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》

Explanatory note 1: 注释1

EU competent authorities need to see how the structure of the active substance is formed. A sufficient number of chemical transformation steps, as defined in the glossary of ICH Q11 (a step involved in the synthesis of the chemical structure of the drug substance from precursor molecular fragments. Typically it involves C-X or C-C bond formation or breaking), need to be included so that the generation, fate and control of impurities can be understood.

Recrystallisation and salt formation steps for late stage intermediates can significantly affect the impurity profile of the active substance. However, information on earlier synthetic steps is also necessary in order to understand the risk of impurity carryover and to demonstrate that the proposed control strategy sufficiently mitigates this risk. Therefore, neither recrystallisations nor salt formations are considered chemical transformation steps, and neither are activities unlikely to have an impact on API purity such as milling or sieving.

欧盟药监当局需要查看原料药的结构是如何形成的。如ICH Q11中的定义（从前体分子片断形成原料药化学结果合成所涉及的步骤），申报资料应包括有足够的化学转化步骤，以了解杂质的生成、去向和控制。后期步骤的中间体的重结晶和成盐步骤可以显著影响原料药的杂质谱。但是，也需要提交较早合成步骤的资料，以了解杂质被带入的风险，及证明所拟的控制策略足以转移该风险。因此，重结晶和成盐均不能被作为化学转化步骤，像粉碎或过筛这样的步骤也不太可能对原料纯度产生影响。

Furthermore, a sufficient number of purification steps need to be documented so that the fate and purge of impurities can be understood. Multiple synthetic transformations carried out in one vessel without intermediate isolations (sometimes referred to as telescoped steps or “one pot reactions”) provide fewer opportunities for purification than if isolation of intermediates were carried out. As with any complex reaction, a high number of variable parameters lead to a higher risk of producing active substance of variable quality. Regulators will therefore expect a commensurately high level of process understanding and control.

另外，要记录下精制步骤所需重复的次数，以了解杂质的去向和清除。在一个容器里进行多个合成转化，而不将中间体分离出来（有时称为叠加反应或一锅煮）则使得纯化的可能性比起将中间体分离出来会更小。这是因为在复杂反应中，更多的变量参数会导致更高的原料药生产质量波动风险。法规人员因此希望对工艺有较高水平的了解和控制，并与风险水平相当。

For these scientific reasons, short synthetic routes will not normally be accepted.

鉴于这些科学上的原因，短的合成路线一般是不会被接受的。

Generally, the detailed description of the manufacturing process (i.e. from the starting materials to the active substance) should cover all the synthetic steps critical to the quality of the active substance. Discussion on the formation, fate, and purge of both actual and

potential (i.e. those likely to be formed based on reaction mechanism, side reactions, degradants, as well as reagents, catalysts, and solvents used) impurities should be presented. To facilitate this, analytical techniques to detect and quantify actual and potential impurities are required.

一般来说，生产工艺的详细描述（例如，从起始物料到原料药）应包括所有对原料药质量比较关键的合成步骤。要提交实际存在杂质和潜在（即，那些基于反应机理可能会生成的杂质，副反应、降解产物、所用的试剂、催化剂和溶剂）杂质的形成、去向和清除的讨论。为达到此目的，需要有用于检测和定量实际和潜在杂质的分析技术。

The documentation presented should enable assessors to consider whether the manufacturing process is robust to variability, whether the process is well controlled and therefore whether it will consistently lead to active substance of appropriate quality. The specification of a starting material should contain suitable limits for known, unknown and total impurities and where appropriate, limits for solvents, reagents and catalysts used during its synthesis.

本文应使得评审员考虑生产工艺是否稳定，工艺是否受到良好控制，从而可以持续地获得具备适当质量的原料药。起始物料的质量标准应包括已知杂质、未知杂质和总杂质的适当限度，以及适当时，包括在合成中使用的溶剂、试剂和催化剂的限度。

Critical Steps:2关键步骤

The controls applied to steps critical for active substance quality should be described in module 3.2.S.2.4 (part 2.C.1.1.2 for veterinary applications). A critical step is defined as one where the process conditions, test requirements or other relevant parameters must be controlled within pre-determined limits to ensure that the active substance meets its specification. Difficulties to remain within pre-determined limits for processing conditions or passing in-process control tests, as well as the consequences of any excursions, should be considered when identifying critical steps.

