FDA Clarifies CMC Flexibility for Cell and Gene Therapies

The FDA has announced that it is formalizing and more clearly communicating a flexible approach to chemistry, manufacturing and control (CMC) requirements for cell and gene therapies (CGTs). The approach outlines how these flexibilities may be applied across clinical development, commercial specifications and process validation as products advance toward Biologics License Application (BLA) submission.

The agency said the clarified framework is intended to help developers navigate manufacturing and quality expectations for CGTs, which are often individualized, produced in small batches and developed under tight timelines. The effort is being led by the FDA’s Center for Biologics Evaluation and Research (CBER), which oversees CGT regulation.

For clinical development, the FDA said manufacturers are not expected to fully comply with cGMP requirements under 21 CFR Part 211 before producing investigational products for Phase II or Phase III trials, and that process and method validation will be assessed using a lifecycle approach, recognizing that controls and testing strategies evolve as manufacturing experience accumulates.

During the investigational stage, sponsors may also use more permissive product release acceptance criteria, as final drug substance and drug product specifications are not required until later in development.

As programs move from early studies to trials designed to establish efficacy for licensure, CBER said it will allow minor manufacturing changes when supported by data demonstrating comparability (this includes evidence that the product remains essentially the same before and after the change) without requiring unnecessarily extensive comparability packages.

The FDA also described flexibility around establishing commercial release specifications, which define the tests and limits a batch must meet before release. Because CGTs often target small patient populations and may not generate large numbers of manufacturing lots, CBER said it may consider appropriately justified flexibility in setting these specifications when reviewing CGT BLAs. In addition, CBER will consider post-approval requests to revise acceptance criteria when manufacturers can demonstrate consistent product quality.

In process validation, the FDA said there may be situations in which Process Performance Qualification (PPQ) lots can be released for distribution before all protocol steps are completed under a concurrent release approach. The agency also clarified that there is no fixed requirement to manufacture three PPQ lots for validation and that the number of lots should be scientifically justified based on overall process understanding and risk.

Growing CGT Pipelines, Investment & Regulatory Updates

Recent 2025 market analysis indicated that more than 2,000 CGT clinical trials are underway, with hundreds of candidates in mid- and late-stage development and thousands of active Investigational New Drug (IND) applications on file with the FDA.

The CGT innovation landscape is also seeing a slew of new deals. In ophthalmology, Eli Lilly plans to acquire Adverum Biotechnologies, bringing in Ixo-vec, a Phase III intravitreal gene therapy for wet age-related macular degeneration that has received Fast Track and Regenerative Medicine Advanced Therapy designations from the FDA. Lilly has also entered into a broad collaboration with MeiraGTx, gaining access to adeno-associated virus vector platforms, promoter and capsid engineering technologies, and in-house GMP manufacturing capabilities for genetic medicines in eye diseases.

At the same time, in a recent JAMA perspective authored by CBER Director Vinay Prasad and colleagues, the FDA outlined its evolving thinking on clinical evidence standards for oncology CAR-T therapies, indicating that randomized controlled trials demonstrating superiority over existing treatments are generally expected to support traditional approval, while single-arm studies may be more appropriate for accelerated pathways in selected settings.

In a separate and very recent regulatory action, the FDA issued a Complete Response Letter to Atara Biotherapeutics for the BLA of its allogeneic EBV-specific T-cell therapy tabelecleucel (Ebvallo) for post-transplant lymphoproliferative disease. The agency confirmed that previously cited GMP deficiencies had been resolved and did not raise new safety concerns, but stated that the single-arm ALLELE trial was no longer considered sufficient to support accelerated approval, citing concerns related to trial design, conduct and interpretability.

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