By Erin Harris, Editor-In-Chief, Cell & Gene
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Our second Cell & Gene Live, Can Innovation Drive Down Cell Therapy Manufacturing Costs? sponsored by Invetech, featured panelists Dr. Mark Gilbert, SVP of R&D of Acepodia; Thomas Lequertier, Head of Cell Therapy Manufacturing Unit of Celyad Oncology; and Ludek Sojka, Ph.D. Chief Technology Officer of SOTIO, who discussed how both autologous and allogeneic cell therapies alike are impacted by the high cost of manufacturing. Indeed, the high cost of producing new cell therapies, particularly gene-edited cell therapies such as CAR T-cell therapy, for example, are notoriously expensive. Advancements in manufacturing are driving costs down, but not at the required pace. The complex manufacturing process that these biological treatments require means that their price is currently at a premium. In this article, we will focus on ways to drive down the cost of manufacturing autologous cell therapies as explained in the Cell & Gene Live event.
The Why Behind Cell Therapy Manufacturing’s Hefty Price Tag
Most cell therapies today are produced one dose at a time, using the patient’s own cells as the starting material. This approach is very labor-intensive, failure prone, and extremely difficult to scale with manual methods. And so it goes with autologous cell therapy manufacturing, as it comprises many handling steps (e.g. density gradient cell processing, washing, and feeding) that require considerable labor-intensive interventions from skilled operators. Skilled labor tends to be the greatest cost followed by materials, which include solutions for processing and QC testing. “The main challenge that we face with autologous CAR T-cells is that they are single-lot products,” says Gilbert. “Therefore, every time we develop a product, we must perform all of the quality testing; we have to repeat multiple steps within manufacturing in order to produce that product. Plus, we incur the complexity of gene modification.” Gilbert notes the surprising aspect that has added or contributed greatly to the cost of manufacturing is the use of viral vectors. Additional expenses are incited, because regulatory authorities treat viral vectors not as a key raw material but rather as a drug substance.
The global viral vector manufacturing market accounted for $227.63 million in 2017 and is expected to reach $1013 million by 2026 growing at a CAGR of 18.0% during the forecast period. According to APNews, based on geography, North America holds the major market share during the forecast period owing to rise in research activities, many regenerative medicine companies, increase in the prevalence of target diseases and availability of funds.
A Shortage in Manufacturing Capacity
If North America holds the major market share, where does it stand on capacity? According to McKinsey & Company, a shortage of manufacturing capacity and talent is exacerbated by logistical issues. The industry faces a well-known viral-vector capacity constraint and a limited number of third-party suppliers, so manufacturers must either invest heavily to build in-house production or lock down contracts with viral-vector manufacturers. In addition, the lenti- or AAV-based approaches are often time-consuming and inefficient. And, the logistics for manufacturing and delivering cell and gene therapies are always hard. Especially with autologous cell therapies, supply chains require a high degree of logistical precision, which is harder in the absence of local manufacturing capacity. The process can be slow — often too slow for patients in the late stages of a disease. But further delays can be caused by any number of local issues when so many different personnel are involved at different sites, using different systems, and when several different couriers might be involved. The slightest disruption — a patient’s apheresis appointment delayed, for example — can disrupt the entire supply-chain flow.
McKinsey & Company further states that the sensitivity of supply chains has been highlighted during the COVID-19 crisis, when two-thirds of cell therapy companies surveyed reported supply-chain disruptions because of travel restrictions.
True Innovation for Autologous Manufacturing
For autologous cell therapies, the major pain points are patient-to-patient variability in the starting material, multiple manufacturing spaces to increase throughput, and variability in the overall yield of the final cell product. There are many closed system and automated technology solutions being developed that will provide incremental improvements to process robustness, reproducibility, and sterility assurance. These technologies may also reduce labor needs per batch helping to reduce costs.