对原料药质量有关键影响的步骤的控制应包括在模块3.2.S.2.4(兽药申报第2.C.1.1.2部分)中。一个关键步骤的定义是该步骤的工艺条件、测试要求或其它相关参数必须控制在预定的限度内，以保证原料药符合其质量标准。在识别关键步骤时，要考虑控制工艺条件在预定限度内或符合中控测试面临的困难，以及超出限度时的后果。

The criticality of a given step is related to its distance (in terms of synthetic steps) from the active substance, the subsequent processing and the overall control strategy being applied. The control strategy mitigates the risk associated with a given critical step, but does not necessarily affect its criticality. Examples of possible critical steps below should be considered in the context of the whole synthesis. The following list is neither exhaustive nor intended to imply that any such step would be mandatorily included in the manufacturing process of the active substance described in section 3.2.S.2.2 of the application (part 2.C.1.1.2 for veterinary applications).

某个特定步骤的关键性与其距原料药的远近（即合成步骤）有关，与后续的工艺步骤和总体控制策略有关。控制策略转移了与特定关键步骤有关的风险，但并不一定会影响其关键性。以下可能的关键步骤例子应在整个合成中进行考虑。以下清单并未列出所有可能，也无意暗示所有这样的步骤都必须包括在申报资料3.2.S.2.2（兽药申报为2.C.1.1.2部分）中对原料药生产工艺描述里。

Critical steps could be for instance:

关键步骤可以是诸如以下的步骤

• Steps involving formation and/or purge of key impurities – if a step purges an impurity which would otherwise be present in the active substance, then it should be considered critical. This could include not only reactive chemistry steps but work-ups, phase separations and crystallisations as well;

• 涉及关键杂质的形成和/或清除的步骤---如果一个步骤具有清除杂质的能力，一旦清除不了，该杂质就会被带入原料药，则该步骤应作为关键步骤。该类关键步骤不仅包括化学反应步骤，也包括后处理、分相和结晶步骤。

• Steps which introduce key structural features of the active substance, for example key functional groups or stereochemistry;

• 引入原料药特征关键结构的步骤，例如关键基团或立体化学结构

• Steps where careful control of stoichiometry, temperature, pH or other process variables is crucial for active substance quality;

• 立体化学、温度、pH值或其它工艺变更的控制对原料药质量至关重要的步骤

• Steps which employ or generate genotoxic compounds;

• 采用或产生基因毒性化合物的步骤

• Steps which employ class I solvents and/or toxic metals;

• 采用一类溶剂和/或有毒金属的步骤

• Complex chemical transformations where multiple variables could impact reaction outcome (multiple reagents, catalysts, solvents, etc.)

• 有多个变量会影响反应结果的复杂化学转化（多试剂、催化剂、溶剂等）

• The final purification step. 

• 最终纯化步骤

The applicant/manufacturer should discuss and identify those manufacturing steps that impact the impurity profile of the active substance as they should be normally included in the manufacturing process described in section 3.2.S.2.2 of the application (part 2.C.1.1.2 for veterinary applications).

申报人/生产商应讨论和识别那些对原料药杂质谱有影响的工艺步骤，因为这些步骤一般应被包括在生产工艺中，在申报资料3.2.S.2.2（兽药申报为2.C.1.1.2部分）中进行描述。

An approach could be to control certain parameters in the specification of a starting material (e.g. enantiomeric purity, genotoxic impurity limits). The acceptability of such proposals will depend on the proximity of a given starting material to the active substance, and thus, the risk to active substance quality.

可以采用的方法之一是对起始物料质量标准中的特定项目进行控制（例如，手性杂质、基因毒性杂质限度）。这类提议是否被接受将取决于该起始物料与原料药的接近程度，及其对原料药质量产生的风险。

Steps which have an impact on solid-state properties are always considered as critical, particularly, if the active substance is used within a solid dosage form, since they may adversely affect dissolution of the active substance thereby affecting bioavailability.

