Considerations and Approaches for Filling Dry-Powder Inhalers - Pharmaceutical Technology

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Considerations and Approaches for Filling Dry-Powder Inhalers
The author reviews key considerations for formulating powders for use in inhalers. This article is part of a special Drug Delivery issue


Pharmaceutical Technology
pp. s21-s25

This article is part of a special issue on Drug Delivery


Figure 1: Composition of dry-powder inhaler products (FIGURE COURTESY OF THE AUTHOR.)
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.

Factors affecting dry-powder inhalers


Figure 2: Characteristics of dry-powder inhaler formulations. (FIGURE COURTESY OF THE AUTHOR.)
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.

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.


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.)
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.

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.


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