January 1, 2005 (Vol. 25, No. 1)

BioProcess U.K. Underscores Need for a National Strategy

The first U.K. bioprocessing forum (“BioProcess U.K.”), which took place in Newcastle recently, united academia and industry with the joint aims of building up a community, defining priorities, and setting national strategy. The Forum emerged from the recent BIGT (Bioscience Innovation and Growth Team) report, “Bioscience 2015,” put forward by the U.K. government, which highlights the importance of a strong bioprocessing sector to U.K. bioscience.

One recommendation is an agenda-setting program of industry events, including this annual forum, to raise the profile of the sector with CEOs and other stakeholders, and kick-start collaboration and networking between academia and industry, as well as between the different disciplines involved in the bioprocessing sector.

The U.K. already has significant bioprocessing capacity and expertise, especially in the northwest and Scotland. A 34 million National Biomanufacturing Centre with 4,100 m2 of capacity will open early 2006 at Speke, near Liverpool. The Center will provide facilities to SMEs to manufacture from proof-of-concept through to clinical trials.

Further Integration

However, according to Tony Bradshaw, the bioprocessing industry development director at the U.K. BioIndustry Association, who is responsible for developing and coordinating the initiatives emerging from BIGT, there is a need for further integration and recognition of the U.K. itself as a bioprocessing cluster.

The establishment of a network of four bioprocessing Centres of Excellence, another BIGT recommendation, should go some way to achieving these aims. The centers will focus on education/training and on research into key areas of bioprocessing.

Other plans, added Bradshaw, include carrying out benchmarking exercises to learn how to better position the U.K. internationally within the bioprocessing sector, and also to do more to support inward investment and U.K. trade agencies in this area.

All these initiatives are needed, because not only is bioprocessing a key enabler for the growth of biotechnologysupporting its commercializationit is also an activity in its own right, according to Sharon Grimster, director of project management and manufacturing at Antisoma (London).

Bioprocessing also involves much more than building and using capacity. “Technology and people are as important as stainless steel,” pointed out Stephen Taylor, general manager of Avecia Biotechnology (Billingham, U.K.), which is why both training and research will be prominent in the new bioprocessing strategy.

The size of the challenge facing the bioprocessing sector must not be underestimated. Biopharmaceuticals now account for more than 15% of licensed drugs, and in 2003 the FDA received more license applications for biotech drugs than for NCEs, a trend which looks set to continue. For trials, commercialization, and ongoing supply of these drugs, high quality and cost-effective bioprocessing facilities are vital.

Time and Money

Most of the challenges in bioprocessing are around time and money, according to Nigel Burns, Ph.D., senior vp of strategic product collaborations at Cambridge Antibody Technology (Cambridge, U.K.). Biologics are complex and costly to produce, not only because of the cost of building a plant (Wyeth’s new Dublin facility cost $1.5 billion). It is also labor intensive and time consumingcurrently it can take as long as 30 weeks to get from a cell line to a monoclonal.

Progress in meeting some of these challenges has been more of a “long march than a great leap forward,” said Dr. Burns. “There have been an enormous number of advances in bioprocessing, including rational design of media, removal of animal derivatives, and improvements in expression systems.”

But these have taken a long time to emerge. In the case of monoclonal antibodies, it has taken over 20 years to go from murine through to today’s fully human products. But Dr. Burns remains optimistic. “We are in a time of fantastic delivery of products. Everyone who works in bioprocessing is privileged to be there.”

The academic community has a lot to contribute to advancing bioprocessing (one exciting feature of the forum was a prize poster display of original research from young scientists around the U.K.).

Professor Chris Lowe, director of the Institute of Biotechnology at Cambridge University, described how microscale biomanufacturing with microfluidics, microarrays, and holographic technology is now being applied to all stages of bioprocessing to rapidly optimize conditions.

In another example of miniaturization, protein purification issues in downstream processing can be addressed with affinity ligand binding, using intelligent combinatorial chemistry and single-bead columns.

The Institute of Biotechnology has been applying some of these new methods in a collaboration with Novo Nordisk (Bagsvaerd, Denmark) for the production of the recombinant clotting protein Factor VIIa. The company wanted to remove the antibody from the immunochromatography purification step because it is expensive to get antibodies approved through the FDA.

The scientists synthesized a single affinity ligand to replace the antibody with a small molecule, and created a library around it which produced the ligand now used to purify the Factor VIIa. This, said Professor Lowe, is the first example of a “designed” ligand for downstream processing going though the FDA.

