Relative Cost-Effectiveness Modeling to Understand the Value of Preparative Chiral Separations in Pharmaceutical R&D
Jeffrey Kiplinger; Paul Lefebvre; Keith Galyan; Emily Showell-Rouse
Chiral chromatography has been used to prepare samples of single stereoisomers for small to mid-scale efficacy, pharmacology, and toxicity testing. Conventional wisdom holds that chromatographic isolation of isomers of drugs becomes less cost-effective as the synthetic scale increases, so efforts to develop a stereospecific synthesis or a “batch resolution” approach are often initiated well before clinical trials begin.
The question of when – at what point in the R&D timeline, or at what scale-up level – chromatographic preparation becomes a cost burden is not often quantitatively evaluated. The choice often depends on balancing the costs of developing a non-chromatographic process (which will be wasted if the compound does not progress to clinical stage) against the cost-effectiveness of chromatography. Traditionally chromatographic efficiency is measured through loading studies, which provide an absolute productivity figure of merit in units such as KKD (kg feedstock/kg stationary phase/day). We suggest that an alternate approach, based on evaluating the relative efficiency of feedstocks produced by different chemistry options, offers a better assessment of cost-effectiveness. For example, partial enrichment of a desired isomer, changes in the impurity profile of a mixture, or protection/deprotection strategies can dramatically influence separation efficiency. Planning to compare production efficiency of different feeds is a rapid process, and offers more information than a final loading study on a synthetic product. Developing a chemistry strategy based on this feedback optimizes R&D program support during drug candidate profiling and de-risking, and facilitates cost-effective decision making prior to and during GMP production.
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