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Technoeconomic evaluation of separation solvents and technologies for Continuous Pharmaceutical Manufacturing (CPM) of four key Drug Substances (DS)


*Corresponding author
Institute for Materials and Processes (IMP), School of Engineering, University of Edinburgh,  Edinburgh, United Kingdom


Continuous Pharmaceutical Manufacturing (CPM) has the potential to revolutionise the pharmaceutical industry via operating and economic benefits over traditional batch techniques. Establishing efficient continuous separation processes following continuous flow syntheses of active pharmaceutical ingredients (APIs) is essential to obtain the desired physical form of drug substance (DS) and successful CPM implementation. Process modelling and optimisation are essential tools for rapid screening of design alternatives to establish cost optimal process configurations for separation unit operations in integrated upstream CPM plants. This paper presents the technoeconomic optimisation for total cost minimisation for the continuous liquid-liquid extraction (LLE) of (S)-warfarin and the continuous mixed suspension mixed product removal (MSMPR) crystallisation of cyclosporine, paracetamol and aliskiren. Optimisation of continuous LLE of (S)-warfarin compares candidate separation solvents and operating temperatures with solvent feed rate and LLE tank residence time as decision variables; optimisation of continuous crystallisation processes compares the number of implemented crystallisers with MSMPR operating temperatures and residence times as decision variables. Capital (CapEx), operating (OpEx) and total expenditures are compared for different designs, elucidating cost-optimal configurations for each API with their attained recoveries and respective operating conditions. This work demonstrates the value of total cost minimisation via nonlinear optimisation prior to expensive experimental investigations and the potential of the economic benefits attainable via CPM for these APIs.


Continuous Pharmaceutical Manufacturing (CPM) has been widely recognised for its potential for significant operating and economic benefits to manufacturing firms over traditionally implemented batch methods (1, 3). Numerous demonstrations of active pharmaceutical ingredient (API) continuous flow syntheses and a focus on process modelling (4) indicate a keen interest of judicious industrial transition from batch to CPM methods. While several end-to-end CPM campaigns (5, 7) are documented, numerous challenges remain in integrated continuous separations, (8) presenting a bottleneck to realising the benefits of fully continuous manufacturing in the pharmaceutical industry. Significant research efforts in continuous separation technologies are addressing this issue.

Continuous purifications and separations following continuous API synthesis are essential in obtaining drug substances (DS) in their desired final form in integrated CPM campaigns.  Liquid-liquid extraction (LLE) is often employed to purify reactor effluent streams prior to subsequent operations, and can be implemented in contin ...