Assessing established practice
Assessing the established setup against the information requirements for knowledge-led product development highlights some
of its limitations. The standard United States Pharmacopeia (USP)/European Pharmacopoeia (Ph.Eur) induction port described in USP General Chapter <601> "Aerosols, Nasal Sprays, Metered-Dose Inhalers, and Dry Powder Inhalers" and Ph. Eur. Section 2.9.18
"Preparations for Inhalation", for example, is well-suited to precision manufacture and delivers reliable, consistent performance,
but it is now widely recognized as having a tendency to significantly underpredict the amount of emitted dose captured by
the upper respiratory tract for some products, relative to clinical data (1). Thus, irrespective of deposition behavior within
the lung, the USP induction port tends to overestimate the extent of whole-lung deposition.
Of equal importance is the fact that this setup requires the application of a constant flow rate through both the device and
the cascade impactor, whereas in clinical use, inhaled products are subject to a range of user breathing profiles. The constant
flow rate required by cascade impactors results in a square wave form, rather than the infinitely variable, broadly bell-shaped
patterns of real patients. Furthermore, impactors ideally require multiple volume changes to guarantee reliable and complete
sizing of the aerosol. This requirement invariably results in a test volume that is greater than the inhalation volume of
at least part of the intended patient population.
Finally, there is the overarching concern of productivity. Cascade impaction has long been recognized as a time-consuming,
manually intensive task, which becomes even more limiting as demands for more valuable and discriminating data grow. Alleviating
the burden of analysis is, therefore, important for continued advancement, especially in R&D environments in which budgets
are being increasingly cut.
Better representation of throat deposition
The goal of more closely simulating deposition in the mouth and throat focuses attention on alternatives to the standard USP/Ph.Eur. induction port. One such is a human throat cast (2–5). These alternatives offer the advantage of accurately reflecting the
physiology of a throat. Experimental work, however, has shown significant differences in deposition behavior between different
throat casts (1). Although these differences are to be expected given the variability in human anatomy, they complicate results
interpretation within the context of standardization and routine analysis. Furthermore, reproducible, precision manufacturing
of such casts is complex, which makes them difficult to mensurate and qualify. Because casts are also not easy to handle or
to interface with the impactor, they are less than ideal from a practical standpoint.
These limitations have stimulated interest in developing solutions that fall between a throat cast and the standard induction
port (6). These solutions include the Alberta Idealized Throat (AIT). Developed by researchers at the Aerosol Research Laboratory
of Alberta (University of Alberta, Canada), the AIT has a standardized and highly reproducible but human-like internal geometry
that lends itself to precision manufacture. Its performance is independent of flow rate and, with both pressurized metered-dose
inhalers (pMDI) and DPIs, it has been shown to collect more of the emitted dose than the USP induction port (1, 7, 8). Indeed,
the ability of the AIT to more closely replicate in vivo deposition behaviour in the throat compared with the USP induction port has been directly confirmed in a number of studies,
some of which include marketed OIPs (9–11). AIT geometries are also available in child and infant forms, which widens their
appeal for in vitro testing (12).