With the first low global warming potential (GWP) propellant-driven MDIs now approved in the UK and endorsed for use in the EU, reformulation has moved from long-term ambition to commercial reality. In this blog, we review progress to date, examine the growing importance of robust bioequivalence (BE) testing, and consider how regulatory expectations are beginning to take shape across major markets.
Multiple, widely prescribed MDIs are being reformulated at pace to reduce environmental impact. For AstraZeneca, the commercial transition to next-generation Trixeo Aerosphere® is already underway, with Chiesi and GSK close behind. However, regulatory approaches and the speed of adoption vary significantly across countries.
In December 2023, we published an initial blog surveying the MDI reformulation landscape. This blog revisits the topic, looking at recent progress, changing testing practice and what emerging regulatory expectations mean for developers.
In this blog:
- The current commercial landscape.
- A closer look at testing and the demonstration of bioequivalence (BE).
- A comparison of progress and regulatory approach in the UK, EU and US.
Estimated reading time: 10 minutes
MDI reformulation: where the market stands now
AstraZeneca, Chiesi and GSK are among the most visible companies progressing low-GWP MDI development.
AstraZeneca was first to market following MHRA approval of next-generation Trixeo Aerosphere® in May 2025. The product uses the propellant HFO-1234ze. A positive opinion from the EMA followed in July 2025, supporting use in the EU. The transition of supply across the UK and Europe is now underway, with regulatory submissions under review in China, the US and other markets*.
Chiesi submitted reformulated Clenil® Modulite® to the MHRA on 5 December 2025 and in addition, presented BE data for its beclometasone dipropionate/formoterol fumarate product, Fostair®. Its low-GWP propellant is HFA-152a. Through its partnership with Bespak, Chiesi is also scaling Carbon Minimal Inhaler (CMI) production capacity in the UK*.
GSK announced positive Phase III trial results for a next-generation HFA-152a version of Ventolin in October 2025, with launch expected from 2026, subject to regulatory approval. With annual global sales of around 300 million salbutamol units, this transition could have especially broad impact*.
For teams already working on low-GWP reformulation, or actively evaluating it, these developments point to three clear conclusions:
- Low-GWP MDIs are already a commercial reality for patients and healthcare providers in parts of the UK and Europe.
- Safety data and regulatory approvals for HFO-1234ze are now established in some geographies, while HFA-152a appears likely to follow, reducing uncertainty for subsequent submissions.
The economics of the MDI market, including propellant supply chains and manufacturing investment, are changing quickly.
Steps toward reformulation: assessing the impact of propellant change
For companies embarking on reformulation, there are several decisions and challenges to address. One of which is the next generation propellant to choose: HFO-1234ze or HFA-152a[i].
Each has a different physicochemical profile and a different marketplace to navigate:
- HFO-1234ze is a relatively new propellant with a production route that remains under patent (Honeywell, US).
- HFA-152a has a more established marketplace but active patenting by the leading supplier (Orbia Fluor & Energy Materials (Koura) UK) may complicate development for some drugs and combinations.
Beyond market economics, key technical steps include:
- Demonstrating that the propellant is suitable for use as a medicinal product.
- Determining compatibility with existing devices and components, and whether any redesign will be needed.
- Robustly demonstrating BE to the reference product.
- Assessing any need for manufacturing line modification; the flammability of HFA-152a is a particular concern.
Safety studies are likely to fall most heavily on the first movers, with followers potentially benefiting from the public availability of pharmacovigilance data. Furthermore, experience so far suggests that device and component compatibility may be less disruptive than during the CFC phase-out, although this will vary by product. As confidence in next-generation propellants grows, and safety profiles for their use become established, demonstrating BE will therefore become the defining challenge on the critical path to commercialisation.
Demonstrating BE: evolving practice
For MDIs, the propellant plays a critical role in mixing and aerosolisation, both of which influence delivery of a respirable dose. When reformulating an MDI, the central question is therefore not only whether a low-GWP propellant is compatible with the drug and other formulation ingredients, but whether the reformulated product can demonstrate comparable performance. That places BE testing, and the quality of the supporting in vitro data, at the centre of any reformulated MDI submission.
The most recent FDA Product-Specific Guidances (18 OIPs revised in May 2026) place greater emphasis on a focused set of in vitro studies for the demonstration of BE, including:
- Single actuation content (SAC).
- Aerodynamic particle size distribution (APSD).
- Realistic APSD (rAPSD).
- Dissolution, where appropriate.
SAC and APSD are long-established, but rAPSD and dissolution studies are newer requirements. Both move in vitro testing towards greater clinical relevance.
