201409 EMA对化学原料药生产起始物料的选择和论证要求思考 - 药群论坛

EUROPEAN MEDICINES AGENCY

SCIENCE MEDICINES HEALTH

16 September 2014

EMA/448443/2014

Committee for Medicinal Products for Human Use (CHMP)

Committee for Medicinal Products for Veterinary Use (CVMP)

Reflection paper on the requirements for selection and justification of starting materials for the manufacture of chemical active substances

化学原料药生产起始物料的选择和论证要求思考

Agreed by CHMP/CVMP Quality working party	11 July 2014
Adoption by CHMP	September 2014
Adoption by CVMP	September 2014

Keywords	Starting material, active substance.
关键词	起始物料、活性物质

Introduction: 概述

This reflection paper aims to clarify some of the expectations of EU competent authorities arising from the guidance found in ICH Q11 (Development and Manufacture of Drug Substances (Chemical Entities and Biotechnological/Biological Entities)1 regarding the information to be submitted in marketing authorisation dossiers to justify the selection of starting materials.

Whilst ICH Q11 is not generally applicable to veterinary products, the principles outlined in this document should apply equally for active substances destined to treat both humans and animals. The document re-produces extracts from section 5 of ICH Q11 verbatim in black text, and provides subsequent commentary on EU expectations in the form of explanatory notes within grey-shaded boxes.

本思考文章目的是澄清由ICH Q11指南（原料药研发和生产（化学实体和生物技术/生物制品实体））引出的，关于上市许可文件提交的用于论述起始物料选择的资料中，欧盟药监机构的态度。尽管ICH Q11并没有普遍应用于兽药产品，在本文中列出的原则还是同样适用于人兽共用活性物质。文件中摘要的ICH Q11第5部分内容以黑体字表示，相应的欧盟态度的解说以注释形式放在灰色阴影方框中。

It should be recognised that this document is not intended as a revision of ICH Q11, and rather as a reflection paper within the EU medicines regulatory network as prepared by the Quality Working Party (QWP).

读者应知本文并无意作为ICH Q11的修订版本，而只是由质量工作组起草，反映了欧盟药监机构网络的思考的文章。

Problem statement: 问题说明

Disagreements between applicants and quality assessors on the suitability of proposed starting materials have become more frequent in recent times. This suggests that the current guidelines,1-3 intentionally high level to allow application to the wide range of chemical syntheses submitted to regulatory authorities, are open to interpretation. Furthermore, it is increasingly common for applicants to propose very short synthetic routes with complex custom-synthesized starting materials. Another trend is for some, or all, of the active substance manufacture to be outsourced to third parties. The use of external sources for any steps in a manufacturing process may lead to a higher degree of risk to quality of the active substance than would be expected were the full manufacturing process to be carried out by the applicant or a single active substance manufacturer alone. This document strives to expand on some of the points in ICH Q11 in order to harmonise opinions between assessors and clarify the requirements for applicants.

近期申报人与质量评审官在起始物料界定上意见不同变得越来越频繁。这显示了现行指南可能被自由解释的情况，而这些指南故意提高了要求申报的化学合成的路线长度。并且，越来越多的申报人意欲申请将复杂的订制合成化合物作为起始物料，而使得申报的合成工艺非常之短。另一个趋势是，一些或所有的原料药生产被外包给第三方。将生产工艺的任何步骤外包的做法都可能会导致原料药质量风险高于由申报人自行生产或一个原料药生产商生产全部生产工艺的情况。本文试图在ICH Q11的基础上对某些问题进行延伸，以期在评审员之间达成一致意见，并向申报人澄清相关要求。

Additionally, the information submitted by applicants or Active Substance Master File (ASMF) holders to justify the selection of starting materials and their proposed specifications is often insufficient to allow adequate assessment of suitability.4 A detailed description of the manufacturing process of the active substance is required, along with a flow chart of transformations employed to synthesize starting materials including all solvents, reagents, catalysts and processing aids used, in order to facilitate a proper assessment. Since steps deemed critical should be carried out under Good Manufacturing Practice (GMP), an appraisal of the criticality of all transformations in the full synthetic route on the quality of the active substance is needed. The description of the manufacturing process should be sufficiently detailed to demonstrate that the process and its associated control strategy will consistently provide active substance of satisfactory quality. Starting materials can only be justified once the criticality of all steps has been discussed. Often, starting materials are selected and then only subsequent steps are discussed. This is not sufficient. A scheme of synthetic steps carried out to synthesize the proposed non-commodity starting materials should be provided as part of the justification of starting material selection.2

