In January, the FDA published, “Considerations for the Development of Chimeric Antigen Receptor (CAR) T Cell Products: Guidance for Industry.” To find out how this guidance impacts the CAR-T industry, GEN talked with Klara Sochorová, PhD, senior quality compliance manager at SCTbio, which is a contract development and manufacturing organization (CDMO) based in Prague.

“If you look at the whole guidance, it provides a comprehensive overview of the entire development,” Sochorová says. For SCTbio, “the critical aspect mainly relies on chemistry, manufacturing, and control—CMC,” she notes.

“The substantial part is related to change management and comparability studies,” Sochorová adds. In submitting a new investigational new drug (IND), for example, the guidance highlights the importance of risk assessment—considering the safety and quality of the product. Sochorová mentions that “within such risk assessment, future actions such as comparability studies or analytical-method revalidation can be found as necessary steps prior to implementing changes.” Due to the complexity of these products and the wide spectrum of possible changes, the chapter only provides some general concepts and detailed instructions for comparability studies cannot be found there. Sochorová adds that SCTbio is used to support sponsors in comparability-study design as well as risk assessment of changes.

On the other hand, Sochorová points out that this guidance includes parts—for example, flow cytometry—where many details are available. For instance, the FDA guidance states that an initial IND submission should include: “A description of the assay, including the flow cytometry antibody panel and the gating strategy used to define each cell population detected” and that “live/dead strain should be included in the flow cytometry panel.” Although Sochorová emphasizes that SCTbio is very familiar with defining the details of flow cytometry used in the development and manufacturing of CAR-T therapies, she adds that the FDA’s guidance “helps a sponsor in articulating information in a manner that is comprehensible to the FDA.”

The other topics relating to flow cytometry focus on ensuring that the equipment and procedures perform properly. This assurance should include calibration and the quality control (QC) process used with a specific flow cytometer or the use of assay controls, she adds.

For the manufacturer of a viral vector used in the production of a CAR-T therapy, Sochorová highlights a sentence from the FDA’s guidance related to a biologics license application (BLA): “During CAR-T cell BLA review, vector manufacturing facilities are subject to inspection.” This emphasizes the importance of maintaining a rigorous quality system and adhering to good manufacturing practices (GMP). However, for a CDMO lacking such a quality system, an FDA site visit could potentially delay the BLA review process. Previous experience with regulatory agency inspections is clearly advantageous.

The FDA’s 36-page document covers a wide range of topics. Some of the other elements that Sochorová mentions are guidance on autologous versus allogeneic CAR-T therapies and single versus multi-site manufacturing. For the latter, she says, “Acquiring consistent products across multiple sites presents a significant challenge.” Despite the challenge, the sponsor of a CAR-T therapy faces the task of ensuring consistent performance across all of its production sites.

Overall, in her assessment, Sochorová observes that the CMC part of the FDA’s guidance does not yield “many unexpected insights.” However, she anticipates that it will provide “substantial clarification,” mainly to preclinical and early-stage cell therapy developers.

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