February 1, 2007 (Vol. 27, No. 3)
Susan Aldridge, Ph.D.
Academia and Industry Are Ironing Out the Wrinkles in Biopharmaceutical Manufacture
The third “bioProcessUK” conference took place in Edinburgh recently, putting the spotlight on the challenges of manufacturing biopharmaceutical medicines, which now account for 30% of the drug pipeline and 10% of sales. bioProcessUK is a government-funded knowledge transfer network that aims to bring together academia and industry working in the sector.
Steve Taylor, Ph.D., chairman of bioProcessUK and vp of business development for Avecia (www.avecia.com), said the group was making progress in expanding the research and education infrastructure, creating networks, and encouraging investment in bioprocessing both within the U.K. and from overseas. This year over £1million of funding has been obtained from U.K. industry for long-term research, Dr. Taylor added.
A recent benchmarking exercise reconfirmed the U.K. as second to the U.S. in the sector. Forty-seven U.K. companies and five non-U.K. companies are developing 34 preclinical and 30 clinical stage biopharmaceuticals in the U.K. This is nearly twice as many products as Germany, the U.K.’s nearest competitor, with France and Switzerland in the third and fourth positions.
Outside Europe, Canada and Australia have significant pipelines, and Japan and South Korea are making steady progress. The U.K. is particularly strong in process development and manufacturing to Phase II but is still relatively weak in the manufacture of Phase III and licensed products.
The next steps for bioProcessUK include identifying centers of excellence within academia to complement the Advanced Center for Biochemical Engineering at University College London. This will help train more graduates; a recent bioProcessUK survey revealed hiring and retaining qualified staff as a constraint upon the growth of the sector.
Another development that will increase the flow of trained people is the Bioprocessing Research Industry Club (BRIC), a £10 million joint initiative between the Biotechnology and Biological Sciences Research Council, the Engineering and Physical Sciences Research Council, and 16 contributing industrial partners, including Avecia, Eden Biodesign, Pall, Millipore, Cobra, Antisoma, and GlaxoSmithKline (GSK).
The first round of funding allocated £5 million to nine projects. A team at the University of Kent has received funding for research into post-transcriptional constraints affecting productivity in yeast and mammalian cell-culture. Meanwhile, researchers at the Universities of Birmingham and Loughborough received an award for work on the microbial physiology involved in the production of difficult recombinant proteins.
At the start of 2006, Abbott (www.abbott.com) announced that Humira, discovered by Cambridge Antibody Technology (www.cambridgeantibody.com), had achieved sales of more than $1 billion in 2005, making it the first British-born biotech blockbuster.
“Antibodies like Avastin and Herceptin represent a paradigm shift in the way in which many diseases are treated,” said Neil Weir, Ph.D., senior vp of research at UCB Celltech (www.ucbgroup.com). “Biologics outpunch their weight in terms of the impact they can have in the therapeutic environment.” He described how the structure of antibodies are now being varied, often by using just a fragment of the whole molecule, to tailor and enhance their properties. UCB has shown this with Cimzia™, a pegylated version of the anti-TNF antibody certolizumab, which is showing promising clinical data in Crohn’s disease and psoriasis.
Steven Musgrave, Ph.D., vp of technical operations at GSK (www.gsk.com), agreed on the significance of monoclonals. “Recombinant proteins continue to dominate, but monoclonal antibodies have shown the highest growth rate, and we expect this to continue. Vaccines, too, may be an important growth area.”
Big pharma is interested in biopharmaceuticals because they can add value for patients and shareholders by addressing unmet medical needs. There is also less competition from generics because of the challenge of showing comparability with a biologic.
GSK is looking at internal growth as a way of developing its interest in biotech. It has set up a Center of Excellence for Drug Discovery (CEDD) dedicated to biopharmaceuticals as a new R&D business unit with two locations in the U.K. and one in Upper Merion, PA. “Within 15 years, biopharmaceuticals will form a significant part of GSK’s portfolio,” said Dr. Musgrave. GSK currently has 25 biologics in development, with the CEDD focusing on monoclonal antibodies, therapeutic vaccines, and proof of concept in gene therapy.
Cell and Tissue Therapies
Cell and tissue therapies also represent an increasingly significant, although challenging, opportunity for the bioprocessing industry. “Manufacturing and distribution are key to this area,” said Mark Bamforth, senior vp, corporate operations and pharmaceuticals, at Genzyme (www.genzyme.com).
Genzyme has a number of autologous cell therapies, including Carticel, a knee cartilage product for damaged or ruptured knees, and a more advanced product called MACI (matrix-induced autologous chondrocyte implantation), involving cartilage cells on a collagen scaffold. Epicel, Genzyme’s skin replacement, is well-known, but the company also has a cardiac cell-therapy and a renal cell-therapy in development.
The manufacturing cycle for such therapies involves processing a patient biopsy, culture, freezing, and vial storage and shipping. “The normal rules of scale-up don’t apply because one batch serves one patient,” said Bamforth. “Quality is crucial and must be taken into account at the earliest possible stage. Quality cannot be inspected in the usual way in cell therapy—it must be built into all aspects of production.”
