2009年新CEP申请中十大常见缺陷（中英文）----Julia

巴西木

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官网地址：http://www.edqm.eu/en

原文网址：http://www.edqm.eu/medias/fichiers/PAPHCEP_10_65_Top_Ten_Deficiencies_New_Application.pdf

Certification of Substances Division 原料药认证部

PPR/cb

PUBLIC DOCUMENT 公开文件

English only/Anglais seulement 仅英文

PA/PH/CEP (10) 65

Strasbourg, June 2010 斯特拉斯堡，2010年6月

Certification of suitability to Monographs of the European Pharmacopoeia

欧洲药典各论适应性证书

TOP TEN DEFICIENCIES

十大常见缺陷

New Applications for Certificates of Suitability

新CEP申请

(End 2009)

Top ten deficiencies found during first assessment of new applications from October to December 2009

在2009年10月至12月期间新申请首评中发现的十大常见缺陷

This document is a summary of the main questions resulting from the first assessment of new applications for Certificates of Suitability (CEP) for chemical purity. It is based on the content of 108 deficiency letters sent to the applicants on applications treated from October to December 2009. 本文是对CEP新交申请首次评审中关于化学纯度的一些主要问题的总结，它是基于2009年十月和十二月初审后发给申请人的108封缺陷信内容整理的。

From the data obtained, the average number of questions for each application is 10 with the actual number of questions ranging from 2 to 20. During this period of reference, no CEP was granted after the first evaluation. 从得到的数据看，每个申请平均问题数为10个，实际问题数从2到20不等，此间没有CEP是在第一次评审后即签发的。

The Top 10 questions are listed below with additional recommendations regarding EDQM requirements added. By including these recommendations - together with the requirements described in the EDQM Guideline “Content of the dossier for chemical purity” PA/PH/CEP (04) 1 (current version) which is available on our website - applicants can improve the quality of their dossiers with a view to facilitating and speeding up the granting of their CEP. 十大问题在下面一一列出，并给出了符合EDQM要求的建议。有了这些建议-与EDQM指南“化学纯度档案内容”（现行版本，在官网可得）中描述的要求一起—申请人可以提高文件质量，有助于并更快地获得CEP。

TOP 1 (3.2.S.2.2) / (3.2.S.2.3): Redefinition of starting material:

第1大缺陷(3.2.S.2.2) / (3.2.S.2.3)：起始原料的重新界定

More and more frequently, applicants propose a one-step synthesis, starting from a complex material in the application. This is generally not acceptable and the complex material is considered as a late, often purchased, intermediate in the synthesis. 越来越多的申请人在申请中提请从结构复杂的原料开始一步合成，这种申请通常不被接受，复杂结构的（通常采购来的）原料会被认为是合成路线中较后的中间体。

Applicants are reminded that the approved starting material is the starting point for GMP and variations, and must be representative of the overall synthetic process and not just a late intermediate resulting in a shortened synthesis. The proposed starting material must be justified. This proposal and justification will be assessed and can lead to a request for redefinition of the starting material. 需要提醒申请人的是批准的起始原料是GMP的起始点和差异点，必须能代表整个合成工艺而不是最后中间体从而缩短合成路线。这个提议和论证会被评价，可能导致要求对起始原料重新界定。

As a consequence, external suppliers may thus become suppliers of intermediates and consequently the relevant declarations (compliance with GMP and willingness to be inspected) from these suppliers must be provided. 作为结果，外部供应商可能成为中间体供应商，而必须出具相应的申明（GMP符合性及愿意接受检查）

TOP 2 (3.2.S.2.3): Absence of discussion on the carry-over of impurities/by-products from key materials:

第2大缺陷：缺乏对关键原料中的杂质/副产物带入产品的讨论

The impurities (related substances, solvents, catalysts) of the key materials (starting materials, intermediates) should be described and their carry-over in the final substance should be discussed. In some cases, a scientific discussion demonstrating/justifying the absence of impurities may replace analytical testing and batch results. 应对关键原料（起始原料、中间体）的杂质（有关物质、溶剂和催化剂）进行描述，应对这些杂质带入最终产品的情况进行讨论。某些情况下，科学以论证杂质不会存在可能代替分析检测和批检测结果。

TOP 3 (3.2.S.2.3): Absence of discussion for Class 1 solvent as contaminant of another solvent:

