Angiotensin-II-receptor antagonists (sartans) containing a tetrazole group (updated March 2021)
Communication after the review of Art 31 referral on angiotensin-II-receptor antagonists (sartans) containing a tetrazole group
In October 2020 the CHMP concluded that the outcome of the Article 31 referral on angiotensin-II-receptor antagonists (sartans) containing a tetrazole group (EMEA/H/A-31/1471) should be aligned with the outcome of the Article 5(3) assessment on nitrosamines (EMEA/H/A-5(3)/1490). The main change concerns the limits for N-nitrosamines, which previously applied to the active ingredients but will now apply instead to the finished products. In line with previous recommendations, companies should have appropriate control strategies to prevent or limit the presence of nitrosamine impurities as much as possible and, where necessary, improve their manufacturing processes. Companies should also evaluate the risk of N-nitrosamines being present in their medicines and carry out appropriate tests.
This leads to the following revised conditions to the MA of tetrazole sartans:
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Conditions to the MA of tetrazole sartans |
Due date |
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A |
The MAH must ensure that the manufacturing processes of the active substances used for their finished products are reviewed for the potential risk of formation of N-nitrosamines and changed as necessary to minimise nitrosamine contamination as much as possible in line with the recommendations adopted by the Committee for Medicinal Products for Human Use on 25 June 2020 in the procedure under Article 5(3) of Regulation (EC) No 726/2004 on Nitrosamines impurities in human medicinal products (Article 5(3) procedure). |
17 April 2021 |
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B |
The MAH must ensure that the manufacturing processes of the finished product is reviewed for the potential risk of formation of N-nitrosamines and changed as necessary to minimise nitrosamine contamination as much as possible in line with the recommendations adopted by the Committee for Medicinal Products for Human Use on 25 June 2020 in the procedure under Article 5(3) of Regulation (EC) No 726/2004 on Nitrosamines impurities in human medicinal products. |
26 September 2022 |
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C |
For all N-nitrosamines, the MAH must ensure a control strategy is in place for active substance batches used for their finished products. |
17 April 2019 (last date of the Commission decisions related to the Article 31 referral adopted in 2019) |
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D |
For N-nitrosodimethylamine (NDMA) and N nitrosodiethylamine (NDEA) the MAH must introduce the following specifications: Limits for NDMA (96 ng/day) and NDEA (26.5 ng/day) should be implemented for the finished product. The limit should be calculated by dividing the respective limit (ng) by the maximum daily dose (mg) of a given product as reflected in the SmPC. The limit will usually need to be included in the finished product specification. Omission from the specification is only justified if it can be shown that the levels of the respective N-nitrosamines are consistently ≤ 10% of the limit defined above and the root cause is identified and well-understood. Skip testing is only justified if it can be shown that the levels of the respective N-nitrosamines are consistently ≤ 30% of the limits defined above and the root cause is identified and well-understood. In accordance with the recommendations adopted on N-nitrosamines impurities in human medicinal products (Article 5(3) procedure), where the co-presence of the above N-nitrosamines has been identified in the same finished product, it must be ensured that the cumulative risk of these N-nitrosamines does not exceed a lifetime cancer risk (lifelong exposure) of 1:100,000. An alternative approach where the sum of these two N-nitrosamines does not exceed the limit of the most potent N-nitrosamine identified (NDEA) may also be used. The approach chosen for a particular case needs to be duly justified by the MAH. The MAH shall ensure that the control strategy for all N-nitrosamines is updated accordingly. |
30 June 2021 |
MAHs have to submit a type IAIN C.I.11.a variation to include the new conditions in the marketing authorisations within 10 days after publication of the Commission Decision.
The MAH should review the new conditions against any variation previously submitted in fulfilment of the previous conditions and submit further variations as necessary, or confirm fulfilment of the new conditions.
For further information please check CMDh Questions & Answers on implementation of outcome of Art. 31 referral on angiotensin-II-receptor antagonists (sartans) containing a tetrazole group.
