Drug Development Through the Looking Glass

For those who struggled through organic chemistry, the mere mention of stereochemistry terms, whether R and S, + and -, or levo and dextro, can bring on cold sweats. But if you are a synthetic organic chemist, chances are that chirality is exactly what hooked you.

The abstractness of chirality, and the difficulty in realizing it at commercial scale, slowed its adoption in everyday pharmaceutical practice for decades. Indeed, for much of their history, pharmaceutical manufacturers pretty much ignored chirality and its potential impact on drug properties — sometimes with tragic results, as with thalidomide.

Eventually drug developers and regulators came to recognize chirality for its potential benefits: less complex pharmacology, improved therapeutic index, lower toxicity, and less waste in manufacturing. Pharmaceutical manufacturers annually produce as much as a thousand tons of product, but, in the process, generate 100 times as much waste. Provided development of a single isomer makes therapeutic sense, chirality can help cut down on side products, spent solvent and other waste products.

This article will look at how contract manufacturers and intermediates suppliers are advancing the state of chiral pharmaceutical manufacturing.

“Chiral switches” were the first stereochemically pristine drugs to emerge from the chiral renaissance of the early 1990s. These previously approved racemates were reinvented, for purposes of life-cycle management, as single-isomer medicines. Examples such as S-ketamine, S-ibuprofen, and S-citalopram became successful products from a marketing standpoint, but were hardly revolutionary in their improved safety and efficacy. The most famous chiral switch, AstraZeneca’s Nexium, substitutes S-omeprazole for racemate. According to experts, however, there is no evidence that the S-isomer works any better than the racemic mixture. Still, a new molecule is a new molecule.

The chiral switch strategy did not last long, however. “You won’t find too many more chiral switches because drugs are now being developed as single isomers,” says Michael Cannarsa, Ph.D., general manager at ChiralQuest (Monmouth Junction, N.J.).

Rough going

With most of the low-lying chiral switches taken, manufacturers began to apply chiral technology to development-stage molecules. The going was tough at first because chiral synthesis undertaken de novo can be very difficult. Reagents tend to be esoteric and expensive — often too expensive for manufacturing scale. Since asymmetric reactions occur under kinetic control, obtaining high enantiomeric excess (ee) often requires low- temperature reactions.

To make matters worse, early chiral specialty companies, typically armed with a few university patents, developed business plans that called for “partnerships” with big pharma customers based on licensing, royalties on sales of finished product and similar intimate relationships. Those are nice deals if you can get them, but drug developers soon began to look elsewhere for chiral technology, or develop it in-house.

Luckily, demand for chiral intermediates — aided in no small way by forward-looking guidances from the U.S. Food and Drug Administration — fueled interest in manufacturing-worthy chiral processes. Today, chirality has become a near-commodity and chiral drug development is a given:

• Of the dozen chemical drugs registered in 2004, nine are chiral;



• About 30% of marketed branded drugs contain one or more chiral centers. Some are sold as single enantiomers, some are not;



• Nearly half of all pipeline molecules possess one or more chiral centers;



• Between 60% and 70% of chiral pipeline molecules are fully synthetic, the rest semi-synthetic;



• Vendors sell custom-synthesized chiral reagents and off-the-shelf reagents by the ton, usually with no strings attached.

FDA’s position

The U.S. Food and Drug Administration began formulating a position on chirality during the late 1980s. The regulatory document “Development of New Stereoisomeric Drugs” (1992, and last updated in 2005) outlined FDA’s expectations for chiral drug development. The Agency bases its position on evolving chiral technology (both for synthesis and resolution), and the recognition that enantiomers may exhibit the complete range of similarity or dissimilarity with respect to safety and efficacy. Above all, developers should apply reasonable scientific principals to chiral drug development, since “the common practice of developing racemates has resulted in few recognized adverse consequences. Although it is now technologically feasible to prepare purified enantiomers, development of racemates may continue to be appropriate.”