对固体形态特性产生影响的步骤都会被认为是关键的，尤其是如果原料药是用于固体制剂生产时，因为这些可能会对原料药的溶出度有不良影响，从而影响到生物利用度。

Tests and acceptance criteria, with justification based on experimental data, performed at critical steps identified in 3.2.S.2.2 of the manufacturing process, should be provided (part 2.C.1.1.2 for veterinary applications).

要提交生产工艺3.2.S.2.2部分（兽药申报为2.C.1.1.2）中识别为关键步骤的检测和可接受标准，以及根据实验数据所做出的论证。

The opportunity to justify a short synthetic sequence exists but this should be for clear scientific reasons and is expected to be the exception rather than the norm. In such cases, steps to synthesize the starting materials should be demonstrated not to be critical (as defined above) to the quality of the active substance, and steps to avoid contamination from non-GMP steps should be integral to the control strategy.

论证一个较短的合成路线也是有可能被接受的，但这需要有明确的科学理由，并且是例外情况，不会是常规。在这种情况下，要证明合成起始物料的步骤对于原料药的质量并不关键（如上定义），避免与非GMP步骤污染的步骤要结合在控制策略里。

Explanatory note 3: 注释3

It therefore follows that steps critical for the purity of the active substance should be performed under GMP, which forms an integral part of any control strategy.

因此，需要在GMP条件下实施对原料药纯度较为关键的步骤并遵守所要求的控制，这是所有控制策略不可分割的一部分

Explanatory note 4: 注释4

In the EU, the requirements of GMP for Active Substances (ICH Q7)5 have been incorporated into “The Rules Governing Medicinal Products in the European Union, Volume 4, Good Manufacturing Practice, Part II: Basic Requirements for Active Substances used as Starting Materials”.6

在欧盟，原料药GMP的要求（ICH Q7）已经结合入欧盟药品管理法第4卷，GMP，第二部分用作起始物料的原料药的基本要求。

For active substances, GMP applies to a manufacturing process from the introduction of starting materials and makes a major contribution to any control strategy.

对于原料药，GMP适用于引入起始物料开始，且对控制策略有重要影响的生产工艺。

GMP guidelines are intended to help ensure that active substances meet the requirements for quality and purity that they are claimed to possess.

GMP指南意在帮助企业保证原料药符合其应有的质量和纯度要求。

EU Authorities are concerned that introduction of impurities into the active substance from non-GMP manufacture, (e.g. from poor cleaning of vessels previously used for other purposes or  

inadequate control of processes), which would not necessarily be picked up by routine analytical testing is a significant risk. The fewer synthetic steps carried out under GMP, the higher the risk to the quality of the active substance.

欧盟药监机构感到担忧的是杂质从非GMP生产步骤（例如，之前用于其它目的罐没有彻底清洁、或工艺控制不充分）引入原料药，而常规分析测试不能监测，则具有较大的风险。在GMP条件下进行的合成步骤越少，对原料药质量造成的风险就越高。

The control strategy in place for a given manufacturing route mitigates the risk associated with the manufacturing process and assures the quality of the active substance. The control strategy ensures the individual batch quality, but relies on GMP to ensure that the conditions necessary for the validity of the control strategy do not change over time. It does not follow that a short route of synthesis can be accepted if a good control strategy is in place, nor that a poor control strategy can be compensated by a longer synthetic route carried out under GMP. Specifications of starting materials, intermediates and the active substance, reaction parameters (stoichiometry, temperature, pH, reaction times, etc.), in-process controls, release testing, and working under GMP all form an integral part of the control strategy.

