(M1030-08-51) Automated In Vitro Population Bioequivalence for Inhaled Products to Meet the FDA Guidance on Budesonide Using Phoenix® WinNonlin®

Purpose: Oral inhaled and nasal drug products (ONDPs) are extensively used in dosage forms. Population bioequivalence (PBE) methods are recommended by the US Food and Drug Administration (FDA) for in vitro in Vivo bioequivalence assessment. FDA guidances describe how PBE can be implemented for the dosage form in detail^1,2,3. FDA guidelines recommend the use of the Population Bioequivalence (PBE) approach to compare the particle and agglomerate Particle Size Distribution (PSD) in the nebulized aerosol between the test (T) and reference (R). At 95% confidence intervals between test and reference, the alpha value is expected to be less than or equal to 0.05 for both reference-scaled and constant-scaled to determine to BE for PSD. Phoenix® WinNonlin templates can be used to guarantee standardization and accuracy of the calculations and statistical analysis needed to show population bioequivalence for in-vitro inhaled products.

Methods: Phoenix templates, in general, provide a means of creating a collection of data-processing and computational tools that can be reused with different datasets. Phoenix templates were developed to meet the specific recommendations outlined in the FDA guidance on budesonide. The templates require some initial input by the user but automate the calculation of the additional partial size distribution parameters and perform the appropriate statistical analysis to test bioequivalence as specified by the FDA guidance. The guidance also recommends the particle size measured at different life stages (beginning, middle, and end) of the container, and the Phoenix templates can handle these data. The parts of the template that do not require user input are locked to guarantee the consistency of the automated calculations.

Results: PBE analysis of budesonide was performed using Phoenix WinNonlin workflows, using datasets provided by the FDA in their guidance. Critical results obtained with Phoenix matched results reported by FDA.

Conclusion: Although numerous steps were required, Phoenix WinNonlin has the capability to perform in-vitro population bioequivalence calculations according to the FDA guidance for budesonide using Phoenix templates that need very minimal input by the user. Phoenix templates can be easily reused with different datasets. The Phoenix templates and example projects presented in this poster are available for download at Certara University.

References: 1. FDA. Guidance for industry. Statistical approaches to establishing bioequivalence. 2001. https://www.fda.gov/downloads/Drugs/Guidances/ucm070244.pdf.
2. FDA. Draft guidance for industry. Bioavailability and bioequivalence studies for nasal aerosols and nasal sprays for local action. 2003. https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM070111.pdf.
3. FDA. Draft guidance on budesonide. 2012.
https://www.accessdata.fda.gov/drugsatfda_docs/psg/Budesonide_Inhalation_Sus_20929_RC_09-12.pdf