The biopharmaceutical industry long has recognized that nutrient feed control is crucial to process development lead-times and to manufacturing quality, yield and cost. Real-time measurement of physical parameters such as pH and dissolved oxygen is insufficient to achieve dynamic feed control. Instead, companies still depend upon predetermined nutrient regimes or periodic extractive sampling and offline analysis, resulting in suboptimal conditions for cell culture, process delays and risk of infection.
The majority of biopharmaceutical processes use a fed-batch nutrient-feeding regime to maintain cell culture activity. Current fed-batch processes rely on predetermined feeding protocols based on nutrient requirement estimates or infrequent sampling and offline measurement of the culture media to determine the concentration of key components. Both these techniques can lead to nonoptimal feeding, with depletion of nutrient and large swings in nutrient concentration, risking the health of the organism and its ability to produce consistent product quality at a high concentration. While attempts have been made to automate these feeding control protocols, the inherent nonoptimal limitations remain. So, developing timely cost-effective manufacturing processes for new biopharmaceuticals requires a radically new approach to feeding control.
A Paradigm Shift
Real-time monitoring of the metabolic activity of the process enables a fundamentally different approach that both automates the process and optimizes nutrient feeding. Metabolic activity is a function of nutrient concentration. For the majority of cell types used in upstream bioprocesses, an increase in feedstock concentration results in an increase in activity until a maximum metabolic rate is reached (the so-called “Monod relationship”). It therefore is possible to use a decrease in metabolic activity as an indicator for reduced nutrient concentration and a trigger for timely feed additions.
This automated closed-loop feeding control (AFC) model differs significantly from the current fed-batch model in two respects. Firstly, the process is monitored continuously without the need for extractive sampling. This “tightens” the control loop and eliminates the risk of process infection caused by sampling. Secondly, using the metabolic activity of the cells to control the feed additions means the cells themselves directly govern the process. This ensures the cells are maintained in a steady more-productive state than is the case with larger, more infrequent nutrient swings. Reducing the levels of cell “stress” increases the efficiency of the process resulting in higher yield. “Happy cells” deliver more product.
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