Clone of What are ATMPs and Why Have They Become a Key Topic of Interest in the Pharmaceutical Industry?
What are ATMPS and Why Have They Become a Key Topic of Interest in the Pharmaceutical Industry?
Advanced therapy medicinal products (ATMPs) are medicines for human use based on genes, cells or tissue engineering. In the United States of America, we often refer to this category of products as Cell and Gene therapy (CGT) products.
The most prominent technology represented in the ATMP or cell and gene product category are CAR T cells. The field of cellular immunotherapy emerged in 2012 when a young girl named Emily Whitehead, diagnosed with Acute Lymphoblastic Leukemia when she was 5 years old, received the first CAR T cell therapy after all other treatment options had been exhausted. CAR T cell therapy saved her life.
The work was led by professors Carl June, David Porter and Stephane Grupp at the University of Pennsylvania. They then published their impressive results in the New England Journal of Medicine in 2017, reporting Phase 1 clinical trial data from 111 patients treated with an autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy, where the objective response rate was 82%, and the complete response rate was 54%. This was remarkable when compared to the results obtained with regular cancer therapies.
WHAT ARE THE MAIN CHALLENGES FOR THE MANUFACTURERS OF SUCH TYPES OF PRODUCTS?
The most common way ATMP products are manufactured involves taking a blood sample from a patient to source the T-cells that are then transformed, in order to make them express a chimeric antigen receptor specific for the cancer antigen. Then the transformed cells are expanded and concentrated. After appropriate Quality Control, to assure patient safety and optimal therapeutic effectiveness, the cells are shipped to hospitals and re-infused into the patient from whom the blood sample originally came. So, we are talking of autologous therapy. All the current commercial products are autologous products. We consider here that the product is the “manufacturing process” to make these ATMP products.
WHAT ARE THE MAIN MICROBIAL RISKS OF THIS PROCESS AND HOW ARE THE PRODUCTS CONTROLED?
The manufacturing of CAR T cells and any other cellular product is considered to be an aseptic process. As cells are biological materials and living products they cannot be sterilized like traditional pharmaceuticals made from small molecules. Microbial control is crucial to avoid any potential contamination that may jeopardize the availability of the product to the patient, bearing in mind, most of the time this could be a patient’s last option for treatment. Another critical attribute of CAR T cells is their short shelf life. Traditional sterility testing according to the harmonized pharmacopeias and taking 14 days to complete cannot be afforded. So, the use of alternative and rapid microbiological methods makes more sense. Currently, automated growth-based methods like the BACTALERT® automated microbial detection system are extensively used by the pharmaceutical industry to make sterility test results available after 5 to 7 days of incubation. However, there is a great need for a technology that allows product release within 24 hours. bioMérieux is investing in this particular area of development.
Two other important quality controls that are mandatory for ATMPs, are the tests for Mycoplasma and endotoxins. There are in the market molecular testing methods like the BIOFIRE® Mycoplasma that produces results in one hour, and new technologies that are environmentally friendly like the use of recombinant Factor C (rFC) for the detection of endotoxins. Furthermore, the microbial control of manufacturing environments is amongst the strategies to have manufacturing areas in control and decrease the risk of contamination.
HOW DO YOU SEE THE EVOLUTION OF THESE PRODUCTS?
Something that is clear, in relation to CAR T cell therapies, is their enormous benefit to patients’ health and well-being. Impacts in health economics are still under evaluation but we can anticipate that it will be extremely positive, as these products are “curative therapies”! Current development activities are carried out by biotech start-ups and established pharmaceutical companies seen through many clinical trials and massive investments in this field. These are strong signs of future changes in the way cancer is effectively treated, but not only, because many other applications like tissue engineering, cells embedded in biodegradables scaffolds and use of somatic cell are also investigated. Improvements in current manufacturing processes, and the adoption of new analytical methods and new process control technologies, will pave the way to make these new products available to everybody that needs them.
SOLUTIONS
bioMérieux has a wide range of solutions potentially suitable for ATMP manufacturers’ needs:
BACTALERT® 3D DUAL T used for sterility testing, as well as raw material and process control
SCANRDI® used for bioburden testing of process water and solutions
3P® for environmental control of manufacturing areas
BIOFIRE® Mycoplasma testing of in process and finished products
ENDONEXT® tests of endotoxins in raw material and finished products
DOCUMENTARY SOURCES
CAR-T Cells: A Systematic Review and Mixed Methods Analysis of the Clinical Trial Landscape
David Pettitt, Zeeshaan Arshad, James Smith, Tijana Stanic, Georg Holländer, and David Brindley
Molecular Therapy Vol. 26 No 2 February 2018
Global Manufacturing of CAR T Cell Therapy
Bruce L. Levine, James Miskin, Keith Wonnacott, and Christopher Keir
Molecular Therapy: Methods & Clinical Development Vol. 4 March 2017
CAR T cell immunotherapy for human cancer
Carl H. June, Roddy S. O’Connor, Omkar U. Kawalekar, Saba Ghassemi, Michael C. Milone
Science 359, 1361–1365 (2018)
https://www.nytimes.com/2019/09/11/health/immunotherapy-heart-failure.html
