FDA finalizes guidance on CMC flexibilities for cell and gene therapies
The US Food and Drug Administration (FDA) has released a final guidance document with immediate effect advising sponsors on chemistry, manufacturing, and controls (CMC) flexibilities for cell and gene therapy (CGT) products developed for biologics license applications (BLAs).
The document marks the third cell and gene therapy guidance released by the agency in 2026 following a draft guidance document on performing safety assessments for genome editing of gene therapy products in April, and a draft guidance document on using a plausible mechanism framework for developing individualized cell and gene therapies. (RELATED: FDA drafts guidance on using next-generation sequencing to assess gene therapy safety, Regulatory Focus 14 April 2026; RELATED: FDA proposes plausible mechanism pathway for ultra-rare disease therapies, Regulatory Focus 23 February 2026)
FDA acknowledged that it can be difficult for sponsors to create CGT products using “traditional product development strategies” due to factors such as the complexity of the product and process, individualized manufacturing needs, small patient populations, fewer manufacturing runs, and shorter product shelf lives, among others.
“Consistent with the statutory and regulatory requirements for biological products, FDA uses a flexible approach to ensuring applicable CMC requirements are met for CGT products,” FDA wrote in the guidance. “FDA’s flexible approach serves to help expedite development, review, and patient access to safe and effective CGT products to treat serious or life-threatening conditions that represent significant unmet medical needs.”
FDA noted that the guidance applies to products under the purview of Center for Biologics Evaluation and Research (CBER), and said sponsors should meet with the agency to discuss a CMC approach before it is implemented.
Flexibilities for development, product validation
The flexibilities available to sponsors of CGT products include phase-appropriate current good manufacturing practices (CGMPs), creating release acceptance criteria appropriate for the investigational study phase, having a risk-based approach for comparability studies, use of prior knowledge during CMC development, and employing voluntary consensus standards during product development and assessment.
For process validation, flexibilities for CMC outlined in the guidance include the development of a process performance qualification (PPQ) approach that “scientifically supports the number of PPQ batches submitted to the BLA,” and the release of clinical or commercial PPQ batches post-licensure to support completed PPQ studies.
“FDA may consider allowing concurrent release of PPQ batches for commercial use after BLA approval if the batches meet the commercial release specification and are within the commercial shelf life,” the agency explained. “In addition, any such batches that meet the phase-appropriate release criteria established under an [investigational new drug application] IND may be used for a clinical investigation.”
Flexibilities for commercial specification, pursuing BLA submission
Commercial specification flexibilities available to sponsors include the creation of a product release strategy that matches the “nature of the product, the manufacturing process, and the number of lots available” during the BLA. FDA said sponsors can also consider using fewer lots, including a single representative lot, if the analytical method validation strategy is scientifically supported.
Sponsors can additionally use manufacturing experience in the post-approval setting to discuss with the agency whether product release acceptance criteria could be reevaluated. “This approach supports the development of more statistically sound acceptance criteria over time,” FDA said.
Other flexibilities include the use of stability data from clinical lots to support expiration dates for commercial lots, potentially granting exceptions for retaining reserve samples from smaller or individualized lots, and the use of alternative analytical methods for reducing sample volume or testing time for some lot release tests.
Real-world application
In a recent public meeting hosted by Friends of Cancer Research and the Parker Institute for Cancer Immunotherapy, Ben Beneski, senior vice president and chief technical officer at Allogene Therapeutics, said he thinks the final guidance would be “really helpful in real-world situations” where products have limited engineering runs or datasets.
If you put a specific number to a specification, “you may end up—even if you try to set it wide—it may not reflect the full variability of the process,” Beneski told attendees.
Beneski said he’s seen situations where the specification seemed appropriate at first, but during later manufacturing, encountered a batch that was approaching the specification.
“We thought, ‘Oh no, maybe there was a manufacturing problem or some issue,’ and it turns out it was just normal variability. That specification is one we’ll have to look at over time as we've gathered more data to change,” he said.
The same situation applies for commercial specifications, Beneski added.
“If we set specifications based on clinical experience, and that clinical experience was generated with a small number of batches, it’s the same problem, that we may find the variability of the process is actually larger than we thought,” he explained.
“Having a life cycle approach to being able to consider adjusting or resetting those specifications as more data becomes available is a really important area of flexibility,” he said.
Kimberly Schultz, director of Gene Therapy Division 2 in the Division of Cellular and Gene Therapies at FDA’s CBER, told attendees at the meeting the agency was “quite surprised to see the misalignment and understanding of how specifications should be set and maintained throughout a lifecycle” in the issue brief from the public meeting.
The issue brief highlights the difficulty of creating meaningful numerical limits based on limited data, and how manufacturers can be pressured to narrow specifications as manufacturing progresses, which can be difficult to widen once established.
Schultz said FDA promotes “a lifecycle approach to specification setting,” which can vary based on the type of product.
“If you have a product where you have a limited number of lots, it is difficult to set a meaningful lot release criteria for that,” she explained. For autologous products, there is a need during the clinical study to develop experience “across that potential patient variability in order to inform your commercial lot release criteria,” she said.
However, two areas of confusion are typically in how to set acceptance criteria and whether a critical quality attribute is a safety attribute.
“We do recommend that you set very wide acceptance criteria during your development. These are not restrictive criteria, but these are things where, if your manufacturing process for some reason is outside of even a wide normal for that lot, come and check in. Make sure that the monitoring for the patient and the risk mitigation strategies are appropriate for that lot,” Schultz explained.
For situations where there is a disagreement on whether a quality attribute is actually a safety attribute, FDA has more flexibility than sponsors might realize, Schultz explained. For instance, the agency does not have a predefined limit for determining a CAR-T cell vector copy number,
"As you can imagine, more integrations leads to higher clinical risk, and so what we expect is that information—from your pre-clinical experience, from your engineering runs—informs what your initial lot release criteria are,” Schultz said.
“There’s a lot of room in between there. And that’s where that conversation, I think, during the pre-IND meeting is informative,” she added.
