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EDQM 发给与亚硝胺有关的合成API的CEP持有人的通知 20191029

首页 > 资讯 > EDQM 发给与亚硝胺有关的合成API的CEP持有人的通知 20191029

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EDQM 发给与亚硝胺有关的合成API的CEP持有人的通知 20191029
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2019-10-30 EDQM

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Since July 2018, EDQM has been actively involved in activities related to the detection and control of nitrosamine impurities in sartan active substances (APIs) with a tetrazole ring for which there are CEPs. These activities have included contacting CEP holders to request data and corrective actions, assessing responses to such requests, GMP inspections of manufacturing sites, suspension of CEPs, where appropriate, and their restoration after appropriate corrective actions had been implemented. Additionally, for any APIs, for new applications for a CEP, during the renewal of a CEP or during any revisions where the synthetic route or sourcing is modified, the potential for presence of such nitrosamine impurities is systematically assessed. EDQM has also been involved in the activities of the OMCL network including coordination of sampling and testing. The Ph. Eur. monographs for the sartan APIs with a tetrazole ring have been revised as a consequence of the presence of nitrosamines in these substances.

自2018年7月以来,EDQM一直积极参与有CEP的四唑环沙坦类API中亚硝胺杂质检测和控制有关的活动。这些活动包括联系CEP持有人要求提交数据和纠正措施、评估对此类要求的回复、对生产场地的GMP检查、适当时搁置CEP,以及在执行适当纠正措施之后的恢复。另外,对于任一API,新CEP申报,以及CEP更新期间或修订CEP对合成路线或来源进行修改时,对此类亚硝胺杂质出现的可能性进行系统性评估。EDQM也参与了OMCL工作活动,包括取样和检测的协调工作。欧洲药典中含四唑环的沙坦类API各论已根据这些物质中亚硝胺杂质出现的情况而进行了修订。

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.

正如EMA和EDQM官网最近宣布的,最近在含雷尼替丁药品中发现了亚硝胺杂质。因此,我们采取了措施搁置相关CEP,等待更多信息能够更好了解该亚硝胺杂质出现的根本原因。

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):

EMA和CMDh已在其网站上发布了文件(EMA/189634/2019 和 CMDh/404/2019)——“供上市许可持有人参考的亚硝胺信息”,要求上市许可持有人(MAH)遵循针对合成API所述的调查流程 (除四唑环沙坦类外)。 尽管EDQM预计该问题不会影响许多物质,但现在将审查范围扩大到所有已获CEP许可的化学合成生产的所有API。 因此,EDQM要求此类CEP的持有者遵循此处描述的流程(这与MAH的步骤方法类似):

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.

步骤1——风险评估:持有CEP的公司应使用 ICH Q9 指南中所列的质量风险管理原则,对其化学合成的API进行亚硝胺形成的风险评估。应采用 ICH M7 指南中所述的有关原料药毒性评估、控制策略和生产工艺变更原则。

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.).

CEP持有人应对物质进行优先级排序,以确定评估的顺序。 供上市许可持有人参考的亚硝胺信息的问答EMA/CHMP/428592/2019 Rev.1 和 CMDh/405/2019 Rev.1 中概述了可以考虑的因素,文件可在EMA和CMDh网站上找到,如果被确定为高度优先的物质,则应立即进行风险评估。风险评估不仅应处理生产工艺中的风险,而且还应处理生产工艺中使用的物料引入的风险(例如,原材料,试剂,溶剂-新鲜溶剂和回收溶剂等)。

The risk evaluation for all CEPs should be concluded at the latest by 26th March 2020.

所有CEP的风险评估最迟应在2020年3月26日之前得出结论。

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.

在没有发现任何风险的情况下,CEP持有人无需向EDQM确认步骤1已经完成。 但是,如果发现风险,则应立即通知EDQM,公司应进入步骤2,确认性检测,并向EDQM报告确认检测结果提供给EDQM的时间表。

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.

对CEP进行的风险评估的步骤一的结果应在任何情况下都传达给客户(即使未发现任何风险),以使MAH可以使用此信息来履行EMA/189634/2019 和 CMDh/404/2019文件供上市许可持有人参考的亚硝胺信息中所述的职责。

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.

步骤2——确认性检测:如果通过风险评估确定有存在亚硝胺的风险,则应根据从步骤1中进行的风险评估得出的优先顺序,使用经过适当验证的灵敏方法进行确认性检测。 高优先级应尽快进行检测。

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).

应该对所有被确定存在亚硝胺风险的API进行检测,并将结果提供给EDQM,并在必要时提供建议以采取后续行动(例如修订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.

如果检测确认亚硝胺杂质的存在,无论检测出的数量是多少,CEP持有人应立即通知EDQM,并提供结果。 在通知EDQM完成步骤3的计划和时间表之后,公司应进行步骤3。

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.

步骤3——修订CEP:如果检测到亚硝胺杂质,则CEP持有人应及时对其申请进行修订,以进行任何必要的变更,例如生产工艺的变更或质量标准的变更以及引入控制。

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.

要求对CEP申请的修订应最迟于2022年9月26日完成,如果有其他理由,则应在更早的时间结束。

CEP holders are reminded that it is their responsibility to complete the procedure described in this announcement for all their impacted CEPs.

提醒CEP持有人,有责任为所有受影响的CEP履行本公告中所述的程序。

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可能会在本审查的任何步骤与CEP持有人联系,以获取有关亚硝胺风险的信息,任何此类要求均应得到及时的全面答复。 如果获得有关CEP的API中亚硝胺杂质水平不可接受的信息,EDQM将对任何CEP采取行动(例如搁置)。

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.

EDQM提醒CEP持有人,他们应在所有情况下(对于步骤1至3,甚至对于未发现风险情况的步骤1)向客户提供与其对CEP进行的风险评估有关的适当信息,以使 MAH可以使用此信息及时履行其职责,如之前提到的EMA/189634/2019和CMDh/404/2019供上市许可持有人参考的亚硝胺信息中所述。

原文地址:https://www.edqm.eu/en/news/announcement-all-cep-holders-synthesised-apis-regarding-presence-nitrosamines

取自“https://login.shilinx.com/wiki/index.php?title=EDQM_%E5%8F%91%E7%BB%99%E4%B8%8E%E4%BA%9A%E7%A1%9D%E8%83%BA%E6%9C%89%E5%85%B3%E7%9A%84%E5%90%88%E6%88%90API%E7%9A%84CEP%E6%8C%81%E6%9C%89%E4%BA%BA%E7%9A%84%E9%80%9A%E7%9F%A5_20191029”
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