Utility of Physiologically Based Biopharmaceutics Modeling (PBBM) in Regulatory Perspective: Application to Supersede f2, Enabling Biowaivers & Creation of Dissolution Safe Space.

Product DRL is a generic IR tablet formulation with BCS Class-III API, available in two strengths: 50mg & 100mg. The reference and test formulations have salt-A & salt-B of API but both products were bioequivalent based on the in vivo bioequivalence study conducted for higher strength 100mg. While leveraging the generic product to different market, the reference product from other market showed slower release than generic formulation resulting in f2<50 in pH 6.8 for both 50mg and 100mg, because of which waiver for BE study couldn't be granted. To support f2 mismatch at 100mg, 50mg and to facilitate biowaiver of 50mg, a Gastroplus® PBBM model was developed & validated. Virtual bioequivalence trials were performed using the slower dissolution profile of other market reference. It was demonstrated that despite slower dissolution, bioequivalence was achieved for test product against other market reference for 50mg & 100mg strengths. Additionally, dissolution safe space was created using virtual dissolution profiles, which indicated that when >85% released up to 60 min there is no impact on bioequivalence. Overall, for molecules with permeability controlled absorption (i.e. BCS-III), very rapid dissolution criteria can be relaxed by defining dissolution safe space thereby enabling more waivers in future.