【正文】 原料藥中雜質(zhì)的控制 The Control of Impurities in Drug Substances 楊仲元 （廣州市藥品檢驗(yàn)所） Yang ZhongYuan （ Guangzhou Municipal Institute for Drug Control) The First Joint USPChP Conference 15 August 2022 Shanghai 原料藥中雜質(zhì)的控制 The Control of Impurities in Drug Substances ? 本部分將討論中國藥典對藥品雜質(zhì)分析的新的指導(dǎo)原則，包括ICH 和其他藥典的有關(guān)要求。 ? This part of the program will focus on the new guideline of the 2022 Chinese Pharmacopoeia for the analysis of drug impurities,including relevant requirements of ICH and other pharmacopoeias 原料藥中雜質(zhì)的控制 The Control of Impurities in Drug Substances ? 本討論包括： ? ICH新原料藥中對雜質(zhì)的指導(dǎo)原則 ? ICH關(guān)于雜質(zhì)指導(dǎo)原則在國外藥典中的引用 ? 中國藥典 (2022)藥品雜質(zhì)分析指導(dǎo)原則 原料藥中雜質(zhì)的控制 The Control of Impurities in Drug Substances ? 雖然 ICH指導(dǎo)原則是對申報新化學(xué)藥和新生物制品的技術(shù)要求，但經(jīng) ICH三方成員國制藥工業(yè)部門和藥品管理部門的協(xié)調(diào)，其原則切實(shí)可行，在保證藥品安全有效，藥品的生產(chǎn)按 GMP的要求，起一定作用，逐步為各國采用。不僅作為申報新藥的要求，有的還作為修訂藥典正文的要求。 ICH新原料藥中的雜質(zhì)指導(dǎo)原則 ICH Guideline on Impurities in New Drug Substances ? 文件 Q3A（ R）為未曾在 ICH 三方注冊過的化學(xué)合成新原料藥申報時關(guān)于雜質(zhì)的指導(dǎo)原則 ? This document is intended to provide guidance for registration application on content and qualification of impurities in new drug substances produced by chemical syntheses and not previously registered in a region or member state. ICH新原料藥中的雜質(zhì)指導(dǎo)原則 ICH Guideline on Impurities in New Drug Substances ? Q3A（ R）雜質(zhì)分類 ? Classification of Impurities ? 有機(jī)雜質(zhì) Organic Impurities ? 無機(jī)雜質(zhì) Inanic Impurities ? 殘留溶劑 Residual solvents ICH新原料藥中的雜質(zhì)指導(dǎo)原則 ICH Guideline on Impurities in New Drug Substances ? 其中有機(jī)雜質(zhì)包括起始原料、副產(chǎn)物、中間體、降解產(chǎn)物、試劑、配位體、催化劑?？梢允墙?jīng)鑒定或未鑒定的 ? The anic impurities include starting materials,byproducts,intermediates, ? Degradation products, reagents, ligands and catalysts( identified or unidentified) ICH新原料藥中的雜質(zhì)指導(dǎo)原則 ICH Guideline on Impurities in New Drug Substances ? Q3A (R) 關(guān)于有機(jī)雜質(zhì)的報告和控制中幾點(diǎn)說明 ? Rational for the reporting and control of anic impurities ICH新原料藥中的雜質(zhì)指導(dǎo)原則 ICH Guideline on Impurities in New Drug Substances ? 為便于理解，先介紹 ICH雜質(zhì)指導(dǎo)原則中的幾個術(shù)語： ? Reporting Threshold: A limit above () which an impurity should be reported. ? 報告限：系指一個限度，大于該限度的雜質(zhì)，應(yīng)該（在申報資料中）報告 ICH新原料藥中的雜質(zhì)指導(dǎo)原則 ICH Guideline on Impurities in New Drug Substances ? Identification Threshold: A limit above () which an impurity should be identified. ? 鑒定限：系指一個限度，大于該限度的雜質(zhì)，應(yīng)作鑒定 ICH新原料藥中的雜質(zhì)指導(dǎo)原則 ICH Guideline on Impurities in New Drug Substances ? Qualification Threshold: A limit above () which an impurity should be qualified. ? 論證限：系指一個限度，大于該限度的雜質(zhì)應(yīng)進(jìn)行論證 ICH新原料藥中的雜質(zhì)指導(dǎo)原則 ICH Guideline on Impurities in New Drug Substances ? Qualification: The process of acquiring and evaluating data that establishes the ? biological safety of an individual impurity or a given impurity profile at the level(s) ? specified. ? 