This document is a summary of the top ten deficiencies identified after the initial evaluation of new applications for Certificates of Suitability (CEP) for chemical purity. It is based on the content of a random sample of 30 deficiency letters selected from the year 2023.

本文是对化学纯度CEP新申请首次评估中发现的前10大缺陷问题的总结，本文是基于2023年随机抽取的30封缺陷信内容进行的总结。

During this period the failure of applicants to satisfactorily address some of the deficiencies described below in their application resulted in an increase in the number of questions raised during requests for additional information by EDQM along with their complexity. Consequently, the timeline for granting of the certificate of suitability was increased.

在申请期间，申请人未能圆满的解决下面描述的部分缺陷，导致EDQM发布的补充资料通知中缺陷数量及缺陷复杂性相应增加，因此CEP证书的批准时间延长。

This document is intended to help applicants avoid such issues. Expanded details on specific points from each deficiency are provided to inform the users but should always be considered in conjunction with the EDQM guideline “Content of the Dossier for Chemical Purity and Microbiological Quality of Substances for Pharmaceutical Use” which outlines the specific requirements for the submission of CEP applications.

本文旨在帮助CEP申请人避免类似的问题。它为使用者提供了每一个缺陷具体要点的更多详细信息，但这些缺陷具体要点的更多详细信息应与EDQM指南“药用物质化学纯度及微生物质量的文档内容”相结合，该指南概括了CEP申请递交的具体要求。

 

TOP 1: 3.2.S.2.2

第一大缺陷：在3.2.S.2.2中

Lack of details and/or poor description of the manufacturing process of the substance from the introduction of starting materials (This includes discrepancies noted between the information given in sections S.2.3 and S.2.4). (12% of all questions)

从起始物料引入至原料药生产工艺缺乏详细的信息或者描述的不完整（这包括与S.2.3和S.2.4章节中信息的差异）。（占总问题的12%）

Specific points:

具体要点：

For synthetic and semi synthetic substances, it is expected that a synthetic flow diagram be provided. All synthetic intermediates should be presented, and if non-isolated, they should be presented within square brackets.

期待为合成和半合成的原料药提供合成流程图。该合成流程图应该体现所有的合成中间体，如果是非分离中间体，应该用方括号中表示。

When reviewing the route of synthesis, assessors check that the information in S.2.2, S.2.3, and S.2.4 is consistent. Applicants should ensure that all raw materials used (including recovered materials) are addressed both in section S.2.2 and S.2.3 and that no reagents are included in error.

审评合成路线时，评审员会检查S.2.2、S.2.3、S.2.4章节的信息是否一致。申请人应确保所有使用的原材料（包括回收物料）在S.2.2和S.2.3章节中都有说明，并且没有错误信息。

The quantities of all raw materials used, and the batch size should be detailed at each stage of the manufacturing process.

在每个生产工艺阶段，都应当详细描述所有使用的原材料的投料量和该阶段的生产批量。

If blending of intermediates or the final substance is performed, the process description should make it clear that it is performed in accordance with ICH Q7 and that batches are fully tested prior to blending.

如果中间体或者原料药需进行混合，工艺描述应当明确此操作符合ICHQ7的要求并且在混合前每个批次都会进行全面检测。

 

TOP 2: 3.2.S.2.4 and TOP 4: 3.2.S.2.3

第二大缺陷：在3.2.S.2.4中及第四大缺陷：在3.2.S.2.3中

Non-adequate or poorly justified specifications proposed to control the quality of isolated intermediates (11% of all questions) and starting materials (7% of all questions).

对分离中间体（占总问题的11%）和起始物料（占总问题的7%）的质量控制所提议的质量标准没有充分的合理性论证。

Specific points:

具体要点：

It is expected that the specifications for starting materials and isolated intermediates include appropriate acceptance criteria for specified, unspecified, and total impurities. Acceptance criteria should be justified based on fate and the carryover of the impurity/ies (this may sometimes necessitate spiking studies). Any potential risk to the quality of the final substance should be discussed.

