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给所有化学合成原料药CEP持有人关于亚硝胺杂质的通知
As has been announced on the EMA and EDQM website recently, the presence of a nitrosamine impurity has recently been identified in ranitidine-containing medicinal products. As a result of this, action has been taken to suspend the relevant CEPs and more information is awaited to better understand the root cause of the presence of this nitrosamine impurity.
EMA and CMDh have published documents on their websites, (EMA/189634/2019 and CMDh/404/2019), “Information on nitrosamines for marketing authorisation holders” which request marketing authorisation holders (MAH) to follow an investigation process described for synthesised APIs (other than sartans with a tetrazole ring). Although EDQM does not expect that this issue impacts many substances, it is now appropriate to expand the review to all other APIs manufactured from chemical synthesis for which CEPs have been granted. EDQM therefore requests that the holders of such CEPs follow the process described here (which is a similar stepwise approach to that for MAH):
正如EMA和EDQM官网最近所宣布，最近在含雷尼替丁药品中发现了亚硝胺杂质。因此，我们采取了措施暂停CEP，等待更多信息，以便更好了解该亚硝胺杂质出现的根本原因。EMA和CMDH已在其官网发布了文件（EMA/189634/2019 和 CMDh/404/2019）“MAH须知—亚硝胺信息”，其中要求MAH按所述流程调查合成APIs（四唑环沙坦类除外）。虽然EDQM并不认为该问题会影响到很多物质，但目前适合将审核扩展至所有其它采用化学合成方法生产，已颁发CEP的原料药。因此EDQM要求此类CEP的持有人执行下述流程（类似于MAH所采取的步骤）：
Step 1 – Risk evaluation: Companies holding CEPs should perform a risk evaluation of their chemically synthesised APIs with regards nitrosamine formation, using quality risk management principles, as outlined in the ICH Q9 guideline. The principles described in the ICH M7 guideline in relation to toxicology assessment, control strategy and changes to the manufacturing process for active substances should be applied.
The CEP holders should prioritise substances in order to establish the sequence in which they are to be evaluated. The factors that can be taken into account are outlined in the dedicated Questions and Answers documents EMA/CHMP/428592/2019 Rev. 1 and CMDh/405/2019, Rev.1 which are available on the EMA and CMDh websites and if any substances are identified as high priority, the risk evaluation should be done immediately. The risk evaluation should address not only risks from the manufacturing process but also those from the introduction of materials used in the manufacturing process (e.g. starting materials, reagents, solvents – fresh and recovered etc.).
The risk evaluation for all CEPs should be concluded at the latest by 26th March 2020.
CEP holders are not required to confirm to EDQM that step 1 has been completed where no risk is identified. However where a risk is identified, EDQM should be immediately informed and the company should progress to step 2, confirmatory testing, and the timescales for when the confirmatory testing results will be provided to EDQM should be indicated to EDQM.
The outcome of step 1 relating to the risk evaluation performed for a CEP should be communicated to the customers in all cases (even if no risk is identified) such that the MAHs can use this information to fulfil their responsibilities as described in the documents, EMA/189634/2019 and CMDh/404/2019 mentioned earlier.
