Nitrosamine impurities in Sartan medicines

N-Nitrosamines in Sartans

To ensure the absence of N-Nitrosamine Impurities is Sartan API’s and Final Products, we use suitable analytical equipment in accordance with EDQM and FDA methodology. The QACS Laboratory quality assurance approach is based on experienced scientific personnel and state of the art analytical equipment.

How N-Nitrosamines came to be present

N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA), both classified as probable human carcinogens, were not identified as impurities of Sartan APIs up until June 2018 and therefore they were not tested for.
This problem arose from a change in the manufacturing process that goes back prior to 2012 but was not flagged as problematic until 2018. Recently, spotlight has been shined on the manufacturing process suggesting that the higher yielding sodium azide/ zinc chloride route in Dimethyl formamide and the necessary quenching by sodium nitrite and its conversion to nitrous acid in the presence of secondary amines will yield N-Nitrosamines.
Since testing begun the majority of Sartan medicines were either found not to contain N-nitrosamine impurities or were present at very low levels. A transition period has now been set in place where companies that manufacture sartan medicines should review their manufacturing process according to strict EMA’s temporary limits, after said period companies will have to demonstrate the absence, in quantifiable levels of these impurities.

Limits

While working towards the goal of non-quantifiable N-nitrosamine impurities, interim limits for NDMA and NDEA have been set in place according to the maximum daily intake of the specific sartan in question.
Products that contain either impurity above the limits or both impurities at any level will not be allowed in the European Union. To assist companies during and after the 2-year transition period QACS laboratory has invested heavily in state-of-the-art equipment to allow the detection of said impurities down to the LOD that will be enforced after the transition period (0.03ppm).

What we test for

Following EDQM and FDA methodologies we offer testing for NDMA and NDEA impurities in Sartan raw materials and final products as outlined hereby:
• UHPLC-APCI-MS/MS analysis according to EDQM suggested CVUA Karlsruhe method
• GC-MS (Headspace) analysis based on EDQM suggested PALG method/FDA method.
• Method Validation can be performed for final products.

QACS continues to follow the investigation set out by the EMA into N-nitrosamines and will incorporate into its methodology, at the time of implementation of new guidelines, the identification and quantification of N-nitrosoethylisopropylamine (EIPNA), N-nitrosodiisopropylamine (DIPNA) and N-nitroso-N-methylamino butyric acid (NMBA).

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