Good Cascade Impactor Practices - Good Cascade Impactor Practices, AIM and EDA for Orally Inhaled Products - page 94

4.2.4 Contribution to Variability from the Drug

Product (Material)

Bonam et al . observed that the APSD of the aerosol delivered by an OIP will have
an intrinsic variability that is truly attributable to the product [ 2 ]. They identified a
number of factors potentially influencing this true APSD variability, including the
following attributes:

(a) Product orientation during storage
(b) Formulation interaction with excipients
(c) Interaction with components of container closer system
(d) Sensitivity to moisture
(e) Product age
(f) Temperature and humidity during storage
(g) Tolerances of device components
(h) Electrostatic effects during de-aggregation of some DPI formulations
(i) Static electrification due to interaction of MDI aerosol particles with noncon-
ducting elastomers used in MDI valve manufacture [ 40 , 73 , 74 ]

All such factors should be studied during product development and are not con-
sidered here in detail because they are specific to the product rather than the CI
method, which is the focus of this chapter.
In addition, Bonam et al . noted that the physicochemical characteristics of cer-
tain OIPs may make the CI method more variable [ 2 ]. For example, suspensions by
nature will tend to produce more variable aerosols than originate from homoge-
neous solutions. This outcome happens because of the intrinsic tendency for particle
sedimentation from the suspending fluid (i.e., sinking) or particle-particle coales-
cence above the suspending fluid (i.e., creaming) in suspensions, thereby adding to
product variability. Furthermore, in the case of suspension-formulated MDIs, the
magnitude of the elapsed time between shaking and actuation (which is part of the
CI assessment “method”) may influence the measured APSD variability. The
accompanying drop in the MDI canister temperature immediately following actua-
tion may affect the measured APSD from a subsequent actuation if insufficient time
is allowed to elapse. 30 s is a widely practiced minimum elapsed time between
replicate actuations to avoid variability in aerosol delivery characteristics arising
from this source.
Bonam et al . also noted that OIPs containing more than one API can present
special challenges for the development of a precise and accurate CI method [ 2 ]. For
example, one of the API components could be a strong chromophore and the other
a weak one, or the particular API might produce a high-density (mass concentra-
tion) aerosol, whereas the other(s) are present in lower mass concentrations in the
formulation. In consequence, the mass of the relatively highly concentrated API
may rapidly reach the limit for stage loading. At the same time, the mass of the rela-
tively lower concentration API(s) present on the same stage might only be close to
or at the LOD level for the same number of inhaler actuations. Alternatively, one