New European Rules to Eliminate Carcinogens in Sartans

Disclosures

February 05, 2019

The European Committee for Medicinal Products for Human Use (CHMP) has recommended new requirements for manufacturing processes for angiotensin II antagonists (sartans) to eliminate the production of nitrosamine impurities.

Companies will have a two-year transition period to make any necessary changes, during which temporary limits on levels of these impurities will apply, the committee recommended at its meeting last week.

After this period, companies will have to demonstrate that their "sartan" products have no quantifiable levels of these impurities before they can be used in the EU.

These recommendations follow the detection in some sartan medications of N-nitrosodimethylamine (NDMA) and N‑nitrosodiethylamine (NDEA), which are classified as probable human carcinogens, leading to several withdrawals of affected drug lots.

The CHMP notes that in its review of this issue, for the vast majority of sartan medicines, these impurities were either not found or were present at very low levels.

Estimate of Highest Cancer Risk

CHMP notes that the highest levels of these impurities were found in lots of valsartan from the Chinese manufacturer Zhejiang Huahai, and it gives an estimate of the highest possible cancer risk with these products. It concluded that if 100,000 patients took valsartan from Zhejiang Huahai every day for 6 years at the highest dose, there could be 22 extra cases of cancer due to NDMA over the lifetimes of those 100,000 patients.

NDEA in these medicines could lead to eight extra cases in 100,000 patients taking the medicine at the highest dose every day for 4 years, the review estimates. The 6- and 4-year periods mirror the duration of time NDMA and NDEA are believed to have been present in valsartan from Zhejiang Huahai.

These estimates have been extrapolated from animal studies and are very low compared with the lifetime risk of cancer in the EU (1 in 2), the CHMP report says.

Companies must now take measures to avoid the presence of these impurities and carry out rigorous testing of their products.

Testing During and After Transition

"While the goal is to have no quantifiable nitrosamine impurities in sartans, interim limits have been set for NDMA and NDEA in line with current international guidelines," according to a European Medicines Agency press release.

"Products containing either impurity above these limits or products containing both nitrosamines at whatever level will not be allowed in the EU."

The limits are based on the maximum daily intake for each impurity derived from animal studies: 96.0 nanograms for NDMA and 26.5 nanograms for NDEA. Dividing these by the maximum daily dose for each active substance gives the limit in parts per million.

The transition period will allow companies to make the necessary changes to their manufacturing processes and to put in place testing regimes able to detect the smallest amounts of these impurities, the CHMP notes.

After the transition period ends, manufacturers must exclude the presence of even lower levels of NDEA or NDMA in their products (< 0.03 parts per million).

These recommendations for NDMA and NDEA will now be sent to the European Commission for a legally binding decision.

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