Lonza [SWX: LONN]

Nuala Trainor

Cell and gene therapies (CGTs) have been rapidly growing in recent years due to successful clinical results. As of Q4 2022, globally, 104 CGTs received full approval (excluding RNA therapy), 13 more are anticipated in the US and EU by the end of 2023 and more than 2,000 are currently in clinical trials. One of the fastest growing segments utilizes T cells; specifically, the use of chimeric antigen receptor (CAR) T cell immunotherapy for hematological malignancies.

Significant investment and innovation are happening in CGTs, with several novel treatment options being developed and six CAR T cell products achieving FDA approval since 2017.Despite the positive outcomes for patients, widespread adoption of CGTs remains limited, with cost and scalability being the primary concerns. The list price of approved CAR T cell therapies ranges from $373,000 to $475,000. The manufacturing methods adopted during clinical trials often do not translate to efficient commercial-scale manufacturing. The cost and scalability challenges can be partially attributed to the fact that personalized medicine cannot utilize conventional manufacturing methods, which are based on producing large batches for mass distribution.

Challenges

Labor, materials, overhead and shipping are the primary challenges with cost and scalability.

The manufacturing of CAR T cell products is very labor-intensive. A typical manufacturing run spans ten days, with multiple manual interventions and various quality control checks required. A dedicated team of three people working the equivalent of five days per product means approximately fifteen full-time equivalent days is required per product. Not only is this expensive, but it is challenging to recruit and train qualified personnel for these complex manufacturing methods.

Materials include consumables and reagents for both production and quality control. Viral vectors, which are used for genetic modifications to target cancerous cells, constitute the highest material cost for current CAR T cell therapies. Vector can often be produced effectively in small volumes, but can be challenging to scale up, leading to bottlenecks in viral vector acquisition.

These products are produced in highly controlled Grade B cleanrooms (ISO Class 7), with open processes occurring in Grade A spaces (ISO Class 5). These spaces have stringent environmental controls and are cleaned extensively between uses; significantly adding to overhead expenses. Cleanroom space can also be difficult to scale up. Custom building a new manufacturing site requires large capital investment. New site construction is a multi-year project, so it is critical to have accurate forecasts of required infrastructure and expected budgetary spend, which can be a challenge in a new and rapidly evolving industry.

Shipping costs and logistics management is another consideration. The incoming patient material and outgoing product are typically cryo-preserved and shipped between the hospital and off-site manufacturing facility. Cryo-preservation and shipping is expensive and time consuming, which can be detrimental to critically ill patients who depend on a quick turnaround for these therapies.

Solutions

To make this therapeutics affordable and scalable, significant changes to current practices need to be implemented. Automated manufacturing systems such as Lonza’s Cocoon® Platform can provide a reduction in both labor and overhead requirements. Automating quality control tests and integrating these with the manufacturing platform would enable further reductions, especially if these can be monitored outside of the cleanroom.

Process optimization can be an effective method of significantly reducing material needs. Material reduction can be facilitated by bio feedback-based automation to culture the cells. Bio feedback enables optimized feeding times and quantities, which can reduce reagent requirements as well as process duration. By reducing cycle time, the labor, material and overhead costs decrease. Process optimization can also be used to reduce viral vector quantity needed by implementing methods to increase transduction efficiency (genetic modification) with a lower quantity of vector. Transduction enhancer coatings and other reagents can be used to reduce the quantity of vector required by improving genetic modification efficiency with a small quantity of vector. Alternatively, non-viral genetic modification techniques such as electroporation using Lonza’s Nucleofector® LV system removes the need for viral vector.

Overhead reductions can be achieved by moving production out of Grade B cleanrooms. To enable this while still maintaining a low risk of contamination, the operations need to be in a closed environment. This can be done by using an isolator or by utilizing a closed automation system. Further efficiency enhancements can be made by reducing the required production footprint. An all-in-one automation system, as opposed to a modular approach with linked equipment, offers greater footprint reduction; especially if these can be stacked or arranged in a manner to best utilize the available space.               

The final challenge is shipping. To address this, manufacturing can be moved to a decentralized model, and potentially point-of-care such as the approach taken by Galapagos NV. Decentralized and point-of-care manufacturing simplifies transportation logistics and minimizes the time needed to deliver these life-saving treatments to patients. To support the scalability and consistency across multiple sites, an easy-to-use automated manufacturing platform must be utilized. It is estimated that the cost of personalized cell-based manufacturing could be reduced by 75 percent by implementing innovative manufacturing solutions.

Cell and gene therapy have made great strides in recent years, with significant growth expected in the coming years. The forecasted compound annual growth rate (CAGR) is 46 percent, generating approximately $86 billion in sales by 2028. To support this rapid growth, it is critical for CGT providers to adopt manufacturing innovation to enhance efficiency, making these products more accessible for the benefit of patients globally.