Impact of Mechanistic Modeling and Simulation Methodologies on Product-Specific Guidance Development for Non-Orally Administered Drug Products.

The U.S. Food and Drug Administration (FDA) publishes product-specific guidances (PSGs), with bioequivalence (BE) recommendations for prospective generics. Developing BE recommendations for non-orally administered drug products including long-acting injectables (LAI), orally inhaled drug products, and drugs applied locally to the skin, ophthalmic, and nasal routes may be challenging because conventional BE methods and considerations for orally administered drug products may not apply. Mechanistic modeling approaches such as physiologically based pharmacokinetic (PBPK) models or computational fluid dynamics (CFD) models are used for the development of BE methods and BE assessment standards in PSGs for non-orally administered drug products, as evidenced by cases provided here. This manuscript discusses in silico methodologies that support PSG development for non-orally administered drug products through the model-integrated evidence paradigm. Specifically for orally inhaled drug products, we highlight modeling and simulation (M&S) recommendations that have occurred in one new PSG that was published for formoterol fumarate; glycopyrrolate inhalation metered aerosol in February 2024 and referred to in 16 other PSGs with different active pharmaceutical ingredients and device types, such that M&S approaches may be optionally used to provide insight on regional drug delivery and support BE assessments. For drug products applied to the skin, we focus on three successful case studies where PBPK models were used to support revised PSG recommendations with reduced need for ex vivo and human studies. Ophthalmic products, LAI, and nasal products illustrated advancements in M&S methodologies that may be potentially used for the development of new or revised PSG recommendations.