N-nitrosamines are a class of organic compounds that include examples that are associated with a potential for a significant carcinogenic risk (part of the “cohort of concern” in ICH M7).

Beginning in July 2018, the European Medicines Agency (EMA) reported the recall of several products containing Valsartan due to N-nitrosodimethylamine (NDMA) contamination.

This initiated investigations by several regulatory agencies resulting in the discovery of N-nitrosamine impurities in sartans and other unrelated compounds. Because the presence of N-nitrosamines in final drug products is a global issue, there have been requests from multiple regulatory agencies for drug product manufacturers to complete risk assessments for the presence or formation of N-nitrosamines in marketed drug products containing chemically-synthesized APIs.

The International Pharmaceutical Excipients Council Federation, (IPEC Federation) recently announces the availability of a new position paper, “The Role of Excipients in Determining N-Nitrosamine Risks for Drug Products”.

This paper describes IPEC Federation’s position on the role of excipients when conducting N-nitrosamine (nitrosamine) risk assessments for drug products.
The presence of N-nitrosamines in drug products continues to be a global concern. Excipients are considered as a potential risk factor during the drug product risk assessment.

The focus of this position paper is to expand on the potential contribution excipients may or may not have on the formation of nitrosamines in final drug products. The presence of nitrites and vulnerable amines in excipients are also considered.

The most substantial risk for the presence or formation of N-nitrosamines in medicinal products comes from the confluence of three factors: a nitrosating agent, a secondary or tertiary amine, and appropriate conditions (for example elevated temperatures, acidic conditions, liquid phase) for the aforementioned to react.

Nitrosating Compounds in Excipients

Concern for nitrosating compounds in excipients has focused attention on nitrites and nitrates, neither of which are powerful nitrosating compounds on their own, but, under certain conditions, can potentially react with other materials to form nitrosamines. Nitrite can form the reactive species nitrous anhydride (N2O3) under mildly acidic conditions.
Nitrates can react to form nitrite through enzymatic reduction, which then can form the reactive nitrous anhydride under acidic conditions.
The report by Wu et al. measured nitrates and nitrites in samples of microcrystalline cellulose (MCC), lactose, pre-gelatinised starch, povidone, crospovidone, sodium starch glycolate (SSG), sodium croscarmellose, stearic acid, hydroxypropyl cellulose (HPC) and silicon dioxide.

Reported levels of nitrites in the excipients ranged from 0.9 ppm (in a sample of HPC) up to 285.6 ppm (in a sample of SSG). Nitrate levels ranged from 3.5 ppm (HPC) to 183.1 ppm (SSG).

So, is it necessary to introduce limits for nitrites in excipients? In general, no, for the following reasons:
  • Implementingformation.limits for nitrites will not alleviate the risk of nitrosamine formation
  • The amount of nitrite present in a drugproduct as a result of an excipient is dependent upon the amount of excipient used in the formulation.
However, a thorough risk assessment on the drug product by the MAH or drug product manufacturer may conclude that the presence of nitrites in an excipient (at any level) is a risk for nitrosamine formation. In such cases, the MAH or drug product manufacturer should mitigate any risk in cooperation with the excipient supplier(s). Here, a limit for nitrites may be appropriate.