Advanced Therapy Medicinal Products

In contrast to simple biologics such as monoclonal antibodies, cell therapies typically have several mechanisms of action (MOAs) that link to the intended therapeutic effect. It is not always straightforward to understand what each of these may be due to the complex nature of interactions with other cell types and the complex biological environments such therapies are exposed to once introduced into a patient.

It is not essential that the potency assay demonstrates the product's MOA but rather that it reduces risk by detecting problems with potency-related critical quality attributes (CQAs) thought to be important for the MOA and its clinical efficacy. It is therefore even more important to begin assay development for cellular therapies at an early stage and that multiple assays are developed to attempt to fully characterize the product. Assays that measure biological activity can be challenging to develop and so the earlier data can be accumulated enhances product understanding and its potency-related CQAs. Such a matrix approach can be very informative and used for sound scientific selection of the most appropriate bioassay(s) for use in QC lot release.

We also highly recommend that clients work closely with regulatory authorities to communicate potential plans for their intended potency assay(s) to provide for an informed approach.

In cases where cell therapies are produced through genetic modification, such as chimeric antigen receptor (CAR) immune cells, vector quality is critical for quality of the final product.
 

Vector safety testing should be implemented to prevent potential contamination of the final cell product and vector copy number should be maintained within defined limits. Other QC lot release assays for vectors should include purity and biological activity, as data informing on strength of the vector is important for achieving the target percentage of the final cell product. Vectors should also be tested for stability if they will be stored for prolonged periods and used for modification of multiple cell batches. 

Cellular products are often produced using a starting material that contains other unwanted cell populations. While manufacturing procedures need to be adequately developed and controlled to produce the final product from a good quality starting material, QC lot release should also be implemented for contaminating cell types and/or cellular debris in the final product.

Flow cytometry is a powerful technique that can be applied to measure surface markers related to both the product and contaminating cell types. It is also used for assessing product viability, a critical potency-related measurement.

 In addition to the cellular product, the final drug product may include other active ingredients intended to enhance or produce the intended clinical effect. Lot release testing must demonstrate the concentration or potency of each of the additional ingredients. If the lot release bioassay cannot demonstrate this then additional analytical procedures must be put in place. 

Traditional safety testing is often not appropriate for many cell therapy products, as time to execute and obtain results are prohibitive.

While allogeneic cell therapies, expanded and banked for cryostorage, may be tested using such conventional analytical methods, autologous cell therapies, developed from the individual patient’s’ own cells, are of limited batch size and have a very short shelf life.

A more rapid risk-based approach to safety testing may be required such as those employing PCR-based techniques.