In a final assessment report, the EMA has published important information for marketing authorisation holders of angiotensin II receptor antagonists (sartans) regarding nitrosamine contamination limits and deadlines for risk mitigation measures.
On 2 April 2019, the EU Commission published legally binding decisions regarding limits for the nitrosamines NDMA and NDEA in the active substances of the preparations candesartan, irbesartan, losartan, olmesartan and valsartan. The final assessment report for these preparations now recommends that these limits be applied to the finished medicinal products (instead of the APIs).
In detail, marketing authorisation holders should take the following into account:
- The manufacturing processes of the APIs and the manufacturing processes of the finished medicinal products must be reviewed with regard to the risk of nitrosamine impurities forming and, if necessary, modified in such a way that this risk is minimised as far as possible.
Deadline for this risk assessment: 17 April 2021 and 26 September 2022, respectively.
- For all nitrosamine impurities, a control strategy shall be established for the APIs used in the manufacture of the finished medicinal products.
Deadline for the establishment of a control strategy: 17 April 2021.
- For finished medicinal products, 96 ng/day for NDMA and 26.5 ng/day for NDEA shall be established. The respective specific limits shall be calculated as follows: nitrosamine daily limit divided by the maximum daily dose of the preparation concerned. These limits shall be included in the relevant finished product specification.
The inclusion of the limit values in the specification may only be withheld if it can be demonstrated that the nitrosamine content is permanently below 10% of the defined limit value and the root cause for the occurrence of the impurity is known and well understood.
For reduced testing (skip testing), the nitrosamine content must be permanently below 30% of the defined limit value.
Where several different nitrosamine species are present, the cumulative risk posed by the nitrosamines in a person taking the medicinal product for life should be below 1 in 100,000 for the risk of cancer. Deadline for establishing these requirements: 30 June 2021.
These limits, which now apply to finished medicinal products, are based on the calculation models and specifications of the ICH guideline M7(R1).