Exploring Custom Synthesis

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

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.

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 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.

Expansions

CMOs also are expanding niche technical capabilities and diversifying into new areas, such as formulation development and dosage manufacturing. In October 2010, SAFC (St. Louis, MO) completed an expansion of its facility in Jerusalem, which provides fermentation of APIs and bulk drugs, including secondary metabolites, cytotoxins, and large-molecule proteins.The expansion in Jerusalem follows a $30-million expansion at SAFC's facility in Verona, Wisconsin, to increase capacity for commercial-scale manufacture of high-potency APIs in 2010.

Fermion, the contract-manufacturing arm of the pharmaceutical company Orion (Espoo, Finland), is investing EUR 5 million ($7 million) in Oulu, Finland, to expand its capabilities in high-potency manufacturing. The expansion is expected to be operational in early 2012.

Piramal Pharma Solutions, the contract manufacturing arm of Piramal Healthcare (Mumbai), completed the latest phase of its investment program to increase production capacity for antibody drug conjugates at its facility in Grangemouth, Scotland, in 2010. The expansion will support the GMP production for the planned launch of new cancer treatment by an undisclosed US-based biotechnology company in 2011.

CMOs historically focused on small-molecule development also are expandinging their toolboxes to include formulation capabilities. For example, in June 2010, the CMO AMRI acquired Hyaluron (Burlington, MA) to add fill–finish and sterile manufacturing capabilities. In November 2010, Cambrex acquired a 51% stake in Zenara Pharma (Hyderabad, Andhra Pradesh, India), a pharmaceutical company focused on the formulation of final dosage form products.

Select CMOs also are expanding through acquisition as bio/pharmaceutical companies divest manufacturing sites as part of adjustments to their product portfolios. For example, in December 2010, Aescia Pharmaceuticals (Newcastle, UK) agreed to acquire three manufacturing sites from the biopharmaceutical company UCB (Brussels) and formed a long-term supply agreement with UCB. The sites are located in Monheim and Zwickau, Germany, and Pianezza, Italy. Aescia also is is investing in a new high-containment facility in Queenborough, United Kingdom. The facility is scheduled to be completed in May 2011. And in June 2010, Aesica acquired R5 Pharmaceuticals, a company specializing in formulation development.

Working with multiple partners

A custom manufacturer is not only charged with the task of developing a synthesis, but also must navigate the changing business relationships that might occur as a drug works its way through development. Such is the case with Regis Technologies (Morton Grove, IL), which first partnered with Rush University Medical Center in Chicago in 1983 to supply GMP quantities of 4-aminopyridine, which was being studied as a treatment for multiple sclerosis (MS). In 1990, the Irish pharmaceutical company Elan (Dublin) licensed the rights relating to 4-aminopyridine (exclusive of the intellectual property rights relating to the synthesis of 4-aminopyridine, which were retained by Regis) to study the drug as a possible treatment for MS.

In 2003, Acorda Therapeutics (Hawthorne, NY) licensed the rights from Elan and pursued development of the drug. Acorda assumed the clinical trials and licensing for 4-aminopyridine (also known as dalfampridine and previously named fampridine while under development with Elan) and partnered with Elan for developing the formulation for the drug. Ampyra is a potassium channel blocker and was found to improve impulse conduction in nerve fibers in which the insulating layer, called myelin, has been damaged. The drug was developed using controlled-release technology developed by Elan, MXDAS (MatriX Drug Absorption System). Ampyra was developed using a hydrophilic matrix, which controlled the rate of release of dalfampridine through a process of diffusion and erosion in the gastrointestinal tract, according to a Jan. 25, 2010, Elan press release. Using this technology, consistent therapeutic blood levels were achieved throughout the dosing period, and side effects associated with the immediate-release formulations of the drug were reduced.

Acorda filed a new drug application for Ampyra, an extended-release formulation of 4-aminopyridine with US Food and Drug Administration in April 2009. The drug was granted orphan-drug status. In January 2010, FDA approved Ampyra (dalfampridine) extended-release tablets to improve walking in patients with MS, according to a Jan. 22, 2010, FDA press release. In clinical trials, patients treated with Ampyra had faster walking speeds than those treated with an inactive pill (i.e., placebo), according to the release. According to a Jan. 22, 2010, Acorda press release, Ampyra demonstrated efficacy in people with all four major types of MS (relapsing remitting, secondary progressive, progressive relapsing, and primary progressive). Ampyra can be used alone or with existing MS therapies, including immunomodulator drugs, according to the Acorda release. Ampyra is marketed in the United States by Acorda Therapeutics and by Biogen Idec (Weston, MA) in markets outside the US. Acorda formed an agreement with Biogen Idec in 2009 for a sublicensing of its existing license agreement with Elan.

Regis initially developed the synthesis for 4-aminopyridine when the compound was first investigated by Rush in Chicago, explains Sean Bradley, director of business development at Regis. Regis supplied the compound to both Elan and Acorda. Regis holds the US and several foreign drug master files for the drug. Compared with other APIs, 4-aminopyridine (C₅H₆N₂) is a relatively "small" small molecule, an isomeric amine of pyridine, with only 13 atoms and one ring, says Bradley. One of the tasks, however, in the synthesis of the compound was to get the drug produced at a high enough purity. "The proprietary process that Regis developed was not at all obvious," says Bradley. "The keys to the success of this effort were understanding the manufacturing process parameters, identifying key impurities, and developing corresponding analytical methods to support the synthesis," he says. "Over the course of the past 25 years, regulatory standards have greatly increased. Regis' process successfully met those regulatory challenges, thereby facilitating Acorda's launch of Ampyra." FDA performed a preapproval inspection of Regis' Morton Grove, Illinois, facility and was given verbal approval by the FDA inspector in May 2009. Regis received the Establishment Inspection Report from FDA certifying the preapproval inspection in November 2009.