Print page

Email page

Drug Development Through the Looking Glass

By Angelo De Palma, Ph.D., Contributing Editor

PharmaManufacturing.com

Contract manufacturers and intermediates suppliers are raising the bar for chiral chemistry in pharmaceutical development.

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.”