As medicine becomes more targeted, a growing number of approved therapies are designed for small subsets of patients or even for particular individuals. Such personalization is positive for patients. but it comes with a downside. As the number of precision medicines grows, so may the challenge of assuring quality; distinct medicines may require a different approach to quality standards.

For nearly two centuries, the US Pharmacopeia (USP) has monitored the quality of medicines in the US and the world. To address this continuing need for quality control, USP has been developing a number of ‘cross-cutting’ standards that can be broadly applied to distinctive medicines. These standards, which are based on common or overlapping manufacturing or quality testing processes, could simplify quality assurance even between different precision medicines, while also accelerating the release of new products to the market. 

“The standards cover a class of treatment options rather than focusing on a single product,” explains Fouad Atouf, who oversees standard-setting for cell- and tissue-derived pharmaceutical as Vice President of Science for Global Biologics at USP. “And they don’t just cover testing of a product during quality control or release, but can be used any time during the life cycle of the development of a product.”

Atouf points to therapies based on hematopoietic stem cell transplantation (HSCT). The approach entails the delivery of progenitor blood cells to help replenish a weakened or malfunctioning immune system. It has been used for decades to treat patients undergoing chemotherapy and radiotherapy for cancer. Lately, researchers are considering it as a treatment for autoimmune disorders, such as multiple sclerosis.

 Fouad Atouf, Vice President of Science for Global Biologics at USP. Credit: USP

In preparation for the procedure, stem cells are harvested from a variety of sources including the patient’s own bone marrow, cord blood, and peripheral blood prior to treatment or from genetically matched donors. Regardless of the source, clinicians need an accurate count of the number of viable stem cells present in a graft in order to ensure that they are administering the proper dose.

To devise a robust and reproducible cell-counting strategy, USP leveraged research by scientists who identified a consistent feature of the stem cells that would distinguish them from other blood or marrow cell types. “The key element is this protein biomarker called CD34, which allows you to identify stem cells,” Atouf explains. The USP team validated through a multi-laboratory study, a standardized CD34 measurement assay based on flow cytometry, a technology that can rapidly count individual cells based on the presence or absence of specific cell-surface markers. 

In parallel, the USP researchers also made available a reference standard comprising a mixture of cells with a pre-defined subpopulation of CD34-positive cells, which can be used to calibrate the flow cytometry instrument and ensure accurate quantitation. “Before you even count the stem cells, you want to make sure your instrument is actually able to measure correctly,” Atouf says. “For a clinical lab or a QC lab that is running lots of tests, once your instrument is calibrated, you can remain confident through the day or the week.”

This standard has proven broadly useful for HSCT, particularly as a growing number of biotechnology companies have begun to explore the commercial development of ‘off-the-shelf’ stem cell products. However, Atouf also sees lots of other potential applications for this CD34 standard as new advances in the cell and gene therapy world continue to make their way into the clinic.

“People are using viral vectors to transduce stem cells and introduce genes of interest,” he says. “If you have a standard like this one, you can count your blood cell preparation and get some understanding of the efficiency of transduction.” For example, this could be useful in the context of producing chimeric antigen receptor (CAR) T-cells, genetically engineered immune cells that have proven to be a potent weapon against a variety of blood cancers. 

Atouf notes that USP has also devised cross-cutting standards for other blood-derived products. Numerous therapies currently exploit proteins that have been isolated from human serum. For example, the protein albumin is used to help boost blood volume in patients who have been serious injured, while preparations of donor-derived immune globulin are delivered as an intravenous infusion to help fend off infection in immune-compromised patients. However, the process of harvesting these therapeutically useful molecules from donor blood can yield preparations contaminated with another, potentially dangerous blood protein known as pre-kallikrein activator. 

This protein stimulates production of a signaling protein called kallikrein, which can in turn initiate a chain reaction of physiological effects in unsuspecting patients. “If you have residual levels above the acceptable limit, that can lead to vasodilation and a drop in blood pressure,” Atouf explains. “Without good control of the levels of kallikrein, you may be putting patients at risk.” To address this, the USP has developed a broadly applicable assay for quantifying pre-kallikrein activator levels in albumin, immune globulin, or virtually any other human serum-derived product.

The number of such cross-cutting standards for biologic therapies is still relatively small, but Atouf sees abundant opportunities for their development. No matter how individualized therapeutic regimens may become, there will inevitably be at least some overlap in the manufacturing processes used to produce them. “These types of broadly cross-cutting standards allow you to focus on the analytical challenges beyond the product itself,” he says. “These are standards that allow you to confirm that your process or method works the way you want it to work.”