Significant progress for the introduction of lower GWP propellants in Metered Dose Inhalers (pMDIs)
Development of pMDIs (pressurized metered-dose inhalers) is a complex process involving revised ways of manufacturing, new clinical trials, and new regulatory approvals. It is reported that at least nine companies globally are developing pMDIs containing lower GWP propellants, with about an even split between HFO-1234ze(E) and HFC-152a. Three companies embarked on full scale Phase 3 clinical trials (see explanatory note) with completion scheduled for mid-late 2025 [1]. Outcomes resulting from these trials for HFO-1234ze(E) and HFC-152a have been published.
UK MHRA approved a reformulated triple-combination therapy MDI with HFO-1234ze(E) as the propellant, following completion of clinical studies. The MDI manufacture said that it expected to launch the HFO-1234ze(E) version, which represents the first approval of an MDI reformulated with a low global warming potential (LGWP) propellant, in the next few months. Beyond the UK, regulatory applications for the next-generation propellant are currently under review in Europe, China and additional countries. OINDP news May 2025.
A manufacturer says Phase 3 trial demonstrated equivalence of HFA-152a formulation of a salbutamol (albuterol) MDI to the HFA-134a formulation. It announced that a Phase 3 trial comparing an HFA-152a formulation of salbutamol (albuterol) MDI to the currently marketed HFA-134a formulation demonstrated therapeutic equivalence. The company also said that safety of the LGWP propellant formulation was comparable. According to the announcement, it expects to have completed regulatory submissions and to have received approval in time for a 2026 launch of the reformulated inhaler. OINDP news October 2025. Salbutamol pMDIs account for about 70% of the doses delivered by pMDIs [1].
A manufacturer announced the completion of its Phase 3 study for a triple-combination therapy, a key milestone in the development of its carbon minimal pMDI portfolio. The study evaluated the long-term safety and tolerability of HFA-152a, a next-generation propellant with significantly lower global warming potential (GWP). The study paves the way for regulatory submissions. Manufacturer’s information.
HFC-152a is flammable with a direct GWP of 124 (AR4, F-gas 2024/573 value) and is included in the HFC phase-down under the F-gas Regulation and Kigali Amendment, but it is not defined as a PFAS. Manufacturing facilities for HFC-152a pMDIs require capital investment to manage fire risk. HFO-1234ze(E) is classed as non-flammable under the applicable test conditions for this application, with a GWP of 1.37 (AR6, F-gas 2024/573 value). One manufacturing process design review and risk assessment determined that HFO-1234ze(E) can be safely introduced into manufacturing facilities. However, consideration is still needed on the flammability of all propellant mixtures with ethanol, which may be used as a solvent in pMDI formulations [1]. Although HFO-1234ze(E) is included in the PFAS definition used for the scope of the revised EU PFAS restriction proposal [2], the outcome of the restriction process is not yet known. HFC-152a is not defined as a PFAS but could be affected by proposed regulations governing the level of PFAS impurities [1]. The currently used pMDI propellants, HFC-134a and HFC-227ea, are both in scope of the PFAS restriction proposal.
References
[1] 2025 TEAP Progress Report – Volume 1, Section 5.8. Updates on metered dose inhalers & 7.5. Propellants in pMDIs (in 7. PFAS: Emerging policies and sector information).
[2] Updated PFAS Restriction proposal (20 August 2025) is available at Per- and polyfluoroalkyl substances (PFAS) - ECHA
Explanatory note: The main focus of phase 3 trials is to demonstrate and confirm the preliminary evidence gathered in the previous trials that the drug is a safe, beneficial and effective treatment for the intended indication. It is the last phase of testing to be completed before the drug's details and clinical trial results are submitted to the regulatory authorities for approval of the drug's release on the open market.