The Regulatory and Compendial Pathways to Acceptance for AIM and EDA Concepts - Good Cascade Impactor Practices, AIM and EDA for Orally Inhaled Products - page 351

mass), will be needed to justify replacing current methods. A vital part of this
process will be demonstrating that EDA is capable of at least matching current
methods and preferably is shown to have better decision-making capability, in the
context of quality control for most OIPs. AIM-based apparatuses may have roles in
the development of testing capacity to work with improved material and process
understanding, implementation of in-process controls prior to fi nal product, and
minimization of capacity spent on end product controls. Given precedents for the
pace of change, compendial and regulatory acceptance will likely take several years
to be realized. This chapter begins by assessing the current regulatory guidance and
compendial requirements with respect to the use of cascade impaction or when
APSD data is required. The second part of the chapter discusses strategy and require-
ments that the pharmaceutical industry involved with OIP assessment is likely to
have to provide to demonstrate that AIM and EDA are “fi t for purpose” and thereby
gain acceptance by the regulators and become a pharmacopeia-approved method.

11.1 Current Guidance

The use of multistage cascade impaction in the context of OIP-generated aerosol
APSD assessment has three principal objectives:

1. As a measure of the product aerosol aerodynamic performance
2. To provide a tool for assessing product quality in commercial product batch
release
3. To establish relationships with potential in vivo performance, through either an
IVIVR or IVIVC

There are issues associated with meeting each of these objectives that limit applica-
bility to the clinical reality of OIP use by the patient requiring therapy. These issues are
discussed further in Chap. 12 . However, as examples, the use of a single constant air
fl ow rate through the CI system cannot represent the inhalation profi le of a patient in
more than a rudimentary way. Furthermore, the APSD of the aerosol cloud produced
under the constant fl ow rate testing conditions may not necessarily be identical with
that of the aerosol which the patient inhales at a variable fl ow rate-time profi le. Inhaler
dosage form is a further complicating factor affecting inhaled aerosol characteristics, as
the testing methods described in the pharmacopeial compendia differ whether the OIP
is an MDI, DPI, or nebulizer. Even if complicating factors on the clinical side such as
patient-to-patient variability, disease condition, and relatively insensitive clinical mea-
sures of effi cacy are ignored, it is not unexpected that current laboratory testing meth-
odology for OIPs falls short by failing to provide unambiguous IVIVR/IVIVCs [ 1 - 3 ].
When using laboratory methodology, whether AIM or full-resolution CI based,
there are therefore many compromises that of necessity have to be made and their
consequences understood. As the community involved with inhaler in vitro perfor-
mance assessment procedures gains a better understanding of the underlying aerosol
physics as well as the limitations of their apparatuses, it should be possible to