As contract manufacturing organizations (CMOs) and pharmaceutical companies gather next month for Informex, the trade show
of CMOs of active pharmaceutical ingredients (APIs) and intermediates, they confront an increasingly challenging environment
for drug development. They face a common pressure to accelerate time-to-market and deliver cost- and time-effective solutions
to technical issues while navigating changing business relationships in an era of industry consolidation and shifting pipeline
priorities. CMOs are responding with targeted enhancements to their toolboxes and manufacturing cacapabilities.
IMAGE: DON BISHOP, PHOTODISC, GETTY IMAGES
Building the toolbox
Asymmetric synthesis is an ongoing area of technical need, and several companies recently have expanded their capabilities
in biocatalysis. In December 2010, DSM Pharmaceutical Products, the custom manufacturing organization of DSM (Heerlen, The
Netherlands) formed a license agreement with c-Lecta (Leipzig, Germany), an industrial biotechnology company. The agreemnt
grants DSM rights to c-Lecta's proprietary alcohol dehydrogenases for enzyme-screening programs and development of manufacturing
routes for manufacturing APIs and intermediates. Alcohol dehydrogenases are used to synthesize chiral alcohols from ketones.
Patricia Van Arnum
Almac (Craigavon, UK) is investing $4 million in biocatalysis research and development. Areas of research include the discovery
of new biocatalytic platforms for producing chiral intermediates, hyper-activation of biocatalysts for reducing enzyme loadings,
and developing drivers for cofactor recycle and mitigating problems with equilibriums. In 2009, the company also launched
carbonyl reductase, transaminase, hydrolase, nitrilase, and nitrile hydratase enzyme screening kits.
As an example of biocatalysis at work, Almac carried out preliminary screening to show that a carbonyl reductase (CRED) bioreduction
could replace a resolution for preparing a chiral alcohol. After identifying a CRED at small scale, the company scaled up
production and integrated the biocatalytic approach into the API process development program and manufactured 30 kg for Phase
I clinical trials, according to an Almac Oct. 7, 2010, press release.
In other developments, Codexis (Redwood City, CA) expanded its offerings in biocatalysis by offering screening kits for a
subset of the range of biocatalysts it offers. The kits contain 24 enzymes from Codexis' collection of biocatalyst variants
from two enzyme classes: ketoreductase and transaminase. The company launched the kits in October 2010. The CMO Cambrex (East
Rutherford, NJ) acquired IEP (Wiesbaden, Germany), an industrial biocatalysis company, in March 2010. In July 2010, Johnson
Matthey (West Deptford, NJ) acquired X-Zyme (Düsseldorf, Germany), a provider of enzymes, particularly oxidoreductases for
producing chiral intermediates. X-Zyme is a 2001 spin-off from Heinrich Heine University's Institute of Molecular Enzyme Technology
CMOs also are adapting their capabilities to serve specific areas in the drug-development spectrum. For example, in September
2010, DSM launched InnoSyn, a route-screening service, which applies various tools such as biocatalysis, homogeneous catalysis,
and continuous chemistry using microreactors to screen catalysts for feasibility studies for chemocatalytic and biocatalytic
steps.The company recently introduced new enzymes such as pig liver esterase (i.e., pharmaPLE), lyases, transaminases, dehydrogenases
and homogeneous catalysts for asymmetric hydrogenations, aromatic substitutions, and oxidations. The company further developed
a nitration reaction using microreactor technology.
In November 2010, Lonza (Basel) formed an alliance with Dalton Pharma Services (Toronto) for providing early-phase chemistry
and kilogram laboratory manufacturing services for small molecules. The move enables Lonza to provide early-phase pharmaceutical
chemical development services to customers in North America. Lonza provides kilogram to large-scale manufacturing capabilities
at its facilities in Visp, Switzerland, and Nansha, Guangdong Province, China.