A Capacity Wave in Biologics Manufacturing

Several pharmaceutical and biotechnology majors are increasing internal capacity, reflecting strength in the biopharmaceuticals market, but softening demand for contract services. Some contract players have moth-balled capacity, but others are expanding and are finding opportunities in specialized technologies.

"There is a solid-growing market for contract biologics manufacturing services," says Sandra Fox, president of HighTech Business Decisions (Moraga, CA, www.hightechdecisions.com), noting that contract manufacturers account for 20–30% of industry-wide biopharmaceutical manufacturing with projected 2006 revenues of $2.5 billion (see Figure 1).

"The industry has had a slight excess of biologics capacity, mainly in small tank sizes," says Fox. "However, a minor shortfall in capacity, formerly predicted for 2009, may now be alleviated based on recent announcements of new internal capacity being built."

Internal capacity buildup

Genentech, Inc. (South San Francisco, CA, www.gene.com) is adding 200,000 L of bioreactor capacity with a new manufacturing facility in Vacaville, California, expected to be licensed by the US Food and Drug Administration in 2009. It also added 90,000 L of bioreactor capacity in 2005 through its $408-million purchase of Biogen Idec's (Cambridge, MA, www.biogen.com) Oceanside, California facility, which is planned to manufacture "Avastin" (bevacizumab). The plant is expected o be licensed by FDA in 2007. It also is adding 20,000 L of capacity in Porriño, Spain for Avastin production, with licensure expected in 2006.

Amgen, Inc. (Thousand Oaks, CA, www.amgen.com) is investing $1 billion over the next four years to expand its biologics manufacturing capacity in Puerto Rico. This includes expanding its bulk production plant for "Neupogen" (filgrastim) and "Neulasta" (pegfilgrastim), an expansion of the built (but not yet licensed) bulk-protein plant for "Epogen" (epoetin alfa) and "Aranesp" (darbepoetin alfa), a new fill–finish facility, and enhancements to its existing fill–finish facility. It also is investing $1 billion in new bulk-protein manufacturing, formulation, and fill–finish facilities in Cork, Ireland.

Figure 1: Global contract biopharmaceutical manufacturing market. (Source: High Tech Business Decisions)

Bristol-Myers Squibb Company (BMS, Princeton, NJ, www.bms.com) plans to invest $660 million in a new large-scale multiproduct biologics plant in the United States, scheduled for completion and operation in 2009–2011.

Johnson & Johnson's Centocor, Inc. (Malvern, PA, www.centocor.com) is building a new 28,000-m² biologics manufacturing facility in Ringaskiddy, Cork, Ireland, which will come on-line by 2010.

Genzyme Corporation (Cambridge, MA, www.genzyme.com) is investing $53 million to expand by 50% its cell-culture manufacturing facility in Allston, Massachusetts to support increased production of "Myozyme" (alglucosidase alfa). It invested more than $500 million for several projects in Europe, including a new biomanufacturing plant in Geel, Belgium, its first for humanized monoclonal antibodies. The Geel facility will manufacture Myozyme and "Campath" (alemtuzumab) and is scheduled to complete its first production runs in 2006. Genzyme also expanded its bulk manufacturing plant in Haverhill, England, built a new biologics fill-and-finish plant in Waterford, Ireland, and completed a new antibody discovery research center in Cambridge, England.

Specialized technologies emerge

Although the increase in internal manufacturing capacity will slightly reduce the growth in demand for contract mammalian cell-culture capacity in 2009, industry observers see a generally healthy market for contract biologics manufacturing based on the growing pipeline of biopharmaceuticals.

"Although mammalian cell culture has been the fastest growing segment for contractors during the past few years, the pace will slow slightly by 2009 as additional internal mammalian cell-culture capacity comes on-line at pharmaceutical and biotechnology companies," says Fox. "Expanded use of microbial fermentation for fusion proteins, antibody fragments, and other novel drug types is beginning to kick up the pace of demand for outsourced microbial fermentation.

