PA/PH/CEP (16) 58 2015-2016年度化学纯度CEP新申报资料十大缺陷

Certification of Substances Department

CSA/Cb

PUBLIC DOCUMENT

(LEVEL 1)

PA/PH/CEP (16) 58

Strasbourg, December 2016

Certification of suitability to the Monographs of the European Pharmacopoeia

TOP TEN DEFICIENCIES

New Applications for Certificates of Suitability for chemical purity

(2015-2016)

2015-2016年度化学纯度CEP新申报资料十大缺陷

Address: 7 Allée Kastner, CS 30026 F-67081 Strasbourg (France)

Tel: +33 (0) 3 88 41 30 30 – Fax: +33 (0) 3 88 41 27 71 - e-mail: cep@edqm.eu

Internet: http://www.edqm.eu

This document is a summary of the ten most frequent questions raised after the initial evaluation of new applications for Certificates of suitability (CEP) for chemical purity. It is based on the content of a sample of 20 deficiency letters sent selected randomly during the second half of 2015 and beginning of 2016.

本文是对化学纯度CEP新申报资料初次审评中发现的最常见十大问题的总结。该总结是基于2015年下半年和2016年初期间随机抽取的20封缺陷信内容。

The top ten most frequent questions are listed below together with expectations and recommendations on how to address the specific deficiencies, with reference to applicable guidelines.

以下列出了十大最常见问题，以及EDQM期望和建议如何解决这些缺陷和相关的适用指南。

This document is intended to help applicants to improve the quality of their dossiers, in order to facilitate and speed up the granting of their CEPs. It should be taken into account while building up a dossier, in combination with the EDQM Guideline “Content of the Dossier for Chemical Purity and Microbiological Quality (PA/PH/CEP 04 1)” available on the EDQM website.

本文意在帮助申报人提高其注册文件质量，以帮助和加快其CEP的颁发。在构建注册文件时，应结合考虑EDQM官网上EDQM指南“化学纯度和微生物质量注册文件内容（PA/PH/CEP 04 1）”的要求。

TOP 1 (S.3.2) 第一位（S.3.2） Absence or deficient discussion on the risk of having potential mutagenic impurities in the final substance. 原料药成品中潜在诱变性杂质风险讨论缺失或有缺陷。

This is applicable to sources of substances which have not yet been introduced in medicinal products available on the European market.

此点适用于目前尚未用于欧洲市场上销售的药品生产的物质来源。

Applicants are expected to provide a complete discussion on mutagenic impurities in their application for a CEP. It is necessary to refer to ICH M7 (in force since January 2016). Any addendum, available on the ICH website, may also be useful reading for product-specific recommended safety values (refer also to Note 5 of ICH M7).

申报人应在其CEP注册申报资料中提交关于诱变性杂质的完整讨论。该讨论应参考ICH M7（自2016年1月起生效）。ICH官网上所有备忘也可能会对于特定产品所推荐的安全值有用（同时也请参考ICH M7注5）。

It is expected that potential mutagenic impurities arising from the synthesis of the substance and its starting materials (if relevant and if not otherwise justified) or from degradation processes are listed and classified in the CEP dossier as per ICH M7. Impurities can be classified with respect to their mutagenic and carcinogenic potential in 5 different classes (refer to table 1 of ICH M7) and actions for control are proposed accordingly. Sometimes no mutagenicity data are available for impurities showing alerting structures and arising from synthetic processes (class 3 impurities as per ICH M7); these impurities should be controlled at or below an acceptable limit or mutagenicity assays should be conducted (refer to Note 2 of ICH M7) in order to understand if the impurity is non-mutagenic (hence class 5) or mutagenic (hence class 2). The outcome of bacterial mutagenicity assays can also be predicted by (Q)SAR methodologies (in-silico studies). According to ICH M7 two (Q)SAR methodologies that complement each other should be applied, one which is expert rule-based and a second one which is statistical-based. The principles set by the OECD should be followed.

