ABSTRACT
Vial breakage during lyophilization reduces yield and can lead to product contamination with glass particulates, personnel interventions during manufacturing and damage to equipment. We present case studies of full-scale commercial lyophilization operations and small-scale laboratory lyophilization studies to understand and mitigate the sources of vial breakage for sterile injectable products. In the first case study, changes to the lyophilization cycle caused the breakage of 11% of the vials. Breakage rates were higher on the top than the bottom shelves and higher for vials on the edges of the shelves than for center vials. Laboratory strain gauge and process parameter ranging studies confirmed the breakage mechanism to be thermal expansion of the frozen plug early in primary drying, the temperature of which was increased by the cycle changes. We postulate that residual heat from steam sterilization coupled with edge effects drove the breakage patterns. In another case study, we reduced breakage from 3.5% to 0.4% in commercial production by changing the freezing temperature from -45°C to -25°C. Laboratory strain gauge studies confirmed reduced incidence and severity of "break-free" / "plugging-off," which occurs when the frozen plug abruptly detaches from the vial sidewalls as it is cooled well below Tg'. The final case study is a "breakage challenge" study in the lab using higher fill volumes and aggressive drying to challenge the strength of vials. For borosilicate vials, breakage rates were dramatically higher after washing and tunnel depyrogenation in commercial manufacturing compared to vials that were used as received. Corning Valor® vials remained unbreakable even after processing. Tin oxide external coating provided borosilicate vials significant protection against damage from vial processing. These case studies illuminate vial breakage mechanisms, show how small-scale strain gauge and breakage challenge studies can be used to nearly eliminate vial breakage during full-scale commercial lyophilization.
