In November 2001, NewBrunswick Scientific Co., Inc.(NBS) organized a two-dayseminar in Nanjing City, China,to discuss new techniques forhigh-yield production ofvaccines.

The conference broughttogether 60 research scientistsfrom vaccine facilities through-out China and featuredEduardo Aycardi as keynotespeaker. He is a rabies vaccinespecialist who, while headingthe R&D department of agovernment-run vaccine facilityin Colombia, South America,became the first recipient offunds for a technology develop-ment project supported by theRockefeller Foundation(www.rockfound.org) and theWorld Health Organization(WHO, www.who.org).

His project’s goal was todevelop a protocol for pro-ducing a low-cost, high-qualityrabies vaccine for human andanimal health care. After 12 years of designing perfusionsystems, developing formula-tions, careful screening, yieldoptimization, and testingpotency and dosage levels, heobtained license in 1999 for hisfacility to produce and sell ahuman rabies vaccine inColombia. Aycardi now helpsresearchers in other developingnations to set up vaccineproduction facilities using thetechnology he helped topioneer.

Aycardi told the Nanjingaudience that his productionmethods, using VERO cellsgrown in an NBS 30-L steriliz-able-in-place bioreactor, can

produce one million doses ofhuman rabies vaccine peryear, using 25 g/L of Cytodex-1 (Amersham PharmaciaBiotech, www.apbiotech.com)microcarrier beads. Just threelab technicians make it happenin a 350-m2 facility under GMPconditions. Guozhong Wang,senior research scientist at theNBS cell culture laboratory,said, “Such high yields havenever before been reportedand are largely attributable tothe NBS bioreactor’s patentedcell-lift impeller and decantingcolumn, which provide the highoxygen transfer, high nutrientlevels, and low-shear growthenvironment the cells requirefor this level of productivity.”

Aycardi’s results are 10 timesthe average titer obtained byfacilities working with rollerbottle processes, the same

yield as thatobtained by aseveral-hundred-liter bioreac-tor system using low-concentration beads withoutperfusion. Such large equip-ment, using large volumes ofcell culture media and serum,can require more than a dozenscientists and over 1,000 m2 offacility space.

Mouse-derived vaccinesrequire thousands of mice forvaccine production. VEROcells can be repeatedly dividedand grown with each subse-quent culture identical to theone that preceded it. The cellsoriginated from African greenmonkey kidneys and areavailable from repositoriessuch as the American TypeCulture Collection (ATCC,www.atcc.org).

Rabies is rampant in manyparts of the world, killing about30,000 people a year. Aycardi’smethodology might be appliedto manufacturing vaccines forother life-threatening diseasesincluding polio and Japaneseencephalitis.

The Nanjing Conference wasone in a series of technicalprograms on fermentation andcell culture techniques thatNBS sponsored in 2001. Formore information on upcomingeducation programs, cellculture product information, ortechnical papers, check out thecompany’s web site atwww.nbsc.com. To learn moreabout Aycardi’s technology,contact him at eraycardi@yahoo.com.

One Company’s SolutionIn February, Avecia (www.avecia.com)announced a $100 million investment programto build an advanced biologics-medicinesmanufacturing facility at Billingham, UK.

“This is Avecia’s largest single investmentsince its formation in mid-1999,” commentedKevin Cox, vice president for biotechnology. “Itwill firmly establish Avecia as a global leader inbiologics contract manufacturing, with inte-grated capability on a single site for develop-ment, trials, and large-scale manufacturing toCGMP standards. The development also

reinforces our position as a contract manufac-turing partner of choice for the biotechnologyindustry — complementing our world-leadingposition in DNA medicines”.

Noting that the United Kingdom is alreadyEurope’s leader in biotechnology research,Cox said: “Avecia’s large-scale biologicsmanufacturing facility at Billingham will estab-lish the UK as a center for biomanufacturing inEurope. Biotechnology is one of the UK’sfastest-growing industries, and our new facilityat Billingham will also act as a catalyst forgrowth and development in northern Englandof complementary businesses, services, andadditional biotechnology investments.” TheUnited Kingdom is second only to the UnitedStates in numbers of biotech medicines indevelopment.

