Genotoxic Impurity Method Development and Methodological Validation

Genotoxic impurities (GTI) refer to compounds that can directly or indirectly damage cellular DNA, produce gene mutation or in vivo mutagenesis, and have the possibility or tendency to cause cancer. The fundamental purpose of studying genotoxic impurities is to control and reduce the risk that they may cause cancer in humans. Carcinogens can be divided into genotoxic carcinogens and non-genotoxic carcinogens according to their mechanism of action. Most of the carcinogens encountered in drug development and production are genotoxic carcinogens. The main mechanism of action of genotoxic carcinogens is to cause DNA damage, while the mechanism of action of non-genotoxic carcinogens is more complex, including oxidative stress, regulation of enzyme activity, cell proliferation and apoptosis. The toxicity of chemical substances that may cause cancer can be divided into three levels: genotoxicity, mutagenicity and carcinogenicity. Most carcinogens and mutagens are genotoxic, but not all genotoxic impurities are mutagenic or carcinogenic.

Claasification of Genotoxic Impurities

Table 1 Impurities Classification With Respect to Mutagenic and Carcinogenic Potential and Resulting Control Actions

Acceptable Intakes of Genotoxic Impurities

Table 2 Acceptable Intakes for an Individual Impurity

Table 3: Acceptable Total Daily Intakes for Multiple Impurities

Control Strategies of Genotoxic Impurities

These strategies of genotoxic impurities include: (a) redesigning the drug substance synthesis to avoid introducing problematic impurities, (b) altering relevant process parameters to remove or reduce such impurities to insignificant levels, (c) deploying process understanding to prove that a particular genotoxic impurity either cannot be formed or will be efficiently removed, (d) conducting toxicity studies to demonstrate that a suspect impurity is not harmful at the low levels envisaged for it.