CMC for cell and gene therapies remains a ‘learning curve’ for Big Pharma

Large pharmaceutical companies are leveraging cell and gene therapy (CGT) technologies to enhance their therapeutic offerings and target a range of diseases. However, for Big Pharma to increase the commercial and economic viability of CGTs, the industry needs manufacturing approaches capable of producing affordable at-scale therapies.

A key constraint in the CGT sector is the chemistry, manufacturing, and control (CMC) process, which is more complex compared to conventional therapies. CMC “has been a big learning curve” for large pharma companies because it is a “fairly new” undertaking for the industry, contends Matthew Hewitt, vice president and chief technical officer of the manufacturing business division at Charles River Laboratories.

“The evolution of the tech in this space is moving at breakneck speed” and CMC remains critical, said Hewitt, who moderated a panel on Tuesday at the Cell & Gene Meeting on the Mediterranean in Rome, Italy, held by the Alliance for Regenerative Medicine (ARM).

Hewitt made the case that CMC has two fundamental components: process development and analytical control. Compared to conventional therapy, he noted that CMC is more complex for cell therapies which involve working with living cells and modified viruses or non-viral vectors for gene therapies designed for gene replacement or editing.

Manufacturing an adeno-associated virus (AAV)-based gene therapy product — for example — requires a multi-step production process that can take a few weeks to complete, depending on the scale of the product and regulatory requirements.

Big Pharma still catching up    

Scientific advances have the potential to become commercial opportunities — a value proposition attracting interest from Big Pharma. According to ARM, 20 of the 30 largest biopharma companies by market capitalization are investing in the development and/or commercialization of CGTs. Yet, despite innovation in the CGT space, companies have struggled to combine scientific progress with scalable, efficient manufacturing.

While CGT advancements continue to drive innovation with significant potential for breakthroughs and market expansion, Big Pharma is still catching up when it comes to developing and manufacturing these complex therapies, according to Ralf Altenburger, senior vice president of cell and gene therapy at F. Hoffmann-La Roche.

“Big companies that have long-standing experience in established modalities are simply not used to programs breaking because of CMC,” said Altenburger. “In cell and gene therapies, that’s completely different. We’ve actually seen a number of programs that broke because they couldn’t make the manufacturing part work and get it under control.”

Altenburger described CMC as a “steep learning curve” for larger pharma companies who have had to get used to the process, which he commented “has a different importance in cell and gene therapies compared to some of the more established ones.”   

Hewitt argued that CGTs have different manufacturing paradigms compared to conventional therapy programs and have different drug review processes. He noted that “in traditional programs, we’re used to 80% non-CMC and 20% CMC” and in the CGT field that mix in importance is flipped to “80% CMC and 20% non-CMC.”

Characterization of CGT processes, products

When it comes to process development versus analytical control, Altenburger said one is not more important than the other in CMC. The two components “absolutely belong together and have to be integrated because you won’t get your process development in shape if you don’t have the appropriate characterization,” he added.

The control strategy for characterization, stability, and batch release is established throughout the manufacturing process using critical process parameters (CPPs), critical quality attributes (CQAs), and in-process controls (IPCs).

At the same time, Altenburger said the industry still has a lot to learn about the characterization of CGT processes and products, an area which requires “overproportionate” investment in his estimation going forward.

“We’re dealing with very complex biological processes — take cell therapies, which are quite frankly not 100% understood,” he concluded. “The more we are in a position to better characterize the process and the product, the more we will understand what ultimately happens and get control over the process.”

Johanna Rossell, senior vice president and general manager for rare disease at Sumitomo Pharma America, told the panel that “Big Pharma is not used to having [CMC] so early in the process,” adding that “the process is the product.”

Ultimately, regulatory authorities like the U.S. Food and Drug Administration (FDA) “want to know that that process is very well controlled” to ensure quality and efficacy, she said.

CMC regulatory relief from FDA

To help both large and small companies, the FDA in January 2026 announced a flexible approach to CMC requirements for CGTs aimed at expediting product development and guiding Biologics License Application (BLA) submissions.

The FDA said more flexible post-approval manufacturing controls will be considered for BLAs and quality specifications may be revised after approval. The agency dropped the requirement for three rounds of Process Performance Qualification (PPQ) before commercial production in certain cases, while allowing the PPQ details to be designed batch-by-batch.

Under the FDA’s new approach to CMC requirements for CGTs, manufacturers may also enjoy more flexible quality controls during later efficacy-focused clinical trials and may implement minor changes to production between Phase I and Phase II trials — if supported by sufficient data.

“The FDA’s approach is based on the need to ensure product quality and compliance while also recognizing that the small patient populations targeted by CGT therapies do not necessarily allow for a large number of manufacturing lots to support the product release specifications,” the agency said in its CMC announcement on CGTs, while encouraging sponsors to “consult” with the FDA throughout the product development process.

Anne-Virginie Eggimann, vice president and chief development officer for Lilly Regenerative Medicine, told Tuesday’s panel that ideally rare gene therapy products would start manufacturing at a single site and register with the same location.

“For larger indications, typically there’s early manufacturing and then you transfer to late-stage commercial manufacturing,” Eggimann said. “We’re having discussions about that — can we just stay in one place.”