An approach to control purity of the drug substance for non-clinical study

*Corresponding author: Yusuke Okubo, Mailing address: Research Laboratories, TOYAMA CHEMICAL CO., LTD. 2-4-1 Shimookui Toyama 930-8508, JAPAN, E-mail: YUSUKE_OKUBO@toyama-chemical.co.jp Tel: +81 (0)76-431-8267 Fax: +81 (0)76-431-8208 Background: Purity of drug substance (API) used for clinical study must be the same or higher than that of API used for non-clinical study (NCAPI). It is important to allow flexibility in developing manufacturing process to design and control the purity of NCAPI. There are various ways to optimize the purity on purpose, such as addition of individual impurities on use of harsh chemical reactions. In the present study, we established a method to ensure the desired purity of NCAPI by adding a separate set of API containing various species of impurities (IMAPI). Methods: Firstly, the target purity of NCAPI was determined by the purity of API used for a two-week repeated dose toxicity study in the dog. Secondly, IMAPI was prepared in lab, and lab experiments were conducted to determine how much IMAPI needed to achieve the target purity of NCAPI at large-scale manufacturing. Thirdly, we conducted largescale manufacturing by addition of IMAPI and confirmed whether the purity of NCAPI was within the desired one. Results: The purity of API used in the dog toxicity study was 97.8%, so we set the target purity at 98%. IMAPI was synthesized with the purity of 82.2%, and added to the reaction mixture in large-scale production. Crystallization and filtration gave 37.4 kg of NCAPI with the purity of 99%, which is slightly higher than the target purity. Conclusions: These results indicate that this method is useful for purity design of NCAPI. Abstract