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BIOPHARMACEUTICALS 'Big pharma' is weaving biotech into its research regime, developing multiple therapeutic indications for protein drugs
RICK MULLIN, C&EN NORTHEAST NEWS BUREAU
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OT LONG AGO, BIOTECHNOLOGY WAS THE ULTIMATE
bugbear topic in the labs of top 10 pharmaceutical companies. It challenged drug researchers' tradi tional grounding in the development of small-mol ecule medicines. It sparked friction between me dicinal chemists, the workhorses of the 20th-century drug bonanza, and biologists, the presumed heroes of a 21st-century genomics revolution. Worst of all, perhaps, biotech challenged drug companies to make fundamental changes to their routine. Despite years ofwork on pharmaceutical proteins at some large drug companies, there persists a polarity of perception regard HTTP://WWW.CEN-ONLINE.ORG
ing large- and small-molecule therapeutics. Big drug companies are typically viewed as committed to small-molecule drugs— even if they employ biotechnology steps in discovery and early development. Ad vances in biopharmaceuticals, on the oth er hand, are credited to the labs of rela tively small, purely biotech companies. History, however, defies these views, ac cording to research heads at large drug firms. They claim their companies are al ready key players in biopharmaceuticals and that their chemists and biologists work effectively on teams that follow science in the direction of large or small molecules without prejudice. Some say the current state is precisely the result of a surprising ly rapid transformation in business and re search over the past three to five years. C & E N / MAY 1 0, 2004
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COVER STORY (moroctocog alfa), a factor A hemophilia acquisition of BASF's Knoll Pharmaceuti drug. But the big target in buying Genet cals did the same for Abbott in Worcester, ics Institute, according to Ruffolo, was proMass., and Ludwigshafen, Germany teomics and genomics discovery and the All of the major drug players had begun manufacturing operations in Andover. biopharma programs prior to their big ac Ruffolo describes Wyeth's biopharma quisitions, however. "People associate efforts as vibrant. Much centers Wyeth and biotechnology with on developing new indications the acquisition of Genetics In for the seven products the com stitute," says Robert RuffoloJr., pany has on the market. New president of R & D at Wyeth. applications for Enbrel, for ex "But it predates that. It goes back ample, are under investigation to the days of our investment in in asthma and heart disease, and Immunex. We've been a biotech the U.S. Food & Drug Adminis company for over a decade." tration approved Enbrel for pso Wyeth acquired its stake in riasis last week. The company is Immunex in 1994, bringing in also working on a range of on its first major protein thera BIG PHARMA/ cology indications using a cellpeutic, Enbrel (etanercept) for BIOPHARMA targeting mechanism employed rheumatoid arthritis. And two by its leukemia drug Mylotarg (gemtuyears later, the firm bought a majority zumab ozogamicin). interest in Genetics Institute, which Mylotarg, in fact, represents a break LARGE ACQUISITIONS include Pfizer's buy had an important bone drug in devel opment as well as recombinant proteins through biopharmaceutical technology, ac of Pharmacia, which gave it a biopharma for hemophilia. cording to Ruffolo: an antibody-targeted product portfolio and a state-of-the-art cytotoxic agent. "That's the Holy Grail, research facility in St. Louis. Similarly, These candidates emerged as InFuse (diwhere you take a powerful poison, in this ^yeth's purchase of Genetics Institute set botermin alfa), a recombinant human bone case calicheamicin, and link it to an anti the drug firm up with manufacturing in protein; Benefix (coagulant factor IX), a body that identifies only the cancer cell." Andover, Mass., and Abbott Laboratories' drug for factor Β hemophilia; and Refacto Mylotarg targets an antigen called CD33 in patients with leukemia. The company is developing another drug, CMC-544, that delivers calichea micin to an antigen associated with nonQuanta BioDesign, Ltd. Hodgkins lymphoma. Ruffolo says the 195 W. Olentangy Street firm's most exciting work in this area is on Suite Ο a candidate called CMD-193, which uses Powell, Ohio 43065 the same targeting technique against the www.quantabiodesign.com Lewis Y antigen, which is associated with Phone: 614-792-2958 "the big four": breast, colon, prostate, and Fax: 614-760-9781 lung cancers. 