Demonstration Method for Control Limits of Organic Impurity

Question

Accepted Answer

1, Scientific literature and main metabolite method:

If the scientific literature has proved that a certain level of an impurity poses no safety concern, then the limit based on that level does not require further justification.

Additionally, if the scientific literature has demonstrated that an impurity is also a main metabolite of the drug substance metabolized in the body, its safety is evident. Therefore, even if the impurity limit exceeds the ICH demonstration limit, it can generally be considered reasonably controlled.

2, Toxicology studies:

Due to the time-consuming and costly nature of toxicology experiments, this method is typically employed when other approaches cannot reasonably research and demonstrate impurities. These studies can be conducted directly with the API or the formulation containing the impurity, or with the isolated impurity.

3, Comparative analysis:

Impurities of the API in the generic drug application can be compared with those in approved reference formulation using the same validated analytical method. This comparison demonstrates that the quality is either superior to or comparable to the marketed drug.