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Regulatory Science in Action: US Food and Drug Administration Updates on In Vitro Bioequivalence Assessments for Metered Dose Inhalers

Bielski E, Newman B.

Respiratory Drug Delivery 2026. Volume 1, 2026: 20-0.

Abstract:

This work presents research examining whether spray pattern, plume geometry, and priming/repriming studies remain necessary components of bioequivalence (BE) assessments for generic metered dose inhalers (MDIs). Plume and aerosol performance of 10 suspension-based albuterol sulfate (ABS) and four solution-based beclomethasone dipropionate (BDP) MDI formulations with varying propellants, actuator designs, and excipients were examined. While spray pattern and plume geometry measurements were confirmed to be sensitive to formulation and device differences, correlation analyses revealed that realistic aerodynamic particle size distribution (rAPSD), particularly when using small Oropharyngeal Pharmacopeia Consortium mouth-throat model at 30 liters per min (LPM), was sufficiently sensitive to capture those same differences and demonstrated strong correlations with aerosol performance outcomes. This suggests that rAPSD can serve as a comprehensive in vitro BE measure that effectively subsumes the information provided by spray pattern and plume geometry studies.

Regarding priming and repriming, a meta-analysis of generic MDI applications found that priming and repriming BE data closely mirrored single actuation content (SAC) BE data at the beginning of unit lifestage. Since SAC testing already covers all lifestages of the drug product, separate BE studies for priming and repriming were deemed redundant. This is also further supported by existing regulatory requirements under 21 CFR 314.94(a)(8)(iv) that require generics adhere to reference listed drug (RLD) labeling, including priming and repriming instructions, and the MDI quality assessment includes a robust set of testing to ensure priming and repriming performance. In conclusion, this assessment supports streamlining MDI BE assessments to critical BE studies which would maintain rigorous equivalence evaluations while reducing development burden and gaining better alignment with global regulatory perspectives.