Why CMC is a key sticking point for cell and gene therapies and how to meet FDA expectations

CMC is a particular hurdle for CGTs because the processes and manufacturing are inherently complex. This poses a challenge for developers for several reasons.  

Unlike more traditional pharmaceuticals, CGTs use complex biologicals that are inherently variable and difficult to control. Consider, for example, that the starting material for an autologous therapy is different for every batch because each patient is genetically unique and the cells collected for the therapy have experienced different treatments like chemotherapy, radiation therapy, and immunotherapy. Manufacturing viral vectors, which are used as tools or as the therapy itself, relies on biological systems which are inherently variable, rather than controlled chemical reactions like small molecules. With CGTs, each drug has a unique manufacturing process that is high-touch and, as such, is subject to quality and reproducibility challenges and open to human error. CGTs also use instruments and materials that may have never been part of a GMP workflow before or may never have been scrutinized under CMC regulations, so there is limited precedent or examples to draw on.  

Additional challenges are posed simply by the size of CGT developers, which are often small biotech companies that perhaps lack the internal expertise for managing these complex processes and may not know where to find that information. Moreover, money can be a barrier and the cost of running studies to meet rigorous procedures and standards can be steep.  

Nevertheless, it is vital that developers ensure their potency, comparability, stability, and manufacturing processes are watertight, since minor changes could have a detrimental effect on product performance and safety. The key to success is effective resource allocation and proactive communication.  

In our experience with CGT developers, there are several recurring CMC issues that arise.

Potency and analytics

Potency is a measure used to correlate the final drug product to clinical effect or therapeutic benefits. That means every batch must pass a potency test before going to the patient. Consider the case of a one-batch-one-dose autologous product versus a widely used headache tablet manufactured in the millions of doses per batch and distributed globally at ambient temperatures. One potency test is sufficient for tens of millions of doses of the headache tablet, but each dose of autologous cell therapy must be tested individually for potency. The differences in complexity and cost in this example are significant. 
A key question that developers must answer is whether the determinant of potency is clearly linked to the mechanism of action (MoA). Some issues we have observed are that the biomarker the developer decided to use could not be definitively linked to the outcome. If the MoA is not well defined, it’s extremely difficult to correlate that to the outcome.  
Another issue that can arise is where the potency markers chosen and the assays developed were established using a previous iteration of the drug product. This comes down to potency and comparability. How was the potency assay designed and does that align with the proposed drug product? Regulators also want developers to demonstrate that they can test potency consistently across different manufacturing sites. Potency assays can be high-touch, manual, and come with a certain level of subjectivity or data interpretation. Training across sites for consistency is critical. 
In some cases, the proposed potency testing may be time consuming and could overlap with the treatment schedule, which means release testing and documentation would not be complete before the patient is due to receive the product. The FDA understands that pragmatism is needed with CGTs and it is important to consider the commercial program from a holistic perspective. 
Given the complex nature of CGTs, it’s therefore vital that developers think critically about potency testing and how it will play out at a commercial level.  

Comparability after change 

Changes made over the course of clinical development or in manufacturing processes can significantly impact product characteristics and performance. Regulators expect developers to demonstrate consistency of quality, efficacy, and safety profiles between batches⁵. However, they also recognize this can be difficult with CGTs and have sought to provide developers with guidance on how to manage these challenges³. 

Similar to the issue of reproducibility of potency testing, regulators want to know that batches across different manufacturing sites are comparable and that developers can demonstrate they are safe and consistent. When dealing with one-batch-one-dose products such as autologous therapies, which, as previously noted, involve high-touch processes, it is important that the setup, standard operating procedures (SOPs), and training are exactly the same at every site involved in order to ensure testing is reproduceable and that only safe drug product is released. Engaging FDA early with a proposed comparability protocol can provide flexibility for future manufacturing changes without requiring full revalidation. 

Our recommendation for effective batch comparability tests is to retain samples from Phase 1 trials in order to establish parameters for later phases and establish a comparability narrative throughout development. These retained samples can also support bridging discussions in later phases, particularly when manufacturing changes are unavoidable. The ideal potency assay should be quantitative, linked directly to the mechanism of action, and confirm lot-to-lot consistency. Since manufacturing processes and potency assays may change during development, monitoring and controlling them is crucial to ensure the final product meets regulatory standards for drug substance safety and quality. 

Facility and inspection-readiness 

During development, companies collect a lot of data, but whether they have data integrity may be questionable. We have seen situations where there are missing or incomplete batch records or inconsistent raw data document retention. The level of documentation for GMP from the time that raw materials enter into the process to the time a final product is ready is often much more comprehensive than goes into the actual file. 

The FDA considers data integrity to be a core GMP compliance issue. If they see some patterns or errors with a developer’s data integrity they may question whether the facility is operating under GMP, and could therefore pose a risk to the developer’s drug product, as well as any other products made at that facility.  

Any site making CGTs is therefore heavily scrutinized to ensure it is free of contamination risks, that it is an aseptic facility, and that cleanroom designs meet rigorous standards. Inspectors will assess whether SOPs are sufficient and that staff have been adequately trained.  

It is worth noting that many CGT developers are working with a manufacturing partner and depend on that partner having the right expertise in place and to be inspection-ready. This is where it would be valuable to have a third-party consultant who can assess contract development and manufacturing organizations (CDMOs) on a developer’s behalf: Can that CDMO assure inspection-readiness? Do they have adequate SOPs and documentation procedures in place? Are their staff properly trained?  

