Nitrosamines

N-Nitrosamines in Sartans

We use suitable analytical equipment to ensure the absence of N-Nitrosamine Impurities in Sartan API’s, Final Products and Waters. QACS quality approach is in accordance with EDQM and FDA methodology.

N-Nitrosamine in other Medicines

Other medicines, such as pioglitazone and ranitidine HCI, have had Nitrosamines impurities. As result more medicines have been placed under scrutiny by EMA and FDA. On the forefront of such testing, QACS ensures safety and quality by implementing methodologies to test for the absence or presence of such impurities in:

  • SARTANS
  • PIOGLITAZONE
  • RANITIDINE
  • ESOMEPRAZOLE
  • CEFAZOLIN
  • OTHERS

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 QACS provides NDMA, NDEA, NMBA, EIPNA, DIPNA, DIPEA impurities testing 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 for final products

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.

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