As the headlines about the climate emergency get ever more chilling, the propellants used in pressurised metered-dose inhalers (pMDI) for the treatment of asthma are once again under intense scrutiny. Frank Judge, consultant chemist at Butterworth Laboratories Limited, believes the industry is behind the curve in rolling out next-generation pMDIs that reflect the latest scientific understanding about the atmosphere and global warming.

Judge says: “Inhaler propellants have been in the spotlight since the late 1970s when the United States National Aeronautics and Space Administration (NASA) launched the Total Ozone Mapping Spectrometer (TOMS) mission aboard its Nimbus-7 satellite to study the concentration and distribution of global atmospheric ozone. The mission collected data from 1979 until 2004.(13,14) Environmental concerns have been the driving force of their evolution over the past decades.

“We are now at another turning point for pMDIs and the excipients they use for API delivery and it’s very likely that regulators step in and shorten the timeline for the phasing out of HFAs. Is the industry ready for this – and what will be the propellant of the future?”

The European Pharmacopoeia (Ph.Eur.) defines pressurised metered-dose preparations for inhalation as “solutions, suspensions or emulsions supplied in containers equipped with a metering valve and which are held under pressure with (a) suitable propellant(s), which can act also as a solvent.”

As a contract testing laboratory, Butterworth has extensive experience in the analysis of propellants with medical applications. Its scientists have been at the coal face of the regulatory changes impacting the industry that have come about as a result of greater awareness of the damage manmade pollution is causing to the climate and planet.

The most significant regulatory milestones to date pertaining to the evolution of propellants are set out in the timeline below:

  • 1981 – scientific consensus grows about the impact on the ozone layer of ionisation of chlorofluorocarbons (CFCs) in the upper stratosphere. In response, the United Nations Environment Program (UNEP) begins negotiations to develop a multilateral agreement for ozone protection.
  • 1985 – the Vienna Convention for the Protection of the Ozone Layer is introduced and this evolves into the Montreal Protocol.
  • 1987 – In September of 1987, 24 nations sign the Protocol and it is introduced two years later. The Montreal Protocol is arguably the single most significant global accord ever tabled by the UN that achieved such a level of universal ratification.(2) The Protocol schedules the phase-down of production of CFCs, with an initial target of a 50% reduction by 1998. MDIs were considered a critical use product and this application involving the use of CFCs is exempted from the protocol schedule. Shortly after the Protocol is negotiated, new scientific evidence conclusively links CFCs to the depletion of the ozone layer, and reveals that significant damage has already occurred(1) as was witnessed by the expanding ‘ozone hole’ being observed by NASA over the Antarctic. Extensive investigations are now underway to identify suitable CFC replacements for use in pMDIs.
  • 1989 – The International Pharmaceutical Aerosol Consortium for Toxicity Testing (IPACT I) is formed to evaluate HFA 134a as a CFC replacement, followed by IPACT II for HFA 227ea in 1990. These consortia comprised the world’s major pMDI manufacturers, who collectively sponsor toxicological testing of HFA 134a and HFA 227ea to demonstrate their compatibility and safety as pMDI propellants.(3)
  • 1990 – In June, the parties to the Protocol meet in London and agree to amendments requiring more urgent controls on CFCs.
  • 1991 – By April, 68 nations have ratified the Protocol. These countries account for more than 90% of the world’s production of CFCs.(1) The London Amendment is published and include a revised 100% phase-down on the production and use of CFCs from January 2000.
  • 2016 – October. The Parties to the Montreal Protocol reach an agreement in Kigali, Rwanda to phase down production and use HFAs. Countries agree to add HFAs to the list of controlled substances and approve a protocol schedule for their reduction by 80% to 85% by the 2040s.

Judge says: “Before the late 1990s, pMDIs were almost exclusively manufactured using the CFCs CFC 11, CFC 12, and CFC 114,(8) and monographs for these were included in the major pharmacopoeias including the Ph.Eur.