第3大缺陷(3.2.S.2.3)：缺乏对一类溶剂在其它溶剂中残留的讨论

Some solvents (e.g. acetone, toluene, ethanol, methanol, isopropanol, xylene, hexane and petroleum ether) may be contaminated with Class 1 solvents (e.g. benzene). Therefore, when these solvents are used in the manufacturing process of the final substance, potential residues of their contaminant in an intermediate or in the final substance should be addressed. 一些溶剂（如丙酮、甲苯、甲醇、乙醇、异丙醇、二甲苯、正已烷和石油醚）可能会有一类溶剂残留（如苯），因此，如果在最终产品生产工艺中使用这些溶剂，中间体或成品中潜在的溶剂残留需要进行说明。

According to the European “Note for Guidance on Specifications for Class 1 and Class 2 residual solvents in active substances, annex to the CPMP/ICH/283/95 Impurities:根据欧洲“活性物质中一类和二类残留溶剂质量标准指南，CPMP/ICH/283/95 杂质 附件”

Guideline for Residual Solvents & CVMP/VICH/502/99 Guideline on Impurities: Residual Solvents”, 残留溶剂指南和CVMP/VICH/502/99杂质指南：残留溶剂

3 options are listed that support the absence of routine testing of the contaminant. 3种可能性均列出以支持常规残留检测

Compliance with this guideline should be demonstrated in the justification of the quality of raw materials used or in the Impurities section. Where one of these 3 options is met and demonstrated as such in the application, a routine test for the Class I solvent in a suitable intermediate or in the final active substance is not required. 符合本指南应在原料质量部分或在杂质部分进行论述。如果符合上述三个选择中的一个，并在申请中进行了这样的论述，则对最终活性物质或中间体的一类溶剂常规测试可以不需要。

TOP 4 (3.2.S.3.2): Genotoxic impurities:

第4大缺陷(3.2.S.3.2)：基因毒性杂质

Compliance with the CHMP Guideline on the Limits of Genotoxic Impurities, EMEA/CHMP/QWP/251344/2006 must be demonstrated for substances obtained by a manufacturing process not yet approved in Europe. The guideline is not applied retrospectively to authorised products unless there is recent data demonstrating the genotoxicity of a specific compound relevant to the application. For substances which fall within the scope of the guideline, a specific discussion as part of the overall discussion on impurities should be provided with regard to impurities with potential genotoxicity. 如果物质的生产工艺尚未在欧洲批准过，与CHMP基因毒性杂质限度指南EMEQ/CHMP/QWP/251344/2006要求的符合性必须进行论述。该指南不适用于回顾性批准，除非有近期的数据来支持与申请相关的已知物质基因毒性的论述。如果物质包括在指南范围内，则在杂质总论中应有一部分专门讨论杂质的潜在基因毒性。

TOP 5 (3.2.S.4.4): Absence of comparison of the quality of the final substance obtained with starting materials from different suppliers:

第5大缺陷(3.2.S.4.4)：缺乏采用不同供应商的起始原料时最终成品的质量比较

A substance may be manufactured using starting materials from different suppliers, which should be specified in the application. Where more than one supplier of the starting materials(s) is used, demonstration should be provided that the quality of the final substance is equivalent whatever the source of starting material; batch analysis results from the substance manufactured from the different suppliers should be provided to confirm that the impurity profile is identical (same impurities/solvents/catalysts). 一种物质的生产可能会采用不同供应商来源的起始原料，在申请中要指明供应商。如果采用不止一家供应商的起始原料，需要论述无论起始原料来源如何，最终成品的质量是等同的，应有批分析结果以确认杂质概况是识别为相同的（杂质、溶剂、催化剂均相同）。

TOP 6 (3.2.S.2.3): Incomplete specifications for the declared starting materials

第6大缺陷(3.2.S.2.3)：起始原料质量标准不完善

The specifications of the declared starting materials are often not sufficient and do not include limits for impurities/solvents/catalysts. 申明的起始原料的质量标准经常不充分，未包括杂质、溶剂、催化剂的限度。

The description of the route of synthesis of the starting materials (flow diagram/flow chart) should be provided to support the description of the impurity profile and the specification. The specification should include suitable limits for related substances (specified/unspecified, individual and total), reagents, solvents and catalysts as needed. 应提供起始原料的合成路线描述（路线图/流程图）以支持其杂质概况和质量标准。质量标准应包括有关物质（已知/未知、单个和总杂质）、试剂、溶剂和催化剂的适当限度。

