Investing in High-Potency Manufacturing

Reflecting strong pipeline potential and growth in the oncology drug market, contract manufacturers of active pharmaceutical ingredients (APIs) and formulation services are investing in high-potency manufacturing.

PHOTO: PHOTOS.COM

Cytotoxic drugs, prostaglandins, opiates, and certain hormones may be classified as potent compounds. Cytotoxic compounds (see sidebar, "Inside the cytotoxic drug market") represent a portion of the oncology drug market. Global sales of oncology drugs were $34.6 billion in 2006, according to IMS Health. These sales represented 5.7% of the global market and were second in market share only to lipid regulators, which held 5.8% of the global market in 2006. In 2006, global sales of oncology drugs rose 20.5%, making this class of drugs the strongest-performing therapeutic class. The growth in oncology drugs far surpassed the average growth (10.7%) of the top 10 therapeutic classes, according to IMS.

The pipeline potential of oncology products is strong. Overall, at the end of 2006, there were a total of 2075 molecules in development, including 95 oncology products in Phase III clinical trials or preapproval stage, according to IMS. Other industry estimates show that 25% of all emerging new chemical entities are highly potent substances, and 60% of these are novel, highly targeted small molecules.

Patricia Van Arnum

Expanding API manufacturing

To meet demand for highly potent compounds, contract manufacturing organizations (CMOs) are expanding. SAFC (St. Louis, MO) is planning to build a new current good manufacturing practices (CGMP) suite for potent API conjugation at its St. Louis manufacturing campus. The new suite will enable the conjugation of highly potent APIs to a variety of targeted delivery molecules, including monoclonal antibodies. The new 600-ft² conjugation suite is expected to be operational in late 2007 and will seek "SafeBridge" certification (see sidebar, "Certification for high-potency manufacturing"). The suite will accommodate early-stage clinical supplies of potent conjugated APIs and be able to expand production into commercial scale.

Highly potent compounds

This investment follows SAFC's recently announced plans to add assets in the United States and Israel for high-potency API manufacturing. These plans include a $4.5-million expansion to introduce additional CGMP pilot-plant and kilo-laboratory capacity at its Madison, Wisconsin, facility. The facility underwent a $12-million, 38,000-ft² expansion program that was completed in 2006.

Inside the cytotoxic drug market

SAFC is also investing $29 million to expand fermentation capacity at its facility in Jerusalem, Israel. The expansion is scheduled for completion in 2009. The enhancement will allow for process development and CGMP manufacturing for large-scale, high-potency, toxic or hazardous drug substances. The 50,000-ft² high-potency fermentation expansion will focus production on secondary metabolites (antibiotic-like molecules), cytotoxins, and large-molecule proteins. A 30,000-ft² area of the new facility was designed to be compliant with Biosafety Level 2 thus, enabling manipulation of human pathogens. Site capabilities include 1000- and 4000-L tank capacities for bacterial and fungal fermentation.

The $4.5-million expansion in Madison will add an additional CGMP pilot- plant and kilo-laboratory capacity and is scheduled to be commissioned in early 2008. The investment also includes the addition of X-ray powder diffraction (XRPD) analytical equipment for advanced solid-form testing to provide on-site CGMP and XRPD analysis of potent compounds. The capacity expansion includes the addition of two 400-L CGMP pilot-plant reactors and two 100-L CGMP portable jacketed reactors into a 1200-ft² large-scale kilo laboratory. The addition will enable large-scale chromatography for process purification.

Lonza (Basel, Switzerland) is investing CHF 80 million ($68 million) for a new manufacturing site in Visp, Switzerland, for large-scale production of highly potent APIs. As part of the investment, Lonza plans to hire approximately 40 new employees by 2009.

Certification for high-potency manufacturing

Lonza is also adding large-scale production of antibody drug conjugates. The manufacture of antibody drug conjugates involves the coupling of a highly active chemical substance with a biotechnologically manufactured antibody. Lonza is investing in a new production unit and supporting development and analytical laboratories, all to be located in Visp. Construction of the commercial-scale plant in Visp began in the last quarter of 2006. Stage I is expected to be on line in 2008. The plant will initially be capable of producing more than 100 kg of antibody drug conjugates per year, and future expansion plans are built into the design. Lonza currently operates laboratory-scale production of drug antibody conjugates and is bringing small-scale pilot facilities on stream in 2007.

Carbogen Amcis (Bubendorf, Switzerland), which offers manufacturing of highly potent APIs, added new high potency analytical and quality-control laboratories at is facilities in Bubendorf, Switzerland, earlier this year. The laboratories are designed to support analytics of highly potent compounds down to an occupational exposure limit of 0.3 μg/m³ .

