The Regulatory and Compendial Pathways to Acceptance for AIM and EDA Concepts - Good Cascade Impactor Practices, AIM and EDA for Orally Inhaled Products - page 360

m aerodynamic diameter. However, using EDA
metrics with the large-to-small boundary size set at or close to the MMAD of
one component may be problematic where the MMAD of the second API com-
ponent is signifi cantly different. Similar considerations would likely apply to
tri-component or more complex combinations, in the event that such products
are formulated for inhaled delivery. It follows that the selection of an appropri-
ate cut point used in the AIM apparatus and proof of EDA sensitivity to all API
components will be critical.
(c) Effect of OIP aerosol MMAD on large-to-small particle boundary size
selection:
A key attribute of the EDA approach is the selection of the cut-point size that
discriminates small from large particles. This boundary is ideally “identical” to
the MMAD of the emitted aerosol. However, depending upon the skewness of
the distribution, it can also be located in the range between 0.3 and 3.0 times
MMAD for adequate sensitivity to distinguish small changes in APSD [ 23 ]. In
the case of a new OIP coming under consideration for EDA evaluation, APSD
data using a full-resolution CI method is the foundation from which the product
MMAD is determined. In addition, however, there needs to be additional data
justifying the selection of the large-to-small particle boundary size, if markedly
different from the MMAD of the product. Such evidence may come from stud-
ies in which small perturbations in the APSD and hence MMAD of the product
aerosol are intentionally introduced in order to evaluate the sensitivity of the
EDA method. It follows that if an AIM-based measurement technique is being
proposed instead of the full-resolution CI to obtain EDA metrics, justifi cation
will have to be provided for the selection of the cut-point size, if different from
the MMAD.
(d) Demonstration of the relationship between CI stage grouping, fi ne-particle dose
(mass), MMAD, etc., to EDA metrics:
There is already a body of evidence [ 24 ] that EDA metrics have better dis-
criminating ability compared with current CI stage groupings/fi ne-particle dose
assessments. Much of this material was presented in detail in Chap. 8 and will
therefore not be discussed further here. It is expected that as the debate sur-
rounding the applicability and limitations of EDA develops, more evidence sup-
porting EDA as being less vulnerable to confounding than stage groupings will
emerge, and such data will be important in securing the necessary validations to
support incorporation of EDA into the compendia.

having its cut-point size at 5 μ

11.4 Regulatory Acceptance

In order for AIM and EDA to be developed as useful tools, it is imperative that vali-
dation studies are published, ideally in peer-reviewed journals, to make visible the
strengths and weaknesses of these approaches. Most progress in the required
direction can be made when the industry shares and moves forward with a set of