Good Cascade Impactor Practices - Good Cascade Impactor Practices, AIM and EDA for Orally Inhaled Products - page 88

(c) Internal dead volume in the CI system: In the context of DPI testing, the
magnitude of the internal dead volume (i.e., the open space within the assembled
CI, including accessories such as the induction port or pre-separator and vacuum
tubing) will influence both the time taken for particles to traverse the system
and be collected and the rise time for the flow rate to increase to the final value
when the flow-control solenoid valve is opened to initiate sampling [ 33 ]. Since
2005, accurate measures of the dead volumes of the ACI, NGI, and multistage
liquid impinger (MSLI) have been available, with and without the various
accessories [ 34 ]. This basic information about the impactor system configura-
tion provides a useful starting point when selecting a CI for a new product. Bias
introduced to APSD measurements by dead volume will be fixed for a given
impactor type and configuration, and ideally the internal volume should be as
small as possible. However, the tradeoff between potential bias arising from
dead volume and other more important constraints, such as ease of (semi) auto-
mation or improved aerodynamic size-separating characteristics, may result in
the choice of a system with a higher internal volume.
(d) Air leakage: Air leakage into the CI can arise from incorrectly placed or defective
seals or misaligned stages, since a partial vacuum always exists within the flow
channel through the CI once flow is enabled through the system. The problem is
particularly prevalent with the standard O-rings used with ACIs, which are prone
to cracking with repeated use and exposure to solvents. Defective seals are most
significant when they occur at stages closest to the impactor exit, where the inter-
nal vacuum is at its greatest with respect to the surrounding atmosphere. It there-
fore follows that although the APSD may be shifted (in some cases significantly),
the magnitude of the displacement being dependent on leak location and size, the
mass balance (MB) for the recovered API should likely be unaffected. However,
if the leakage caused an increase on inter-stage deposition, MB might be reduced
unless internal losses are included in the analysis [ 3 ]. However, broader metrics,
such as API mass balance, may be useful at tracking operator-introduced bias,
when testing OIPs in early development. Air leaks are detected and prevented
through periodic visual inspection and replacement of defective seals, and careful
attention to system assembly. A final system suitability check can also be made
by comparing the volumetric flow rate at the impactor inlet (at ambient atmo-
spheric pressure) with that measured downstream of the system at the vacuum
pump (corrected for the local reduced pressure) [ 30 ] or by the measurement of
flow resistance (pressure drop) across the entire CI system (Sect. 4.3.2 ). However,
even if these checks are made, it is possible for a small leak between stages to go
unnoticed. As part of the CI method development, Bonam et al . observed that it
would be prudent to study the effect of leaks on the APSD of the product through
the use of designed experiments, e.g., by introducing controlled leaks through
small cuts in O-rings and observing the changes in APSD resulted from such
simulated failures [ 2 ]. This information could later be used for root-cause analy-
sis when atypical APSD profiles are observed, in combination with reassessment
of the tested unit to confirm that the failure is not related to the product.