欧洲注册：新CEP申请十大常见缺陷2015-2016

GMP学习中

TOP TEN DEFICIENCIES

New Applications for Certificates of Suitability (2015-2016)

for chemical purity

纯化学类新CEP申请十大常见缺陷（2015-2016）

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.

本文件总结了纯化学类CEP证书新申请首次审评所产生的十个最常见的问题。根据2015年下半年和2016年初期间随机抽取的20封缺陷信的内容编制的。

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.

下面列出了最常见的十个问题，以及如何参考适用的指南解决具体缺陷的期望和建议。

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.

本文件旨在协助申请人提高其注册文件的质量，以促进和加快CEP的授予。在建立注册文件时，应结合EDQM网站上提供的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) Absence or deficient discussion on the risk of having potential mutagenic impurities in the final substance.

TOP 1 (S.3.2)对最终产品中含有潜在致突变杂质风险的讨论缺失或存在缺陷。

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

适用于尚未在欧洲市场上销售的药品中产生的物质来源。

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).

申请人应在其CEP申请中提供关于致突变杂质的完整讨论。应参考ICH M7（自2016年1月起生效）。ICH网站上的任何附录也可能会对特定产品所推荐的安全值是有用的（也请参阅ICH M7的注释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.

应根据ICH M7将成品和起始物料（如相关且未另作论证）合成中或降解过程中形成的潜在致突变杂质在CEP注册文件中列出并进行分类。可以根据其潜在的致突变性和致癌性将杂质分为5类（参见ICH M7表1），并制定相应的控制措施。有时，对于一些具有警戒结构的杂质和合成过程中产生的杂质（ICH M7规定的3类杂质），没有可用的致突变性数据，则应将这些杂质控制在可接受的限度或以下，或应进行致突变性测定(参见ICH M7注2)，以确认该杂质不具有致突变性（属于5类）还是具有致突变性（属于2类）。可以通过(Q)SAR方法（模拟研究）预测细菌致突变性测定的结果。根据ICH M7，应该应用两种相互补充的(Q)SAR方法，一种基于专家规则，另一种基于统计。应该遵循OECD制定的原则。

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.

为了确定物质中（潜在的）致突变杂质的可接受限度，有必要将（潜在的）致突变杂质的“可接受摄入量”除以该物质的最大日剂量。为了确定致突变杂质的可接受摄入量，可以使用“少于寿命”（LTL）概念。ICH M7的注释7对识别这种可接受摄入量非常有帮助，ICH M7也对如何识别多种杂质的可接受总摄入量提供了指导。

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.

一旦充分确定了可接受的限度，根据这些杂质的性质及其在最终物质中出现的概率，预计将根据ICH M7给出的四个建议（从选项1到选项4）制定控制策略。应提供批数据作为支持（如果认为必要），并应描述所使用的分析方法。可以开展清除研究，以支持基于选项3和选项4的方法。吹扫研究应充分发展和合理，所使用的所有物理化学参数（反应性、溶解度、挥发性、电离性、物理过程等）应与研究一起给出和讨论。

TOP 2 (S.2.3): Absence or insufficient discussion on fate and carryover of related substances of starting materials (included) to the final substance.

TOP 2 (S.2.3):缺少对起始物料（包括）到最终产品的有关物质的残留和去向的讨论或讨论不充分。

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.

起始物料的杂质概况应进行完整的确证。这意味着申请人需要知道在起始物料中可能发现哪些杂质，特别是关于有关物质，因为通常这些杂质可以根据工艺所预见的化学反应产生的分子，形成中间体的杂质并可能形成最终产品中的潜在杂质。在充分确证起始物料的杂质概况后，不仅需要详细讨论杂质从起始物料转移到最终产品的问题，还需要详细讨论它们的去向:它们与起始物料一起引入工艺中会发生什么。未反应完全的起始物料在最终产品中的残留也应进行讨论。如果认为必要，应提供充分的证据（如分析数据、文献、工艺开发或工艺验证的信息等）作为支持。

TOP 3 (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.

TOP 3 (S.2.2, S.2.4):缺乏对起始物料到成品的生产工艺的详细和/或简单描述(合成、叙述性描述、流程图、回收和返工工序)。S.2.2和S.2.4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.

应详细描述工艺过程，包括所有使用的化学品及其用量，进行的所有操作及所有相应的操作条件（如温度、压力、时间等）。工艺应详细描述，因为这是审评员获得信息的主要来源，依据这些信息，审评员可以对潜在杂质形成和工艺去除杂质的潜在能力进行评估。S.2.2应描述中控信息（作为生产工艺描述的一部分），S.2.4应对中控进行详细说明（可接受标准和分析方法），包括对分离中间体进行的控制。在注册文件的这两个部分中给出的信息不应该有不一致的情况。

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.

在注册文件S.2.2中应描述工艺的最大批量或批量范围。应与S.4.4所述批量一致。

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

这些要求同样适用于外购中间体的生产步骤，应在CEP申请中充分说明。

TOP 4 (S.2.3): Non-acceptable starting materials, necessity to redefine them earlier in the process.