应按ICH M7的分类在CEP注册文件中分类列出原料药合成过程中、起始物料合成过程中（如相关并且没有另做论证时）以及原料药降解过程中所产生的潜在诱变性杂质。杂质可以按其诱变性和致癌可能性分为5类（参见ICH M7表1），并据此制订相应的控制措施。有时，一些显示出警示结构的杂质和合成工艺中产生的杂质可能无法获得诱变性数据（按ICH M7分类应为第3类），则应将这些杂质控制在等于或低于可接受限度内或诱变水平内（参考ICH M7注2），以厘清该杂质究竟是非诱变性（则应为第5类）还是诱变性（则应为第2类）。根据（Q）SAR方法学（电脑模拟研究）也可以预测细菌诱变检测的结果。根据ICH M7，应采用2个（Q）SAR方法学相互补充，其中一个应是依据专家规则，另一个则依据统计规则。应遵守OECD所设定的原则。

In order to set an acceptable limit for (potential) mutagenic impurities in the substance it is necessary to divide the “acceptable intake” of the (potential) mutagenic impurity by the maximum daily dose of the substance. In order to identify the acceptable intake for a mutagenic impurity, the “less-than-lifetime” (LTL) concept may be used. Note 7 of ICH M7 is very helpful to identify this acceptable intake, and ICH M7 also gives guidance on how to identify acceptable total intakes for multiple impurities.

为了设定原料药中（潜在）诱变杂质的可接受限度，有必要根据原料药的最大日剂量对（潜在）诱变杂质的“可接受摄入量”进行区分。为了识别出诱变杂质的可接受摄入量，可以使用“小于生命周期”（LTL）概念。ICH M7注7在识别此可接受摄入量方面会很有用，ICH M7也给出如何识别多个杂质总体可接受摄入量的指南。

Once an acceptable limit is adequately identified, it is expected that a control strategy is developed according to the four proposals given by ICH M7 (from option 1 to option 4), according to the nature of those impurities and their probability to be present in the final substance. Batch data should be given in support (if deemed necessary) and the analytical methods used should be described. Purge studies may be developed in support to approaches based on option 3 and option 4. Purge studies should be well-developed and justified and all the physico-chemical parameters used (reactivity, solubility, volatility, ionisability, physical processes, etc) should be given with the studies and discussed.

一旦对可接受限度进行充分的识别，则应根据这些杂质的属性，根据其在原料药成品中出现的可能性，以及根据ICH M7（方法1至方法4）所给出的4个方法建立控制策略。应提交批数据对其予以支持（如果认为有必要），应描述所用的分析方法。可以进行杂质清除研究以支持根据方法3和方法4所制订的方法。杂质清除研究应彻底并进行论证，在研究中所用的所有理化参数（反应性、溶解性、挥发性、离子化能力、物理处理等）均应同时提供并进行讨论。

TOP 2 (S.2.3) 第二位（S.2.3） Absence or insufficient discussion on fate and carryover of related substances of starting materials (included) to the final substance. 起始物料中有关物质（包括起始物料自身）残留和去向讨论缺失或不充分

The impurity profile of molecules identified as starting materials should be well characterised. This means that applicants need to know what kind of impurities can be found in starting materials, in particular with regard to related substances since usually these are molecules that can react according to the chemistry foreseen by the process, leading to impurities in intermediates and potentially in the final substance. Once the impurity profile of starting materials is sufficiently characterised a detailed discussion is expected not only with regard to carryover of impurities from starting materials to the final substance but also with regard to their fate: what happens to them once introduced in the process along with the starting material. Carryover of unreacted starting materials themselves should also be discussed. If deemed necessary, adequate evidence (e.g., analytical data, literature, information from process development or process validation, etc.) should be given in support.

