Laser Measurement and Numerical Simulation of Elastomer Stopper Motion during High-Altitude Shipping of Pharmaceutical Syringes.

During high-altitude shipping of pre-filled syringes, pressure differentials can cause the elastomer stopper to move unintentionally. This motion represents a risk to container closure integrity and drug product sterility. To understand and quantitate this risk, we combined high-accuracy laser measurements and numerical simulations of stopper motion. We tested the effects of syringe barrel siliconization, stopper design, syringe orientation, and altitude rate on stopper displacement; only the siliconization factor had a significant effect. Our observations were compared with two mathematical models based on Boyle's Law and a force balance approach. For well-lubricated syringes, stopper motion was reasonably predicted by Boyle's Law (residual ≤ 10%). When the lubricant amount was reduced, Boyle's Law failed to accurately predict stopper motion (residual ≈ 40%). To simulate stopper motion more accurately, we developed a dynamic model in MATLAB-Simulink to incorporate the dry and viscous friction inherent to the lubricated interference fit. Using a Coulomb-viscous subroutine, deviations from Boyle's Law were successfully explained in terms of the displacement, but the system dynamics were not fully accurate. The combination of laser measurements and numerical simulation has yielded unique insight into stopper motion during high-altitude shipping. These tools can provide valuable input to a risk-based drug development strategy to enable global distribution of pre-filled syringes.