“The benefits of these propellants were their physical and chemical characteristics including stability, low boiling point, low toxicity, and inert pharmacology. When first introduced for use, the CFCs underwent virtually no toxicological testing(9). They also readily dispersed or solubilised many active pharmaceutical ingredients (APIs).”

The Protocol led to increased use of hydrocarbons such as butane and iso-butane as propellants, in a variety of industries, however, these were not suitable for sensitive respiratory API delivery. The largest single application of pMDIs then, and continues to be, for the administration of the APIs, beclometasone, corticosteroid, salbutamol, salmeterol, budesonide, and formoterol, for the treatment of asthma. Drug formulations can include more than one of these actives, and are often accompanied by percent levels of ethanol to aid the solubility of the APIs.(9) The last CFC-driven pMDI sold in the UK contained a beclometasone-based formulation, manufactured by Teva and Neolab. This production finally ceased in 2010.(8)

HFAs – a new chapter 

The next step in the evolution of propellants used in pMDIs was the use of HFAs, an important development, Judge argues, as this class of propellants had many of the beneficial physical and chemical characteristics of CFCs but had no ozone-depleting potential. Studies of HFA 134a and HFA 227ea were carried out by the International Pharmaceutical Aerosol Consortium for Toxicity Testing (IPACT), which was comprised of the world’s major pMDI manufacturers.(3)  These studies were carried out between 1990 and 1994.

“The only negative characteristics identified by the IPACT I and II studies were that, not surprisingly, both HFAs should be expected to lower the normal 100% oxygen levels in the lungs to a range of between 81% and 93% depending on the number of actuations administered, and also the physical characteristics of pMDI used (this had also been true of CFCs).(3) It was however found that both were pharmacologically active and could act as smooth muscle relaxants. When inhaled, these and all other fluorinated hydrocarbons have smooth muscle relaxant properties in the gut, vasculature, uterus, and lungs (bronchial smooth muscle) via calcium channel blocking, which is the end physiological response to HFAs resulting from their action on magnesium sulfate and beta2-agonists.(9)

“Dossiers resultant from the IPACT I and II studies were submitted to all of the major world health authorities including the European Health Authority Committee for Proprietary Medicinal Products (CPMP).”

In 1994 the CPMP ruled that HFA 134a could be a suitable alternative to the CFCs when demonstrated to comply with the approved quality specifications. A year later, a similar conclusion from the CPMP followed regarding HFA 227ea.(3) Still, it would be many years before these HFAs would see use commercially in pMDIs for human use because of the requirement for toxicological testing to establish the compatibility and safety of each proposed API formulation in conjunction with its propellant, and the subsequent review and approval of each specific Drug Master File (DMF) by the CPMD. 

In the case of HFA 227ea, the specification of Solvay (formerly Hoechst AG, now Daikin) was adopted and published by the CPMP since it had been the manufacturer and sole supplier of HFA 227ea used in IPACT II toxicological studies.(3) No monograph for HFA 227ea was published in the Ph.Eur. Solvay had submitted its DMF including its specification for HFA 227ea as part of the IPACT II dossier.(3) The generic names Apaflurane for HFA 227ea (1,1,1,2,3,3,3-Heptafluoropropane) and Norflurane for HFA 134a (1,1,1,2-Tetrafluoroethane) were adopted and used extensively from the late 1990s.

In 2016, Norflurane was the most extensively used propellant in the manufacture of pMDIs(9) and its regulatory specification is defined in the current Ph.Eur. monograph no. 2257 for Norflurane (04/2013:2257 corrected 10.0). The 1990 IPACT I protocol for the toxicological testing of Norflurane had been incomplete and the anaesthetic activity of Norflurane was missed.(9) The Norflurane study in humans included inhalation in short doses at a maximum of only 0.8% in air.(9) For perspective, the highly active isoflurane is the most potent of the currently used inhalation anaesthetics, and a sustained level of 1.15% is required to render 50% of human subjects unconscious of pain.(11) Recreational abuse of pMDIs containing Norflurane became common, and it was reported that endurance Olympic athletes using Norflurane pMDIs had a performance advantage.(12) Toxicological testing in the UK now complies with the more stringent protocols of the Organisation for Economic Co-operation and Development (OECD), the International Conference on Harmonisation (ICH), and the European Chemicals Agency (ECHA) among others and it is unlikely that such anaesthetic activity would go unnoticed.

