance and observed known EP impurities A (0.25), B(0.46%) and C (0.20%), and an unknown impurity 1 (0.18%). The m

43、aximum daily dose for OME is 120mg. It is reported that impurity B is a degradation product and metabolite, impurities A is also a degradation product, while impurity C is a synthetic impurity. Table 1. ICH Thresholds for Impurities in New Drug SubstancesMaximum Daily Dose-1Reporting Threshold2,3Ide

44、ntification Threshold 3Qualification Threshold 32g/day0.05%0.10% or 1.0mg per day intake (whichever is lower)0.15% or 1.0mg per day intake (whichever is lower)2g/day0.03%0.05%0.05%1 The amount of drug substance administered per day.2 Higher reporting thresholds should be significantly justified.3 Lo

45、wer thresholds can be appropriate if the impurity is unusually toxic.31練習(xí)-雜質(zhì)控制限度的設(shè)置和論證Active ingredient maximum daily doseReporting ThresholdsIdentification Threshold*Qualification Threshold* 1g0.1%N/AN/A 1g0.05%N/AN/A 10mg 2gN/A0.2% or 2mg TDIN/A 100mg 2gN/AN/A0.2% or 3mg TDI 2gN/A0.10%0.15%Table 2

46、. ICH Thresholds for Degradation Products in New Drug Products* Take the lower figure, % or total daily intake (TDI)32練習(xí)-雜質(zhì)控制限度的設(shè)置和論證Use the above Tables 1 and 2 as references and other knowledge you learned from this course to establish appropriate controlling limits and fill into Table 3 for Impur

47、ities A, B and C for both drug substance and drug product if necessary.It is not required to establish a limit to control impurity C for drug product. However, the HPLC method for degradation products should be capable of detecting and separating impurity C from other impurities. Why?Why can a limit

48、 for a degradation product be considered qualified even it exceeds the ICH limit?33FDA對(duì)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(guó)藥典（USP）2008年修正了第節(jié)，重新命名為殘留溶劑（Residual solvents）。ICH將藥品生產(chǎn)及純化過(guò)程中常用的69種有機(jī)溶劑按照對(duì)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(duì)人體致癌和對(duì)環(huán)境有害的溶劑，在藥品制造過(guò)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(wú)

49、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(duì)人體低毒的溶劑，可用于生產(chǎn)過(guò)程中。其殘留溶劑的量如果不高于0.5%則無(wú)需論證。未分類溶劑：指目前沒(méi)有足夠毒性資料的溶劑，如異丙醚（Isopropylether）。由于無(wú)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(duì)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(guò)1.5微克。34ICH Q3C and USP General Chapter “

50、residual solvents in pharmaceuticals are defined as organic volatile chemicals that are used or produced in the manufacturing of drug substance or excipient, or in the preparation of drug products.” Note: “residual solvents” refers to the amount not removed during the purification of the product35US

51、P: Residual SolventsGeneral Notices Statement: All articles are subject to be tested for residual solvents (Delayed implementation)Monograph Changes Residual solvents: meets the requirements added in all monograph (Delayed Implementation)Revised retracted36Residual Solvents :Main PointsDriving force

52、: Safety of the patient; recommended use of less toxic solventsTesting is to be performed only for solvents “l(fā)ikely to be present” Used or produced in the final manufacturing step Used in previous steps and not removed by a validated procedureThe limits for acceptable concentrations listed in the Ch

53、apter are for drug products, not for its components37Residual Solvents :Main PointsThe concentration in the drug product may beCalculated from the concentrations of components Determined experimentally; mandatory ifSolvents are used in its manufactureCumulative calculation exceeds limitsManufactures

54、 of drug products may rely on data provided by the suppliers of componentsProvides unambiguous identification and qualification methodIncludes options to allow use of materials that exceed the limits established38Residual Solvents :Main Points, Continued“The procedures described in this general chap

55、ter are to be applied wherever possible. Otherwise, manufactures may select the most appropriate validated analytical procedure for a particular application.” (ICH and EP take similar approach, see Validation of Compendial ProceduresSubmission of alternative methods is not required.39ScopeICH “The g

56、uide does not apply to existing marketed products.”USP (and EP) “This general chapter applies to existing drug substances, excipients and medical products whether or not they are the subject of a monograph of the Pharmacopeia”.40Risk-based classification of solventsClass 1 -Unacceptable toxicities;

57、should be avoided, unless their use can be strongly justified in a risk-based assessment.Class 2 -Less severe toxicities; should be limited.Class 3 -Less toxic; should be used where practical. Note: Other solvents may be used but only after approval from a regulatory agency.41SupplierUSP Limits in e

58、xcipients for each excipient Limits are not specifications for each excipientSome excipients used as drug productsManufacturer of drug product has to calculate, based upon PDE and limit.USP withdrew requirement in excipient monographsA requirement is listed in General Notices; no need for unnecessar

59、y testing.42SupplierGenerally, Class 1 Solvents such as benzene are no longer being used in producing excipients.Many produced with Class 2 or 3.Eliminating or lowering solvent levels may change quality and performance for certain functions.Take advantage of calculation option.43SupplierManufacturer

60、s of pharmaceutical products need certain information about the contents of residual solvents in drug substances or excipients in order to meet the criteria of this general chapter.Only Class 3 solvents are likely to be present. Loss on drying is less than 0.5%.Only Class 2 solvents X, Y,are likely