对特定的生产路线采用控制策略可以转移与生产工艺相关的风险，保证原料药的质量。控制策略保证了各单批次的质量，而GMP则可以保证控制策略有效性所需的条件不会随时间而变化。这并不是说，如果具有良好的控制策略就可以只在将很短的合成路线在GMP生产，或者在GMP下实施较长的合成路线来弥补较差的控制策略。起始物料、中间和原料药的质量标准、反应参数（化学计量、温度、pH值、反应时间等）、中控制、放行测试，以及在GMP条件下操作，所有这些都是控制策略不可分割的一部分。

Although there are no objections to the manufacturers of starting materials operating under the principles of GMP, statements from applicants/manufacturers such as “we commit to carrying out manufacture of starting materials to GMP and are willing to be inspected” are not acceptable since production of the API starting material is currently excluded from application of the EU GMP Guide. Furthermore there is no current regulatory framework for inspection and no transparency exists for applicants and inspectors in steps prior to the starting materials. Likewise, assessors will not accept third party confidential information, sometimes proposed by starting material or intermediate manufacturers or suppliers of any raw materials used in the synthetic process, in order to seek approval of an advanced intermediate as a starting material. Any acceptance of GMP declarations of this nature would not translate to the lifecycle of the product where subsequent changes in the supply chain or to steps prior to the starting materials may not be subject to the same declarations which could neither be requested nor enforced.

尽管并不反对起始物料的生产商在GMP原则下操作，申报人/生产商出具声明如“我们承诺在GMP条件下生产起始物料，我们愿意接受检查”是不会被接受的，因为原料药起始物料的生产现在不在EU GMP指南的适用范围内。并且，现在也没有检查程序，起始物料之前的步骤对于申报人和检查人来说也并不透明。同样的，审阅人员不会接受第三方的保密资料，这些提议有时是由起始物料或中间体生产商或合成工艺所用原料的供应商提出的，目的是将一个高级中间体作为起始物料。如果说曾经接受过这类的GMP声明，那么并不表示在产品的生命周期都是需要的，也就是说如果之后对供应链有变更，或对起始物料前的生产步骤有变更，可以不需要提交相同的声明。当局不会要求或强制提交该声明。

Once approved, any subsequent change to the synthetic route involving re-definition of the starting materials must be proposed, justified and assessed according to same principles outlined in this reflection paper. Statements such as “this intermediate or starting material can be supplied by other qualified suppliers” cannot be accepted unless details of their source are provided and then only after regulatory assessment.

在被批准后，如果对合成路线的变更需要重新界定起始物料，则必须根据本阐述文章中列出的相同原则进行提议、论述和评估。当局不会接受类似“该中间体或起始物料可以由其它被确认的供应商提供”的声明，除非申报人提交了其来源的详细资料，并且当局完成了法规评审。

The practice of shortening some of the branches of an approved synthetic route through the submission of updates or variations to an ASMF, to a CEP dossier or to Module 3.2.S (part 2.C.1.1 for veterinary applications), is often linked to the contracting out of part of the synthetic route. That means redefinition of what was previously an intermediate to be the new starting material. Accepting the new proposed starting material however, reduces regulatory oversight and may weaken the control strategy. This is especially important when linked to further lifecycle changes in the supply chain which may adversely affect the overall quality of the active substance. The shortening of manufacturing processes is therefore unlikely to be considered acceptable without a strong scientific rationale.

通过现ASMF、CEP文档或模块3.2.S（兽药申报为2.C.1.1部分）提交更新或变更来缩短已批准的合成路线的某些分支常常因为将合成路线的一部分外包出去了。这表示要对之前作为中间体的物料重新定义为新的起始物料，但是接受所提议的新的起始物料将会降低法规监管力度，弱化控制策略。如果进一步与生命周期内对供应链的变更相关联，而这种变更可能对原料药整体质量产生负面影响，则这种关注显得尤为重要。因此，如果没有非常好的科学理由，缩短生产工艺是不太可能被接受的。

Explanatory note 5: 注释5

The term “significant structural fragment” is frequently misinterpreted by applicants as meaning structural proximity to the active substance. In this context however, the phrase applies to materials which contribute to the final molecular structure of the active substance, as opposed to reagents, catalysts, or solvents. Justification of a late intermediate as starting material by claiming it is a significant structural fragment is not considered a valid argument as this could apply to any intermediate in the manufacturing process.