'And we are back in business, now, in Alzheimer's," he says, following a failed vaccine program. AAB-001, a synthetic version of the protein that the vaccine was meant to trigger, is going into clinical tri als. In all, Wyeth has 10 proteins in devel opment, Ruffolo says. He maintains that Wyeth's pursuit of biopharmaceuticals has always been di rected by an open approach to drug dis covery that does not favor large- or smallmolecule drugs. Η This approach is part of a new way of HO Ο ^ Ο ΑΑΛ Ο ·. ,· Ο . , . Ο ·. Ο .. Ν Ο Ο Ο Ο Ο O R thinking at companies where medicinal Ο chemistry has generally held sway, Ruffo R = Fmoc, CBZ, maleimide, H lo says. "We've gotten mature enough and good enough at this so that we no longer think small molecule whenever possible. Now we ask, 'What's the best approach?'" At the same time, Wyeth has backed NEW dPEG™ derivatives ~ see our new online catalog its internal efforts with more than 100 Check our website at www.quantabiodesign.com collaborative agreements with small biotech companies and other partners. These large firms, however, have put a distinctly "big company" stamp on biopharmaceuticals, beginning with buying into the business. Most biopharma prod ucts in the top drug companies' portfolios were acquired along with the biotech firms that developed them. Others were ac cessed through partnerships. Through ac quisition, major companies have also tak en over well-established biopharma R&D and manufacturing operations. In most cases, the big drugmakers avoid ed the risks taken by biopharma pioneers. Research directors say their companies purposely held off on major commitments until technologies matured. Once in the game, however, these executives claim that they wield the advantage of scale, working biotechnology into a broad range of ther apeutic research categories.
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COVER STORY "Partnerships are virtually dictated by Among the top 10 drug companies, made a key move, purchasing a majority patent complications," Ruffblo says. They Roche has the longest involvement in biointerest in biopharmaceutical pioneer are also the most direct means to access pharmaceuticals, according to Jonathan Genentech. Roche upped its manufactur new technologies. Knowles, president ofglobal research, being capabilities with the acquisition of ginning with its production of vitamin C Boehringer Mannheim in 1998 and fur Wyeth recently entered a partnership from paprika in the 1930s. In the 1980s, ther extended its reach two years ago by with the Belgian firm Galapagos Genomics acquiring a majority stake in that provides access to GalapaChugai. gos' R N A interference (RNAi) Biologies Small molecules technology for osteoporosis. With 4 0 % of its sales coming Amgen | B B W ^ W B ^ B W B j B W ^ M B ^ Frank Walsh, senior vice presifrom biopharmaceuticals—top Wyeth ^Êtt^KÊÊÊÊIfÊÊÊÊÊIÊÊÊÊÊÊÊÊÊÊM dent of discovery research, says products include Rituxan (rituxRoche | — φ — ^ — φ — W Wyeth had an "embryonic" imab) for non-Hodgkins lym GlaxoSmithKline B B B B É H H H B H B p H H H H H I RNAi program and chose partphoma and erythropoietin for Merck ^MM^BBBJBBMJHM MMIIM nership to ramp up fast once it treating anemia—Roche is the Average for top 20 firms • • • É H H É H H ^ H H É H H H Î ascertained the importance of second largest biopharma firm in Takeda Π Η Η Η Η Η Η Η Η Η Η Η Η Η Η Ι the technology. O t h e r recent the world by sales, Knowles Bristol-Myers Squibb Ε Η Η Η Ε Η Η Η Ε Η Η Ε Ι Ι Η Η Η Η Ι partnerships include deals with claims. Of Roche's 61 new mo Sankyo • • • É H H H H H H H H H B H H H I Caprion Pharmaceuticals to Pfizer )fMÊÊÊ^ÊIÊÊÊÊ^ÊIÊÊÊÊÊÊIÊÊÊtÊIÊÊMlecular entities, 15 are proteins, identify biomarkers and with AstraZeneca • • • • • • • • • • • • • • • B Knowles says, and more than 80 Neurome to use quantitative of its approximately 250 discov 0 20 40 60 80 100 Percent neuropathology in the area of ery candidates are proteins. Half SOURCE: Wood Mackenzie central nervous system disorders. of these are credited to Genen tech and a quarter to Chugai. Wyeth also looks to partners CHANGING COURSE A breakdown of clinical for production of many of its development candidates among the top Like Wyeth, Roche is apply products: Refacto is manufacpharmaceutical companies shows