【正文】 fied.,第五十頁(yè)，共七十一頁(yè)。,Establishing Exposure Limits (Appendix 3 in the General Chapter),Permitted Daily Exposure (PDE) derived from the Noobservedeffect level (NOEL) in animal studies. For Class 1 solvents, exposure limits are determined using a large safety factor (10,000 to 100,000) For Class 2 solvents, PDE was calculated from NOEL, weight adjustments and correction factors (e.g. extrapolating between species and accounting for variability between individuals),第四十六頁(yè)，共七十一頁(yè)。 no need for unnecessary testing.,第四十二頁(yè)，共七十一頁(yè)。 should be avoided, unless their use can be strongly justified in a riskbased assessment. Class 2 Less severe toxicities。 mandatory if Solvents are used in its manufacture Cumulative calculation exceeds limits Manufactures of drug products may rely on data provided by the suppliers of components Provides unambiguous identification and qualification method Includes options to allow use of materials that exceed the limits established,第三十八頁(yè)，共七十一頁(yè)。,USP: Residual Solvents,General 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 retracted,第三十六頁(yè)，共七十一頁(yè)。 未分類(lèi)溶劑：指目前沒(méi)有足夠毒性資料的溶劑，如異丙醚（Isopropylether）。其殘留量必須嚴(yán)格控制在規(guī)定的范圍內(nèi)。)的指導(dǎo)原則”。)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 Impurities 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 for a degradation product be considered qualified even it exceeds the ICH limit?,第三十三頁(yè)，共七十一頁(yè)。zh236。,練習(xí)雜質(zhì)控制限度(xi224。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%。 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。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(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%。,卡托普利（Captopril）有機(jī)雜質(zhì)控制(k242。)限度設(shè)置和論證 卡托普利（Captopril) 原料藥的合成路線(xiàn),第二十八頁(yè)，共七十一頁(yè)。,Impurity Limit Establishment: Examples SemiSynthetic or Synthetic Chemical?,“Why is the FDA asking us to qualify an impurity observed in this semisynthetic drug substance? Aren’t semisynthetics excluded from the 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 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 semisynthetic moieties. Hence, the new recommendations would apply to such drug substances.,第二十六頁(yè)，共七十一頁(yè)。 Example: Simvastatin EP Imp A, Degradation Product: Proposed to increase the limit from 0.5% to 1.0%. Rationale: 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.,第二十二頁(yè)，共七十一頁(yè)。)、穩(wěn)定性研究數(shù)據(jù)(sh249。,第二十一頁(yè)，共七十一頁(yè)。根據(jù)ICH的雜質(zhì)指導(dǎo)原則Q3A(R)和Q3B(R)。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)。)。)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(chēng)RLD，參照藥品）進(jìn)行對(duì)比研究。zh236。 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。nd249。zh236。 ICH Establishing Acceptance Criteria for Impurities,Acceptance criteria (limits) for impurities 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 no higher than the official compendial limit. If qualified by an FDAapproved 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 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 impurity’s limits.,第十五頁(yè)，共七十一頁(yè)。 x236。li224。,第十三頁(yè)，共七十一頁(yè)。 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。 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)的控制限度。 Drug Product Manufacturing Processes,第十一頁(yè)，共七十一頁(yè)。 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(zhuān)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)、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。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。,第九頁(yè)，共七十一頁(yè)。 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)。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