Abstract
The container-closure system (CCS), specifically the glass vial, plays a pivotal role in heat transfer during lyophilization, thereby influencing process efficiency and product quality. Therefore, a change in CCS without corresponding changes in the lyophilization process may alter the process performance and product quality. To this end, a systematic evaluation was conducted to determine the CCS variables, formulation characteristics, and lyophilization process parameters at the highest risk of process failure or loss of product quality upon changes in CCS without concomitant changes in the lyophilization process. The mass flow rate and vial heat transfer co-efficient of vials with similar nominal dimensions obtained from two different manufacturers were compared over varying primary drying pressure conditions (i.e., 50 - 400 mTorr). Next, we studied the impact of the vial position in the freeze-dryer on the risk to product quality at pressure conditions showing maximum variance in heat transfer characteristics of the two vials. Further, the risk to primary drying efficiency and product quality upon switching vial manufacturer was evaluated using two model biologic formulations with different solid contents. In addition, the effects of annealing and controlled ice nucleation on mitigating the risk to process efficiency and product quality on changing the vial manufacturer was also assessed. Finally micro-CT imaging coupled with artificial intelligence/machine learning (AI/ML) analysis was conducted to help provide a mechanistic understanding of the varying risk to process performance and product quality of the two model formulations. Differences in vial geometry specifically vial bottom curvature caused variations in vial heat transfer characteristics particularly at higher chamber pressures (>200 mTorr) and specifically for vials placed in center of the freeze-dryer shelf. The heat transfer coefficient of center vials from Manufacturer A was ∼25% higher than those from Manufacturer B, resulting in reduced primary drying time and enhanced process efficiency. The impact of switching the vial manufacturer was more pronounced for the lower-solid formulation (F05), which also exhibited greater microstructural changes. Implementation of annealing and controlled ice nucleation minimized the variability in vial performance and associated risk to process efficiency and product quality. Micro-CT imaging confirmed micro-collapse as a contributing factor to observed performance differences. Changes to vial manufacturer associated with variations in vial dimensions may pose significant risk to process efficiency and quality of freeze-dried products. This product risk is dependent on the process parameters, position of the vial in the freeze-dryer and physicochemical characteristics of the drug product. Further, the vial heat transfer co-efficient (Kv) may be a good indicator of the risk to process efficiency and product quality upon switching vial manufacturer, however Kv does not reflect potential risk associated with microstructural changes. Based on the observations in this study, consideration of CCS attributes during process development is essential in designing robust lyophilization processes and ensuring consistent process and product performance.