Fabian Steinebach, Daniel Karst and Massimo Morbidelli
Continuous integrated manufacturing of therapeutic proteins is a new paradigm that is being considered not only to decrease capital and operating costs but mainly to improve product quality and facilitate regulatory issues. With reference to a specific commercial mAb, we analyze a few steady state runs where all steps (perfusion, capture and polishing) are integrated and operated as a single unit. The use of simulation models to keep the various units within specifications while reducing production costs is discussed.
We show that, as expected, the final protein quality is different compared to state-of-the-art batch processing. The lower residence time in the bioreactor and the higher loading in the multi-column capture step lead to post-Protein A pools with more uniform product quality. Hence the performance of subsequent polishing steps is improved. Additionally, it is shown that continuous process polishing with the MCSGP technology overcomes the purity-yield tradeoff of classical batch chromatography. This cascade of beneficial correlations in integrated continuous manufacturing results in higher productivities and yields of improved product quality. This conclusion is discussed quantitatively by comparing product quality (i.e. glycoforms, charge isoforms, aggregates and fragments) in continuous integrated and classical batch production units, measured, in both cases, after the bioreactor, the capture and the polishing steps.