Genotoxic impurities in pharmaceutical manufacturing: Sources, regulations, and mitigation

Pharmaceutical regulatory agencies such as the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have raised concerns regarding the presence of genotoxic impurities (GTIs) in APIs that could impact negatively on human health. Compounds categorized as GTIs actually include a broad range of unrelated chemicals with very different structures and from very different chemical families. APIs (active pharmaceutical ingredient) streams may contain genotoxic alkyl halides impurities when a reaction takes place in alcoholic solvent at reflux temperature in the presence of hydrogen halides or alkali halides and strong acids. The quantity of genotoxic impurities in drug products is strictly controlled by regulatory authorities that have set limits to ensure patient safety. To ensure compliance with the required low GTI concentrations, a significant effort during development is necessary. At the most rigorous level, the strategy outlined in the regulatory authority's guidelines is to avoid the use of any genotoxic chemical over the entire synthetic route, regardless of whether the genotoxic chemical is used as a reagent, starting compound, catalyst, or solvent. The risk of having GTIs present and the cost of the efforts to avoid or remove them from APIs are contributory factors to the cost of production of new drugs.