Cultivating an ecosystem that optimizes manufacturing: an interview with Dalip Sethi
In this interview, Dalip Sethi discusses how automation and AI are shaping cell and gene therapy, their potential role in establishing industry standards and the influence needed to drive the industry forward.
Dalip Sethi, Commercial Lead for the Cell and Gene Therapy Portfolio at Terumo in North America (NJ, USA), holds a doctorate and has completed his post-doctoral studies from Thomas Jefferson University of Medicine (PA, USA), where his studies focused on receptor-targeted gene delivery agents. He has been in the cell and gene therapy industry since 2010, working on various technologies, including methods for the manufacturing of modified T-cells and gene delivery agents.
In his career, Dalip has worked in various business, research and development (R&D), and clinical roles. At Terumo, he has led the R&D teams. The team has published various articles including CD3+ T-cells and CD34+ hematopoietic stem cell expansion protocols using the Quantum System, a hollow fiber-based perfusion technology that mimics the body’s environment for optimal cell growth. Dalip now leads the Commercial team and co-chairs the Process Automation, Analytics and Development Committee for the International Society for Cell and Gene Therapy. The committee is focused on process analytical technologies and exploring the role of AI and machine learning in the cell and gene therapy industry. He also serves as a board member on the Colorado BioScience Association (CO, USA).
Can you tell us a little bit about Terumo’s collaborations and partnerships in the cell and gene therapy space?
Cell and gene therapy is an exciting and complex field. Since no single company or stakeholder can succeed alone, we have formed various collaborations and partnerships. Some recent examples include a partnership with CiRA (Kyoto, Japan), where we’re working on an automated, scalable process for producing high-quality iPSCs using our Quantum Flex Cell Expansion System. This is an exciting collaboration because CiRA is a leader in the iPSC space, and Terumo provides automated technologies.
In addition, we recently announced a collaboration with FUJIFILM Irvine Scientific (CA, USA) to create ready-to-use protocols for T-cell expansion. FUJIFILM provides Good Manufacturing Practice (GMP)-grade media, while Terumo offers automated technology, making it easier for customers to manufacture T cells in a GMP-compliant manner.
We also have a collaboration with Nova Biomedical (MA, USA), where we are integrating the Quantum Flex with their technology to enable automated sampling methods. This is important because automated sampling allows for more frequent measurements, which helps us better understand the cell culture conditions and optimize processes.
What are the key hurdles in making CAR-T therapies more widely accessible for patients with limited treatment options?
CAR-T therapies are complex, living drugs that require complex manufacturing processes and coordination among multidisciplinary teams. However, these types of teams aren’t available at every hospital or community center, so this limits access to a select group of hospitals.
Another challenge is the cost of manufacturing. CAR-T therapies range from US$375,000 to US$545,000, putting a significant burden on both payers and patients, particularly in terms of co-pays and out-of-pocket costs, primarily due to the expensive manufacturing process.
These hurdles are always a topic of discussion in this field and the stakeholders are looking at ways to reduce the costs and expand the accessibility of CAR-T therapies. One of the ideas is to bring these therapies closer to the patient into an outpatient setting, which could potentially increase accessibility. Another idea is to reduce the cost of manufacturing by implementing automated technologies. Automated technologies, like the Quantum Flex, allow for more consistent production in a functionally closed, automated system, reducing the need for highly skilled labor. Additionally, implementing automation in the fill-and-finish process, which is typically manual, can further reduce costs and improve efficiency and process control. The automation of labor-intensive steps is crucial for making CAR-T therapies more scalable, with the potential to enable increased accessibility.
How do you approach the affordability and accessibility of CAR-T therapy in the market?
We aim to provide automated solutions and technologies, along with process analytical technologies, to help reduce manufacturing costs and minimize variability.
When we think about patients, there’s biological variability and this can lead to variable cellular starting material for autologous manufacturing. Automated systems allow manufacturer’s to control process variables to better accommodate the variable cellular material and potentially manufacture the required cell product. It is also critical that data is available to the manufacturing professionals to make these decisions. That’s why I’m passionate about process analytical technologies, which help guide decisions such as adjusting the cell culture perfusion rate to allow optimal culture conditions for a particular cell type. Providing those analytical technologies along with manufacturing technologies enables manufacturers to work towards increasing their production capability and scalability.
