Evaluation of Differences in Dosage Form Performance of Generics Using BCS-Based Biowaiver Specifications and Biopharmaceutical Modeling-Case Examples Amoxicillin and Doxycycline

Abstract

Drug products containing the antibiotics amoxicillin (500 mg as trihydrate) or doxycycline (200 mg as hyclate or monohydrate) with varying qualitative excipient composition were obtained from the German market and their biopharmaceutical properties were characterized in compendial quality control tests, dissolution tests run under BCS-based biowaiver conditions and dissolution tests using biorelevant media. Observed differences in disintegration time and dissolution rate were assessed according to BCS-based biowaiver dissolution specifications and in virtual bioequivalence trials using GastroPlus™. Great variation was observed in dosage form performance, and 2 out of 5 drug products for each active ingredient failed to demonstrate in vitro similarity using the BCS-based biowaiver specifications, with coning being identified as a key hindrance. Nonetheless, all drug products investigated were found to be equivalent in virtual trials, concordant with their market approval status, indicating that the current BCS-based biowaiver criteria are over-discriminating. To bridge the gap between in vitro and pharmacokinetic assessment of bioequivalence, modification of the experimental setup with the use of Peak Vessels™ and the validation of dissolution specifications with virtual bioequivalence trials appear to be promising approaches. However, neither approach is currently foreseen by the harmonized ICH M9 BCS-based biowaiver guidance.

Keywords: Bioequivalence; Biopharmaceutical characterization; Biopharmaceutics Classification System (BCS); Dissolution; GastroPlus modeling; Solid dosage form(s); Solubility.