CMC Series (X): Genotoxic Impurities in Drug Impurity Research Strategies

Regarding impurities, substances different from the active ingredient are collectively referred to as impurities. These ingredients are usually ineffective, irrelevant to the purpose of the active ingredient, or substances with other toxic side effects. The quality research process of drugs is to carry out qualitative and quantitative research on substances different from active ingredients through the analytical methods currently mastered by human beings, and to formulate and evaluate the safety limits of these impurities based on ICH, pharmacopoeia and other relevant guiding principles and combined with literature data. Impurities in drug research and development can be divided into organic impurities (related to process and drug structure), inorganic impurities and residual solvents.

The existence of impurities usually brings potential safety risks, which are harmful and useless to patients. Among them, highly toxic and highly active impurities and genotoxic (mutagenic, carcinogenic, etc.) impurities are the control priorities in the process of drug research and development. The research ideas are usually the characterization of impurities, the preparation of impurities, the structural confirmation and characterization, the formulation of limits, the formulation of control methods, the development and verification of highly sensitive analytical methods, etc.

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For the principles of drug development, the research ideas of relevant ICH guidance documents are usually followed, namely the International Conference on International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use; ICH).

ICH is an international organization jointly initiated by the EU, the United States and Japan in 1990 to coordinate the existing differences in the technical requirements for human drug registration in the three member countries. On March 15, 1994, ICH Q3 was approved by the Steering Committee to enter the second stage and solicited public opinions. The impurity research in the drug research and development process has entered people's systematic attention. Starting from March 30, 1995, ICH successively released Q3A (impurity in new bulk drugs), Q3B (impurity in new preparations), Q3C (impurity: residual solvent guide) and Q3D (elemental impurity guide), the unified impurity research standard of ICH member countries and countries following ICH principle is established, and the impurity control strategy and limit requirements are put forward in detail [1].

With the progress of science and technology and the improvement of analytical methods, as well as people's understanding of the discipline and the in-depth study of compounds, it is found that some impurities can induce gene mutations and lead to chromosome breakage and rearrangement at very low concentrations, which are potentially carcinogenic. These impurities are defined as mutagenic impurities. Q3A and Q3B can only provide guidance for the characterization and control of most impurities, and guidance for DNA-reactive impurities is very limited. On February 6, 2013, ICH M7 (Genotoxic Impurities) was approved by the Executive Committee and released for public reference, providing a feasible framework scheme for the identification, classification, characterization and control of mutagenic impurities for pharmaceutical research and development and production, and for controlling the potential carcinogenic risks of impurities. So far, the framework of ICH for the study of impurities in drugs has been basically completed.

The impurities are classified according to their mutagenic potential and carcinogenicity, and the initial analysis of actual and potential impurities is usually based on data on the carcinogenicity and bacterial mutagenicity of impurities obtained through database and literature searches, and the hazard assessment classifies them as Category 1, Category 2 or Category 5. If these data are not available, a structure-activity relationship (SAR) assessment to predict bacterial mutagenicity should be performed. According to the evaluation results, it is divided into 3 categories, 4 categories or 5 categories [2].