Low volume aseptic filling: Impact of pump systems on shear stress

Abstract

Low volume aseptic filling of parenterals, particularly monoclonal antibodies is becoming increasingly important with the development of more and more intravitreal drugs and high concentrated formulations. Especially monoclonal antibodies are very delicate products to fill and the use of the right fill finish equipment plays an important role during process development. Protein aggregation can occur under conditions described in literature and can be influenced by the fill finish processing. The mechanism of product stress inside the filling systems is yet not fully understood. This study evaluated three different dosing systems to assess protein degradation caused by the shear rate during low volume filling of monoclonal antibodies. The newly developed quantitative liposomal shear stress model revealed the highest shear rate in the radial peristaltic pump, followed by the rotary piston pump and the linear peristaltic pump. In contrast to that, we found the highest sub-visible particle counts (>2 µm) in the rotary piston pump. We used computational fluid dynamics for a better and deeper understanding of filling processes inside the different dosing systems. Our results document that the rotary piston pump creates a recirculation zone inside the cylinder, where the protein formulation could be trapped and be exposed to the shear stress multiple times resulting in a cumulative shearing. This finding could serve as an explanation for the highest sub-particle counts in low volume filling using a rotary piston pump.