定义为起始物料的分子的杂质概况应进行完整的确证。这意味着申报人需要知道在起始物料中可能会发现哪类杂质，尤其是有关物质，因为这些杂质是可以根据工艺进行预测的分子，会形成中间体中的杂质，并可能形成原料药成品中潜在的杂质。在充分确证了起始物料中的杂质概况后，不仅应对起始物料中杂质残留至原料药成品中的情况进行讨论，还应对其去向进行讨论：与起始物料一起引入工艺后它们发生了什么事情。未反应完全的起始物料自身在原料药成品中的残留也应进行讨论。如果认为有必要，应提交充分的证据（例如，分析数据、文献、工艺研发或工艺验证中所获得的数据等）予以支持。

TOP 3 (S.2.2, S.2.4) 第三位（S.2.2，S.2.4） Lack of details and/or poor description of the manufacturing process of the substance from the introduction of starting materials (synthesis, narrative description, flow charts, recovery and reprocessing procedures). Incongruences noted between information given in section S.2.2 and section S.2.4. 引入起始物料之后的原料药生产工艺描述（合成路线、叙述性描述、流程图、回收和返工程序）不够详细和/或太差。在S.2.2部分和S.2.4部分所提供的信息不一致。

The manufacturing process should be described in details including all used chemicals along with their quantities, all the operations conducted and all the corresponding operational conditions adopted (in terms of temperatures, pressures, times, etc.). The process needs to be well-described since this is the main source of information that allows assessors to take position on potential formation of impurities and on the potential ability of the process to remove impurities. In-process controls should be mentioned in section S.2.2 (as part of the description of the manufacturing process) and details should be given in section S.2.4 (in terms of acceptance criteria and analytical methods), including controls implemented on isolated intermediates. It is expected that no incongruences are noted while comparing information given in these two sections of the dossier.

应详细描述生产工艺，包括所有使用的化学品及其用量、所有执行的操作以及所有采用的对应操作条件（温度、压力、时长等）。工艺应进行详细描述，因为这是评审人员获得信息的主要来源，依据这些信息，评审人员方可评估可能形成杂质的情况，以及工艺清除杂质的潜在能力。在S.2.2中应描述中控内容（作为生产工艺描述的一部分），在S.2.4中应提交详细信息（关于可接受标准和分析方法），包括对分离中间体所实施的控制。在注册文件中这两部分所提交的信息相比较不应有不一致的内容。

The maximum batch size or the batch size range the process described in the dossier refers to should be given in section S.2.2. This information should be congruent with the size of batches described in section S.4.4.

在S.2.2部分应提交注册文件中所述工艺的最大批量或批量范围。该信息应与S.4.4中所述的批量一致。

These requirements apply equally to the manufacturing steps for outsourced intermediates, which should be fully described in the CEP applications.

这些要求同等适用于外购中间体的生产步骤，这部分内容应在CEP申报资料中进行全面描述。

TOP 4 (S.2.3) 第四位（S.2.3） Non-acceptable starting materials, necessity to redefine them earlier in the process. 起始物料不能接受，需要重新定义工艺中更早的物料作为起始物料。

Starting materials are the starting points for GMP and variations/revisions and they should be representative of the overall synthetic process. Starting materials should be identified and selected according to the requirements set by ICH Q11 and any additional related available guidance. These are considered as mandatory readings before initiating the exercise of defining starting materials. The reasons why the proposed starting materials are considered as adequate and in line with applicable guidelines should be explained in details in the dossier, in section S.2.3.

起始物料是GMP和变更/修订的起始点，他们应代表全面合成工艺。起始物料的界定和选择应依据ICH Q11和其它所有相关可获得的指南所设定的要求。在开始对起始物料进行定义之前必须阅读这些指南。在S.2.3部分应详细解释为何认为所提议的起始物料是充分的，并且符合适用的指南。

If found not acceptable by the assessors, starting materials should be redefined back in the process and this may have major consequences on the manufacture and on the content of the dossier. Manufacturers initially proposed for those non-acceptable starting materials become manufacturers of intermediates (subject to EU GMP Part II and willingness to be inspected) and the dossier should be completely restructured accordingly, since the process from new starting materials to intermediates should be described in section S.2.2. Therefore applicants are expected to select carefully their starting materials.

