Process Analytical Technology as an enabling tool for scale up of crystallization, filtration, drying and milling

Abstract

Many active pharmaceutical ingredients (APIs) are purified by crystallization and most of such crystals are needle crystals whose size distribution is subject to stringent regulations. Predicting the needle size distribution upon crystallization, filtration, drying and milling is essential for smooth scaleup and interruption free operations. In this work we report an enabling technology for biopharmaceutical manufacturing that consists of a Monte Carlo based population balance solver coupled with standard computational fluid dynamics calculations. We have demonstrated the use of this to develop a scaleup tool that can predict needle crystal size distribution for a 200x scale up. The great advantage of this approach is that the scaleup protocol only needs to be calibrated at the laboratory scale where the quantities of the expensive API required are small and manageable and process analytical tools are robust. It can then be deployed to pilot or even plant scale with confidence. The protocol can predict crystal size D90 with less than 10% deviation from the measured values for a 200x scaleup through crystallization, filtration, drying and milling operations.