June 15, 2005 (Vol. 25, No. 12)
Susan Aldridge, Ph.D.
Recent Trends in Outsourcing, Disposables, and Systems for High Expression of Products
The market in biologics could be worth $3.5 billion by 2010, with opportunities offered both by new biopharmaceuticals and old ones coming off patent, said consultant Monica Darnborough, Ph.D., formerly head of the U.K. government’s bioscience unit. Addressing the “BioLogic Europe” conference held in Geneva recently, she added that, for once, there appears to be no obvious shortfall in manufacturing capacity.
However, Europe faces many challenges, according to David Chiswell, Ph.D., chairman of the U.K. BioIndustry Association (BIA). R&D and healthcare spending are still much less than in the U.S., drugs take longer to get to the patient, the new European Clinical Trials Directive is seen as an extra regulatory hurdle, and the lack of a single market, a single patent, and a single Stock Exchange are ongoing issues that are not likely to be solved soon.
But Europe has a tradition of excellence which can be built on and there have been some significant achievements recently. For instance, the U.K. government has earmarked several million pounds for bioprocessing research, in response to recommendations from the Bioscience Innovation and Growth Team (BIGT) plan.
“BioProcess UK is off to a flying start,” said Dr. Chiswell. BIA has also helped secure tax credits for bioscience R&D, lobbied on the Human Tissue Act to allow continuation of stem cell research, and been involved in the award of 100 million of public money for clinical research in the National Health Service. “This shows we can influence and change things,” he added.
Johan Vanhemelrijck, Ph.D., secretary general of Europabio said, “We often forget to tell politicians and the authorities about all the good things biotech is doing.” To this end, he described the Bioimpact Study (www.bioimpact.org) in which a group of French and U.K. medical experts looked at the positive impact of 10 biologics, such as interferon and TNF therapies.
On regulatory issues, he pointed out that the EMA is producing a “Road Map” to help smaller companies, and there is also work on improving the framework for developing orphan drugs in Europe, an area where biotech is often a driver as rare diseases are usually genetic and can be remedied by supplying the deficient protein. For Europe in general, though, Dr. Vanhemelrijck commented that “Coherence and continuity of policy remain a real challenge.”
Outsourcing Versus In-House Production
Whether or not to outsource the production of a biologic is an issue that continues to generate debate, with companies having different strategies. “Having control of your own manufacturing at a certain stage, if you’re a small biotech, is critical,” commented Michael Buschle, Ph.D., CTO for the vaccine company Intercell (Vienna, Austria).
He suggested outsourcing at early stage, but bringing production back in-house for commercial manufacture. Intercell has reached Phase II with a classic attenuated inactivated virus vaccine for Japanese encephalitis, and this is being produced in their dedicated GMP 3,000-m2 facility in Livingston, U.K.
In contrast, a peptide vaccine, also in stage II for hepatitis C, is being outsourced as its manufacture is seen as less complex than that of a biologic. “If you want to develop products, you need to be able to manufacture them to modern regulatory requirements,” Dr. Buschle added.
There may indeed be advantages to keeping manufacturing in-house, but many companies still prefer to outsource. In fact, it is estimated that almost half of all biopharmaceutical companies now contract out at least part of their manufacturing.
A major reason for the surge in outsourcing in recent years is the increased number of products in the pipeline and the growing number of new players in the business, many of whom have limited experience or manufacturing capacity.
Wynne Weston-Davis, M.D., medical and development director of Evolutec Group (Reading, U.K.), explained that outsourcing is a necessity for a virtual company such as Evolutec, which now has a third compound in Phase II. Virtuality is a business model that emerged along with the dot-com revolution in the 1990s and works for organizations that have not been able to raise much money.
Experience has shown what shouldand should notbe outsourced, said Dr. Weston-Davis. Project management at all stages needs to be kept in-house, along with target selection and development planning. But many other activities, such as documentation, can economically and safely be outsourced so long as the right contractor is chosen.
From the contractor’s point of view, John MacLennan, Ph.D., business development consultant at Xoma (Berkeley, CA), which has recently set up a contract manufacturing business, explained that it was important to check that a client was realistic in their idea of time to market and general expectations, as some are more “mature” than others.
Process and technology transfer between client and contractor can be especially challenging. It is not unusual for the client to end up with a slightly modified process, and this must be supported by data.
At an early stage, processes may be poorly defined and the unexpected will often occur, as each protein and antibody is unique. “Clear, regular, and open communication is the most important issue for both contractor and client,” Dr. MacLennan said.
FIT Biotech (Tampere, Finland), which is developing a DNA vaccine for HIV, uses contractors for many different activities, such as preclinical safety and toxicology, media and buffer preparation, and clinical trial monitoring, according to Tytti Krkkinen, Ph.D., vp of production.