另外，由申报人或ASMF持有人提交的论证起始物料选择合理性的资料，和其拟定的质量标准常常不够充分，让评审人员无法进行足够的适用性评估。为了便于做出适当的评估，需要提交原料药生产工艺的详细描述、起始物料合成的流程图，包括所有溶剂、试剂、催化剂和工艺助剂。由于被界定为关键的步骤需要在GMP条件下实施，所以要对在整个合成路线中各转化步骤对原料药质量的关键程度进行评价。生产工艺的描述必须足够详细，以证明工艺和其相关的控制策略能持续地保证原料药具有令人满意的质量。只有对所有步骤的关键性都进行了讨论，才能对起始物料进行论述。而我们经常看到申报者是先选择了起始物料，然后才对后续步骤进行讨论，这是不够充分的。对于非商业化起始物料，需要提供一份其合成步骤图，作为起始物料选择合理性论证的一部分。

ICH Q11 and explanatory notes: ICH Q11和解释

5. Selection of starting materials and source materials 起始物料和源物料选择

5.1 General principles 一般原则

5.1.1 Selection of starting materials for synthetic drug substances 合成原料药起始物料的选择

The following general principles should be considered in determining where the drug substance manufacturing process begins (i.e., in selecting starting materials).

在决定原料药生产工艺要从哪里开始（即选择起始物料）时，应考虑以下通则：

? In general, changes in material attributes or operating conditions that occur near the beginning of the manufacturing process have lower potential to impact the quality of the drug substance;

? 一般来说，原料特性或操作条件的变化越是靠近生产工艺的起始端，则对原料药质量的影响可能性就越小

? The relationship between risk and number of steps from the end of the manufacturing process is the result of two factors, one concerning the physical properties of the drug substance and the other concerning the formation, fate, and purge of impurities. The physical properties of a drug substance are determined during the final crystallisation step and subsequent operations (e.g., milling, micronising), all of which occur at the end of the manufacturing process. Impurities introduced or created early in the manufacturing process typically have more opportunities to be removed in purification operations (e.g., washing, crystallisation of isolated intermediates) than impurities generated late in the manufacturing process, and are therefore less likely to be carried into the drug substance. However, in some cases (e.g., when peptides or oligonucleotides are synthesised on a solid support), there is a more limited relationship between risk and number of steps from the end of the manufacturing process;

? 风险与距生产工艺尾端步骤数之间的关系取决于2个因素，一个是原料药的物理特性，另一个是杂质的形成、去向和清除。原料药的物理特性是由最终结晶步骤和之后的操作决定的（例如，粉碎、微粉），所有这些都发生在生产工艺的尾端。相对生产工艺较后步骤产生的杂质，在较早的工艺步骤引入的杂质一般在精制操作中被清除的可能性更大（例如，洗涤、中间体分离结晶）。但是，在有些情况下（例如，在固体支架下合成的肽或寡核苷酸），风险与距生产工艺尾端步骤数之间的关系可能是比较有限的。

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。

Regulatory authorities assess whether the controls on the drug substance and drug substance manufacturing process can be considered adequate, including whether there are appropriate controls for impurities. To conduct this assessment, enough of the drug substance manufacturing process should be described in the application for regulatory authorities to understand how impurities are formed in the process, how changes in the process could affect the formation, fate, and purge of impurities, and why the proposed control strategy is suitable for the drug substance manufacturing process. This will typically include a description of multiple chemical transformation steps.

法规当局将评估原料药和原料药生产工艺的控制是否充分，包括对杂质的控制是否适当。为了实施该评估，在申报资料中要提交足够详细的原料药生产工艺描述，以使得法规当局可以了解杂质在工艺中如何形成、工艺变化如何影响杂质的形成、去向和清除，为什么所拟的控制策略适合于原料药生产工艺。这一般是要包括对多个化学转化步骤的描述。

Explanatory note 2: 注释2

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

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。

When the proposed starting material is itself an active substance covered by a monograph of the European Pharmacopoeia (Ph. Eur.), and when the active substance manufacturer has demonstrated the suitability of the Ph. Eur. monograph as evident by a valid Certificate of Suitability to the monographs of the European Pharmacopoeia (CEP) for the proposed starting material, this would be accepted. Alternatively, such a starting material may already be the active substance in a marketing authorisation in the EU. However, clear evidence that the marketing authorisation is still valid and that the starting material is manufactured under GMP to the same quality standard as the active substance in the already-authorised product, (manufacturer, site, process, impurity profile and specifications), should be provided in the dossier.

如果所拟定的起始物料本身就是一种原料药，包括在欧洲药典各论中，且原料药生产商已证明欧洲药典质量标准适用于该起始物料，该起始物料持有CEP，则是可以接受的。另一种情况是，该起始物料可能已经作为原料药被用于欧盟上市许可的制剂中。不管怎样，在申报资料中要提交上市许可仍处于有效状态的明确证据，以及起始物料在GMP下生产，符合已上市产品中所用原料药相同的质量标准。

1. Manufacturing steps that impact the impurity profile of the drug substance should normally be included in the manufacturing process described in Section 3.2.S.2.2 of the application.

