Biomedical Engineering Reference
In-Depth Information
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
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