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

Evaluating the Impact of Physiological Properties of the Gastrointestinal Tract On Drug In Vivo Performance Using Physiologically Based Biopharmaceutics Modeling and Virtual Clinical Trials

“…Hofs€ ass and Dressman recently reported building a PBPK absorption model for amoxicillin and doxycycline and conducting virtual BE studies with some modifications to the default model values, i.e., the mean gastric pH was set to 2.7 and varied between 1.2 and 4.5, and the mean gastric transit time of 0.28 h was varied between 0 and 0.8 h. In addition, the percentage of fluid volume in the small and large intestine was set to 7.5% and 2%, respectively. 75 These values are closer to those reported in vivo and the effect of varying these parameters in a population can be assessed better. Depending on the formulation, various GIT parameters may need to be modified accordingly (e.g., gastric transit time may need to be greatly extended for non-disintegrating formulations).…”

Physiologically Based Pharmacokinetic/Pharmacodynamic Modeling to Support Waivers of In Vivo Clinical Studies: Current Status, Challenges, and Opportunities

“…The current BCS-biowaiver approach has been widely criticized for being overdiscriminating and overly strict, excluding opportunities not only for scientifically justified extensions to certain BCS class II compounds but also for drug substances which are in theory eligible for BCS-based biowaivers but failed to comply with criteria in the dissolution performance. − Several publications have implemented PBBM approaches, including VBE, to investigate the variables limiting drug absorption, support possible BCS-based biowaiver extensions, and recommend specifications based on the in vivo performance. ,− On the other hand, it has been suggested that products containing drugs belonging to BCS class I and III might exhibit a high risk of bioequivalence failure due to their intrinsic pharmacokinetic properties (e.g., if they have a high first-pass effect or short half-life) and that the eligibility of their products for biowaiver might need to be revised . Further concerns have been raised, especially for products including BCS class III drugs, on the potential interactions of different excipients with gut transporters, which in turn could lead to increased risk for bioequivalence. − On the whole, it seems that regulatory confidence in the performance of PBPK models for justification of biowaivers is still rather tentative.…”

Investigation of Dissolution Performance of Hard Gelatin Capsule Products Using Various Sinkers

“…Additionally, the influence of external factors (for example vibration) and internal factors (for example air bubbles in the dissolution medium, vibration, stirring speed) is lower compared to conventional round-bottom vessels (7). Therefore, not only is the dissolution rate increased when peak vessels are used, it will also be more complete (6,7,20). As this simple modification reduces several artifactual effects commonly encountered in dissolution, peak vessels have often been recommended as a good alternative to increasing the rotation speed.…”

“…However, the disadvantages of using a sinker for the dissolution test (as discussed in sections 2 and 3 above) should be considered, and a sinker should be identified that does not artifactually change the dissolution in other ways. With respect to coning, the use of a sinker should be discouraged because there are more efficient ways to counteract this problem such as increasing the rotation speed or using peak vessels (6,7,20).…”

“…But, as this beneficial effect on the coning was only observed for one sinker type (CLIPS sinker, acetaminophen capsules, 75 and 100 rpm), the negative effects appear to outweigh any positive effect for most of the sinker types. Thus, we cannot recommend using a sinker to overcome coning; increasing the rotation speed or peak vessels should be considered instead (6,7,20).…”