Good Cascade Impactor Practices - Good Cascade Impactor Practices, AIM and EDA for Orally Inhaled Products - page 85

6. Bias introduced by the experienced operator: It is perhaps less well documented
than the previous cause of unintentional variability, but even well-trained and
experienced operators can develop habits that lead to repetitive mistakes in
technique. Such errors can often be small, but taken together they can accumu-
late so that the rate of measurement failures increases above typical. Bonam et al .
proposed that biases from individual operators could be detected through use of
control charts (e.g., mass of API reported on key stages tracked as a function of
time), and upon further investigation, they might be traced to one of the errors
listed above [ 2 ]. Control charts are particularly useful with repeated testing of
established products. However, broader metrics, such as API mass balance, may
be more useful at tracking operator-introduced bias when testing OIPs in early
development.

4.2.2 Contribution to Variability from “Machine”

An APSD measurement is never “absolute” but depends on the technique [ 9 - 12 ],
instrument calibration [ 13 ], its intrinsic size resolution [ 14 ], as well as the dynamic
nature of the aerosol cloud as it interacts with the environment when it enters and
passes through the CI (e.g., evaporation of volatile species or hygroscopic growth
[ 15 ]). Therefore, the outcome of an APSD measurement should always be reported
along with the specific instrument and technique used.
Compared to other types of analytical measurement, a CI does not have an
inhaler-aerosol-like reference material that is ultimately traceable to the interna-
tional length standard, such as a standardized polydisperse aerosol, with which to
validate the method [ 16 ]. In that sense, every CI measurement is unique.
Monodisperse certified reference particles do exist as an alternative to a polydis-
perse standard [ 16 ], but their valid application is a slow and difficult process [ 17 ],
which is unsuited to being used on a regular basis to verify CI performance [ 18 ].
This lack of a simple-to-do calibration procedure utilizing standard particles of
known aerodynamic size has made CI data prone to bias and increased variability
prior to the introduction of stage mensuration as an alternative and fully traceable
approach to CI performance verification [ 18 , 19 ].
The application of stage mensuration is therefore recommended in the compen-
dial procedures for OIP aerosol aerodynamic particle size analysis in both European
and US pharmacopeias [ 20 , 21 ]. This process is the automated measurement of
individual nozzles of each stage by computer-aided image analysis and has now
become the current technique of choice [ 18 ]. Recently published data confirm that
bias introduced by several widely used and commercially available mensuration
systems is small [ 18 ]. Furthermore, a collective measure of average diameter for a
multi-nozzle stage, termed effective diameter, D eff , calculated in terms of the
area- weighted median ( D median ) and area-weighted mean ( D *) diameters of the group
of nozzles in accordance with the expression [ 19 ]