CEP程序中ICH Q3D的实施（中英文）

Certification of Substances Division 物质认证中心

LS/CB

PUBLIC DOCUMENT

(LEVEL 1)

PA/PH/CEP (16) 23

Strasbourg, August 2016

Certification of suitability to the Monographs of the European Pharmacopoeia

Implementation of ICH Q3D in the Certification Procedure

CEP程序中ICH Q3D的实施

Addresses	Role	Date
TAB	For adoption	July 2016
TAB	Adopted by correspondence	August 2016

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

原文下载网址：https://www.edqm.eu/sites/default/files/implementation_of_ich_q3d_in_the_certification_procedure_august_2016.pdf

译文仅供参考

注：原文中final substance通指原料药及其它药用物质，在翻译中为简化，均译为原料药。

1. Background背景

The ICH Q3D guideline on elemental impurities is effective in the European Union from June 2016 for new marketing authorisation applications and from December 2017 for authorised medicinal products.

ICH Q3D元素杂质指南自2016年6月起在欧盟范围内对新上市许可申报开始生效，自2017年12月起对已批准的药品生效。

This document is intended to serve as guidance on how to implement ICH Q3D in the procedure for “Certification of Suitability to the monographs of the European Pharmacopoeia” (CEP).

本文件意在作为指南，指导在CEP程序中如何实施ICH Q3D。

ICH Q3D covers 24 elements (classified under the following classes 1, 2A, 2B and 3) and gives permitted daily exposure (PDE) in drug products. ICH Q3D is not limited to reagents and catalysts in drug substance or excipients, but also considers all contributions from manufacture including manufacturing equipment, water and container-closure system.

ICH Q3D覆盖了24种金属（分为1类、2A类、2B类和3类），并且给出了其在药品中的允许日暴露量（PDE）。ICH Q3D并不仅局限于原料药和辅料中的试剂和催化剂，同时也考虑到了所有生产中可能引入的情况，包括生产设备、水和容器密闭系统。

The ICH Q3D guideline emphasises developing a risk-based control strategy to limit elemental impurities which is summarised in an appropriate “Risk Management Summary” document.

ICH Q3D指南强调了开发基于风险的控制策略来限制元素杂质，该方法在“风险管理总结”文件里进行汇总。

2. Scope 范围

This document describes the policy for elemental impurities in substances covered by a Certificate of Suitability to the monographs of the European Pharmacopoeia (CEP).

本文描述了CEP证书所覆盖的原料药中元素杂质的政策。

This document covers pharmaceutical substances introduced in medicinal products within the scope of ICH Q3D. For products outside the scope of Q3D, the applicant should control adequately the levels of elemental impurities in their substance.

本文覆盖了被引入ICH Q3D范围内药品的原料药。对于不在Q3D范围内的药品，申报者应对其原料药中的元素杂质进行充分控制。

The reference documents taken into consideration when elaborating this policy are:

在起草本方针政策时所考虑的参考文件有：

―   ICH guideline Q3D on elemental impurities (EMA/CHMP/ICH/353369/2013) and associated ICH training modules

―   ICH Q3D元素杂质指南（EMA/CHMP/ICH/353369/2013）和相关的ICH培训模块

―   Elemental Impurities in marketed products. Recommendations for implementation (EMA/CHMP/QWP/109127/2015)

―   已上市药品中的元素杂质，实施建议（EMA/CHMP/QWP/109127/2015）

―   Implementation strategy of ICH Q3D guideline – Draft (EMA/404489/2016)

―   ICH Q3D指南实施策略---草案（EMA/404489/2016）

This policy is applicable to new, renewed and revised CEPs granted from the 1st September 2016 (provided the applicant/holder has made reference to ICH Q3D principles in their application).

