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FDA Seeks Stakeholder Input on How to Regulate Point-of-Care Cell, Gene Therapy Manufacturing

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BALTIMORE – Though there are no policies overseeing either centralized or point-of-care strategies for cell and gene therapy manufacturing, the US Food and Drug Administration is actively seeking stakeholder engagement regarding potential point-of-care (PoC) guidelines.

Representatives from the FDA and commercial businesses discussed this topic in a panel session at the American Society of Gene & Cell Therapy annual meeting on Friday.

"There is a need for analytical comparability for [PoC] manufacturing processes in order to be able to … show that the same product is being made at all sites," Kimberly Schultz, director of Division Two, Office of Gene Therapy at the FDA, said. She added that, at the moment, the FDA is evaluating each submission on a case-by-case basis.

At the end of last year, the FDA issued a draft guidance aimed at supporting drug developers bringing novel cell and gene therapies to market. Those guidelines included nonbinding recommendations for potency testing, aimed at ensuring that each dose of a bespoke cell and gene therapy is reliably and consistently produced and works as intended. As each dose of these emerging therapies is customized for an individual patient, it can differ in important ways from a dose made for another patient.

The FDA also issued an updated draft guidance last year on assay comparability, which Schultz said is "geared towards manufacturing," but otherwise continues to gather data and comments.

The agency's Center for Drug Evaluation and Research further launched the Framework for Regulatory Advanced Manufacturing Evaluation (FRAME) initiative last year as part of its effort to establish such a regulatory framework to support the adoption of "advanced manufacturing technologies."

FRAME covers a variety of these technologies, including continuous manufacturing, distributed manufacturing, and artificial intelligence, while serving as a way for the FDA to gather input from stakeholders on how to best understand how emerging technologies might fit into a regulatory framework. It also, Schultz said, provides a template for seeking regulatory convergence with international regulators.

Schultz said that while the agency is looking into various distributed manufacturing and testing models, it still envisions a role for a centralized form of oversight to ensure quality control across a manufacturing network.

The big question, Schultz said, is what expectations to hold someone to when evaluating different manufacturing strategies.

"What would the testing look like? How does that compare to normal expectations for manufacturing of a biological product? We're trying to figure out, as a community, how and if this fits into the regulatory framework," she said.

During the panel session at ASGCT, stakeholders from around the field noted the pros and cons of the centralized and point-of-care manufacturing models, particularly how they relate to regulatory requirements. Cell and gene therapy makers have been calling for more concrete guidance on approval criteria, as regulatory pathways to approval can be unclear at present.

"Point-of-care manufacturing is significantly more economical," said Rimas Orentas, scientific director and cofounder of nonprofit Caring Cross and one of the session panelists.

Drawbacks to the centralized manufacturing model, he continued, include complex logistics such as coordinating sample transfer between companies, hospitals, and third-party logistics providers, the expenses involved in establishing a central manufacturing facility, and the number of personnel needed to manufacture the product and to maintain the chain of custody.

"Each company has to establish its own way of maintaining that centralized manufacturing flow and its own facilities," he added, "and that price goes back into the price of the product."

Caring Cross has been actively developing PoC CAR T-cell therapy manufacturing strategies and technologies aimed at making CAR T-cell therapy affordable for low-to-middle income countries. Earlier this year, it rolled out a system of mobile manufacturing units in Brazil as part of a collaboration with Fundação Oswaldo Cruz, a biological research and development foundation associated with Brazil's Ministry of Health.

Therese Choquette, another panelist and head of analytical and translational sciences at Switzerland-based Tigen Pharma, said that automation will be needed to adopt PoC models. A large, centralized lab, she said, benefits from high-throughput instrumentations with a skilled workforce comprising specialists in different types of methods.

"This does not work [in] decentralized manufacturing," she said. "We cannot place a big flow cytometer for half a million dollars at each manufacturing site. So we need to change the instrumentation. We need low-throughput instrumentation, and these need to be benchtop-sized [and] automated."

Choquette stressed that technological development will play an important role in the transition to distributed models, as companies sometimes struggle to meet CAR T-cell demands, even with current automation capabilities.

Choquette said that Tigen plans to adopt a more distributed manufacturing approach in the future but is still evaluating its options for how to do so.

The FDA's Schultz noted that a key issue with PoC manufacturing, particularly with respect to cell therapies, is maintaining consistency when using fresh samples obtained from patients.

"Fresh product means that you have an extremely short timeline to do your release testing," Schultz said, referring to the testing that ensures product purity and safety. This, she noted, places a premium on developing replicable and rapid analytical methods.

Cell and gene therapy delivery system maker Lupagen has come up with a potential solution to that obstacle that its cofounder and CSO, David Peritt, another session speaker, said "enables us to have our cake and eat it, too."

The Dallas-based company has created a bedside device that it calls an "extracorporeal lymph node," which draws cells out of a patient and incubates them with a lentiviral vector for about 15 minutes, after which the cells are washed and returned to the patient.

"It's literally just a binding chamber," Peritt said.

The advantages of this relatively simple system, he explained, are that it facilitates a high transduction efficiency while enabling a provider to "steal" a portion of the sample before it goes back into the patient. This sample can then be incubated and all needed assays performed.

Critically, Peritt said that this enables researchers to mitigate some of the analytic challenges that come with the sometimes "huge" patient-to-patient variability that can naturally occur.

Schultz said that the FDA is sensitive to the complexity of trying to regulate PoC cell and gene therapy manufacturing and is trying to engage with as many stakeholders as possible before issuing any guidance.

"There are so many moving parts to the [PoC] manufacturing space, and we want to avoid being like a freight train barreling through," she said.