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

• DOI: 10.1021/acs.chemrestox.1c00369
• Publication Date: 2022-02-25T14:43:51Z
• Authors: Krista L. Dobo; Michelle O. Kenyon; Olivier Dirat; Maria Engel; Andrew Fleetwood; Matthew Martin; Susan Mattano; Alyssa Musso; James Christopher...; Alexandros Papani...; Patricia Parris; Jessica Whritenour; Shu Yu; Amit S. Kalgutkar
• Keywords: Nitrosamine

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 In past 2 years, number drug containing certain active ingredients have been withdrawn or recalled from market presence carcinogenic low-molecular-weight N,N-dialkylnitrosamine impurities.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