Policy of Multisource Drug Products in Latin America: Opportunities and Challenges on the Application of Bioequivalence In Vitro Assays.

BACKGROUND: The replacement of traditional in vivo bioequivalence studies by in vitro dissolution assays, based on the biopharmaceutical classification system (BCS), has emerged as an important tool for demonstrating the interchangeability of multisource products. This paper summarizes the current implementation of the BCS-based biowaiver for the development of multisource products in Latin America, and identifies several challenges and opportunities for greater convergence and application of BCS regulatory requirements. METHODS: Differences and similarities between the current BCS-based biowaivers' guidelines proposed by two relevant regulatory agencies for the Latin American region (FDA and WHO) and the new ICH harmonization guideline were identified and compared. An update of the BCS-based biowaiver guideline for Latin American countries was also considered, based on the respective regulatory information on bioequivalence studies, which is publicly available. RESULTS: About 50% of the Latin American countries analyzed have no information on the implementation of any bioequivalence standards, while in the countries where bioequivalence studies are considered, the acceptance and application of BCS-based biowaiver requirements is quite heterogeneous. This situation contrasts with the international trend of global harmonization for BCS-based biowaiver guidance, suggesting the need in Latin America to identify opportunities and overcome challenges to improve the development of BCS-based biowaivers to avoid costly and time-consuming in vivo bioequivalence studies. CONCLUSIONS: The study shows that the region is in a position to improve access to safe and effective medicines at a reasonable cost by applying BCS-based biowaiver guidance.

Integrating theoretical and experimental permeability estimations for provisional biopharmaceutical classification: Application to the WHO essential medicines.

The accuracy of the provisional estimation of the Biopharmaceutics Classification System (BCS) is heavily influenced by the permeability measurement. In this study, several theoretical and experimental models currently employed for BCS permeability classification have been analysed. The experimental models included the in situ rat intestinal perfusion, the ex vivo rat intestinal tissue in an Ussing chamber, the MDCK and Caco-2 cell monolayers, and the parallel artificial membrane (PAMPA). The theoretical models included the octanol-water partition coefficient and the QSPeR (Quantitative Structure-Permeability Relationship) model recently developed. For model validation, a dataset of 43 compounds has been recompiled and analysed for the suitability for BCS permeability classification in comparison with the use of human intestinal absorption and oral bioavailability values. The application of the final model, based on a majority voting system showed a 95.3% accuracy for predicting human permeability. Finally, the present approach was applied to the 186 orally administered drugs in immediate-release dosage forms of the WHO Model List of Essential Medicines. The percentages of the drugs that were provisionally classified as BCS Class I and Class III was 62.4%, suggesting that in vivo bioequivalence (BE) may potentially be assured with a less expensive and more easily implemented in vitro dissolution test, ensuring the efficiency and quality of pharmaceutical products. The results of the current study improve the accuracy of provisional BCS classification by combining different permeability models.