The pMDI Propellant of Tomorrow: Regulatory History and the Emergence of HFO 1234ze(E)

A Turning Point for the Ozone Layer

In the early 1980s, scientists were sounding the alarm: chlorofluorocarbons (CFCs), widely used in refrigeration, aerosol sprays, and medical inhalers, were depleting the ozone layer. The upper stratosphere, our planet’s protective shield against harmful ultraviolet radiation, was under threat. The United Nations Environment Program (UNEP) responded by initiating global negotiations to safeguard the ozone layer. These efforts culminated in the 1985 Vienna Convention for the Protection of the Ozone Layer and later the Montreal Protocol. By 1987, 24 nations had signed the Protocol, which came into force in 1989. Today, it is considered one of the UN’s most successful global agreements, achieving near-universal ratification. By 1991, 68 nations — representing over 90% of global CFC production — had ratified the Protocol(1). That same year, the London Amendment introduced a complete ban on CFC production and use starting in January 2000.

The Pharmaceutical Challenge

For the pharmaceutical industry, CFCs weren’t just industrial chemicals — they were the heart of pMDIs (pressurised metered-dose inhalers). Recognising this, the Protocol allowed pharmaceutical manufacturers extra time to transition, provided they were actively developing alternatives. Before the late 1990s, nearly all pMDIs relied on CFC-11, CFC-12, or CFC-114(2). These compounds were listed in major pharmacopoeias, including the European Pharmacopoeia (Ph.Eur.). The last CFC-based pMDI in the UK, a beclometasone inhaler made by Teva and Neolab, remained on the market until 2010 — more than a decade after the Protocol’s original deadline(2).

Enter HFAs: The First Sustainable Alternative

The 1990s saw a breakthrough: hydrofluoroalkanes (HFAs). This new class of propellants offered the chemical stability and performance of CFCs without harming the ozone layer. Leading pMDI manufacturers joined the International Pharmaceutical Aerosol Consortium for Toxicity Testing (IPACT) to ensure HFA 134a and HFA 227ea were safe for widespread use(3). By 2000, HFAs had effectively replaced CFCs in inhalers. By 2016, HFA 134a had become the most widely used pMDI propellant(4), with regulatory specifications defined in Ph.Eur. monograph no. 2257 for Norflurane. But there was a catch: while HFAs protect the ozone layer, they have a high global warming potential (GWP). HFA 134a and HFA 227ea are 1,430 and 3,220 times more potent than CO₂ per metric ton(5).

The Kigali Amendment: Linking Ozone Protection to Climate Action

To tackle the climate impact of HFAs, world leaders reconvened in Kigali, Rwanda, in 2016. The result was the Kigali Amendment to the Montreal Protocol, committing nations to phase down HFCs by 80–85% by the 2040s. Developed countries began with a consumption freeze in 2023, followed by accelerated reductions by 2028. This global action is projected to prevent up to 105 billion tonnes of CO₂-equivalent emissions and avoid as much as 0.5°C of warming by 2100(6). The agreement demonstrates how international policy can address environmental challenges in tandem — protecting both the ozone layer and the climate.

HFO 1234ze(E): The Propellant of Tomorrow

As of 2026, attention is shifting to hydrofluoroolefins (HFOs), particularly HFO 1234ze(E), which promises to be the pMDI propellant of the future. HFO 1234ze(E) is ozone-safe, has a lower GWP than CO₂, and appears to have fewer physiological side effects than Norflurane. Toxicological studies have been completed, and regulatory approval has been granted in the UK, Europe, and the USA. Early adopters include Kindeva Drug Delivery, Honeywell, AstraZeneca, Chiesi, and Recipharm — signalling a new era where patient care and environmental responsibility go hand in hand.

References

(1) Montreal Protocol 1991 Assessment; United Nations Environment Program, Report of the Halons Technical Options Committee, December 1991
(2) https://www.centreformedicinesoptimisation.co.uk/phase-out-of-chlorofluorocarbon-cfc-containing-pharmaceutical-metered-dose-inhalers/#:~:text=Pharmaceutical%20metered%20dose%20inhalers%20(pMDIs,CFCs%20is%20being%20phased%20out
(3) https://www.daikinchem.de/sites/default/files/pdf/Propellants/Daikin%20Propellants%20-%20Solkane%20227,%20134a%20pharma.pdf
(4) https://aacijournal.biomedcentral.com/articles/10.1186/s13223-017-0202-0
(5) https://www.epa.gov/climate-hfcs-reduction
(6) https://www.unep.org/ozonaction/who-we-are/about-montreal-protocol