FDA Advise on Risk Assessment for Manufacturing Changes for HCT Products
(Friday, July 14, 2023)
Some manufacturing changes could affect the biological properties of human cellular and tissue-based products (HCTPs) to an extent that may require a new IND or a BLA supplement. Unlike drug products, HCTPs are manufactured with limited information on several key aspects of process and product characterization lending them to higher risk when changes are made. FDA’s latest guidance addresses key concerns with changes to the manufacturing processes for HCTPs.
Changes are an important part of manufacturing regulated products. A manufacturer may want to make changes to a manufacturing process for a variety of reasons, including improving product quality, expanding product supply, or improving manufacturing efficiency. Each change requires risk assessment for its impact on product quality, stability, and potency. Manufacturers are required to prospectively assess the risk of each change and take appropriate measures to address each risk issue. It is harder to do that for HCTPs (regulated as Cellular and Gene Therapy (CGT) products) which are characterized by limited knowledge of product quality attributes, complex manufacturing processes, and other issues. While these issues are acceptable for product release, any changes to the manufacturing process are more challenging than for other biological products.
FDA’s new guidance discusses risk management for manufacturing changes for CGT or HCT products list specific issues that must lead to major regulatory interactions. The main concern is that a proposed change to improve product quality, manufacturing efficiency, or product effectiveness and/or safety, may make the pre- and post-change products different and, therefore, not comparable.
FDA strongly recommends prospective risk assessment which includes analytical comparison and may require non-clinical and even clinical comparability studies. Certain changes such as changing the starting material, changes to final product characteristics, changes to scaffold or matrix or excipients, and changes to the manufacturing steps or components most likely would require a new IND for products in clinical trials, and supplements to the products marketed under BLAs. The guidance is silent on products that are marketed without an IND/BLA, the classical HCTPs, but it would be safe to assume that these recommendations apply to those products as well without the added requirement to report to the FDA.
Dr. Mukesh Kumar
Founder & CEO, FDAMap
Linkedin: Mukesh Kumar, PhD, RAC