Staying Ahead of Green Propellant Regulations in pMDIs

For more than half a century, pressurized metered-dose inhalers (pMDIs) have been the backbone of respiratory care. They’ve helped millions of people breathe easier, offering a portable, reliable and fast-acting way to deliver critical therapies. However, the propellants that power these devices come with an environmental cost. Traditional hydrofluorocarbons (HFCs) used in inhalers are potent greenhouse gases and are a key target for reducing environmental impact, as mandated by regulators worldwide.

In Europe, the U.S., Asia and other countries, new legislation is accelerating the transition to next-generation propellants (NGPs) with dramatically lower global warming potential (GWP). For pharmaceutical companies and pMDI developers and manufacturers, this is a complex scientific, regulatory and manufacturing challenge. The good news is that with the right foresight and preparation, it’s also an opportunity to make inhaled medicines more sustainable while safeguarding the needs of patients and ensuring pMDI product performance.

In this article, we’ll explore the evolving regulatory landscape, unpack the scientific and technical challenges of reformulating with green propellants and outline strategies companies can take to future-proof their pMDI portfolios.

A wave of regulation is reshaping the pMDI landscape

The pressure to move away from high-GWP HFCs has been evolving over the past decade. The 2016 Kigali Amendment to the Montreal Protocol set the stage by mandating a global phasedown of HFC production and use. Signatory countries, including the U.S., U.K. and all EU member states, have committed to an 85% HFC reduction by 2036.¹

That global commitment is now being translated into regionally specific laws:

• Europe: The updated EU F-Gas Regulation (EU 2024/573), which took effect in March 2024, accelerates the HFC phasedown and removes the medical-use exemption for inhalers.²
• U.K.: Post-Brexit, the U.K. retained its own F-gas framework, aligned with the EU and Kigali timelines.³
• U.S.: The American Innovation and Manufacturing (AIM) Act empowers the EPA to phase down HFCs. The agency is actively shaping rules for “essential uses” like pMDIs, but the emphasis still lies with greener propellants.⁴

The urgency of this legislation is reflective of the carbon footprint of a single HFC-based inhaler, which can be equivalent to driving a car more than 100 miles.⁵ For policymakers focused on climate targets, tackling this is a key priority in the effort to reduce environmental impact.

At the same time, regulators are tightening exemptions that once shielded inhalers from climate legislation. That means companies that delay may find themselves unable to supply existing pMDI products to patients.

Why switching propellants is more challenging than it sounds

On the surface, the solution might seem simple: swap the current propellant for a greener one. In reality, nothing about this transition is straightforward. The propellant does not act alone in an inhaler and it is not readily interchangeable—it’s an integral part of the final, safe and effective drug product.

Switching from traditional HFC propellants, HFA-134a or HFA-227, to NGPs like HFA-152a or HFO-1234ze requires a complete re-evaluation of the inhaler system, including simultaneous formulation and device development:

• Formulation science: The propellant affects solubility, stability and suspension of the drug formulation. Even a chemically similar NGP like HFA-152a can require new excipients or process changes to maintain stability. Due to solvency considerations, products propelled by HFO-1234ze can also require re-engineering.
• Device compatibility: The propellant interacts with the canister, valve and device seals. Each material must be tested to ensure it won’t degrade or leach impurities into the drug.
• Patient performance: Reformulated products must demonstrate bioequivalence and deliver the same therapeutic effect through consistent plume geometry, particle size distribution and lung deposition.
• Manufacturing safety: HFA-152a is classified as flammable, which means facilities must be engineered with compliant equipment and strict safety protocols.
• Regulatory hurdles: A propellant switch is considered a new product by regulators. That means a fresh data package covering toxicology, efficacy, stability and safety is required.

In short, there’s no such thing as a simple substitution. Reformulating with NGPs requires deep technical expertise across formulation, device engineering and regulatory affairs.

NGP propellants: environmental, patient and economic benefits 

Another reason this transition is so complex is that it’s not just about compliance but about balancing three competing priorities: environmental stewardship, patient care and economic stability.

On the environmental front, the numbers are stark. pMDIs contribute a relatively small share of total healthcare emissions, but because HFC propellants have a GWP substantially higher than CO₂, their impact is disproportionately large. A wholesale shift to NGPs could cut the carbon footprint of inhalers considerably. That’s a win not just for climate targets but for the industry’s social license to operate.

Pharma is under growing pressure from policymakers, investors and patients to align with environmental commitments. Inhalers have become a visible test case for how seriously the sector takes its responsibility to contribute to climate solutions.

At the same time, pMDIs are medicines first and environmental products second. Inhalers remain indispensable, particularly for acute rescue therapies where the quick actuation of a pressurized device is unmatched.

If patients are pushed too quickly onto unfamiliar devices like dry-powder or soft-mist inhalers, adherence could suffer. Research already shows that device misuse is one of the leading causes of poor asthma control. Patients who are stable on pMDIs may resist switching if it means learning new techniques or managing bulkier devices. Compromised adherence could lead to more exacerbations and more hospital admissions.

Balancing climate goals with patient realities means ensuring that NGP pMDIs are available, reliable and trusted, so patients can continue to access the devices they know and use effectively.

Finally, the economics are equally critical. Supplies of legacy HFCs are shrinking as chemical producers ramp down production in line with the Kigali amendment, driving up prices for what’s left. For pharma companies, this adds volatility to production costs and threatens the affordability of existing products.