"Fusion proteins can be made in mammalian cell-culture or microbial fermentation; those fusion proteins that require a high amount of glycosylation obviously need to be made in the mammalian cell-culture systems," explains Fox.

BMS's "Orencia" is a fully human soluble fusion protein, approved in 2005 to treat rheumatoid arthritis. In May, FDA approved Lonza's (Basel, Switzerland, www.lonza.com) third-party manufacturing facility to support Orencia production.

DSM Biologics (Parsippany, NJ, www.dsm.com) and Crucell NV (Leiden, Netherlands, www.crucell.com) are partnered with UMN Pharma for using the "PER.C6" cell line for UMN Pharma's UMN-O3 project for developing fusion proteins to treat muscular dystrophy and metabolic diseases. DSM Biologics has coexclusive rights with Crucell to license the PER.C6 cell line, a production platform for recombinant proteins and monoclonal antibodies.

Crucell and DSM Biologics will provide UMN Pharma with CGMP manufacturing through DSM's manufacturing facilities in Groningen, Netherlands. DSM's position in PER.C6 technology is an important part of its biologics strategy. DSM moth-balled its contract biologics facility in Montreal, Canada at the beginning of 2006 and strategically decided to concentrate its contract manufacturing activities in Groningen to support licensees of the PER.C6 technology.

Merck KGaA's (Darmstadt, Germany, www.merk.de) pharmaceutical business also has fusion proteins under clinical development.

In addition to fusion proteins, antibody fragments and antibody-drug conjugates represent a niche area of biologics manufacture. "Antibody fragments are typically made in microbial fermentation systems," explains Fox. "For antibody-drug conjugates, the antibody portion of the drug is made in mammalian cell culture, but the toxin conjugate may be made in a microbial system. The antibody-drug conjugates require several steps, usually performed by different contractors."

Examples of antibody fragments under regulatory review are Genentech's "Lucentis" (ranibizumab) and UCB's (Brussels, Belgium, www.ucb.be) "Cimzia" (certolizumab pegol), an anti-TNF alpha antibody fragment. These drugs are manufactured using Xoma Ltd.'s (Berkeley, CA, www.xoma.com) bacterial cell expression technologies.

Seattle Genetics, Inc. (Bothell, WA, www.seattlegenetics.com) is developing two antibody-drug conjugates: SGN-35, an anti-CD30 antibody-drug conjugate, and SGN-75, an anti-CD70 antibody- drug conjugate. For SGN-35, Seattle Genetics is using antibody manufactured by Abbott Laboratories (Abbott Park, IL, www.abbott.com), has contracted with Albany Molecular Research (Albany, New York, www.albmolecular.com) for GMP manufacturing of Seattle Genetics' proprietary drug-linker system, and is working with a contract manufacturer to conjugate the antibody to the proprietary drug-linker system.

Contract manufacturers expand

Chief among the contract players expanding in biologics manufacture is Lonza, which in February, completed its acquisition of UCB-Bioproducts, the peptide manufacturing division of UCB. The move gives Lonza peptide manufacturing facilities in Braine-l'Alleud, Belgium and capabilities in liquid-phase peptide synthesis to complement its existing capabilities in solid-phase peptide synthesis and recombinant technology.

Lonza is investing $250 million to build a new large-scale mammalian cell-culture plant in Singapore, its second large-scale mammalian manufacturing plant. The Singapore plant will include as many as four mammalian bioreactor trains, each with a flexible capacity of 1000-20,000 L with purification suites. The plant is being constructed over two phases, with the final build-out of the plant scheduled for completion at the end of 2009.

Lonza is adding new mid-scale biologics capacity at its Portsmouth, New Hampshire facility with plans to begin construction of a new mid-scale production plant (as much as 6 × 5000 L) in the second quarter 2006 and is reactivating a mid-scale line (2000 L). On a larger scale, Lonza is on track to start up in June 2006 its fourth 20,000-L reactor.

