Root Cause Investigation of Rubber Seal Cracking in Pre-filled Cartridges: Ozone and Packaging Effects.

Unlabelled: Pre-filled syringes/cartridges as primary packaging for parenterally delivered biopharmaceutical liquids consist of multiple components, including containers made of glass or plastic, and stoppers/plungers and disk seals (septa) made of rubber materials. Cracking of rubber components may be cosmetically unacceptable and in extreme cases may compromise enclosure integrity. The purpose of this study was to investigate the root cause of septum cracking and evaluate parameters/solutions to delay or prevent cracking from occurring. Custom-made chambers capable of tightly controlling ozone levels were assembled to deliberately create septum cracks. Cracks were qualitatively assessed by optical microscopy and quantified using image analysis by ImageJ. The results confirmed that ozone attack is the root cause of septum cracking during storage, and the stress-the result of crimping on the glass cartridge by the aluminum lined seal-made the septum particularly vulnerable to ozone attack. Ozone concentration as low as 10-40 ppb (levels routinely detected on a busy street) could crack the stressed septum in hours while days of ozone exposure at 50 ppm could not cause the unstressed septum to crack. Under ozone attack cracks initially grow in length and width uniformly across the stressed area and then stop progressing, perhaps due to residual stress release. Although the use of impermeable barriers could prevent cracking completely, this study suggested that any form of packaging barriers, including a highly permeable Tyvek® sheet, could postpone cracking by slowing down ozone diffusion and convection. We demonstrate that simple double packaging-placing the Tyvek®-lidded blister tray in a cardboard carton-could sufficiently protect the stressed septum for years in a surrounding environment with ozone at normal indoor levels (≤2 ppb).

Lay Abstract: Pre-filled syringes/cartridges as primary packaging for parenterally delivered biopharmaceutical liquids contain multiple components, including a disk seal (septum) made of rubber materials. Cracking of rubber components may be cosmetically unacceptable and in extreme cases may compromise enclosure integrity. The septum, if not appropriately packaged, might crack under uncontrolled storage environment. The purpose of this study was to investigate the root cause of septum cracking and evaluate parameters/solutions to delay or prevent cracking from occurring. Custom-made chambers capable of tightly controlling ozone levels were assembled to deliberately create septum cracks. The results confirmed that ozone attack is the root cause of septum cracking during storage, and the stress-the result of crimping on the glass cartridge by the aluminum lined seal-made the septum particularly vulnerable to ozone attack. Ozone concentration as low as 10-40 ppb (levels routinely detected on a busy street) could crack the stressed septum in hours. Although the use of impermeable barriers could prevent cracking completely, this study suggested that any form of packaging barriers, including a highly permeable Tyvek® sheet, could postpone cracking by slowing down ozone diffusion and convection. This investigation will raise awareness of manufacturers of pre-filled cartridge/syringe parenteral products to storage and packaging requirements for the long-term physical stability of cartridge components as small as the rubber septum.