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欧洲药典对原料药中磺酸酯类基因杂质的五个新通则 已有6人参与
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以下是欧洲药典对原料药中基因杂质的五个新通则，通过中文翻译分享给虫友，如有不当欢迎指正。同时希望哪位虫友能分享EP8.7中该内容的五个专著。期待！ 欧洲药典对原料药中基因杂质的五个新通则 （Five new General Chapters in the European Pharmacopoeia on Genotoxic Impurities in Pharmaceutical APIs） 磺酸经常用于原料药的生产中。磺酸可能用在成盐过程，原料药合成中活化基团或酸催化。工艺中如果用到短链醇，如甲醇、乙醇或异丙醇，则可能会和磺酸生成磺酸酯。它们可能有潜在基因毒性（DNA烷基化）。 Sulfonic acids are often used for the manufacture of pharmaceutical APIs. They serve as counterions in crystallisation processes, as protective groups or acid catalysts in API syntheses. Here, if short-chain alcohols such as methanol, ethanol or isopropanol are present, the formation of esters of these sulfonic acids can occur, which may have a genotoxic potential (alkylation of DNA). 2008年欧盟药典委员会成立了甲磺酸盐工作组，拟定了5个不同磺酸物的通则，这些通则在EP增补8.7中公布，将自2016年4月1日开始生效。通则标题如下： The Mesilate Working Party which has been appointed in 2008 by the European Pharmacopoeia Commission has elaborated five General Chapters on different sulfonates which have been published in the European Pharmacopoeia Supplement 8.7 that came into force on 1 April 2016. The General Chapters are as follows: 2.5.37甲磺酸中的甲基、乙基和异丙基甲磺酸酯（Methyl, ethyl and isopropyl methanesulfonate in methanesulfonic acid） 2.5.38原料药中的甲基、乙基和异丙基甲磺酸酯（Methyl, ethyl and isopropyl methanesulfonate in active substances） 2.5.39甲磺酸中的甲磺酰氯（Methanesulfonyl chloride in methanesulfonic acid） 2.5.40原料药中的甲基、乙基和异丙基甲苯磺酸酯（Methyl, ethyl and isopropyl toluenesulfonate in active substances） 2.5.41原料药中的甲基、乙基和异丙基苯磺酸酯（Methyl, ethyl and isopropyl benzenesulfonate in active substances） 2016年2月25日EDQM报道，欧盟药典委员会甲磺酸盐工作组完成2.5.41章，标志着工作组的工作结束。同时，委员会还决定修订原料药-磺酸盐各论中的”生产“部分，采用另一份标准文件来替代。根据此标准文件，在原料药生产中对基因毒性杂质应进行风险管理。文本如下： As reported in a press release from the EDQM dated 25 February 2016 the completion of Chapter 2.5.41 marks the end of the Mesilate Working Party, as decided by the Ph. Eur. Commission. Simultaneously, the Commission had also decided to revise the section "Production" in APIs-Sulfonates monographs and replace it by an additional standard text according to which the principles of risk management have to be used in the manufacture of APIs with regard to the genotoxic impurities. The text is as follows: “【xxx酯】具有基因毒性，而且是【xx原料药】的潜在杂质。生产过程中应考虑质量风险管理原则，同时考虑起始物料、工艺能力和验证。通则【2.5.XX】可以用来帮助生产商。” “It is considered that [XXX esters] are genotoxic and are potential impurities in [name of the API]. The manufacturing process should be developed taking into consideration the principles of quality risk management, together with considerations of the quality of starting materials, process capability and validation. The general method [2.5.XX] is available to assist manufacturers." EP通则一般来说只有当它们在各论中被引用时具有约束力，唯一的例外是当只是作为参考时为建议。这适用于上述五个通则。在“生产”部分的新文件内容，目的是警示上市许可的申请人此类磺酸杂质相关的风险。并没有强制申报人实施通则中所述的分析测试，但需要在申报文件中采用风险评估的方式充分论证这些杂质不会存在。最终决定这些论证是否充分是药监当局的评估。 Basically, the General Chapters of the European Pharmacopoeia will only be binding when they are referred to in a monograph; the only exception is when the reference made has only a recommendation character. This applies to all these five General Chapters. The purpose of the new text segment in the "Production" sections is to alert the applicant of a marketing authorisation of the risk related to such sulfonates impurities. He / she is not obliged to perform the analytical testing described in the general monographs; it is rather sufficient to strongly justify the absence of these impurities by means of a risk assessment in the application. The ultimate decision whether this justification is suffiicient lies with the assessor of the competent authority. |
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