that major drug ing its R&D firepower to mov tured by Biovitrum in Stockfirms are paying increasing attention to largeing approved protein therapeu holm and GlaxoSmithKline molecule, primarily protein, therapeutics. Biopharma tics into new disease areas. For (GSK) is an outside supplier of leader Amgen"s clinical pipeline breakdown is example, Rituxan, a product that Benefix, according to Michael included for comparison. Genentech initially licensed from E. Kamarck, senior vice presiIdee Pharmaceuticals, is showing dent for biopharmaceuticals. promise in rheumatoid arthritis Wyeth makes Benefix, InFuse, and othand other autoimmune diseases, Knowles the company was among the first firms to er biopharmaceuticals in its Andover fasays. produce interferon-α, at its Nutley, Ν J., cility, which was recently expanded at a laboratories. Roche was the first to put a Overall, Knowles notes an evolution cost of $350 million. The company will recombinant interferon-α protein into the away from a prejudice favoring small mol add significantly to its manufacturing clinic, and its Roferon-Awas approved for ecules. "People hang on to what they be base with a $1.5 billion facility in Grange melanoma in 1986. lieve works," he says. "There was a great Castle, Ireland, where it will produce a deal of small-molecule prejudice, because This was followed by Pegasus, a PEGwide range of products. that's where a great many of the mediylated interferon-α. Then, in 1990, Roche
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cines of the 7 0 s came from. All of the neurotransmitter-based pharmacology that led to the drugs of the 70s, '80s, and '90s is based on bringing organic chem istry together with pharmacology. There is probably still a major prejudice saying that some diseases' internal mechanisms cannot be approached by biotherapeutics. I can imagine at some companies that can lead to tension." MINDS HAVE CHANGED since the late 1990s, however, as protein drugs gained a track record, Knowles says. "Some years ago, nobody understood why antibodies might be important," he says. "We could understand how Epogen might work, be cause it's a natural hormone, but antibod ies are artificial mechanisms. Only in the past five years has it been understood that antibodies can be extraordinarily potent therapeutic agents, that they can do things that small molecules can't." Abbott has followed a similar track in building a biopharma presence, purchasing Knoll Pharmaceutical in 2001. With the acquisition, Abbott established a central ized biologies group that operates as a re source for discovery and research in all therapeutic areas. It took over Knoll's R&D base in Ludwigshafen. The deal also landed Abbott its corner stone biopharmaceutical, Humira (adalimumab), for rheumatoid arthritis. The company currently has clinical trials for Humira in six other indications, accord ing to Alejandro A. Aruffo, president of the Abbott Bioresearch Center. Abbott has been using its new biotech research strength to stoke the pipeline. ABT874, an IL12 antibody, recently com pleted Phase II trials for Crohn's disease, and the company is currently enrolling patients in early clinical trials for multiple sclerosis. 'As with Humira, we believe the anti-IL12 drug will be effective in the treat ment of multiple autoimmune diseases," Aruffo says. Abbott's new infrastructure for bio tech research has opened up choices in discovery, Aruffo says, and protein op tions now have equal standing with small molecules. "Our philosophy is to look at the molecular targets that drive a dis ease and at the standard of care for the disease. Then we ask, 'What's the best approach?' " In fact, he says, small molecules have hit brick walls in some areas. "There are a lot of companies saying they are going to re place insulin with a small molecule," Aruf fo says. "Well, we've been waiting a long time, and it ain't happened yet. We let sci HTTP://WWW.CEN-ONLINE.ORG
ence dictate the choice rather than try to artificially force a choice." Industry sources agree that the two largest drug companies, Pfizer and GSK, are playing a fast game of catch-up in bio pharma. GSK, which organized its R&D into six "centers of excellence for drug dis covery" or CEDDs, two years ago, added a seventh CEDD this year for biopharmaceuticals. The company currently has no commercial biopharma drug, but it paral lels Roche in the number of large-molecule
