Risk Assessments Now Needed for Nitrosamines in APIs and Drug Products

January 14, 2020

In 2018, nitrosamine impurities, including N-nitrosodimethylamine (NDMA), were found in a number of angiontensin II receptor blockers, which are blood pressure medicines known as "sartans". Nitrosamines are chemical compounds classified as probable human carcinogens on the basis of animal studies. The US FDA established 96 ng is an acceptable daily intake for the general population.

This finding led to product recalls and strict new manufacturing requirements for this class of medicines. Subsequently, a nitrosamine impurity has been detected in batches of ranitidine, an over-counter (OTC) medicine used to treat heartburn and stomach ulcers. 

In Europe, to address the concern of low-level nitrosamines in medical products, the European Medicines Agency (EMA) Committee for Medical Products for Human Use (CHMP) is now requiring a robust evaluation of the risk of nitrosamines being present in approved products containing chemically synthesized APIs, including generics and OTC products for existing/marketed drugs and new authorization applications. The risk assessment should be conducted following the approach outlined in the ICH M7 guidelines, documented using prescribed templates, and if the risk is identified, the appropriate risk-mitigating measures, including analytical verification of the absence of nitrosamines may be needed. If nitrosamines are detected, this must be communicated to the EMA. The deadline for the evaluation is 26 March 2020. They have stated that a risk-based approach can be utilized to prioritize the evaluations and confirmatory testing. Additionally, risk evaluation is now required in new authorization applications.

Risk evaluation documents for existing products do not need to be submitted to EMA but should be made available upon request. Companies should inform competent authorities if a nitrosamine is present in a product, irrespective of the amount detected. This may require manufacturing process changes and it is suggested that companies liaise with competent authorities in these situations.

The EMA Q&S document provides a list of currently identified root causes for the presence of nitrosamines.
The US FDA has also voiced concern about the presence of nitrosamines in drug products. To date, statements are limited recalls on the angiontenson II receptor blocker “sartan” class of medicines, ranitidine/nizatidine, and investigations regarding the identification of nitrosamines in some batches of metformin.

SafeBridge Consultants are a team of Board Certified or equivalent toxicologists with significant experience in hazard assessments, including ICH M7 evaluations. Together with Ph.D. chemists available to evaluate drug synthesis pathways to predict potential nitrosamine formation under various potential processing conditions, we can provide necessary expert technical advice to meet this regulatory need. Please contact Allan Ader, Ph.D., DABT, Managing Director via email for further information and assistance with nitrosamine risk assessments. 


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