New cell and gene therapies are rapidly being translated into the clinic. The potential for these new therapies is driving the industry to develop safe and reproducible cell culture systems. Increasingly, this has meant including the development of a unique, chemically defined (CD) and animal component free (ACF) medium as a standard part of the cell and gene therapy development process.
A few basic definitions are important to help navigate a market where defined media are becoming more and more common:
- A CD, or synthetic medium, is a cell growth medium with a known chemical composition.
- Xeno-free or Xenogeneic-free medium is a growth medium free of components from species other than the native species you are working with. In cell and gene therapies, for example, this typically means only human-derived components can be used with human cell lines.
- ACF medium does not contain any human (e.g. cytokines and growth factors) or animal components (e.g. serum).
Safety is the main driver for the increasing focus on ACF media. The risk of introducing pathogenic agents (like prions) through animal components is of great concern in the development of clinical-grade therapies. Using ACF medium is by no means an absolute requirement for cell and gene therapies. However, products that are developed using animal components will face greater regulatory hurdles. Further, animal components are undesirable for clinical and commercial processes because of the potential to cause supply chain issues. Developers who rely on media containing animal components must ensure they have multiple suppliers to deal with shortages.
CD media are advantageous because they can increase efficiency and reduce costs. Along with the proprietary advantage to knowing every component of your medium, a defined medium will improve reproducibility and allow for a more accurate prediction of the product yield from a particular process. Increasing reproducibility is critically important for successful process scale-up. In the basic science laboratory, variability of 10-15% in the output of a cell culture protocol may not have a significant effect; however, at the clinical and commercial scale this level of variability could have a tremendous impact. Additionally, CD media can be optimized to reduce process costs by selectively minimizing the use of expensive components.
Custom media development requires specialized expertise and equipment. Outsourcing to a contract development manufacturing organization (CDMO) is often the best option for therapy developers. Most CDMOs use a bottom-up approach that involves screening combinations of known media, mixed at different ratios, to determine which mixture supports the best cell growth. Once an optimized medium has been selected, additional supplements are identified using information in the literature.
CCRM has pioneered a discovery-based, top-down approach for media development that integrates mass spectrometry analysis, high-throughput cell culture screening enabled by a liquid handling robot, validation, and scale-up. Our one-of-a-kind, fully automated approach will deliver media that are tailored to the cell or gene therapy of interest. A key advantage is our in-house validation and scale-up capabilities, which allow for significant cost savings and streamlining of the development process.
We are continually advancing our media development capabilities. We have optimized our approach using adherent cells, single cells in suspension, and cellular aggregates. We are now able to screen thousands of small-scale cell cultures in parallel, both for cell growth and phenotype, using a flow cytometry-based high-throughput method. Future work will focus on adapting our approach to media optimization for virus production by incorporating ddPCR-based screening assays.
From our experience working with clinical-stage clients, we have learned that the most successful development programs begin with media optimization. Early consideration of this aspect of your product is critical to prevent delays and streamline the downstream regulatory processes. We believe it is never too soon to start thinking about custom media development.