drug candidates in the clinic. GSK's pipeline includes interleukin-18, a treatment for im munologically sensitive cancers, such as melanoma and renal cell cancer, currently in clinical trials. Early-stage candidates in clude monoclonal antibodies for severe neu rological disorders and DNA vaccines for cancer and viral infections. Pfizer, on the other hand, came out of nowhere in biopharma when it bought Pharmacia last year. It now has a research and pilot facility for both mammalian cell
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COVER STORY culture and fermentation in St. Louis, as well as a product portfolio. This includes Genotropin (somatropin), a growth hor mone; Fragmin (dalteparin sodium), for hip replacement treatment; and Exubera, an inhaled insulin. "The fact that we had biopharma prod ucts for the first time gave the company a real boost," says Martin Mackay, senior vice president for R&D. Mackay notes that Pfizer has collaborated with Abgenics, Cambridge Antibody Technology, and MorphoSys since the early 1990s, access ing tools such as transgenic mice and phage-display technologies. This prelimi nary work indicated that antibodies showed promise. "There were a lot of diseases t h a t seemed t o be amenable t o antibody therapy once t h e antibody world had matured sufficiently to be able to make them viable," Mackay says. Pfizer's in terest in biopharmaceuticals factored in to t h e decision t o acquire Pharmacia and the integration of the biotech assets following the deal. In short, the timing was right, according to MacKay "The decision to pursue anti bodies had mostly to do with technology's maturation," he says. "We really watched antibodies though the 1990s, and through the mid-'90s we didn't feel the field was mature enough to sustain an internal drive." That drive is now under way Mackay says Pfizer has 14 drug targets in develop-
ment across six therapeutic areas with 20 protein therapy programs in discovery "Our aim is to identify targets amen able to antibody therapy," Mackay says. " W h e n we first started this drive in 2000, we really had no idea how many would come for ward. But t h e scientists keep on coming up with new targets amenable to this type of therapy." The company has identified 10 new targets in the past two years. "Five targets p e r year isn't near the size of our low-molecular-weight pipeline," Mackay says, Ruffolo "but it is a significant piece of the portfolio." Pfizer's heightened commitment to biotech is one of the sources of culture change that the com pany has had to con tend with in the wake of two major acquisi tions. iCWe have been a low-molecular-weight company that hadn't played in this area," Mackay notes. "You have to believe there was some bias to lowmolecular-weight drugs. But there are no internal barriers now, due to internal re sults and data." Biologists, chemists, and drug metabo lism experts now work on project teams, he says. "Chemists and biologists sit across the hall from each other. At many times in our
Large firms have put a distinctly "big company" stamp on biopharmaceuticals.
history, we had chemists and biologists in different buildings. Even at different sites." Mackay insists that Pfizer is at no real ο ο
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will be interesting to see just how much of it we do internally and how much exter nally," Mackay says. "We have some deci sions to make about how we handle the production of marketed products." The ability of large drug companies to enter new businesses via acquisition is part of a great leap forward in biotech, Mac kay says. "If we had to build the St. Louis
facility from scratch, it would be quite a hurdle to get over." In fact, he says one lesson from Pfizer's experience with biopharmaceuticals is that even the largest company can make fundamental changes rap idly "It is not overstatement to call it a radical transfor mation in a three-year time period," Mackay states. "From a standing start to sprinting is a good feeling. For an industry criticized for being big and clumsy, we couldn't have been more nimble in this area." Approaches to the mar ket are similar among top 10 companies, but views on the future of biopharmaceuticals vary. Companies involved longest take a more conserva tive view. "There probably is some finite number of targets for protein therapeutics," Knowles says. "I don't know what it is. In another 10 years, there will be few proteins and we will focus more on small molecules.
