Practical and Science-Based Strategy for Establishing Acceptable Intakes for Drug Product -Nitrosamine Impurities

The potential for -nitrosamine impurities in pharmaceutical products presents a challenge for the quality management of medicinal products. -Nitrosamines are considered cohort-of-concern compounds due to the potent carcinogenicity of many of the structurally simple chemicals within this structural class. In the past 2 years, a number of drug products containing certain active pharmaceutical ingredients have been withdrawn or recalled from the market due to the presence of carcinogenic low-molecular-weight ,-dialkylnitrosamine impurities. Regulatory authorities have issued guidance to market authorization holders to review all commercial drug substances/products for the potential risk of -nitrosamine impurities, and in cases where a significant risk of -nitrosamine impurity is identified, analytical confirmatory testing is required. A key factor to consider prior to analytical testing is the estimation of the daily acceptable intake (AI) of the -nitrosamine impurity. A significant proportion of -nitrosamine drug product impurities are unique/complex structures for which the development of low-level analytical methods is challenging. Moreover, these unique/complex impurities may be less potent carcinogens compared to simple nitrosamines. In the present work, our objective was to derive AIs for a large number of complex -nitrosamines without carcinogenicity data that were identified as potential low-level impurities. The impurities were first cataloged and grouped according to common structural features, with a total of 13 groups defined with distinct structural features. Subsequently, carcinogenicity data were reviewed for structurally related -nitrosamines relevant to each of the 13 structural groups and group AIs were derived conservatively based on the most potent -nitrosamine within each group. The 13 structural group AIs were used as the basis for assigning AIs to each of the structurally related complex -nitrosamine impurities. The AIs of several -nitrosamine groups were found to be considerably higher than those for the simple ,-dialkylnitrosamines, which translates to commensurately higher analytical method detection limits.