Assets portfolio review through specific criteria make it possible to define performance factors requested for cutting the costs and speeding up the access to market. This primary analysis is a driver to target the relevant candidates for continuous process development. One should not only focus on productivity lever but also on the way to manufacture: hazard and safety management, raw materials consumption or quality challenges such as selectivity or narrow operating windows. Doing this exercise on Sanofi projects portfolio leads to the selection of a drug substance synthesis from which we want to highlight the three last stages. The associated development work is related to one chemical and two physical steps consisting in a deprotection of acetyl group followed by an intermediate crystallization to control the purity whereas the polymorphism is managed thanks to an additional isolation step. Starting from grams scale on the bench, chemistry has been transposed from batch to conti with a promising intensification factor of 400. In spite of this, thinking from batch, like blinders, prevents to explore the overall input of continuous processes. Consequently, the development program has been reshaped with a global solvent screening approach for all stages together. As a main result, the intensification factor rise up to 8000. In addition, in the case described, continuous solid generation process offer the opportunity to play with supersaturation and kinetic. Finally thanks to this mindset we were able to control both chemical and physical quality in designing one single isolation stage. Once this manufacturing strategy has been selected, a scale up risk analysis put the light on solid handling, filtration and drying operations, justifying a demonstration pilot at hundred kilograms scale. The success of these pilot trials is feeding tableting studies while a basic engineering for tomorrow agile plant is set up.  <br/>

Drug substances continuous process development: From the bench to demonstration pilot

2019 Fall National Meeting

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