对原料药杂质谱有影响的生产步骤一般要包括在申报资料3.2.S.2.2部分生产工艺描述中。

Explanatory note 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。

??Each branch of a convergent drug substance manufacturing process begins with one or more starting materials. The Good Manufacturing Practice (GMP) provisions described in ICH Q7 apply to each branch beginning with the first use of a starting material. Performing manufacturing steps under GMP together with an appropriate control strategy provides assurance of quality of the drugsubstance.

如果原料药生产工艺有多个支链，则每个支链追溯至其使用起始物料起都适用ICH Q7的GMP条款。在GMP条件下实施生产步骤和适当的控制策略一起为原料药质量提供保证。

Explanatory note 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。

l A starting material should be a substance of defined chemical properties and structure. Non-isolated intermediates are usually not considered appropriate starting materials;

l 一种起始物料应该具有明确的化学特性和化学结构。没有分离出的中间体一般不能考虑作为适当的起始物料。

? A starting material is incorporated as a significant structural fragment into the structure of the drug substance. “Significant structural fragment” in this context is intended to distinguish starting materials from reagents, solvents, or other raw materials. Commonly available chemicals used to create salts, esters or other simple derivatives should be considered reagents.

l 一种起始物料作为重要结构片断，结合到原料药的结构中。本处“重要的结构片断”意在将起始物料与试剂、溶剂或其它原料区分开来。通常容易获得的化学品，用于生成盐、酯或其它简单衍生物的应作为是试剂。

Explanatory note 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.

术语“重要结构片断”常被申报人错误地解释为原料药结构相近。在本文中，该短语适用于对原料药最终分子结构有贡献的物料，与试剂、催化剂或溶剂是相对的。声明一个较高级的中间体是一个重要的结构片断，从而论证其可以作为起始物料会被认为是无效的。因为如果这样的话，那么生产工艺中的所有中间体都可被作为起始物料了。

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:

Scientific 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

For purposes of this guideline, a semi-synthetic drug substance is one in which the structural constituents have been introduced by a combination of chemical synthesis and elements of biological origin (e.g., obtained from fermentation or by extraction from botanical material). In some cases, it might be appropriate for the applicant to describe the manufacturing process starting from the source material (microorganism or botanical material). However, if it can be demonstrated that one of the isolated intermediates in the synthetic process complies with the principles outlined above for the selection of starting materials for synthetic drug substances, that isolated intermediate can be proposed as the starting material. The applicant should specifically evaluate whether it is possible to analytically characterise the proposed starting material, including its impurity profile, and whether the fermentation or botanical material and extraction process impact the impurity 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 information. It is the responsibility of the applicant to show that a commercially available starting material is not custom synthesised, but a commodity material used in a non-pharmaceutical market, and to provide supportive documentation in the dossier demonstrating so. It is also a requirement to demonstrate that the quality of a commercially available starting material is adequate for use in the manufacture of an active substance. To enable the assessment of any requirement for further purification of a commercially available material, the information on the impurity profile should be presented for assessment.

仅仅声明一种物料是商业可获得，而没有其它支持性资料，可能会被认为是不够充分的，不能证明其可以作为起始物料。申报人有责任说明该商业可获得的起始物料不是订制合成的，而是非制药市场所用的商业化物料，在申报资料中提交支持性文件进行证明。还要证明商业可获得的起始物料的质量足以满足原料药的生产使用要求。为使得评审人员可以评估对商业可获得物料进一步精制的必要性，还需要提交杂质谱的资料。

5.2.2 Justification of starting material selection for semi-synthetic drug substances 半合成原料药起始物料选择的论证

If an isolated intermediate is proposed as the starting material for a semi-synthetic drug substance, the applicant should provide a justification that explains how the proposed starting material complies with the general principles for the selection of starting materials outlined above in Section 5.1.1. Otherwise, the applicant should describe the manufacturing process starting from the microorganism or botanical material, as appropriate, and these materials should be qualified.

如果提议将一个分离出的中间体作为半合成原料药的起始物料，则申报人要提交一份论述，解释所拟的起始物料是如何符合5.1.1部分中所列的起始物料选择通则的。否则，申报人则应描述从微生物或植物原料开始的生产工艺，适当时还应对这些物料进行确认。

References: 参考文献

1. ICH Guideline Q11 on Development and Manufacture of Drug Substances (chemical entities and biotechnological / biological entities) CHMP/ICH/425213/2011 (ICH Q11)
ICH Q11原料药研发和生产指南（化学实体和生物技术/生物实体）

2. Chemistry of New Active Substances (CPMP/QWP/130/96, Rev 1)
新活性物质的化学部分

3. Chemistry of active substances 3AQ5A
活性物质化学部分

4. Active substance-master-file procedure CHMP/QWP/227/02
活性物质主文件程序

5. ICH Guideline Q11 on Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients CPMP/ICH/4106/00 (ICH Q7)
ICH Q11 活性药用成份GMP指南

6. 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
EU GMP第二部分：作为起始物料的活性物质的基本要求

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