The Regulatory and Compendial Pathways to Acceptance for AIM and EDA Concepts - Good Cascade Impactor Practices, AIM and EDA for Orally Inhaled Products - page 352

develop a wider array of methodology than exists at present. However, a goal for
new methods to achieve is that they may be both universally applicable across OIP
categories, and at least equal or better, improving the quality of the data for the
intended purpose.
Looking at the fi rst part of this goal in more detail, it is self-evident that it is
desirable that the compendial methodologies in place to assess OIP aerosol proper-
ties have common utility across as many categories of inhaler (i.e., pMDIs, DPIs,
etc . ) as possible. However, it has to be recognized that minimizing the number of
compendial apparatuses for AIM-based measurements, though attractive, should be
balanced against the fact that OIPs are a very diverse group of products, probably
requiring a degree of specialization in the AIM-based apparatuses that are ulti-
mately developed for their assessment. Such a situation is not unique within the
scope of the compendia; for example, several systems, each with their own specifi c
purpose, characteristics, and limitations, have been developed for the assessment of
tablet dissolution. Notwithstanding the above considerations, minimization of AIM-
based options should certainly be considered at the outset of pharmacopeial method
development, in order to avoid the development of a plethora of procedures having
only minor differences that are customized for each inhaler variant within a given
class of OIP. That said, it has to be recognized that the therapeutic areas treated by
inhalers are quite varied, in that both local and systemic action can be targeted, so
that OIPs within a given class may vary substantially both in mode of operation and
formulation type(s) delivered. These characteristics are likely to facilitate develop-
ment of many methods differing only between inhaler types but essentially deter-
mining the same performance attribute. In the more fl exible environment created by
the adoption of strategies such as Quality by Design [ 4 ], it is likely that regulatory
agencies looking to provide product market approval will have different perfor-
mance measurement needs than those focused on ensuring consistent “in-market”
quality, e.g., post-market product surveillance. It follows that despite the overarching
desire to limit method proliferation, different approaches to in vitro testing method-
ology for aerosol properties, by either full-resolution or abbreviated CI, may have to
be accepted as appropriate during the life cycle of a particular OIP (see Chap. 6 ) .
At the present time, many regulatory agencies require the use of multistage cas-
cade impaction for the determination of OIP APSD based on the mass of drug sub-
stance as one of the principal means for determining likely clinical performance in
terms of dose delivery to the receptors in the lungs. In the USA, the 1998 draft FDA
Guidance for Industry covering chemistry, manufacturing, and controls of pMDIs
and DPIs indicates that the choice of CI should allow determination of an APSD of
the whole dose including the small particle size fraction [ 5 ]. This requirement is
echoed in the equivalent documentation produced by CDRH in relation to the 510(k)
premarket approval process for medical devices, such as spacers, valved holding
chambers, and general-purpose nebulizers [ 6 ]. The draft FDA-CDER guidance fur-
ther states that the number of actuations ( of the inhaler ) needed to determine APSD
by multistage CI should be kept to the minimum, justifi ed by the sensitivity of the
analytical method used to quantitate the deposited drug substance. The amount of
drug substance deposited on the critical stages of the cascade impactor should be