Evaluation of orally disintegrating tablets: regulatory pathways, administration practices and harmonization of bioequivalence study design

Abstract Orally disintegrating tablets (ODTs) are a solid oral dosage form designed to rapidly disintegrate in the mouth without the need for water, improving patient compliance—particularly among pediatric, geriatric, and dysphagic populations. Despite their advantages, ODTs pose formulation and regulatory challenges due to their unique administration characteristics and potential for pregastric absorption. This review examines the regulatory approval pathways for ODTs, including 505(B)(1), 505(B)(2), 505(J), and 505(J)(2)(C), and highlights examples of marketed ODT products approved through each pathway. The differences in in-vivo absorption behavior between ODTs and conventional tablets are discussed, including their influence on pharmacokinetic parameters such as Cmax, Tmax, and AUC. Emphasis is placed on the impact of water co-administration on ODT bioavailability, where factors like fluid volume and administration route can alter drug dissolution and absorption. This paper evaluates product-specific guidances (PSGs) and reference listed drug (RLD) labeling for 39 ODT products approved before the release of the FDA’s guidance, M13A guidance on Bioequivalence for Immediate-Release Solid Oral Dosage Forms. Of these, 17 ODT PSGs recommended different instruction for administration of water than that from their respective product labeling. These PSGs were subsequently updated to align with FDA M13A guidance recommendations. Lastly, this paper provides a comprehensive framework for optimizing bioequivalence assessments of ODTs and supports future development of ODT formulations for new and generic drugs.