Nitrosamine Impurities in pharmaceutical products - a “burning” topic for the industry

Davide Tartaglione, Senior Regulatory Affairs Consultant, BioPharma Product Testing Italy, DavideTartaglione@eurofins.com

N-nitrosamines are a family of well-known impurities and are included in the “cohort of concerns” list in the ICH-M7 guideline, as their intake can be associated with significant carcinogenic risk.

In 2018, traces of N-nitrosodimethylamine (NDMA) and N-Nitrosodiethylamine (NDEA) found in some sartans active pharmaceutical ingredients (APIs) caused several market recalls. In a later phase, detection of these impurities in other classes of medicine, such as ranitidine and metformin, raised additional concerns about patient safety.
The FDA and the EMA are driving the regulatory review and defining new requirements: temporary limits for most common nitrosamines are currently being set based upon the Maximum Daily Intake; European Pharmacopoeia monographs are also being updated to include new mandatory tests for five sartans. The general expectation is that limits will be further lowered in the future in a move towards an ideal absence of these compounds.

Investigations reveal that, in addition to the use of nitrosating agents, secondary amines and contaminated materials, impurities could also be associated with the use of recovered solvents and cross-contamination when different processes run on the same line. The EMA committee does not exclude that additional sources could be identified in the future.

In this context, the EMA and other regulatory authorities asked all Marketing Authorisation Holders to review all products containing chemical-synthetised APIs: in case the initial risk-assessment of the manufacturing processes cannot exclude potential contamination, this has to be followed by confirmatory analysis of the product. Testing can be challenging due to low limits and complex matrices. Positive results must be immediately communicated to
competent authorities in order to agree on contamination control strategies. Manufacturing Authorisation Holders (MAHs) can also benefit from a transition period of up to two years to apply for variations in processes, specifications, and finally ensure complete risk mitigation. 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  itrosamine levels in drug substances and drug products.

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