On May 5, the FDA quietly released a new guidance document with considerations regarding its existing policy flexibilities for chemistry, manufacturing and controls issues in cell and gene therapy products. Here, AgencyIQ breaks down what’s in that document and the discussion of it at a timely May 6 Friends of Cancer Research workshop.
Catching up: manufacturing challenges for cell and gene therapies
- Cell and gene therapy product applications are reviewed by the Center for Biologics Evaluation and Research’s Office of Therapeutic Products. Formerly known as the Office of Tissues and Advanced Therapies, OTP also reviews therapeutic vaccines and plasma-derived and coagulation products. Part of the reason for the office’s 2022 rebrand and reorganization was to accommodate the surge in CGT products submitted to the FDA in the previous five years and to “improve functional alignment, increase review capabilities, and enhance expertise on new cell and gene therapies.” OTP’s acting leader is VIJAY KUMAR, a nephrologist who has been at the agency since 2020.
- Since the FDA approved its first gene therapy product in 2017, the agency has quickly racked up experience reviewing the CGT class. OTP currently lists about 50 licensed CGT products on its webpage. The FDA has leveraged this experience to build out its CGT guidance portfolio, issuing a range of recommendations for CGT products broadly as well as for specific product types. Among that broader set of guidances are documents covering manufacturing, potency, follow-up testing and early-phase trials, among others. OTP has also held a series of workshops and town halls since 2021 covering cell and gene therapy topics. In April, the FDA held its first workshop focused on CGT products for pediatric populations. [Read full AgencyIQ analysis here.].
- Manufacturing topics have featured heavily in FDA advice to the field, though challenges remain. CGT chemistry, manufacturing and controls, or CMC, issues have important nuances given their inherent complexity. As a class, their manufacture is substantially more complex and, because they consist of cells, viruses and nucleic acids, more variable than traditional pharmaceutical and biologic medicine like pills or proteins. OTP touched on some of these topics in a town hall it held in October 2025. The meeting, its first in 2025 and 10th overall, focused on gene therapy manufacturing, CMC and facility readiness for Biologics License Applications and post-licensure changes. OTP staff fielded 42 questions during the meeting, which AgencyIQ compiled and categorized in this analysis.
- In early 2026, on the eve of the J.P. Morgan Healthcare Conference, the FDA issued a rare Sunday press release describing the flexibility it will afford developers of cell and gene therapies when enforcing CMC requirements. The approach described by the agency wassn’t all new but hadn’t been communicated in such broad fashion previously. “CBER is proactively communicating about regulatory flexibilities that were previously applied case-by-case to select CGT therapies,” OTP’s Kumar said in the statement. “It is vital that every sponsor, no matter the CBER reviewer team they engage with, understand what types of regulatory flexibility may be scientifically acceptable.”
- On a related webpage, the FDA outlined how it would flexibly interpret CMC requirements related to clinical development, commercialization and process validation. The described approach is a mixture of FDA acknowledgement of certain realities in cell and gene therapy, along with acceptance of looser or changing product criteria in certain settings. Taken together, the FDA’s statements and the quotes from its leaders indicate that these flexibilities have been available in some fashion, but perhaps not to everyone. [Read full AgencyIQ analysis here.]
A new guidance on CMC for CGT
- On May 5, 2026, the FDA quietly published a direct-to-final, “Level 2” guidance document titled, “Chemistry, Manufacturing, and Controls Flexibilities for Developing Human Cellular and Gene Therapy Products for a Biologics License Application.” The document is relatively brief, spanning just 10 pages; as a level 2 guidance, it is meant to “address existing practices or minor changes in FDA’s interpretation or policy.” As stated in the document’s introduction, “FDA is issuing this guidance to help clarify FDA’s use of CMC flexibilities, to inform sponsors, and to facilitate the development of safe, effective, and high-quality CGT products in preparation for a BLA submission.”
- The document contains a caveat that some issues still need to be addressed on an individual basis. “The extent of the CMC data necessary and the suitability of a CMC flexibility may vary depending on the stage of development, the manufacturing process, and the product,” the agency wrote, continuing, “For sponsors considering pursuing a BLA, FDA may seek additional data and information on a case-by-case basis to ensure that the requirements for licensure can be met. Sponsors are strongly encouraged to engage with FDA early and throughout CGT product development.”
