The transition to low-global-warmingpotential (low-GWP) propellants is one of the most significant changes to pressurised metered dose inhaler (pMDI) development in decades. The environmental driver is clear. The pharmaceutical challenge is considerably more complex.
A pMDI is not simply a drug formulation packaged with a propellant. It is a coupled formulation – container closure – device system in which the propellant contributes directly to metering, atomisation, plume formation, evaporation, and aerodynamic behaviour. Changing one of the fundamental physical components of that system can therefore affect formulation behaviour, device interactions, aerosol generation, dose delivery, regional deposition, and ultimately the evidence required to demonstrate acceptable product performance. The EMA’s current lowGWP pMDI guidance reflects that breadth, covering quality, non-clinical, and clinical considerations rather than treating propellant replacement as a narrow formulation change.
The development objective is therefore not simply to demonstrate that a reformulated product produces acceptable analytical results. It is to understand whether the aerosol journey remains appropriate from device to patient. That requires a broader set of questions: How does it fly? Where does it land? What arrives? These are connected questions, but they are not answered by the same measurement. That three-part framework sits at the centre of the current Proveris low-GWP scientific strategy.
The low-GWP transition creates an opportunity to reconsider when those questions are asked. Rather than relying heavily on a full, expensive, compendial test package early in development when formulations, valves, actuators, and instructions for use may still be changing, a more efficient strategy is to generate a greater density of rapid, mechanistic, and comparative information first. More resource-intensive testing can then be concentrated on candidates that have already been characterised and understood. This is the principle behind Proveris by Design™ (PbD): generate actionable evidence early, follow the mechanism, add realism where its required, and confirm the selected product rigorously.
Low-GWP Reformulation Changes a Connected System
The scientific challenge begins with aerosol generation. Following actuation, a metered volume of pressurised formulation passes through the valve and actuator and undergoes rapid pressure reduction, flash evaporation, and atomisation. The aerosol then continues to evolve after leaving the device as droplets or particles interact with surrounding air and volatile components evaporate. Low-GWP propellants do not have identical thermophysical properties to the currently used HFA-134a. Reviews of HFA-152a and HFO1234ze(E) have highlighted these differences and their potential consequences for formulation and atomisation. Recent experimental studies reinforce the point. Duke and colleagues compared solution pMDIs formulated with HFA-134a, HFA-152a, and HFO-1234ze(E) using APSD, laser diffraction, and high-speed imaging. In the systems studied, HFA-152a produced greater actuator and throat deposition and different plume behaviour, while HFO-1234ze(E) was more similar to HFA-134a in APSD but still showed differences in plume development. A subsequent suspension study demonstrated that the presence of suspended drug further modifies the relationship between propellant properties and spray structure, including flash-evaporation behaviour and plume width.
