Inhalable and Nasal Biologics: Analytical, Formulation, Development, and Regulatory Considerations.

Abstract

Background: Delivering large molecules and biologics via inhalation or intranasal routes allows these innovative therapies to directly target the respiratory tract, access the richly vascularized lymphatic tissue in the nose for vaccination, bypass gastro-intestinal and first-pass hepatic metabolism for systemically active drugs, and provide a convenient alternative to injections. These advantages are driving significant growth in research and development within this field. However, before such products can reach the market, they must undergo rigorous nonclinical studies and clinical trials and address challenges related to formulation, manufacturing, analytical testing, quality standards, and regulatory review. Methods and Results: This report summarizes discussions among leading experts from industry, academia, and regulatory bodies on how to apply general Chemistry, Manufacturing, and Controls (CMC) principles, alongside bioequivalence (BE) considerations, to the development of inhalable and nasal biologics (INBs). It also explores the balance between these requirements and the established techniques for medical aerosols. In the absence of explicit regulatory guidelines for the development of INBs, this article reviews applicable literature, including guidelines from the US FDA and EMA for biologics, on the one hand, and for small-molecule inhalation and nasal drug products, devices, and combination products, on the other. The original discussions reflected here took place at the 2023 workshop co-organized by the International Society for Aerosols in Medicine (ISAM) and the International Pharmaceutical Aerosol Consortium on Regulation & Science (IPAC-RS). Subsequent recent developments have also been added. The article describes regulatory expectations, the selection of delivery systems and formulation types, and analytical techniques for assessing product quality attributes of INBs. Several specific cases are presented in detail, including regulatory considerations for generic peptides, the approval package for one of the first marketed biologics for inhalation, and analytical detection strategies for viral-based products delivered to the lungs. Conclusions: Looking ahead, the future of INBs includes opportunities to treat and potentially cure diseases that currently have no effective treatment or that require repeated injections. Continued collaboration among researchers, developers and regulators will be key to advancing these therapies, ultimately benefiting patients and improving health outcomes. The future of INBs looks promising!.