本方针政策适用于自2016年9月1日起颁发的新的、更新的以及修订的CEP（如果申报者/持有人在其申报中引用ICH Q3D原则的话）。

3. Implementation of the policy 政策实施

The applicant is given 2 possible options in a CEP dossier:

在CEP申报文件中，申报者有2个选择：

?   Provide a Risk Management Summary (RMS) for elemental impurities which may be present in the manufacturing process of the final substance.

?   提供可能会出现在最终原料药的生产工艺中的元素杂质风险管理摘要（RMS）

?   Do not provide a Risk Management Summary (RMS).

?   不提供风险管理摘要（RMS）

The EDQM encourages applicants to provide a RMS. Submitting a RMS in a CEP application provides significant benefit as it will facilitate the risk assessment for the medicinal product.

EDQM鼓励申报者提供一份RMS。在CEP申报中提交RMS会带来巨大好处，因为它有助于对药品进行风险评估。

3.1 Risk Management Summary Provided 提供风险管理摘要

Applicants should clearly identify this option in their application.

申报者应在其申报材料中清楚说明其选择。

A Risk Management Summary report should be provided in module 3 of the dossier, in the form of a Table, as described in Annex 1 of this document (preferably in CTD section 3.2.S.3.2 “Impurities”). This summary should detail the rationale used to conduct the study, and include a justification of the control strategy implemented following the risk assessment.

风险管理摘要报告应在申报文件的第3模块中提交，采用表格方式，按本文件和附录1所述形式（最好是在CTD第3.2.S.3.2“杂质”部分中）。该摘要应详细说明用于研究的原理，在风险评估后面说明对所实施的控制策略的论证。

It should be noted that where insufficient data is given for this option, the application will be considered as if no RMS is provided.

要注意，如果此选择中所提供的数据不充分，申报会被作为未提交RMS对待。

3.1.1 Requirements for CEP Applications CEP申报资料的要求

As well as considering the principles outlined in ICH Q3D, the following points should also be taken into account when taking the RMS approach for a CEP application.

与考虑ICH Q3D中列出的原则一样，在选择CEP申报的RMS方法时也要考虑以下要点：

How to build the RMS 如何构建RMS

?   The RMS should consider all potential sources of contamination; including elemental impurities intentionally introduced into the process, contributions from raw materials (such as water), equipment, and packaging.

?   RMS应该考虑所有可能的污染源，包括有意引入到工艺中的元素杂质，来自于原料（例如水）中、设备中以及包装中的元素杂质。

The intended route of administration / use of the substance should be indicated, which forms the basis of the risk management discussion. Reference to unrealistic routes of administration or uses not pertaining to the known use of the substance will not be accepted.

原料药的用途/既定的摄入方式要说明，它是风险管理讨论的基础之一。参考不现实的摄入途径或用途，而并不包括已知的原料药用途是不会被接受的。

?   The RMS should consider all elemental impurities mentioned in ICH Q3D (as per the table 5.1 “Elements to be considered in the Risk Assessment”). Meaning that:

?   RMS应考虑在ICH Q3D中提到的所有元素杂质（如表5.1“在风险评估中要考虑的元素”）。含义如下：

l  Class 1 and 2A elements, as well as all elements intentionally added in the manufacture whatever their classification should be systematically discussed.

l  第1和第2A类元素，和所有在生产中有意加入的杂质（不论其分类如何），均应进行系统讨论。

l  If relevant, and depending of the use of the substance, Class 3 elements should be discussed.

l  必要时，根据原料药的用途不同，第3类元素也应进行讨论。

l  Justification as to why specific elemental impurities were included in the scope of the RMS is considered useful information and should be included.

l  论证为什么某些元素杂质被包括在RMS范围内，这是有用的信息，需要包括在其中。

How to define the control strategy 如何定义控制策略

?   The control strategy should focus on the absence or presence of elemental impurities in the final substance.

