Good Cascade Impactor Practices - Good Cascade Impactor Practices, AIM and EDA for Orally Inhaled Products - page 87

Even with the CI-based method including validation of the CI system itself opti-
mized, unnoticed biases and variability may remain, making it difficult to comply
with an a priori specification which disregards data from that particular impactor
and method. Careful method development work should therefore be done in an
attempt to try to identify and counteract all major sources of imprecision and bias.
Bonam et al . [ 2 ] went on to describe the various sources of impactor-related vari-
ability in more detail:
(a) Jet dimensions, stage cutoffs, calibration, and mensuration: The process of con-
verting API mass-weighted deposition data obtained from a multistage CI into
an APSD depends on the established magnitudes of the stage d 50 sizes, as has
been described in Chap. 2 . Although ideally every CI of a given design should
have an identical d 50 for a given stage, several studies have shown that stages of
so-called identical CIs have often slightly different nozzle sizes, due either to
manufacturing variations or by wear, corrosion, or accumulation of debris
[ 25 - 27 ]. It is self-evident that time- and use-dependent processes that result in
partial plugging, wear, and corrosion will change the actual size of the nozzles
of a given stage and, therefore, its d 50 value. These effects can ultimately result
in shifts of API mass between stages and, therefore, introduce bias accompa-
nied by increased variability of APSD measurements, especially when data
from several impactors are used together [ 25 ].
(b) Flow rate, flow profile, acceleration, and control: It is well known that CI stage
d 50 sizes are affected by the flow rate at which the measurement system is
operated, decreasing as flow rate increases and vice versa [ 28 ]. Relatively speak-
ing, nozzle-diameter-caused variability in d 50 is likely to be small in terms of its
overall impact on performance and is relatively easily monitored [ 29 ]. Flow-
rate-induced variability, however, is likely to be more significant and less trac-
table, given the fact that in the pharmacopeial method, the specified flow control
is typically no better than ±5% of the nominal flow rate [ 20 , 21 ]. An alternative
to the pharmacopeial method, using a flowmeter calibrated for the entering,
rather than exiting, flow rate has been shown to yield similar performance [ 30 ].
Flow-rate variability therefore is an important source of APSD measurement
uncertainty in addition to changes in stage d 50 values. In contrast to the latter which
tends to change only gradually through repeated use, the flow-rate setting may
vary from one instance of using a given CI to the next instance of using the same
impactor. For MDIs, stage d 50 sizes are determined by the magnitude of the (con-
stant) flow rate achieved during testing; for DPIs, in addition, the flow-time profile
(rise time, acceleration) affects stage d 50 values and consequently the measured
APSD. The magnitude and direction of these effects depend on the CI design and
internal geometry, in particular the magnitude of the internal dead volume [ 31 ,
32 ]. It is therefore important to define the vacuum tube length for repeated use of
the same impactor type in order to keep the dead volume as constant as possible.
The airflow rise time could also be measured as part of the installation checks of a
new instrument setup. In summary, flow-rate bias can be minimized if flowmeters
are well maintained, properly calibrated, and regularly qualified.