Cambrex (East Rutheford, NJ) is adding laboratory space to its high potency site in Charles City, Iowa. The project adds 11,500 ft² with five new process development and kilo-laboratory production suites for highly potent APIs. The expansion also includes enhanced facilities for analytical development and quality control. Cambrex expects the expansion to be completed in early 2008.

Aptuit (Greenwich, CT) gained high-potency manufacturing capabilities with the acquisition of EaglePicher Pharmaceutical Services. Aptuit completed its purchase of EaglePicher Pharmaceutical Services earlier this year.

NPIL Pharma (Mumbai, India) also recently expanded its high-potency substance facility in Grangemouth, Scotland. The Grangemouth facility provides contract manufacturing of cytotoxics and prostaglandins for preclinical and clinical development. The expansion includes the recruitment of 16 additional technical and operational employees and a roughly $500,000-investment in containment upgrades. The hardware investment brought more CGMP capacity for clinical trial materials on stream in late 2006. The new containment upgrades to an existing GMP suite include additional high-integrity barrier isolation for the safe handling for Category IV–V toxins for conjugation to monoclonal antibodies and targeting agents. NPIL Pharma gained the Grangemouth facility as part of its acquisition of the custom manufacturer Avecia Pharmaceuticals in December 2005.

Ferro Pfanstiehl Laboratories (Waukegan, IL) expanded its manufacturing capabilities for highly potent APIs last year. In 2006, the company commissioned a new Class IV (performance-based exposure control level) containment facility in Waukegan, Illinois. The facility is designed for low-volume production of highly potent APIs, including small-molecule new chemical entities in early-phase development. The 2000-ft² addition offers production of preclinical through commercial quantities ranging from 1–5 kg. The kilo laboratory complements product batch capacities of 3–50 kg in Ferro Pfanstiehl's existing commercial containment facility in Waukegan.

Gains in secondary manufacturing

CMOs involved in dosage-form manufacturing are also expanding capabilities for highly potent substances. Earlier this year, Almac Sciences (Craivagon, Northern Ireland) formed a pact for fill-and-finish services with the Center for Pharmaceutical Science and Technology (CPST) at the University of Kentucky. In February of 2007, the university spun off the CPST into a private company, Coldstream Laboratories. Coldstream will provide intravenous formulation and sterile fill of cytotoxics and potents for clinical-trial applications. CPST opened a new $17-million sterile manufacturing facility in May 2006. By 2011, the Coldstream facility is projected to have annual revenues of $15 million and employ up to 50 science-based and other professional staff. The collaboration positions Almac Sciences in upstream offerings in cytotoxics. Almac also offers contract manufacturing of high-potency APIs at its facility in Craigavon, Northern Ireland.

Baxter BioPharma Solutions (Round Lake, IL) recently completed the lyophilization capacity expansion at its cytotoxic contract-manufacturing facility in Halle, Germany. The expansion added two large-scale lyophilization units to increase the site's total cytotoxic lyophilization capacity to four dedicated lyophilizers.

Encap Drug Delivery (Livingston, Scotland) is building a £3-million ($6.1-million) pharmaceutical development and manufacturing facility in Livingston, Scotland. The facility will include dedicated, high-containment suites for formulation development and the clinical and commercial manufacture of high-potency and cytotoxic compounds. The facility is scheduled to be operational by June 2008.

NextPharma Technologies (London) is investing EUR 16 million ($23 million) to more than double its sterile cytostatics (oncology) manufacturing capacity at Braine l'Alleud, Belgium. The investment adds a second production line to increase lyophilization capacity for the US, European, and Japanese markets. The investment program will be undertaken in stages between mid-2007 and 2010.

Pharmatek Laboratories (San Diego) is adding cytotoxic and high-potency drug-development capabilities to its pharmaceutical chemistry development services. Services for cytotoxic and high-potency compounds include analyticalmethod development, preformulation testing, formulation development, manufacturing for early-phase clinical trials, release testing, and stability testing and storage.

Pharmatek's cytotoxic and high-potency development services will be carried out in a separate dedicated facility. Its manufacturing capability includes two validated and licensed Class 100,000 high-containment suites designed with barrier technology for the CGMP manufacture of final-form drug products.

Patricia Van Arnum is a senior editor at Pharmaceutical Technology, 485 Route One South, Bldg F, First Floor, Iselin, NJ, 08830, tel. 732.346.3072, pvanarnum@advanstar.com