?   控制策略应关注元素杂质是否出现在最终物质中

?   Absence of an elemental impurity can be concluded when it is shown with convincing evidence that it is purged to a level which is consistently below 30% of the calculated concentration limit based on the indicated route of administration and based on the option 1 daily intake (as per table A.2.2 of the ICH Q3D guideline), in a minimum of 3 commercial batches or a minimum of 6 pilot batches of the final substance.

?   一种元素杂质是否出现可以采用具有说服力的证据来证明其被清除至一定程度，一致地低于根据所指的摄入途径和第一选择日服用量（如ICH Q3D指南的表A.2.2）所计算浓度限度的30%以下。检测数据应来自原料药的至少3批商业批次或者至少6批中试批次。

?   When applicable, a justified specification for elemental impurities in the final substance should be introduced. For any elemental impurity intentionally introduced into the last synthetic step of the process, a specification in the final substance is expected (as this is associated with an elevated risk for impurities being carried forward), unless it is consistently and convincingly demonstrated that the process is capable to purge the impurity from the final substance to a level which is below 30% of the calculated concentration limit.

?   适用时，在原料药中应引入经过论证的元素杂质质量标准。对于所有在工艺的最后合成步骤中有意加入元素杂质，在原料药中均应有质量标准（因为它可能会让杂质带入的风险升级），除非能持续并具有说服力地证明工艺能够从原料药中清除发质达到所计算浓度限30%以下的水平。

?   Screening results of several batches for elemental impurities alone cannot be considered as a risk management approach, but may support a RMS as described above. This might be done in a similar manner as is illustrated in appendix 4 of the guideline ICH Q3D.

?   筛选几个的批次的元素杂质结果本身并不能当作是风险管理方法，但可以支持上述RMS。这可以采用ICH Q3D指南的附录4中所说明的相似的方法来完成。

?   For the analytical methods used:

?   对于所用的分析方法：

l  For screening purposes: The analytical methodology used should be mentioned along with minimum validation information such as indication of the specificity and sensitivity of the method (LOD/LOQ).

l  为了筛选的目的：所用分析方法应有最低程度的验证信息，例如，专属性和方法灵敏度（LOD/LOQ）.

l  Control included in the specification of the final substance: A detailed description of the analytical method used should be provided which is suitable to be annexed to the CEP. The analytical method should be validated in accordance with the requirements of ICH Q2.

l  包括在原料药质量标准中的控制：要提供详细的分析方法描述，描述要适合作为CEP的附录。分析方法应根据ICH Q2的要求进行验证。

3.1.2: Information reported on Certificates of Suitability  CEP中报告的信息

When a RMS is provided, this will be mentioned on the CEP.

如果提供了RMS，则在CEP上将会提及。

A table summarising the conclusions of the RMS will be appended to the CEP as per the example given in Annex 1 of this document. This table is intended to carry necessary information about the level of contamination of the substance source, in order to implement the ICH Q3D component approach in the finished medicinal product.

在CEP上会附入RMS结论的总结表格，样例见本文件的附录1。此表意在给出关于原料药来源污染水平的必要信息，以便在制剂成品中实施ICH Q3D的组份方法。

Any relevant specification, as proposed by the applicant, will be mentioned on the CEP together with the corresponding analytical method.

所有申报人拟定的相关的质量标准与对应的分析方法将会在CEP上提到。

Note: The EDQM assessors will not make a final conclusion on compliance with ICH Q3D, as this should be done within the context of the marketing authorisation application for the medicinal product in which the substance covered by the CEP is introduced.

