Justification of Widened Dissolution Specifications of an Extended Release Product Using Physiologically Based Biopharmaceutics Modeling

Abstract

Drug product meeting the dissolution specifications is crucial in order to ensure consistent clinical performance. However, in certain cases wider dissolution specifications may be required based on product behavior. While justification of such wider specifications may be challenging from a regulatory context, approaches such as physiological based biopharmaceutics modeling (PBBM) can be utilized for this purpose. Product DRL is a fixed dose combination product consisting of an immediate (IR) and extended release (ER) portions. For the ER portion, the dissolution specifications consisted of four time points and a proposal was made to relax the specification at the 2h time point (from 50-70% to 45-67%) to reduce the batch failures at commercial scale. To support wider specification, a PBBM was developed and extensively validated with literature & in-house studies. Virtual bioequivalence was performed using the pivotal clinical study data. Virtual dissolution profiles for proposed wider specifications were generated using three different approaches. Incorporation of lower and upper dissolution profiles into the model indicated absence of impact on in vivo performance thereby justifying the specifications. Regulatory acceptance of proposed specifications with PBBM indicated the significance of using modeling approaches to reduce repeated testing thereby facilitating faster approvals.