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

Abstract

Recent observations of N-nitrosamine presence in nonsartan medicinal products have led to product recalls and regulatory requests for marketing authorization holders to assess their portfolios for chemically synthesized active pharmaceutical ingredients (APIs), associated drug products (DPs) and packaging for the potential presence of N-nitrosamines. As part of the overall risk assessment for nitrosamine formation, the identification of nitrosating agents potentially present during API or DP manufacture is required. Process water is ubiquitous to manufacturing, and consequently the accurate determination of nitrite content in process water will support an understanding of the potential for nitrosamine formation from nitrite in process water for a given API or DP manufacturing process. Herein, we report the development of two ultrasensitive ion chromatography analytical methods for the quantification of the amount of nitrite in purified and potable water, respectively. Various samples, including a range of water types and geographical locations, have been tested using these methods. Water samples from various sources from multiple manufacturing sites were successfully analyzed with the aid of these methods. 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 pKa 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 (pKa 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. For drug products, the use of WFI generated by distillation poses no nitrosamine risk formation due to the low levels of nitrite. Likewise, purified water used in wet granulation drug product processes is a vanishingly small risk for nitrosamine formation. It is also an insignificant risk for nitrosamine formation in drug product formulation.