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Ifyou look at the number of biotherapeutics in the portfolios of large drug compa nies, you will definitely see a dramatic in crease over the past few years. But I'm not sure how far that will go. It can't go all the way, because these are injectables." Wyeth's Walsh agrees, noting that longterm development programs often end in a small molecule. For example, in a bone therapy project in which Wyeth is bring ing an antibody into Phase I trials, a smallmolecule follow-up is already in the works. Aruffo, on the other hand, has a less clear view of an end of the road. "There doesn't seem to be a near-term barrier to the number of targets for proteins," he says. The key to growth, however, is to develop equal strength in large- and small-mole cule therapeutics. This view, he says, is sup ported by recent moves at biopharmaceutical companies to advance small-molecule programs. Just as Abbott purchased Knoll, Amgen recently acquired Tularik, he says. "Those companies that can bring forth the best benefits, unconstrained by require ments to pursue large molecules or small molecules, will be doing better down the road."B
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COVER STORY up that could ultimately destroy value." Beyond clients' cost concerns, Cox says, simply meeting future demand for biolog ies will keep producers focused on im proving efficiency But capacity is a diffi cult 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. RICK MULLIN, C&EN NORTHEAST NEWS BUREAU "This is a new development," Cox says. "Not long ago, everyone said we were gen erally short on capacity A number of com ONTRACT MANUFACTURERS OF are paying attention to effectively scal panies reacted very quickly to that."There ing up production rather than just push biopharmaceuticals say supply was significant investment in and demand for products made ing products through to proofearly-stage production at the of-concept using t h e least by both mammalian cell culture same time that a number of expensive process feasible at the and microbial fermentation products failed in clinical trials, pilot scale. have reached a kind of delicate balance fol freeing up large-scale capacity, lowing several years of capacity buildup. Kevin Cox, vice president of he says. "The middle is tight be Attention is now shifting to improving biotechnology at Avecia, says his cause no one has concentrated process efficiency and increasing yield in company's biopharmaceutical on that range," Cox says, "^et it's biologies manufacturing to keep up with a clients and their investors are the area most clients are inter market that continues to grow rapidly becoming more sophisticated in ested in scaling up these days." regard to long-term process de Nick Shackley, vice president of sales Mark Carver, head of bio sign. "Investors have changed and business development at Cambrex, ad BIG PHARMA/ technology R & D at Avecia, focus from early-stage to later dressed this shift in a recent presentation BIOPHARMA points out that meeting capaci stage molecules," Cox says. at the Chemists' Club in New Ifork City ty needs will require increasing the effi "They come to us and ask, 'How robust is Shackley provided an overview of current ciency of cell cultures. This work is already the supply chain? W h a t effort has been projects that will bring hundreds of liters under way, however, as the complexity of put into addressing the appropriate scale ofnew manufacturing capacity on-line over the pharmaceutical proteins going into of manufacture?' They are challenging us the next two years. He also illustrated the production increases, he says. about whether we are putting the appro need for more capacity in the near term, priate investment in ahead of time, or given projections that growth in biophar Avecia, which is scaling up its micro whether there are problems being stored maceuticals, currently 15% annually, will bial capacity in Billingham, England, has outpace that of the overall phar ο a nascent business in mammalian maceutical sector. I cell culture. Cox says the compa5 ny is hoping to transfer its mi ls crobial process know-how into ef SHACKLEY NOTED that demand ficient process development in for biologies produced via mam the mammalian cell arena and malian cell culture will continue to claims the company is in an ideal outpace demand for microbial-proposition to work with customers duced materials. He attributes this on early-phase mammalian cell discrepancy in part to the com development. mercial success of complex, largevolume monoclonal antibodies, Cox says the industry's capacity which can only be produced in balance is translating into slowed mammalian cells. investment. "Not only have we not invested in large mammalian ca According to Shackley the stain pacity," he says, "we've also been less steel buildup of recent years is going stepwise on microbial." The unsustainable. Rather than merely firm has decided to hold off on in investing in additional capacity con stalling a third 5,000-Lvessel orig tract producers will also need to inally planned for Billingham. beef up process design expertise. Improving efficiency will require At Lonza, a lead contract pro producers to take "a holistic ap ducer of mammalian cell culture proach to process development at biologies, there is a constant push an early stage, based on strong sci to improve gene expression tech ence and experience.,' nology, cell screening, and purifi cation in order to boost yields, says Contract manufacturers across John R. Birch, chief scientific of the sector agree that cost of goods ficer. The company has a propri and product life cycle are growing E N D O F T H E L I N E Despite projections of etary glutamine synthetase gene considerations as the biologies continued growth in biologies, contract producers expression system. "In our most market matures. Clients, they say, say the recent capacity push is unsustainable.
