Equipment and solutions
To address this capability gap, bench-scale powder handling technologies such as Xcelodose (Capsugel, Cambridge, UK), Powdernium
(Symyx Technologies, now Accelrys Inc, San Diego, CA), and the Quantos Perfect Dosing System (Mettler-Toledo, Columbus, OH)
have each found niche application in the small-scale microdosing of inhalation powders. These technologies are being used
in research and development (R&D) studies as well as in current good manufacturing practice (CGMP) production of Phase I and
II clinical-trial materials (1). The data shown in Figure 4a, which are derived from studies conducted in Catalent's Research
Triangle Park, North Carolina, facility using the Mettler-Toledo Quantos system demonstrate that powder blends containing
micronized API and inhalation-grade lactose can be accurately and reproducibly delivered across, in this instance, a target
fill-weight range of 1–25 mg without any powder segregation (2, 3). This assertion is demonstrated by the linear correlation
between API assay value per powder aliquot and the total mass of powder dispensed. In this study, percent relative standard
deviations (%RSD) of < 1% were achieved for fill weights in the range 5–25 mg and < 2.5% for fill weights between 1 and 2.5
mg (n=10 replicate measurements). These results were obtained without any optimization of the filling process, thereby suggesting
that with further optimization, filling precision could be increased.
Figure 4a (left): Effect of powder fill weight on blend concentration—segregation. Figure 4b (right): Effect of filling process
on ærosol performance—compaction. NGI is Next Generation Pharmaceutical Impactor (Westech Instruments, Marietta, GA). (FIGURE
COURTESY OF THE AUTHOR.)
Additionally, the author received a fine-particle dose of > 50% (i.e., defined as the proportion of the dose delivered from
the device with an effective cut-off diameter (< 5 µm), using inertial impaction for the formulation delivered from a simple
capsule-based device (i.e., Monohaler, Plastiape, Italy), generated using a Next Generation Pharmaceutical Impactor (NGI,
Westech Instruments, Marietta, GA). These data are presented in Figure 4b.
In this latter study, the dose from a single capsule was discharged into the impactor at a flow of 100 L/min. Hence, it can
be implied from the comparatively high aerosol efficiency of this simple formulation/device combination that the dry-powder
formulation must have been dispensed into the device during the filling process with minimal compaction of the powder blend,
thus allowing the API to be readily aerosolized from the carrier material on actuation of the device. Furthermore, it should
be noted that through the judicious application of the same processing-equipment configuration, filling procedures, and the
use of common personnel, it was possible to achieve effective process transfer and ensure excellent correlation in performance
of the clinical product with respect to the early R&D development lots.
Scale up. Although it is possible to conduct effective fit-for-purpose filling trials using small-scale semi-automated equipment, such
equipment is not scaleable in a viable manner to allow application for the onward development of a commercial product (1).
A commercial product must be produced in large quantities at high speed and with the appropriate degree of consistency required
to ensure reproducible product quality. Therefore, one cannot develop a product beyond clinical proof of concept without having
in place an effective scale-up path.
As depicted in Figure 3, it is important to bridge the gap from clinical products to commercializable products filled on high-speed,
semi-automated filling equipment. It is also crucial to consider the effect of changes to the filling process, equipment,
formulation, or to the type of device on the product's pharmaceutical performance (e.g., dose delivery, fine-particle dose),
especially when progressing to later stages of clinical development. For example, in these later development stages, higher
speed equipment that is tailored to a particular device or product will need to be introduced.
If a simple, low-cost, off-the-shelf, capsule-based inhaler is used for early clinical studies, a more sophisticated inhalation
device may be selected for the registration and commercial-product stages. In such a case, it is likely that the new device
might generate different aerosol performance and produce differences in dose delivery and fine-particle mass. Technical and
clinical studies would be needed to bridge the early clinical and product development data to that of the product under development
In a similar manner, changes made to the mode of device filling or filling equipment can also affect powder flow, segregation
within the powder stream or bed, powder compaction, and so forth. Any one of these variables, or many other potential sources
of variability, can confer significant changes in the initial performance of the product or in its performance over time (i.e.,
stability and shelf-life).