Pharmaceutical, Clinical, and Regulatory Challenges of Reformulating Pressurized Metered-Dose Inhalers to Reduce Their Environmental Impact

Abstract

The chlorofluorocarbons (CFCs) that were used as propellants in early pressurized metered-dose inhalers (pMDIs) had substantial ozone-depleting potential. Following the Montreal Protocol in 1987, the manufacture of a range of ozone-depleting substances, including CFCs, was gradually phased out, which required the propellants used in pMDIs to be replaced. Current pMDIs use hydrofluoroalkanes (HFAs) as propellants, such as 1,1,1,2-tetrafluoroethane (HFA-134a). Although these HFAs have no ozone-depleting potential, they have a high global warming potential (GWP), and consequently, their use is being phased down. One option for the discontinuation of HFA use in inhalers would be to discontinue all pMDIs, switching patients to dry powder inhalers (DPIs). However, a switch from pMDIs to DPIs may not be a clinically appropriate option for some patients; furthermore, the full lifecycle carbon footprint and the overall environmental impact of different inhalers should be considered. An alternative is therefore to reformulate the current HFA pMDIs to use low-GWP propellants, such as 1,1-difluoroethane (HFA-152a). This article summarizes the various steps and challenges associated with this change, illustrated using data from the inhaled triple combination of beclomethasone dipropionate, formoterol fumarate, and glycopyrronium bromide, a complex formulation of three molecules in a solution that contains liquid-phase propellant.

Keywords: global warming; hydrofluoroalkanes; inhaler; ozone depletion.

FIG. 1.

Relative carbon footprint lifecycles of pMDIs and DPIs (based on information in Panigone et al. and Murphy et al.). *The feasibility and environmental effectiveness of a postal inhaler recovery and recycling scheme was evaluated in the UK in 2021 and 2022. All components of returned pMDIs were recycled; DPIs were incinerated to produce energy-from-waste. DPIs, dry-powder inhaler; pMDI, pressurized metered-dose inhaler.

FIG. 2.

Key considerations when reformulating a pMDI.

FIG. 3.

European Medicines Agency bioequivalence criteria, applied to inhaled formulations.

FIG. 4.

Relative total systemic exposure following administration of BDP/FF/GB via pMDI with HFA-152a propellant vs. HFA-134a, both administered without charcoal block (Reprinted from Rony et al. Pulm Pharmacol Ther 2024;102299, copyright 2024, with permission from Elsevier). *Indicates a primary endpoint. The solid vertical lines at 80% and 125% indicate the bioequivalence criteria. n = 59 for Study 1 and 62 for Study 2, except ^a58; ^b61; and ^c60. The adjusted mean ratio is the ratio of adjusted geometric means of log-transformed data. AUC_0–t, area under the plasma concentration—time curve between time zero and the last quantifiable timepoint; B17MP, beclomethasone 17 monopropionate; BDP, beclomethasone dipropionate; C_max, maximum plasma concentration; FF, formoterol fumarate; GB, glycopyrronium bromide; pMDI, pressurized metered-dose inhaler.

FIG. 5.

Relative lung availability following administration of BDP/FF/GB via pMDI with HFA-152a propellant vs. HFA-134a, both administered with charcoal block (Reprinted from Rony et al. Pulm Pharmacol Ther 2024;102299, copyright 2024, with permission from Elsevier). *Indicates a primary endpoint. The solid vertical lines at 80% and 125% indicate the bioequivalence criteria. n = 59 for Study 1 and 63 for Study 2, except ^a58; ^b57; ^c56; ^d55; ^e62; ^f61; and ^g59. The adjusted mean ratio is the ratio of adjusted geometric means of log-transformed data. AUC_0–t, area under the plasma concentration—time curve between time zero and the last quantifiable timepoint; B17MP, beclomethasone 17 monopropionate; BDP, beclomethasone dipropionate; C_max, maximum plasma concentration; FF, formoterol fumarate; GB, glycopyrronium bromide; pMDI, pressurized metered-dose inhaler.

FIG. 6.

Comparison of primary pharmacokinetic parameters following administration of BDP/FF/GB via pMDI with HFA-152a propellant vs. HFA-134a, both via spacer (Reprinted from Rony et al. Pulm Pharmacol Ther 2024;102299, copyright 2024, with permission from Elsevier). *Indicates a primary endpoint. The solid vertical lines at 80% and 125% indicate the bioequivalence criteria. n = 67 for medium strength and 66 for high strength, except ^a65; ^b64; and ^c63. The adjusted mean ratio is the ratio of adjusted geometric means of log-transformed data. AUC_0–t, area under the plasma concentration—time curve between time zero and the last quantifiable timepoint; AUC_0-30min, area under the plasma concentration—time curve from time zero to 30 min; B17MP, beclomethasone 17 monopropionate; BDP, beclomethasone dipropionate; C_max, maximum plasma concentration; FF, formoterol fumarate; GB, glycopyrronium bromide; pMDI, pressurized metered-dose inhaler.