The Regulatory and Compendial Pathways to Acceptance for AIM and EDA Concepts - Good Cascade Impactor Practices, AIM and EDA for Orally Inhaled Products - page 361

common goals in relation to either but preferably both concepts. Fortunately, in the
past 5 years, teams comprising industry experts in OIP in vitro assessment, both
within the IPAC-RS and EPAG organizations, have been collaborating on many of
the common practical issues associated with AIM and EDA, from which various
publications have been created that are referred to in many locations within this
topic. Such documentation provides a sound basis from which meaningful discus-
sions on how to develop the necessary stakeholder consensus concerning the
approaches may be had with the key regulatory agencies in Europe and North
America in order to gain acceptance of AIM and EDA concepts.
Initial informal discussions with individual regulators, both in Europe and the
USA, have provided cautious optimism that these concepts could have a future in
OIP aerosol in vitro assessments [ 25 , 26 ]. However, further evidence-driven open
publications together with perhaps more formal direct dialogue with the key regu-
latory agencies and compendial chapter committees will be critical if these con-
cepts are to move from good ideas to practical reality as key components in the OIP
life cycle.
The current thinking on AIM and EDA by the various stakeholders was outlined
at an IPAC-RS-led satellite meeting held as part of the RDD Europe conference in
the spring of 2011 [ 27 ]. At that meeting, the FDA representatives reiterated the
position of their organization that better science should lead to better regulations.
They also emphasized that they are open to discussion on alternative approaches to
control strategies. They accepted that AIM would be a useful research tool and that
it could save time, providing a larger throughput. AIM-based methods also have the
potential to be more environmentally friendly than the current full-resolution CI
approach. It appears that the following approach would be a suitable solution from
the European regulatory perspective [ 26 ]:
1. Adoption of AIM methodology as option in Ph. Eur. monograph 2.9.18 (with no
specifi c confi guration). Seek harmonization with USP/JP at the outset.
2. Inclusion of EDA concept with associated ISM and LPM/SPM metrics in Ph.
Eur. Chap. 2.9.18 as optional methodology.
3. Amend Ph. Eur. monograph on preparations for inhalation by deletion of fi ne-
particle dose as mandatory test and replacement with a more general requirement
to adopt limits for those parameters that are able to discriminate between accept-
able and unacceptable batches.
Beyond these promising signs of eventual acceptance, some issues were raised
that still need to be addressed. Most of these concerns are related to statistical
aspects of EDA, such as (a) how various APSD fractions are correlated with EDA
metrics, (b) whether different APSDs can share the same LPM/SPM ratio, and (c)
how bimodal APSDs can be interpreted by an EDA-type approach.
There is also an overarching concern whether there is a loss of information
potentially available from full CI stage data, by having EDA metrics alone. This
consideration would be most relevant in a QC test where, in the USA, the FDA
requires a specifi cation set on several size fractions (usually at least 4), whereas
EDA would provide only two metrics, the LPM/SPM ratio and ISM . Given these