Filling Unit Operation for Biological Drug Products: Challenges and Considerations

Abstract

One of the key unit operations during the aseptic fill-finish process of parenteral products, such as biologics, is the filling process of the formulated, sterile filtered drug substance into primary packaging containers. The applied filling technology as well as the process performance majorly impacts final drug product quality. The present review provides an overview of commonly used filling technologies during fill-finish operations of biologics including positive displacement pump systems such as radial peristaltic pump, rotary piston pump, rolling diaphragm pump, or innovative systems such as the linear peristaltic pump, as well as time-over-pressure filling technology. The article describes the operating principle of each pump system and reviews advantages and drawbacks. We highlight specific considerations for individual systems, such as the risk of protein particle formation and particle shedding from wear and tear of tubing, and discuss current literature about general challenges associated with the filling process, such as hydrogen peroxide uptake, adsorption phenomena to tubing material, and needle clogging. We suggest process development and process characterization studies to assess the impact of the filling process on product quality, and lastly provide an outlook about the use of disposable equipment during filling operations related to sustainability considerations.

Keywords: Biotechnology; Extractable volume; Fill-finish process; Filling; Filling needle; Injectables; Oxidation; Particle shedding; Particulate contamination; Peristaltic pump; Processing; Protein aggregation; Proteins; Rolling diaphragm pump; Rotary piston pump; Stability; Time pressure pump.