N-nitrosamines impurity testing

Nitrosamine compounds are potent genotoxic carcinogens in several non-human species and are classified as probable human carcinogens by the International Agency for Research on Cancer (IARC).

Since June 2018, several N-nitrosamines have been detected in several batches of drug substances, initially from Sartans, but now the concern of the heath agencies has been extended to all drug substances and also to drug products. 

Although initially were detected N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA) also by the time other N-nitrosamines were added to these two.

Heath agencies required to the pharmaceutical companies to do a risk assessment about the possible presence of such N-nitrosamines in their products and experimentally demonstrate that are not present in the case of the risk assessment anticipate their possible presence. The list of the N-nitrosamines that must be tested should be obtained from the risk assessment.

We offer our experience in testing N-nitrosamines impurities. We have available general methods by HS-GC-MS and LC-MS/MS for the N-nitrosamine analysis in API and drug products. These methods can be adapted with minor modifications to the client API or drug product.

The N-nitrosamines available are described in the list below. New nitrosamines will be added in the future and under request of the clients.

  • NDMA: N-Nitrosodimethylamine
  • NDEA: N-Nitrosodiethylamine
  • NDIPA: N-Nitrosodiisopropylamine
  • NEIPA: N-Nitrosoethylisopropylamine
  • NDBA: N-Nitroso-di-n-butylamine
  • NMEA: N-nitrosomethylethylamine
  • NDPA: N-nitroso-di-n-propylamine
  • NMBA: N-Nitroso-N-methyl-4-aminobutyric acid
  • NPYR: N-Nitrosopyrrolidine
  • NPIP: N-Nitrosopyperidine
  • NMOR: N-Nitrosomorpholine
  • NDELA: N-Nitrosodiethanolamine
  • MNPZ: mono-N-Nitrosopiperazine 
  • DNPZ: di-N-Nitrosopiperazine
  • NDPhA: N-nitroso-di-phenylamine

Kymos proposes an approach to comply with the request of the Regulatory Agencies, optimizing costs and time. This proposal consists in two steps:

a.    Screening of the target nitrosamines requested by the client from the list of above. A default limit established for this screening is 0.03 ppm for all N-nitrosamines listed, which is the future limit established by the health agencies.  Higher limits can be established depending on the product or client’s request. 
b.    In the case that one or more nitrosamines are at or above the established limits, a development and validation of a quantitative method will be required and agreed with the client. 

sartans.png

Contact form

Files must be less than 2 MB.
Allowed file types: pdf doc docx odt.