Reactor design for continuous monoclonal antibody precipitation based upon micro-mixing

BACKGROUND Precipitation has been applied for the processing of important therapeutics, including monoclonal antibodies (mAbs). The scale-up has proven to be a challenging task due to the complexity of the reactions and transport processes involved. This requires a good understanding of the molecular processes underpinning precipitate formation. The aim of this study was to build a micro-mixing model for the precipitation of a mAb in continuous tubular reactors using ammonium sulphate. The effect of micro-mixing on precipitate formation (with respect to size, strength, and nature) was evaluated. An ultra scale-down (USD) centrifugation methodology was applied to determine the ease of precipitate clarification. RESULTS The results demonstrated that the final mean particle size decreased with increased micro-mixing, and was obtained with short residence times. Antibody yields in the tubular reactors were consistently above 90% and were shown to be independent of the mixing. Similar particle sizes between a lab and pilot-scale reactor were correlated with the average energy dissipation rate. The smaller particles obtained from improved micro-mixing had higher fractal dimensions that correlated with minimal breakage upon exposure to turbulent shear. Precipitates were easily clarified at the USD scale (> 95% clarification), but less so at pilot-scale (< 80% clarification). CONCLUSION Precipitation is a rapid process where the final precipitate properties are controlled by the flow conditions. Therefore, the process can be manipulated to acquire a certain particle size range. A high-throughput precipitation process is also possible. However, further investigation into large-scale precipitate recovery is required. (c) 2020 Society of Chemical Industry

Automated summary

This study established a micro-mixing model for monoclonal antibody precipitation in continuous tubular reactors, finding that increased micro-mixing led to smaller particle sizes and high antibody yields independent of mixing. Precipitates were easily clarified at small scale, but less so at pilot-scale.