A Monte Carlo simulation-based approach to define target fill volume and stopper insertion depth for manufacturing...

Fill volume and stopper insertion depth are important parameters that require definition and de-risking prior to commercial-scale manufacture of pre-filled syringe combination products. Due to cost and time constraints, it is not practical to conduct extensive development runs in the manufacturing facility to optimize and validate process parameter settings. In response to this need, we used Monte Carlo simulations to predict the outcome variability by modeling input parameters using their expected statistical distributions. Governing equations were developed for the desired outcomes of deliverable volume and air gap size. Input variables included sterile barrier height, frictional force, and syringe and stopper dimensions, for which the values were determined either by laboratory measurement, specifications provided by vendors, or conservative assumptions representing worst-case scenarios. Results from these simulations were used to set the target values and tolerance ranges for both fill volume and stopper insertion depth to maximize the probability that manufactured PFS batches would meet acceptable criteria for deliverable volume and sterility.