Investigating and Addressing Challenges Associated with Filling Protein Drug Products.

The fill-finish process for vials and syringes, although considered standard in the biopharmaceutical industry, comes with numerous technical challenges when manufacturing high concentration products. This paper includes case studies, illustrating the operational challenges associated with the filling unit operation for three of the commonly used filling technologies for biopharmaceutical products - piston pump, time over pressure pump and peristaltic pump. First case study consists of a piston pump filling operation and evaluates impact of product related parameters such as a) protein concentration, b) product viscosity and c) surface tension. The second study encompasses peristaltic pump filling. It delves into characterization of fluid flow and pump parameters while examining failure modes such as product drying. The third case study details challenges with time-pressure filling operation. In summary, for the three filling technologies, the operational challenges encountered during bench-scale and manufacturing operations implicate drug product-nozzle interactions (drying of high-viscosity material), inadequate pump clearances (piston, again, drying + seizure) and lack of optimized control parameters as key factors contributing to filling line stoppages. In each instance, recommendations are provided to mitigate these operational challenges.