The Role of Excipients In Determining N-Nitrosamine Risks for Drug Products

See the nice infographic prepared by IPEC Federation on the hot topic of Nitrosamine Risk Determination:

THE BACKGROUND

N-nitrosamines are a class of organic compounds, some of which are associated with a potential for a significant carcinogenic risk.

In July 2018, the European Medicines Agency reported the recall of several products containing Valsartan due to NDMA (N-Nitrosodimethylamine) contamination.

Regulatory agencies have requested drug manufacturers to assess the risk of N-nitrosamines’ presence or formation in marketed drug products.

The most substantial risk for the presence or formation of N-nitrosamines in drug products comes from the convergence of three factors.

IPEC FEDERATION POSITION

Nitrosamines in Excipients

The risk is very low. One excipient has been known
to potentially contain a nitrosamine: triethanolamine
(Trolamine Ph. Eur.). The corresponding nitrosamine
impurity is N-nitrosodiethalonamine.

Vulnerable Amine Compounds in Excipients

The potential risk coming from a vulnerable
amine present in an excipient will depend on
the formulation composition.

NITROSATING COMPOUNDS IN EXCIPIENTS

Concerns about nitrosating compounds in excipients have highlighted nitrites and nitrates, which can potentially react with other substances in drug formulations to form nitrosamines under certain conditions.

Nitrate is not seen as a significant contributor to nitrosamine formation in drug products, since the reduction of nitrate to form a nitrosating agent like nitrite is very unlikely during excipient and drug product manufacturing.

NITRITES IN EXCIPIENTS

The concentration of nitrites may differ by excipient chemistry, manufacturer and batch.

Process water, raw materials, and excipient processing conditions could be sources of nitrites. However, process water is typically of low concern: recent research performed globally has shown nitrite levels in drinking water are typically well below the WHO limit and sub-ppb in purified water.

Nitrites are found in commonly used excipients, but reducing their level is not easy. It is not practical to eliminate them, and other factors and options need to be considered. e.g. scavengers.

The impact of nitrites in a given excipient should be evaluated for each drug product for any potential risk.

IPEC Federation asbl
The Federation of the International Pharmaceutical Excipients Council
Rue Marie de Bourgogne 52 – 1000 Brussels

Source: www.ipec-federation.org