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.
Alternative
Media
The “final frontier” for revolutionary media
development may lie in markets other than traditional mammalian cell
culture-based manufacturing, particularly in stem cells and media for
“non-traditional” expression systems.
Numerous vendors offer media for stem cell
cultures.
Through its Chemicon business unit Millipore
sells HEScGRO™ animal component-free media for human embryonic stem cells;
Stemgent’s NutriStem™ media is fully defined and animal component-free; Life
Technologies sells several types under the Gibco brand, including StemPro® for
neural stem cells, as does Aruna Biomedical with its AB2™ Neural Progenitor
Expansion media Kit. Through its Hyclone brand Thermo Scientific sells a range
of products for both human embryonic and adult stem cells.
One tends to think of stem cell media as being
radically different from conventional cell culture media, but this is not the
case. Stem cell media consists of conventional cell nutrients such as lipids,
vitamins, minerals, and amino acids, plus a proprietary blend of cytokines and
co-factors that favor expansion or differentiation.
“I don’t know that there are specific
differences between media used for mesenchymal stem cells or for other
mesenchymal cells,” explains Jim Musick, Ph.D., president of Vitro Diagnostics.
“Media requirements depend more on the cell’s origin—mesenchymal, endodermal,
epidermal—than whether it’s a stem cell or not.”
If anything, stem cell culture media are
evolving toward greater simplicity—a recapitulation of media/feed strategies
for biopharmaceutical manufacturing. A paper in the May 2011 issue of Nature
Methods by James Thomson at the University of Wisconsin describes a stem cell
culture medium, E8, that has been stripped of all unnecessary components.
Chemically defined E8 medium reduces variability
in human embryonic and induced pluripotent stem cell cultures resulting from
inconsistencies in albumin. E8 contains no albumin at all, and was pared of
other ingredients that Thomson and co-workers deemed to be unnecessary.
Thomson found that albumin was required to
reduce the toxicity to cells of mercaptoethanol, so he omitted this ingredient
and found that albumin was no longer required.
David Welch, Ph.D., senior market development
manager at Life Technologies, describes such media as “lean” media—both
cost-effective and efficient at maintaining stem cells in whatever state of
potency is desired.
Early on, Dr. Welch explains, stem cell
researchers “threw everything they could think of” into media formulations in
an attempt to maintain cells in a multipotent or pluripotent state. “But as the
push toward chemically defined media progressed, these investigators struggled
with finding a carrier to replace BSA or human albumin."
Algal
Cell Culture Media
Alternative expression systems remain the
Rodney Dangerfields of biomanufacturing, yet they continue to generate
interest.
A 2010 paper in Plant Biology Journal reported
that algal cell culture can compete with bacterial and mammalian cell cultures
for the production of therapeutic proteins. The authors, among them Stephen
Mayfield at the University of California, San Diego, and scientists from
Hayward, CA-based protein-engineering firm ProtElix, demonstrated the
feasibility of producing a variety of therapeutic proteins, including
cytokines, VEGF, and antibodies in inexpensive algal cultures.
Algal cultures are much more robust than
mammalian cell culture and, unlike bacteria, produce properly folded,
glycosylated proteins. Most salient: In the paper, Mayfield noted that algae
were “considerably cheaper” than mammalian expression systems.
As with stock CHO cell culture media,
end-users prefer “take out” to home cooked. Algal media is simple, consisting
mostly of salts and minerals. (Being plants, algae employ carbon dioxide as
their carbon source.) “As we spoke with customers, we heard that making up
algal media is a pain,” says Lisa Stillwell, product development manager at
Life Technologies, which claims to be the “first to market” for algal media
under the Gibco brand.
These products, Stillwell notes, are
“significantly less complex” than CHO media. Some provide little more than
minerals and elements—no vitamins, amino acids, or undefined components like
hydrolysates or animal sera, although some algae require acetate as the carbon
source for optimal growth.
Angelo DePalma, Ph.D.
GEN
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