There are commercial challenges in cell therapy. Manufacture is costly, there are long clinical development times, and there is a need for training in the clinic. In terms of patient volume, cell therapy is still suboptimal—that is, it only reaches a fraction of the patients who could benefit.
Regulation is another issue, and there is a lack of a clear framework at present, said Bamforth. “Lack of regulation can kill such products.”
The U.K. has a 10-year plan to build a cell therapy industry, as outlined in the recent Stem Cell Initiative. To this end, bioProcessUK coordinated a Department of Trade and Industry Global Watch mission to California. This had U.K. experts visiting over one dozen organizations, including the California Institute of Regenerative Medicine, Geron, Advanced Cell Technology, and Advanced BioHealing. Mission leader Chris Mason, Ph.D., of University College London, explained, “We wanted to look at the state of the cell- and tissue-therapy industry in the U.S., seeking out the technologies that minimize cost of goods and increase effectiveness of these products.”
Mike Leek, Ph.D., vp of operations at Intercytex (www.intercytex.net), said, “Cell therapy presents a number of unique regulatory and quality challenges. There is no rule book.”
Geron (www.geron.com), for instance, has developed a good relationship with regulators during preclinical work on telomerase-modified dendritic cells and has been working to remove animal components from production.
Advanced BioHealing (www.advancedbiohealing.com) is about to relaunch Dermagraft®, a wound-healing product it acquired from Smith and Nephew (www.smith-nephew.com) but won’t be shipping to the E.U. because of concern over patchy regulation. This situation may improve as the E.U. proceeds with its new guidelines on advanced therapies.
Many companies have not yet had to face up to the challenges of GMP because their cell/tissue therapy products were at an early stage.
Angela Scott, head of cell culture operations at Angel Biotechnology (www.angelbio.com), reported on cryopreservation, shipping, and distribution issues. “These should not be considered as separate steps to be added on at the end,” said Scott. Some companies were looking for alternatives to DMSO as a cryopreservation agent for their cells. Various systems were being developed for shipping, which, said Scott, should be regarded as mobile storage. Airport x-ray screening can be damaging for cell/tissue therapy products in transit.
Automation has much to offer the regenerative medicine industry because quality can be operator dependent. Moreover, manufacturing is especially labor-intensive and needs to be done under aseptic conditions. Rosemary Drake, Ph.D., director of business development at The Automation Partnership (TAP; www.automationpartnership.com), said that all the California companies realized the need for automation as a way of decreasing costs, increasing productivity and process consistency, and decreasing errors.
However, few had yet reached a stage of development where automation was a must, and VCs are notoriously reluctant to bear this kind of capital cost. Cytori (www.cytori.com) was using its Celution™ cell-preparation equipment, which separates, isolates, and concentrates cells. Advanced BioHealing and Advanced Cell Technology(www.advancedcell.com) were both using TAP’s Cellmate ™ robot.
Bo Kara, head of expression and cell sciences at Avecia, reported that companies were using fairly standard systems to go from cell bank or tissue sample through manufacturing to product. “In the U.S., they are focused on reimbursement; they will work backwards from this to decide whether it is worth their while to manufacture the product.” Cost of goods is, therefore, a big issue—one that will not be solved by automation alone.
As far as raw materials are concerned, autologous cell-therapies are based on patient tissue samples, which are manipulated and expanded into product to be re-applied to the same patient. Also, there can be growth differences between cells from different individuals, which makes manufacturing unpredictable.
The Cytori adipose cell product being developed as a cardiac therapy involves minimal manipulation and uses a tissue-processing machine provided free to the clinic. This, said Kara, is a potentially important route to return on investment.
Nick Medcalf, bioprocessing manager for Smith and Nephew’s research center, discussed validation issues. Removal of murine feeder-cells, adoption of serum-free media, and the replacement of natural supplements with recombinant versions are all seen as desirable. There is also a need for a better understanding of the impact of environmental variability on cell phenotype.
Finally, Philip Aldridge, project director at the Centre for Excellence for Life Sciences, described business models and strategies being adopted by the California regenerative-medicine industry. He found many classic biotech approaches such as technology platform leverage. “Achieving proof of principle is seen as key. Some companies are working hard at this, maybe at the expense of bioprocessing and scaling issues.”
Some thought bioprocessing was their strength, others that their product could not be scaled-up, while others had a keen desire to understand the science better to develop assays for process comparability.
Aldridge said some organizations are extremely aware of the regulatory issues and the need for early FDA involvement. In general, it was believed these products ought to be regulated as biologics. Wisely, many companies are working with clinicians at a early stage of development.
Dr. Mason said there was much for the U.K. to learn from California’s regenerative-medicine initiative. The U.K. has a few excellent companies already, as well as a sensible regulatory environment. “We are now beginning to see results from the U.K. Stem Cell Initiative,” commented Dr. Mason.
One major development will be the opening of the U.K. Stem Cell Bank. The U.K. also has a good potential market for cell/tissue therapy through the National Health Service and is used to medical tourism.
U.K. weaknesses include a cautious investment environment and limited support for translational initiatives, while regulation and reimbursement continue to be concerns. “U.K. regenerative-medicine companies must continue to watch the U.S. carefully,” Dr. Mason concluded. “There are opportunities for us there in licensing and in automation technology.”