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Contract manufacturers of biopharmaceuticals
say supply and demand for products made by both mammalian cell
culture and microbial fermentation have reached a kind of delicate
balance following several years of capacity buildup. Attention
is now shifting to improving process efficiency and increasing
yield in biologics manufacturing to keep up with a market that
continues to grow rapidly.
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BIG PHARMA/
BIOPHARMA |
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Nick Shackley, vice president of sales and business development
at Cambrex, addressed this
shift in a recent presentation at the Chemists' Club in New York
City. Shackley provided an overview of current projects that will
bring hundreds of liters of new manufacturing capacity on-line
over the next two years. He also illustrated the need for more
capacity in the near term, given projections that growth in biopharmaceuticals,
currently 15% annually, will outpace that of the overall pharmaceutical
sector.
SHACKLEY NOTED that demand for biologics produced
via mammalian cell culture will continue to outpace demand for
microbial-produced materials. He attributes this discrepancy in
part to the commercial success of complex, large-volume monoclonal
antibodies, which can only be produced in mammalian cells.
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END OF THE LINE Despite projections of continued
growth in biologics, contract producers say the recent capacity
push is unsustainable.
AVECIA PHOTO |
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According to Shackley, the stainless steel buildup of recent
years is unsustainable. Rather than merely investing in additional
capacity, contract producers will also need to beef up process
design expertise. Improving efficiency will require producers
to take "a holistic approach to process development at an early
stage, based on strong science and experience."
Contract manufacturers across the sector agree that cost of
goods and product life cycle are growing considerations as the
biologics market matures. Clients, they say, are paying attention
to effectively scaling up production rather than just pushing
products through to proof-of-concept using the least expensive
process feasible at the pilot scale.
Kevin Cox, vice president of biotechnology at Avecia,
says his company's biopharmaceutical clients and their investors
are becoming more sophisticated in regard to long-term process
design. "Investors have changed focus from early-stage to later
stage molecules," Cox says. "They come to us and ask, 'How robust
is the supply chain? What effort has been put into addressing
the appropriate scale of manufacture?' They are challenging us
about whether we are putting the appropriate investment in ahead
of time, or whether there are problems being stored up that could
ultimately destroy value."
Beyond clients' cost concerns, Cox says, simply meeting future
demand for biologics will keep producers focused on improving
efficiency. But capacity is a difficult thing to gauge. According
to Cox, capacity is now adequate for pilot- and large-scale production
of both mammalian cell and microbial proteins, but it will be
short in the midrange.
"This is a new development," Cox says. "Not long ago, everyone
said we were generally short on capacity. A number of companies
reacted very quickly to that." There was significant investment
in early-stage production at the same time that a number of products
failed in clinical trials, freeing up large-scale capacity, he
says. "The middle is tight because no one has concentrated on
that range," Cox says. "Yet it's the area most clients are interested
in scaling up these days."
Mark Carver, head of biotechnology R&D at Avecia, points
out that meeting capacity needs will require increasing the efficiency
of cell cultures. This work is already under way, however, as
the complexity of the pharmaceutical proteins going into production
increases, he says.
Avecia, which is scaling up its microbial capacity in Billingham,
England, has a nascent business in mammalian cell culture. Cox
says the company is hoping to transfer its microbial process know-how
into efficient process development in the mammalian cell arena
and claims the company is in an ideal position to work with customers
on early-phase mammalian cell development.
Cox says the industry's capacity balance is translating into
slowed investment. "Not only have we not invested in large mammalian
capacity," he says, "we've also been going stepwise on microbial."
The firm has decided to hold off on installing a third 5,000-L
vessel originally planned for Billingham.
At Lonza, a lead contract
producer of mammalian cell culture biologics, there is a constant
push to improve gene expression technology, cell screening, and
purification in order to boost yields, says John R. Birch, chief
scientific officer. The company has a proprietary glutamine synthetase
gene expression system. "In our most recent work, we have been
screening for highly producing cell lines and developing optimum
media feeds," Birch says. "We've gotten in excess of 4 g per L
of monoclonal antibody."
