Novel cell and cell-based therapies require stringent manufacturing, testing, and oversight to ensure integrity, function, and above all else, patient safety upon administration. Tissue-derived cellular products are considered to be manufactured products and are regulated as such. Thus, you must ensure that your cell manufacturing process is aligned to current Good Manufacturing Practice requirements. (Note the “current”. This means that these are evolving requirements, so you must stay up-to-date!) In the United States, human cells, tissue and cellular- and tissue-based products (HCT/Ps) are regulated by the Center for Biologics Evaluation and Research (CBER), a division of the U.S. Food and Drug Administration (FDA).
When manufacturing cell and cell-based products, a production facility under strict Quality Control must be used. Ideally, this facility includes the cell manufacturing suites, the storage space for raw and finished product and any laboratory/testing areas. Thus, (1) facility design, access, and maintenance, (2) equipment purchase, installation and operational qualification (I/OQ), use and maintenance and (3) raw material specifications, purchase, use, and storage must all be carefully controlled. For cell and cell-based therapies, terminal sterilization of the final product is often not possible. As such, quality by design (QbD) is highly important in cell therapy, with stringent testing conducted on the tissue Donor (our next blog post in this series will cover this topic) to preclude the risk of contamination at the source. In addition, facility and equipment standards and monitoring must be instituted to ensure the aseptic processing of cell and cell-based products. To this end, closed systems and single-use disposables should be used whenever possible to minimize the risk of contamination. Therefore, a cGMP manufacturing facility must include clean rooms which control for temperature, humidity, pressure and air particulates, preventing any contamination of manufactured products due to the environment, materials, human handlers and cross-contamination from other products manufactured in the same facility. As such, there should be a uni-directional flow of materials and people through these areas and personnel must follow proper gowning procedures. Facilities and equipment requirements are defined under US FDA 21CFR§211 and 21CFR§1271.
Such Quality Systems entail everything from personnel training, to proper documentation of all aspects of your cell manufacturing process, to audits and qualification of vendors for reagents and raw materials, to release of the end product based on certain Critical Quality Attributes (CQAs) and standard testing procedures (STPs) for testing of your cell and cell-based products for these attributes. Quality Assurance must also track any deviations and quickly implement Corrective and Preventative Actions (CAPA) to rectify them and preclude their repetition. To this end, Quality Assurance works hand-in-hand with Operations and Manufacturing to ensure standardized, well-documented procedures are implemented, resulting in consistent, reproducible, safe end products. US FDA 21CFR§1271 Section 160 outlines the establishment and maintenance of a Quality Program. In addition, US FDA 21CFR§211 addresses Quality Control for cGMP manufacturing, and Section 22 specifically outlines the responsibilities of the Quality Control Unit.
The level of processing and manufacturing oversight that is needed for a cellular therapy depends on a number of factors including, but not limited to, the tissue source, the proliferation and differentiation potential of the cells, the type of manipulations performed as a part of your cell modification/manufacturing process, the intended use of the cells, the anticipated method of cell integration into recipient tissues and organs, the nature of the clinical trial and the number of patients who will be exposed to the cellular product. Thus, requirements for early-phase clinical trials may be vastly different, and less rigorous, than those for later phase clinical trials, and subsequently for commercialization. Understanding these processes and oversight needs at each clinical stage is critical to successfully moving through the clinical trial process towards rapid commercialization.