CEP程序内ICH Q3D的实施

Implementation of ICH Q3D within the CEP Procedure

CEP程序内ICH Q3D的实施

In August 2016, the EDQM released a policy document entitled "Implementation of ICH Q3D in the Certification Procedure" (PA/PH/CEP(16)23). According to the literal adoption of the ICH Q3D Guideline in the General Chapter 5.20 of the European Pharmacopoeia, regulating the handling with elemental impurities within the CEP procedure is the next step for a consistent implementation of this guideline.

在2016年8月，EDQM发布了一份题为“在CEP程序中ICH Q3D的实施”(PA/PH/CEP(16)23)的政策文件。根据EP在5.20中对ICH Q3D指南的文献采纳，在CEP程序中规范元素杂质处理是此指南协调实施的下一步。

The document describes in two main chapters which data on elemental impurities are required for a new CEP application and for the revision/renewal of an existing CEP. An important part of the document is the Annex 1 providing the example of a risk management summary (RMS) which lists the 24 elements of the ICH Q3D guideline in a table. Applicants have to enter in the table limits and information about each element which is involved in the risk management or which has been added intentionally. Moreover, the intended routes of administration of the API, as well as its intended use have to be indicated.

文件在2个主要章节中描述了新CEP申报中需要哪些元素杂质相关数据，对现有CEP修订/更新中需要哪些。文件中一个重要的部分是附录1，它提供了一个风险管理总结（RMS）的样例，其中以表格方式列出了ICH Q3D指南中的24个元素。申报者必须在表格内输入风险管理所涉及，或者是有意加入的每个元素的限度和信息。另外，API摄入途径以及既定用途也要说明。

Please find hereafter a short summary of the data on elemental impurities expected by the EDQM from an applicant or a CEP holder.

下面是该文件的简短摘要：

New application for a CEP with submission of a RMS 新CEP申报中RMS提交

• All potential sources of impurities (e.g. raw materials, excipients, equipment, packaging) have to be discussed as well as the intentionally added elements
• 所有潜在的杂质来源（例如，原料、辅料、设备、包装）以及有意添加的元素都必须讨论
• All class 1 and 2A elements have to be considered. Class 3 elements should only be considered when a later use on humans (dosage form) is intended
• 必须考虑所有1类和2A类元素。人药生产后期（制剂）中有意添加的3类元素要考虑。
• Each consideration has to be justified
• 每种考虑都必须进行论证
• The control strategy should concentrate on the absence/presence of elemental impurities in the finished product, i.e. in the final API
• 控制策略应集中在元素杂质在成品，即在最终API中是否出现
• The absence of an elemental impurity means: convincing evidence that they are purged under a level of 30% of the calculated limit based on the dosage form and the daily intake (according to table A.2.2 of the ICH Q3D guideline) and derived from measurements of at least 3 commercial batches or at least 6 pilot batches of the finished product
• 元素杂质不存在表示：具有说服力的证据证明元素杂质被清除至根据剂型和日服用量（根据ICH Q3D指南表A.2.2）计算的限度的30%以下，数据来自对至少3批商业批次，或至少6批中试成品生产的检测数据
• If necessary, a justified specification for elemental impurities in the final product should be indicated
• 必要时，应说明在成品中元素杂质经过论证的标准
• Results of the screening if several batches can support a RMS but cannot replace it
• 如果有几个批次可以支持一份RMS，结果可以筛选，但不能替换它
• Analytical methods don't have to be completely validated for screening investigations. But if they serve as control of the specification of the final product, they have to be described in detail and validated according to ICH Q2
• 筛选调查所用的分析方法不需要进行完整验证。但如果它们用作成品质量标准控制，则必须根据ICH Q2详细描述并进行验证
  

The EDQM points out that the submission of a RMS is in any case advantageous.

EDQM指出，RMS的提交在任何情况下都是有优势的。

New application for a CEP without submission of a RMS 新CEP申报如果没有RMS

• Analytical data have to be provided for each elemental impurity.
• 必须为每种元素杂质提交分析数据
• A specification in the final product has to be indicated for each element intentionally added in the last synthesis step.
• 在成品中的质量标准必须给出每种有意添加在最后合成步骤中的元素杂质
• For the analytical methods, validation data according to ICH Q2 have to be submitted.
• 必须提交根据ICH Q2所做的分析方法验证数据
  

Requirements for existing CEPs and CEP revisions 现有CEP和CEP修订的要求

With the publication of edition 9.0 of the European Pharmacopoeia (January 2017), General Chapter 2.4.8 (Test for Heavy Metals) will be removed from the monographs for substances which fall under the scope of ICH Q3D. CEP holders won't be contacted individually by the EDQM unless their CEP contains a limit for elemental impurities which has been calculated according to option 2a of the General Chapter 5.20 set in edition 8 of the European Pharmacopoeia. In that case, a revision of the CEPs will be automatically initiated by January 2017.

随着EP9.0的公布（2017年1月），通则2.4.8（重金属检测）将从ICH Q3D范围内的物质各论中取消。除非CEP中含有元素杂质限度，并且是根据计算EP8中通则5.20里第2a方法计算的，否则EDQM不会单独联系CEP持有人。在此情形下，对CEP的修订将会在2017年1月自动启动。

In the following cases, CEPs revisions are possible, respectively necessary:

在以下情形下，CEP可以根据需要进行修订：

• The CEP holder submits only a RMS (without further changes to the manufacturing process of the control strategy). This possibility exists at any time during the lifecycle of the dossier.
• CEP持有人只提交RMS（没有其它生产工艺控制策略变更）。这种可能性在申报文档生命周期中任何时间都是可能的。
• Changes to the manufacturing process: If the changes influence the elemental impurity profile, a RMS and/or supporting data have to be submitted. The validity of an already submitted RMS should be verified. If required, the RMS has to be updated.
• 对生产工艺的变更：如果变更影响元素杂质概况，则必须提交RMS和/或支持性数据。已提交的RMS的有效性应进行核查。必要时，RMS必须进行更新。
• Changes to the control strategy (another analytical procedure or specification) without changes to the manufacturing process:  if the changes influence the elemental impurity profile, a RMS and/or supporting data have to be submitted. The validity of an already submitted RMS should be verified. If required, the RMS has to be updated.
• 对控制策略的变更（另一个分析方法或质量标准），而对生产工艺没有变更：如果变更影响了元素杂质概况，则必须提交RMS和/或支持性数据。已提交RMS的有效性应进行核查，必要时必须更新RMS。
  

The same requirements apply to CEPs whose renewal is pending. The EDQM recommends to submit a RMS in the course of the renewal of a CEP.

相同要求适用于将要更新的CEP。EDQM建议在更新CEP的过程中提交RMS。

The regulations described in this policy document will apply as of September 1st 2016 for all new, renewed or revised CEPs. Notwithstanding the above, the document can be commented on via the EDQM helpdesk.

在此政策文件中描述的规定将自2016年9月1日起适用于所有新的、更新的或修订的CEP。尽管如果，文件目前是草案，可以通过EDQM帮助台提交意见。

Note: At the 19th APIC/Cefic European Conference on Active Pharmaceutical Ingredients on 23 - 25 November 2016 in Barcelona, Spain, Hélène Bruguera -  head of EDQM's certification division - will present the latest developments in the CEP procedure. You can find more information at: www.api-conference.org.

注：在2016年11月23-25日西班牙巴塞罗那举办的第19届APIC/CEFIC欧洲API会议上，EDQM认证中心会介绍CEP程序中最新进展。更多信息参见官网。