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recent work, we have been screening for highly producing cell lines and develop ing 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 1 g per L. Only in recent years have a significant number of producers pushed into the 1- to 3-g-per-Lrange. "There is cer tainly more emphasis on process efficien cy," he says. "But you don't benefit from process improvements immediately, be cause 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 of ficer of Clonex Development, a Chicagobased biotech process engineering firm, explains that there are mechanical, chem ical, and biological means of boosting pro duction. Much of the focus is on staving off cell death, or apoptosis, generally accom plished through the addition of chemical agents such as glycine and caffeine, or through the addition ofproteins that pro long cell life. Cell life can also be lengthened via genetic engineering with tumor sup pressant genes, he says. Some of these methods can produce a fourfold yield in crease, he adds. HOWEVERp optimizing cell lines before they are designed into a process can pro duce even higher yields, Primiano main tains. Clonex, he says, has developed a pro prietary 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 syn thesis machinery expands, all of which accelerate the amount of protein pro duced by a cell. "Most major companies go with an antiapoptotic approach, using chemical factors like glycine t h a t can produce a similar ef fect," he says. "I think it's much simpler to engineer a cell line once and be able H y d e to use it." Executives with major contract manu facturing firms contend that while chem ical and biological apoptotic fixes are of ten applied to boost production, the companies are, in fact, working steadily on optimizing cell lines and pioneering HTTP://WWW.CEN-ONLINE.ORG
THE BUILDUP CONTINUES Acquisitions and capacity expansions among contract biologies manufacturers EXPANSION ( D ACQUISITION
Avecia Sandoz Boehringer Ingelheim Cambrex Bio Science Contract Production Marathon Diosynth Covance Collaborative Dow BioAlliance DSM Lonza
YEAR
MICROBIAL
YEAR
10,000 13,000
2003 2003
2001
2,500
2004
2001 2001
15,000
2003
MAMMALIAN YEAR
16,000 240,000 500
2004 2005 2004
18,000 60,000 60,000
2003 TBA 2004
2000
15,000
TBA
SOURCE: Cambrex
ο -ο more efficient gene expression systems. I Dow Chemical, for example, has devel < oped a microbial gene expression tech III nology based on Pseudomonasfluorescein,a 5 high-expression bacterium that maintains the critical solubility and activity charac teristics of the proteins it expresses. Nick Hyde, Dowpharma business director, says the system generally produces lower lev els of metabolic by-products than Esch erichia colt and other standard expression platforms, while increasing product puri ty and overall yield. SCALE-UP Avecia, which is bringing new microbial fermentation on-line in Patrick Lucy, business development Billingham, England (shown), has leader for microbial proteins, says Dow taken part in the recent round of newcalls on process design and genetic engi capacity investments. neering capabilities from across the com pany "Dow uses tools such as genomics and bioinformatics—typical drug discov T h e industry is just waking up to this." ery tools—to optimize the expression sys As it does, contract manufacturers will tem for each customer. That is what dif be called on to work more closely with cus ferentiates Dow from our competitors, tomers, Cambrex's Shackley predicts. Ά ο This is not an off-the-shelf good contract manufacturing operation \ protein. We customize incorporates a modicum of consultancy in < these strains for optimal exto their business," he says. "You have to \ pression with our capabili- discuss options and determine what's ] ties in San Diego, which are worth exploring in order to improve pro η world class." ductivity and get the cost of goods down." Cox at Avecia agrees. "Some cus Indeed, sources agree tomers appreciate the need to address t h a t process design ex efficient process design up-front," he pertise and customization says. "Others with limited financing want services are moving to the it done quick and cheap. They have dif competitive forefront in ferent expectations and desires. Where biologies. "People discuss we add the most value is in taking on ear the capacity gap," Avecia's ly-stage partners and working with them Carver says. "But there is through their journey." a shortage of high-quality development capability Avecia, like others, will move into the out there. That has not been addressed new competitive fray, leading with its by simply building loads of new facilities. pedigree, Cox says. "We have a quarterIt's relatively easy to raise tens of millions century of process-developing experience of dollars and put some stainless steel in biologies," he says. "That's where we on the ground. It's much more difficult came from and the skill we bring to the to have the right people on the ground. market." • CL
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