Applying the AIM Concept in Support of Developing Improved In Vitro–In Vivo Relationships for OIPs - Good Cascade Impactor Practices, AIM and EDA for Orally Inhaled Products - page 367

measurements with AIM-pHRT apparatus(es) with both full-resolution CI data and
particle deposition profi les utilizing imaging methods, such as gamma scintigraphy,
positron emission tomography, or possibly magnetic resonance imaging. The chap-
ter concludes with the results from the fi rst laboratory-based evaluation of an AIM-
pHRT system based on the ACI equipped with the recently commercialized “Alberta
Idealized Throat” (AIT) adult upper airway geometry.

12.1 A Roadmap for Improved Comparisons of Laboratory-

Generated OIP Performance Measures with Clinical Data

An AIM-based approach can potentially be used to compare and correlate in vitro
APSD data with the likely particle deposition profi le in the HRT that should ideally
be linked with clinical effects [ 1 , 2 ]. The relationship between deposition locations
in the lower HRT and the clinical effect of the drug being delivered in aerosol form
depends on the action of the API(s) in relation to appropriate receptors at different
locations within the respiratory tract. Some drug products may be designed to pen-
etrate deep into the periphery of the lung [ 3 , 4 ], although others may be intended for
deposition primarily in central or upper airways for maximum effectiveness [ 5 , 6 ].
In Chap. 2 , it was explained that the size selectivity of the HRT is relatively poor
compared with that of a CI. It can therefore be argued that any further detail in terms
of size resolution beyond the three fractions CPM , FPM , and EPM , traditionally
reported when reducing the raw data from full-resolution CIs into stage groupings,
is superfl uous from the clinical perspective [ 7 ]. Interestingly, only three size
fractions—oro- or nasopharyngeal, tracheobronchial, and alveolar deposition—are
used in the fi eld of occupational health to describe the inhalation of potentially toxic
particles [ 8 ].
Furthermore, similar size fractions based on the mass of particulate matter <10.0,
2.5, and 1.0 µm aerodynamic diameter ( PM 10 , PM 2.5 , and PM 1.0 ) defi ne bounds for
respiratory tract-relevant deposition fractions related to atmospheric environmental
pollutants (Fig. 12.1 ) [ 8 ]. Given this albeit indirect evidence from related fi elds of
study involved with inhalation of potentially harmful aerosol particles, it can be
argued that any more detailed fractionation of the APSD in the context of therapeu-
tic drug delivery to the respiratory tract both dilutes the essential information to
assess clinical safety and effi cacy and has the potential to magnify intrinsic data
variability.
Replacement of the right-angle bend USP/Ph.Eur. induction port (Fig. 12.2 )
should be considered as the fi rst step towards the development of either full-
resolution or abbreviated CI measurements that provide data for comparison with
lung deposition profi les.
Although the right-angle bend internal geometry suffi ces for measurements
related to OIP quality control, where the emphasis has to be on simplicity as a
key component of method robustness, this inlet pathway differs markedly from
actuality [ 9 ]. Apart from considerations concerning the effect of real upper airway