Theoretical Basis for the EDA Concept - Good Cascade Impactor Practices, AIM and EDA for Orally Inhaled Products - page 156

A significant change from the typical mean aerodynamic particle size should
therefore be detectable as a change in the LPM / SPM ratio, and a significant change
in the sized portion of the inhalable dose should be reflected in a change in the ISM .
In addition, any significant change in the APSD impacting both the mean and the
area under the APSD should be detectable as changes in both metrics.
Tougas et al. [ 11 ] showed that the aerodynamic particle size boundary differen-
tiating LPM from SPM can be selected based on the characteristics of the target (i.e.,
nominal) APSD and depends on the product being tested. Therefore, the boundary
does not have to be a universal value for all OIP types and products. Furthermore, it
should not be considered as a necessity for it to have clinical significance, although
it may be chosen to be related to a clinically meaningful particle size established in
prior clinical trials on a particular product. Ideally, this boundary should be selected
so as to maximize the sensitivity of these metrics to meaningful changes in APSD
from the perspective of measuring product quality.
Even though the boundary size demarcating LPM and SPM is potentially unique
to every OIP, the impaction equipment used for the proposed testing need not be
unique to every product. Importantly, the proposed method is relatively robust to the
choice of the boundary (Fig. 7.8 ). In addition, the CI could be operated at a different
flow rate to adjust the boundary between LPM and SPM using the simple and well-
defined relationship between flow rate through the system and stage cutoff size that
is described in Chap. 2 . Furthermore, the range of possible MMAD values (and
therefore selection of boundaries) is not large for inhalation products since they are
all intended to target the lung. For example, among the eight products from the
IPAC-RS database, which were purposely selected to be as diverse as possible
(Table 7.1 ), Tougas et al. showed that only three different boundaries (2.1, 3.3, and
4.7 μm aerodynamic diameter) were required. It is likely that these locations will
prove to be suitable for all OIPs, and consequently only two or three versions of an
AIM-type instrument/method would be needed.
Figure 7.8 provides experimental evidence from analysis of CI results taken from
the IPAC-RS database concerning selection of the boundary. The precision of the
relationship between the ratio metric LPM / SPM and MMAD is insensitive to the
placement of that boundary over a wide range. Each point in this figure character-
izes the quality of the correlation between LPM / SPM and MMAD for a given bound-
ary location associated with a specific OIP. The boundary location in this analysis
was moved such that the corresponding ratio varied over four orders of magnitude
around unity. The value of unity for LPM / SPM by definition represents the bound-
ary location that is coincident with the MMAD for the APSD in question. Both
panels of this illustration depict the goodness of fit of the regression between ratio
LPM / SPM and MMAD as a function of the average ratio for a given product. Using
average ratio as the abscissa allows comparison across all OIPs studied in a single
plot based on how close the boundary is selected relative to the MMAD for each
product.
The upper plot shows the relationship with respect to a conventional goodness-
of-fit statistic [coefficient of determination ( R 2 )] for each regression as a function of
the average ratio. Due to some shortcomings of this statistic when applied to survey