Decoding FDA’s new flexible CMC requirements for cell and gene therapies

This blog is part of The Regulatory Navigator series, where we explore the evolving regulatory landscape with actionable insight from Parexel's experts, sharing their experience to maximize success for clinical development and patient access.

On January 11, 2026, the FDA announced information about the agency’s flexible approach to overseeing chemistry, manufacturing and control (CMC) requirements for cell and gene therapies (CGTs).¹  

While highlighting the agency’s initiatives to facilitate the development of CGTs, the FDA announcement does require some clarifications and context for CGTs sponsors to understand how to implement the flexibilities into their development programs.  

Here we discuss some of the critical points covered in the announcement and provide our insights:  

1. Clinical trial material (CTM) manufactured for Phase I (first-in-human, FIH) trials need not comply with current good manufacturing practice (cGMP) requirements 

FDA has clarified that before an investigational CGT product is manufactured for Phase II or III trials, the manufacturer will not be expected to comply with the requirements specified in 21 CFR part 211.²  

Important advantages of this flexibility are expedited and cost-efficient early-stage development, since sponsors (particularly in start-up biotech settings where most CGT are developed) spend a significant amount of time and resources selecting CDMOs for process development and cGMP manufacturing. This often requires heavy upfront investment, albeit less than the costs of sponsors setting up their own GMP manufacturing. The time required for GMP manufacturing and capacity constraints are also rate-limiting factors for CGT development.  

However, there are two potential downsides to the flexibility for Phase I CTM: 

a. Delayed CGT approval or market launch due to lack of early-stage cGMP drug product 

Some CGT sponsors pursue the 'one-and-done' model, wherein one pivotal Phase II/III trial, or even a Phase I trial, is conducted to support approval. While Phase I studies are intended primarily to assess product safety and tolerability, in the case of CGT products efficacy data can become available as a part of the Phase I study (e.g., during a Phase I/II study, an 11-year-old boy with profound hearing loss since birth became the first patient to experience restored hearing within 30 days of being treated with AK-OTOF, a gene therapy being developed by Akouos).3 In such cases, the burden of getting cGMP drug product manufactured for the pivotal trial and soon-to-be commercial process can be challenging if Phase I CTM was not produced under cGMP conditions. 

b. Potential safety concerns with the Phase I CGT product 

cGMP requirements establish the minimum standards for manufacturing, processing, packing, or holding of human and animal drug products to ensure product quality and safety. FDA regulations and policies also specify requirements for investigational products. The regulations mandate that manufacturers conduct in-process controls and tests, assess the prevention of contamination, and monitor for changes in the quality attributes of in-process materials. Additionally, FDA statute states that cGMP must be in effect for the manufacture of each batch of investigational drug used during Phase I clinical trials.4 Also, manufacturers are expected to establish controls based on identified hazards for the manufacturing setting that follow good scientific and QC principles.4  

CGT sponsors who leverage FDA’s allowance of non-GMP conditions for Phase I CTM for their CGT products should consider the potential safety concerns that may be raised (e.g., those related to environmental monitoring, especially in multi-product facilities) and the potential risk of inconsistencies in process execution. 

2. During transition from Phase I to efficacy pivotal studies, risk-based data showing the comparability of the pre-change and post-change product is adequate to support minor manufacturing changes 

This is a welcome reminder to developers that small changes with low risk do not require a huge and costly comparability analysis, but that comparability assessment should be commensurate with the risk of the change. A good approach to ascertainment of comparability is always to begin with a risk assessment, formal or even informal during early phase, and consideration of the impact of the change on the preliminary critical quality attributes identified so far. 

3. FDA will apply flexibility in establishing product release specifications in its review of CGT BLAs, where appropriate and consistent with the nature of the product and manufacturing process 

Flexibility in product release specifications, even at the BLA review stage, will allow developers to truly explore analytical parameters and hone-in on product characterization. In many cases, the lots manufactured for CGTs are small, in terms of batch size, and limited in number compared to other biologics. Thus, material requirements for certain tests are difficult to meet, making it harder to set specifications in early stages of development. CGT developers are often reluctant to set even wide and preliminary specifications for analytical methods, even though such specifications are subject to further refinement as product development progresses. Part of the reluctance stems from the fear of having to reject drug substance or drug product lots due to the failure to meet specifications set early on.  

The FDA’s flexibility in product release specifications, even at the BLA review stage, will alleviate CGT sponsor concerns and encourage thoughtful determination of parameters. Developers should, however, still plan for development and implementation of robust and reproducible analytical methods and continue to rely on rigorous (statistical) approaches in justifying specifications beyond licensure. 

4. FDA will also apply flexibility in the number of Process Performance Qualification (PPQ) lots necessary for process validation 

The FDA does not have a regulatory requirement for a particular number of PPQ lots; however general manufacturing practice has been to produce 3 drug product lots as a part of the process validation campaign. In addition to clarifying that 3 lots are not “required,” the FDA has further explained that the agency will now review whether PPQ protocols justify the appropriate number of lots based on overall process understanding.  

The FDA’s flexibility with regard to process validation will benefit all CGT sponsors who frequently feel burdened to comply with the need to produce 3 or more PPQ lots. This burden is particularly felt by sponsors developing CGTs outside the US but planning to seek FDA approval for their therapies, and especially if they already produced PPQ lots using raw materials that do/may not comply with USP to support approval in other countries. Demonstrating process understanding and control, using previous data and without having to produce 3 new PPQ lots, would certainly help such sponsors.  

At the same time, it is important to bear in mind that the number of PPQ lots should be determined based on considerations specific to each product and manufacturing process. For example, for many patient-specific autologous CGTs, 3 batches would be considered too few.  

Conclusion 

Overall, we believe the FDA’s recently announced flexibilities for CGT manufacturing will help streamline CMC strategies for these therapies. There are, of course, other changes that could further the FDA’s initiative to expedite CGT development, such as flexibility with regards to device compatibility studies and testing requirements for residuals (especially for safe reagents used in the initial process steps). 

Sponsors must still carefully approach the nuances and potential trade-offs, particularly regarding early-stage manufacturing decisions and safety considerations. Our team of ex-regulators stands ready to help companies navigate this new CGT landscape, leveraging years of experience in CGT development and deep understanding of FDA expectations to optimize your CMC strategy while maintaining robust quality standards. Contact us today to discuss how we can support development of your CGT program. 

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References 

1. Flexible Requirements for Cell and Gene Therapies to Advance Innovation | FDA, January 11, 2026 
2. Code of Federal Regulations, Title 32, PART 211—CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED PHARMACEUTICALS 
3. Philippidis A. Akouos Therapy Restores 11-Year-Old Boy’s Hearing After 1 Month, Human Gene Therapy, 2024;35(5-6):135-138 
4. FDA Guidance for Industry, CGMP for Phase 1 Investigational Drugs, July 2008 

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