Nitrite in Pharmaceutical Manufacturing Water: Development of an Ultra-Sensitive Analytical Method, Typical Data, and Discussion of Potential Nitrosamine Formation in Drug Substance and Drug Product from Water

Dr. Kumar et al. published a paper on nitrite in a variety of different types of water.

https://pubs.acs.org/doi/10.1021/acs.oprd.4c00037

Twenty-one out of twenty-two purified water samples analyzed had nitrite levels that were below the quantitation limit of the method, i.e. <0.1 ppb. All potable water samples analyzed had nitrite levels that were <3.5 ppb. The results are contextualized to illustrate the amounts of nitrosamine that could be formed from process water during API and DP manufacture. For API manufacturing, the use of purified water, even under acidic conditions and in the presence of vulnerable amines, will not lead to significant nitrosamine formation in the product because there is so little nitrite present. For potable water, in most cases, only operations performed under acidic conditions (pH less than 7) may lead to significant conversion of nitrite. Basic amines, typically dialkyl amines, with a pK a of 10 and more, will have negligible formation of their corresponding nitrosamines over a 24 h time period, even at the worst case pH of 3.15. Less basic amines (pK a of less than 10) under acidic conditions (pH less than 7) may lead to significant conversions within 24 h, and for these cases the overall nitrosamine formation risk will depend on the water type, the amount of water used, and the downstream purge opportunities in the manufacturing process.

7 Likes

Glad to see there is finally an article on this topic. We need to forward it to every excipient manufacturer.

2 Likes

Thank you! This is something I had been looking for. I am actually a bit surprised by the generally low level of risk.

2 Likes