Formation of N-Nitrosamine Drug Substance Related Impurities in Medicines: A Regulatory Perspective on Risk Factors and Mitigation Strategies

An excellent paper posted to OPRD by Răzvan C. Cioc et al. from EMA is now published. This paper is a review article on NDSRIs and explores the current technical knowledge surrounding the formation of NDSRIs, including the risk factors, reaction conditions, and potential mitigation strategies. And it highlights both the scientific progress made and discusses the significant gaps in mechanistic knowledge still remaining. Comprehensive issues related to NDSRI can be reviewed through it.


@Yosukemino, great article!

The theme I’d like to discuss is “Nitrite Scavengers.”

As pointed out by @MarkS (Processes 2022, 10(11), 2428) the nitrite scavenging activity does not directly translate
into N-nitrosation inhibitory effectiveness, indicating other reaction pathways may take place (any insights or suggestions?)

Furthermore, it is of utmost importance to recognize that not every suggested scavenger exhibits “flawless” reactivity. For instance, the interaction between nitrite and histidine results in diverse products, with experimental evidence revealing the major product to be mutagenic (

Has anyone encountered such challenges, or would like to add comments on this subject?


This whole article is as if someone has looked inside my head, pulled together all of the threads that are in there, put them into a sensible order and then expanded on them (slightly in some areas and greatly in others).

There has been much focus on the nitrites (rightly so), but do we need to broaden our thinking in regard to aldehydes (specifically formaldehyde) and peroxides? What is the reaction kinetics for these routes versus nitrites?

There are so many factors at play for any particular API and formulation that the answer may/will be different for every product, and may require the use of multiple scavengers/antioxidants to cover all of the potential formation routes - especially from products that could contain multiple potential nitrosamines formed from different routes. It may be a balancing act between the reduction of the formation of one NDSRI and the acceleration of the formation of a different NDSRI within one product.


This is an interesting read to accompany it.

(PDF) Reactive Impurities in Excipients: Profiling, Identification and Mitigation of Drug–Excipient Incompatibility (