(233b) A Systems Approach for Design of Intensified Bio-Pharmaceutical Processes

The use of biocatalytic process technologies as a supplement to conventional chemical synthesis has gained particular attention in recent years since new options for sustainable and environmentally benign processes can be established. Biocatalysis offers numerous advantages for achieving end quality specifications, such as high purity, high-yield and high selectivity, and ambient conditions of operation. Despite the advantages that biocatalytic technologies offer, there are still many challenges for their sustainable implementation, such as the integration of the biocatalytic step with neighboring operations, which can be additional chemical reactions (one-pot synthesis) and/or separation operation (in-situ product removal, ISPR). Besides, the implementation of an industrial-scale bioprocess usually takes considerable time for development some of which can be reduced by using established process systems engineering techniques, such as model-based and computer aided synthesis/design techniques. These techniques need to be adopted for applications in bio-pharmaceutical process development.

In this work a systematic model-based generic methodology for design and development of intensified bioprocesses satisfying the product quality parameters as indicators for selection is presented. The methodology focuses on the (bio)reaction(s)/downstream processing stages of a bioprocess and considers ISPR and one-pot synthesis procedures as well as technical and economical aspects, to achieve the goal of intensified process development that will maximize the product yield, selectivity, productivity, biocatalyst stability and product purity as well as profitability, while trying to minimize energy requirements by employing fewer processing steps and higher yields in each step. This methodology consists of seven steps. Step 1: Problem definition, where the objectives for quality by design are established. Step 2: Collection of all known data for the system under consideration. Step 3: Development and validation of a generic model to be used for process-product analysis. Step 4: Generation of the intensified alternatives using synthesis/design algorithms. Step 5: Verification of the alternatives trough model-based simulation. Step 6: Optimization of the feasible alternatives to identify the optimal. Step 7: Validation of the optimal alternative for final selection.

Application of the developed model-based methodology will be described and highlighted for the synthesis of N-acetylneuraminic acid (Neu5Ac). Neu5Ac is an interesting pharmaceutical intermediate due to its anti-viral, anti-cancer and anti-inflammatory functions. The synthesis of Neu5Ac is a particularly interesting example since it is characterized by an unfavorable equilibrium, high amount of waste per kilogram of product and difficult downstream processing. Therefore, improved feasible alternatives of Neu5Ac synthesis have been generated, modeled and validated using this methodology.