A hybrid computational-analytical model for the prediction of stopper displacement in drug product prefilled syringe.

Controlling the displacement of the plunger stopper within prefilled syringes (PFS) during air transportation is critical to maintain the sterility of the drug prod product. The presented computational-analytical hybrid model predicts stopper displacement during transportation at elevated altitude by integrating multi-physics principles including Newton's second law of motion, the ideal gas law, solid mechanics and Monte Carlo Simulations The hybrid model comprises four key components: stopper displacement prediction, manufacturing metric prediction, sensitivity study of input parameters, and design optimization. Model validation was performed against empirical experimental data from five PFS container closure configurations, demonstrating predictive accuracy with errors less than ±5%. The sensitivity study of the simulation model concludes that the stopper initial position, syringe barrel ID, filling volume, stopper rib OD and PFS syringe length are the top five parameters contributing to the stopper displacement. The design optimization function of the simulation model has been demonstrated through an example of optimizing the stopper initial position and fill volume to achieve the pre-defined stopper displacement. This work establishes a simulation model for predicting the stopper displacement of a PFS during air transportation, optimizing PFS container closure system design, fill and finish manufacturing process and ensuring reliable performance during transportation, with potential implications for improving drug product safety and delivery efficiency.