Exploring Custom Synthesis - Pharmaceutical Technology

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Exploring Custom Synthesis
Contract manufacturers strengthen their toolboxes and partnerships as they navigate the changing drug-development model.


Pharmaceutical Technology
Volume 35, Issue 1, pp. 48-54


IMAGE: DON BISHOP, PHOTODISC, GETTY IMAGES
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.

Building the toolbox


Patricia Van Arnum
Biocatalysis. 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.

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 in Germany.

Targeted offerings. 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.


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