如果评审人员认为所界定的起始物料不能接受，则起始物料要重新界定，顺着工艺路线前推，这可能会对生产和注册文件的内容产生重要影响。最初所拟的未被接受的起始物料的生产商就变成了中间体的生产商（要符合EU GMP第II部分要求，并且愿意接受现场检查）。而由于在S.2.2中需要描述自新的起始物料到中间体的工艺，因此注册文件整体要相应地重新构架。因此，申报人应谨慎选择其起始物料。

TOP 5 (S.2.3) 第五位（S.2.3） Non-adequate or poorly justified specifications in place to control the quality of starting materials. 起始物料质量标准不充分或论证不足，无法控制起始物料质量。

The quality of molecules identified as starting materials should be sufficiently characterised and kept under control by adequately justified specifications. It is expected that specifications in place to control the quality of starting materials mirror their manufacturing processes. The specification of a starting material should include tests for identity and purity (e.g., controls on impurities), and acceptance criteria for assay, specified, unspecified and total impurities, residual solvents, reagents, mutagenic impurities etc as needed. Tests and acceptance criteria should be based on process knowledge and control strategy. The analytical methods used should be suitably validated and described in section S.2.3. The justification of the specification should include evaluation of the risks and the ability of the subsequent steps to purge impurities. Assurance should be given in the dossier that there are no risks of having uncontrolled impurities in the final substance potentially above acceptable limits. These are risks always kept in mind by assessors while evaluating applications in the context of the Certification Procedure.

被界定为起始物料的化学分子的质量应进行充分确证，并且受到充分论证的质量标准的控制。申报人应制订适当的质量标准来控制起始物料的质量，质量标准应与其生产工艺相对应。起始物料的质量标准应包括鉴别和纯度检测（例如，杂质控制）以及所需的含量、特定杂质、非特定杂质和总杂质、残留溶剂、试剂、诱变杂质等的可接受标准。检测项目和可接受标准应依据工艺知识和控制策略制订。所用分析方法应经过适当验证，并在S.2.3中描述。质量标准的论证应包括对后续步骤清除杂质能力以及风险的评估。在注册文件中应确保在原料药成品中不会存在未受控杂质可能高出可接受限度的风险。评审人员在认证程序下评审申报资料时始终会牢记对这些风险予以关注。

TOP 6 (S.2.3) 第六位（S.2.3） Non-adequate or missing specifications (and analytical methods) for reagents and solvents (recovered and recycled included) used to manufacture the substance from the introduction of starting materials. 引入起始物料后原料药生产所用试剂和溶剂（包括回收和套用）质量标准（和分析方法）不充分或缺失。

It is expected that specifications, including analytical methods in place are described in section S.2.3 for all chemicals and reagents used to manufacture the substance from the introduction of starting materials. It is also expected that a purity test is included in the specification and that a reasonable mass balance is shown by the specification, unless otherwise justified. Specifications in place to test recycled materials before being reused should be given. Any relevant difference comparing to the corresponding specification for the fresh material should be highlighted and the potential impact these differences might have on the quality of the final substance should be discussed.

申报人应在S.2.3部分描述自起始物料引入开始原料药生产中所用所有试剂和溶剂的质量标准，包括分析方法。申报人还应在质量标准中包括纯度检测，质量标准中应显示出合理的质量守衡，另有论证者除外。应提交回收物料在再次使用之前检测所用的质量标准。应与对应的新鲜物料的质量标准进行对比，并重点显示出其相关的差异情况。如这些差异可能对原料药成品质量产生潜在影响，则应进行讨论。

TOP 7 (S.3.2) 第七位（S.3.2） Non-adequate or missing discussion on carryover of reagents and elemental impurities to the final substance. 原料药成品中试剂和元素杂质残留讨论不充分或缺失。

A discussion (as part of the general discussion on the impurity profile of the substance in section S.3.2) on fate and carryover to the final substance of reagents is expected, as applicable. If elemental impurities are used or likely to be present, a discussion on their carryover is expected. For elemental impurities, the guidelines of reference are ICH Q3D and the related EDQM document PA/PH/CEP (16) 23 available on the EDQM website.