“I do believe that innovation will come incrementally to autologous cells,” explains Gilbert. “But when you are talking about true innovation, think back to the first principles of cell source and look for pools of allogeneic cells as a source or a cell line. NK cell lines that are available offer that opportunity. The second piece is the complexity of genetic modification — if there is a way to avoid genetically modifying cells yet redirect them to the target for a reasonable period — that becomes a real innovative shift from a regulatory standpoint and will probably reduce costs significantly.”
The Importance of Partnership
The typical early-stage cell therapy company lacks the resources for implementing internal manufacturing capabilities. Instead, they outsource to fulfill their manufacturing demands, particularly during pre-clinical and early stages of clinical development. Different products have different needs, but Cell & Gene Live panelists strongly suggest that biotechs identify a reputable market partner that focuses on automation.
For autologous therapies, the patient stands at the beginning and end of the supply chain, and therefore, proximity of manufacturing to patients is key to reducing complexity. The partnership should be comprised of a fully integrated offering, including logistics, scheduling, distribution, chain of custody, chain of identity, etc. “Of course, before you identify a market partner, be sure to evaluate the products already on the market,” explains Gilbert. “There are different products that allow for very efficient culturing of cells. We evaluate those products, those devices, first. And then, we potentially work with the partner to focus on the automation aspect to develop something more specific for the products.”
The shifts in the industry toward improving manufacturing efficiencies will lead to a positive change in the cost structure of personalized medicine. Specifically, this will allow for more cost-effective manufacturing of autologous cells.
Planning Manufacturing Systems that Grow with Your Cell and Gene Therapies
By Marisa Reinoso, Sr. Product Marketing Manager, Cell Therapy, Invetech
Cell and gene therapies (CGT) have the potential to reduce total disease costs by 18-30%, amounting to an aggregate cost savings of more than $33B over 10 years. If the industry can reduce the costs of manufacturing, these savings would increase significantly.
CGT manufacturing requirements evolve from pre-clinical to clinical and commercial development, often significantly escalating costs at each step. There is universal agreement in the industry that closing, integrating, and automating manufacturing operations can drive significant cost reductions. Consequently, for most CGT manufacturers the question is not whether to close and automate, but rather when and how. What does an optimal manufacturing roadmap look like? How do you balance manufacturing flexibility with robustness and cost-effectiveness?
Planning for integration and automation in your manufacturing processes as therapeutic demand increases is a good way to manage the high costs of cell therapy manufacturing. This also helps to manage your changing needs for flexibility, scale, and robustness.
The industry is in urgent need of a range of stand-alone modules to automate the performance of unit operations reliably. These stand-alone unit modules also need to be interconnectable, so that CGT manufacturers can connect them as scale demands increase. By having stand-alone modules that can be integrated, cell therapy manufacturers can have both the flexibility to optimize unit processes, and the automation and robustness that is needed with larger scale production.
Currently, the industry does not have a broad menu of systems or modules capable of executing manufacturing operations that support integration. A practical approach is to use a combination of off-the-shelf manufacturing modules, configurable platforms, and a process-specific integration strategy to support progression from process development to GMP manufacturing and ultimately to commercial scale manufacturing. The key is to carefully evaluate and select-off-the shelf technology that can be incorporated into future robust, configurable systems when your demand increases.
This approach can minimize tech transfer costs, because by integrating modular units into a configurable system, the risk of additional qualification and validation studies is minimized as your process scales. By selecting off-the-shelf unit modules that can transition to integrated manufacturing systems, CGT manufacturers can set their manufacturing roadmap to incorporate a high level of flexibility while remaining cost-effective.
 Alliance for Regenerative Medicine. ARM Global Regenerative & Advanced Therapy Medicine Sector Report: H1 2020 – Innovation in the time of COVID-19. Washington, D.C. Accessed: Feb 5, 2021. https://alliancerm.org/sector-report/h1-2020-report-pdf
 Invetech. Navigating the Cost and Time of Cell Therapy Manufacturing Process Automation. Accessed: Feb 5, 2021. https://www.invetechgroup.com/insights/2019/10/cell-therapy-manufacturing-process-automation-cost-time/