A design of experiment applied to pMDI manufacture in order to explore the impact of the critical process parameters on product performance

Silvia Belotti, Matthew Edwards, Simon Bryan, Andrew Brown

Salmeterol Xinofoate (SX) is a long-action β2 adrenoceptor agonist used in asthma and COPD treatment as a bronchodilator. The aim of this work was to evaluate the effect of specific Critical Process Parameters (CPPs) on the aerodynamic performance of an SX pMDI using a Design of Experiment (DoE). The CPPs chosen were the homogenisation time, the mixer speed and the vessel temperature. The Critical Quality Attributes (CQAs) identified as affecting the product performance were the fine particle dose, emitted dose and the total drug content (TDC).
In this study, the formulation used was kept constant at 99.95% (w/w) HFA134a and 0.05% (w/w) SX. The mixing time and the recirculation time prior to product filling were also kept constant both at 30 min. A full factorial design was generated using Minitab (Minitab17 Statistical Software, 2010) to evaluate the CPPs effects.
The aerodynamic assessment of the batches was assessed by Andersen Cascade Impactor (ACI) at 28.3L/min (n=10 shots per ACI). Data such as ACI and TDC for each batch were determined using an appropriate HPLC method in triplicate.
In summary, the use of a DoE increased the process and product understanding. For all of the three CQAs, the highest values (TDC higher than 5.8mg/can, ED higher than 20μg, FPD higher than 9.5μg) are reached when the CPPs have their highest levels (homogenisation time 36min, mixer speed 200rpm and vessel temperature 12ºC) but this batch has also an high variability, so further investigations are proposed to confirm the relationship.

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