起始物料、分离中间体的质量标准应该包含特定杂质、非特定杂质及总杂质的适当的可接受标准。该可接受标准的论证应依据杂质的去向及转移（这方面可能有时候要做加标试验）。应当对原料药质量的任何潜在的风险进行讨论。

It is expected by assessors that any major and recurrent impurities;

a) Will be identified and/or characterised.

b) Will be specified individually at justified acceptance criteria based on fate and carryover discussions.

对于任何主要的和反复出现的杂质，评审员期望：

a)      进行鉴别或结构确证。

b)     应当基于去向和转移来单独讨论其可接受标准的论证。

If the proposed acceptance criteria for unspecified impurities are wider than those proposed for specified impurities, this should be well justified.

如果提议的非特定杂质的可接受标准比特定杂质的可接受标准更宽，应当进行充分的论证。

Discrepancies in mass balance (sum of assay and total impurities) should be addressed. Where rationales for a discrepancy exist, these should be explained.

应阐述质量守恒(含量和总杂质的和)的问题，当质量不守恒情况存在时，应当加以解释。

 

TOP 3: 3.2.S.3.2

第三大缺陷：在3.2.S.3.2中

Absence or deficient discussion on the risk of having potential mutagenic impurities in the final substance. (7.5% of all questions)

缺乏对原料药中潜在致突变杂质风险的讨论或讨论不充分。（占总问题的7.5%）

Specific points:

具体要点：

CEP applicants are expected to provide a specific discussion in their dossier regarding potential mutagenic impurities based on their understanding of the manufacturing process for the substance. This should include those:

a) introduced during the manufacturing process (e.g., reagents, starting materials, etc.)

b) arising from the synthesis of the final substance

c) formed as a result of degradation.        

CEP申请人应基于对原料药生产工艺的理解，在他们提交的资料中针对潜在致突变杂质进行详细讨论。包括：

a)   生产工艺中引入的（如：试剂、起始物料等）

b)   原料药合成过程中产生的。

c)   降解产生的。

Such impurities should be listed and classified (class 1 to class 5) in the dossier in accordance with ICH M7. For mutagenic impurities, a suitable control strategy in accordance with the principles of ICH M7 should be proposed.

应根据ICHM7的要求，在申报资料中列出这些杂质并被分类（1至5类）。对于致突变杂质，应根据ICHM7的要求制定适当的控制策略。

The Threshold of Toxicological Concern (TTC) for an impurity should be determined in accordance with ICH M7. For the calculation of the TTC, the Maximum Daily Dose (MDD) of the drug substance should be based on the Human Medicine European Public Assessment Report (EPAR), Summary of Product Characteristics (SmPCs), or agreed literature such as Martindale, while the appropriate acceptable intake should be based on an appropriate duration of use as described in ICH M7.

应该根据ICHM7制定杂质的毒理学阈值（TTC）。计算TTC时，原料药最大的日剂量（MDD）应基于人用药欧洲公开审评报告 (EPAR)、产品特性总结（SmPCs）或者公认的文献如马丁代尔来确定，而适当的可接受摄入量应基于ICH M7中所述的适当的服用期来确定。

ICH M7 option 3 controls for mutagenic impurities should be justified with suitable spiking and/or carryover studies.

ICHM7选项3，对于致突变杂质的控制应通过适当的加标和/或转移研究来论证。

ICH M7 option 4 controls should be supported by a demonstration that, based on understanding of the process and impact on residual impurity levels (including fate and purge knowledge), the level of the impurity in the drug substance will always be below the acceptable limit. Option 4 controls may additionally need to be supported by analytical data (e.g., spiking and/or carryover studies).

ICHM7选项4的控制，应该基于对工艺的理解及对残留杂质水平的影响（包括去向及清除知识），原料药中杂质的水平将会永远低于可接受标准限度的证据来证明。选项4控制可能需要有额外的分析数据支持（如加标研究和/或转移研究）。

 

TOP 5: 3.2.S.2.3

第五大缺陷：在3.2.S.2.3中

Absence or inadequate acceptance criteria (and/or analytical methods) for raw materials (incl. recovered materials) used in the manufacture of the final substance, from the introduction of starting materials. (7.1% of all questions)

缺少自起始物料引入至在原料药生产中使用的原材料（包括回收物料）的可接受标准（和/或分析方法），或者信息不充分。（占总问题的7.1%）

Specific points:

具体要点：

Applicants should ensure that suitable specifications are provided for all raw materials used in the manufacturing process for the final substance.

