Product Life Cycle Approach to Cascade Impaction Measurements - Good Cascade Impactor Practices, AIM and EDA for Orally Inhaled Products - page 141

been due in part to the mistaken view that MMAD would be the only quality metric.
Systematic movements in MMAD (indicative of shifts in APSD in terms of the
aerodynamic diameter scale) must be controlled together with the total mass that is
collected by the impactor ( IM ).
Systematic movements in IM are indicative of shifts in mass output from the OIP
and may or may not be related to movements in APSD. If detecting shifts in APSD
is important (while also controlling IM ), then detecting changes in MMAD is impor-
tant since they are directly related. If this premise is accepted, then it follows that
EDA is a superior approach because it provides a better way to detect MMAD shifts
than either stage groupings from full-resolution CI measurements or mass deposited
in a particular size range (be it a particular grouping or related to a particular mass
fraction of potential clinical relevance, such as FPM ).
In some situations, it is believed that MMAD could be used directly as a QC
metric without the need for EDA—namely, when full-resolution CI data are avail-
able. If, however, the additional goal is to reduce labor and time resources for QC
testing, then AIM-QC would be more effi cient than full-resolution ACI testing, and
consequently, the EDA ratio LPM/SPM (which is directly linked to MMAD ) would
be the metric of choice.

6.5.2 CI Data for Clinical Signifi cance Versus Product

Quality Confi rmation

In Chap. 5 , it was shown that for the effective application of EDA, the location of
the LPM -to- SPM boundary size should be selected based on the underlying purpose
of the test. If the goal is to maximize the ability of metrics ISM and LPM/SPM to
detect changes in APSD, then setting that boundary equal to MMAD should provide
the optimal outcome in terms of method sensitivity.
The question can be asked: Are these EDA-based metrics and the associated
changes in APSD that are detected clinically relevant? The answer is a qualifi ed yes ,
to the extent that the entire APSD profi le is clinically relevant, since all impactor-
sized particles are likely to deposit somewhere within the respiratory tract (ignoring
losses upon exhalation). However, it is important to appreciate that the underlying
intent for these metrics is to serve as best possible tools to provide assurance that the
APSD of the clinical batches matches the target specifi cations and in addition, to
confi rm quickly and reliably in the QC environment whether a given OIP has an
APSD within agreed specifi cations. By themselves, therefore, these metrics and
associated particle subfractions do not claim to be and do not need to be refl ective
of the API deposition profi le in precisely specifi ed regions of the HRT or of the
ultimate clinical response due to drug-receptor interaction. In this context, it is
worth noting the precedent that current APSD metrics based on grouped stages from
full-resolution CI data have not been directly linked to clinical performance either.
Given the large inter-patient variability in clinical trials whose intent has been to
elicit dose-response relationships, in addition to the seldom considered added