Frontrunners in Automated Cell and Gene Therapy Manufacturing

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Over the past two decades, 32 cell and gene therapies (CGTs) have been approved by the regulatory authorities worldwide, and more than 2000 novel products are under clinical investigation (1). However, many patients do not have access to these life-saving therapies, partly due to the complexity and high cost of manufacture (2). But how can CGTs be made more cost-efficient given the high labour and facility costs?

According to Miguel Forte, CEO, of Kiji Therapeutics, France, and president of the International Society for Cell & Gene Therapy, “It is clear that CGTs have the opportunity to deliver enormous value to patients; nonetheless, manufacturing is complex, and it has been challenging to deliver the product. Innovative technologies and services have enabled the industry to move towards an automated, closed-system approach that is easier and safer to operate and is less costly and closer to the patient.”

Technological advances in manufacturing

Cell therapies can be derived ex vivo from autologous cell therapies (patient to patient), allogenic cell therapies (donor to patient), or in vivo cell therapies (cell line to patient). Each approach requires manufacturers to tailor the biomanufacturing process to generate specific cell types (and/or vectors), safely, efficiently, and cost-effectively. Manufacturing tools have tended to lag behind scientific advances in CGTs leading to bottlenecks in cell production. Currently, most CGT manufacturers use disconnected single-step/modular or semi-automated solutions; however, the industry is migrating towards fully automated cell therapy manufacturing processes (3). And this approach could significantly reduce manual intervention, risk of contamination, and human error; improve product quality and speed of delivery; and reduce production costs (4).

According to David Smith, vice president of Development, BioCentriq, “Labour costs, and facility costs are sky high, which have led to high price points, particularly in autologous cell therapies where production is 1:1. Automation is a key part of improving costs, reducing labour both in and outside the clean room, and implementing release by exception can help to reduce bottlenecks. Companies are trying to integrate unit operations whether it’s an ‘all-in-one-box’ approach or a ‘unit-operator’ approach where units can be plugged in or out and are integrated within robotic systems to offer greater flexibility.”

For instance, Lonza’s Cocoon Platform and Miltenyi Biotec CliniMACS Prodigy offer an ‘all-in-one-box’ approach providing a closed, automated system for patient-scale cell therapy manufacturing from cell isolation, activation, transduction/transfection, expansion, and harvest within a validated cell manufacturing system (5,6). CliniMACS Prodigy modular Instruments can also be run in parallel to provide large-scale batch production.

UK-based Ori Biotech launched its IRO platform developed in 2024 in collaboration with CTMC (a joint venture between Resilience and MD Anderson Cancer Center). This platform automates the activation, transduction, expansion, and harvest of a wide range of cell types to rapidly scale up manufacturing from the clinic to the commercial setting (7).

Paris-based Astraveus SAS has developed the Lakhesys Benchtop Cell Factory, an end-to-end solution for the manufacture of adherent, non-adherent, and inducible pluripotent stem cells (iPSCs) (8). The company has raised €16.5 million in seed financing and received a €10.4 million grant from the French government as part of its “Innovation in Biotherapies and Bioproduction” initiative, to advance the development of its technology (9).

Several companies are developing integrated bioreactors, robotic systems, and smart monitoring technologies that can support a ‘unit operator’ approach.

UK-based Cellular Origins, launched Constellation, a closed fully automated, and configurable robotic platform for CGT manufacture in 2023 (10). In May 2023, it forged a partnership with ScaleReddy (a joint venture between Bio-Techne, Fresenius Kabi, and Wilson Wolf) to automate its CGT manufacturing workflow using Cellular Origin’s robotic system (11). According to Jason Jones, Global Business Development lead, Cellular Origins, “Our company integrates existing, proven technologies with mobile robotics to provide fully automated factories that can be scaled up to manufacturers’ requirements, minimize risks, and are GMP [good manufacturing compliance] compliant. We can achieve a 30-fold increase in space efficiency and manufacture and a 16-fold labour reduction, equating to a 51% reduction in cost-of-goods and enabling manufacture 24/7, 365 days a year.”

Swiss-based Limula has taken a different approach and developed a modular solution that combines a bioreactor and centrifuge into one device for on-demand and at-scale manufacturing of cell therapies (12). In May 2024, the company raised CHF 6.2 million (US$6.8 million, €6.24 million) in seed funding to develop its automated CGT manufacturing platform, the funding round was over-subscribed highlighting the interest that venture capitalists have in this field (13).

UK-based MicrofluidX has developed a space-saving stackable multi-bioreactor instrument—the Cyto Engine Stack. Each bioreactor can be controlled and monitored independently, to allow cell therapy manufacturers to expand their manufacturing capacity without increasing the facility footprint. The first Cyto Engine product is scheduled for launch in early 2025 (14).

Other companies have focused on leveraging digital tools and advanced analytics to streamline the manufacturing process. For instance, UK-based Autolomous has launched AutoloMATE Launchpad, a cloud-based CGT platform that allows for the scalability and adaptability of different CGT modalities (15). According to Alexander Seyf, the CEO of Autolomous, “Addressing manufacturing challenges effectively demands a shift towards more integrated and automated systems. By leveraging digital tools and advanced analytics, we can enhance process control, increase reproducibility, and reduce labour-intensive procedures which, in turn, decrease costs significantly. Moreover, digitization can streamline data flow across the manufacturing process, ensuring that critical information is accessible and actionable. This integration leads to improved decision-making, faster turnaround times, and ultimately, more standardized production of therapies.”