We also consider the technology transfer element on the manufacturing side. Many companies rely on Contract Manufacturing Organizations and efficient technology transfer is vital to improving accessibility. Technologies that allow for easy process transfer between different facilities make scaling out easier. For example, with Quantum Flex, the cell processing application protocol can be written on a computer, published to a device and the user can run it from the place of their choice. This software system allows for process reporting and monitoring without the need to go into the GMP room. This is an important aspect about scaling out these therapies and increasing the accessibility through the manufacturers.
How is technology helping to optimize CAR-T therapy development, from manufacturing to patient selection?
Beyond the manufacturing technologies we’ve discussed, we play a big role in the cell collection space. The Spectra Optia platform is the most widely used cell collection system in North America, with over 94% of the market share. Cellular starting material is the critical component for the manufacture of gene-modified cell therapies. When we discuss cell collection, a lot of variables go into making sure the manufacturer has the right number of target cells collected. Our deep understanding of the system allows us to support physicians, nurses and manufacturers by providing insights on cell collection methods and how to optimize them.
On the manufacturing side, there’s always a debate about whether to use an all-in-one system or modular unit operations. I believe modular operations are the future because they offer scalability, which is essential as these therapies are introduced earlier in treatment and the population of addressable patients grows exponentially. To provide cell therapies at that scale, the providers should be able to do multiple processes at a time. If one uses a machine that’s dedicated to a single patient for 15 to 20 days, it’s not efficient. Unit operations allow multiple cellular materials to be processed at once, so scaling out becomes much easier.
Another exciting development is the effort to reduce the manufacturing timeline. Manufacturers are aiming to shorten the process from 20 days to as little as 3–4 days, which would make a huge difference. It would reduce the need for bridging therapies and minimize patient wait times.
Lastly, the industry is looking at how to reduce the number of cells needed. Some patients, particularly the pediatric population in certain conditions, may not have enough good-quality cells to start with. In these situations, automated technologies may provide a path to manufacture the required cell dose. We recently collaborated with Biocentriq (now Made Scientific; NJ, USA) to demonstrate how we can start with low-density CAR-T cells in a hollow-fiber bioreactor and reach clinically relevant doses with excellent viability and memory phenotype.
How do you see CAR-T therapy evolving to better align with each patient’s treatment journey and timing?
CAR-T technology is evolving to offer flexibility in scaling the process based on a patient’s needs. Starting materials can have a variable number of target cells. Automated technologies can allow for better selection, modification and culture at different seeding densities. This may allow the manufacturers to reach the target cell dose with varying number of cells from the starting material.
CAR-T therapy is also becoming more outpatient- or community-based. Standardization and optimization of cell collection, processing and labeling are making it easier for outpatient settings to adopt these therapies. The infusion process is improving, with some patients already receiving infusions in outpatient settings, though they must stay within a defined radius of the clinic for the first few weeks. As more data is gathered, algorithms should help physicians decide whether outpatient or inpatient settings are best for each patient.
Manufacturing closer to the patient presents challenges due to the complexity and need for skilled personnel. However, automated systems are enabling these processes to move to outpatient or regional settings. Full outpatient manufacturing may take time, but as technologies become easier to use and standardize, this shift will become more feasible.
While current CAR-T therapies are approved for blood cancers, the next frontier is solid tumors. There is also optimism about progress in CAR-T therapies for autoimmune diseases. This marks an exciting evolution in the field.
As we think about the future, we’re constantly looking for ways to improve processes and introduce innovations to make sure we’re providing the best tools for healthcare professionals. It is our mission to serve society through healthcare.
Ultimately, we want to support the amazing physicians, developers and nurses who rely on these technologies to serve more patients. When it comes to accessibility and serving more people, we’re a key player in collaboration with external stakeholders, as well as our own internal teams — scientific, engineering and operations. Together, we’re driving the ecosystem forward. I’m thrilled to be part of this journey and excited to see how these technologies will transform the cell and gene therapy field.
Disclaimer
The opinions expressed in this interview are those of the interviewee and do not necessarily reflect the views of RegMedNet or Taylor & Francis Group.