FDA asks that companies consider implementing appropriate manufacturing and control procedures to assure a product’s stereoisomeric composition, including tests to quantify stereoisomers. If the pharmacokinetics are the same, a chiral assay or an assay that monitors one of the enantiomers may be used. Sponsors must also investigate pharmacology in vitro, in animals, or in humans “unless it proves particularly difficult.” A desirable racemate toxicology profile would ordinarily support further development without investigating individual enantiomers.

If the racemate passes standard toxicology testing, sponsors interested in developing a single isomer must then conduct “abbreviated, appropriate” safety and efficacy studies “to allow the existing knowledge of the racemate available to the sponsor to be applied to the pure stereoisomer.” Such studies would include “the longest repeat-dose toxicity study conducted (up to three months), and the reproductive toxicity segment II study in the most sensitive species, using the single enantiomer.”

If no difference is noted between racemate and pure isomer, fine. In cases where the single enantiomer is more toxic, sponsors must determine why and consider the “implications for human dosing.” Finally, where little difference is observed in activity of the enantiomers — by far the most likely circumstance — then racemates may be safely developed with FDA’s blessing.

Getting chiral

In the old days there were only three ways to obtain chiral compounds:

• direct isolation from natural sources;
• resolution of racemates;
• asymmetric synthesis.

Although modern pharmacopoeias still include natural products and their simple analogs, medicinal chemists rely on these compounds mostly as starting materials or building blocks. Amino acids, sugars, terpenes and vitamin C often serve as simple starting points for a host of complex chiral intermediates.

More detailed chiral structures rely on semi-synthesis. The two best-known examples are Taxol, which is manufactured in four steps from a compound isolated from the English yew, and desogestrel, the steroid contraceptive whose starting material is isolated from dioscorea root and converted, through ten chemical steps, into the drug.

But with each new chiral process, it seems that manufacturers must reinvent the wheel. “Although many synthetic tools are available for introducing chirality in the laboratory, the challenge is to perform these reactions on industrial scale,” says Ronald Gebhard, Ph.D., R&D director at DSM Pharma Chemicals (Geleen, Netherlands).

When asymmetric synthesis is impractical at large scale, manufacturers fall back on classical and enzymatic resolutions, which are inherently wasteful since each pass theoretically yields just 50% of the desired product. Unless the undesired isomer can be recycled through re-racemization, it must be discarded as waste, along with spent resolving reagents and solvent.

Dynamic resolutions

Much effort has therefore been devoted to developing dynamic resolutions which provide high chemical yield and an ee approaching 100%. These work by cycling the unwanted product through re-racemization and further resolution steps. For example, DSM employs a proprietary, dynamic, one-pot kinetic resolution which replaces classical resolution. The company is also keen on methods that avoid resolution altogether, especially asymmetric hydrogenation and enzymatic reactions employing hydroxy nitrile lyases, aldolases and reducing enzymes like alcohol dehydrogenase. Enzyme reactions, for molecules that are reasonably water-soluble, provide close to 100% chemical and enantiomeric yield.

DSM maintains three manufacturing sites (Venlo, Netherlands, Linz, Austria and South Haven, Mich.) and a kilogram shop in Regensburg, Germany. All produce active pharmaceutical ingredients and advanced or registered intermediates. Less-advanced starting materials are sourced from partner companies in India and China, and new technology is constantly added to the company’s portfolio from universities and start-up firms.

DSM is among a handful of contractor/vendors to whom big pharma entrusts “route scouting” — applying advanced synthetic methods and process technologies to intensify processes and drive down the costs of lengthy syntheses. Introducing chirality is often the key step in developing these “breakthrough” synthetic routes.

