Kindeva

For more than half a century, pressurised metered-dose inhalers (pMDIs) have been a cornerstone of respiratory care because of their portability, reliability and fast-acting performance. However, environmental legislation is now accelerating the transition from traditional hydrofluorocarbon (HFC) propellants to next-generation propellants (NGPs) with lower global warming potential (GWP).

The Kigali Amendment to the Montreal Protocol mandates an 85 percent reduction in HFC production and use by 2036. Regional regulations are translating that global goal into specific, time-bound requirements. In Europe, the updated EU F-Gas Regulation (EU 2024/573) removes the medical-use exemption for inhalers, accelerating the phasedown of high-GWP propellants. The U.K. has retained a similar framework, while in the U.S., the American Innovation and Manufacturing (AIM) Act gives the Environmental Protection Agency (EPA) authority to manage an orderly reduction in HFCs. Each region has its own timelines and criteria, but the direction of travel is clear: greener propellants are the future.

For pharmaceutical developers, this shift introduces scientific, regulatory and manufacturing complexity on a scale similar to the phase-out of chlorofluorocarbons (CFCs) in the 1990s. As a result, choosing the right manufacturing partner is now more critical than ever. The right partner can help ensure compliance, safeguard patients and enable a smooth transition towards more sustainable inhaler products.

Why switching propellants is no simple task

Replacing a high-GWP propellant like HFA-134a with a greener alternative such as HFA-152a or HFO-1234ze requires a complete re-evaluation of the inhaler system. The propellant choice affects every aspect of the pMDI’s performance and design. Shifting to a new propellant changes vapor pressure, density and surface tension, which can alter plume geometry, particle size distribution and lung deposition.

The device materials, valves and canisters must also be tested for compatibility and stability, and formulations may require new excipients or process modifications to maintain performance.

Furthermore, each reformulated product must demonstrate bioequivalence and safety through a new regulatory submission. Manufacturing facilities must also be equipped to safely handle flammable NGPs like HFA-152a, requiring ATEX-compliant systems, rigorous safety protocols and specialised storage and filling equipment.

“As the supply of legacy HFCs declines and demand for NGPs increases, the pMDI supply chain will face pressure. Companies must ensure their chosen partner has secured access to NGPs and critical device components.”

Given these complexities, the ideal MDI manufacturing partner is one that already operates NGP-ready facilities and has hands-on experience with formulation, device compatibility testing and regulatory submissions for inhaled combination products.

The importance of an integrated drug-device development approach

As pMDIs are combination products, the drug formulation, device engineering and manufacturing process are intrinsically linked. Any change in one area affects the others. For this reason, companies must move beyond siloed workflows and embrace integrated drug-device development.

An experienced contract development and manufacturing organisation (CDMO) with end-to-end capabilities can help by assessing the full system together. This minimises the risk of unforeseen incompatibilities, shortens development timelines and ensures that the reformulated product delivers consistent therapeutic performance.

Integrated development also streamlines regulatory interactions. In the U.S., combination products fall under FDA oversight; in the EU, both the European Medicines Agency (EMA) and notified bodies evaluate pMDIs. A partner who understands these multi-agency frameworks can help navigate submissions efficiently and anticipate questions before they become delays.

Evaluating supply chain resilience and scalability

As the supply of legacy HFCs declines and demand for NGPs increases, the pMDI supply chain will face pressure. Companies must ensure their chosen partner has secured access to NGPs and critical device components.

Scalability is another essential factor and the transition to low-GWP propellants will require manufacturing lines that can handle both current and next-generation formulations in parallel during the transition phase. Leading CDMOs have already begun investing in dual-use infrastructure and long-term supply agreements to safeguard clients against volatility in material availability or pricing.

Keeping patients at the centre of innovation

While environmental goals are driving much of the current transition, the end goal must always remain patient care. pMDIs remain vital for delivering fast-acting therapies, particularly for emergency relief. A poorly managed transition risks patient confusion or reduced adherence if familiar inhalers become unavailable.

The right manufacturing partner will prioritise performance equivalence and patient usability throughout reformulation. By maintaining consistent plume geometry, ease of actuation and reliable dosing, developers can ensure that next-generation pMDIs meet sustainability goals without compromising efficacy or patient trust.

What to look for in an ideal MDI manufacturing partner

Selecting the right partner for this new era of pMDI development requires balancing scientific, operational and strategic priorities. Key considerations include:

● Technical readiness: Proven capabilities in handling and manufacturing with NGPs like HFA-152a and HFO-1234ze.

● Regulatory expertise: Experience in navigating global submissions for combination products and understanding region-specific rules.

● Integrated approach: Ability to co-develop formulation, device and process in a single, coordinated workflow.

● Infrastructure and safety compliance: ATEX-certified facilities and validated processes for flammable propellants.

● Supply chain resilience: Established relationships with propellant and component suppliers to ensure continuity.

● Scalability: Flexible manufacturing lines to support commercial-scale production without disrupting existing supply.

● Patient focus: A commitment to maintaining therapeutic consistency and usability during and after reformulation.

Building a sustainable future through collaboration

The shift to next-generation propellants is one of the most significant transformations the respiratory drug-delivery sector has faced in decades. It will test the industry’s scientific ingenuity, regulatory agility and manufacturing resilience. However, it is also an opportunity to build a more sustainable, patient-centred model for inhalation therapy.

By choosing partners with deep inhalation expertise, robust infrastructure and a collaborative mindset, companies can not only meet environmental targets but also ensure continuity of care for millions of patients worldwide.