Stability and sterility specifications 

Analysis of CRLs issued by the FDA shows some overlap between stability and sterility issues. 

The FDA highlighted some concerns with real-time stability data, noting in several CRLs that the data was sparse and was not tied to relevant critical quality attributes (CQAs). Ensuring temperature stability is crucial, particularly for CGTs, which are highly temperature sensitive. Suggested actions involve collecting real-time data from the outset, conducting degradation mapping, and establishing a provisional shelf-life along with a justifiable extension strategy.  

The FDA requires manufacturers to prove through shipping validation studies that the container preserves sterility across different conditions, and that sufficient temperature controls are put into place. While beyond the realm of FDA approval, sponsors should also consider whether the site-of-care can manage these products in a way that won’t affect their stability. It is important to consider the entire product journey from a holistic perspective when building your strategy. 

Additionally, the FDA expects sponsors to choose third-party logistics providers with expertise in cold chain management and just-in-time delivery, capable of validating each segment of the shipping process. As recent CRLs have shown, shipping validation failures are showing up more frequently with CGTs, not just for sterility, but also for adequate container closure justification and incomplete cold chain traceability. FDA CRLs since 2023 and into 2025 repeatedly cite container closure and cold-chain validation failures, underscoring these as active regulatory pressure points. 

Control strategy 

Too often, CGT developers rely on end-product testing rather than proactive control of critical process parameters (CPPs) linked to CQAs. Identifying CPPs and CQAs early, even during characterization of these therapies, goes a long way to defining the control strategy.   

A best practice is to look at the complete control process from the beginning of production to the end and map where in-process testing and release testing need to take place in order to fit those CQAs. It’s worth noting that this is not just about meeting FDA expectations; equally, it’s good science to clearly map critical parts of the process and to be able to say why they are critical.  

Another best practice is to conduct mock inspections or regulatory audits. The FDA will not only assess the developer’s dossier but will check in-process controls and conduct data checks when they look at a company’s records. Inspectors are increasingly data-driven and any gaps in CPP/CQA control or documentation will not only delay approval but will also raise red flags over product integrity. Positioning CPP/CQA controls within a risk-based quality framework, such as ICH Q9(R1)⁴, can demonstrate proactive compliance and inspection readiness. 

There are a number of strategies CGT developers can adopt to meet the rigorous CMC requirements laid out by the FDA and other health authorities.  

Bring in external consultants who understand the field and can provide advice on standards, guidance, and health authority expectations. There is a lot of guidance available, but it does require knowledge of the regulations and experience with where to look. Having a partner that can pinpoint the right information for developers can be invaluable.  

Establishing a cross-functional governance team to review assays and decisions throughout the development and commercialization process can mitigate issues before they arise. Such a team should not only include CMC experts, but also translational experts, statisticians – indeed, anyone involved in the assay, even tangentially. Have these experts collaborate through different stages of the product through commercialization. 

These types of cross-functional collaborations are becoming increasingly important in light of initiatives such as Project Optimus⁷, which seeks to reform dose optimization and dose selection with oncology drug development. What that means is the potency assay will have to be better defined to determine optimal efficacy and tolerability early in development⁸. We expect regulators to tighten their scrutiny of mechanism-linked potency assays amid the increased emphasis on dose optimization. As such, having cross-functional expertise throughout development will become even more important.  

Taking advantage of early scientific advice from the regulators should be another priority. One such program is the FDA’s Support for clinical Trials Advancing Rare disease Therapeutics (START) pilot, which has had positive feedback from several participants. During the annual meeting of the American Society of Gene and Cell Therapy (ASGCT) in May 2025, it was revealed that participants in the START pilot program held numerous impactful meetings with FDA. These communications helped shave significant times off development timelines, even by several years, thanks to clear advice on CMC readiness⁹. This feedback underscores the importance of communication, the cornerstone of effectively navigating regulatory requirements. 

Type C meetings with the FDA and even Type D meetings, which are designed to focus on one or two questions, offer an opportunity to gain alignment with the regulators early on. Go into those meetings with specific, pointed questions and demonstrate knowledge of the relevant guidance. Unfortunately, developers often don’t know what to ask and take a scattergun approach to FDA engagement, which inevitably results in not getting relevant advice. The agency is focused on ensuring developers are implementing the best scientific practices, so having a clear plan is imperative and engaging with a third-party expert to review and pick out relevant specific questions to ask will help developers get the advice they need.  

In addition to engaging with consultants, speak with key opinion leaders who can offer different perspectives in a specific therapeutic category. 

Regulators are eager to support innovation. They want to help developers bring life-changing and life-saving therapies to patients, and they understand the huge potential of CGTs. Proper planning, thorough understanding of CMC requirements and the potential issues a CGT might face, and proactive engagement with experts and regulators will help developers mitigate CMC issues that often occur, limit the risk of receiving a CRL, and streamline the development process.  

To learn more about improving manufacturing quality to reduce regulatory risk for CGTs, watch Cencora's on-demand webinar here.

Louis Cicchini, Ph.D., is Director of Scientific Affairs for Cell & Gene Therapy (CGT) at Cencora. He specializes in strategic planning for advanced therapies, focusing on the development and implementation of cross-functional commercialization strategies that enhance access to CGTs. 

Michael Day, Ph.D., is Senior Director of Regulatory Strategy and CMC at Cencora. Mike brings more than 25 years of regulatory, CMC, and quality experience, including direct interactions with FDA on CRLs and BLA submissions in cell and gene therapies.