Physical Causes of APSD Changes in Aerosols from OIPs and Their Impact on CI Measurements - Good Cascade Impactor Practices, AIM and EDA for Orally Inhaled Products - page 72

altogether, where the latter is feasible. The avoidance of low ambient relative humidity,
the grounding of operators handling the apparatus, the use of electrically conductive
and grounded surfaces, and, as a last resort, ionization of the air-stream containing
the aerosol have each been found useful in this respect [ 64 ]. Evaporative changes to
the APSD have to be considered where volatile species (i.e., water, ethanol) are
present. Mitigation measures include cooling of the CI, a procedure that is recom-
mended for the evaluation of aerosols derived from preparations for nebulization in
the USP [ 81 ] and Ph. Eur. monograph chapters [ 49 ]. Finally, condensation of mois-
ture on hygroscopic particles can be significant with certain OIPs, such as those
containing cromones. This effect can be controlled by operating the CI system in an
ambient environment set to a stable RH that is either kept as low as possible, if the
object is to prevent hygroscopic growth as is likely to be the case in a QC environ-
ment or at conditions near to saturation, in order to simulate the environmental
conditions in the upper airway upon inhalation.
It is important to stress at this stage in the topic that none of these underlying
physical processes is likely to give rise to the development of fine structure in the
original APSD. Thus, the entire APSD is affected by each process. If discretized
into a finite number of size bins (essentially the function of the CI as a size fraction-
ator), the magnitude of changes to the API mass weighting assigned to each bin,
moving from the smallest to largest size bins or vice versa, will always vary in a
continuous but gradual way. Chapter 9 contains more information about possible
changes to OIP APSD in the context of determining situations in which the related
concept, effective data analysis (EDA), might fail.

3.3.3 Detectability of APSD Changes by the Cascade

Impaction Method

In vivo aerodynamic performance is considered a Quality Target Product Profile
(QTPP) property for OIPs [ 82 ], since the aerosol particle size characteristics affect
delivery of drug to the respiratory tract (see Chaps. 2 and 12 ) .
Currently, aerodynamic particle size testing by the cascade impaction method is
the primary in vitro method in the regulatory environment used for assessing perfor-
mance of OIP-generated aerosols (Chap. 2 ) . The purpose of such in vitro testing is
to act as a surrogate for in vivo testing with patients in order ultimately to provide
assurance to stakeholders that such patients receive product within demonstrated
acceptability limits derived from clinical trial data. This goal is ideally best achieved
when the in vitro measurements can be related directly to in vivo aerodynamic per-
formance that is in turn linked with intended outcomes for the disease modality
being treated. Given the limited success thus far in the search for suitable IVIVRs/
IVIVCs to link laboratory with clinical measures of OIP aerosol performance [ 16 ],
this goal must be achieved indirectly. Under these circumstances, the impactor-
based measurement approach to APSD characterization becomes the active control
strategy tool for assessing the capability of an OIP to meet appropriately defined