Improving Inhaled Product Testing: Methods for Obtaining Better In vitro-In vivo Relationships - Pharmaceutical Technology

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Improving Inhaled Product Testing: Methods for Obtaining Better In vitro-In vivo Relationships
Even in an industry in which all product development is complicated by the intricacies of human biology, orally inhaled products (OIP) stand out as singularly demanding.


Pharmaceutical Technology
Volume 37, Issue 2

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).


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