The U.S. Food and Drug Administration (FDA) has issued final guidance for cell and gene therapy (CGT) manufacturers to help ensure the potency of their products throughout the product lifecycle, from early-phase investigational new drug submissions through biologics license application approval and continued post-market verification.

“Patients who receive cellular and gene therapies are often battling serious or life-threatening conditions, such as cancers and rare diseases, and they deserve the assurance that the product administered to them will perform as intended,” Karim Mikhail, director of the FDA’s Center for Biologics Evaluation and Research (CBER), said in a statement.

The FDA final guidance, which replaces the agency’s 2011 testing guidance for CGT products, is meant to guide manufacturers to test and verify that every batch meets a defined standard of potency by providing recommendations that can be integrated into their current quality systems to achieve the intended therapeutic effect.  

“By law, manufacturers are expected to verify that their products work as intended, from the time of approval through post-approval monitoring,” the agency said in its announcement. “This final guidance provides FDA’s current thinking and recommendations on how manufacturers can meet that requirement.”

Among the topics addressed in the final guidance are controls for variability in raw materials, testing during manufacturing, and lab tests that confirm each batch is biologically active in a way that matches its intended therapeutic effect. The document also provides specialized considerations for products with short shelf lives, viral vector gene therapies, and patient-specific therapies.

Assays are a critical part of assuring the potency of CGT products, according to the FDA. However, the agency notes that developing assays that measure the potency of CGT products — and their corresponding acceptance criteria — can be challenging.

“In this guidance document, we emphasize that potency assays and their corresponding acceptance criteria should be designed to make meaningful contributions to potency assurance by reducing risks to product potency,” the FDA’s document states. “We provide illustrative examples of approaches to potency assay development that are grounded in quality risk management principles.”

At the same time, the FDA said that due to the diversity of CGT products and the product-specific nature of potency assays, the recommendations in the final guidance regarding the selection and design of potency assays are intentionally general. The potency assurance strategy laid out its guidance document also includes complementary approaches that do not increase sponsor requirements, according to the agency.

The FDA will hold a December 10 webinar to help CGT manufacturers understand and implement the guidance. 

Industry responds positively to final guidance

The Alliance for Regenerative Medicine (ARM), a Washington, D.C.-based advocacy organization championing the benefits of engineered cell therapies and genetic medicines, said in a statement that it welcomes the FDA final guidance on potency assurance.

“Assuring potency through the whole manufacturing process (design, materials, in-process controls, and release testing) rather than through a single lot-release test better reflects how cell and gene therapies are made and gives developers more ways to demonstrate that every lot will perform as intended,” said Monica Veldman, director of global regulatory policy at ARM. 

Veldman noted the FDA’s clarification that its approach in the final guidance does not add new requirements or call for a separate quality system — which she said is important, particularly for smaller companies and academic developers. 

“The next priority should be consistent, phase-appropriate application across review teams, especially for rare disease and accelerated programs where potency data are inherently limited,” Veldman added. “We look forward to continuing this work with CBER.”

Farlan Veraitch, founder and chief scientific officer at Ori Biotech, also welcomed the FDA final guidance on potency assurance.

“Potency is shaped by the manufacturing process long before release testing, so linking process parameters to product quality early gives developers the best chance of catching drift before it reaches patients,” Veraitch said. “Well-controlled, automated processes can help, provided biological performance is preserved and demonstrated.”

Ori Biotech is looking to overcome cell and gene therapy manufacturing challenges by automating and digitizing critical processes. Last year, Ori Biotech’s IRO platform received the FDA’s Advanced Manufacturing Technology (AMT) designation, which the company contends will potentially enable developers using the automation platform to have earlier and more frequent FDA engagement, accelerating regulatory filings.

“As a holder of FDA AMT designation, we’d welcome clarity on how designated-technology information can support a sponsor’s potency strategy, and on comparability when moving from manual to automated manufacturing,” Veraitch added.