CAR T cell therapy is revolutionizing the way cancer is treated, offering a targeted and personalized approach that has resulted in long-term remission for many patients. As the clinical pipeline is being populated with a steady stream of emerging therapies, manufacturers are looking for ways to scale and improve the manufacturing process in order to lower costs and meet regulatory requirements.
One approach to streamlining some of the current barriers in manufacturing is the use of automated, closed systems with integrated software controls. These systems can offer numerous benefits over traditional open systems, including process standardization, lower manufacturing costs, increased batch-to-batch consistency, and reduced risk of contamination.
In this article, we will explore the differences between open and closed systems for manufacturing CAR T cell therapies as well as examine the benefits and drawbacks of each approach. We will also explore the role of single-use technologies (SUTs) in closed system manufacturing and discuss the regulatory considerations that CAR T cell manufacturers must navigate.
For more information, check out the accompanying chapter on closed system automation (chapter 7) in our Cell Therapy Handbook.
Closed vs. open systems
Open systems, especially involving cell processing and culture, are commonly utilized in the research setting due to their simplicity and low cost. However, they have a number of drawbacks when it comes to clinical manufacturing. One major concern is the risk of contamination, as open systems expose the cell therapy product to potential environmental contaminants, while requiring increased user interaction. This can lead to manufacturing failures, batch-to-batch variability and make it more difficult to meet regulatory standards. In addition, open systems are often more labor-intensive and require larger footprints, making it difficult to scale up production.
Closed systems, on the other hand, are designed to avoid exposure of the product to the room environment. This is typically achieved through the use of sterile barriers and connectors or through the incorporation of single-use technologies (SUTs) such as bioreactors and tubing. Closed systems offer a number of benefits over open systems, including reduced risk of contamination, improved batch-to-batch consistency, and the ability to operate in a grade C manufacturing facility rather than a more expensive grade A or grade B facility. They also offer greater flexibility in terms of facility design, as they can be placed in a controlled but non-classified environment.
The importance of automation in GMP manufacturing
To complement the incorporation of closed manufacturing tools into a workflow, the implementation of automation to the workflow can eliminate a large range of challenges and can be a critical part of large-scale cGMP manufacturing. The EMA suggests that “The use of automated equipment may ease compliance with certain GMP requirements and may also bring certain advantages in respect to product’s quality.” Automation would improve operator safety, reduce human errors, and enable processing robustness and reproducibility.
Automated systems can simplify operations overall. Manual procedures that have multiple steps or require multiple operators can be combined within a single machine with a single operator, reducing the product turnover time and the number of personnel required in the operation space. As a result, facility production capacity will increase. The overall cost of goods for similar quantities of cell therapy products will significantly decrease. Thus, while the initial investment for automated systems may seem high, the overall benefit is often higher and may ultimately lower cost over time due to requiring less operators, consumables, and time.
An added benefit of the incorporation of automated processes into a complex zero failure tolerance setting is the enablement of customers to implement analytics and characterization testing into the workflow. This added benefit could significantly reduce manufacturing failure rates by allowing for checkpoint analysis throughout the process, allowing for corrective adjustments to be made during the process, instead of resulting in a final product that is unusable. This would also reduce the cost of the therapies by decreasing COGS and mitigating the risk of manufacturing failure that would otherwise prevent patient treatment.
Existing closed automation systems in cell therapy manufacturing
Several steps in patient-specific cell-based therapy development (e.g., CAR T) can be implemented using an automated, closed system: cell isolation, expansion, editing, processing, and formulation. Two categories exist based on the degree of automation: integrated closed systems and modular closed systems.
Integrated closed systems are fully automated. They are all-in-one, easy-to-use, and designed as an end-to-end, one-patient-at-a-time solution. Once employed, the integrated closed instruments are dedicated to producing a specific patient’s cell product for a certain period of time (usually 1-2 weeks). This approach uses automation and closure of a single machine for a specific patient or purpose and integrates several steps into a complete workflow.
Modular closed systems can offer more versatility in application, with each instrument primarily optimized for a single unit operation. This approach does not restrict bioprocessing companies to a single supplier—they can choose instruments that are best suited for individual steps in the process. More importantly, manufacturers have the flexibility to develop and optimize new processes using existing workflows and instrumentation as needed.
An example of synergistic workflow integration is the use of the CTS Rotea Counterflow Centrifugation System to isolate PBMC/CD3 T cells and the subsequent use of the G-Rex system to expand the T/CAR T cells (see the white paper on this topic).
Table 1 summarizes some current cell processing automated systems and their parameters.
Table 1. Comparison of common cell processing systems.
|Modular system||Integrated system|
|Core technology||Counterflow centrifugation1||Electric centrifugation motor and pneumatic circuitry for piston drive2||Spinning membrane filtration³||Acoustic cell processing4||Magnetic separation5|
|Input volume||30 mL–20 L||30 mL–3 L||30 mL–22 L||1–2 L||1–2 L|
|Input cell capacity||10 x 109||10–15 x 109||3 x 109||1.6 x 109||3 x 109|
|Cell processing time||45 min||90 min||60 min||40 min||N/A|
- Rotea system; 2. Sepax™; 3. LOVO®; 4. ekko™; 5. CliniMACS Prodigy®
Digital integration of the CAR T cell therapy manufacturing workflow
Software-driven, digital integration plays an essential role to support full automation across the entire cell therapy manufacturing workflow. Digital integration can improve manufacturing productivity and process control by monitoring the entire workflow starting from sourcing raw materials through product delivery to the clinic. This tracking can ensure data integrity, traceability and regulatory compliance, plus aid in the scale up of the process. Ideally, a mature manufacturing environment would connect production (hardware and controllers), control layers (e.g., supervisory controls), and manufacturing execution systems. Software tools can offer the ability to mine and analyze data from upstream and downstream batch records across batches for real-time optimization and troubleshooting.
Gibco CTS Cellmation Software for the DeltaV System is an off-the-shelf, digital solution that allows users to connect their Thermo Fisher cell therapy instruments within a common DeltaV network to control workflows across multiple instruments in a 21 CFR Part 11 compliant environment.
For more information on the topic of digital automation, check out this webinar and article.
Tremendous efforts have been made to make CAR T cell therapies more effective, safe, and persistent in helping treat patients. Yet, there is significant room to grow the manufacturing process to reduce errors, manufacturing failures, lot-to-lot variation, and contamination. These errors commonly result from the use of open processes with manual handling. Using closed automated systems that integrate the complicated, multistep CAR T workflow can easily overcome these challenges. The use of closed integrated systems improves consistency, purity, and safety while helping to lower overall manufacturing costs. These benefits can contribute to making cell therapies more affordable and accessible to patients in the future.
This article provides a brief overview of the numerous challenges and considerations that a cell therapy manufacturer must address while selecting an automation system for scaling up their cell therapy manufacturing. For more in-depth discussions on these topics, we recommend reading up on the accompanying chapter in our Cell Therapy Handbook.