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This paper focuses on the regulatory aspects of propellant switch programs for pressurized metered dose inhalers (MDIs) where products currently regulated by the United States Food and Drug Administration (FDA) are involved. These include MDIs as approved products through new drug applications (NDAs), approved generic MDIs through abbreviated new drug applications (ANDAs) and ANDAs in development that will be associated with an approved new drug application (NDA) as the reference listed drug (RLD). 22 August 2024 Inhalation Point of view: MDI propellant switching in the 2020's vs. 1990's: Commentary, perspective and recommendations In this opinion article, Rik Lostritto proposes that successful switch scenarios may be achievable via the US FDA's prior approval supplement (PAS) pathway for both NDAs and ANDAs that are currently approved. Richard (Rik) Lostritto, PhD Lostritto Consulting After retiring from the United States Food and Drug Administration (FDA) in 2022, Dr. Richard (Rik) Lostritto works as an independent consul- tant. While at the FDA (1995-2022), he served as a Reviewer, Team Leader, Division Director, Acting Biopharmaceutics Lead, and from 2015-2022, as Associate Director for Science in the Office of Pol- icy for Pharmaceutical Quality (OPPQ). Prior to joining the FDA, Dr. Lostritto served as Pulmonary Formulations Team Leader at Boehringer Ingelheim Pharmaceuticals, Inc. (1992-1995) and Assistant/ Associate Professor of Pharmacy at the University of Connecticut (1983-1992). is article represents his own views, as an indepen- dent consultant. He does not represent any organiza- tion, company or health authority. Abstract is paper focuses on the regulatory aspects of pro- pellant switch programs for pressurized metered dose inhalers (MDIs) where products currently regulated by the United States Food and Drug Administration (FDA) are involved. ese include MDIs as approved products through new drug applications (NDAs), approved generic MDIs through abbreviated new drug applications (ANDAs) and ANDAs in devel- opment that will be associated with an approved new drug application (NDA) as the reference listed drug (RLD). ere is much to be learned from the previ- ous MDI propellant switch of the1990's. at earlier change was much more dramatic than the current scenario for a number of reasons, including the rad- ically different physicochemical nature of the 1990's hydrofluorocarbon (HFC) propellants and the out- dated in vitro testing programs available at that time. At the heart of the matter are several critical regula- tory parameters and questions yet to be decided upon by the FDA. ese include how much weight will be attributed to modern comparative in vitro data (pre- to post-switch), and what (if any) clinical equivalence data are necessary to support a successful propellant switch program. Further, from the regulatory per- spective, is the propellant itself viewed as an ordinary inactive ingredient or is it imbued with particular physicochemical properties (a case requiring proof ) that would make it necessary for a generic and its RLD to share the identical propellant (or propellent mix) that are otherwise shown to perform similarly? Requiring submission of NDAs or ANDAs in support of propellant switch programs for MDI products that are already approved could lead to a number of otherwise avoidable negative pub- lic health outcomes. ese include elimination of generic MDIs altogether, innovator and generic drug shortages, product withdrawals and greatly increased MDI costs for a large group of at-risk,