Counting the cost of chromatography
Dr Pilar Franco, of Chiral Technologies Europe, considers the costs and benefits of chromatography to obtain single enantiomers of active pharmaceutical ingredients (APIs)
Dr Pilar Franco, of Chiral Technologies Europe, considers the costs and benefits of chromatography to obtain single enantiomers of active pharmaceutical ingredients (APIs)
The manufacturing process for several pharmaceutical drugs utilises Simulated Moving Bed (SMB) technology. As a result chromatography is increasingly accepted as a viable process to obtain single enantiomers of active pharmaceutical ingredients (APIs). Several companies around the world, including UCB Pharma, Bayer, Lundbeck, Daicel, Aerojet, Honeywell and Finorga, have demonstrated that the continuous separation of multi-ton quantities of enantiomerically pure drugs per year is feasible and economically competitive. Technological advances regarding the chromatographic systems and the availability of bulk chiral stationary phases (CSPs) with excellent batch-to-batch reproducibility are primarily responsible for this progress.1,2
cost-effective strategy
Contrary to popular belief, the implementation of SMB technology and the rational development of chromatographic methods leading to high productivity levels have demonstrated that chromatography can be a cost effective strategy. In the majority of situations the manufacturing costs will be a major factor in deciding whether the chromatography route will be implemented.
Each process will have to be considered on its own merits and costs. The viability and success of a chromatographic process to progress to industrial scale essentially depends on the right choice of the operating conditions. Particular attention must be paid to the role of productivity and its impact on the manufacturing costs of active pharmaceutical drugs.
The main cost contributors of a chromatographic industrial process are investment, maintenance, labour, stationary phase, solvent and energy. The productivity will have an impact on the scale of the chromatographic system to be used, the labour, energy and solvent needed. Therefore, it will have direct consequences on the reduction of production time and costs (see Figure 1). This productivity, defined as amount of product separated per time unit and amount of stationary phase (usually expressed as kg enantiomer/kg CSP/day), is controlled by the features of the CSP and the chromatographic method.
Competitive preparative applications will be feasible only on a CSP that has a high loadability for the given compound, in solvents where the sample has a minimum solubility (>10g racemate/L mobile phase). In this context, polysaccharide-derived CSPs are among the most broadly used supports for preparative separations due to their relatively high loading capacity. Their use in combination with mobile phases, including pure polar solvents as mobile phases, such as alcohols or acetonitrile, has led to a number of successful SMB industrial applications.
choice of CSP
The correct choice of the appropriate CSP for the chromatographic process is one of the key factors to make a chromatographic process competitive, as it is the parameter that has the highest impact on productivity. Any progress in the identification of new CSPs should be of significance for future developments. Intensive investigations in this area are currently under way to explore new CSPs, enhancing all the parameters having a direct influence on the productivity and cost.
Chiral Technologies undertakes chromatographic screening on its commercially available Chiralcel and Chiralpak columns, as a practical tool to select the best separation for a given compound. Most recently the screening has been broadened to an extensive polysaccharide-derived CSP library (more than 50 different CSPs) for industrial scale projects.3
The main goal of the CSP library approach is the identification of the optimal combination - CSP plus chromatographic conditions - leading to the highest productivity rates for a specific compound. This broader choice of CSPs will not only assist in reducing costs, but will also introduce new selectivity profiles with different solvent mixtures as mobile phases, which may improve the solubility of the racemic compounds to be separated.
promising concept
Enhancements in productivity of nearly five-fold have been achieved using certain supports of the CSP library for some pharmaceutical compounds. These successful results demonstrate that the CSP library is a promising concept to enhance productivity in the industrial separation of enantiomers, and the implementation of some of the new CSPs in industrial projects is already under consideration.