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

Background:Purity of drug substance (API) used for clinical study must be the same orhigher than that of API used for non-clinical study (NCAPI). It is important toallow flexibility in developing manufacturing process to designand control the purity of NCAPI. There arevarious ways to optimize the purity on purpose, such as addition of individualimpurities on use of harsh chemical reactions.Inthe present study, we established a method to ensurethe desired purity of NCAPI by adding a separate setof API containing various species of impurities (IMAPI).
Methods: Firstly, the target purity ofNCAPI was determined by the purity of API used for a two-week repeated dosetoxicity study in the dog. Secondly, IMAPI was prepared in lab, and labexperiments were conducted to determine how much IMAPIneeded to achieve the target purity of NCAPI at large-scalemanufacturing. Thirdly, we conducted large-scale manufacturing by addition ofIMAPI and confirmed whether the purity of NCAPI was within the desired one.
Results: The purity of API used in the dogtoxicity study was 97.8%, so we set the target purity at 98%. IMAPI wassynthesized with the purity of 82.2%, and added to the reaction mixture inlarge-scale production. Crystallization and filtration gave 37.4kgofNCAPI with the purity of 99%, which is slightly higher than the target purity.
Conclusions:Theseresults indicate that this method is useful for purity design of NCAPI.