申请人应确保原料药生产工艺中使用的所有原材料提供了适当的质量标准。

Specifications of raw materials used late in the manufacturing process should not contain wide acceptance criterion without any suitable justification being provided. The impact of the use of these materials (incl. recovered materials) on the impurity profile of the final substance should be addressed.

在没有提供任何合适的论证情况下，生产工艺后续步骤中使用的原材料的质量标准应不能过宽。应阐述使用的这些物料（包括回收物料）对原料药杂质概况的影响。

In case material of fish origin or a peptone is used in the manufacturing process, the EDQM requirements should be met.

若生产过程中使用了鱼源物料或者蛋白胨，则应符合EDQM的要求。

 

TOP 6: 3.2.S.2.2

第六大缺陷：在3.2.S.2.2中

The reprocessing and recovery of raw materials are inadequately addressed. (6.1% of all questions)

原料的返工和回收处理没有充分地阐述。（占总问题的6.1%）

Specific points:

具体要点：

Reprocessing: In accordance with the EU “Guideline on the Chemistry of Active Substances” in Section 3.2.S.2.2 CEP applicants are expected to provide a detailed narrative description of any reprocessing step and to define the triggers for this reprocessing. Statements such as “Reprocessing is a repetition of the approved step X” are not considered appropriate replacements.

返工：根据EU“活性药物化学指南”，CEP申请人应在3.2.S.2.2章节提供任何返工步骤的详细描述，并且定义返工的起因。诸如“返工是重复已批准的步骤X”这样的描述是不恰当的。

Recovery: In Section 3.2.S.2.2 CEP applicants are expected to suitably identify the point in the manufacturing process from where materials are recovered, to describe in detail how they are recovered, and to clearly identify where they are reintroduced in the process.

回收：在3.2.S.2.2章节中， CEP申请人应明确物料是在生产工艺中的哪一步进行回收的，详细描述其是怎么样被回收的，并且明确的标明在工艺中哪个生产步骤被重新引入。

 

TOP 7: 3.2.S.3.2

第七大缺陷：在3.2.S.3.2中

Absent or deficient risk assessment related to Nitrosamines. (4% of all questions)

亚硝胺杂质的风险评估缺乏或者评估不充分的。（占总共问题的4%）

Specific points:

具体要点：

New CEP applications (chemical, semi-synthetic, products of fermentation, or herbals) are expected to include a comprehensive risk assessment for the presence of nitrosamines based on the principles outlined in the ICH Q9 and ICH M7 guidelines, as well as the current EMA Q&A document on nitrosamines (incl. its Appendix 1).

根据ICHQ9和ICH M7指导原则和现行EMA关于亚硝胺的问答（包括它的附件1），CEP新申请（化学的、半合成的、发酵产品或者草药）的申报资料中应包含关于亚硝胺杂质存在的全面风险评估。

The risk assessment should address not only risks from the manufacturing process but also those from the introduction of materials used in the manufacturing process (starting materials, reagents, solvents – fresh and recovered, etc.) as well as degradation. Any risk concerning the formation and carryover of nitrosamines should be suitably addressed, taking into account the above-mentioned EMA Q&A document.

风险评估应阐述不仅仅来源于生产过程的风险，也可能来源于生产过程中使用的物料（起始物料、试剂、溶剂-新鲜的或回收的溶剂等）及其降解产物的风险。关于亚硝胺杂质的形成和转移的任何风险都应当根据上述EMA的问答进行适当的阐述和讨论。

 

TOP 8: 3.2.S.3.2

第八大缺陷：在3.2.S.3.2中

Failure to adequately address the origin, fate, and carryover of related substances into the final substance. (4% of all questions)

没有充分阐述原料药中的有关物质的来源、去向、转移。（占总问题的4%）

 

Specific points：

具体要点：

A discussion based on Ph. Eur. impurities alone is generally not considered as sufficient, and the discussion on related substances should address the formation, carryover and fate of other impurities (e.g., starting materials, intermediates, process related impurities, and degradants).