Some customers, usually venture-cap drug companies, provide what Gebhard calls a “university route” that is often difficult to scale up. In such cases, DSM’s chemists will develop a workable synthesis, often employing biocatalysis to cut down on chemical steps. However, nine out of ten times the “tech package” DSM receives from customers already includes well-defined chemistry. “Our value in those instances is not so much novel chemistry, as responsiveness, on-time delivery within specs and competitive costs at scale.”

Large chemical companies have been quite successful in building chiral product and service businesses. Chiral intermediates are a core product offering for chemical giant BASF (Florham Park, N.J.). The company’s ChiPros line of chiral building blocks includes imidazoles, vinyl ethers, amines, acids, alcohols and epoxides — about 100 intermediates in all, about half of which are chiral amines.

To attract new business and maintain its expertise level, BASF constantly augments its ChiPros catalog through a combination of core chiral chemistry and proprietary biotechnology, applied to a “multitude” of pharmaceutical drug candidates and intermediates, says business development director Frank Stein, Ph.D. The company has recently developed a new production process, expanding its technology platform for optically active styrene oxides and aliphatic alcohol. The new process, based on dehydrogenase biocatalysts, allows for the production of high-purity intermediates.

Like all companies in this business, BASF must grow to keep up with demands of the marketplace. At the recent Informex conference in Orlando, Fla., the company presented data on creation of new chiral alcohols from epoxides, amino alcohols and amino acids. However, the company does not aim at the broadest possible chiral intermediate and reaction portfolio, preferring market-driven, high-yield, high-ee, best-in-class technologies that solve the widest range of problems. “We draw on whatever technologies make sense,” says Stein. Among those are biocatalysis, from which BASF creates 50 different chiral amines, dehydrogenases for chiral alcohols and nitrolases for chiral organic acids.

To keep up with new opportunities for chiral materials, BASF has doubled its chiral business development team. This group anticipates the market’s needs for chiral synthons and intermediates by scouring public and private databases for chiral pipeline compounds. When something promising shows up, the team proposes possible chiral synthons and intermediates to serve the needs of development, scale-up, and manufacturing. “We talk with chemists and in some cases provide very small quantities of new building blocks,” says Stein.

With its 2001 acquisition of U.K.-based Chirotech, Dowpharma (Midland, Mich.) has redoubled its efforts at providing a complete chiral tool kit to pharmaceutical customers. “Chirality is very dear to our hearts,” says Mark Cassidy, Ph.D., business director for small molecules. “There’s not a single therapeutic class today that is not affected by it.” Dowpharma’s specialties are asymmetric hydrogenation, chiral hydroformylation and biocatalysis, for which the company utilizes both proprietary and commercially-available catalysts and enzymes.

With the diversity of NCEs, drug sponsors can no longer rely on a single transformation or capability. “Customers don’t want that one-size-fits-all approach,” says Cassidy.

“We operate in a custom market and the business models we practice also must be customized to meet to our customers’ needs.” Dow supplies early-stage chiral synthons and registered starting materials through Asian manufacturing partners. More advanced, regulated chiral intermediates are manufactured in Europe or at Dowpharma’s main facility in Midland. Proprietary chiral intermediates, catalysts and biotransformations may also be supplied or licensed to customers or their designated contractors.

Sourcing and outsourcing

Chiral reagents and simple intermediates are increasingly sourced overseas. James Gao, Ph.D., sales manager at D-L Chiral Chemicals (Monmouth Junction, N.J.) represents custom- and bulk-synthesis companies in his native China. “We learned very well from Wal-Mart,” says Gao. “We buy cheaply from Asia and sell here at a premium.”

Most of the chiral compounds Gao purchases from Chinese firms are basic building blocks and derivatives of simple chiral starting materials. One of the companies he represents, AllyChem (Dalian, China), sells (R)-(+)- and (S)-(-)-2-Methyl-2-propanesulfinamide, a relatively new reagent whose chirality resides on sulfur instead of the more usual carbon. Chiral sulfinamides, which synthesize enantiomerically pure amines and alcohols from aldehydes, were invented by Prof. Jonathan Ellman at the University of California, Berkeley, and are sold by several vendors as “Ellman’s chiral amine reagents.”

