Risk Assessment and Quality Control of Trace Mutagenic Impurities Triggered by the Nitrosamine Contamination Issue

<p>Contamination of valsartan drug substance with N-nitrosodimethylamine (NDMA), a well-known strong genotoxic carcinogen, was reported in 2018. Since then, regulatory authorities have issued notification to perform a risk assessment of contamination of nitrosamines as impurities in drug substance synthesis and drug product manufacturing processes for all marketed drugs. In Japan, a notification for risk assessment of nitrosamine impurity contamination was issued on October 8, 2021.</p><p>Once a risk of contamination is identified, an appropriate control strategy is required to reduce the amount of nitrosamines to a level at which there is negligible carcinogenic concern or to zero. To reduce the contamination level, the M7 concept requires control to less than or equal to 1 in 105 carcinogenic risk and the EMA has provided a default value of less than or equal to 18 ng/day for compounds without robust carcinogenicity data. This default value is set on the basis of carcinogenicity data such as NDEA, which is the most potent carcinogenic among all nitrosamines. However, there is a report suggesting that not all nitrosamines are strongly carcinogenic. While the ICHM7 Guideline provides an assessment of mutagenicity using QSAR, nitroso compounds have been handled as "impurities that should not be contaminated" in the Cohort of Concern. Therefore, they are a class of compounds for which QSAR has not been optimized and carcinogenic risk cannot be estimated appropriately. Therefore, the Agency and industry are discussing what information is needed and how to proceed with the evaluation of mutagenicity and carcinogenicity risks of this compound class.</p><p>In this presentation, the presenter introduces the background and the risk assessment method of nitrosamine impurities and the discussion points between the regulatory authorities and the industry.</p>