Challenges and Solutions to Manufacturing of Low-Viscosity, Ultra-High Concentration IgG1 Drug Products: From Late Downstream Process to Final Fill Finish Processing.

Abstract

Challenges in the manufacturing of high-concentration antibody formulations have seldom been discussed. These are observed mainly from late downstream operations where the antibody gets concentrated to its final strength to final fill finish processing and containerization of the product. The present paper summarizes the challenges typically observed in manufacturing and processing of high-concentration antibody products and provides turnkey solutions to these typical challenges in order to have a consistent and robust manufacturing process for these products. Immunoglobulin G1 (IgG1) has been used as a model protein for studying the challenges and providing solutions to them. The late downstream challenges, like increased viscosity limiting further concentration, can be resolved by use of viscosity modifying agents in the formulation. Replacement of the conventionally used 'A' screen membranes with 'D' screen or using single pass tangential flow filtration can further provide an in targeting higher concentrations for the same protein with lesser shear and aggregation. Using a 0.5 µm/0.2 µm asymmetric or bilayered membrane instead of the conventional 0.2 µm membrane resulted in better flux during filtration of a high-concentration IgG1 formulation. In-process holding time during the filling operation was optimized to be <60 min based on the nozzle drying time for the high-concentration IgG1 formulation. An appropriate control strategy of replacing filling nozzles and performing periodic fill weight checks was proposed for the fill-finish process of a high-concentration IgG1 formulation.