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.

A Quality by Design Approach to Microbial Retention Validation.

Regulatory and manufacturing requirements exist for performance of product-specific microbial retention testing on sterilizing filters. The implementation of a Quality by Design approach to sterilizing filtration supports a paradigm that would obviate the need for product-specific testing for early-stage products that do not have the quantity of material required to perform such testing easily and efficiently. Process and product parameters were varied to determine their effect on microbial retention to define a design space. To minimize the burden of filter validation retention studies for early-stage (Phase 1) manufacturing, it is recommended that manufacturers perform a risk assessment to confirm their product and process conditions are within the established design space. For later stage product development prior to marketing authorization, product-specific filter validation testing is expected.

Investigation of Fogging Behavior in a Lyophilized Drug Product.

Vial "fogging" is a common observation in lyophilized biological products and has been reported in the pharmaceutical industry. In addition to unappealing appearance, severe fogging that reaches the shoulder or neck of the vial can potentially compromise the container closure integrity of the vials. In this study, we performed experiments to identify parameters impacting the fogging phenomena in lyophilized drug product vials. Glass vial surface properties were found to have a significant impact on vial fogging. In line with prior published research, the study demonstrates that fogging can be mitigated by using glass vials with hydrophobic surface (such as siliconized vial or TopLyo® vial) and by extending the prefreeze 5°C hold during the lyophilization cycle. Moreover, this study shows that extending the annealing at -5°C or -10°C can also significantly reduce the fogging. Increased formulation viscosity and exclusion of a surfactant can mitigate the fogging behavior of the lyophilized product. The study shows that container closure integrity as determined by headspace analysis and vacuum decay is not compromised for the "fogging" drug product vials for this model monoclonal antibody container using a worst-case model of lyophilized "neck-wet" vials.