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.
After nitrosamine impurities were detected in valsartan batches at a Chinese API manufacturer in 2018, the EU Commission initiated a referral procedure under Article 31 of Directive 2001/83/EC on 5 July 2018. As part of this referral procedure, the Committee for Medicinal Products for Human Use (CHMP) was mandated to assess the impact of these impurities on the risk-benefit balance for medicinal products containing valsartan. Based on the CHMP's initial assessment report, the EMA published a request in early 2019 (updated in April 2019) for medicinal product manufacturers "Sartan medicines: companies to review manufacturing processes to avoid presence of nitrosamine impurities" to review their manufacturing processes for the presence of nitrosamine impurities.
In September 2019, the CHMP was mandated to conduct a procedure under Article 5(3) of Regulation 726/2004. The CHMP's subsequent 90-page assessment report entitled "Nitrosamine impurities in human medicinal products", published on 9 July 2020, contains comprehensive recommendations for medicinal products with chemically defined APIs and biological medicinal products.
Within the framework of a follow-up procedure, the EU Commission commissioned the CHMP to assess the extent to which the results of this Article 5(3) procedure affect the procedure under Article 31 of Directive 2001/83/EC for medicinal products containing sartans. As a result of this follow-up procedure, the "Assessment Report" was published at the end of February 2021. This final assessment report relates to the sartan preparations candesartan, irbesartan, losartan olmesartan and valsartan.
Recommendations from the assessment report for sartan preparations
Based on the first assessment report of the CHMP, the EU Commission published legally binding decisions on 2 April 2019 regarding the 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 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. For this review, the recommendations of the assessment report "Nitrosamine impurities in human medicinal products" shall be taken into account. Deadline for this risk assessment: 17 April 2021.
The manufacturing processes of the finished medicinal products shall be reviewed with regard to the risk of formation of nitrosamine impurities and, if necessary, modified in such a way that this risk is minimised as far as possible. For this review, the recommendations of the assessment report "Nitrosamine impurities in human medicinal products" shall be taken into account. Deadline for this risk assessment: 26 September 2022.
For all nitrosamine impurities, a control strategy shall be established for the APIs used in the manufacture of the finished medicinal products. The recommendations of the assessment report "Nitrosamine impurities in human medicinal products" shall be taken into account. 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).