Regulatory challenges in complex generics: A focus on liposomal and nanoparticulate drug products

Complex generics, particularly liposomal and nanoparticulate drug products, pose unique regulatory challenges due to their intricate formulations, specialized delivery mechanisms, and physicochemical properties. Unlike traditional generics, these formulations require rigorous characterization, bioequivalence assessments, and in-depth in vitro and in vivo studies to ensure therapeutic equivalence. Regulatory agencies such as the FDA, EMA, and ICH have developed specific guidelines, yet differences in global regulatory frameworks persist, adding complexity to the approval process. Key hurdles include demonstrating sameness in composition, stability, and clinical efficacy, necessitating advanced analytical techniques and alternative bioequivalence methodologies like physiologically based pharmacokinetic (PBPK) modeling and in vitro–in vivo correlation (IVIVC). Manufacturing consistency, batch-to-batch reproducibility, and quality control further complicate the regulatory landscape, requiring stringent validation protocols. This review explores the evolving regulatory pathways, recent advancements in characterization tools, and the role of AI in streamlining approvals. Harmonizing international guidelines and fostering industry-academia collaboration will be crucial in overcoming regulatory barriers and accelerating the market entry of complex generics. The insights presented herein will aid pharmaceutical scientists, regulatory professionals, and policymakers in navigating the challenges associated with developing and approving liposomal and nanoparticulate generic drugs.