- The structure and content of the document closely mirror the January announcement, adding additional detail. The articulated flexibilities are sorted into the same three buckets as the earlier announcement: clinical development, process validation and commercial specification. The guidance, however, adds a fourth bucket for “additional flexibilities.”
- During clinical development, the guidance describes implementation of “phase-appropriate current good manufacturing practice (CGMP)” and confirms that it does not expect developers to comply with 21 CFR 211 for Phase 1 studies and those that intend to “establish basic safety, rather than the efficacy of the drug product.” The theme of phase-based relaxation of requirements is also carried over to release acceptance criteria, which the FDA says it will be “relatively permissive” about for early-stage products, “if such criteria do not compromise safety.”
- The guidance also addresses its expectations for certain data types in clinical development. In recognition that CGT products can have “limited process knowledge, limited product quantities, and complex manufacturing processes,” the guidance says that FDA may accept “limited” comparability data for minor, low-risk investigational product manufacturing changes. The guidance also says that “The Agency may consider proposals submitted to FDA with appropriate justification to leverage CMC knowledge across similar CGT products and, if applicable, critical components, such as analytical methods, method validation, lot release specifications, stability data, comparability data, and process development and process validation data.” A likely related FDA guidance titled “Leveraging Prior Knowledge in the Development of Human Gene Therapy Products Incorporating Genome Editing” was cleared for publication by the White House Office of Information and Regulatory Affairs on March 31; the cause for the delay in its release is unclear.
- The guidance further explains its flexibilities regarding process validation through process performance qualification, or PPQ strategies. The guidance says that “FDA does not specify a minimum number of PPQ batches in the biologics licensing requirements or CGMP regulations,” but rather, the number of batches should be scientifically and contextually supported. Further, the guidance explains that “When PPQ production limitations exist, FDA may consider a flexible approach for the completion of PPQ studies post-licensure.”
- In line with the January announcement, the guidance provides insight into expectations for establishing a commercial specification within the BLA. These flexibilities collectively recognize that CGT sponsors often face challenges in having few product lots available for analysis. The FDA says it “may consider flexible approaches for establishing product release specifications when it is not feasible to define statistically robust commercial acceptance criteria at the time of initial approval.” Similar to the articulated PPQ flexibilities, the FDA also says that it does not specify a minimum number of lots to be used in analytical method validation studies and may consider those “using a single representative lot, when appropriate.” In some cases, the FDA encourages sponsors to consider committing to post-approval reevaluation of product release acceptance criteria, with any changes subsequently submitted via a prior approval supplement.
- The document’s section on “additional flexibilities” touches on areas not addressed in the January announcement. Here, the FDA says that it will consider an alternative to the generally recommended minimum of three lots and six months of stability data to inform commercial expiration dating. This could include data from clinical rather than commercial lots, or data from similar products. The section also makes clear that the FDA can consider exceptions to its requirement for biologics manufacturers to “retain sufficient material from each lot of product manufactured for six months after the expiration date.” The section concludes with a note that the FDA may consider the use of alternatives to compendial lot release testing if the methods are validated and meet relevant “standards of accuracy, sensitivity, specificity, and reproducibility.”
- The guidance closes the loop and formalizes the FDA’s existing announcement and accompanying webpage with additional details provided about the agency’s existing policies and flexibilities.However, the document does not offer policy changes, but rather provides information about what could be offered to sponsors in certain circumstances. The guidance will likely be most useful to CGT sponsors facing challenges with small numbers of product lots, such as those manufactured for few patients – or just one.
Regulators, stakeholders discuss and react at a May 6 meeting
- One day after the new guidance was published, the Friends of Cancer Research and the Parker Institute for Cancer Immunotherapy hosted a public meeting on “Unlocking Next-Generation Therapies” that aligned closely with the document’s content. As previewed in the meeting’s issue brief, the event provided “targeted dialogue” on three topics: (1) early-phase clinical development and strategy, (2) chemistry, manufacturing, and controls expectations and lifecycle management, and (3) clinical trial design and evidentiary expectations.
- Friends of Cancer Research Vice President of Science Policy MARK STEWART opened the meeting with an anchoring presentation. “We’ve seen a number of recent guidances and initiatives that reflect real openness to adapting existing frameworks for these products,” he said, highlighting documents published in recent years as well as the May 5 title. “So, in our conversations, it’s not necessarily that there’s a lack of flexibility, per se, but it’s really what happens between guidance and practice, and how one interprets and operationalizes the content of these guidance documents,” he said.
