Research On The Key Technology Of Control And Evaluation Of Drug Impurities

The impurities of drug was the key research objective in my doctoral dissertation. A systematic review of the domestic and foreign research status and developments trends based on drug impurities were present in such paper. To overcome the problems of preparation, limitation and control technology for drug impurity, we provided several technology systems based on preparation of reference material, toxicity evaluation and analysis of impurity profile, which focus on the drugs with high risk and large clinical dosage, and provided technical support for domestic pharmaceutical research, quality control and supervision.1. Research on the key technology of drug impurity reference standardsTo conquer the problem of insufficiency, hard of preparation and high-priced impurity reference substance in China, we developed a rapid preparation technology of chemical impurity reference substance with high purity based on the strengthening the source conditions.It has been found that one impurity in drug gradually undergone degradation in specific degradation conditions with other impurities hardly degraded. We can strengthen the degradation with controlling the reaction conditions (to prevent side effects and secondary degradation) to change active pharmaceutical ingredients (API) to be the desired impurity. The technology was named "Key Technology for Preparing Impurity based on Strengthening the Source Conditions"(KTPISSC) based on the principle of preparation, which has such superiorities including one-step reaction, high yield, easy preparation, lower cost and easy industrialization.Unknown impurities of levofloxacin, ofloxacin and clarithromycin were studied by KTPISSC. Five parameters including the reaction solvent, temperature, pH, reaction time, crystallization were applied to check the practicability of KTPISSC. We achieved five preparation methods with fast response, low cost and high purity. And the results prove that KTPISSC is practicable for the preparation of chemical impurities which have the same degradation rule between different varieties, which has a wide field of application with good prospects.In addition, we firstly established a calibration and uncertainty evaluation method for levofloxacin impurity, furthermore, we established a perfect preparation technology system for drug impurity reference standards. This current study provides a new thought of simulation for preparing other drug impurities.2. Research on the key technology of toxicological evaluation of drug impuritiesThe toxicological evaluation of impurity is an important basis for the determination of quality control level. However, the current lack of corresponding laws and technical requirements seriously influenced the control level of impurity in the pharmaceutical standards of our country. In recent years, Genotoxic impuritiy is an important factor to affect drug safety. The advanced countries and organizations have paid more and more attention and introduced stricter regulations for the control of genotoxic impurity. This paper established a research program to evaluate drug impurity toxicology and carried out genetic toxicity evaluation of drug impurity especially in accordance with the latest international requirements and progress.According to the latest international requirements and progress, this paper firstly introduced the key technology of in silico toxicological evaluation, such as Quantitative structure-activity relationship(QSAR). Under the guidance of International Conference on Harmonisation (ICH) M7, two unknown impurities of levofloxacin including descarboxyl levofloxacin and levofloxacin N-oxide were studied for toxicological assessment systematically. Through the esperiment of in silico, Ames, Mouse lymphoma assay (MLA), and the assay of China hamster lung cells (CHL) chromosome aberration, we determined the two genotoxic impurities and then provided the basis for the limitation of impurity. This study provide a good reference for the toxicological evaluation of other impurities.The impurity toxicological evaluation technique in this paper is supported by the National Pharmacopoeia Committee. Based on the research contents of this paper, our application for 2015 annual national pharmacopoeia committee special topic about drug standards’ improving is approved. The title of the subject is "Genetic toxicity evaluation of the known impurities contained in Chinese Pharmacopoeia follow the ICH M7 guidlines".3. Research on key technology of injection impurity profilesLevofloxacin lactate injection was chosen as research object because of its wide application and high risk of injection. Combined the testing results of raw materials and preparations with the research on the synthesis and degradation route of levofloxacin lactate, and the preparation, spatial configuration, and toxicological evaluation of unknown impurities,,impurity control method of levofloxacin lactate injection and its raw materials, we determined the profiles of impurity including source, structure, biological activity and the quality control method of 6 impurities from levofloxacin. At the same time, we established a detection method that can effectively keep the content of impurity in the raw material and levofloxacin lactate. Formulations under designed level. The established method provides a theoretical basis for process optimization and ensuring the control of quality in the drug production, circulation and storage process.The validation methodology and results of testing the sample proved the impurity control method established by us is superior to the method of Chinese Pharmacopoeia. Which can present the content of impurity encapsuled in levofloxacin lactate injection accurately. Furthermore, the method can avoid misjudgment to improve the quality of products.This study provides a beneficial reference for the improvement of national drug standards and the evaluation of correspondence related to generic drug.