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(5) How can these requirements be put into practice?
如何实施这些要求 The production and storage of the active substances and preparations concerned should be subjected to a risk analysis taking account of the following points (not an exhaustive list) . 相关原料药和制剂的生产和储存必须进行风险分析考虑下列几点（此表还需完善） ? Does the production of the active ingredient involve the use of lower aliphatic alcohols, such as methanol, ethanol, n-propanol, or isopropanol, in the presence of methanesulfonic acid (or isetionic acid, benzolsulfonic acid, paratoluolsulfonic acid) or the corresponding acid chlorides? 原料药的生产过程中是否用到低脂肪醇，如甲醇，乙醇，正丙醇或异丙醇；是否使用了甲磺酸（羟乙磺酸，苯磺酸，对甲苯磺酸）或相对应的酰基氯? If so, is the formation of alkyl mesilates or the analogous alkyl besilates and alkyl tosilates minimized and is followed by an efficient purification stage? 如果有用到上述物料，是否已把甲磺酸盐烷基或类似的苯磺酸盐烷基和甲苯磺酸盐烷基的结构减少到{zd1}；经过有效的精制后，依然有这些结构（物料）的残留? Does the cleaning procedures for equipments, particularly those in contact of sulfonic acid reagents involve the use of lower aliphatic alcohols? 在仪器清洗过程中，特别是指那些与磺酸试剂接触的仪器的清洗是否用到低脂肪醇? ? Is the quality of the starting materials methanesulfonic acid (benzolsulfonic acid,paratoluolsulfonic acid, isetionic acid) checked for alkyl- or arylsulfonic acid ester impurities (e.g.EMS and MMS in methanesulfonic acid) and the corresponding acid chlorides? Are appropriate specifications and validated testing methods available for this? 检查起始物料甲磺酸(苯磺酸，对甲苯磺酸，羟乙磺酸)的质量，检测是否存在烷基或芳基磺酸酯杂质(比如：在甲磺酸中的甲磺酸甲酯和甲磺酸乙酯)以及相对应的相对应的酰基氯？是否有合适的标准和有效的检测方法来检验它？ ? Is it ensured that when using sulfonic acids contaminated with sulfonic acid esters or relatedcompounds as the starting materials for producing the active ingredient the TTC for the potential genotoxic impurities in the active substance is not exceeded? The cumulative risk of various alkyl- or aryl-substituted sulfonic acid ester impurities should be taken into account. 当受到磺酸酯或相关物质污染的磺酸作为制造原料药的起始原料时，是否确认了原料药中有潜在基因毒性的杂质没有超过毒理学的阈值？需要考虑多种烷基或芳基磺酸酯杂质的累积风险。 ? Is the quality of recycled solvents controlled for the enrichment and carry-over of sulfonic acid ester impurities (e.g. EMS in ethanol, MMS in methanol, IMS in isopropanol) 回收溶剂中有关磺酸酯杂质的富集和残留是否进行质量控制(比如，乙醇中存在甲磺酸乙酯。甲醇中存在甲磺酸甲酯，异丙醇中存在甲磺酸异丙酯) ? Can the formation of alkyl- or aryl-sulfonic acid esters be excluded during the storage of an active substance that exists in the form of a mesilate, besilate, tosilate or isetionate/diisetionate, or in the related preparation? 在原料药（存在甲磺酸盐，苯磺酸盐，对甲苯磺酸盐，羟乙磺酸盐的结构）贮藏或相关制备过程中，是否不含有烷基或芳基磺酸酯的结构？ ? Can the formation of alkyl- or aryl-sulfonic acid esters be excluded during the processing of mesilate, disetionate, besilate or tosilate active substances to make the finished preparation, e.g.when using alcohols for granulation? Is a sufficiently sensitive method available to detect these impurities in the pharmaceutical dosage form (at the TTC)? 在原料药（存在甲磺酸盐，苯磺酸盐，对甲苯磺酸盐，羟乙磺酸盐的结构）制剂过程中，是否不含有烷基或芳基磺酸酯的结构。(比如，使用酒精制粒？是否有足够灵敏的方法用于检测在制剂中的这些杂质)（当这些杂质达到毒理学的限度）？ |