注：EDQM评审员不会做出是否符合ICH Q3D要求的最终结论，因为这需要在引用CEP的制剂的上市许可申报的情况下作结论。

3.2 No Risk Management Summary provided不提交风险管理摘要

3.2.1 Requirements for CEP Applications CEP申报的要求

If no risk assessment has been performed, then the following points should be addressed in the CEP application:

如果不进行风险评估，则在CEP申报中要说明以下各点：

l  Any elemental impurities (whatever the Class) intentionally introduced in the manufacture of the final substance should be declared and data showing their level in the final substance should be provided.

l  所有有意引入到原料药生产中的元素杂质（不论归属哪类）均应声明，并提供数据显示其在原料药中的水平。

l  For any elemental impurity intentionally introduced into the last synthetic step of the process, a specification in the final substance is expected (as this is associated with an elevated risk for impurities being carried forward), unless it is consistently and convincingly demonstrated that the process is capable to purge the impurity from the final substance to a level which is below 30% of the appropriate concentration limit (based on option 1 of table A.2.2 of the ICH Q3D guideline).

l  所有有意引入到工艺的最后合成步骤的元素杂质，应在原料药中建立质量标准（因为与带入杂质风险评估有关），除非有连续并具有说服力的数据证明工艺有能力将杂质从最终原料药中清除至低于适当关注限度的30%以下的水平（基于ICH Q3D指南表A.2.2的方法1）。

l  The limits applied for the control of elemental impurities in the final substance should reflect the process capabilities, and the PDE of ICH Q3D may be used as reference.

l  应用于最终原料药中元素杂质控制的限度应反映工艺能力，在ICH Q3D中的PDE值可以用作参考。

l  The method used to control elemental impurities in the final substance should be described in detail (in a format to be annexed to the CEP) and validation data according to ICH Q2 should be submitted.

l  用于最终原料药中元素杂质控制的方法应详细描述（以能够附入CEP的格式），要提交根据ICH Q2所进行验证的数据。

3.2.2: Information reported on Certificates of Suitability CEP上报告的信息

All intentionally added elemental impurities will be listed on the CEP, regardless of the levels found in the final substance. Alternatively if no elemental impurities are intentionally added in the process, this will be mentioned on the CEP.

无论在最终原料药中发现的水平如何，所有有意加入的元素杂质均会被列在CEP上。而如果没有在工艺中有意加入元素杂质，则会在CEP上说明。

The CEP will not contain any information regarding the absence of any elemental impurities in the final substance.

CEP不会包括任何关于最终原料药中不含有元素杂质的信息。

Limits for elemental impurities in the final substance, as implemented by the CEP holder will be included on the CEP.

元素杂质在最终原料药中的限度会根据CEP持有人实施的情况包括在CEP上。

Note: The EDQM assessors will not make a final conclusion on compliance with ICH Q3D, as this should be done within the context of the marketing authorisation application for the medicinal product in which the substance covered by the CEP is introduced.

注：EDQM评审员不会做出是否符合ICH Q3D要求的最终结论，因为这需要在引用CEP的制剂的上市许可申报的情况下作结论。

4. Existing CEPs and requirements for revisions 现有CEP和修订要求

No systematic revision of existing CEPs is foreseen from the publication of this document, except for those mentioned in section 4.3.

除第4.3部分提及的情况外，自本文发布开始并不要求对现有CEP进行系统性修订。

The following points should be considered by holders of existing CEPs:

现有CEP持有人应考虑以下情况：

4.1: Clarification Regarding the Test for Heavy Metals as per Ph. Eur. General Chapter 2.4.8 关于根据EP通则2.4.8重金属检测的说明

From Ph. Eur. Edition 9.0 onwards (implementation date January 2017), the test for heavy metals as per General Chapter 2.4.8 is removed from monographs for substances which are within the scope of ICH Q3D.

自EP 9.0开始（实施日期为2017年1月），根据通则2.4.8进行的重金属检测将从包括在ICH Q3D范围内的物质各论中移除。

The process is the same as for implementation of revised monographs of the Ph. Eur. in marketing authorisation applications, it is therefore expected that the substance specification is aligned with the revised Ph. Eur. monograph for the substance within six months of its publication.

