Regulatory and Scientific Complexities in Application of the Proposed Prior Approval Supplement Pathway for Substitution of the Low Global Warming Potential Propellants in the Marketed Metered Dose Inhalers.

Abstract

Due to the Greenhouse effect of the hydrofluoroalkane gases, transition of the currently marketed pressurized Metered Dose Inhalers containing these propellants to their new versions with Low Global Warming Potential propellants has been initiated. Both the regulatory authorities and MDI manufacturers are actively engaged in making this transition efficiently and cost-effectively. Traditionally, regulatory approval of propellant changes in MDIs has entailed lengthy and very expensive product development in new drug applications. Recently, however, a Prior Approval Supplement pathway that is commonly used to support scaleup and post approval changes in drug products has been proposed for regulatory submissions to support replacement of the approved hydrofluoroalkane with the MDIs using low global warming potential propellants. However, it is recognized that propellant substitutions in MDIs are not simple excipient changes, as they may influence a variety of critical quality attributes relevant to the safety and efficacy of the inhalers. Therefore, even though the proposal for consideration of propellant substitutions as post approval changes is novel and its regulatory acceptance by the FDA would be revolutionary, its application is complicated in view of the applicable regulatory and scientific considerations. This paper provides an analysis of the regulatory and scientific complexities relevant to the proposed pathway.