Gene therapy approvals stalled by FDA manufacturing flaws

FDA and EMA crack down on flawed manufacturing of gene therapies

Last year, 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 [1], providing greater transparency into the agency's decision-making process. Additionally, FDA has rejected or delayed several new cell and gene therapy (CGT) biologics license application (BLA) submissions due to problems with manufacturing readiness. According to the manufacturers of these products, deficiencies included process control gaps, inadequate stability data, unvalidated analytical methods, and ongoing issues following Good Manufacturing Practice (GMP) inspections [2]

These CMC and GMP issues are well-documented in Europe, where most biological products and all ATMPs go through the Centralised Procedure (CP) with the European Medicines Agency (EMA). The agency has a long-established documentation framework and each product is subject to European public assessment reports (EPARs) [3], whether approved or denied authorization. The release of the CRLs from FDA now allows observers to more rigorously assess areas of respective interest and concern between the health authorities.

Shining a light on CMC

One of the core challenges with developing an ATMP is characterizing the process and getting well-understood critical quality attributes (CQAs.) Having those robustly understood and justified is key to unlocking a lot of the other CMC challenges [4]. A frequently identified CMC issue is potency, particularly getting a relevant potency assay that links to a meaningful CQA that accurately reflects the mode of action of the product. While potency issues are not new, the more complex the therapy, the harder it can be for manufacturers to convince regulators that their CQAs are meaningful and justified and will link back into the clinical efficacy that needs to be demonstrated in clinical trials.

This is relevant not only for potency but also for comparability - another issue highlighted in the CRLs. This refers to the pre- or post-change data when scaling, transferring sites, or changing materials. These changes inevitably occur during product development, particularly with biological products. Unless comparability is linked to meaningful CQAs it is hard to make a compelling case to support those changes.

The same is true for stability. Without stability data linking back to meaningful attributes of the product, it is hard to demonstrate that within reasonable parameters the product is stable over its shelf life and during transfer and transport. Steps to avoid negative findings from the regulators include generating real-time data early, carrying out degradation mapping, and establishing an interim shelf-life supported by a well-justified extension plan.

The CRLs also identify challenges with regards to manufacturers' control strategies - another issue commonly highlighted in EPARs. They also reinforce the need to have an appropriate manufacturing environment, ensuring that all facilities comply with standard GMP requirements, including sterility assurance. ATMPs are often made in small facilities using novel manufacturing technologies, nonetheless, the same requirements for GMP sterility assurance still apply. Positioning CPP/CQA controls within a risk-based quality framework, such as ICH Q9(R1)5, can demonstrate proactive compliance and inspection readiness.

Manufacturers must ensure they build in all the compendial requirements governed by the European Pharmacopoeia that control sterility and appropriate control and characterization of the process [6].