For many laboratories, the challenge is now practical execution. Two areas are particularly important:
- rAPSD: Uses more representative test conditions, such as mouth-throat models and patient-relevant breathing profiles, to provide a closer link between in vitro performance and likely clinical behaviour. Measurement requires significant modification to compendial APSD set-ups.
- Dissolution: Provides complementary insight into the likely in vivo fate of deposited particles and may help differentiate formulations with similar characteristics, such as APSD, but have potentially different therapeutic effects. There are currently no compendial methods to draw upon, although some consensus is emerging around areas such as dose selection.
More generally, reformulation studies call for repeated DDU and APSD testing to support efficient progress; the analytical burden is considerable. Where newer propellants introduce additional handling considerations, including flammability, test set-ups also need to reflect the practical realities of working with these systems.
And across BE testing, discriminating power is critical. The aim is to detect meaningful differences between the reference and reformulated product. Against this backdrop, automation becomes increasingly valuable. Used appropriately, automation can reduce operator-dependent variability, improve workflow efficiency and strengthen data integrity across high-volume comparative studies.
In MDI testing, this is particularly relevant for shake, fire and flow-control steps, as well as drug recovery, where manual handling can influence consistency. Areas especially suited to automation include:
- Device priming and actuation, supported by automated shake, fire and flow-control platforms such as Vertus® III and DecaVertus® III.
- Drug recovery, supported by tools ranging from simple agitation devices to integrated systems such as the Sample Recovery System™ (SRS) 100i.
Automation tools such as Vertus® III (top left), DecaVertus® III (top right) and the Sample Recovery System™ (SRS) 100i (bottom) enable high-productivity testing while simultaneously enhancing data integrity.
As BE requirements become clearer and automation tools develop, low-GWP MDI developers are in a strong position to build productive, well-controlled, repeatable test set-ups. These create a firm foundation for progress. However, the regulatory framework remains neither fully proven nor harmonised across all jurisdictions.
Regional variability: acceleration and uncertainty
The timetable for F-gas phase-down varies by country. Although MDI propellants represent only a small fraction of total F-gas use, this mismatch sets the scene for uneven global progress. Regulation, market incentives and healthcare economics will further influence how quickly reformulation progresses in each region.
The EU and UK: faster timelines, clear guidance
At present, the EU appears to have the most momentum for reformulation with:
- An accelerated F-gas phase-down timetable introduced in 2024, including significantly tighter production caps.
- Recently updated guidance on demonstrating BE and on specific data requirements when transitioning to low-GWP propellants.
- The first low-GWP MDI has already been endorsed for use (as discussed).
Conditions in the UK are also supportive. High MDI use and NHS Net Zero targets help create a clear market for lower-GWP alternatives.
The US market and FDA guidance
In contrast, progress in the US appears slower and more uncertain.
FDA commentary on low-GWP MDI submissions highlights the growing importance of Product-Specific Guidances for both new and generic drugs. At the same time, the safety profiles of next-generation propellants are further from being established in the US, adding an early burden for developers. The submission pathway remains untested.
The US also lacks the same national healthcare decarbonisation pressure seen in the UK, though MDIs similarly dominate inhaler prescribing, with the cost of DPIs and SMIs discouraging switching[i].
All these factors make the pace of change harder to predict.
Conclusion: what developers should focus on next
Early reformulation progress is encouraging and could help reduce the environmental impact of respiratory medicines. At the same time, the conventional MDI and propellant markets are becoming harder to navigate. For companies considering reformulation, the priorities are becoming clearer:
- Monitor emerging regulatory frameworks closely across target markets.
- Make full use of available guidance to support the core task of demonstrating BE.
- Design test set-ups that generate robust, discriminating and comparable data.
As reformulation progresses, laboratories will need testing workflows that are not only compliant with emerging guidance, but also controlled, repeatable and scalable in day-to-day practice.
Planning a low-GWP MDI reformulation study?
Speak to Copley about building a controlled, repeatable and traceable testing workflow, from actuation and flow control to APSD analysis and drug recovery.
References
[i] J N Pritchard ‘Is the transition to low global warming propellants in metered dose inhalers on track?’ Inhalation Jan 2025.
[ii] J J Feld ‘Lowering Inhalers’ Carbon Footprint: Climate Friendly pMDI Alternatives’ Pulmonology Advisor, April 2025. Available to view at: https://www.pulmonologyadvisor.com/features/inhalers-carbon-footprint-and-pmdi-alternatives/
* Note: all company information is derived from the press releases published on the relevant company websites.
