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 372

The relationships between respiratory tract internal dimensions, complexity in
terms of modeling anatomic structures in the aerosol fl ow pathway, and their asso-
ciation with meaningful IVIVRs continue to be a hotly debated area [ 9 ]. It is
foreseeable that as inlets representing different patient age classes (i.e., infant, small
child, and adult) are developed [ 17 - 19 ], this debate will intensify.
There can be large inter-patient variability in clinical trials to elicit dose-response
relationships with inhaled medication [ 20 , 21 ], in addition to the less frequently
considered added variability introduced with disease-modifying patency of airways
in the respiratory tract and resulting lung function [ 22 , 23 ]. Hence, small shifts in
mass within the size ranges related to CPM and FPM subfractions in the event that
the boundary is set at either 4.7 or 5 µm aerodynamic diameter in an AIM-pHRT
system in order to match full-resolution data following North American or European
practices, respectively, are unlikely to have measurable clinical consequences. This
situation may be true even when a convincing IVIVR is established, as could be
argued is potentially possible for some bronchodilator-based formulations [ 2 ]. To
put in another way, the precision of existing CI-based methods for determining
these QC metrics greatly exceeds the precision available to the clinician for the cor-
responding clinical metrics such as forced expiratory volume in 1 s ( FEV 1 ), forced
expiratory fl ow from 25 to 75 % of vital capacity ( FEF 25-75 % ), and similar indicators
of airway patency obtainable from well-established spirometric measurements to
assess obstructive disease [ 24 ]. The higher precision of in vitro methods is likely to
become even more apparent for other therapeutic modalities such as inhaled anti-
infl ammatory products, where IVIVRs are not yet established with confi dence [ 2 ].

12.2 Criteria for Abbreviated CI Systems Appropriate

for Comparison with Clinical Data

The qualifi cation of the clinical batches of OIP drug product together with the labo-
ratory assessment of certain add-on devices (spacers and VHCs used with MDIs)
that substantially affect the size properties of the emitted aerosol also necessitates
the measurement of APSD-based data that may not always be appropriate to ana-
lyze in terms of the EDA metrics LPM / SPM and ISM . The main reasons for such a
limitation are as follows:

1. The boundary between LPM and SPM is intended to be chosen to be as close as
practical to the MMAD of the product in order to optimize the sensitivity of these
metrics to small changes in APSD [ 25 ]. Depending upon the formulation in
question, this limit may be at a signifi cantly fi ner size than the traditional limit of
5 µm aerodynamic diameter used for discriminating particles that penetrate
beyond the upper respiratory tract to the airways of the lungs in adults.
2. The metric ISM excludes the mass of API that is collected in the induction port
(and pre-separator if used). These amounts are important in the assessment of
add-on devices (spacers and valved holding chambers) that are widely used with
MDIs to mitigate upper airway deposition [ 26 ].