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Relative cost-effectiveness modeling to understand the value of preparative chiral separations in pharmaceutical R&D

corresponding

JEFFREY P. KIPLINGER
Averica Discovery Services Inc. 260 Cedar Hill Street, Marlborough, MA 01752, USA

Abstract

Strategy during early drug development requires attention to the profiling and de-risking of the drug candidate and to planning for supply as the preclinical and clinical programs progress. Supplying chiral drug candidates as single stereoisomers adds a layer of complexity. Chiral resolution by chromatography is considered an expensive alternative for large scale production, but in preclinical development it may not be cost effective to invest in a later stage production process. In this article, we discuss ways to improve the cost equation in favor of chromatography – to ensure that near term program needs are met and to reduce the costs of large scale or commercial production.


Drug development is an increasingly long and expensive process.  While much of the cost comes from risk management, much comes from efforts to develop and use the best scientific knowledge when intending to give a new therapy to humans. One way this is done is to focus on specificity of action, reducing dosage and off-target toxicity concerns. Chirality – stereoisomerism, or right- and left-handedness - is a property of many molecules that can be taken advantage of to enhance specificity of drug action (1).  Because of this powerful strategy, new drug products are overwhelmingly chiral molecules developed as single enantiomers – 76% in 2001 compared with 21% in 1991 (2).  Regulatory guidance charges sponsors with investigating efficacy, bioavailability, toxicity, and stability of all isomers of a new molecule.   Risk management played a role in the change – thalidomide is a good example of a racemic drug with one effective and an opposite toxic enantiomer – but market value played a bigger role, as developers motivated by differential isomeric activity moved fast to develop target-specific single enantiomer drugs.
Developing a chiral molecule re ...




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