Good Cascade Impactor Practices - Good Cascade Impactor Practices, AIM and EDA for Orally Inhaled Products - page 93

the type of OIP being characterized, as well as the preferences of regulatory
agency involved with the product submission [ 2 ]. For example, the NGI operated
at 15 L/min has been identified for the assessment of preparations for nebulization
in both Ph. Eur. monograph 2.9.44 [ 68 ] and its equivalent in 2012 in develop-
ment for incorporation as Chapter 1601 in the US Pharmacopeia [ 72 ]. As well
as affecting its size-discriminating capability, the CI design influences the inter-
nal airflow characteristics and, therefore, the magnitude of nonideal deposition
on internal surfaces. These processes in turn influence both the variability and
potential bias of CI results.

4.2.3 Contribution to Variability from the Measurement

and API Analysis

HPLC or UPLC combined with some form of spectroscopy (UV-visible light
detection, fluorescence, or mass spectrometry) is widely applied to assay API
deposited on CI stages. Fluorescence detection is limited to APIs that fluoresce at
detectable wavelengths, and MS, though highly sensitive and discriminating, is a
relatively sophisticated and expensive technique, requiring careful sample prepara-
tion, especially if volatile species are present.
Although UPLC, being a newer technique, is in the process of becoming more
widely adopted, HPLC-UV-visible spectrophotometry is a well-characterized and
easily standardized technique that is available in almost all laboratories carrying
out OIP testing. Despite its familiarity, this is another area contributing to both
random and systematic uncertainty of CI measurements. For example, one of the
difficulties of using this type of assay for API recovery and quantitation may be
poor chromophore properties of the API. Often, low amounts of the API are
recovered for assay because the collection stage under consideration has its
p articular d 50 size located far from the center of the APSD. Under such circum-
stances, the mass of API recovered could be near to its limit of detection (LOD)
or limit of quantitation (LOQ) established for a given method. Another difficulty
can be the high number of dilutions and wide ranges of concentrations for a given
API delivered from multiple strengths of an inhaled product. In a given dataset
encompassing maximum and minimum strengths, the mass of API recovered
from each stage of the set of stages contained in the CI may range from the LOQ
for the lowest strength tested for stages with d 50 values distant from the aerosol
MMAD to 150% of the highest deposition for the highest strength tested collect-
ing on stages having d 50 values closest to the MMAD. The number of actuations
used per determination might need to be adjusted to enable an accurate and pre-
cise detection method. Additionally, there may be product-specific complications
contributing to the overall method variability, for example, use of highly volatile
solvents (which may be necessary for certain APIs), leading to erratic results due
to solvent evaporation during pipetting. Careful method development, involving
iterative evaluation and optimization, may help minimize variability arising from
the API recovery and analysis procedures.