Affinity Ligand Technology

Affinity ligand technology is also being applied by a new company, Purely Proteins (Cambridge, U.K.), which will supply proteins on any scale to accelerate drug discovery. “We want to be able to provide all the proteins in the proteome,” said David Bailey, Ph.D., Purely Proteins’ CEO.

Specific sectors within bioprocessing also have their own unique challenges. Paul Kemp, Ph.D., CEO of Intercytex (Manchester, U.K.), described how in tissue engineering, with living products, scaling out must replace scaling up. Intercytex has several products in the area of wound healing and hair replacement in clinical trials.

“One unanticipated issue and hidden cost is shipping and packaging, because of the limited shelf life of the product. Manufacturing a living product is challenging because the process is the product,” said Dr Kemp.

John Birch, Ph.D., CSO from Lonza (Slough, U.K.) pointed out that monoclonal antibodies are the fastest growing category of biopharmaceuticals, and manufacturing involves facing key issues relating to volume, demand, and speed of production.

“So far, there have probably been more opportunities for process improvement in upstream processing,” he said. “I expect attention to shift toward downstream improvements as our upstream processes get better. We need to use all that stainless steel more effectively.”

In upstream operations, cell screening technology has been important to find the all-too-rare high-producing cell lines, and there is a focus on how to predict growth characteristics of cell lines at an earlier stage.

“Improving host cell lines is going to be hugely important going forward,” notes Dr. Birch, adding that selecting variants, such as CHO cells that will go into suspension or those with anti-apoptotic characteristics can be very fruitful (apoptosis is a natural form of cell death).

There are also the first attempts at metabolic engineering. “Progress in the future will come from improving cell lines. CHOs in suspension have 40 times the productivity of ordinary CHO cells,” he said. “The increasing volume of demand is a real driver for improving these processes.”

It is also worth looking into other production systems for biologics. Dr. Birch said that while mammalian cell culture will continue to dominate, it is not impossible that there’ll be a shift toward bacterial production in future.

E. coli or fungi might be used to produce monoclonal antibodies, because it may be possible to engineer the relevant glycosylation pathways into these production cells. This would eliminate the problem of biologics from microbial production systems not having the proper glycosylation pattern needed to make them clinically active.

In the future, biopharmaceuticals might even be designed as much for their ease of manufacture as for their therapeutic potential. Genomic and proteomic tools ought to help in this respect by increasing our knowledge of cell physiology.

Bioprocessing has a wide range of supply needs, including high quality media for fermentation and cell culture. HyClone, a long-established media producer from Logan, UT, recently opened an expanded facility in Cramlington (near Newcastle) to help meet the needs of the growing bioprocessing community in the U.K. and elsewhere in Europe.

The company is part of the Perbio Science organization of U.K. and Belgium which, in turn, has become a part of Fisher Scientific, which wants to increase its footprint in biomanufacturing. HyClone Europe manufactures sterile liquid products and disposable bioprocessing containers.

“We respond to the way the industry is goingit is all about disposables and animal-derived component-free media,” said Mike Bell, director of operations at Cramlington.

The new facility has four production suites dedicated to sterile animal-derived and animal-derived component-free media dry powdered media, and disposable bioprocess containers. There is also a new 2,300 L/hour water-for-injection system.

Segregation of animal and non-animal media in separate suites is a “key design feature” of the new facility according to Bell. The 2,500-m2 facility is a four-fold increase on previous capacity and will cater to the increased requirements as biologicals come through to market.

The disposable bags with tubes and connectors are made of five layers of medical grade plastic film and can be used at all stages of production. HyClone aims to be a one-stop shop with its single-use containers, media, and chromatography buffers.

One of HyClone’s customers is Avecia Biotechnology, a sponsor of BioProcess U.K. The company provides custom manufacture of microbial and mammalian-based therapeutics. The company’s new Advanced Biologics Centre (ABC 5000) is a twin 5,000-L production facility for microbial fermentation to meet customers’ needs as they move rapidly toward making approved products.

This complements the original 1,000-L facility which has been dedicated to early-phase manufacturing. “We support customers through the whole development journey,” comments Kevin Cox, vp for biotechnology at Avecia.

Recently, the company became involved in the production of defense vaccines against anthrax and plague for the U.S. government, switching the company to drug development as well as contract manufacturing. Avecia won a $9 million contract from the NIH, followed by a $72 million contract in 2003 for Phase II for the anthrax project. The contract for plague vaccine is worth $51 million.

The anthrax vaccine raises antibodies that target the antigen that otherwise allows the bacterium’s “lethal factor” and “edema factor” into the host cell. The company has a lot of IP around this project, and the product is being made for both pre- and post-exposure use. The plague vaccine is based on a similar principle and Phase I trials are about to start.

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