Evaluation of toxicological profile of omeprazole degradation impurities in an intravenous drug product: omeprazole-sulfone and omeprazole-N-oxide

Omeprazole (OMZ) is a widely used Proton Pump Inhibitor for the treatment of acid-related gastrointestinal disorders. Degradation during the manufacture and storage of the drug substance or drug product may lead to the formation of impurities. When these impurities exceed the qualification threshold defined by ICH Q3B(R2), toxicological evaluation becomes essential. This study aimed to assess the genotoxic and systemic toxicity potential of OMZ-sulfone (impurity D) and OMZ-N-oxide (impurity E), which are OMZ degradation impurities and are formed during the manufacturing and storage of the drug product using an integrated in silico, in vitro, and in vivo approach. Alternative qualification strategies, such as the use of metabolism data and compendial limits, were considered but found insufficient to confirm the safety of the impurities. In silico predictions using multiple QSAR platforms classified OMZ-sulfone as non-mutagenic (class 4 impurity), while OMZ-N-oxide exhibited structural alerts not found in the parent compound, necessitating further testing as a class 3 impurity. Ames test results confirmed that OMZ-N-oxide was non-mutagenic in five S. typhimurium strains up to 1000 µg/plate. A 14-day repeated-dose toxicity study in rats receiving an OMZ product containing both impurities showed no mortality, clinical signs, or adverse effects on hematological, biochemical, or histopathological parameters. These findings indicate that OMZ-N-oxide does not pose a genotoxic or systemic toxicity risk under the tested conditions. OMZ-sulfone was also predicted to be non-mutagenic. Overall, both impurities may be considered safe when present above the qualification threshold, supporting their continued monitoring and control in OMZ-containing pharmaceutical products.

14-day toxicity study; Ames test; Bacterial reverse mutation assay; ICH M7 (R1) guideline; Sprague–Dawley rat; in silico prediction; mutagenicity.