In the mid-1990s, Birch says, yields in mammalian cell batch
systems were well under 1g per L. Only in recent years have a
significant number of producers pushed into the 1- to 3-g-per-L
range. "There is certainly more emphasis on process efficiency,"
he says. "But you don't benefit from process improvements immediately,
because when you get to late-stage clinical trials, processes
are locked in. It takes a few years for new process technology
to work its way through to products being made at high volume."
Thomas Primiano, chief executive officer of Clonex
Development, a Chicago-based biotech process engineering firm,
explains that there are mechanical, chemical, and biological means
of boosting production. Much of the focus is on staving off cell
death, or apoptosis, generally accomplished through the addition
of chemical agents such as glycine and caffeine, or through the
addition of proteins that prolong cell life. Cell life can also
be lengthened via genetic engineering with tumor suppressant genes,
he says. Some of these methods can produce a fourfold yield increase,
he adds.
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SCALE-UP Avecia, which is bringing new microbial
fermentation on-line in Billingham, England (shown), has taken
part in the recent round of new-capacity investments.
AVECIA PHOTO |
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HOWEVER,
optimizing cell lines before they are designed into
a process can produce even higher yields, Primiano maintains.
Clonex, he says, has developed a proprietary means of triggering
premature senescence in cells, stopping the process of mitosis
and causing cells to grow larger: Mitochondria increase in number,
secretory systems expand, and protein synthesis machinery expands,
all of which accelerate the amount of protein produced by a cell.
"Most major companies go with an antiapoptotic approach, using
chemical factors like glycine that can produce a similar effect,"
he says. "I think it's much simpler to engineer a cell line once
and be able to use it."
Executives with major contract manufacturing firms contend
that while chemical and biological apoptotic fixes are often applied
to boost production, the companies are, in fact, working steadily
on optimizing cell lines and pioneering more efficient gene expression
systems.
Dow Chemical, for example,
has developed a microbial gene expression technology based on
Pseudomonas fluorescens, a high-expression bacterium that
maintains the critical solubility and activity characteristics
of the proteins it expresses. Nick Hyde, Dowpharma business director,
says the system generally produces lower levels of metabolic by-products
than Escherichia coli and other standard expression platforms,
while increasing product purity and overall yield.
Patrick Lucy, business development leader for microbial proteins,
says Dow calls on process design and genetic engineering capabilities
from across the company. "Dow uses tools such as genomics and
bioinformatics--typical drug discovery tools--to optimize the
expression system for each customer. That is what differentiates
Dow from our competitors. This is not an off-the-shelf protein.
We customize these strains for optimal expression with our capabilities
in San Diego, which are world class."
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Hyde
DOW CHEMICAL PHOTO |
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Indeed, sources agree that process design expertise and customization
services are moving to the competitive forefront in biologics.
"People discuss the capacity gap," Avecia's Carver says. "But
there is a shortage of high-quality development capability out
there. That has not been addressed by simply building loads of
new facilities. It's relatively easy to raise tens of millions
of dollars and put some stainless steel on the ground. It's much
more difficult to have the right people on the ground. The industry
is just waking up to this."
As it does, contract manufacturers will be called on to work
more closely with customers, Cambrex's Shackley predicts. "A good
contract manufacturing operation incorporates a modicum of consultancy
into their business," he says. "You have to discuss options and
determine what's worth exploring in order to improve productivity
and get the cost of goods down."
Cox at Avecia agrees. "Some customers appreciate the need to
address efficient process design up-front," he says. "Others with
limited financing want it done quick and cheap. They have different
expectations and desires. Where we add the most value is in taking
on early-stage partners and working with them through their journey."
Avecia, like others, will move into the new competitive fray,
leading with its pedigree, Cox says. "We have a quarter-century
of process-developing experience in biologics," he says. "That's
where we came from and the skill we bring to the market."
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