(448c) Design of Continuous Processes for Organic-Synthesis Based Production of Active Pharmaceutical Ingredients – a Methodology

The pharmaceutical industry is nowadays investing a large amount of resources in the development of optimized production technologies in order to decrease the manufacturing costs. Continuous pharmaceutical production has emerged as a relatively unexplored field within this industry, with the potential to improve quality and efficiency, and decrease risk, waste and production costs as compared to traditional batch manufacturing. However, the change from batch to continuous-based production is not straightforward and requires a multi-scale approach.

Many already existing active pharmaceutical ingredients (APIs) produced in batch mode consist of two or more separate production stages, with isolation and storage of intermediates. In order to exploit the full benefits of continuous production, the different stages should be connected in a feasible manner while preserving an acceptable degree of quality. Secondly, each of these stages may involve several solvent exchange steps and as a consequence a large solvent use. Changing the production to continuous mode offers a good opportunity to remove unnecessary solvent exchange steps and minimize solvent use. Thirdly, each unit operation in the process may be redesigned to obtain more efficient heat and mass transfer or to fit better to the particular physics or chemistry of the process. For example, the classical continuous reactor designs such as plug flow reactor or continuously stirred tank reactor (CSTR) may be modified to adapt to the kinetics of the reaction or to allow multiple phases. Operations which are relatively simple to carry out in batch mode such as those involving solids or requiring long residence times pose severe challenges in a continuous production environment. In fact, not every operation in a process should be run in continuous mode and hybrid operation (continuous unit operations combined with batch operations) should be enabled. Last but not least, each unit should be flexible enough to allow different operating conditions, in order to reach optimal conditions or to respond to disturbances in the process. A large amount of knowledge about the process is required in this step, and different modeling tasks will be involved.

In this paper a methodology for the design of continuous processes for organic-synthesis based production of APIs will be presented. This methodology systematically explores the opportunities that continuous production offers at different levels of detail, from the process flowsheet to the basic process modeling through the unit operation design. Executing each step in this method requires gathering some data and employing several methods. The methods applied have been used before in many different fields and are selected from the literature when needed. The application of the methodology will be exemplified with a case study - the production of an API developed by Lundbeck A/S.