the inhaler gas cliff

Problem statement

Roughly 800–825 million pressurised metered-dose inhalers (pMDIs) are made each year, using about 10,700 tonnes of the hydrofluorocarbons HFC-134a and HFC-227ea in 2021; inhaled salbutamol, "by far the most used treatment worldwide, mainly as inexpensive HFC pMDIs," accounts by some estimates for more than 60 percent of pMDI use and "well over half of all inhaled doses of medication." Those propellants are Annex F gases scheduled for phase-down under the Kigali Amendment, and their pharmaceutical-grade supply is a single thread: MCTOC reports that "bulk pharmaceutical-grade HFC-134a manufactured in the United Kingdom is exported around the world," that India and potentially China have capacity "however, certification by pMDI manufacturers of new supply chains for pharmaceutical-grade HFC-134a is difficult to achieve," and that continued supply "would need" technical-grade HFC-134a from Japan and/or the United States delivered "to the single purifier of bulk pharmaceutical-grade HFC-134a located in the United Kingdom" — while "technical-grade HFC-134a plants operate at a minimum capacity below which it becomes technically challenging or impractical to continue to manufacture HFC-134a (below 60–70% of normal running rate)." Low-GWP replacement propellants (HFC-152a and HFO-1234ze(E)) exist and originator companies are launching reformulated products, but reformulation is "a lengthy and costly process," and the unsolved problem is the timing mismatch: refrigerant-driven demand for HFC-134a may collapse — taking the pharmaceutical feedstock with it — before affordable low-GWP salbutamol inhalers exist in the Article 5 (developing-country) markets that depend on locally made, sub-brand pMDIs.

Why this matters

MCTOC states that "access to affordable inhaled medicines for chronic respiratory diseases is severely limited in low- and middle-income countries, which causes avoidable morbidity and mortality," that "in Article 5 parties, locally made pMDIs are more affordable than some imported brands," and that soft-mist inhalers "are generally likely to be unaffordable in Article 5 parties for most patients." Its 2022 warning is direct: the Kigali Amendment's "70% reduction of production and consumption from baseline for Annex F HFCs in non-Article 5 parties in 2029 is likely to impact and limit the global supply of pharmaceutical-grade HFCs for pMDIs, at which time it is also possible that an adequate supply of lower GWP pMDIs might not yet be available to meet patient demand," and "timely transition and access to new technology could avoid large price increases with the loss of generic salbutamol HFC-134a pMDIs if or when HFC-134a supplies are shut down for technical and economic reasons." The climate stake is real too — 88–98 percent of a pMDI's carbon footprint is propellant released during use or disposal — which is why regulators are tightening; the equity stake is that the tightening lands first on the cheapest device used by the poorest patients.

What’s been tried and why it hasn’t worked

MCTOC recalls that under the Montreal Protocol "the use of CFCs as propellants for pMDIs was successfully phased out worldwide without significant adverse impact to medical care," which is the template everyone cites; but that transition moved to a destination gas that was not itself controlled. This time, as of the 2022 report, "three pharmaceutical companies and one major contract development and manufacturing organization (CDMO)" — together over 70 percent of U.S. and European pMDI revenues — had announced HFC-152a or HFO-1234ze(E) launches for 2025, yet "there is only one company that has publicly announced reformulation of a reliever pMDI," "for many companies it is unclear whether this would be financially justified," and multinational manufacturers based in Article 5 countries were "investigating prototype formulations ... although none have yet announced plans to launch products," partly because "the current suppliers of pharmaceutical grade HFC-152a and HFO-1234ze(E) have several patents pending or granted in this field." TEAP's 2024 update reports "ten or more companies globally with active programmes," including generic manufacturers in Article 5 parties, but only four had disclosed programmes, each had "embarked upon Phase 3 efficacy studies" completing mid–late 2025, so "the first lower GWP pMDIs may not reach the market until 2026"; "many classes of inhaled therapies have yet to enter clinical trials"; the European Medicines Agency has issued transition guidance but "in other markets, such as the United States, no formal guidance is available"; and "some companies have indicated that there may be too great a risk of insufficient commercial return to make it worthwhile investing in a lower-GWP development program." Regulatory signals also cut across each other: the 2024 EU F-gas revision accelerates the phase-down of pMDI HFCs and schedules HFC-152a itself for phase-out by 2050 unless a critical-use exemption is added, and ECHA's draft PFAS restriction "would, in their current form, ban the use of HFC-134a, HFC-227ea, and HFO-1234ze(E)." Meanwhile HFC-227ea prices have "already" risen significantly and HFC-134a was expected to follow after the 2025 non-Article 5 step-down.

What would unlock progress

MCTOC's own list of enabling conditions is a policy-and-logistics agenda: "global and national frameworks that establish clear market signals," "continuity in, and stability of, the supply of pharmaceutical-grade HFCs," coordinated regulatory approvals with clear guidance on the clinical data needed for a propellant switch "when there are no other substantial changes in the formulation," and flexibility within HFC phase-down frameworks (e.g., pharmaceutical carve-outs, as the EU has provided for 2025–2029) so that "adequate bulk HFC-134a and/or pMDIs are available ... in their own markets, and in their export markets," a need that "may persist for up to 10 years." Technically, what would help most is a generic-friendly, non-patent-encumbered reformulation route for salbutamol in one of the low-GWP propellants and manufacturing know-how for handling flammable HFC-152a in Article 5 filling plants. The adjacent precedent is the Montreal Protocol's essential-use exemption machinery for CFC MDIs, which bought time market by market during the last transition.

Entry points for student teams

A systems-modelling team could build the supply-cliff model the reports imply but do not publish, using the Ozone Secretariat's Article 7 data centre (https://ozone.unep.org/countries/data), which publishes production and consumption of Annex F HFCs by party and year with no registration: model party-level HFC-134a supply against the Kigali step-downs, pharmaceutical demand by region, and low-GWP pMDI launch dates by molecule and market, to identify the year and countries in which generic salbutamol pMDI supply is most at risk and what stockpile or exemption volume would bridge it. Plant-level production and the 60–70 percent minimum-run-rate threshold are not published anywhere public — that number comes from MCTOC's text, and plant capacity should enter the model as a scenario parameter to be swept, not as a dataset to be obtained. A pharmaceutical-sciences team could produce the desk half of the reformulation question rather than the bench half: compare HFO-1234ze(E) and HFC-152a against HFC-134a on vapour pressure, density, and phase behaviour from the NIST Chemistry WebBook (https://webbook.nist.gov/chemistry/), assemble elastomer and valve-material compatibility from published seal-swell and refrigerant-compatibility literature, map the patent landscape on free full-text patent search (https://patents.google.com/), and end at a specified test plan — which spray-pattern, plume-geometry and cascade-impactor measurements an Article 5 manufacturer's lab would have to run, at what acceptance criteria — since the measurements themselves need pressure-filling equipment, impactor instrumentation and API handling that no student lab has. A policy team could draft a Montreal Protocol decision text for a time-limited pharmaceutical-grade HFC-134a essential-use pathway with a sunset tied to low-GWP availability. Relevant skills: chemical/process engineering, pharmaceutical formulation, health policy, supply-chain modelling.