Good Cascade Impactor Practices - Good Cascade Impactor Practices, AIM and EDA for Orally Inhaled Products - page 84

4. CI sample collection and subsequent analysis for API: From an analyst's perspective,
the procedure for API recovery from the CI and subsequent quantification of mass
deposited in each component part of the system offers multiple opportunities for
errors. Furthermore, the potential for loss of API on disassembly of the impactor
prior to API recovery should not be ignored [ 2 ]. Therefore, careful handling of the
assembled CI, together with collection surfaces containing deposited API upon dis-
assembly, is highly important. In addition, a robust technique for recovering API
material is critical, as is proper organization of samples to prevent wrong dilutions
and incorrect sample vial filling [ 2 ]. It is well known that the operation of pipetting
aliquots of recovery solvent will also contribute to random method variability, since
more careful pipetting will result in a complete discharge of liquid, whereas less care-
ful operation is likely to result in some liquid left over in the pipette. Bonam et al.
therefore suggested that the use of automated pipettes should be considered as stan-
dard practice [ 2 ]. Another potential source of variability they identified is due to the
use of different volumes for stage dissolution or for dilution of recovered samples,
e.g., in order to obtain the same concentration for all API stage-by-stage samples to
be quantified using HPLC/UPLC analysis. They therefore recommended that poten-
tial errors and increased variability should be weighed against potential benefits of
this procedure. Evaporation of solvent during sample recovery will give an overesti-
mation of the API amount and its effects should be minimized, e.g., by inclusion of
an internal chemical standard in the solvent used for recovery. If the HPLC/UPLC
method has good linearity, it is also possible to dispense the same volume of internal
standard solution to each impactor stage/cup/throat and to the standard used for API
quantitation. In this case, the sample solution is transferred directly to the LC vial and
the exact volume transferred is of no importance. Bonam et al . noted that the exact
concentration of the internal standard solution is not critical as long as the internal
standard dispenser is repeatable and the same dispenser is used for both samples and
standard solutions [ 2 ].
5. Operator stress and fatigue: It is self-evident that during complex operations, such as
those associated with the CI measurement process, stress and fatigue always deterio-
rate human performance. The consequence is an inevitable increased incidence of
errors. Stress and fatigue can be minimized by limiting the number of samples to be
analyzed per operator per working day. In addition, mechanical aids and procedural
steps might be introduced to counteract potential operator-related errors. For exam-
ple, to prevent delivery of an incorrect number of doses to the impactor, Bonam et al .
suggested that the use of “counters” linked to actuation of the airflow valve may be
considered for DPIs, or the weighing of MDIs could be used before and after the CI
test to verify the correct number of doses actuated [ 2 ]. As another example, to enable
detection of a mix-up of vials from different stages during API analysis, for unimodal
and lognormal APSD distributions, plotting log-probability versus log-particle-size
and calculating the regression coefficient could be used as a system suitability tool.
Furthermore, mixed-up dilutions could be avoided by using the same amount of
solvent for each impactor stage or by eliminating the dilution step altogether if the
detection sensitivity and API detection method linearity allow.