Theoretical Basis for the EDA Concept - Good Cascade Impactor Practices, AIM and EDA for Orally Inhaled Products - page 146

7.1 Introduction

It is often stated that the aerodynamic particle size characteristics of orally inhaled
products (OIPs) are critical to their performance [ 1 ]. What remains ill defined is
exactly what is meant by particle size characteristics. In a simplistic sense, aerosol
particles need to be small enough to reach the intended deposition site in the human
respiratory tract, but not so small that they are exhaled and not deposited [ 2 ]. There
is a further consideration that aerosol particles are not too large and consequently
end up in the GI tract posing a potential safety concern [ 3 ]. While there has been
some discussion concerning monodisperse aerosols and specific targeting of sites
within the human respiratory tract [ 4 - 8 ], the current commercial technologies
employed in OIPs are limited to producing polydisperse aerosols. Further compli-
cating the situation are the technical challenges posed in obtaining in vivo/in vitro
data specifically elucidating the relationship between aerosol properties and recep-
tor locations that are presumed to be related to the in vivo response (safety and
efficacy) associated with OIPs [ 9 , 10 ].
The basic premise of EDA is that the fundamental critical quality attribute (CQA)
of an OIP with respect to particle size is the multivariate APSD that is characteristic
of a particular product [ 11 ]. In other words, OIPs are designed to deliver an aerosol
with a nominal APSD containing the appropriate chemical composition of active
pharmaceutical ingredient (API) and associated excipients (if the latter are present
as part of the formulation).
Given that basic premise, EDA was designed specifically to address quality con-
trol (QC) decisions with respect to the APSD [ 11 ]. In other words, it was intended
to be sensitive enough to be able to detect small changes to the APSD. In general
terms, the goal of end-product QC testing is to confirm that a particular batch of OIP
product in question is of suitable quality. In the case of EDA, the testing is intended
to confirm that the particular OIPs under assessment, when actuated under normal
conditions of use, generate aerosols possessing expected APSD characteristics
defined from the outcome of product development efforts and subsequently approved
by regulatory authorities. Note that this process of assurance necessarily takes the
form of sampling a relatively small number of units and measuring properties of the
aerosols seen to be critical to the performance of the OIP in question. Thus, rela-
tively few aerosols generated by these samples are actually assessed, and the deci-
sion concerning the quality of the entire sampled batch is ultimately made from the
outcome of these assessments. This process leads to three primary considerations:

1. The properties measured should be relevant to detecting significant abnormali-
ties from the expected APSD.
2. The measurements should possess sufficient precision and accuracy over the
range of interest.
3. The decision process based on the measurements should reliably make correct
inference about the quality of the batch by appropriately minimizing and balanc-
ing the risk of decision errors, i.e., judging a batch suitable when it is not suitable
and conversely judging a batch unsuitable when it is suitable.