TOP 7 (3.2.S.4.3): Suitability of the monograph to control the impurity profile of the final substance 控制最终成品的杂质概况时各论适用性

The suitability (or unsuitability!) of the European Pharmacopoeia monograph to detect and limit all related substances present in the final substance should be demonstrated, even if a suitable in-house method is used for their control. This discussion should also address how potential/actual impurities from the described route of synthesis are controlled. If the monograph method is not suitable, an additional method should be proposed for such impurities unless it can be demonstrated that these impurities routinely are absent. 即使采用了自建方法控制成品中的杂质，EP各论是否可以检测出和控制杂质的适用性（或不适用性）仍需要进行论述。这些讨论还需要说明根据合成工艺而判断可能的/实际存在的杂质如何被控制。如果各论方法不适用，应建立附加检测方法以进行控制，除非证实这些杂质常规下不会出现。

Alternative methods may be used by the applicant, provided they have been shown to be equivalent to the ones of the monograph. Such methods should be described and their validation data given in the dossier. Such alternative methods will not be appended to the CEP if those of the monograph are considered appropriate to control the quality of the substance. 申请人可能会采用替代检测方法，如果这些检测方法证明与各论中的方法等同，此时需要对方法进行描述并将验证数据包括在文件中。如果各论方法被认为可以控制物质的质量，这些替代方法不会被附加到CEP中。

To demonstrate the equivalence between the monograph and in-house methods, cross validation data must be provided (eg. results of testing the same batches with both methods, showing compliance with specifications). 为证明各论方法与自建方法的等效性，需要提供交叉验证数据（即同批次采用两种方法检验的结果，均符合质量标准）

TOP 8 (3.2.S.6): Specification for container closure system 容器密闭系统质量标准

A brief description of and the specifications for the container closure system (primary & secondary packaging) should be included in the application. 在申请中应包括一份简单的容器密闭系统（内包装和外包装）质量标准的描述。

For primary plastic packaging material, a declaration that the requirements of the CHMP guideline on plastic immediate packaging materials (CPMP/QWP/4359/03 – EMEA/CVMP/205/04) are met, should be provided. Any equivalent declaration is also accepted. 需要提供一份申请，说明所使用的内包材符合CHMP指南（CPMP/QWP/4359/03 – EMEA/CVMP/205/04）中关于直接接触物料的塑料内包材的要求。其它等同的申明也可以接受。

TOP 9 (3.2.S.3.2): Compliance with the requirements of the Ph. Eur General Monograph 2034: limit for unspecified impurities 与欧洲药典通论2034中标准符合性：未知杂质的限度

The general monograph (GM) 2034 Substances for Pharmaceutical Use overrules the limit for unspecified impurities described in the specific monograph when they are different. In such a case, a suitable limit for unspecified impurities should be set and if appropriate, an additional validated method should be developed to control these impurities. When the specific monograph does not limit total impurities a limit should be proposed. 总论（GM）2034药用物质使用适用于与各论中未知杂质不同的未知杂质。在这种情况下，应为未知杂质设定一个适当的限度，适当时应开发方法对这此杂质进行控制。如果各论中未给定总杂质限度，应给定一个。

Where the specific monograph is out of the scope of the GM 2034, the principles described e.g. setting appropriate limit for unspecified impurities and for total impurities should be applied. 如果各论不包括在GM2034范围内，仍需要符合杂质限度界定原则，如界定未知杂质和总杂质限度。

TOP 10 (3.2.S.2.3): Solvent recovery: 回收溶剂

Information related to solvent recovery should be included in the description of the manufacturing process. The steps where solvents are recovered and the recovered solvents used should be highlighted. Section 3.2.S.2.3, Control of Materials, should be completed by a comparative table of specification for fresh and recovered solvents, and any differences between the specifications should be justified. 与回收溶剂有关的信息应包括在生产工艺的描述中。溶剂回收的步骤和回收溶剂的使用应明显标示。在3.2.S.2.3部分中，物料控制部分，应有一个新鲜溶剂和回收溶剂质量标准的完整比较表，所有的不同均应有论述。

冰城

好资料啊，对于原料药出口的可以研究下

一沙一叶

学习一下。

小李飞刀

支持一下。

怀谷

谢谢楼主！