論證：系指對單個雜質(zhì)，或含規(guī)定量已知或未知雜質(zhì)的新原料藥獲得生物安全性數(shù)據(jù)并進(jìn)行評價的過程 ICH新原料藥中的雜質(zhì)指導(dǎo)原則 ICH Guideline on Impurities in New Drug Substances ? The applicant should provide a rationale for establishing impurity acceptance criteria that includes safety considerations. The level of any impurity present in a new drug substance that has been adequately tested in safety and/or clinical studies would be considered qualified. ? 申報者應(yīng)提供設(shè)定雜質(zhì)限度的理由，包括安全性的理由。新原料藥中含有的一定量的任何雜質(zhì)，經(jīng)安全性試驗(yàn)或臨床研究，即認(rèn)為是論證了的。 ICH新原料藥中的雜質(zhì)指導(dǎo)原則 ICH Guideline on Impurities in New Drug Substances ? ICH規(guī)定的雜質(zhì)報告限 鑒定限 論證限 ICH新原料藥中的雜質(zhì)指導(dǎo)原則 ICH Guideline on Impurities in New Drug Substances ? 1. 說明在合成、純化和貯存中該新原料藥實(shí)際和可能存在的雜質(zhì) ? The applicant should summaries the actual and potential impurities most likely to arise during synthesis, purification and storage ? 應(yīng)依據(jù)合成的化學(xué)反應(yīng)，可能帶來雜質(zhì)的原料，以及降解產(chǎn)物 ICH新原料藥中的雜質(zhì)指導(dǎo)原則 ICH Guideline on Impurities in New Drug Substances ? 2. 申報者應(yīng)敘述檢測新原料藥中雜質(zhì)的實(shí)驗(yàn)研究 ? The applicant should summarize the laboratory studies conducted to detect impurities in the new drug substance ? 應(yīng)報告研究開發(fā)規(guī)模和商品規(guī)模批生產(chǎn)結(jié)果，穩(wěn)定性強(qiáng)制試驗(yàn)的結(jié)果 ICH新原料藥中的雜質(zhì)指導(dǎo)原則 ICH Guideline on Impurities in New Drug Substances ? 3. 敘述按 Q3A（ R）附表 1 對新原料藥中大于鑒定限的實(shí)際存在雜質(zhì)進(jìn)行的結(jié)構(gòu)確證研究 ? The studies conducted to characterize the structure of actual impurities present in the new drug substance at a level greater than the identification threshold given in attachment 1 should be described ICH新原料藥中的雜質(zhì)指導(dǎo)原則 ICH Guideline on Impurities in New Drug Substances ? 按擬訂工藝的商業(yè)化生產(chǎn)任一批大于鑒定限的任何雜質(zhì)均應(yīng)做鑒定 ? Any impurity at a level greater than the identification threshold in any batch manufactured by proposed mercial process should be identified ICH新原料藥中的雜質(zhì)指導(dǎo)原則 ICH Guideline on Impurities in New Drug Substances ? 在建議貯存條件下進(jìn)行的穩(wěn)定性試驗(yàn)中發(fā)現(xiàn)的任何大于鑒定限的降解產(chǎn)物均應(yīng)做鑒定 (鑒定不成功的，應(yīng)附相關(guān)資料 ） ? Any degradation product observed in stability studies at remended storage conditions at a level greater than the identification threshold should be identified ICH新原料藥中的雜質(zhì)指導(dǎo)原則 ICH Guideline on Impurities in New Drug Substances ? 對不大于鑒定限的潛在的具顯著毒性或藥理作用的雜質(zhì)，應(yīng)研究分析方法 ? Analytical procedures should be developed for those potential impurities that are expected to be unusually potent, producing toxic or pharmacological effects at a level not more than the identification threshold ICH新原料藥中的雜質(zhì)指導(dǎo)原則 ICH Guideline on Impurities in New Drug Substances ? Q3A （ R） 對分析的要求 ? 在注冊申報中應(yīng)有成文的依據(jù)，說明分析方法經(jīng)過驗(yàn)證，并適合于雜質(zhì)的檢出和定量 ? The registration application should include documented evidence that the analytical procedures are validated and suitable for the detection and quantification of impurities ICH新原料藥中的雜質(zhì)指導(dǎo)原則 ICH Guideline on Impurities in New Drug Substances ? Q3A (R) 對定量限的要求 ? 分析方法的定量限不能大于報告限 ? The quantitation limit for the analytical procedure should be not more than the reporting threshold ICH新原料藥中的雜質(zhì)指導(dǎo)原則 ICH Guideline on Impurities in New Drug Substances ? Q3A （ R）對雜質(zhì)對照品的要求 ? 分析方法中檢驗(yàn)雜質(zhì)用的對照品，按其用途，應(yīng)經(jīng)評價并確定（結(jié)構(gòu)） ? Reference standards used in the analytical procedure for contr