On the flip side, an unmanaged switch to alternative devices could impose heavy costs on healthcare systems. In the U.K. alone, analysts estimate that replacing pMDIs with dry powder devices could cost the NHS an additional $127 million per year,⁶ a figure that doesn’t capture indirect costs such as retraining clinicians and educating patients.

For payers, policymakers and pharma alike, the most economically sustainable path is to reformulate pMDIs with NGPs, not abandon them. That way, costs remain manageable, supply chains remain stable, and patients retain access to familiar devices.

The road ahead: strategies for staying ahead of regulations

So, what can pMDI developers do today to stay ahead of evolving rules and avoid costly delays? The key is to act now, with a clear and proactive strategy that balances science, regulations, manufacturing and patient needs.

1. Start regulatory planning early

Every region is moving at its own pace and regulations are changing quickly. Companies should map regulatory milestones across their key markets now, building transition timelines that account for approval lead times and potential bottlenecks.

2. Evaluate propellant options pragmatically

HFO-1234ze has promising research data, but its solvency properties mean it may be more suitable for new formulations or niche cases. On the other hand, HFA-152a has properties closer to HFA-134a and is emerging as the near-term workhorse for most reformulations. Choosing which NGP to pursue wisely and early will prevent wasted investment.

3. Consider the entire drug-device product, not just the propellant

As pMDIs are combination drug-device products, formulation, device and manufacturing must be co-optimized. Developers should invest in integrated testing approaches that evaluate performance, stability and usability together rather than in silos.

4. Keep the patient front and center

Regulatory agencies will expect proof not just of bioequivalence but also of patient usability. Reformulated pMDIs must be intuitive, reliable and trusted by patients to ensure adherence. Engaging with patient groups early can provide valuable insights during this step.

5. Build resilience into the supply chain

Adopting NGPs will put pressure on chemical suppliers, component manufacturers and filling facilities. Securing reliable sources of propellants and device parts now will help reduce the risk of bottlenecks later.

Collaborating to prepare for NGP success

No company must navigate the NGP transition alone. The scale of the technical, regulatory and infrastructure changes present a powerful opportunity for collaboration. When pharma innovators, chemical suppliers, device engineers, regulators and contract development and manufacturing organizations (CDMOs) work together, they can combine expertise, share risk and accelerate solutions that no single player could achieve in isolation.

The most successful partnerships will be those that integrate deep inhalation science with purpose-built pMDI infrastructure. Organizations that have already invested in NGP-ready manufacturing lines, developed expertise in handling flammable propellants and built regulatory experience with inhaler submissions can provide a solid foundation for enabling the NGP switch.

Learning from the past

The pMDI industry has successfully navigated this kind of transition before: from CFC propellants to HFAs in the 1990s. That shift demonstrated the importance of early planning, coordinated communication and investment in purpose-built infrastructure. It also showed that collaboration reduces the duplication of efforts and builds confidence with regulators and patients alike. The current NGP transition is even more complex, but those lessons are highly relevant, and developers and partners should aim to learn from experience.

Ultimately, the transition to low-GWP propellants will be defined not by the technical hurdles alone but by how well the industry collaborates. Partnerships that integrate scientific expertise, manufacturing capability, regulatory foresight and patient insight will determine pMDI success and how quickly patients and the planet benefit.

Working toward a more sustainable future, one breath at a time

The mandated phasedown of high-GWP propellants marks a turning point for the pMDI sector and respiratory care. By reformulating inhalers with low-GWP propellants, the industry can help reduce the carbon footprint of a critical therapy platform while preserving the convenience, portability and effectiveness patients depend on.

Success will come from thoughtful planning and early action. Developers and manufacturers that take steps now by aligning with regulations, selecting the right propellant strategies, investing in the right infrastructure and collaborating with experienced partners will be well-positioned to navigate the transition smoothly.

Greener pMDIs are moving quickly from aspiration to reality. With careful preparation and collaboration, the industry can deliver pMDIs that reduce environmental impact while maintaining the safety, effectiveness and usability that patients depend on. In this way, the shift to NGPs can help support both patient health and broader sustainability goals.

References:

1. Explanatory memorandum on the Kigali Amendment to the Montreal Protocol on substances that deplete the ozone layer, Kigali Amendment to the Montreal Protocol on Substances that Deplete the Ozone Layer

2. Regulation (EU) 2024/573 of the European Parliament and of the Council of 7 February 2024 on fluorinated greenhouse gases, amending Directive (EU) 2019/1937 and repealing Regulation (EU) No 517/2014, Official Journal of the European Union

3. Fluorinated gas (F gas): guidance for users, producers and traders, UK Government

4. Protecting Our Climate by Reducing Use of HFCs, United States Environmental Protection Agency

5. Asthma inhalers and climate change. What is this decision aid about? National Institute for Health and Care Excellence

6. Costs of switching to low global warming potential inhalers. An economic and carbon footprint analysis of NHS prescription data in England. DOI: 10.1136

Craig Sommerville is Senior Vice President at Kindeva Drug Delivery, a global leader in combination drug delivery solutions. With decades of expertise in inhalation science and manufacturing, Kindeva partners with pharmaceutical companies to advance sustainable therapies and navigate complex regulatory transitions.