Improved quality control metrics for cascade impaction measurements of orally inhaled drug products (OIPs).

This study of aerodynamic mass-weighted particle size distribution (APSD) data from orally inhaled products (OIPs) investigated whether a set of simpler (than currently used) metrics may be adequate to detect changes in APSD for quality control (QC) purposes. A range of OIPs was examined, and correlations between mass median aerodynamic diameter and the ratio of large particle mass (LPM) to small particle mass (SPM) were calculated. For an Andersen cascade impactor, the LPM combines the mass associated with particle sizes from impactor stage 1 to a product-specific boundary size; SPM combines the mass of particles from that boundary through to terminal filter. The LPM-SPM boundary should be chosen during development based on the full-resolution impactor results so as to maximize the sensitivity of the LPM/SPM ratio to meaningful changes in quality. The LPM/SPM ratio along with the impactor-sized mass (ISM) are by themselves sufficient to detect changes in central tendency and area under the APSD curve, which are key in vitro quality attributes for OIPs. Compared to stage groupings, this two-metric approach provides better intrinsic precision, in part due to having adequate mass and consequently better ability to detect changes in APSD and ISM, suggesting that this approach should be a preferred QC tool. Another advantage is the possibility to obtain these metrics from the abbreviated impactor measurements (AIM) rather than from full-resolution multistage impactors. Although the boundary is product specific, the testing could be accomplished with a basic AIM system which can meet the needs of most or all OIPs.

Minimizing variability of cascade impaction measurements in inhalers and nebulizers.

The purpose of this article is to catalogue in a systematic way the available information about factors that may influence the outcome and variability of cascade impactor (CI) measurements of pharmaceutical aerosols for inhalation, such as those obtained from metered dose inhalers (MDIs), dry powder inhalers (DPIs) or products for nebulization; and to suggest ways to minimize the influence of such factors. To accomplish this task, the authors constructed a cause-and-effect Ishikawa diagram for a CI measurement and considered the influence of each root cause based on industry experience and thorough literature review. The results illustrate the intricate network of underlying causes of CI variability, with the potential for several multi-way statistical interactions. It was also found that significantly more quantitative information exists about impactor-related causes than about operator-derived influences, the contribution of drug assay methodology and product-related causes, suggesting a need for further research in those areas. The understanding and awareness of all these factors should aid in the development of optimized CI methods and appropriate quality control measures for aerodynamic particle size distribution (APSD) of pharmaceutical aerosols, in line with the current regulatory initiatives involving quality-by-design (QbD).