Media vs. Cell-line Engineering
Experts still dispute whether cell line engineering or culture medium are predominantly responsible for the dramatic improvement in protein titers. One can find experts on both sides of the issue. Dr. Burrier believes both factors contribute and that coupling media technologies with cell line development provides the best chance of arriving at a super-productive culture. He stresses the importance of a high-titer clone as a starting point from which the benefits of process optimization, including media work, increase productivity.
Dr. Burrier agrees that media becomes the productivity opportunity but only if cells are already programmed to produce protein in the 1–2 g/L range. At this point two- to fivefold productivity gains become a media and process optimization exercise.
“If you start with a cell line producing only 100 milligrams per liter, there is no way you’re getting up to one to five grams per liter simply by optimizing the media and process. Companies first need to utilize technologies for cell line improvement, then concentrate on the media,” Dr. Burrier explains.
Bruce Lehr, director of marketing at SAFC Biosciences (www.safcbiosciences.com), similarly believes that media, while important, pales next to cell-line engineering as a productivity exercise. “There certainly is interplay between cell engineering and media, and if you can match those activities earlier, there is a real potential to obtain productivity gains more easily.”
To Lehr, however, the gradual replacement of animal-derived components (ADCs) in cell cultures has been the most significant trend over the past year.
Biomanufacturers continue to demand not just ADC-free media, particularly for new processes, but are specifying that such media be manufactured in an ADC-free production environment. HyClone, for example, maintains manufacturing suites for liquid and powder products that have never seen animal components, in addition to conventional media formulation suites for formulations that require animal-derived ingredients.
Moreover bioprocessors are beginning to avoid, whenever possible, all nondefined or undefined components like soy or wheat hydrosylates and yeastolates (yeast hydrolysates).
Many established processes still employ serum-based media, however. “Biomanufacturers are not going back and redoing old processes with defined media,” Lehr notes. “Most work on defined media takes place during process development and early clinical trials.”
Best-in-class biomanufacturers are also increasingly relying on media platforms to standardize production in preferred cell lines, while boosting productivity during individual cell cultures through feed additives. Top companies increasingly look to media suppliers for supply chain management, raw material characterization, sourcing, risk management, and compliance.
“Companies are increasingly willing to outsource these noncore activities,” Lehr comments. The trend toward outsourcing creates opportunities for media suppliers, “and not just for supplying media.”
SAFC Biosciences provides the full spectrum of media products and services, from front-end cell line cloning, medium and feed development, optimization, process scale-up, manufacturability, and manufacturing-scale media and supplement supply, according to Lehr. The company has also entered the downstream processing marketplace through its Bioease™ line of biodisposables, and with liquid and powder buffers for purification processes. “With increases in upstream productivity, downstream opportunities continue to arise,” says Lehr.
Although about 90% of SAFC’s media sales are of the customized variety, developers often begin with off-the-shelf media and work with the company on modifications, eventually arriving at a production-worthy medium.
Powdered media has become the norm for large processes. “Generally people switch from liquid to powder as processes grow,” says Tom Fletcher, director of technology at Irvine Scientific (www.irvinesci.com). Irvine sells animal-derived-component-free media, primarily for CHO cell cultures. The company’s business nearly doubled last year, with much of that growth coming from European and Asian markets.
Like many media suppliers, Irvine is not just a media vendor, but a provider of custom media and feeding strategy services. The company sells mostly custom media, although many customers still demand off-the-shelf basal or classical media.
In development-services mode, Irvine works with customers’ cells at its facility or may collaborate remotely by sending test batches of media to customers and tweaking the formulation based on experimental results. “We’re very flexible in that regard,” says Fletcher.
The company recently expanded powder manufacturing to keep up with demand for custom media, which according to Fletcher has nearly doubled during the past year. The upgrade includes continuous milling technology, acquired more than a year ago but just recently validated. Irvine reports that it can now supply powdered media in quantities from 1 kg to 5,000 kg. It has also opened a cell culture, media-development, and prototype-production facility in Tokyo.