适用时，申报人应对原料药成品中试剂的残留和去向进行讨论（作为S.3.2部分原料药杂质概况常规讨论的一部分）。如果使用了或者有可能出现元素杂质，则应对其残留进行讨论。对于元素杂质，可供参考的文件有ICH Q3D和EDQM官网上的EDQM文件PA/PH/CEP (16) 23。

TOP 8 (S.2.4) 第八位（S.3.4） Non-adequate or poorly justified specifications in place to control the quality of isolated intermediate. 控制分离出的中间体质量的质量标准不充分或论证不足。

Sometimes poorly justified specifications are proposed for isolated intermediates. It is expected that the impurity profile of isolated intermediates is sufficiently characterised and kept under control by adequate specifications. This piece of information (as part of the control strategy of the substance) is particularly important for intermediates which are isolated late in the process, for intermediates that show low purity, or when an impurity is tested in an intermediate instead of the final substance. Also in these cases acceptance criteria should be justified in relation to the fate and carryover of impurities (see top 9).

有时候分离出的中间体所拟的质量标准论证很差。申报人应对分离中间体的杂质概况进行充分确证，并通过充分的质量标准对其进行控制。对于在工艺后期所分离出的中间体、显示出含量较低以及在中间体中检测代替在原料药中检测的杂质来说这部分信息（作为原料药控制策略的一部分）尤其重要。在此类情形下，可接受标准也应联系杂质的去向和残留进行论证（参见第九位）。

TOP 9 (S.3.2) 第九位（S.3.2） Absence or insufficient discussion on fate and carryover of impurities from synthetic intermediates (included) to the final substance. 合成中间体中的杂质（包括中间体本身）在原料药成品中残留和去向讨论缺失或不充分。

Isolated intermediates are most of the times contaminated by related substances that can react the same way as the intermediate to give intermediate-like and eventually final substance-like impurities. Hence a discussion based on evidence (e.g., analytical data, literature, information from process development or process validation, etc.) on fate and carryover of impurities present in intermediates is expected in the dossier. It is necessary to take into account impurities controlled in isolated intermediates in the section on impurities (S.3.2) and in the discussion on the suitability of the Ph.Eur monograph to control the quality of the substance. The risks of having uncontrolled impurities in the final substance potentially above acceptable limits should be addressed. Demonstration of absence in the final substance of the last synthetic intermediates is also expected.

分离出的中间体中很多情况下均会受到有关物质的污染，这些有关物质可能会与中间体有类似的反应从而产生类似中间体的杂质，最终生成与原料药成品类似的杂质。因此，应在注册资料中提交中间体中出现的杂质的残留及去向方面证据（例如，分析数据、文献、工艺研发或工艺验证资料等）的讨论，还应在杂质部分（S.3.2）和EP用于控制原料药质量适当性讨论中考虑在分离出的中间体中受控的杂质。应说明在原料药成品中可能含有高于可接受限度的非受控杂质的风险。另外亦应证明原料药成品中不存在最后一步反应的中间体。

TOP 10 (S.2.3) 第十位（S.2.3） Non-adequate or missing information on the synthesis of starting materials and their manufacturers. 起始物料合成信息及其生产商信息不充分或缺失。

A brief description of the preparation of the starting materials (flow diagram of the process, including solvents and reagents used), along with name(s) and address(es) of their manufacturers (not their suppliers) is expected to be found in section S.2.3 of the dossier. This is to evaluate the suitability of the proposed starting material and its specification. In case more than one source of the same starting material is used, quality equivalence should be demonstrated by means of batch data collected on the final substance manufactured using all the possible sources of the same starting material.

注册资料的第S.2.3部分中应包括有起始物料制备的简要描述（工艺流程图，包括所用溶剂和试剂），以及其生产商（不是中间商）的名称和地址。其目的是用于评估所拟申报的起始物料及其质量标准是否合适。如果同一起始物料使用了不止一个来源，则应使用来自所有可能来源的该起始物料生产原料药成品，收集批数据用以证明其质量等同性。

来源：julia

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