(T1330-07-41) Using Different Approaches for Evaluation of Aerodynamic Particle Size Distribution Data in Cascade Impaction Test for Orally Inhaled Drug Products (OIDPs) Bioequivalence

Purpose: The comparative aerodynamic particle size distribution (APSD) study using cascade impactors (CIs) is one of required tests for demonstrating equivalence (BE) of orally inhaled drug products (OIDPs). The information obtained from cascade impactor test is a “profile” of drug mass measured on each of the individual deposition sites. The BE is typically established by the population bioequivalence (PBE) analysis of impactor-sized mass (ISM), with mass median aerodynamic diameter (MMAD), geometric standard deviation (GSD) and fine particle mass (FPM, defined as deposition fraction less than 5 mm) as supportive evidence. The median of the modified chi-square ratio statistic (MmCSRS) is another method for BE evaluation because it evaluates ISM profile and the reference scaling to account for differences in the variability. The purpose of this study is to compare the PBE of ISM and MmCSRS_25 (upper bound of confidence interval below 25% acceptance line for given reference variability) approaches for evaluation of BE, using CI test data from representative OIDPs submitted in Abbreviated New Drug Applications (ANDAs).

Methods: APSD data of test and reference products of 16 OIDP ANDAs (from year 2006 – 2020) including nebulizers, MDIs and DPIs were investigated. Both criteria of PBE on ISM and MmCSRS_25 on ISM profile comparisons were evaluated. Three supportive parameters including PBE on FPM, MMAD and GSD were also evaluated. For MmCSRS on ISM, the acceptance limit was set at 25% difference (MmCSRS_25). The percentage of PBE analysis and MmCSRS_25 passing rate were calculated.

Results: The APSD data for all the nebulizers passed PBE analysis on ISM, FPM, MMAD and GSD. Consistently, these data also passed the MmCSRS_25 on ISM. The APSD data for the 6 MDI and 3 DPI applications all passed PBE analysis on ISM. Additionally, key parameters, FPM, MMAD and GSD, passed PBE analysis except one set of APSD data for MMAD. Among the DPI applications, the passing rate was 98.3% (59 out of 60), 100% and 100% for the PBE analysis on FPM, MMAD and GSD, respectively. The data for the 6 MDI applications shows that 62.5% (5 out of 8) of MmCSRS analysis passed MmCSRS_25. The data for the 3 DPI applications show that 93.3% (56 out of 60) MmCSRS analysis passed MmCSRS_25. The DPI that failed PBE on FPM at 30 L/min for component X also failed MmCSRS_25 on component X and Y at 60 L/min for the high strength, and component X at 60 L/min and 90 L/min for the low strength. However, there’s no distinct link between the failure of PBE on FPM and MmCSRS, as the failure was observed at different airflow rates.

Conclusion: The outcome of the MmCSRS test is strongly influenced by the deposition variability on individual CI deposition sites. The higher variability across the means for the test product in comparison with the reference product may be one reason for the test product failing the MmCSRS test, even though the mean deposition values between test and reference products are comparable. Furthermore, the MmCSRS test is a profile analysis and the failed outcome may not be explained by deposition variability alone. The sensitivity of analytical method, e.g., limit of quantification for analyzing some deposition fractions may also contribute to the failing MmCSRS. The failure of MmCSRS test is an indicator of deposition differences between the T and R products, but the totality of evidence including device similarity, formulation sameness, other in vitro tests recommended for the specific drug product, and in vivo studies (e.g., pharmacokinetic and clinical efficacy studies) are also taken into account in ensuring BE between test and reference products. The results of PBE and MmCSRS_25 are in line with each other for nebulizers. The MmCSRS_25 acceptance criteria applied in MDIs and DPIs may be too stringent which may be due to the distinct amount of emitted dose and shorter mean residence time than those for nebulizers. Whether the MmCSRS test is an ideal method to evaluate BE for the APSD study of MDIs and DPIs needs further evaluation, especially >25% difference between test and reference for MmCSRS criteria. More research work may be needed to determine the implication of MmCSRS profile comparisons to establish APSD equivalence for the generic OIDPs.