By: Tom Daly and Karl Bass

The inhalation industry’s shift to low Global Warming Potential (GWP) propellants is well underway. Regulatory phase-downs of existing hydrofluoroalkane (HFA) propellants, a shrinking supply base and corporate net-zero targets have made the move to HFA-152a and HFO-1234ze(E) a practical priority for most pharmaceutical developers. Major companies are already deep into development, with the first low carbon pressurized Metered Dose Inhaler (pMDI) products now reaching regulatory approval. For those following, the challenge is completing the transition efficiently and with acceptable risk.

But choosing a propellant is only the first step. Both next-generation alternatives have distinct physical and chemical properties that affect each stage of development. These differences affect how formulations behave as suspensions or solutions, how the system performs when combined with the valve, actuator and canister, and what infrastructure a filling site needs to operate safely at scale. Managing that complexity efficiently is a priority across the industry.

At Bespak®, the specialist inhalation CDMO, the answer has been a digital-first development approach: using computational simulation to reduce risk and accelerate decision-making across the full pMDI lifecycle.

Starting with the Formulation

The two propellants present different challenges from the outset. HFA-152a has a lower density and different molecular characteristics than current options, as well as dynamic viscosity, all of which affect suspension stability, droplet size and drug solubility. HFO-1234ze(E), with near-zero GWP, behaves more similarly to today’s HFA-134a, though its spray characteristics still require careful attention during development.

For developers reformulating existing products, this means verifying that aerodynamic performance — particle size, fine particle fraction and dose consistency — is preserved, alongside a clear understanding of how device geometry interacts with the new propellant.

Bespak’s formulation development capabilities span early feasibility work characterizing drug-propellant behavior through to in vitro aerodynamic performance testing, giving developers reliable data on formulation behavior before committing to full-scale development. That breadth of experience across both propellants substantially reduces the risk of costly late-stage reformulation.

Modelling Before Manufacturing

The metering valve refill is a less-studied area in pMDI development. After each actuation, propellant must refill the metering chamber before the next dose can be delivered, and inconsistent refill directly compromises dose consistency.

Bespak has applied computational fluid dynamics (CFD) to model this event across all four propellants currently in development or use. The data shows meaningful differences: by 300ms post-actuation, HFA-152a achieves 88.3% liquid fill compared to 75.9% for HFO-1234ze(E), a difference with direct implications for dose consistency. The modelling shows these differences can be compensated through adjustments to valve inlet geometry, tested virtually rather than through repeated physical prototypes. Engineers can explore process variables digitally and identify manufacturing-ready solutions before committing to a physical build.

Bespak also uses advanced statistical modelling to map the full design space of the metering valve, which has over 100 design inputs influencing more than 20 performance outputs. This allows critical variables to be identified and manufacturing tolerances optimized, without the time and material cost of large-scale physical trials. The approach has been validated to within 1% of real-world manufacturing data, and in one recent project it avoided the need for up to five tons of plastic in molding trials. The same framework is now being extended to model drug-propellant interactions alongside valve mechanics, moving towards an integrated formulation and device development approach.

Getting the Hardware Right

These simulation outputs inform real product decisions. The Bespak® BK357 valve platform is trusted across suspension and solution formulations in highly regulated markets worldwide, and it served as the proving ground for low GWP optimization. Transitioning to HFA-152a and HFO-1234ze(E) required careful materials work: HFA-152a’s molecular properties increase the risk of propellant leakage and moisture ingression through standard elastomers. The solution was a hybrid BK357 configuration with EPDM seals and a bromobutyl neck gasket, validated for near-zero leakage and formulation stability with both propellants.

Life Cycle Assessments (LCAs) run alongside the development process, ensuring material choices also contribute to reducing overall carbon impact. Decarbonization, in short, extends beyond propellant selection to the choice of hardware materials.

From Development to Patient Supply

Simulation de-risks development; manufacturing capability converts that work into patient supply. Bespak is the first CDMO to manufacture pMDIs at commercial scale with HFO-1234ze(E), with HFA-152a commercial capability following. Five low carbon pMDI lines are now operational or under construction at the Holmes Chapel site, providing an integrated pathway from feasibility through clinical supply to full commercial production.

In March 2026, Chiesi Group expanded its partnership with Bespak to advance its Carbon Minimal Inhaler program, selecting Holmes Chapel as a key manufacturing source on the grounds of shared sustainability values, technical excellence and supply chain resilience. For developers navigating the same transition, it underlines the value of a CDMO with proven digital development capability and the manufacturing infrastructure to match.

About Bespak

Bespak offers a fully integrated service for developing and manufacturing inhaled and nasal drug products, devices and components for the global pharmaceutical market. With a long history in the development and commercial supply of pressurized Metered Dose Inhalers (pMDIs), Bespak supplies a major proportion of the world’s pMDI valves and actuators. Built on established expertise but ready for the future, Bespak is a long-term innovation partner committed to driving sustainability in the industry. The company has both established capacity and ongoing expansions to enable the manufacture of pMDIs with low Global Warming Potential (GWP) propellants.