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A Novel Simulation-Based Approach for Comparing the Population Against Average Bioequivalence Statistical Test for the Evaluation of Nasal Spray Products on Spray Pattern and Droplet Size Distribution Parameters

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Abstract

The aim of this work is to evaluate average bioequivalence (ABE) and population bioequivalence (PBE) statistical approaches so as to identify which approach is most suitable for in vitro bioequivalence (IVBE) testing of nasal spray products. For droplet size distribution (DSD) and spray pattern (SP), in vitro data were collected using a well-established nasal spray on the market (Nasonex®, manufactured by Merck Sharp & Dohme Limited). Simulations were performed using in vitro data to comparatively investigate ABE and PBE tests. For highly variable parameters such as SP area, this study clearly demonstrates that the level of agreement between ABE and PBE test conclusions is much smaller as compared with that of DSD Dv(50), which was found to have moderate variability. PBE approach dictates equivalence for both means and variances, and was found to handle both SP and DSD parameters with similar passing rates compared to the passing rates from the ABE approach. However, pronounced asymmetric behavior of PBE empirical power curves for highly variable SP area was observed. A modified PBE statistical approach is proposed for DSD span and Dv(50) in vitro parameters, where acceptance criteria would be based on comparison of reference/branded product to itself as part of “pre-IVBE study” via innovative statistical bootstrap simulations. Due to inherent high variability of the SP area parameter driving pronounced asymmetric behavior of PBE power curves, and due to unclear in vivo relevance for SP area and ovality, authors propose that SP parameters be used as development and quality control tools rather than for demonstration of IVBE.

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Acknowledgements

The authors would like to thank analyst Elena Arsova for conduction of experimental tests.

Author information

Authors and Affiliations

  1. Faculty of Pharmacy, University of Ljubljana, Aškerčeva cesta 7, 1000, Ljubljana, Slovenia

    Jernej Grmaš, Rok Dreu & Rade Injac

  2. Lek Pharmaceuticals d.d, Verovškova 57, 1526, Ljubljana, Slovenia

    Jernej Grmaš

  3. CAIR-Centar d.o.o., Maksimirska 116, Zagreb, Croatia

    Vesna Lužar-Stiffler

  4. Department of Mathematics, Faculty of Science, University of Zagreb, Bijenička c. 30, Zagreb, Croatia

    Vesna Lužar-Stiffler

  5. Sandoz LatAm, 5200 Blue Lagoon Drive No 650, Miami, Florida, 33126, USA

    Rade Injac

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  1. Jernej Grmaš
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  4. Rade Injac
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Correspondence to Jernej Grmaš.

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Appendix

Appendix

Table II Results of In Vitro Study Testing
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Table III Statistic and p Values for Normality Check of Data Distributions
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Fig. 10
figure 10

Summarized data for groups based on regional differentiation

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Fig. 11
figure 11

Summarized data for groups based on type of pump differentiation

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Grmaš, J., Lužar-Stiffler, V., Dreu, R. et al. A Novel Simulation-Based Approach for Comparing the Population Against Average Bioequivalence Statistical Test for the Evaluation of Nasal Spray Products on Spray Pattern and Droplet Size Distribution Parameters. AAPS PharmSciTech 20, 38 (2019). https://doi.org/10.1208/s12249-018-1223-9

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