Looking to the future

Judge says HFAs have defined our success in addressing the problem of ozone depletion but believes our current understanding of atmospheric science now poses an even more critical challenge, that of global warming. We must limit the expected rise in temperature caused by the emission of greenhouse gases to a maximum of 2°C, to avoid catastrophic world disasters. “This will require the ending of production and use of HFAs,” says Judge.

“While HFAs have zero ozone-depleting effect, they have a global warming potential (GWP) immensely greater than that of CO2. HFA 134a and HFA 227ea for example, have respectively 1,430 and 3,220 times the GWP of CO2 per metric ton of emission.(5)” 

In 2016, the parties to the Montreal Protocol reached an agreement in Kigali, Rwanda to phase-down production of HFAs. Countries agreed to add HFAs to the list of controlled substances and approved a protocol schedule for their reduction by 80% to 85% by the 2040s. The first reductions by developed countries has already begun. Some developing countries will freeze HFC consumption levels in 2024 and 2028. Under the Kigali Amendment, actions to limit the use of HFAs under the Montreal Protocol are expected to prevent the emissions of up to 105 billion tonnes of carbon dioxide equivalent of greenhouse gases, helping to avoid up to 0.5°C of global temperature rise by 2100, the single largest contribution the world has made towards keeping the global temperature rise below 2°C.(2)

The schedule of the Kigali Amendment may well be brought forward as new research reveals that human fossil fuel emissions are threatening to create the level of global warming years earlier than expected – and could see the world breach the critical 1.5°C number by 2029 rather than the mid-2030s as previously thought. So, what will come next?

Scientists at Butterworth propose hydrofluoroolefin HFO 1234ze(E) (1,3,3,3-Tetrafluoroprop-1-ene) could become the pMDI propellant of tomorrow.

“HFO is not ozone-depleting, has a global warming potential less than that of CO2, and has fewer physiological side effects than Norflurane,” says Judge, who worked at Huntingdon Life Sciences before joining Butterworth more than thirty years ago. Toxicological studies allowing the use of HFO 1234ze(E) in pMDIs have already been completed and approved by regulators in the UK, Europe and the USA and Judge urges the industry to start exploring next-generation pMDIs like Honeywell, Kindeva Drug Delivery, and AstraZeneca.

In November 2021, Kindeva Drug Delivery announced that it was installing a new pMDI line capable of filling HFO 1234ze(E) and that it expected to launch two products containing HFO 1234ze(E) by 2025.

Last February, Honeywell and AstraZeneca announced a joint venture reporting that Honeywell’s proprietary HFO 1234ze(E) ‘Solstice Air’, will be used in AstraZeneca’s next-generation pMDIs for the treatment of the respiratory conditions asthma and chronic obstructive pulmonary disease. Chiesi and  Recipharm have also both reported that they expect to release pMDI products containing HFO 1234ze(E) before 2025. 

Frank Judge worked as a scientist for Huntingdon Life Sciences in Suffolk, UK, before 30 years of service with Butterworth Laboratories Limited in Teddington, Middlesex, UK. He is a consultant chemist. This article has been written to provide a summary of the history of propellants used in pMDIs from the 1980s onwards, bringing together information from a variety of sources, gained from Butterworth’s experience of analysing the materials involved.

  • Montreal Protocol 1991 Assessment; United Nations Environment Program, Report of the Halons Technical Options Committee, December 1991.
  • https://www.Honeywell-Solstice%C2%AE-ze-Brochure_EN.pdf
  • Ph.Eur. Norflurane monograph 2257 (04/2013:2257 corrected 10.0)
  • Pharmacology and Therapeutics for Dentistry (Seventh Edition), Steven I. Ganzberg, Daniel A. Haas, 2017.