其流程与EP在上市许可申报中各论修订实施的流程相同，因此要求在发布之后6个月内，原料药质量标准与修订后的EP各论保持一致。

Holders of existing CEPs will not be individually contacted by EDQM, and likewise no request for revision should be submitted. However, in exceptional cases where the manufacturing process includes a risk of elemental impurities being present in the substance and the removal of the heavy metals test from the specification means there is no control of this risk, then appropriate actions should be taken and the dossier updated.

EDQM不会单独联系现有CEP的持有人，也不会要求提交修订。但是，如果生产工艺让原料药有含有元素杂质的风险，重金属检测从质量标准中移除意味着对此风险失去控制，则应采取适当的措施并更新申报文件。

4.2: Clarification Regarding Tests for Specific Metals in a Substance Monograph关于原料药各论中特定金属的检测说明

For individual monographs which contain specific tests for elemental impurities, it is expected that these tests are part of the specification unless otherwise justified (and approved by EDQM).

对于包括有元素杂质特定检测的原料药各论，除另有论证（并由EDQM批准）外，要求将检测作为质量标准的一部分。

4.3: Clarification Regarding CEPs Containing a Limit for a Metal Residue Based on the Option 2a Calculation as per Ph. Eur. General Chapter 5.20 关于CEP中按照EP通则5.20方法2a计算金属残留限度的说明

For existing CEPs which contain a limit for a metal residue based on the option 2a calculation of the General Chapter 5.20 described in the 8th edition of Ph. Eur., or of the EMA guideline EMEA/CHMP/SWP/4446/2000, the holders of these CEPs will be informed individually by EDQM, and a revision of the relevant CEPs will be automatically initiated by January 2017.

现有CEP中，如果包括有一个金属残留的限度是按照EP8里通则5.20中方法2a进行的计算，或者是按照EMA指南EMEA/CHMP/SWP/4446/2000进行的计算，则持有人将收到EDQM的通知，并且这些相关CEP会从2017年1月开始自动进行修订。

4.4: Triggers to initiate a revision of CEP applications concerning elemental impurities  启动CEP申报中关于元素杂质的修订

4.4.1 Introduction of a RMS without other changes  引入RMS而没有其它变更

CEP holders are given the possibility to introduce a RMS as part of a revision application (when there are no changes to the process or to the control strategy for the substance), by submitting a request for revision classified as “minor by default”. This request for revision may be submitted at any time during the lifecycle of the dossier, except during an on-going procedure.

CEP持有人可以引入RMS作为修订申报的一部分（当工艺或原料药的控制策略没有变更时）。这时应提交修订申请分为为“默认轻微”。除了有程序正在进行时以外，此修订申请可以在文档的生命周期中任何时间提交。

4.4.2. Changes to the manufacturing process 对生产工艺进行变更

Changes to the manufacturing process should be classified according to the EDQM “Guideline on Requirements for Revision/renewal of Certificates of Suitability to the European Pharmacopoeia Monographs (PA/PH/CEP (04) 2)”. If the changes have an impact on elemental impurities, CEP holders are given the possibility to submit a RMS.

对生产工艺进行变更应根据EDMQ“CEP修订/更新要求指南(PA/PH/CEP (04) 2)”进行分类 。如果变更对元素杂质有影响，CEP持有人可以提交一份RMS。

If a RMS has already been introduced in the CEP application, the validity of the RMS should be verified and discussed and if needed an update should be provided. Only significant changes in elemental impurity levels, leading to a different conclusion should be reported.

如果RMS已经在CEP申报中引入，则应核对RMS的有效性并进行讨论，必要时应提交更新。只有当元素杂质水平有重大变更时，才会需要报告其导出的不同结论。

If no RMS is provided or present in the application, sufficient information should be submitted as described above (section 3.2).

