Most discussions about dry powder inhalers understandably concentrate on what happens during the few seconds in which the patient inhales: how efficiently the formulation is fluidised, how effectively agglomerates are broken apart, and how much of the resulting aerosol reaches the lungs. But for many modern inhaled formulations, there is another equally important period to consider — the months or years before the patient ever opens the dose.
A dry powder formulation does not necessarily remain unchanged simply because its appearance hasn’t changed. Many engineered powders, particularly spray-dried formulations, can be sensitive to atmospheric moisture. Even relatively small amounts of absorbed water can alter particle surfaces, increase cohesion, change the mechanical properties of the powder and affect the way agglomerates form and subsequently break apart. Depending on the formulation, moisture can also contribute to physical or chemical changes in the drug product itself. An aerosolisation system can only work with the powder that reaches it; if the formulation has changed during storage, even the best-designed inhaler may be starting from the wrong place.
This becomes particularly important as inhaled medicines move beyond the traditional highly potent small molecules used for asthma and COPD. Biologics, peptides, vaccines, mRNAs and other complex molecules may be intrinsically more sensitive to their storage environment, and they are often formulated using sophisticated particle-engineering processes precisely to achieve particular aerodynamic and physical properties. Considerable effort may have gone into controlling particle size, morphology, density, surface composition and solid-state characteristics. It seems slightly contrary to engineer that particle beautifully, and then give its packaging anything less than equal attention.
This is why we have always regarded the primary package as part of the Quattrii system, rather than simply the container in which the dose happens to be stored.
An aerosolisation system can only work with the powder that reaches it; if the formulation has changed during storage, even the best-designed inhaler may be starting from the wrong place.
Quattrii uses individually sealed aluminium-laminate coldform blisters. Coldform is extremely useful in this context because the aluminium layer provides an impermeable barrier to moisture ingress, while individual dose sealing means that each dose remains protected until immediately before use. Opening one dose does not expose the remaining doses to ambient air, and there is no bulk powder reservoir that is repeatedly opened, closed and exposed to whatever humidity happens to be present in the patient’s environment.
There is also an important architectural consequence. Packaging is sometimes treated surprisingly late in device development: first develop the formulation, then select an inhaler, and finally work out how to package the dose. That sequence can create compromises, particularly if the eventual package geometry is poorly matched to the volume of powder, the aerosolisation mechanism or the moisture sensitivity of the formulation.
For a moisture-sensitive formulation, the primary package is part of the drug-delivery system.
With Quattrii, the blister is considered from the outset. Its volume, material, forming limits, seal geometry, piercing behaviour and interaction with the aerosolisation system are all parts of the same problem. As described earlier in this series, that does not mean that every aerosolisation function must be performed within the blister itself. In carrier-based Quattrii it plays an active role in deagglomeration and classification, while in carrier-free Quattrii it provides the protected dose volume and supports the initial fluidisation and extraction of the formulation before the more demanding aerosolisation work is performed elsewhere in the system. In both cases, though, the primary package is integral to the architecture.
That becomes especially relevant when dose size increases. A few milligrams of a conventional formulation may fit comfortably into a small blister or capsule, but perhaps 30, 50 or even 70 mg of a low-bulk-density spray-dried powder occupies a surprisingly large volume. The package therefore needs to solve several problems simultaneously: hold the required mass, protect it throughout shelf life, present it reproducibly to the inhaler, and do so in a geometry that does not compromise the subsequent aerosolisation process.
There is also a simple economic argument. If the active material is inexpensive and readily manufactured, losing a proportion of it through environmental degradation is undesirable. If the formulation contains an expensive biologic whose manufacture is difficult, energy-intensive and resource-intensive, preventing avoidable degradation becomes considerably more important. Protecting the formulation is therefore not just a stability question; it can also affect dose consistency, product wastage and the overall efficiency of the therapy.
For the next generation of inhaled medicines, we think primary packaging deserves to move much closer to the beginning of the development conversation. The formulation scientist, packaging engineer and inhaler designer are all ultimately trying to preserve the same thing: a carefully engineered dose that remains in the required condition until the exact moment the patient needs it.
This blog post was originally published as part of a series of LinkedIn articles, written by David Harris.