Genotoxic Impurity (or Genotoxic Impurity, Genotoxic Impurity, GTI) refers to the compound itself directly or indirectly damage to cellular DNA, produce gene mutation or in vivo mutation, with the possibility of carcinogenicity or tendency. Potential genotoxic impurity (Potential Genotoxic Impurity , PGI) from the structure of similar genotoxic impurities, there is a warning, but without experimental proof of aflatoxins, nitrosamines, methyl sulfonate esters, and other compounds are common genotoxic impurities, many chemotherapeutic drugs also have a certain degree of genotoxicity, and their adverse reactions are caused by the genotoxicity of chemotherapy drugs on normal cells. drugs to normal cells due to genotoxicity, such as cisplatin, carboplatin, fluorouracil and so on.
2Why focus on the study of genotoxic impurities
Genotoxic substances are characterized by a very low concentration can cause damage to the human body's genetic material, which can lead to genetic mutations and may contribute to the development of tumors. Because of their strong toxicity, they pose a strong threat to the safety of medication, and in recent years, there have been more and more cases of widespread medical errors and forced recalls by the FDA due to trace amounts of genotoxic impurities found in marketed medications, causing huge economic losses for pharmaceutical companies. For example, a well-known international pharmaceutical giant launched the HIV protease inhibitor Viracept (Viracept, mesylate) in the European market, in July 2007, the EMA suspended all its marketing activities in Europe, because of the discovery of excessive residues of ethyl methanesulfonate in its product, ethyl methanesulfonate is a classic genotoxic impurity, the company paid a huge price for this, the The cause of the residue exceedance was first investigated internally, as ethanol was left behind due to incomplete removal during instrument and equipment cleaning, and reacted with the methanesulfonic acid to form ethyl methanesulfonate. After being asked to address the contamination, the company was also asked to conduct toxicity studies to better assess the risk to patients. Meanwhile as many as 25,000 patients were exposed to this known genotoxicity. It wasn't until all of these issues were resolved that EMA reinstated its marketing authorization in Europe.
In recent years, regulatory agencies such as the ICH, FDA, and EMA have made clearer requirements for genotoxic impurities, and more and more pharmaceutical companies are focusing on the control and detection of genotoxic impurities during the development of new drugs.