N-Nitrosamine contamination of drug products: regulatory challenges in a constantly evolving scenario

Davide Tartaglione, Senior PharmaConsultant, Eurofins BioPharma Product Testing, Italy, DavideTartaglione@eurofins.com

Two years have passed since N-nitrosodimethylamine (NDMA) contamination was first discovered in a batch of Valsartan. The carcinogenic risk associated with compounds of the N-nitroso family and the great media coverage led to one of the widest mobilisations of scientists and regulatory experts. After similar contamination was identified in different drugs such as ranitidine, nizatidine, and metformin, it became clear that the issue was not limited to a short list of manufacturers. FDA, EMA, and other international agencies started an intense collaboration to share experience, data, and knowledge.

At first, regulators had to carefully balance possible drug shortages with the need to ensure patients health; marketing of contaminated drugs with a valid clinical alternative, such as ranitidine, was suspended in the US and Europe as a precaution, although the decision does not yet seem definitive. Where this approach was not feasible (i.e. for Sartans), strict temporary limits on levels of these impurities were introduced in the Test section of the related Ph. Eur. Monographs as well as a general chapter (2.4.36) for all active substances. Regulatory decisions were based upon the necessity of increasingly sensitive and specific testing methods (such as Hi-Res techniques), and the common opinion that an in-depth review of the manufacturing processes would be needed to mitigate the risk of contamination.

As a result, a risk based evaluation for all drugs is required by EMA. The extended deadline for this step is now March 2021. In a recent guidance for industry issued by FDA at the beginning of September, the US agency fully aligned with Europe. Notably, biological products are now included, even though they were not initially considered due to very low risk of contamination. This change in approach aligns with the agency’s expectations to cover all marketed and newly submitted drugs.

EMA is also running a lessons-learned exercise. As a result, the international guidelines that are now effective for controlling mutagenic impurities, such as ICH M7, will most likely undergo a long and complex revision cycle to avoid the repetition of similar situations in the future.

Eurofins BioPharma Product Testing network of GMP labs has the capability and capacity to assist clients through all the steps of the investigation process - from initial risk assessment to analytical methods validation and from screening and confirmatory testing to routine quality control in order to confirm nitrosamine levels in drug substances and drug products.

For more information, visit: www.eurofins.com/bpt