Performance Characterization of EDA and Its Potential to Improve Decision Making in Product Batch Release - Good Cascade Impactor Practices, AIM and EDA for Orally Inhaled Products - page 167

relative to decision making associated with OIP disposition in the QC environment.
The strategies involve (1) measurement system analysis (MSA), (2) operating charac-
teristic curves (OCC), and (3) principal component analysis (PCA). A general descrip-
tion of these techniques and their basic concepts is provided in the first part of the
chapter, while the computational details and results for each of the employed strate-
gies are given following the same order in the later part of the chapter. All results point
to the conclusion that compared to grouped stages, the LPM / SPM ratio from EDA is
more accurate and more sensitive to APSD changes. Each of the examination strate-
gies used different statistical methodologies, based on different assumptions, and one
of the approaches used a different set of data independent of the other two. Yet the
same qualitative conclusion validating the superior decision-making ability of the
EDA concept was reached, regardless of approach.

8.1 Introduction

The current practice generally used by the FDA for assessing changes in APSD is
based upon selected stage groupings from full-resolution, multistage CI testing.
Each grouping represents a different portion of the APSD profile, in which the total
mass in each stage grouping is compared to specified acceptance limits [ 1 ]. The
grouped-stage approach typically includes the deposition sites of the impactor sys-
tem that are non-sized (e.g., actuator, induction port (throat), pre-separator), plus
three groupings that represent the upper, middle, and lower size fractions of the sized
material captured in the CI. In practice, the “coarse tail” grouping may or may not
include the first impactor stage (sometimes referred to as stage 0), for which, in the
case of the ACI, there is no upper cutoff limit and, therefore, for which there can be
no definitive size range. In the latter case, the first stage (S0) is usually included in
the non-sized grouping, and this has been done in this chapter. The remaining stages
were allocated to three sized groupings for the present analysis (groups 2, 3, and 4,
as defined in Table 8.1 ), which is consistent with the current FDA practice [ 2 ].
The reader will recall from previous chapters that the two metrics used in EDA
assessment are (1) the large-to-small particle ( LPM / SPM ) ratio of API mass and (2)
the sum of LPM and SPM collected in the impactor-sized portion of the emitted dose
from the inhaler (Fig. 8.1 ).

Table 8.1 Typical stage groupings adopted by FDA
[ 2 ] and used in the comparisons within this chapter;
identities for each grouping are based on the 8-stage
nonviable ACI and are described in Fig. 8.1
Grouping ACI stages

1 Group 1 (actuation adapter-S0)

2 Group 2 (S1-S3)

3 Group 3 (S4-S6)

4 Group 4 (S7-filter)