Louis Cicchini, PhD, and Michael Day, PhD

Louis Cicchini, Ph.D., Director of Scientific Affairs for Cell & Gene Therapy (CGT) at Cencora; and Michael Day, Ph.D., is Senior Director of Regulatory Strategy and CMC at Cencora.

The growth of cell and gene therapies (CGTs) has brought both promise and complexity to healthcare. While these products are transforming patient care, CGTs present new and dynamic regulatory challenges for companies and health authorities, particularly when it comes to Chemistry, Manufacturing and Controls (CMC).

These issues were underscored recently when the US Food and Drug Administration (FDA) published more than 200 complete response letters (CRLs) that had been issued between 2002 and 2024 for products that have since been approved. In publishing the CRLs, the FDA’s objective is to help developers that are submitting new applications to learn from mistakes made by others.

Of the FDA-approved CGTs currently on the market, at least 10 had at one point received a CRL — all of which cited CMC concerns. CGTs use complex biologicals, both in the manufacturing and in the final drug product, which makes them inherently variable. If potency, comparability, stability, or manufacturing readiness are not bulletproof, FDA questions whether later lots truly match the lots that demonstrated clinical benefit. The bar is high because minor changes in process can have major effects on product performance and safety.

The CRLs identify several major quality issues found during reviews of biologics license applications (BLAs).

This is a measurement that can be used to correlate the final drug product to clinical effect or therapeutic benefits.

Some call outs in the CRLs concluded that the biomarker the developer used could not be definitively linked to the outcome, which would occur if the mechanism of action is not well defined. FDA has also repeatedly flagged potency assays that do not adequately reflect the product’s mechanism of action or that rely on legacy methods without appropriate bridging. Another issue raised in several instances was that the assays that were developed were established using a previous iteration of the drug product, highlighting a legitimate comparability concern.

Developers can reduce the risk of delays and align product quality testing with regulatory expectations by identifying critical quality attributes (CQAs) for a product’s safety, efficacy and quality. For example

 — which should be measurable, scalable, and reasonable to assess during the compressed timelines of a commercial program — can help to ensure the final product is consistently manufactured.

This refers to pre- or post-change data when scaling, transferring sites, or changing materials. Regulators want to know that a previous iteration of the drug product is comparable to the current iteration. This isn’t only relevant across study phases. Manufacturers should also be able to demonstrate consistent drug product production across all proposed manufacturing sites.

Another frequent concern noted in CRLs is inadequate bridging between clinical and commercial material, where sponsors failed to demonstrate that later-stage or scaled-up lots were truly representative of the material used in pivotal trials.

Sponsors can address comparability concerns by ensuring each chosen manufacturing site has produced multiple compliant batches. Additionally, it is important to retain and fully characterize samples from early trials for side-by-side testing during scale-up, site transfer, or method changes. Since manufacturing processes and potency assays may change during development, monitoring and controlling them is crucial to ensuring the final product meets regulatory standards for drug substance safety and quality. A key step here is to keep a “living” comparability narrative.

One recurrent issue raised in the CRLs was that standard operating procedures (SOPs) were not sufficient and that staff on site did not have adequate training to make a consistent and safe drug product. To ensure a manufacturer can produce a safe and reliable drug product, FDA wants evidence that the manufacturing facility is free of contamination risks, that it is an aseptic facility, and that cleanroom designs meet rigorous standards.

Key steps sponsors can take include conducting mock pre-approval inspections and ensuring the staff is familiar with SOPs, ideally using a third-party consultant to identify any issues and check SOPs.

Among issues flagged by the FDA were that real-time stability data was sparse and that specifications were not tied to clinically relevant to CQAs. Temperature stability is key, and regulators want assurance that the vials are not deteriorating and contaminating the drug product.

Recommended steps include generating real-time data early, performing degradation mapping, and setting an interim shelf-life with a defensible extension plan. The FDA wants manufacturers to demonstrate in shipping validation studies that the container maintains sterility under a variety of circumstances. Moreover, FDA will want to know that the sponsor has selected 

third-party logistics partners with cold chain

 and just-in-time delivery experience who can validate every leg of the shipping routes.

FDA expects CQAs and critical process parameters (CPPs) to be defined early as part of a control strategy. The agency is looking for a complete control process across the production lifecycle and for manufacturers to map any process testing and release testing that needs to take place to fit the CQAs.

The FDA will be checking the manufacturer’s process controls and data integrity when they inspect records and batches. So, manufacturers will need to be able to demonstrate how they have collected the data and show they have a rigorous control strategy in place.

While a setback, receiving a CRL is not an insurmountable barrier. Nevertheless, deficiencies can result in delays that may require the developer to file for an extension and conduct costly new studies, such as conducting a long-term stability test or doing further research to link the potency assay to the mechanism of action.

Manufacturers can reduce their risk of receiving a CRL by embedding best practices in the organization, including:

Establishing a cross-functional governance team to review assays and decisions throughout the development and commercialization process.

Engaging with the FDA early on for scientific advice and by taking advantage of initiatives such as the Support for clinical Trials Advancing Rare disease Therapeutics (START) pilot program, or other regulatory pathways aimed at boosting communication. Go into those meetings with specific questions and demonstrate knowledge of the relevant guidance.

Speaking with key opinion leaders, who can offer different perspectives in a specific therapeutic category, and consult third-party experts who can help developers establish comprehensive plans to monitor and manage process changes.

By implementing proactive planning and proven best practices, manufacturers can save time and resources and set themselves on a pathway to success.

The opinions expressed in this article are solely those of the authors and relies on publicly available information from the FDA described above, as well as the authors’ own expertise. The view expressed do not constitute legal advice, and Cencora, Inc., strongly encourages readers to review available information related to the topics discussed and to rely on their own experience and expertise in making decisions related thereto.

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.

https://www.cencora.com/specialties/cell-and-gene-therapy

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How cell and gene therapy developers can lessen the chances of receiving FDA complete response letters through the use of proactive chemistry, manufacturing, and controls strategies.