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

Abstract

The potential for N -nitrosamine impurities in pharmaceutical products presents a challenge for the quality management of medicinal products. N -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 In the past 2 years, a number of drug products containing certain active pharmaceutical ingredients have been withdrawn or recalled from the market due to the presence of carcinogenic low-molecular-weight N , N -dialkylnitrosamine impurities. Regulatory authorities have issued guidance to market authorization holders to review all commercial drug substances/products for the potential risk of N -nitrosamine impurities, and in cases where a significant risk of N -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 N -nitrosamine impurity. A significant proportion of N -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 N -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 N -nitrosamines relevant to each of the 13 structural groups and group AIs were derived conservatively based on the most potent N -nitrosamine within each group. The 13 structural group AIs were used as the basis for assigning AIs to each of the structurally related complex N -nitrosamine impurities. The AIs of several N -nitrosamine groups were found to be considerably higher than those for the simple N , N -dialkylnitrosamines, which translates to commensurately higher analytical method detection limits.

Predicting DNA-Reactivity of N-Nitrosamines: A Quantum Chemical Approach

“…In the case of cyclic aliphatic rings, intramolecular ring closure is possible via reaction with the terminal aldehyde group (Figure 4). 19,27 Both acyclic and cyclic carbocations are known to be DNA-reactive species. 27 (DE) One potential pathway is direct DNA alkylation where the aliphatic and aromatic diazonium cations mostly react via S N 2/S N Ar mechanism with DNA, which includes N 2 elimination, because their corresponding carbenium ions are usually instable.…”

“…This trend corresponds to the SAR analysis of ring systems based on TD 50 values. 18,19 Within the calculated activation energies, there is no unique trend visible. The values are similar to values obtained for aliphatic compounds.…”

“…Special Mechanistic Aspects of Cyclic Molecules. As shown in Figure 4, cyclic aliphatic molecules keep the aldehyde group during the metabolic activation, which could lead to an intramolecular ring closing (step DR) after the nitrogen elimination step D. 19,27 The Gibbs free energy of step DR is shown in Figure 8.…”

“…Furthermore, Dobo et al categorized unique/complex impurities that were identified as potential low-level impurities into 13 groups with common structural features. 19 Their carcinogenicity data was reviewed for structurally related NAs relevant to each of the 13 structural groups, and acceptable intakes were individually derived on the basis of the most potent NA within each group using a conservative approach. The acceptable intake limits of each group were applied to readacross approaches as previously done for individual, structurally related complex NA impurities.…”

Determination of Genotoxic Impurity N-Nitroso-N-methyl-4-aminobutyric Acid in Four Sartan Substances through Using Liquid Chromatography–Tandem Mass Spectrometry

“…N-nitrosamine impurities are considered as a kind of potential human carcinogens [ 1 , 2 ]. Carcinogenicity experiments of 4-methylnitroamino-1, 3-pydinyl butanone and N-nitroso nornicotine in animals revealed that it could induce the tumors of lung, nasal cavity and liver in F344 rats, as well as the tumors of lung, trachea and nasal cavity in Syrian gold hamsters [ 3 ].…”