INTERNATIONAL CONFERENCE ON HARMONISATION GUIDELINES ON THE LIMITS OF GENOTOXIC IMPURITIES IN DRUG PRODUCT

Abstract

An impurity in a drug substance as defined by the International Conference on Harmonisation (ICH) guidelines is any component of the drug substance that is not the chemical entity defined as the drug substance. Similarly, an impurity in a drug product is any component of the drug product that is not the chemical entity defined as the drug substance or an excipient in the drug product. Genotoxic compounds have the potential to damage DNA at any level of exposure and that such damage may lead/contribute to tumour development. Thus for genotoxic carcinogens it is prudent to assume that there is no discernible threshold and that any level of exposure carries a risk. A threshold of toxicological concern (TTC) value of 1.5$ \mu$g/day intake of a genotoxic impurity is considered to be associated with an acceptable risk (excess cancer risk of <1 in 100,000 over a lifetime) for most pharmaceuticals. From this threshold value, a permitted level in the active substance can be calculated based on the expected daily dose. Higher limits may be justified under certain conditions such as short-term exposure periods.