Cell and gene therapy manufacturing challenges to persist in 2025

Dec. 23, 2024
As potentially curative therapies, CGTs offer hope to millions of patients but remain complex and difficult to manufacture at scale.

From a regulatory perspective, 2024 was a breakthrough year for cell and gene therapies (CGT), with the first FDA-approved engineered cell therapy for solid tumors and the first FDA approval for a gene therapy directly administered to the brain. 

Another positive trend was investment in the sector through the third quarter of 2024, which surpassed total investment in all of 2023, according to the Alliance for Regenerative Medicine (ARM). However, the bad news: investment was far below the pandemic peak and manufacturing remains a major challenge for the industry due to a lack of standardization and the fact that scale-up has often been an obstacle to regulatory approval and commercialization.

Brian Scanlan, operating partner-life science at private equity firm Edgewater Capital Partners, told Pharma Manufacturing that investors have cited manufacturing hurdles as among the reasons to be more cautious about the sector.

When it comes to CGT manufacturing capacity, Scanlan said that “on the cell and gene side, there’s been a fair amount of excess capacity.”

Mike Lehmicke, ARM’s senior vice president for science and industry affairs, agrees that overcapacity is a significant problem for the industry.

“If you look at CDMO capacity, this is true on the viral vector and the cell therapy side, there’s essentially overcapacity right now,” Lehmicke told Pharma Manufacturing. “There was a lot of building to meet real demand during the pandemic, when it was pretty easy to get money to buy real estate and build facilities.”

However, currently “a lot of CDMOs are [operating at] less than 50% of capacity because they’re primarily supplying things for clinical trials and it’s not a consistent demand curve,” according to Lehmicke. “There aren’t enough commercial products to sustain that level of capacity and also there’s a lot of new players.”   

In CPHI’s 2024 Annual Report, Scanlan authored an update on the CRO/CDMO sector, calling the situation a “mixed bag of demand” for companies targeting cell and gene therapies.

“Clinical phase demand for services in this area should continue to improve, however early phase CGT companies have been hit disproportionately hard in 2023 and continuing into 2024,” Scanlan wrote. “CRO/CDMO’s focused here should expect slow demand to continue well into 2025.”

A complex problem   

While these potentially curative therapies offer hope to millions of patients, they remain complex and difficult to manufacture at scale with manufacturing remaining the Achilles heel of the CGT sector.

A 2023 U.S. Government Accountability Office (GAO) report found that while regenerative medicine technologies — including cell and gene therapies and tissue-engineered products — are highly promising, they are being hamstrung by the lack of widely accepted standards and guidelines to govern their use, development, and manufacture.

The GAO pointed to three challenges holding back the widespread and efficient manufacture of these products: the lack of infrastructure, the difficulties in ensuring quality, as well as workforce shortages.

“The cell, tissue, and organ products being developed for regenerative medicine will require more complex manufacturing facilities than are currently used to produce small-molecule drugs,” the GAO said. The report also noted that “stakeholders often lack consensus on how to measure quality for regenerative medicine products” with “few standardized reference materials that can be used to evaluate a finished product.”

According to an ARM whitepaper published in October 2024, resolving CGT manufacturing challenges will require a “creative and consistent effort” from stakeholders across the board.

ARM’s Lehmicke told Pharma Manufacturing that while progress has been made in the CGT sector, some of the challenges currently are the same as they were five years ago.

“A lot of the technology hasn’t substantially changed over the past five years,” Lehmicke said. “There have been some companies that have successfully scaled to an extent on the viral vector side — like up to 2,000-liter bioreactors — companies like Forge Biologics and Pfizer and some others.”

When it comes to these capabilities, Lehmicke observed that “they’re not really for commercial products, so it’s kind of hard to know if we have enough CDMOs that are at that level to sustain a situation where we would have 20, 30, or 40 gene therapy products commercially approved.”

Lehmicke added that “there isn’t enough pull-through on the viral vector side to know if we’re actually at the capacity where we need to be in the U.S.”

