已上市药品中元素杂质实施建议

26 February 2015 EMA/CHMP/QWP/109127/2015

Committee for Medicinal Products for Human use (CHMP)

Elemental impurities in marketed products. Recommendati** for implementation

已上市药品中元素杂质实施建议

Products should comply with the ICH/CHMP Guideline for Elemental Impurities under the following timeframe: 药品应按以下时间框架符合ICH/CHMP元素杂质指南：

Product产品	Should complywith Guideline from: 自以下日期开始要求符合指南
New Marketing authorisation for newproduct (containing new active substance)	June 2016
新产品新上市申报（含有新活性物质）	2016年6月
New Marketing uthorization forproduct containing an establishedactive substance	June 2016
含有已有活性物质的新上市产品	2016年6月
Marketed products including newmutual recognition applicati** ofalready approved products	December2017
已上市产品，包括已批准产品的新互认申报	2017年12月

Reminder 提醒

1.  Classification 分类

Following classes of elemental impurities are defined:

对元素杂质按以下定义进行分类：

·         Class 1: elements with high toxicity by all routes of administration; possible from different sources

·         1类：所有摄入途径均具有高毒性的元素，可能有不同来源

·         Class 2: elements with route dependent toxicity:

·         2类：毒性依据摄入途径不同有差异的元素，分为2A和2B两子类：

·         A: possible from different sources; and

·         A类：可能有不同来源，以及

·         B: less likely unless intentionally added to the manufacturing process.

·         B类：除有意加入生产工艺中以外出现可能性较小

·         Class 3: elements with low toxic potential by the oral route

·         3类：口服低毒元素

2.    The guideline covers elemental impurities from all possible sources (including equipment), since toxicity isindependent of the source of an impurity. To ensure control for elements likely to be present at a safe level the guideline describes the principles of a risk-based approach to be followed.

指南覆盖了所有可能来源的元素杂质（包括设备），因为其毒性取决于杂质的来源。为了确保对可能会达到安全限度的元素进行控制，指南描述了应遵守的基于风险的方法原则。

Implementation for existing marketed products已上市药品的实施

In order to have a common approach among National Competent Authorities and to avoid an unnecessary workloaddue to a lot of variati**, the following proposals below are made.

为了在不同国家药监之间保持相同的做法，避免由于太多差异引起不必要的工作量，特给出以下建议：

1.    Each national authority should notify to the MAH in its own country about this new guideline according to itsnational information procedure.

每个国家药监局应采用国内信息沟通程序通知其自己国内的MAH本新指南。

2.    During the transition period the MAH should perform a risk assessment of the manufacture of the medicinal productcovering all potential sources such as active substance starting materials, reagents, catalysts, process water,excipients, equipment, container closure materials etc. It is envisaged that parts of this risk analysis may be commonfor several products while others may be product specific. The risk assessment should form the basis for a controlstrategy that is able to ensure compliance with the Permitted Daily Exposures (PDE:s) given in the guideline for eachelement. In the guideline it is indicated by the classification which elements should be included in the risk assessmentbased on the circumstances. Whether additional controls or acti** will be necessary is dependent on the outcomeof the risk assessment.

在过渡阶段，MAH应实施药品生产风险评估，覆盖所有潜在来源，例如，活性物质起始物料、试剂、催化剂、工艺用水、辅料、设备、包装容器植物等。可以想象这些风险分析中有一部分可能对于几个药品来说是一样的，而其它的产品则可能是各有不同。风险评估应成为控制策略的基础，可以确保所有元素符合指南中允许日暴露限（PDE）。在指南中，有对元素进行分类，说明哪些元素应根据实际情况包括在风险评估中。是否需要有额外的控制或措施则应依据风险评估的结果来确定。

2.1.      In all cases a thorough risk assessment should be performed and documented. It should be available forinspection.

所有情况下，均应实施完整风险评估并记录。检查时应可以提供。

2.2.      No variation is necessary if the outcome of the risk assessment is that, in order to comply:

如果风险评估的结果如下，则不需要进行评估：

2.2.1        No further controls on elemental impurities to materials such as the designated active substance starting material, synthesis intermediates, active substance, excipients or the finished product are needed.

对物料元素杂质不需要进一步控制，例如，指定的活性物质起始物料、合成中间体、活性物质、辅料或制剂成品。

2.2.2        No replacement or change of quality of materials such as the designated active substance starting material, synthesis intermediates, active substance, excipients or of the manufacturing equipment isneeded.

不需要替换或改变物料质量，例如，指定的活性物质起始物料、合成中间体、活性物质、辅料或生产设备材质。

2.2.3        No change of the manufacturing process is needed.

不需要改变生产工艺。

2.3.      In other cases a variation is needed. It should be categorised according the Variation Guidelines(Official Journal 2013/C 223/01) and accompanied with the documentation required there. In addition,the variation should contain a short summary of the risk assessment and the conclusi** drawn.

其它需要变更的情形。应根据变更指南进行分类（官方杂志2013/C 223/01），提交变更所需的文件。另外，变更中应包括一份风险评估摘要，以及得出的结论。

3.    Where a control of an elemental impurity is warranted, an elemental specific method is requested by the guideline.Therefore, a non-specific compendial test for heavy metals will not be accepted.

如果需要对某元素杂质进行控制，指南就要求制订元素杂质专用方法。这时，将不会接受非专属性的重金属药典方法。

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来源：网络博客

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谢谢分享，金属元素2018.01.01应该真的实行了