Chiral sulfinamides have an interesting history that parallels that of chiral reagents in general. Though these reagents have been available since 1997, they were unpopular due to their high cost. As recently as 2005 one vendor sold them for about $60 per gram, which is far too expensive for drug making. In 2004, Advanced Asymmetrics (Millstadt, Ill.) came up with a bulk price of $20,000 per kilogram but was soon undercut, the next year, when Suven Life Sciences (Monmouth Junction, N.J.), began offering sulfinamides for a mere $7,500 per kilo. Allychem soon countered with a price of $2,500 and expects to get the cost down to under $1,000 by the end of 2006.

ChiralQuest (Monmouth Junction, N.J.) began as a chiral products company by licensing 10 chiral hydrogenation catalyst patents originating in the laboratory of Prof. Xumu Zhang at Penn State University, and then adding more products. “Chiral hydrogenation has been around for about 35 years,” notes general manager Mike Cannarsa, Ph.D., “but until Zhang’s technology came along very few applications were practical at industrial scale.”

Asymmetric hydrogenation uses inexpensive hydrogen gas and reagents which, while costly, are used in catalytic amounts so their actual cost contribution is low. Hydrogenation reduces most multiple bonds (carbon-carbon, carbon-oxygen, carbon-nitrogen) cleanly and in high chemical and stereochemical yield. Although chiral hydrogenation is a relatively straightforward operation, many pharmaceutical manufacturers — especially start-ups — are unwilling or incapable of carrying out the reaction.

ChiralQuest’s business model includes every permutation of reagent sales, licensing and contract manufacturing. “However, many manufacturers are hesitant to enter complicated licensing deals or partnerships,” Cannarsa admits. Because of this, chiral intermediates represent the “sweet spot” for specialty chirality firms like ChiralQuest.

ChiralQuest sells not just catalysts, but also higher-value intermediates manufactured in its own facilities or with Chinese partners. The company maintains a Chinese pilot-scale subsidiary, CQJ (Shanghai), which supplies scale-up and R&D services, and serves as an interface to other Chinese suppliers.

Chiral drug development has affected contract manufacturing organizations (CMOs) as well. Full-service API contractors like Cambrex (East Rutherford, N.J.), which has 60-plus ongoing projects, use classical resolution and chiral chemistry, plus high-energy reactions and enzyme-based synthesis. Cambrex’s proprietary enzyme processes can churn out chiral intermediates at the ton scale, for example in producing generic amphetamine. “Our specialty is chiral amines,” explains Nick Shackley, VP of business development, “but we take on projects and customers of all stripes.”

From its perspective as an API manufacturer, Cambrex has not noticed any dramatic increase in demand for chiral products and related services. “There’s been a steady trend towards more complex molecules, which tend to be chiral,” says Shackley. “The technology has improved similarly over time, but there haven’t been any dramatic shifts or blockbuster chiral technologies emerging either.”

Although the chirality hype of the early 1990s has subsided, chirality is more relevant than ever. Do we see many cases where one enantiomer kills and the other cures? “No,” says Cannarsa of ChiralQuest. “But drug pipelines are nevertheless flush with single-enantiomer chiral compounds, and the chemistry is now doable, almost commoditized. Because drug manufacturers are comfortable with it, they will use it.”

Increasingly, chirality is viewed as just another property of pharmaceutical molecules. Although a good deal of consolidation has occurred in the last decade among pure-play chirality companies, the opportunities have never been greater for devising new chiral reagents, intermediates, services and, above all, processes. “The market wants proven, scalable, cost-effective chiral solutions,” says Cassidy of Dowpharma. “Drug developers face enough challenge and uncertainty during clinical trials. They don’t need to worry about the uncertainties of synthesis as well.”