Product Life Cycle Approach to Cascade Impaction Measurements - Good Cascade Impactor Practices, AIM and EDA for Orally Inhaled Products - page 142

variability introduced with disease modifying patency of airways in the respiratory
tract, small shifts in mass within the size ranges related to LPM and SPM s ubfractions
are unlikely to have measurable clinical consequences [ 12 ]. This situation may be
true even when a convincing IVIVR is established, as could be argued is potentially
possible for some bronchodilator-based formulations [ 10 , 13 ]. Put in another way,
the precision of existing CI-based methods for determining these QC metrics
greatly exceeds the precision available to the clinician for the corresponding clini-
cal metrics such as forced expiratory volume in 1 s ( FEV 1 ), forced expiratory fl ow
from 25 to 75% of vital capacity ( FEF 25-75 % ), and similar indicators of airway
patency obtainable from well-established spirometric measurements to assess
obstructive disease [ 14 ]. The higher precision of in vitro methods is likely to
become even more apparent for other therapeutic modalities such as anti-infl amma-
tory products, where IVIVRs are not yet fully established [ 15 ]. In view of these
considerations, caution is advised when utilizing CI-generated APSDs in the devel-
opment of IVIVRs or IVIVCs. Further consideration of this topic is covered in
Chap. 12 , in which the type of additional measures that should be considered is
discussed in the context of making the CI-based measurement process approximate
more closely to actual OIP use.
Another clinically related question that has been asked is as follows: Could one
use historical therapeutic-class information to set population-based specifi cations
for APSD? In response, EDA-based specifi cations would allow for such a universal
approach with OIPs across a particular therapeutic class. Importantly, however, data
from grouped stages using full-resolution CI measurements will not be useful. This
potentially counterintuitive outcome arises because the decisions about which
stages to group and how to set those specifi cations will depend on the specifi c APSD
profi le for each OIP, irrespective of API.

6.6 Concluding Thoughts

Both full-resolution and abbreviated CI measurements should be employed to fulfi ll
different goals in support of the various phases through the life cycle of an OIP. This
chapter has provided a road map to assist the developer wishing to implement AIM
as part of an ongoing process to improve productivity in the measurement labora-
tory and at the same time, to retain sensitivity to important changes in APSD.
The establishment of strong correlations between particle size-related metrics
that are obtained from the selected abbreviated CI to the corresponding particle
size-related data from a full-resolution system is an important goal. This target
should ideally be achieved as early as possible in the OIP development process, ide-
ally developing specifi cations common to both techniques.
In the commercial phase, it should be possible to release product using abbrevi-
ated impactor measurements combined with EDA to interpret the data. This type of
data interpretation represents a simpler, yet statistically more powerful approach to
analyze the APSD data in a quality control setting (see Chaps. 7 and 8 ). It also has