The regulatory framework for Biopharmaceutics Classification System (BCS) class III drug products provides a pathway for streamlined biowaivers in drug development, eliminating the need for expensive and time-consuming bioavailability and bioequivalence studies while maintaining quality standards. To qualify, the Test must align with the excipients of the Reference product, while variations in flavor, color, and preservatives are allowed. Quantities of excipients, including changes in grade and percentage, must remain comparable, with cumulative differences not exceeding 10%. However, excipient modifications may affect drug release, potentially necessitating further evaluation for equivalence. Additionally, in cases where very rapid dissolution is not met, it limits the use of a BCS class III-based biowaiver for demonstrating bioequivalence. This article examines the regulatory landscape across regulatory agencies surrounding the application of physiologically based biopharmaceutics modeling (PBBM) to support BCS class III biowaivers, providing insights into the current level of acceptance and expectations. Additionally, it addresses the scientific and regulatory challenges associated with implementing PBBM, highlighting knowledge gaps and obstacles that could hinder adoption in regulatory decision-making. The article also presents case studies demonstrating practical approaches to leveraging PBBM and risk assessment for BCS class III biowaivers, offering valuable insights into successful applications and potential future directions.

By Lanyan Fanga, Shereeni Veerasinghamb, Yunming Xuc, Alfredo Garcia-Arietad, Sivacharan Kolliparae, Yuvaneshwari Kanagasabapathyf, Tausif Ahmedg, Frederico Severino Martinsh, Sandra Suarez-Sharp