The State of Cell Therapy Manufacturing with the Rise of Approved Products
The approval of three cell therapy products in 2024 underscores the importance of manufacturing at scale. Dr Arvind Natarajan, SVP, Process and Analytical Development at Iovance Biotherapeutics Inc, sheds light on the current manufacturing landscape and the elements that change as a company moves from clinical to commercial stage manufacturing.
What is the current status of cell therapies today?
It's an exciting time to be in cell therapy manufacturing and commercialization, particularly in the oncology space. This year alone, we've seen the US approval of three cell therapy products: Iovance’s Amtagvi® (lifileucel), Adaptimmune’s afami-cel and Autolus Therapeutics’ obe-cel. Altogether, nine cell therapy products have been approved for oncology indications since 2017.
All approved cell therapy products represent a blockbuster market, with cumulative sales of $1.25 billion in the third quarter of 2024. The market will continue to grow in the next few years, particularly with the new products and expanded indications for legacy CAR T therapy products that have been approved this year.
Is the industry ready to meet that rise in demand?
As cell therapy products get initial approvals and expand into new indications, the industry is going to continue to increase capacity to meet the demand growth.
For example, at Iovance, we're continuing to grow staffed capacity very rapidly each month to meet the rising demand. Our in-house manufacturing facility in Philadelphia is built to serve thousands of patients annually, with expansion underway to accommodate long-term growth.
Fortunately, the core manufacturing technologies for the approved products have been around for a while and we can leverage prior experience. Newer technologies are being explored in the clinical setting for future adoption. Prodigy, for example, is widely used in both clinical and commercial manufacturing today but was the “new kid in town” while I was working on one of the first approved CAR-T products at Novartis several years ago.
"There is a fundamental limitation on speeding up manufacturing turnaround times. Instead, we work within these parameters to optimize our manufacturing process."
Would any of the newer technologies represent a significant paradigm shift in production?
The process for producing autologous cell therapies is tied to the fundamentals of biology so newer technologies are unlikely to make a huge impact. When starting material comes from the patient, you have a fixed number of cells as the input. The input is variable and unique to each patient, however, each lot we manufacture for output must meet a certain dose count. In addition, cells can only grow at a certain rate, so there is a fundamental limitation on speeding up manufacturing turnaround times. Instead, we work within these parameters to optimize our manufacturing process as well as our quality and release testing and overall logistics.
I am excited about the future potential for next generation approaches, such as engineered or genetically modified cell therapy products, to potentially expedite, streamline and optimize our processes. Do we need to do all of the cell expansion ex vivo? Clinical trials are exploring an output of smaller doses that allow those cells to engraft and grow within the cell, and the patient essentially becomes the bioreactor.
Where could you see advances in technology impacting the process?
In addition to exploring cell expansion in vivo, as I mentioned, a lot of development efforts are focused on completing the end-to-end process without significant intervention. The active ingredient is live cells that cannot be terminally sterilized. Instead, our process builds in sterility assurance from the start, including closed methods of moving fluids from one container to another.
We must provide the right nutrients, maintain appropriate levels of byproducts and ensure cell-to-cell interaction while maintaining a closed system and sterility assurance throughout each step. Some of our technologies have bioreactors attached to the system, others have a robotic arm from the incubator to points of interest.
What is the process to go from clinical-stage to commercial-stage manufacturing?
All autologous cell therapies follow a scale-out model. The problem statement is, “How do you reproduce the same thing consistently and reliably?”
Process validation and demonstrating clinical efficacy from the proposed launch process are critical for transitioning to commercial manufacturing. The scale out should be built into the base planning process. For example, Iovance made a strategic decision fairly early to invest in our own manufacturing facility and to launch with both our own facility and a CDMO for capacity flexibility to meet demand from our commercial launch as well as our ongoing clinical trials.
What are the bottlenecks or constraints to be aware of?
Manufacturers need an end-to-end perspective. In addition to having control with our own facilities, we must secure critical inputs and scale the entire ecosystem to meet demand.
We strategically manage our entire supply chain, including redundancies, to reliably source elements required for manufacturing such as proprietary reagents, formulations, specific media, sterile consumables and cold-chain supply chain to interface between the treatment sites and manufacturing centers.
Plan for success from the very beginning as you go into clinical development, because early decisions have a downstream impact. Think big, in terms of being able to support the expected demand for both near and longer terms.
"Process validation and demonstrating clinical efficacy from the proposed launch process are critical for transitioning to commercial manufacturing."
What is an example of thinking proactively for commercial-stage manufacturing?
Bioreactors in cell therapy manufacturing are more-or-less fixed by a certain point, because you only need a certain amount of cells to provide to the patient. By contrast, conventional biologics scale up from 500 to 2000 liter bioreactors.
We scale out by individual lots. For example, once we demonstrate the ability to manufacture one lot per day, we think about the future capacity to scale to five lots a day, and the plan to demonstrate we can scale from one point to another. Again, this is an end-to-end plan and not just the manufacturing process. The FDA is interested in maintenance of product quality as you scale out.
What is your advice on sourcing?
Diversity in the supply chain is necessary for risk mitigation, particularly for single-source materials or consumables. New vendors or changes in vendor locations create some level of change control to demonstrate that you’re still getting material that behaves the same within the process.
A risk assessment determines the technical and regulatory packages that help support that change. The risk is correspondingly higher and requires a much more rigorous evaluation of analytical comparability for media or consumables as they get closer to the drug product.
In a post-approval environment, for example, the FDA wants to ensure changes are not adversely impacting the product’s safety or quality. The most rigorous requirement to demonstrate no impact, clinical comparability, is time-consuming and expensive.
What is changing in the broader environment?
As the industry matures, the general assessment, even from a regulatory standpoint, will evolve and change.
Cell therapies are becoming a mainstay treatment in oncology, and we have evolved from CAR-T to include new classes of approved cell therapies. It is encouraging that academia, industry and regulators are working together to figure out how we can ensure we provide high-quality products to patients in a way that facilitates available capacity to meet the demand.
