A Multi-laboratory in Vitro Study to Compare Data from Abbreviated and Pharmacopeial Impactor Measurements for Orally Inhaled Products: a Report of the European Aerosol Group (EPAG)

Abstract

Abstract. Fine particle dose (FPD) is a critical quality attribute for orally inhaled products (OIPs). The abbreviated impactor measurement (AIM) concept simplifies its measurement, provided there is a validated understanding of the relationship with the full resolution pharmacopoeial impactor (PIM) data for a given product. This multi-center study compared fine particle dose determined using AIM and PIM for five dry powder inhaler (DPIs) and two pressurized metered-dose inhaler (pMDI) products, one of which included a valved holding chamber (VHC). Reference measurements of FPD PIM were made by each organization using either the full-resolution Andersen 8-stage non-viable impactor (ACI) or Next Generation Impactor (NGI). FPD AIM was determined for the same OIP(s) with their choice of abbreviated impactor (fast screening impactor (FSI), fast screening Andersen (FSA), or reduced NGI (rNGI)). Each organization used its validated assay method(s) for the active pharmaceutical ingredient(s) (APIs) involved. Ten replicate measurements were made by each procedure. The upper size limit for FPD AIM varied from 4.4 to 5.0 μm aerodynamic diameter, depending upon flow rate and AIM apparatus; the corresponding size limit for FPD PIM was fixed at 5 μm in accordance with the European Pharmacopoeia. The 90% confidence interval for the ratio [FPD AIM /FPD PIM ], expressed as a percentage, was contained in the predetermined 85-118% acceptance interval for nine of the ten comparisons of FPD. The average value of this ratio was 105% across all OIPs and apparatuses. The findings from this investigation support the equivalence of AIM and PIM for determination of FPD across a wide range of OIP platforms and measurement techniques.

Comparative Assessment of In Vitro and In Silico Methods for Aerodynamic Characterization of Powders for Inhalation

“…Similar findings referring to the higher FPF values obtained by TSI in comparison to NGI, due to the difference in the cut-off value for FPF, were observed by Omer et al [33]. Higher FPF values obtained by FSI in comparison to NGI have already been recognized as a limitation of FSI [27,70], although some studies showed no significant differences between FSI and NGI results, e.g., [23,30]. The highest level of correlation (R 2 = 0.9440) with the lowest values of RMSE and NMRSE (4.669 and 0.173, respectively) was observed between FPF results from NGI and TSI, while the correlation between NGI and FSI, and TSI and FSI results was less pronounced (Table 6).…”

“…Therefore, the availability of different in vitro methods can impede regulatory evaluation. Some studies compared two or three in vitro methods for aerodynamic assessment of DPIs [23,[26][27][28][29][30][31][32][33], but their results were inconclusive. While some of the studies indicated similarities between ACI and NGI results [26,29,31], there were also reports on diverging results obtained by these two methods [28,29].…”

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“…the medium-to-small airways and peripheral bronchioles). The FPD of an aerosol cloud is the proportion of drug mass included in aerosolized particles with an aerodynamic diameter B5.0 lm [5,30]. More than 60% of the drug dose expelled by Respimat Ò falls within an FPD of B5.0 lm [31], which accentuates sedimentation of particles in the smaller bronchi and bronchioles [32].…”

Development and evaluation of flubendazole inhalable nanoparticles for lung cancer treatmen

“…For Pulmicort® (Tubuhaler®), a decrease in MMDA was observed when increasing flow rate from 30 to 90 L/min for NGI, whose results were smaller than those obtained for ACI at 28.3, 45, and 60 L/min (YOSHIDA et al, 2017). It is important to clarify that when standardized and validated, a fair correlation between different apparatus, as abbreviated impactors and pharmacopeial impactors (NGI or ACI) can be established, as shown in a multi-laboratory study for 5 different orally inhaled products (NICHOLS et al, 2016), but there is still room for in vitro-in vivo correlation improvement. In 2009 the first organoid derived from a single stem cell was obtained, and presented capacity for self-proliferation and differentiation (XIA et al, 2019).…”