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A Regulatory Roadmap for the Transition to Low Global Warming Propellant Pressurized Metered Dose Inhalers: A Proposal for Discussion

Lostritto RT.

Respiratory Drug Delivery 2024. Volume 1, 2024: 161-176.

Abstract:

The switch to low global warming propellants (LGWP) includes pressurized metered dose inhalers (pMDIs). The replacement LGWP propellants exhibit similar physicochemical properties to the currently used pMDI hydrofluoroalkane propellants (HFA-134a and HFA-227) unlike the properties of HFAs compared to the chlorofluorocarbon (CFC) propellants they replaced in the 1990s. New drug applications (NDAs) were justifiable during the CFC to HFA transition based on the very different propellant characteristics, and the general state of scientific knowledge regarding pMDIs.

Requiring new NDAs now, which did not exist in the 1990s could jeopardize currently approved generic pMDIs through the withdrawal or unavailability of the RLD pMDI products. This article proposes that the LGWP propellant change for currently approved RLD and generic pMDIs can be feasibly supported through a data-based prior approval supplement (PAS) submission to US Food and Drug Administration (FDA). The PAS pathway is more timely, efficient, and is a more relevant regulatory instrument for today’s propellant switch scenario. The PAS pathway could help to avoid drug shortages and product withdrawals compared to the requirement for new NDAs. Existing approved specifications coupled with relevant statistical approaches may serve as the cornerstone for comparing pre- to post-propellant change performance. A robust data-based comparison may be made for a regulatory assessment of concordance for post-propellant change performance. The importance and utility of minor dimensional changes to the metering valve and actuator mouthpiece are discussed as low risk-high benefit options which may be used to target critical performance attributes such as delivered dose uniformity (DDU) and aerodynamic particle size distribution (APSD) in attempts to ensure the reformulated pMDI performs concordantly with that which is already approved. A controversial notion whereby the propellant would be regulated as a molecularly distributed device constituent component in the pMDI combination product is provided to stimulate discussion around new ideas of potential applicability to facilitate propellant changes or initial development programs for future pMDI products.