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Uncompromised Container Closure Integrity at cryogenic temperatures
The challenge of storing drugs at low temperatures
The field of cell and gene therapy is experiencing rapid growth, with a significant number of ongoing clinical trials and the anticipation of numerous product approvals in the coming years. A critical aspect in delivering these transformative treatments is the ability to preserve their quality attributes through low-temperature storage and cryopreservation. However, this introduces challenges, particularly concerning the integrity of the container closure system (CCI) at cryogenic temperatures.
The AT-Closed Vial® technology offers a comprehensive solution to address these challenges in the fill and finish process of cell and gene therapy products. This technology revolves around a ready-to-fill polymer vial (COC body and TPE stopper) that is molded and closed under ISO 5 conditions, eliminating contamination risks from the outset.
A key advantage of the AT-Closed Vial® is its ability to secure Container Closure Integrity (CCI) during cryopreservation
The robustness of the AT-Closed Vial®
Material selection
The use of Cyclic Olefin Copolymer (COC) for the vial body and a proprietary Thermoplastic Elastomer (TPE) for the stopper ensures materials suitable for cryogenic temperatures with similar low-temperature behaviour
Manufacturing Process
Manufacturing Process: Precise molding and robotic assembly with tight tolerances (±0.02 mm repeatability) ensure optimal fitting of the vial components
Gamma Irradiation and Chemical Bonding
Sterilisation by gamma irradiation, combined with the compression between the stopper and vial body, creates a chemical bonding between the COC and TPE. This bonding plays a significant role in maintaining CCI at low temperatures
Unique Filling Process
The vial is filled through the stopper with a sterile needle, which then mechanically recloses. A subsequent one-second laser shot re-seals the needle trace, and a sterile cap is added for protection. This process maintains a functionally closed system throughout filling, minimising contamination risks
Testing and validation
Our whitepaper covers the extensive validation efforts that demonstrate the resistance of the AT-Closed Vial® to (ultra) cold temperature storage. These include:
- Dye Ingress Tests: Demonstrating maintained CCI after long-term storage at various cryogenic temperatures (e.g., -80°C and in liquid nitrogen) for up to 15 months
- Closure Integrity Tests at Different Conditions: Showing that CCI remains intact even after four years of storage at various temperatures (-20°C to 40°C) and humidity conditions
- Laser Headspace Analysis (LHA): Studies using Frequency Modulation Spectroscopy showed no change in headspace oxygen levels or increased pressure in AT-Closed Vials stored in the vapour phase of liquid nitrogen (-165°C), indicating uncompromised integrity. In contrast, traditional glass vials with butyl stoppers showed significant leakage under the same conditions
- Analysis of Chemical Bonding: Techniques like Scanning Electron Microscopy, Raman spectroscopy, and mass spectrometry confirmed material transfer and chemical bonding between the stopper and the vial body, contributing to CCI
- Computed Tomography (CT) Scans: Visualising the maintained contact between the stopper and body of the AT-Closed Vial® at cryogenic temperatures, further supporting CCI
- Helium leak test: ongoing testing
In conclusion, the AT-Closed Vial® technology offers a robust and validated solution for maintaining container closure integrity of cell and gene therapy products during cryogenic storage.
Its unique design, material composition, and manufacturing process, coupled with a closed filling system, address critical challenges in this rapidly evolving field. The extensive validation data supports its suitability for ensuring product quality throughout the lifecycle, making it a preferred choice for numerous sponsors in the cell and gene therapy. The ability to scale the filling process and adapt to different container sizes further enhances its utility for developers .