发布时间 : 星期三 文章化学原料药生产起始物料的选择和论证要求思考 - 图文更新完毕开始阅读
profile of the drug substance. Risks from microbial and other contamination should also be addressed.
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:
It 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 inexplanatory note 2, and considering the potential for variability in fermentation process or extraction step, then it should be carried out under GMP.
再次强调的是，半合成起始物料应符合上述起始物料通则，这已经在注释6里做了总结。如果根据注释2中的定义，发酵步骤或提取步骤被认为是很关键，考虑到发酵工艺或提取步骤中变化的可能性，其应该在GMP条件下操作。
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
Applicants should identify all proposed starting materials or source materials and provide appropriate specifications. Proposed starting materials for synthetic and semi-synthetic drug substances should be justified.
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:
Information 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 starting material is appropriate in light of the general principles for the selection of starting materials outlined above in Section 5.1.1. This can include information on: 申报人应提交资料，根据5.1.1部分所列的起始物料选择通则，论述为什么各所拟起始物料是适当的。论述可以包括以下资料
? The ability of analytical procedures to detect impurities in the starting material ? 分析方法可以检测到起始物料中的杂质
? The fate and purge of those impurities and their derivatives in subsequent
processing steps
? 这些杂质及其在之后工艺步骤中的衍生物的去向和清除，
? How the proposed specification for each starting material will contribute to the
control strategy
? 所拟的各起始物料的质量标准如何实现控制策略 Explanatory note 9:
The suitability of a starting material needs to be justified against the principles in section 5.1 as a whole, rather than against selected individual bullet points. Critical to satisfactory justification of a starting material, and for the assessment of the justification, is the description of the formation, fate and purge of impurities. The dossier must contain an appropriate discussion on known and unknown impurities including residual solvents, catalysts, metals and reagents. The starting material specifications should include tests and acceptance criteria for specified, unspecified and total impurities (including (potential) genotoxins) and where appropriate, limits for solvents, reagents and catalysts used during their synthesis. An inadequate discussion on impurities renders evaluation of the proposed starting
materials and their specifications impossible.
起始物料的适用性需要根据5.1部分中的原则作整体论述，而不只是针对选择的单个项目进行论述。要让起始物料的论述让人满意，对论证内容进行评审时最关键的是描述杂质的形成、去向和清除。申报文件中必须包括对已知和未知杂质的适当讨论，包括残留溶剂、催化剂、金属和试剂。起始物料质量标准应包括已知、未知和总杂质（包括潜在的基因毒性）的检验方法和可接受标准，适当时，应包括原料药合成中所用溶剂、试验和催化剂的限度。如果对杂质的讨论不够充分，评审人员就无法对所拟的起始物料及其质量标准进行评估。 The applicant should provide, as part of the justification, a flow diagram outlining the current synthetic route(s) for the manufacture of the drug substance, with the proposed starting materials clearly indicated. Changes to the starting material specification and to the synthetic route from the starting material to final drug substance are subject to regional, post-approval change requirements. In addition, regional requirements concerning starting material suppliers may also be applicable.
申报人应提交原料药现行生产的合成路线流程图作为论述的一部分，在其中清楚标明所拟的起始物料。对起始物料质量标准和起始物料到原料药之间合成路线的变更要符合地方对预批准变更的要求。另外，地方当局对起始物料供应商的要求也是适用的。 Explanatory note 10:
The quality of the proposed starting material must be sufficient, in combination with the control strategy, to ensure the quality of the active substance. The manufacturing route of a starting material and information on manufacturers* should also be provided to allow an adequate assessment of the suitability of starting materials and their specification. If any synthetic steps used to manufacture the starting materials are considered critical and are either close to the active substance (in terms of number of synthetic steps) or impact its impurity profile, then the re-definition of starting materials to an earlier point should be considered, bearing in mind the whole synthetic route and the control strategy (see explanatory note 2).
所拟起始物料的质量必须达到足够的标准，与控制策略一起，用于保证原料药的质量。起始物料的生产路线和生产商资料也需要在申报资料中提交，以使得评审人员能对起始物料和其质量标准的适用性进行评审。如果起始物料生产中某合成步骤被认为是关键的，并接近原料药（指合成步骤数）或对杂质谱有影响，则应考虑重新定义起始物料，将其移至较前的点，这时一定要考虑整个合成路线和控制策略（参见注释2）。
It is emphasized that it is the legal responsibility of the marketing authorisation holder to maintain the quality of the active substance throughout its lifecycle. Implicit in this is that changes to the synthetic route to the starting materials should always be assessed for their impact on the quality of the active substance, and any
resultant modifications such as changes to specifications or manufacturers of the starting material(s) should be applied for by way of appropriate variations. The active substance manufacturer, which may frequently be independent of the applicant, has a very important role to play in this and is also responsible for ensuring the quality of the active substance it manufactures.
要强调的是上市许可持有人承担着法定责任，要在其生命周期中维护原料药的质量。在此表示的意思是，起始物料合成路线的变更都要评估其对原料药质量的影响，所有可能会产生影响的修订例如，起始物料质量标准或生产商的变更应进行适当的变更申报。原料药生产商，通常是独立于申报人的，在此扮演了非常重要的角色，也有责任保证其所生产的原料药的质量。
* When ICH Q11 mentions starting material suppliers, this is interpreted within the EU as manufacturers.
当ICH Q11提到起始物料供应商时，在EU内是作为生产商来解释的。
An applicant generally need not justify the use of a commercially available chemical as a starting material. A commercially available chemical is usually one that is sold as a commodity in a pre-existing, non-pharmaceutical market in addition to its proposed use as starting material. Chemicals produced by custom syntheses are not considered to be commercially available. If a chemical from a custom synthesis is proposed as a starting material, it should be justified in accordance with the general principles for the selection of starting materials outlined above in Section 5.1.1.
一般来说，申报人不需要论证其采用商业或获得的化学品作为起始物料。商业可获得的化学品通常是指作为已存在、除其起始物料的用途外，非制药行业市场的商品。订制合成的化学品并不是商业可获得的。如果提议一个订制合成的化学品作为起始物料，则应根据5.1.1部分所列的起始物料选择通则进行论述。
In some instances, additional purification steps by the drug substance
manufacturer might be called for to ensure the consistent quality of a commercially available starting material. In these instances, the additional purification steps should be included as part of the description of the drug substance manufacturing process. Specifications should normally be provided for both incoming and purified starting material.
在有些情况下，原料药生产商可能会对起始物料进行额外的精制，以保证商业获得的起始物料质量稳定性。在这种情况下，应将精制步骤包括在原料药生产工艺中，作为其一部分。要提交进厂起始物料和精制后的起始物料的质量标准。 Explanatory note 11:
A statement that a material is commercially available may not be considered sufficient to justify it as a starting material without additional supporting