The company’s contractors are in the U.S., the U.K., Sweden, Belgium, and Finland. “The most important thing when evaluating a contractor is experience in a particular field such as DNA or gene therapy,” she said. Company size is also importantsmall ones have more flexibility, larger ones more experience; regulatory expertise on both sides is essential.
In Finland, there are national centers such as BioCity, Turku, and BioMedicum Helsinki, which offer contract research, GMP compliant animal testing, and many other services. But FIT chooses to do all its production in-house because they feel this gives them the flexibility they need to get to clinical trials without being dependent on anyone else.
Companies are also moving increasingly toward disposables in biomanufacturing, because they eliminate the need for sterilization and cleaning in place and the associated validation costs, as well as reducing the risk of cross-contamination.
HyClone (Logan, UT) and Baxter Bioscience (Hayward, CA) co-developed a Single-Use Bioreactor (SUB) for stirred tank batch animal cell culture, consisting of a permanent stainless steel support and a disposable plastic bag of 250-L capacity (50-L and 1,000-L versions will be available soon).
The SUB is designed to allow conventional stirring and aeration through an integrated and disposable rotating shaft ceiling. “This is the first disposable system which allows for classical mixing technology,” said Frank Wolpers, HyClone’s industrial sales director, Europe. “This makes it a lot easier to convert people’s mind set toward disposables.”
Studies carried out at Baxter, which has recently set up a contract manufacturing service, have compared production of Phase I batches in the SUB and in a traditional stirred tank bioreactor and found material to be equivalent, which is what companies want.
Solvay Pharmaceuticals (Olst, The Netherlands), a vaccine company which provides prefilled syringes, has also started investing in disposables for filling operations. This is done in an isolator unit, to eliminate contamination from personnel, and the company is using a transfer set supplied by Stedim (Aubagne, France) to move materials in and out.
The set includes Stedim’s disposable RAFT (Rapid Aseptic Fluid Transfer) system with other disposable components. Solvay’s rationale for disposables, said Jan-Eric Zandbergen, manager of sterile production, is to use them where cost is reasonable and to use dedicated items where the cost is higher.
“Disposables do away with the need for cleaning and cleaning validation, as well as avoiding cross contamination. This is a huge benefit over stainless steel.”
Recently, Stedim had a cost comparison carried out by BioPharm Services, which showed an overall 56% reduction in costs using disposables compared to stainless steel in an operation aimed at filling 20-million syringes a year. Zandbergen said, “We are fine tuning the system at present but our conclusion is that we would choose disposables again.”
Systems for High Expression of Product
Another important issue in biomanufacturing is developing systems for high expression of product. Beate Stern, Ph.D., co-founder of UniTargeting Research (Bergen, Norway), explained how the company is exploiting the engineering of constructs for high secretion of protein.
This began with the discovery that the 3′-UTR (untranslated region) of a gene is important in targeting mRNA toward intra- or extracellular expression of a protein. Manipulation of both the signal peptide and the UTR has led to “super secretion” of a number of commercially important proteins.
“Changing the UTR can have dramatic effects that no one would have expected,” said Dr. Stern. UniTargeting Research has shown proof of principle in collaborations with Angel Biotechnology (Newcastle, U.K.), a CMO, where a shift to higher-producing cells was achieved, and with the University of Bergen, where higher secretion of endostatin in a cell-encapsulated brain tumor treatment was shown.
Meanwhile, transgenic production systems are making significant progress. Probably the most advanced product is anti-thrombin III which is being produced in goat milk by GTC Biotherapeutics (Framingham, MA). “This will be the first new approved production technology for 20 years,” said program director, Dan Couto.
Bayer Crop Science (Monheim, Germany) is concentrating on “green biomass” as a production system which, according to business development manager, Ulrich Steiner, Ph.D., should lead to significant timeline and cost reductions compared to mammalian cell culture in the future.
Such transgenic technologies are targeted toward companies developing products, and needing to supply a market, rather than researchers. They may be especially valuable in expressing proteins which cannot be obtained in more conventional systems.
Using Chicken Eggs
Finally, Leandro Christmann, Ph.D., director of transgenic technology at AviGenics (Athens, GA) cited chicken eggs as a production system with especially low financial risk. The infrastructure for extracting therapeutic protein from egg white (at 6 g per egg) is already in place because of the egg industry.
The system allows fast and scalable production9 to 15 months from gene to human clinical material and 30 months to commercial scale.
Cytokines, monoclonals, polyclonals, interferon, GCSF (granulocyte colony stimulating factor), and EPO (erythropoietin) have already been produced in the system; Phase I trials of an undisclosed proteinthe first of a biotherapeutic in an avian production system, the firm claimshave been successful, and Phase II is in progress.