Vacuum compatible spring wire system for mass measurement of vials during lyophilization

Pharmaceutical lyophilization (vacuum freeze-drying) stabilizes aqueous formulations, commonly in vials, by removing 99.9% of their water. Failure to remove enough water leads to unstable products, so measuring the amount of water removed throughout the process is critical. Current technologies can measure the total rate of water removal from a batch of vials or destructively measure the final water content of sample vials, but they cannot monitor individual vials in situ. An in-line measurement for the water content of every vial would assess variation in the drying process, enabling process improvements and vial-specific optimizations. This work presents a mass sensor that achieves this individual vial measurement throughout the lyophilization process.

This mass sensor consists of two partial helical springs holding a suspended vial. As water sublimates from the vial during drying, the position and orientation of the free ends of the helical springs change. This change is amplified by sensing arms and measured by a camera outside of the vacuum chamber. Optical fiducials at the ends of the sensing arms enable high-fidelity measurement of the amplified motion. This sensor provides individual vial mass information, allowing tracking of its sublimation rate, without affecting the lyophilization process.

The sensor design was evaluated by building ten sensors for 10R vials with a 3 mL fill. After calibration, these sensors achieved a median offline testing error of 13 mg, which improved to 6.5 mg when calibration coefficients were updated using the maximum a posteriori method. When the sensors were tested in a lyophilization environment, the median error in their final mass measured increased to 50 mg, likely due to micro-slip of the sensor assembly contact regions between measurements introduced hysteresis. Nevertheless, per vial sublimation rates are measured accurately and used to infer drying endpoints.