第一步：风险评估：持有CEP的公司应根据ICH Q9指南中所列的质量风险管理原则，对其化学合成的APIs执行亚硝胺形成的风险评估。毒性评估、控制策略和生产工艺变更原则参考ICH M7指南中所述。
CEP持有人应对其物质进行优先排序，以确定评估顺序。可考虑的因素已在专用问答文件EMA/CHMP/428592/2019Rev. 1和CMDh/405/2019, Rev.1中列出，该文件可从EMA和CMDH官网下载。如果有任何物质被识别为优先级别，则应立即进行风险评估。风险评估应不仅说明来自生产工艺的风险，还要说明生产工艺中所用物料引入的风险（例如，起始物料、试剂、溶剂-新溶剂和回收溶剂等）。
所有CEP的风险评估最迟应在2020年3月26日之前完成。
如果未识别出风险，完成第一步时CEP持有人不需要向EDQM确认。但如果识别出风险，则应立即通知EDQM，并且进入第二步—确认性测试，并告知EDQM何时可向EDQM提交确认性测试结果。
第一步中对CEP已执行的风险评估结果，在任何情况下均应告知客户（即使未识别出风险），使得MAHs可使用此类信息履行EMA/189634/2019 和 CMDh/404/2019文件中所述的义务。
Step 2 – Confirmatory testing: in the event that a risk of presence of nitrosamines is identified as a result of the risk evaluation, confirmatory testing should be carried out using appropriately validated and sensitive methods in accordance with the prioritisation deriving from the risk evaluation conducted in step 1. Substances identified as high priority should be tested as soon as possible.
All APIs identified to be at risk of presence of nitrosamines should be tested and the results provided to EDQM with, if needed, a proposal for subsequent actions (such as revision of the CEP).
CEP holders should inform the EDQM immediately if the tests confirm the presence of a nitrosamine impurity, irrespective of the amount detected, and provide the results. The companies should then progress to step 3 after informing EDQM of the plan and timescales to complete step 3.
第二步：确认性测试：如果风险评估识别出亚硝胺杂质风险，则应根据第一步风险评估所得出的优先序列，采用经过适当验证的灵敏的分析方法进行确认性测试。识别为高风险的物质应尽快检测。
所有识别出具有亚硝胺杂质风险的API均应进行检测，并将检测结果与后续必要的措施提交给EDQM（譬如修订CEP）。
如果检测确认检出亚硝胺杂质，无论检出多少，CEP持有人均应立即通知EDQM，并提交检测结果，通知EDQM开展第三步的计划和时间表，随后开展第三步。
Step 3 – Revision to the CEP: Where nitrosamine impurities have been detected, CEP holders should apply for a revision to their application(s) in a timely manner to introduce any required changes, such as amendment of the manufacturing process or changes to specifications and introduction of controls.
The required revisions to the CEP applications should be concluded at the latest by 26th September 2022 or at an earlier time if otherwise justified.
第三步：修订CEP：如果检出亚硝胺杂质，CEP持有人应及时修订其申报资料，增加需要的变更，如修订生产工艺或变更质量标准，增加控制措施。
所需CEP申报修订最迟于2022年9月26日或更早时间完成。
CEP holders are reminded that it is their responsibility to complete the procedure described in this announcement for all their impacted CEPs.
EDQM may contact CEP holders for information on the risk of nitrosamines at any step of this review and any such requests should be responded to fully and in a timely manner. EDQM will take action on any CEP (e.g. suspension) where information becomes available regarding an unacceptable level of nitrosamine impurities in the active substance which is the subject of a CEP.
EDQM reminds CEP holders that they should provide the appropriate information relating to the risk evaluation they have performed for their CEP to their customers in all cases (for steps 1 to 3, and for step 1 even if no risk has been identified) such that the MAHs can use this information to fulfil their responsibilities in a timely manner as described in the documents, EMA/189634/2019 and CMDh/404/2019 mentioned earlier.
在此提醒CEP持有人有义务对其所持有受影响的CEPs完成本通知所述的程序。
EDQM可能会联络CEP持有人，告知本审评任何步骤中关于亚硝胺风险的信息。如收到EDQM要求，持有人应及时全面回复。如果获得相关信息认为CEP的亚硝胺杂质处于不可接受水平，EDQM将对CEP采取措施（例如暂停）。
EDQM提醒CEP持有人，在任何情形下（对于第一步至第三步，以及第一步，即使未识别出风险），应向其客户提交已执行的CEP风险评估资料，使得MAH可使用该信息及时履行在前面提到的文件EMA/189634/2019和 CMDh/404/2019中所述的义务。
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