Filling of High-Concentration Monoclonal Antibody Formulations into Pre-Filled Syringes: Filling Parameter Investigation and Optimization

Abstract

Syringe filling, especially the filling of high-concentration/viscosity monoclonal antibody formulations, is a complex process that has not been widely published in literature. This study sought to increase the body of knowledge for syringe filling by analyzing and optimizing the filling process from the perspective of a fluid's physical properties (e.g., viscosity, concentration, surface tension). A bench-top filling unit, comprising a peristaltic pump unit and a filling nozzle integrated with a linear actuator, was utilized; glass nozzles were employed to visualize liquid flow inside the nozzle with a high-speed camera. The desired outcome of process optimization was to establish a clean filling cycle (e.g., absence of splashes, bubbles, and foaming during filling and absence of dripping from the fill nozzle post-fill) and minimize the risk of nozzle clogging during nozzle idle time due to formulation drying at or near the nozzle tip. The key process variables were determined to be nozzle size, airflow around the nozzle tip, pump suck-back (SB)/reversing, fluid viscosity, and protein concentration, while pump velocity, acceleration, and fluid/nozzle interphase properties were determined to be relatively weak parameters. The SB parameter played an especially critical role in nozzle clogging. This study shows that an appropriate combination of optimal SB setting, nozzle size, and airflow conditions could effectively extend nozzle idle time in a large-scale filling facility and environment.

LAY ABSTRACT: Syringe filling can be considered a well-established manufacturing process and has been implemented by numerous contract manufacturing organizations and biopharmaceutical companies. However, its technical details and associated critical process parameters are rarely published. The information on high-concentration/viscosity formulation filling is particularly lacking. The purpose of this study is three-fold: (1) to reveal design details of a bench-top syringe filling unit; (2) to identify and optimize critical process parameters; (3) to apply the learning to practical filling operation. The outcomes of this study will benefit scientists and engineers who develop pre-filled syringe products by providing a better understanding of HC formulation filling principles and challenges.