Applying the AIM Concept in Support of Developing Improved In Vitro–In Vivo Relationships for OIPs - Good Cascade Impactor Practices, AIM and EDA for Orally Inhaled Products - page 387

12.5 Guidelines for Developing AIM-pHRT Systems

If attempting to modify other full-resolution cascade impactors (not ACI or NGI)
or to develop a new abbreviated apparatus, it would make sense to have guidelines
for what constitutes an AIM-pHRT system. The following general considerations for
the AIM-pHRT approach can be summarized, based on knowledge acquired to date
(see in particular the validation studies described in this chapter and in Chap. 10 ) :

1. An anatomically appropriate inlet should be used, based either on the Alberta
idealized adult throat approach or a cast of an anatomically correct upper airway.
If a cast is used, it should be preferably produced from MRI imaging rather than
directly from cadaveric material to avoid possible deformation of the airway due
to tissue collapse. The lining of the interior surfaces of the inlet should be thor-
oughly wetted with an appropriate low-volatile liquid to simulate the action of
the mucosa as particle collecting media.
2. Dead space before the fi rst impaction stage that matches as closely as possible
that of the full-resolution impactor used as the reference instrument, especially if
working either with MDI-based solution formulations containing low-volatile
species or with DPIs, where the airfl ow rise time profi le, should ideally mirror
that achieved with the full-resolution system. In the case of DPI testing, adding
a fi rst impaction stage to match the full-resolution impactor will not by itself be
suffi cient to mirror the volume and fl ow resistance of the full impactor.
However, in the case of the ACI, it would be a practical alternative to retain
the redundant stages in the abbreviated impactor, but locate them beneath the
fi lter stage (e.g., in the stage order: 0, 2, 5, Filter, 1, 3, 4, 6, 7) to achieve this goal.
3. The fi rst size-fractionation stage for the separation of fi ne from coarse particle
fractions should be chosen such that its D 50 size is fi xed as close as possible to
5 µm aerodynamic diameter at the fl ow rate of intended use. Note, however, that a
lower size limit closer to 3 µm aerodynamic diameter may be appropriate if testing
OIPs and associated add-on devices are intended for infant or small child use [ 64 ] .
4. The second size-fractionation stage for the classifi cation of extra-fi ne particles as
a subfraction of the fi ne particle fraction should be chosen to have its D 50 value
close to 1.0 µm aerodynamic diameter at the fl ow rate of intended use, as this
size represents an upper limit where signifi cant portion of the inhaled particles
may be exhaled without depositing in the lungs [ 65 ].
5. A backup fi lter should be used to collect the extra-fi ne particles. Note that the
micro-orifi ce collector (MOC) may be appropriate in the case of modifying the
NGI, except if used at fl ow rates <30 L/min, for instance, in the evaluation of
nebulizing systems at 15 L/min [ 66 ].

On this basis, the adaptation of the FSI (MSP Corp., St Paul, MN, USA), or any
similar impactor, as an AIM-pHRT system may be limited, even though it could be
used with an anatomically appropriate inlet without diffi culty. Its dead volume is
fi xed, and it lacks a second size-fractionating stage to capture the EPF component.
Nevertheless, this abbreviated CI could still be used to determine FPF / CPF , and the
importance of the fi xed dead space limitation is likely to be DPI-dependent.