Considerations for the development and practice of cascade impaction testing, including a mass balance failure investigation tree.

APSD MEASUREMENTS OF OINDP are performed in order to characterize the size distribution of particles emitted from the OINDP device. APSD measurements are performed during drug product development for characterization studies, clinical release, and stability studies. In addition, some type of APSD measurement is usually required for release of the final commercial product as part of a comprehensive program to ensure quality of marketed batches. These measurements are made using a CI/MSLI that fractionates the incoming aerosol into several classes with well-defined limits in terms of aerodynamic particle size. It is normal to collect data from a CI/MSLI measurement initially as mass of API collected on each of the components of the apparatus (e.g., induction port, pre-separator (if used), stages of the CI/MSLI, and back-up filter). After determining the mass of API on each component of the apparatus (normally via HPLC with spectrophotometric detection or via direct spectrophotometric analysis), the arithmetic sum of the obtained individual values is calculated, expressed as % of target delivery per actuation, and is referred to as the mass balance (MB). MB is useful in determining whether an expected mass of drug has been captured by the impactor to provide a reliable measurement of the APSD, but by itself does not ensure that the APSD results are valid. MB should therefore not be used alone as a system suitability test when assessing APSD. The PQRI Particle Size Distribution Mass Balance Working Group was formed in late 2001 to examine several issues concerning the MB specification recommendations in the following FDA Guidances for Industry: