Biomedical Engineering Reference
In-Depth Information
100
Alveolor/lnterstitium
Extrathoracic
Bronchial
80
60
Bronchiolar
40
20
0
0
5
Aerodynamic Diameter (
10
15
µ
m)
Fig. 2.3
Collection efficiencies of the ACI stages (
Q
= 28.3 LPM) and of morphological regions
of the lung (PIFR = 28.3 LPM;
V
= 2 L; healthy male) (
from
[
10
]
—used with permission)
used, at a minimum there should be three to four groupings to ensure future batch-
to-batch consistency of the particle size distribution.” Currently, these specifications
often require that the ratio of the upper to lower allowed mass of API on stage
groupings be 1.5:1 or 2:1. However, these ratios are based neither on drug class
specific nor on mechanism of action, or on clinical factors, such as patient age and
disease modality.
In relation to single clinical dose testing, the corresponding European regula-
tory guidance [
6
], which is harmonized with equivalent Health Canada (HC) guid-
ance [
12
], focuses on the determination of fine particle mass with
d
ae
< 5
m and
only refers to pooling of mass on stages in the context of limited analytical sensi-
tivity for the API. For APSD determination, the EMA and HC guidance documents
state: “individual stage particle size distribution data should be provided for the
batches used in these studies, as well as data on batches representative of the com-
mercial process.”
From the perspective of product QC, however, OIP performance metrics based
on stage groupings or even stage-by-stage data are confounded with respect to
changes in APSD, for example, because mass transferred from one group to an
adjacent group in direction of either increasing or decreasing aerodynamic size is
inevitably associated with a compensating decline in the mass associated with the
demonstrated that a suboptimal performance of these metrics for product quality
control (QC) purposes exists compared to the capability of the EDA method.
μ
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