Developing Analytical Tools for the Analysis of Genotoxic Impurities in Active Pharmaceutical Ingredients
GTIs are compounds that can induce genetic mutations, chromosomal breaks, and/or chromosomal rearrangements in humans. Additionally, these compounds can also exhibit potential carcinogenic activity. The United States Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have imposed stringent regulations on the amount of GTIs present in pharmaceuticals. Depending on the dose and duration of exposure, the allowable daily intake (ADI) can be as low as 1.5 μg/day, which in perspective, would be translated to low parts-per-million (ppm) or sub-ppm concentration ranges of GTIs in drug substances. This highly conservative threshold also applies to pharmaceutical impurities containing structurally alerting functional groups that may possess genotoxic activity. Although GTIs that enter human body may come from drug substances, excipients, degradants, or metabolites, the major source of GTIs is usually active pharmaceutical ingredient (API) manufacturing, which may require the use of genotoxic reagents, solvents, and catalysts. Thus, monitoring the presence of various GTIs in drug substances is of great importance for the pharmaceutical industry.
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