Good Cascade Impactor Practices - Good Cascade Impactor Practices, AIM and EDA for Orally Inhaled Products - page 83

expected to continue to be a significant contributing factor to the overall CI test
outcomes. Key issues relating to this contributor to overall method inconsistency
were identified as follows:
1. CI Assembly: Bonam et al . noted that operator training in impactor assembly is cru-
cial, in particular with stack designs such as the ACI, due to the need to assure correct
stage order as well as ensuring that there is a proper seal between impactor stages [ 2 ].
They proposed that under such circumstances, a gantry-type system could be used to
ensure that the stack is properly aligned. Proper sealing could be checked via leak
tests and/or pressure-drop tests or by including a differential mass flowmeter between
the induction port and the impactor exit. They proposed that a checklist may be a
helpful aid, particularly for an inexperienced operator. However, even with proper
training, it is evident from discussions with laboratory management that occasional
errors in the assembly of ACI-type impactors are likely, given the complexity of the
process, leading to “failed” CI tests. For example, incorrect ordering (switching) of
CI stages or misalignment of collection plates in an ACI are inadvertent errors that
may happen even to a well-trained operator. In the case of the NGI, a complete set of
collection cups can be fixed permanently into a carrier that makes the process of
loading and unloading the impactor more efficient. Furthermore, for this CI, the stage
order is fixed due to the integral nature of the impactor body itself [ 5 ].
2. Impactor handling and sample introduction: In 2001, Purewal, reporting on an
EPAG-based assessment of test methods to check OIP performance under both nor-
mal and unintentional use conditions, reported that proper training in sample collec-
tion is critical because of a wide variety of different test methods, including variations
in inhaler handling and introduction of the sample to the CI [ 6 ]. Even with proper
training, individual differences between operators (e.g., inhaler shaking frequency
and intensity, delay between shaking and actuation, alignment of inhaler to ACI,
actuation) may go unnoticed but may result in different systematic biases (e.g., dose-
through-use trends) and also may contribute to the seemingly random variability
when results are compared from several operators or even from the same operator on
different occasions. For example, Purewal commented that a different rate of actuat-
ing an MDI may lead to different cooling of the canister and, therefore, different
evaporation behavior of the propellant, leading to variations in measured APSD, even
when the inhaler units are identical. Using a bench timer may help standardize this
aspect of the method and minimize the associated variability. Stewart et al. [ 7 ] and
Miller et al. [ 8 ] have observed that automation of some of the steps in the CI measure-
ment process may further reduce this type of variability.
3. API analytical method (commonly HPLC with either UV-visible spectrophotometric
or fluorescence detection): When HPLC is used for API assay, Bonam et al. noted
that an analyst might introduce an “individual” bias into APSD results by preparing
the HPLC standard at the upper or lower limit of the predefined range. Under such
circumstances, all recoveries from the CI stages would either be slightly over- or
underestimated. It is self-evident that similar considerations would apply with newer
assay methods, such as ultrahigh-pressure liquid chromatography (UPLC) that is
frequently combined with mass spectrometric API identification.