FDA Delays Cell and Gene Therapy Approvals Following CMC Issues

A surge in US Food and Drug Administration (FDA) rejections and delays has highlighted chemical, manufacturing and controls (CMC) as a major barrier to approval in cell and gene therapy development.

Last month, both Ultragenyx and Capricor received FDA Complete Response Letters (CRLs) citing CMC concerns. This followed the publication of over 200 CRLs by the FDA, with analysis revealing that 74% of CRLs issued between 2020 and 2024 were in response to quality and manufacturing deficiencies.

The FDA declined to approve Ultragenyx’s gene therapy for Sanflilippo syndrome type A, requesting additional information and improvements regarding manufacturing-related issues and observations from manufacturing facility inspections. Capricor announced that its cell therapy candidate for Duchenne muscular dystrophy-associated cardiomyopathy had also been rejected based on a need for additional clinical data and outstanding items in the CMC section of the application.

These cases highlight just how often manufacturing issues stall the regulatory progress of advanced therapies, regardless of a therapy’s scientific promise.

The source of cell and gene therapy manufacturing challenges

Cell and gene therapies often utilize accelerated clinical pathways to expedite approval. The FDA’s Accelerated Approval Program enables drugs for serious and life-threatening illnesses that address an unmet medical need to be approved based on a surrogate endpoint or an intermediate clinical endpoint with a reasonable probability of predicting clinical benefit. “This can be a double-edged sword, as the compressed timeline puts CMC at great risk,” Dr. Clare Blue, senior CMC translation consultant for cell and gene therapy at eXmoor Pharma, told Technology Networks.

In addition to reduced timelines for development, the diversity of cell and gene therapies places a greater emphasis on early-stage development decisions. Early decisions, such as where to source cells and the choice of vector, can have far-reaching consequences that shape not just the product’s performance, but also its manufacturability and scalability.

“Due to the nature of these therapies, the manufacturing process, starting materials and quality attributes may be unique to each individual product, scale-up can be challenging, few CDMOs (Contract Development and Manufacturing Organizations) have proven capability in late-stage/commercial manufacturing requirements and there are limited validated platform processes available,” explained Blue. “Validating a process from scratch is costly for developers, so the strategy may be to submit a less robust Module 3 BLA/MAA (Biologics License Application/Market Authorization Application) package with the intention to address any gaps as post-marketing commitments. All these factors impact the ability to deliver the comprehensive CMC requirements for a robust filing submission in the timeline available to developers.”

When discussing cell therapies, Dr. Bo Wiinberg, chief business development officer at the Novo Nordisk Foundation Cellerator, highlighted the importance of making the right choices early in the process development. “It’s important from the beginning of your development process to consider the result, for example, is the process scalable? Is the technology used in development transferable to manufacture? If you get these initial steps wrong, changing things further along the process is almost prohibitively expensive,” he said.

The decision to prioritize early clinical milestones is often used to approach small molecule development, where you can tweak the process based on learnings from Phase 1 trials. This approach has made its way into the advanced therapy space, where cost constraints and investor focus on clinical outcomes mean manufacturing maturity is often deprioritized.

As regulatory expectations around manufacturing evolve, “it is vital that developers implement a robust CMC strategy early in development with the late phase and commercial requirements in mind,” stated Blue. “Selection of a manufacturing partner and utilization of CMC experts with proven capability in later-stage manufacturing and process validation is important to help define an early CMC strategy that is sufficiently robust to support the product through all stages of development.”

“Where possible, use prior experience, expertise and the information available through the available FDA CRLs to adopt a risk-based approach, and engage with regulators throughout product development to seek endorsement on the CMC approach. Work with investors to align on the criticality of a robust CMC strategy,” advised Blue.

Adapting to ever-changing CMC requirements

The regulatory requirements for advanced therapy manufacturing are rising, but the future for developers isn’t all bleak. The standardization of processes and advances in manufacturing and digital platforms are helping developers navigate the changing CMC regulatory landscape.

Looking ahead, Blue believes that the “establishment of platform processes (where applicable), utilisation of AI, automation and PAT (Process Analytical Technology)” will be key to preventing issues when seeking FDA approval of CMC processes. These advances have the potential to help developers “better understand both product and process and reduce variation to make manufacturing and process validation more robust,” Blue concluded.

For cell and gene therapy developers, the message from the FDA is clear that robust, early CMC planning isn’t optional. From facility readiness to data integrity and process scalability, the path to approval hinges not just on clinical innovation, but on execution.