如果在申报资料中没有提供或呈交RMS，则应按上述要求提交足够的信息（第3.2部分）。

4.4.3. Changes to the control strategy for the substance (changes to analytical methods or specification, without changes to the manufacturing process) 原料药控制策略的变更（分析方法或质量标准变更，不变更生产工艺）

Such changes should be classified according to the EDQM “Guideline on Requirements for Revision/renewal of Certificates of Suitability to the European Pharmacopoeia Monographs (PA/PH/CEP (04) 2)” and may include:

此类变更应根据EDQM“CEP修订/更新要求指南(PA/PH/CEP (04) 2)”进行分类，可能包括：

-      Changes to limits for elemental impurities in the final substance: addition/deletion/tightening/widening

-      原料药中元素杂质限度变更：增加/删除/加严/放宽

-      Changes to the method(s) used to control elemental impurities in the final substance.

-      原料药中元素杂质控制所用方法变更

If a RMS has already been introduced in the CEP application, the validity of the RMS should be verified and discussed and if needed an update should be provided. Only significant changes in elemental impurity levels, leading to a different conclusion should be reported.

如果RMS已经在CEP申报中引入，则应核对RMS的有效性并进行讨论，必要时应提交更新。只有当元素杂质水平有重大变更时，才会需要报告其导出的不同结论。

4.5: Renewal 更新

The renewal application presents a good opportunity for CEP holders to submit a RMS in their application.

更新申报给CEP持有人一个非常好的机会，可以在其申报资料中提交RMS。

During assessment of the request for renewal, the EDQM will systematically review the control of elemental impurities against the policy described in this document.

在更新申请的评估过程中，EDQM会根据本文中所述的政策要求对元素杂质的控制进行系统性审核。

When granted, renewed CEPs will be in line with the policy described in sections 3.1 or 3.2 of this document.

如果颁发更新的CEP，则新CEP符合本文中第3.1部分或3.2部分所述的政策要求。

CEPs which have already been renewed will be updated only if CEP holders have made changes impacting elemental impurities.

已经更新过的CEP只有在CEP持有人提交对元素杂质有影响的变更时才会更新。

_______________________

Annex 1 附录1

Example of Risk Management Summary  风险管理总结样例

This table has to be completed by the applicant. 本表应该由申报者填写完成

Intended route of administration / Use of the substance: ……………………
摄入途径/物质使用方式：
Element	元素	Class 级别	Intentionally added? 是否有意加入？	Considered in risk management? 在风险管理中是否需要考虑？	Conclusion 结论
Cd	镉	1	*	Yes	**
Pb	铅	1	*	Yes	**
As	砷	1	*	Yes	**
Hg	汞	1	*	Yes	**
Co	钴	2A	*	Yes	**
V	钒	2A	*	Yes	**
Ni	镍	2A	*	Yes	**
Tl	铊	2B	*	*	**
Au	金	2B	*	*	**
Pd	钯	2B	*	*	**
Ir	铱	2B	*	*	**
Os	锇	2B	*	*	**
Rh	铑	2B	*	*	**
Ru	钌	2B	*	*	**
Se	硒	2B	*	*	**
Ag	银	2B	*	*	**
Pt	铂	2B	*	*	**
Li	锂	3	*	*	**
Sb	锑	3	*	*	**
Ba	钡	3	*	*	**
Mo	钼	3	*	*	**
Cu	铜	3	*	*	**
Sn	锡	3	*	*	**
Cr	铬	3	*	*	**

* Yes / No 是/否

** The following statements may be used: “Absent” (meaning less than 30% of ICH Q3D option 1 limit, as defined under 3.1.1) / “maximum level : < X ppm”

可以使用以下声明：“不存在”（表示低于ICH Q3D方法1限度的30%，即3.1.1中定义的限度）/“最高水平：<X ppm”

It is not necessary to include individual batch results in the above table. CEP holders should ensure that the substance complies with the maximum level indicated.

不需要在上表中包括单个批次的结果。CEP持有人应保证原料药符合所显示的最高水平。

来源：http://zhuyujiao1972.blog.163.com/blog/static/98694727201671010338230/