Good Cascade Impactor Practices - Good Cascade Impactor Practices, AIM and EDA for Orally Inhaled Products - page 95

API might be a hydrophilic compound and the other a hydrophobic one, resulting in
the potential for different collection characteristics if the surface coating of the col-
lection substrate on the stages is also markedly hydrophobic or hydrophilic.

4.2.5 Contribution to Variability from Interactions Between

Contributing Causes

Bonam et al., in concluding their assessments on causes of CI method variability,
also considered the possibility of interactions between the four factors previously
considered separately (material, man, machine, and analysis) [ 2 ]. From Fig. 4.2 , it
is evident that some factors appear more than once, that is, they arise in more than
one category of influences governing the overall variability of the CI method. For
example, the number of inhaler actuations may conceivably affect the APSD uncer-
tainty through man (e.g., due to repetitive stress or differences in delay times when
firing multiple actuations), machine (e.g., due to stage overload and particle bounc-
ing), measurement (e.g., due to the limit of detection when the number of actuations
is small), and material (e.g., due to suspension resettling time). In another example,
incorrect device cleaning may induce particle growth, giving rise to a man-material
interaction component of variability. Specifically designed experiments might be
conducted to separate variability components. However, the total mass collected
from the CI system (mass balance) may be used more routinely as a diagnostic tool
to distinguish between a method-related and product-related abnormality when
deviating APSD results are observed [ 3 , 75 ].
Bonam et al . advised method developers to be aware of this degree of potential
complexity either when optimizing a given CI-based measurement procedure or
conducting an investigation for deviating results [ 2 ].

4.3 Summary of GCIP

Recognizing the complexity of the CI methodology and its importance in the assur-
ance of OIP quality, the Product Quality Research Institute (PQRI), a forum for tech-
nical interaction between the USFDA, the pharmaceutical industry, and academia,
formed the APSD-Mass Balance Working Group in 2002 to address issues associated
with API recovery from multistage CI measurements [ 76 ]. Although the main focus
of this activity was on resolving the appropriate specification for mass balance from
multistage CI measurements, during the course of discussions, it became evident that
the complexity of the compendial methods was one of the most important contributors
to the variability associated with this measure of system suitability.
The GCIP guidance document developed from this working group [ 3 ] was its
main achievement and provided the basis for subsequent investigations into how the
methodology could be simplified.