Many cell therapy manufacturing processes use open unit manipulations. As a result, they are at risk of potential contamination that can result in manufacturing batch failure. The processes therefore rely on end-to-end aseptic processing to ensure the final drug product is safe and free of potentially harmful contamination.
Addressing these risks has led BioPhorum to publish Cell and gene therapy closed systems – closure analysis of a mock autologous cell therapy process. This documents a ‘mock’ process for manufacturing a generic autologous CAR-T product operated through a series of process steps combining open and closed system elements.
The paper demonstrates the systematic application of a closure analysis method on an ex vivo gene therapy process and has extensive appendices containing the process flow diagrams for each step. The closure analysis method used was based on BioPhorum’s Drug Substance Closed Systems Playbook.
Each appendix has a detailed closure analysis indicating the specific transfer input/output point marked on the diagram and an assessment of the ‘as-is’ condition. It also contains recommendations if a re-design is recommended, a suggested option for any re-design and an updated closure analysis of the suggested mitigation.
If readers do not have the time to work through each of the 12 appendices, there is a helpful overview map of the process flow diagrams, where each process box contains a hyperlink to the full diagrams in the appendices. This will help readers look at an appendix and just see the main issues and the options to solve them. Also, two appendices are summaries of the closure mitigations and closure analysis, enabling readers to see the mitigations and resultant impact on closure rating in a snapshot outside of the full manufacturing process.
The methodology will benefit other engineers when designing a process, such as those in gene therapy, by systematically evaluating each unit operation and classifying the level of closure. By taking this approach, engineers can design or improve a therapy manufacturing process and reduce the risk of contamination from open processes.
Technologies are being developed to provide a future state where cell therapy manufacturing processes will be scalable, automated, closed, and modified to fit nuanced or niche industry needs. However, with current technology limitations, a deliberate approach to process design is required to achieve an acceptable level of ‘closure’. Using the analysis in this BioPhorum paper means a controlled, closed, end-to-end cell therapy manufacturing process can be developed to produce a safe drug product with a low risk of process contamination.