Confidently detect and quantify genotoxic and potential mutagenic impurities in APIs and drug products
Genotoxic impurities, and more specifically, mutagenic impurities in APIs and drug products pose a significant risk to patient health, even in trace amounts. These impurities can interact with DNA, leading to mutations and potentially cancer. Active pharmaceutical ingredients (APIs) with structural moieties such as N-nitrosamine, hydrazine, epoxide, and aziridine possess a higher possibility of mutagenic activity. These mutagenic impurities can arise from various sources, namely (1) impurities developed during the manufacturing process of a drug substance, including starting materials, intermediate, reactants and by-products, (2) degradation products generated during formulation or storage, (3) environmental contaminants.
Recently, regulatory agencies like the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) detected N-nitrosamines impurities (NDMA, NDEA, NMBA, etc.) in several blood pressure medicines (sartans) as well as in heartburn and stomach ulcers medicines (ranitidine). These findings not only led to drug product recalls, regulatory actions, and loss of business, but also to the establishment of new, more stringent guidelines to evaluate mutagenic impurities. The proposed limits on these mutagenic impurity levels, both in drug substances and drug products, are well below the limits for non-mutagenic impurities as mentioned in ICH Q3A. To be compliant with these regulatory guidelines, sensitive analytical techniques are required to detect and quantify the impurity levels ranging from ppm to ppb. Agilent offers both gas and liquid chromatography coupled with high sensitivity triple quadrupole mass spectrometry and high-resolution quadrupole time-of-flight mass spectrometry that can confidently help meet the global regulatory requirements for the detection and quantification of these N-nitrosamine impurities both in the API and final drug product.
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