- In the first panel, OTP head Kumar weighed in on how the office exercises flexibility in practice, saying they are open to applicable flexibilities that do not compromise scientific rigor. He explained that regulators “routinely” see a large disconnect between a CGT sponsor’s clinical and CMC development programs that creates a bottleneck, especially in oncology. He shared an anecdote, “So we had a situation not too long ago where a company submitted a briefing package and their plans for a BLA and our clinical review team and the CMC review team, based on their analysis and reading of the package, were about 18 months apart on when the company would come for a BLA.” A meeting between regulators and sponsor confirmed that their teams themselves were truly that far apart. “There is a joke among some of the CMC reviewers that when an IND is allowed to proceed, clinical takes the bullet train and CMC takes the choo-choo train,” said Kumar.
- When the moderator LOLA FASHOYIN AJE, former FDA official and current head of regulatory science at AstraZeneca, pressed Kumar for solutions, he provided a vision for future trials. “We had the phase one, phase two, phase three development, and now we are moving towards a default single adaptive design trial,” he said, describing a similar concept to Commissioner MARTIN MAKARY’S vision for seamless, continuous trials. According to Kumar, alignment of the CMC timeline should be a “core element” of the design of these studies.
- In a subsequent panel focused directly on CMC flexibility, KIMBERLY SCHULTZ pushed back on the event white paper’s discussion of FDA’s numerical acceptance criteria recommendations. She said, “Quite honestly, we were quite surprised to see the misalignment in understanding of how specification should be set and maintained throughout a life cycle in the issue brief, compared to that which we promote through our FDA review processes.” Schulz explained that the agency recommends “very wide acceptance criteria” during development, continuing, “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 also weighed in on how sponsors can leverage prior knowledge in practice. One example, in her view, would be “CAR T cells that are manufactured using the same process but target different antigens.” She also discussed opportunities for information to be leveraged across sponsors through partnerships. Schultz acknowledged that process characterization can be resource intensive for small companies and said that the agency has seen success when multiple sponsors with “similar process or the same critical components across products” work together to share data and “split the cost and burden.”
What’s next?
- Taken together, the FDA’s new guidance provides additional detail on a range of flexibilities that will likely be welcomed by CGT sponsors. At the same time, the discussion at the workshop the following day showed that there are still areas where industry would appreciate further flexibility.
- Sponsors looking for a granular look at flexibilities in action can reference the recently released Summary Basis for Regulatory Action document for Regeneron’s OTARMENI (lunsotogene parvec-cwha), a gene therapy for hearing loss approved under the auspices of the Commissioner’s National Priority Voucher pilot program on April 23. The document offers a numbered list of 11 specific regulatory flexibilities exercised in the review process across several disciples. From the CMC perspective, the summary states that the FDA used “acceptance of relatively wide commercial lot release acceptance criteria based on data from limited number of lots that were available because of rare disease indication,” with the sponsor committing to reassessment as a postmarketing commitment. In addition, the agency allowed “a drug product shelf-life set based on a conservative extrapolation of limited stability data that are available, because of expedited clinical development.”
- CGT stakeholders could expect significant additional guidance development in 2026, according to CBER’s guidance agenda for this year. Several important guidance documents should be finalized, including the FAQ document on “developing potential cellular and gene therapy products.” The guidance was most recently issued in draft form in Nov. 2024, featuring answers to 36 questions grouped into four topics: interacting with the FDA, product development considerations, conducting nonclinical studies and conducting human trials. [Read full AgencyIQ analysis here.] The agenda also features some noteworthy new topics, such as a new draft on potency assessment of active immunotherapy products, a category that includes products like checkpoint inhibitors used to treat cancer. The EMA maintains its own guideline on this topic, so the FDA may look to harmonize with international regulators. [Read AgencyIQ’s deep dive on the agenda here.] However, at the time of writing, CBER and OTP both lack permanent leadership, which could have implications for the pace of guidance publication.
Featuring previous research by Ned Pagliarulo.
To contact the author of this item, please email Amanda Conti ( aconti@agencyiq.com).
To contact the editor of this item, please email Kari Oakes ( koakes@agencyiq.com).