TOP 4 (S.2.3): 拟定的起始物料不被接受，需要重新定义工艺中更早的物料为起始物料。

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/修订的起点，应该代表整个合成工艺。起始物料的界定和选择应根据ICH Q11和其他所有相关可获得的指南规定的要求。在开始定义起始物料之前应阅读上述指南。在S.2.3节中应详细说明拟议的起始物料的选择是充分的，并符合所有适用的指南。

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.

如果审评人员认为拟定的起始物料不可接受，则需要重新定义起始物料，需要顺着工艺往前推，这可能会对生产和注册文件的内容产生重大影响。最初拟定的未被接受的起始物料的生产商变为中间体的生产商(符合EU GMP Part II，并愿意接受检查)，由于需要在S.2.2中重新描述自起始物料到中间体的工艺过程，注册文件整体应完全重组。因此，申请人应该慎重选择起始物料。

TOP 5 (S.2.3): Non-adequate or poorly justified specifications in place to control the quality of starting materials.

TOP 5 (S.2.3):起始物料的质量控制不充分或论证不足。

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.

被确定为起始物料的分子的质量应充分确证，并由充分论证的质量标准加以控制。预期控制起始物料质量的质量标准应反映其生产过程。起始物料的质量标准应包括鉴别和纯度的测试（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、残留溶剂、试剂、致突变杂质等的可接受标准。测试和可接受标准应基于工艺知识和控制策略确定。所使用的分析方法应经过适当的验证，并在S.2.3中说明。质量标准的论述应包括对风险和后续步骤清除杂质的能力的评估。在注册文件中应保证最终产品中不存在未受控杂质可能超过可接受限度的风险。审评员在认证程序的背景下评估申请始终会牢记对这些风险予以关注。

TOP 6 (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.

TOP 6 (S.2.3):从引入起始物料开始，用于生产最终产品的试剂和溶剂（包括回收）的质量标准(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.

应在S.2.3节中描述从引入起始物料开始用于生产成品的所有化学物质和试剂的质量标准和分析方法。除非另有论述，还应在质量标准中包含纯度测试，并在质量标准中显示出合理的物料平衡。应提供回收物料在再次使用前检测的质量标准。应与新鲜物料的相应质量标准进行对比，标出相关差异情况，并应讨论这些差异可能对最终产品质量产生的潜在影响。

TOP 7 (S.3.2): Non-adequate or missing discussion on carryover of reagents and elemental impurities to the final substance.

TOP 7 (S.3.2):缺少对最终产品中试剂和元素杂质残留的讨论或讨论不充分。

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.

如果适用，应对最终产品中试剂和元素杂质残留和去向进行讨论(作为S.3.2节中关于产品杂质概况的一般性讨论的一部分)。如果使用了元素杂质或可能存在元素杂质，则应讨论其残留问题。对于元素杂质，参考指南为ICH Q3D和EDQM网站上的EDQM文件PA/PH/CEP(16)23。

TOP 8 (S.2.4): Non-adequate or poorly justified specifications in place to control the quality of isolated intermediate.

TOP 8 (S.2.4):分离中间体的质量控制不充分或质量标准论证不足。

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).

有时对分离中间体的质量标准论述不够合理。分离中间体的杂质概况应得到充分的确证，并通过适当的质量标准加以控制。对于在工艺后期分离的中间体、显示出低纯度的中间体，或者在中间体中检测代替在最终产品中检测的杂质来说，这部分信息（作为最终产品控制策略的一部分）尤为重要。在这些情况下，可接受标准应结合杂质的残留和去向进行论证（见TOP 9）。

TOP 9 (S.3.2): Absence or insufficient discussion on fate and carryover of impurities from synthetic intermediates (included) to the final substance.

TOP 9 (S.3.2):缺乏对杂质从合成中间体(包括在内)到最终产品的残留和去向的讨论或讨论不充分。

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.

分离的中间体大多数时候会受到有关物质的污染，这些物质以与中间体相同的方式反应，产生类似中间体的杂质和类似最终产品的杂质。因此，注册文件中应基于证据（如分析数据、文献、工艺开发或工艺验证的信息等）讨论中间体中存在的杂质的残留和去向。在杂质部分（S.3.2）和讨论Ph.Eur各论对最终产品质量控制的适用性时，有必要考虑到分离中间体的杂质控制。应说明最终产品中不受控制的杂质可能超过可接受限度的风险。另外还应证明最终产品中不存在最后一步反应的中间体。

TOP 10 (S.2.3): Non-adequate or missing information on the synthesis of starting materials and their manufacturers.

TOP 10 (S.2.3):起始物料的合成信息及其生产商的信息缺失或不充分。

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.

在注册文件的S.2.3节中提供起始物料制备的简要描述（工艺流程图，包括所用的溶剂和试剂）以及制造商（不是供应商）的名称和地址。这是为了评估拟定的起始物料及其质量标准是否合适。如果使用多个来源的起始物料，应通过收集使用所有可能来源的起始物料的最终产品的批数据来证明质量等同。

声明：文章转载于【注册圈】，来源于【EDQM】，文章版权归原作者所有，本文仅做转载分享~