2017年版ema《化学原料药生产起始物料的选择和论证要求思考》（中英文对照）2

2017年版ema《化学原料药生产起始物料的选择和论证要求

思考》（中英文对照）2

续All the general principles above should be considered in selecting Starting Material(s), rather than strictly applying each general principle in isolation (see Example 4, Section 10.4). 在选择起始物料时，要考虑上述所有的通则，而不仅仅单独考虑严格适用某一个原则（参见例4，第10.4部分）。Explanatory note 6: 注释6Scientific reasoning with appropriate justification, considering the whole synthetic approach and control strategy, and incorporating all the various principles outlined above, should be used in order to justify the selection of the starting materials. Often, applicants/manufacturers will select just a few criteria and use them to justify starting material selection, e.g.: “Compound X is a well-characterised isolated material of defined chemical properties and structure, and constitutes a significant structural fragment of the active substance. Therefore it is selected as a starting material as per ICH Q11.” This line of argumentation is not comprehensive and therefore not acceptable. Control strategy alone is not a sufficient justification of a starting material. Equally, a long synthetic process will not necessarily compensate for a poor

control strategy.

在论述起始物料的选择时，要采用适当的科学原理进行论述，考虑整个合成方法和控制策略，结合上列所有各类原则。通常，申报人/生产商会选择少数几个标准，使用它们对起始物料的选择进行论述，例如，“化合物X特性清楚，被分离，具有清楚的化学特性和结构，成为原料药的重要结构片断，因此根据ICH Q11它被选择作为起始物料”。这样的论述不够全面，因此不会被接受。仅仅只有控制策略的话，是不足以作为起始物料的论证依据的。同样，合成路线很长并不能弥补很差的控制策略5.1.2 Selection of starting materials for semi-synthetic drug substances 半合成原料药的起始物料的选择在本指南中，半合成原料药是指原料药结构是由一部分化学合成结构和生物来源结构（例如，发酵、植物原料提取）合并而成。在有些情况下，申报人可以从来源物料（微生物或植物原料）开始描述生产工艺。当然，如果可以证明在合成步骤中分离出的一个中间体符合上述合成原料药起始物料选择的原则，则所分离出的中间体也可以提议作为起始物料。申报人尤其应评估是否可能对所拟的起始物料进行特性分析，包括其杂质谱、发酵或植物原料和提取工艺对原料药的杂质谱是否有影响。要说明微生物和其它污染所带来的风险。

Explanatory note 7: 注释7It is re-emphasised that a

semi-synthetic starting material should comply with the general principles for starting materials already discussed above and summarised in explanatory note 6. If the fermentation step or extraction step is considered to be critical following the definition in explanatory note 2, and considering the potential for variability in fermentation process or extraction step, then it should be carried out under GMP.5.2 Submission of information for starting material or source material 起始物料或来源物料的资料提交申报人应识别所有拟定的起始物料或源物料，提交适当的质量标准。应论证所拟的合成和半合成原料药的起始物料。Explanatory note 8: 注释8Information on the manufacturers and suppliers of starting materials should be provided, including name and address, and a scheme of the synthetic route used to manufacture them, showing all reagents, catalysts and solvents used. Without this information, the suitability of specifications cannot be adequately assessed. 要提交起始物料生产商和供应商的资料，包括名称、地址、生产所用合成路线图、标示所用的所有试剂、催化剂和溶剂。没有这些资料，就无法对质量标准的适用性进行适当评审。 The specification for a starting material should address impurities and is expected to consider suitable limits for known, unknown impurities and total impurities and where appropriate,

limits for solvents, reagents and catalysts used during synthesis of a starting material. The acceptance criteria should be established based on origin, fate and purge of impurities present in the starting material, and where appropriate, should be designed to detect isomeric or other impurities which are potentially reactive and which may be carried through to the active substance.

起始物料的质量标准应包括杂质，应考虑对已知、未知杂质和总杂质制订适当的限度，适当时还要制订起始物料合成中所用的溶剂、试剂和催化剂的限度。应根据起始物料中出现杂质的来源、去向和清除情况建立可接受标准，适当时，应设计检测异构体和其它可能反应，并带入原料药的杂质。 Analytical methods used should be validated. A tabulated summary of the results of the validation carried out should be provided if critical for the quality of the active substance However, it is not necessary to provide a validation report. 所用的分析方法应进行验证。如果分析方法对于原料药的质量非常关键，则需要采用表格总结的方式提交验证结果。当然，并不需要提交验证报告。

5.2.1 Justification of starting material selection for synthetic drug substances 合成原料药起始物料选择的论证The applicant should provide a justification for how each proposed