Rising demand. Biologics account for over 20%of all new drug approvals, and currently over

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HOTTopicsHOTTopicsAddressing the Shortagein Manufacturing Capacity

250 microbially derived biologic medicinesare in clinical trials. Biologics manufactur-ing is set to continue as one of the fastestgrowing sectors in fine chemicals. Currentcapacity is close to full use, and industrydemand for contract manufacturing ofbiologics is forecast to more than doubleby 2005 — to over $700 million.

Global sales of biologics are currentlyabout $16 billion, a small but rapidlygrowing part of the $320 billion healthcare sector. Biologics account for about20% of all new drug approvals by FDA.Expansion of the development “pipeline”(because of advancements in biotechnol-ogy research and increased understand-ing of human genetics) could makebiologics sales reach $30 billion by 2005.Manufacturing of such products couldaccount for $3–6 billion of that value.

Growth projections sharply exceed currentand expected future production capacity ofboth the biotechnology sector and majorpharmaceutical companies. Additionalmanufacturing capacity made available byservice providers will be vital to satisfymarket demand and to ensure that newmedicines can be brought into use rapidlyand reliably. Currently, the annual contractmanufacturing market for biologics isestimated at $300 million. That is pro-jected to increase to over $700 million bythe end of 2005. Currently, microbialfermentation and mammalian cell cultureseach account for roughly 50% of thecontract manufacturing market.

Extending capabilities.The first phase ofAvecia’s biologicsinvestment will betwo 5,000-L fer-mentation streams,each with indepen-dent harvesting andpurification suites tooffer multiproductmanufacturing.With plant construc-tion starting soon,first commercialproduction shouldbegin in 2003. A

second-phase development will add two15,000-L capacity fermentors and theirassociated purification streams. Thescheduled completion date is in 2005, andthe facility will run four large-scale manu-facturing campaigns simultaneously.

The investment program complementsAvecia’s existing Advanced BiologicsCentre (ABC) at Billingham, opened in1998. It produces protein-based vaccinesand new medicines for early clinical trialson scales up to 1,000 L.

Industy Expert AdviceA January 2002 panel discussion regard-ing new approaches to overcomingbiomanufacturing capacity shortfalls wasmoderated by Stefan Loren, managingdirector of Legg Mason Wood Walker(www.leggmason.com), and attractedabout 200 high-level pharmaceuticalexecutives. Aaron Heifetz, senior vicepresident of technical operations forCambrex Bio Science, Inc. (www.bscp.com), joined industry experts fromGenentech (www.gene.com), Biogen(www.biogen.com), and Applied MolecularEvolution (www.amevolution.com).

Panel participants agreed that biomanu-facturing capacity requirements areforcing sponsors to consider increasingtheir internal plant capacities, placing newproduction with contract manufacturingorganizations (CMOs), and leveragingexisting capacity with current CMOs. With

capacity shortfalls piquing the interest ofestablished and early-stage biotechnologycompanies, panel members found itparticularly important for young compa-nies seeking capital to demonstrate asound manufacturing strategy, likely to bebased on outsourcing.

“Market and research firm HighTechBusiness Decisions recently reported thatCMOs are nearing 90% capacity utilizationrates for mammalian cell culture andmicrobial fermentation,” stated Heifetz.“We’re seeing an influx of increasinglyhigher-dosage projects, which requirelarger volumes of manufacturing. As aresult, our team at Cambrex Bio Science isactively evaluating alternatives to increaseproduction, scale, and capacities.”

Although CMOs are rapidly increasingcapacity, Heifetz stressed the importanceof considering alternative or complemen-tary strategies for overcoming capacityissues. One such approach is by startingplanning cycles early, initiating processdevelopment to increase yields andreduce working volumes, and educatingclients on the importance of building long-term relationships with CMOs. Heifetz andhis industry peers concurred that throughstronger alliances, pharmaceutical com-panies and CMOs can better forecast,schedule, and manage biomanufacturingdemand. BP

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