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.