Product Life Cycle Approach to Cascade Impaction Measurements - Good Cascade Impactor Practices, AIM and EDA for Orally Inhaled Products - page 132

as possible to the MMAD . However, as will be seen in the following chapters on the
EDA concept, precise alignment with the MMAD is not essential if the choice of
stage cut point available at the chosen fl ow rate for these measurements is restricted
by the hardware availability. If there is a particular (e.g., clinical) need to control
some other type of change encountered in a given product, the boundary could be
placed elsewhere, as determined and justifi ed during product development. One
alternative boundary placement that could be considered is around 5 m aerody-

namic diameter, which would be in accordance with the current European pharma-
copeial method [ 2 ], and therefore aligned with the appropriate EMA guidance [ 3 ].
Although the work by Tougas et al. has shown that the boundary between LPM
and SPM can be anywhere between 0.3 and 3.0 times the MMAD value without
sacrifi cing signifi cant sensitivity to detect changes in MMAD [ 4 ], setting a single
boundary may not work for all OIPs. In such circumstances (which would be for the
product developer to decide, based on the evidence from full-resolution CI measure-
ments), it may be necessary to introduce a second boundary to distinguish between
fi ne and extra-fi ne particles. Under such circumstances, EDA could still be used to
assess movements in MMAD based on the ratio of coarse to fi ne particle fractions
(analogous to LPM and SPM ), but the measure of extra-fi ne particle mass would be
separate. Since extra-fi ne particle mass, by being a component of the fi ne particle
fraction, and fi ne particle mass are linked measures, an EDA-type approach based
on these two metrics would be inappropriate. However, in principle, it may be pos-
sible, by combining fi ne and coarse particle masses as a single metric termed, for
convenience, super-micron mass, to compare extra-fi ne particle mass and super-
micron mass by the EDA approach to follow changes in MMAD . However, to the
best knowledge of the authors, this approach has not been done thus far, and caution
is therefore advocated.
For an AIM-pHRT impactor, published research has focused on extra-fi ne and
fi ne particle fractions defi ned as <1.1

µ

m aerodynamic diam-
eter, respectively [ 5 - 8 ], which seem to be relevant in light of available clinical evi-
dence that is discussed in Chap. 12 . The specifi c sizes appropriate for a given
product need to be considered based on the APSD profi le of the product and the
clinical importance of various size ranges for the active ingredient in question. The
question of clinical relevance remains an area of active research with no single
answer yet, so the sponsor is advised to review all pertinent current literature and
sponsor's own studies to guide the selection of size ranges. Other considerations,
such as the use of alternative induction port/throat geometries and breath simulation
that are appropriate with this type of abbreviated system, are described in Chap. 12 .

µ m and <4.7 or <5.0 µ

6.3 Qualifying AIM-Based Systems Against an Appropriate

Full-Resolution CI

Regardless of the abbreviated or full-resolution systems that are chosen, there are
common concerns, such as the magnitude of internal wall losses, particle bounce,
and re-entrainment, all of which require attention as potential sources of bias, as