The biotech industry has experienced consolidation over the last several years, says Bruce Lehr, director of global marketing at SAFC Biosciences. “A smaller number of large companies are emerging as major players, and within those the tendency is to develop their own cell-line production platforms and the media and feed as well.”
In the past, media companies were more involved in the design of client-specific media development and enjoyed a robust business from smaller biotech companies. Today, companies with promising late-stage products are being rapidly acquired by larger pharmaceutical or biotech firms that tend to perform their own media development. Vendors like SAFC assist in media development wherever they can but are increasingly being called upon to manufacture media and feeds that companies develop on their own.
Development-stage companies that for financial or logistics reasons cannot invest in costly and complex media development still outsource these activities, reports Lydersen. “The methodology used to optimize both the basal media formulas and the concentrated solutions used in fed-batch fermentation processes is evolving rapidly,” with increased emphasis on robotics (for generating large numbers of samples) and metabolomics to determine rate-limiting metabolic pathways within the cells. “But in addition to these emerging technologies, media optimization still relies on scientific insight and practical experience to optimize media for specific clones.”
Once a medium is developed, vendors are called upon to assess manufacturability, to eliminate animal-derived components, and, whenever possible, to substitute chemically defined ingredients or whole media for animal-derived components and plant hydrolysates. Chemically defined media do not attempt to duplicate all the ingredients of media derived from animal products, yeast, or plants. Instead, they are based only on the ingredients that are confirmed active and essential to cell growth or productivity. “The idea is to deliver a consistent product each time,” Lehr says.
With all the buzz over animal-free components it becomes easy to forget traditional media. Academic and government researchers still use classical culture media, so media suppliers need to provide products that meet these needs as well.
Media specialty firms are, in addition, expected to solidify the media/feed supply chain, help customers source raw materials, provide traceability, and conduct additional analytical or biological testing to assure that the materials are fit-for-purpose in their intended application.
Last year, SAFC introduced CD Fusion Hydrolysate, which directly replaces plant and yeast hydrolysates in many CHO-cell applications. CD Fusion Hydrolysate has been enthusiastically received by industry, according to Lehr, and several customers are qualifying the media for late-stage manufacturing.
Another product, CHO CD fusion medium, is a complete, chemically defined medium for growing CHO cells for use in therapeutic production while maintaining cell growth and productivity.
Nature vs. Nurture
The question of nature vs. nurture in cell culture—the relative dominance of cell-line development and media/feed strategies—has proponents on each side of the argument, but most experts are somewhere in the middle. Carrier sees nature vs. nurture as a false tradeoff. Increasingly, developers view the two activities as complimentary and interdependent.
“Molecular tools have been touted as the principal drivers of high titers, but cell optimization cannot deliver on its promise if it is not matched with an appropriate host cell line or the right media,” Carrier says. The interplay of cell optimization and growth environment is an iterative process, which moreover needs to be exploited earlier in development.
“Nurture has traditionally been a later-stage activity, but we now know it must be adopted earlier in process development to achieve all the benefits of molecular biology. Every process today that boasts productivity of five to ten grams per liter has undergone multiple iterations of nature and nurture, and achieved its high productivity in stepwise fashion,” Carrier adds.
The interdependence of media and cell-line development, and the complexity of achieving the highest possible productivity, are recurring themes in the nature vs. nurture debate. Thermo Fisher Scientific, for example, uses metabolomics data to drive the development of media and feed supplements. If one were to categorize the company’s predilection, it would probably be more nurture.
“Our clients are aware of the advantages of selecting the right clone, but they do not spend a lot of time finding the perfect clone,” notes Pence. Advances on the nurture side, he adds, can make up for less than perfection in a cell’s innate productivity. “Drug developers are more concerned with getting a cell line that folds the protein of interest properly. They often take three to five such clones and move them along their evaluation and optimization process rather than dragging out cell selection.”