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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 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 prior to being sterilized by gamma irradiation, eliminating contamination risks from the start. The AT-Closed Vial® technology has been used since 2009 for cell and gene therapy products, with more than 500 equipment in operation today and several drug products approved in the AT-Closed Vial®.
A key advantage of the AT-Closed Vial® is its ability to secure Container Closure Integrity (CCI) during cryopreservation. Robust by design, the AT-Closed Vial® has been tested in various conditions to ensure its resistance to cold temperatures.
The robustness of the AT-Closed Vial®
Materials
The use of Cyclic Olefin Copolymer (COC) for the vial body and a proprietary Thermoplastic Elastomer (TPE) for the stopper ensures suitability for cryogenic temperatures with similar low temperature behavior
Manufacturing Process
Precise molding and robotic assembly with tight tolerances (±0.02 mm repeatability) ensures optimal fitting of the vial components
Gamma Irradiation and Chemical Bonding
Sterilization 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, minimizing contamination risks, and ensures a restored CCI after F&F.
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: Demonstrating that CCI remains intact even after four years of storage at various temperature) and relative humidity conditions
- Laser Headspace Analysis (LHA): Studies using Frequency Modulation Spectroscopy exhibited 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 exhibited 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; different solutions are available to accommodate the needs from process development to commercial manufacturing.