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.
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):
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.).
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.
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.
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.
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.
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 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.
