This article is part of a special issue on Drug Delivery
Dry-powder inhalers (DPIs) are complex multifaceted systems designed to reproducibly deliver an efficacious dose of medicine
in an appropriate, aerodynamic range of sizes to enable the treatment of systemic or topical diseases (see Figure 1). Variables
that influence the performance and stability of DPIs include the formulation, device, and processes by which the formulation
is prepared (e.g. blending, spray-drying) and filled into the device.
Figure 1: Composition of dry-powder inhaler products (FIGURE COURTESY OF THE AUTHOR.)
Factors affecting dry-powder inhalers
Formulation. Most DPI formulations contain a mixture of active pharmaceutical ingredient (API) and an inert carrier material such as lactose.
As shown in Figure 2, various attributes of the powder formulation must be considered and managed through the preparation
processes and when filling the material into the relevant DPI device or primary device pack (e.g., capsule, preformed blister,
blister disc, or geometrical array). In the ideal world, inhalation powder formulations are insensitive to atmospheric and
environmental conditions such as light, oxygen, and humidity; are uniform in concentration; flow well; have a low tendency
to agglomerate; and do not compact during filling. Under such circumstances, the API might be expected to readily disperse
under low energy conditions to produce a uniform and respirable aerosol with an acceptable fine-particle dose. For topical
inhalation aerosols, aerodynamic particle-size distributions in the region of 2–5 Ám are typically targeted.
Figure 2: Characteristics of dry-powder inhaler formulations. (FIGURE COURTESY OF THE AUTHOR.)
However, powders do not always exhibit these ideal properties. More often, powders are susceptible to moisture which can lead
to changes in surface morphology and/or aggregation. In addition, non-uniformity and concentration gradients can result from
segregation within the powder bed. These and other factors must be effectively managed during the preparation of formulations
and their filling into DPI devices, regardless of device format.
Device. The DPI device into which the formulation is filled can also affect the selection of filling method and equipment. The types
of DPIs range from simplistic, low efficiency, passive devices to high(er) efficiency, active delivery devices in which the
aerosolization process is driven by an external energy source. In terms of powder filling, the most relevant variables are
the size, shape, and array of cavities into which the powder is to be deposited. Reservoir-based devices contain a relatively
large powder hopper compared with devices designed to deliver pre-metered powder doses, typically in the 1–30 mg range, usually
into either capsules or preformed blister cavities. In this context, the dispensing of powders in the fill weight range of
1–30 mg is defined as microdosing.
Cavity arrangement can affect productivity. For example, the unit operations required to fill and index a circular array of
cavities in a disc might require more time than filling a blister strip that indexes linearly. To overcome such device complexities,
unique and tailored filling solutions are beneficial.
Although in simple terms, the process of filling DPI products merely requires the reproducible dispensing of powder aliquots
into a cavity, the microdosing of ordered mixtures containing irregularly shaped particles of different particle-size distributions
and mixed surface morphology represents a significant technical challenge. The need for device-specific equipment for high-speed
operations and consistent processing adds to this challenge.
Filling. Figure 3 demonstrates the different factors to be considered (e.g., equipment, speed, scale) when developing either a clinical
product and/or a commercial product. Figure 3 also indicates potential batch sizes or the number of filled doses required
to support a product evaluation during its development. In formulation feasibility (i.e., pre-investigational new drug/investigational
medicinal product dossier), for example, up to and including clinical proof-of-concept (i.e., Phase IIa) batch sizes in the
region of 100–5000 doses are adequate not only for enabling clinical evaluation but also for the execution of pharmaceutical
development studies. Consider also that fully automated filling solutions are expensive and, as mentioned, tend to be designed
to accommodate a specific device format.
Figure 3: Considerations of development stage in filling dry-powder inhalers. IND is investigational new drug. Ph is Phase.
NDA is new drug application. MAA is marketing authorization application. (FIGURE COURTESY OF THE AUTHOR.)
The challenge, therefore, has been in the development or identification of fit-for-purpose, manual or semi-automated filling
equipment with the capability and functionality to handle inhaled powders in support of early DPI development studies. Although
commonly used for early feasibility studies, manual dispensing of single-digit milligram quantities of powder is extremely
labor-intensive and requires great manual dexterity. The nature of such manual operations can result in significant fill-weight
variability, thereby causing an unnecessary number of rejected doses. Manual operations for inhalation delivery systems also
have the potential to cause the powder to compress or to compress in an inconsistent manner. Such factors can contribute to
variable delivery from the DPI device causing variability in key product-performance measures such as delivered dose uniformity
and fine-particle dose. Such variability can lead to poor decision-making on the part of the inhalation development scientist
regarding the suitability of a formulation or product for further development.