In Visp, Switzerland, Lonza is building a commercial-scale biopharmaceutical manufacturing facility with microbial fermentation capacity of two production trains of 15,000 L. Start-up is scheduled for the beginning of 2007. A third line currently is in the development stage. This investment involves a long-term supply agreement with UCB, announced in 2005, for manufacturing "PEGylated" antibody fragments.

Lonza also is investing CHF 14 million ($12 million) to expand its clinical-scale mammalian manufacturing capacity at its facility in Slough, UK, scheduled to be on-line in the fourth quarter 2006.

Boehringer Ingelheim (Ingelheim, Germany, www.boehringer-ingelheim.com) is investing EUR 70 million to modernize and expand high-yield fermentation processes for mammalian cell cultures at its biopharmaceutical production facility in Biberach, Germany, scheduled for completion in 2007.

Boehringer Ingelheim further invested EUR 80 million to add a new biopharmaceutical production plant in Vienna, Austria. The plant opened in April 2005, doubling its microbial production capacity to bring its total fermentation capacity to 12,000 L (two 6000 L-fermenters).

Contract peptide players advance

Among the major contract peptide producers expanding, Bachem (Bubendorf, Switzerland, www.bachem.com) is investing $9 million to expand production capacity for the CGMP manufacture of peptide active ingredients at its facilities in Torrance, California, scheduled to be completed by mid-2006.

Polypeptide Laboratories, Inc. (Torrance, CA, www.polypeptide.com) is in the process of substantially increasing its peptide manufacturing capacity in Torrance, California, Malmo, Sweden, and Hillerod, Denmark. The expansions increase solid-phase peptide synthesis capacity, complementing its large-scale, solution-phase synthesis capabilities in Malmo and Hillerod, and also expand its pre-GMP development capabilities in the United States. Completion of the first phase of the expansion in Torrance is scheduled by the end of June 2006, notes Sharoni Gergely, Polypeptide's marketing account manager.

In May 2006, Peptisyntha (Torrance, CA, www.peptisyntha.com) expanded peptide manufacturing in Torrance by tripling capacity by adding two GMP suites (50-L reactors and 8-in. columns for purification with tray lyophilizers) for solid-state peptide synthesis.

"We expanded to increase capacity for supplying GMP peptides for all phases of drug development," explains Satish Joshi, executive vice-president. Peptisyntha also operates a large-scale (3000 L) solution-phase peptide facility in Brussels, Belgium. Peptisyntha is a subsidiary of Solvay SA. Solvay acquired a controlling interest in Girindus SA, a producer of oligonucleotides and radiolabeling services in 2005, giving Peptisyntha a position in radiolabeled peptides.

Another player in the contract peptide market is Group SNPE's NeoMPS (San Diego, CA, www.neomps.com), which operates peptide manufacturing facilities in Strasbourg, France, and San Diego, California.

Synthetech, Inc. (Albany, OR, www.synthetech.com), a producer of specialty amino acids and derivatives, peptide fragments, and chiral intermediates, recently entered the specialty resin market for solid-state peptide synthesis with the acquisition of Colorado Biotechnology Associates Inc., which includes technology for attaching specified terminal amino acids to the resin used as a solid-state support. It scaled up production of the Merrifield resin to a 100-kg batch size. It has prepared Wang and aminoethyl resins on a multikilo pilot scale and larger batches are planned in the near future.

Others target contract market

Pharmaceutical companies also are filling the supply chain. Genentech has an agreement with Wyeth Pharmaceutical's contract manufacturing facility in Andover, Massachusetts to produce the bulk drug substance for Genentech's "Herceptin" (trastuzumab). Wyeth expects to receive licensure by the end of 2006.

Roche Colorado (Boulder, CO, www.rochecolorado.com), a contract producer of peptides, manufactures commercial supplies of "Fuzeon" (enfuvirtide), the fusion inhibitor to treat HIV developed by Roche and Trimeris (Morrisville, NC, www.trimeris.com).