January 15, 2010 (Vol. 30, No. 2)

Angelo DePalma Ph.D. Writer GEN

Vendors Are Adapting Their Product Offerings as well as Production and Distribution Strategies

As cell culture goes, so goes biomanufacturing. The slow, downward evolution in manufacturing scale, while at some level lessening demand for cell culture media, nevertheless creates opportunities for more specialized media products and services.

Several factors are responsible for the shift from mega-cultures to more manageable production batches. Most prominent are ongoing improvements in protein titers for CHO and other cell lines, advances in personalized medicine and cell-based therapies, the emergence of nonantibody protein drugs and biosimilars, and vaccine development.

“As a result of interest in personalized medicine and titer improvements, vendors must fill the need for smaller volumes of media in disposable formats,” says Laurie Donahue-Hjelle, Ph.D., director of cell culture product development at Life Technologies. Personalization of biotherapies creates opportunities, she says, to test products for multiple indications.

The one-drug-fits-all model, of which blockbuster drugs are one manifestation, may be fading. Under this scenario multiple products, manufactured in smaller batches, will replace one or two big sellers for leading indications. Every such product will require smaller quantities of highly specialized media.

The emergence of nonmonoclonal antibody products (e.g., blood factors, replacement enzymes) is another factor contributing to bioprocesses shrinking in size. MAbs are typically high-dose drugs produced in large batches. The manufacture of lower-dose replacement proteins, cytokines, and enzymes, for example, is expected to take less production volume.

Cell-based therapies, another facet of personalized medicine, will require media that support the growth of human stem, progenitor, and primary cells used in human therapy. Media for primary cells differs from CHO media in the supplements and the required attachment substrates, although many of the processing lessons learned in protein therapeutics can be directly applied.

Biosimilars are still nowhere near as important as generic small molecule drugs, but Dr. Donahue-Hjelle and colleague Trent Carrier, Ph.D., believe that the eventual success of generic biopharmaceuticals will further change the types and quantities of cell culture media customers demand. “Supporting customers in these emerging markets is a new area for cell culture media companies,” Dr. Carrier says. “These new business models are no longer based on 20,000-liter processes. Media companies have to figure out how to manufacture, inventory, and manage the delivery logistics to support these new models and their novel dynamics and usage trends.”

Meeting the changing demands for cell culture media will require vendors to adapt and modify not just their product offerings, but the approach to producing and distributing media and nutrients.

To better integrate molecular and cell culture needs, Life Technologies is creating a series of kits that combine vectors, GMP-banked host cells, and cell culture media into streamlined workflows for biotherapeutic developers. The first of these kits, the OptiCHO™ Protein Express Kit, was launched earlier this year. Offerings in 2010 include a kit, based on Invitrogen’s CHO-S cell line, that will link transient expression and stable cell-line workflows together.

Concern over the H1N1 influenza strain has led to fears of border closings and large pockets of humanity being cut off from life-saving vaccines. Thankfully that situation has not materialized, but it has spurred interest in local or regional small-scale vaccine manufacture, and with it the need for platform media that is easily created and shipped to distant production sites.

Thermo Fisher Scientific has been active in this area, developing media products optimized for production at 1,000–2,000 L volumes. “We have been building out our infrastructure around the world, and now have field-based experts who can go onsite to demonstrate how media products can be used and to support setup of these processes,” says Brandon Pence, associate director of market management.

Related to the “agile vaccine” idea is the trend toward ready-to-use products, says Ken Lydersen, CSO at Irvine Scientific. “This creates opportunities for suppliers to provide value-added products and services like cell-line and media optimization.”

Irvine, which currently produces more than 1,000 tons per year of powdered media, will double its capacity with the addition of a second cGMP manufacturing site in Tokyo. The plant is expected to come online early in 2011. The company specializes in rapid turnaround of prototype media formulas through its Express Media Service, reports Lydersen.


Irvine Scientific says that it specializes in rapid turnaround of prototype media formulas through its Express Media Service.

Industry Consolidation

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. 


Companies like SAFC Biosciences are developing their own cell-line production platforms and media and feed as well.

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.”

Sidebar: Using PER.C6 and XD to Increase Volumetric Productivity

According to Crucell, PER.C6® cells are becoming a popular platform for vaccine and recombinant protein manufacture due to the cells’ extremely high productivity, excellent safety record, scalability, and robust performance under high-shear conditions in serum-free media.

Percivia, a joint venture between Crucell and DSM Biologics, works extensively to develop platform technologies using PER.C6, particularly with XD™, an approach to cell culture that reportedly achieves volumetric productivity approaching 30 g/L.

What’s significant about this combination of cells and bioreactor technology is that it uses off-the-shelf media with minimal tweaking. “We really don’t do much in the way of media optimization,” says John H. Chon, Ph.D., director upstream process development at Percivia. “The media you use for your seed train works fine.”

Dr. Chon has instituted one major media improvement: using more concentrated media—about twice the standard concentrations—that is possible because XD is a highly efficient perfusion process and PER.C6 cells tolerate extremely high cell densities and concentrations of nutrients and recombinant mAb products, he says.

As a proponent of PER.C6, Dr. Chon is partial toward innate cell productivity compared with media development as the principal driver of cell culture productivity but recognizes that both are factors. “I’d say that nature and nurture are complimentary.”

Dr. Chon makes two observations on cell culture media markets:

  • Every media manufacturer has a flagship medium that serves as a magic elixir for every cell line, but the top vendors provide a strategy for improving and customizing that product for individual customers.
  • Cost-conscious end-users, particularly development-stage companies, can rarely afford the high costs of media development. Most, therefore, rely on vendors for such services. “The problem is that a media formulation is intellectual property, and under the terms of agreement it may belong to the vendor and not the drug developer.” Further on, when products reach late-stage testing, these sponsors (or companies that acquire them) may find themselves paying up to $50 per liter for media containing as little as $1 worth of ingredients.


Fed-batch bioreactor used for media and process development at Percivia.

Previous articleReporting from J.P. Morgan Healthcare Conference
Next articleStem Cell Utility Limited by Lack of Ethnic Diversity