In 2024, US-based Cellares, became the first Integrated Development and Manufacturing Organization (IDMO) to offer a high-throughput fully, automated smart manufacturing platform Cell Shuttle. In April 2024, the company signed a US$380 million (€349 million) supply agreement for the manufacture of chimeric antigen receptor-T cell therapies with Bristol-Myers Squibb, and it announced a similar agreement with Kite in June (16,17).

The future of CGTs

Over the next decade, the demand for CGTs is expected to grow as they move further up the treatment cascade and target more common diseases. It will be essential for companies to address the challenges associated with scaling up the manufacturing process to provide high-quality, consistent autologous and allogenic cell products while adhering to stringent regulatory standards. Fully automated space-saving modular technologies will allow manufacturers to steadily scale up capacity and adapt to demands (18).

Smith notes, “CDMOs [contract development and manufacturing organizations] are looking at the trajectory of pipeline products and questioning where and when they need to invest in new facilities and technologies. Manufacturing is one of the biggest areas of risk in CGT developments, but if we can de-risk the process by deploying robust engineered manufacturing processes and automation, we can reduce the cost of autologous cell manufacture and increase the speed and flexibility to meet individual needs. On the allogenic side, the processes tend to be on a larger scale, and the drug product cost is shared amongst many patients. Although automation can assist in cost reduction, the burden is less steep than for autologous, that said, many of the same automation tools can be used across processes, and the industry is looking to standardize manufacturing.”

In the longer term, the industry could move towards a more decentralized manufacturing model that utilizes automated point-of-care technologies to enable on-sitepreparation of CGTs in or near hospitals, helping to bring therapies closer to the patient.

“The current acute unmet need is on scaling centralized systems, but we’ve had some interesting conversations around decentralization negating operator variability/increasing process comparability and digitalization of information of the product and opening up facilities at the national, regional, and near-hospital levels depending on the therapy and medical need,” observes Jones.

References

1. Citeline, Gene, Cell, and RNA Therapy Landscape Report. Q1 2024 Quarterly Data Report. 11 Apr 2024.
2. Harrison, P.T., Friedmann, T. Correction: Cost of Gene Therapy. Gene Therapy, 2024, 31, 195-196.
3. Batty, R. Closed, Automated Cell Therapy Manufacturing–Is Your Facility Ready? TechTalk, NNE.com. 8 May 2022.
4. Harris, R. Cell Therapy Manufacturing Shifts to Automatic. Genetic Engineering & Biotechnology News. 4 Oct 2021.
5. Lonza. The Cocoon® Cell Therapy Manufacturing Platform. Lonza.com (accessed July 2024).
6. Miltenyi Biotec. CliniMACS Prodigy Instrument. miltenyibiotec.com (accessed July 2024).
7. Ori Biotech. Ori Biotech Unveils IRO Platform at Annual International Society for Cell & Gene Therapy Conference. News Release. 29 May 2024.
8. Astraveus. Lakhesys™ Benchtop Cell Factory - Astraveus - Enable a Healthier Tomorrow. astraveus.com (accessed July 2024).
9. PRNewswire. Astraveus Raises €16.5 Million Series Seed Round to Advance the Development of its Automated, Microfluidic Cell and Gene Therapy Manufacturing Platform. News Release. 27 Jun 2023.
10. Cellular Origins. Cellular Origins Launches Constellation™, Its Configurable Robotic Platform to Enable Scalable Manufacture of Advanced Therapies. News Release. 31 May 2023.
11. Cellular Origins. Cellular Origins Partners with ScaleReady to Simplify, Standardize, and Automate Cell Therapy Manufacturing. News Release. 11 May 2023.
12. Limula. The Future of Cell and Gene Therapy is Automated. News Release. (accessed 10 July 2024).
13. Limula. Limula Raises CHF 6.2 Million in an Oversubscribed Seed Round to Develop an Automated Cell and Gene Therapy Manufacturing Platform. News Release. 21 May 2024.
14. Microfluid. MicrofluidX Secures Innovate UK Award to Advance High Throughput. News Release. 19 Dec. 2023.
15. Autolomous. Autolomous Releases the CGT industry’s First Free eBR Builder, autoloMATE Launchpad, to Empower Digital Planning. News Release. 29 May 2024.
16. Cellares. Bristol Myers Squibb, and Cellares Announce a $380M Worldwide Capacity Reservation and Supply Agreement for the Manufacture of CAR T Cell Therapies to Bring the Promise of Cell Therapy to More Patients, Faster. Press Release 22 Apr. 2024
17. Cellares. Cellares Announces Agreement with Kite to Evaluate Its Cell Shuttle Automated Manufacturing Platform. Press Release. 27 June 2024.
18. Spivey, C. Small Footprint Automated Closed Production Platforms for CAR-T and Other Advanced Therapies. Pharm. Technol., 2023, 47 (4) 28-30.

About the author

Cheryl Barton, PhD, is director of PharmaVision, info@pharmavision.co.uk.

Article details

Pharmaceutical Technology Europe
Vol. 36, No. 7
July/August 2024
Pages: 14–16

Citation

When referring to this article, please cite it as Barton, C. Frontrunners in Automated Cell and Gene Therapy Manufacturing. Pharmaceutical Technology Europe, 2024, 36 (7), 14–16.