仅仅基于欧洲药典的杂质进行讨论一般认为是不充分的，对有关物质的讨论应阐述其它杂质（例如：起始物料、中间体、工艺相关杂质和降解产物）的形成、转移及去向。

The suitability of the Ph. Eur monograph to control impurities, not present in the transparency list of the monograph (i.e., additional in house impurities), for which a control in the final substance is proposed or required (e.g., found above the reporting threshold), should be addressed.

对于并不存在于各论公开杂质列表中（例如，额外的内控杂质）但拟在或要求在原料药中进行控制（例如，发现超出报告的阈值）的杂质，应当阐述EP各论对该杂质控制的适用性的问题。

In the context of the related substances discussion it is expected that statements such as “not detected” or “less than limit of quantification” be supported by the provision of the LOD / LOQ for the associated method.

在讨论有关物质的描述中，应通过提供相关方法的LOD/LOQ来支持诸如“未检出”或者“低于定量限”的描述。

 

TOP 9: 3.2.S.3.2

第九大缺陷：在3.2.S.3.2中

Deficient discussion on residual solvents. (4% of all questions)

对残留溶剂的讨论不充分。（占总问题的4%）

Specific points:

具体要点:

In the context of the discussion on residual solvents, it is expected that statements such as “not detected” or “less than limit of quantification” be supported by provision of the LOD / LOQ for the associated method.

在讨论残留溶剂的描述中，应通过提供相关方法的LOD/LOQ来支持诸如“未检出”或者“低于定量限”的描述。

The origin of impurities that are formed as by-products of the manufacturing process, but which are also common solvents (e.g. acetic acid, ethanol), should be clarified.

源于生产工艺中产生的副产物，同时也是常用溶剂（如乙酸、乙醇）的杂质，应进行澄清说明。

Where relevant, CEP applicants are expected to discuss the potential presence of Class 1 solvents (e.g. Benzene / Carbon tetrachloride /1,2-Dichloroethane / 1,1-Dichloroethene / 1,1,1-Trichloroethane) as contaminants of other solvents and to demonstrate compliance with the requirements of ICH Q3c Annex 1.

如适用， CEP申请人应对作为其他溶剂污染物的1类溶剂（例如，苯、四氯化碳、1,2-二氯乙烷、1,1-二氯乙烯、1,1,1-三氯乙烷）进行讨论，并且证明符合ICHQ3c附件1的要求。

 

TOP 10: 3.2.S.2.3

第十大缺陷：在3.2.S.2.3中

Failure to suitably identify starting materials. (3.5% of all questions)

没有恰当的定义起始物料。（占总问题的3.5%）

Specific points:

具体要点：

Starting materials should be identified and selected according to the requirements outlined in ICH Q11 and the associated Q&A document. The reasons why the proposed starting materials are considered acceptable and in line with applicable guidelines should be explained in detail in the dossier, in Section S.2.3.

应该根据ICHQ11及其Q&A文件的要求定义和选择起始物料。应在提交的S.2.3章节中，详细地解释提议的起始物料被认为可接受的原因以及与相应的指南的符合性。

Identification of a substance that contributes a significant structural component to the final substance as a reagent is not acceptable. In accordance with ICH Q11 such substances should be identified as starting materials.

将构成原料药重要结构片段的物质作为试剂是不可接受的。根据ICHQ11，这些物质应被定义为起始物料。

 

In addition to the information provided above, applicants are encouraged to ensure they stay up to date on news about the CEP procedure, relevant trainings, and on the work of EDQM in general (including the elaboration and revision of Ph.Eur monographs) by consulting the EDQM website www.edqm.eu.

除了上面提到的信息之外，鼓励申请人通过EDQM网站www.edqm.eu确保持续关注CEP程序的新信息、相关的培训和EDQM日常工作（包括欧洲药典各论的详细描述和修订）。

Applicants are also reminded that from the EDQM website they may also access tools to assist them in the preparation of their application for a CEP, including policies and guidelines, FAQ, the EDQM Helpdesk, and the possibility to request a technical advice meeting with the Certification department of the EDQM.

也提醒申请人在CEP申请的准备过程中可通过EDQM网站获得工具来得到帮助，包括政策和指南、常见的问题解答、EDQM的帮助平台以及请求EDQM认证部门举行技术咨询会议的可能性。