Michaela Doláková is chief microbiologist at SCTbio.

Michaela Doláková

3D Rendering of Molecular Interaction in CAR Chimeric Antigen Receptor | Image Credit: © Alpha Tauri 3D - stock.adobe.com

Cell and gene therapies are rapidly emerging as promising alternatives to treat patients with severe forms of cancer, particularly hematological malignancies, due to their targeted efficacy and high potency. These types of therapies are often referred to as advanced therapeutic medicinal products (ATMPs) and are gaining traction in the public arena as a result of FDA’s approval of chimeric antigen receptor (CAR) T-cell therapies. Six different CAR T-cell therapies are now approved by FDA for the treatment of certain types of lymphomas, some forms of leukemia (1), and most recently, multiple myeloma (2).

CAR T-cell therapies involve genetically engineering a patient’s own or a donors’ T-cells to target and destroy cancer cells. They are highly complex and potentially risky treatments that are showing clinical and commercial success where other available treatments have failed.

Due to the specialized nature of CAR T-cell therapy and the vulnerability of patients with compromised immune systems, sterility is essential for these treatments. As CAR T-cell products are made up of living cells, it is not possible to perform sterilization (e.g., sterile filtration) of the final product. Therefore, safe and effective CAR T-cell therapies rely on rigorous sterility testing to ensure patient safety and product quality.

Sterility testing of autologous cell therapies

In autologous cell therapies, such as CAR T-cells, sterility testing is an essential and critical step in the batch release process under the Code of Federal Regulations, Title 21, parts 210 and 211 for current good manufacturing practices (CGMP) for finished pharmaceuticals and parts 600 to 680 for additional biological product standards (3). Assurance of final product sterility also relies on procedural measures that effectively prevent contamination of biological materials, such as cleanroom technology and other GMP standards.

Rapid Sterility Methods for CAR T-cell Therapies

The compendial sterility test is recognized by the industry for its adherence to regulatory standards and for its reliability. Compendial testing involves direct inoculation of the CAR T-cell sample into two different media (4), for growth of aerobic and anaerobic microorganisms, followed by incubation at different temperatures. During incubation, visual examination of media is performed by checking turbidity. However, the final examination of the medium for evidence of microbial growth occurs after a 14-day incubation period. This extended lead-time can be challenging for patients in urgent need of treatment once the drug product is manufactured, particularly if the final formulation cannot be cryopreserved and has a short shelf-life. The limited amount of a sample, combined with the time sensitivity and critical need of severely sick patients, means a faster sterility method is required.

The development of more rapid sterility testing methods offers significant advantages. It can be beneficial for frozen CAR T-cell products, expediting the time from product manufacture to patient administration, which is crucial in the treatment of severely sick patients in the late stages of disease. To ensure the deployment of safe and effective therapies to patients, the industry needs to evaluate and promote effective rapid sterility methods.

When referring to this article, please cite it as Doláková, M.; Horková, V.; Sochorová, K.; Rožková, D. Rapid Sterility Methods for CAR T-cell Therapies. 

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A combination of rapid sterility methods with the industry standard compendial method should ensure maximum safety.