January 15, 2012 (Vol. 32, No. 2)

Angelo DePalma Ph.D. Writer GEN

According to “The Dynamic Media, Sera, and Reagent Market in Biotechnology”, a 2010 report from BCC Research, sales of cell culture media, sera, and reagents will grow from $2.3 billion in 2009 to an estimated $3.9 billion by 2015.

Global demand for media is creating a boom industry, and not only for pure-play media companies.

For example, in December 2011, Corning Life Sciences acquired Mediatech, a VA-based manufacturer of Cellgro® brand media, basal salt solutions, antibiotics, sera, and specialty media; in August, GE Healthcare Life Sciences acquired PAA Laboratories, which researches and manufactures cell culture products for producing vaccines and therapeutic proteins.

Media supply has become a huge issue with the rise of biotech in Asia. In 2010, Irvine Scientific opened an 18,500 square-foot cell culture media manufacturing facility in Tokyo. Irvine commissioned the facility to serve the growing demand for media in Japan and elsewhere in Asia, and to provide “redundancy” with its 75,000 square-foot facility in Santa Ana, CA, to which it added a 23,000 square-foot warehouse in early 2011. The first products rolled off the Tokyo facilities production line in April 2011.

Country of origin has become a major quality parameter for media and ingredients, which is one reason why biomanufacturers prefer to source close to home. Quality auditing and animal-component-free audits extend back to the suppliers of ingredients and equipment used to make media components, not just the media itself. Thus, media ingredient suppliers must maintain manufacturing systems and employ ingredients that may be verified and validated according to their customers’ needs.

Vertical Integration

PAA was the latest in a line of GE acquisitions that began with its purchase of Amersham in 2004, followed by Whatman (filtration) and Wave Biotech (disposable process containers). GE’s business strategy continues to provide a “scalable, start-to-finish bioprocess solution,” says Harry Brack, formerly COO at PAA and currently with GE.

Before the merger, PAA had invested heavily in media manufacturing and a product portfolio that extends from research to manufacturing scale. The PAA business segment is expected to grow to global proportions with the help of GE’s financial and global marketing presence.

The PAA deal was, in part, an acknowledgement that upstream processing affects downstream operations: quality in, quality out. “We realized that we needed the internal competence and insight that can only be gained by maintaining an organic supply upstream and downstream” Brack adds. “It’s more about optimizing the process and viewing it holistically versus separating upstream and downstream operations.”

Media development has reached a plateau of sorts with respect to the most significant trend of the 2000s: a shift from serum- and animal component-containing media to serum-free and chemically defined media. “We’ve come to the end of that particular story,” Brack explains. What remains to be done amounts to fine-tuning media for specific CHO strains, and optimizing feed strategies.

Production yields and volumetric productivity are similarly leveling off according to Brack, who does not expect that titers will rise anywhere nearly as dramatically over the next decade as they have since 2002. That does not mean that large-scale bioprocessing will be standing still. Enhancements will come in the form of compressed development and cycle times, shorter time-to-market, and higher product quality through clone selection rather than media improvements.

If anything, cell culture development is shifting toward more highly targeted but simplified strategies employing platform media and simplified feeding strategies through which cells grow easily without optimization or adaptation. “These approaches streamline the process of going from clone to clinical material,” says Brack.

Chemically Defined Media

Merck Millipore is relatively new to the cell culture media market. Its fledgling business is based on Merck Group’s long experience with chemical raw materials and processing, which is ideally suited to the larger industry trend toward chemically defined media, according to Jörg von Hagen, Ph.D., head of process development at the company.

Merck Group has two cell culture media teams. Merck’s Woburn, MA, facility concentrates on proprietary CHO media, while its Darmstadt, Germany, unit focuses on customized GMP media and feeds. The German business, which works on animal-derived component-free (ADCF) products as well as media with animal-derived ingredients and chemically defined cell culture media, takes recipes from European and Asian customers and scales them up for production. “We hope to leverage this expertise for North America as well,” Dr. von Hagen says.

Merck Group will restrict its target market to GMP pilot-scale and production-scale processes, which makes sense given the company’s strong regulatory and GMP credentials and expertise in sourcing high-quality chemical ingredients. “We want to produce tons rather than liters,” Dr. von Hagen adds.

Duplicating media for an established process can be difficult. Media suppliers never disclose the “secret sauce” that makes their products work with specific cell lines. Ingredients do not strictly follow Chemical Abstracts Services “CAS numbers”—unique identifiers for chemical ingredients. Ingredients as well-characterized as bovine serum albumin may differ significantly in purity, composition, and activity depending on the source and manufacturer. The same is true for media additives like glucose or sodium chloride, or in the case of supplemental feeds, amino acids.

These ingredients may contain impurities at the nanomolar range that are fine for development work but unsuitable for large-scale bioprocesses. “You can easily wind up with certain impurities, at undesirable levels, if you don’t have the right quality practices in place for trace elements at every stage of production,” Dr. von Hagen says. “Raw materials become critical as you scale up. Maintaining a sourcing strategy that provides bulk raw materials of high quality is not always easy.”

Media purity has become increasingly important as well. Several vendors now sell filters specifically designed for cell culture media. For example Pall offers the disposable Novasip Ultipor VF media filtration capsule filters, and Millipore’s Express SHC and SHR filters are used for scaleup of cell culture culture media. In December, 2011, Thermo Fisher Scientific introduced a 0.1-micron polyethersulfone membrane specifically for filtering media.

Media development has entered a phase more characterized by tweaking than radical breakthroughs. Media specialist InVitria recently won an NIH grant to develop chemically defined ADCF media for vaccine manufacturing. CEO Scott Deeter explains that ADCF vaccine production media exists, and some such products are chemically defined, but their performance lags behind that of media containing animal products. “Traditionally, there has been a trade-off between performance provided by undefined media compared to the consistency of well-defined media.”

InVitria will use two of its products, Optiferrin (recombinant transferring, an iron-carrying protein) and Cellastim (recombinant human albumin) to increase consistency and performance, and in the case of Optiferrin, the elimination of the downstream purification burden of iron chelators. In early 2011, InVitria presented data demonstrating a significant improvement in performance for stem cell culture media containing these two proteins.

Researchers at InVitria conduct experiments using animal component-free cell culture supplements at the firm’s cell culture lab in Fort Collins, CO.

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