Case Study – Altus Pharmaceuticals

Mixing Scale-Up for Crystallization Process

Situation

A pharmaceutical process was developed at small bench scale based on a process chemistry found during the high-throughput screening/discovery stage. At small scales, complete mixing was fast and easy to achieve. During process scale-up, diffusion in the process reactor was significantly slower, leading to process irreproducibility due to concentration gradients. However, high stirring power requirements precluded a direct “scale-up” of required mixing energy. This problem plagued the company with production delays and a general inability to consistently produce on-spec products at pilot scale. Complicating factors included avoiding transitional regimes (such as near impeller periphery), shear-thinning fluids, and a high shear requirement for blending two disparate fluids.

Approach

The goal was to achieve complete process mixing with a mixing energy that is both technically and economically scalable to large-scale processing. IMPACT designed and executed a series of mixing screening experiments to determine the boundaries of an acceptable operating region, or to determine where and how the process failed due to poor mixing. Once these operating limits were identified, and the governing parameters for mixing were established, a novel scale-up design was proposed based on a modification of existing mixing equipment. The successful approach specified two mixing zones; a high energy/shear mixing zone during feed introduction and another lower speed mixing zone for bulk mixing.

Results

Based on this scale-up road map, a pilot facility was designed and installed ensuring reliable, reproducible, and cGMP-capable processing. This arrangement generated consistently high quality product at pilot scale thereby meeting the client’s development milestones and enabled the company to successfully execute an IPO during this period. In addition, the process ultimately has been scalable to commercial production.