Biomedical Engineering Reference
In-Depth Information
assessments by the compendial methods in which the flow rate is maintained at a
fixed value, development of DPI a product often involves testing at multiple flow
rates. It is a relatively easy process with a full-resolution CI to interpolate the mass
of API in particles finer than a fixed size limit, typically 5.0
m aerodynamic diam-
eter, from the cumulative mass-weighted APSD obtained at each required flow rate,
even though the individual stage d 50 values change. In contrast, since interpolation
is not possible when using an AIM-based CI, as an APSD is not generated, a differ-
ent upper stage would be needed for testing at each required flow rate in order to
maintain a stage d 50 fixed at the appropriate value.
At this point then it is fair to say that while the AIM concept, in the physical
form of the Twin Impinger, was seen as a convenient and efficient analytical tool for
relatively coarse differentiation, doubts remained about its sensitivity. The theoreti-
cal work by Tougas et al . [ 11 ] on the development of EDA metrics that is described
in detail in Chaps. 7 and 8 , followed some time after these initial practical studies.
In summary, EDA points the way to achieve better measurement precision in asso-
ciation with OIP APSD-related data by the following approaches: adoption of a
ratio of LPM to SPM rather than individual mass fractions, simultaneous use of
ISM, and the selection of an optimal boundary value for LPM/SPM on the basis of
MMAD value.
Limited interest in AIM precursor concepts continued through the 1990s, a
decade marked at its closing by the development of the full-resolution NGI on the
basis of the very latest understanding of inertial impaction [ 14 ]. In the context of
AIM-based equipment, during the mid-1990s, Van Oort and Downey [ 15 ] and Van
Oort and Roberts [ 16 ] returned to the issue of reducing the analytical burden by cut-
ting the number of size fractions, this time by simply reducing the number of stages
used in an Andersen CI stack (see Chap. 5 ) . In these works, for the first time, there
was recognition of the importance of tailoring the boundary between the two size
fractions used for EDA to suit the product under test. Based on full-resolution data
gathered using an ACI (or NGI), analysis was focused on the stages where most of
the drug collects to give size fractions that could more precisely and successfully
capture changes in OIP APSD.
Unfortunately, at that time and up until the early part of the next decade, the sug-
gestion of an abbreviated way of working failed to gain traction with the regulators
[ 17 ], who favored full-resolution APSD measurements, diminishing interest in con-
tinued development of simplified systems. However, since then much has changed.
In particular, the regulatory landscape has altered dramatically with the introduction
of new concepts, perhaps most importantly Quality by Design, an approach designed
to promote product and process development on the basis of thorough and secure
knowledge [ 18 ]. Nevertheless, there are legitimate concerns that this new way of
working will significantly increase the analytical burden. Hence, both the pharma-
ceutical industry and regulatory agencies alike have become more receptive to new
approaches, based on sound science, which may help reduce the amount of testing
required. Interest in the use of AIM systems based on both the ACI and NGI has
therefore been renewed.
μ
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