Figure 5: Approaches for filling dry-powder inhalers. IND is investigational new drug. Ph is Phase. NDA is new drug application.
MAA is marketing authorization application. Omnidose is a tradename. (FIGURE COURTESY OF THE AUTHOR. FIGURE 5 IS REPRODUCED
FROM HARRO HOFLIGER AG/COURTESY AUTHOR.)
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Ideally, the inhalation development scientist should consider the selection of a mode or mechanism of powder-formulation filling
for early formulation feasibility and then replicate that same unit filling operation throughout the product's development
life cycle. Figure 5 provides one example of a scale-up pathway for DPI filling. In this scenario, the unit operation of filling
is conducted using a fixed-volume cavity precision bored into a rotating drum. As the formulation is fed to the filling head,
an aliquot of powder is drawn into the drum bore through the application of a small, negative air pressure. This negative
pressure is maintained as the drum is rotated until the filled cavity is in the six-o'clock position, at which point a small
positive pressure is applied to dispense the powder aliquot into the respective dose packaging format (e.g., capsule, preformed
blister).
Appreciable development work can be required to optimize the cavity geometry and operating pressures for a particular powder
(e.g., active concentration, flow, bulk density) and its target fill weight. However, in general terms, the effect of these
factors on the filling process are consistent irrespective of process scale. When scaling the filling process, if the unit
filling operation is maintained as constant, the major considerations for the process engineer can reduce to those factors
affecting throughput product (e.g., uniformity of powder feed, form/seal/cut configuration, number and array of filling heads,
in-process verification of accuracy and reproducibility) as opposed to optimization of the unit-filling process. As a result,
the likelihood of consistent product quality, consistent product performance and potential to shorten development timelines
is greatly enhanced.
In the laboratory scale equipment presented in this example, the process is operator driven (i.e., the powder is dispensed
into the small hopper located above the single cavity filling drum). A vacuum line is attached to the filling drum, and using
a foot pedal, the operator applies vacuum to the powder to fill the cavity. The operator manually rotates the drum to the
dispense position and, again using the foot pedal, applies positive pressure to dispense the powder into the capsule or blister.
Operation at this scale requires blisters to be preformed and sealed manually. Intermediate scale semi-automated equipment
operates in a similar fashion, however the drum will include multiple filling cavities and contain automation features.
Typically, at this semi-automated scale of operation, the device cavities may be pre-formed, sealed, and cut manually off-line
(if blisters) with statistical off-line fill-weight verification. Although significant operator intervention still occurs
at this scale, filling throughput in the region of 1000–2000 doses per hour is feasible depending on the device configuration.
In the high-speed scenario, all operations occur on-line under high throughput.
Figure 6: An integrated dry-powder inhaler (DPI) filling process scale-up path. (FIGURE COURTESY OF THE AUTHOR.)
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Figure 6 contains some examples of alternative proven methods for the filling of powder-based pharmaceutical products along
with an opinion on suitability for the processing of inhalation powders. In this context, the dosing principle refers to the
specific mode within which the powder is dosed rather than providing any reference to the powder feeding mechanism.
Conclusion
In conclusion, accurate, reproducible, and cost-effective, equipment-based solutions are available to support formulation
feasibility and proof-of-concept clinical studies for molecules in DPI devices. However, application of such approaches requires
the developer to bridge the technical and clinical programs when working toward product commercialization. Although more
expensive, the most robust approach to filling process development, enabling a more rapid path to market, is to adopt a scaleable
process from the outset right through the product development life cycle.
Acknowledgments
This article represents a partial synopsis of a presentation given by Dr. Davies-Cutting at Management Forum, Dry Powder Inhaler
Conference, London, July 2010. Special thanks to Harro Höfliger for the use of certain images and data.
Craig J. Davies-Cutting, PhD, is director of inhalation products and technologies, at Catalent Pharma Solutions in Research Triangle Park, North Carolina,
tel. 919.465.8430, fax 919.481.4908, craig.davies-cutting@catalent.com
.
References
1. Micro-dosing Equipment Fills Niche in R&D, Clinical Trial Materials, Tablets & Capsules, March 2009.
2. L. Mao et al., proceedings of Drug Delivery to the Lungs XIX, Edinburgh, UK, 2008, pp. 195–199.
3. L. Mao et al., "Fast into Man Model for Dry Powder Inhaler (DPI) Development," presented at AAPS, Los Angeles, CA, 2009.
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