At ARM’s annual Cell & Gene State of the Industry Briefing in January 2024, Peter Marks, director of the FDA’s Center for Biologics Evaluation and Research, said that gene therapies are currently at a “critical juncture” due to a combination of factors, including manufacturing challenges. Marks made the case that current manufacturing platforms limit gene therapy production.

“The problem is the setup cost for these small gene therapies is just way too high in proportion to the return on investment — so we have to figure out a way to get over that,” Marks said.

The need for automation

Some components of certain regenerative medicine products can be reliably manufactured, such as the “DNA and viral vectors used to alter a cell’s genome — a key part of gene and cell therapies — can be produced at large scales,” according to the GAO.

However, the GAO notes that “producing complete products, such as CAR T cell that may cure certain types of cancer, currently requires technicians to perform many steps manually” and that “regenerative medicine technologies and therapies will require increased levels of automation if they are to be widely accessible and affordable.”

Lehmicke points out that cell therapy manufacturing for CAR T cells and other cell therapies use viral vectors and still involve mostly manual processes, though there have been some “pretty interesting” developments in terms of automated manufacturing and analytics — which are starting to be adopted in the industry.

Cell therapies are experiencing “unprecedented” growth, according to Betty Woo, vice president of cell, gene and advanced therapies at Thermo Fisher Scientific, who told Pharma Manufacturing that automation can reduce the cost and time of manufacturing, as well as eliminate “the potential errors associated with open processes with human intervention.”

Automation and closed processes are designed to address “those errors and inconsistencies brought about through manual and open steps in the manufacturing process,” Woo said, noting that manual processes are labor-intensive requiring a costly skilled workforce.

“We need to make sure through all of this that the biology is maintained,” which Woo said is achieved by monitoring via analytical processes and constant process controls. At the same time, she contends that companies that are implementing automation “are attacking the parts of the workflow that are the most painful” for them currently — not by adopting an end-to-end approach, but on a piecemeal or modular basis.  

In the CAR T field, Woo points to advances over the past couple of years, particularly when it comes to speeding up the processes involved.

“Traditional CAR T manufacturing took three weeks or more and we have definitely — over the last few years — seen a lot more focus on accelerated processes and process intensification, so that now you even hear about manufacturing processes that are occurring in a matter of days and with higher potencies,” Woo said.

Investing in CGT manufacturing

In addition to CDMOs, Big Pharma is looking to expand their presence in the CGT sector and “whether they’ve publicly disclosed it or not, they’ve made investments in this space,” according to Lehmicke, who argues that larger, well-resourced companies are positioned to commercialize cell and gene therapies.

Companies including Astellas, BMS, Eli Lilly, J&J, Kite Pharma, Novo Nordisk, and Pfizer are members of ARM, the Washington, D.C.-based trade group that represents the CGT industry.

Manufacturing is “a big challenge for Kite who has treated like 25,000 CAR T patients and BMS just announced 10,000 [patients],” Lehmicke said. Still, he contends that “the large manufacturers like Kite and BMS actually don’t view manufacturing capacity and efficiency to be their biggest problem today — they’ve internalized a lot of their manufacturing which is still highly manual, but they’ve gotten very good at it.”

In the short term, these types of companies “don’t have a great incentive to adopt the risk and the cost of automating — although, I’m sure they’re thinking about it,” Lehmicke concluded. Manual processes are “where we’re going to be for awhile.”     

About the Author

Greg Slabodkin | Editor in Chief

As Editor in Chief, Greg oversees all aspects of planning, managing and producing the content for Pharma Manufacturing’s print magazines, website, digital products, and in-person events, as well as the daily operations of its editorial team.

For more than 20 years, Greg has covered the healthcare, life sciences, and medical device industries for several trade publications. He is the recipient of a Post-Newsweek Business Information Editorial Excellence Award for his news reporting and a Gold Award for Best Case Study from the American Society of Healthcare Publication Editors. In addition, Greg is a Healthcare Fellow from the Society for Advancing Business Editing and Writing.

When not covering the pharma manufacturing industry, he is an avid Buffalo Bills football fan, likes to kayak and plays guitar.