Predicting the metabolic condition of a cell culture

A system for monitoring and/or controlling a bioreactor which includes the cell culture of cells of a specific cell type, comprising:

• one or more processors;
• a first interface for receiving measurements from the bioreactor containing the cell culture;
• and
• a volatile or non-volatile storage medium comprising:
• a metabolic model of a cell of the specific cell type, the metabolic model including a plurality of intracellular metabolites and extracellular metabolites and a plurality of intracellular and extracellular fluxes, the metabolic model including stoichiometric equations specifying at least one stoichiometric relationship between one of the intracellular and one of the extracellular metabolites;
• a trained machine learning program logic-MLP;
• and
• a program logic that, when executed by the one or more processors, causes the one or more processors to perform, at each of a plurality of points in time during the cultivation of the cell culture, the steps of:
• receiving a plurality of measurement values measured at said point in time via the first interface, the measurement values comprising concentrations of a plurality of extracellular metabolites of the metabolic model in the culture medium of a cell culture and a measured cell density of the cells in the cell culture;
• inputting the received measured values as input parameter values to the MLP;
• predicting extracellular fluxes of the extracellular metabolites at a future point in time by the MLP using the received measurement values, the future point in time being a point in time subsequent to the time of receipt of the measurement values, wherein the extracellular fluxes are uptake rates of the extracellular metabolites into a cell and/or release rates of the extracellular metabolites from a cell into the medium;
• performing metabolic flux analysis to calculate the intracellular fluxes at the future point in time using the predicted extracellular fluxes and the stoichiometric equations of the metabolic model;
• comparing the predicted intracellular fluxes with reference values or reference value ranges for intracellular fluxes of the respective one or more intracellular metabolites;
• determining that a deviation of the calculated intracellular flux of at least one of the intracellular metabolites from a corresponding respective reference value or reference value range exceeds a limit value;
• and
• sending a control command to the bioreactor to automatically initiate steps which change the state of the bioreactor or the medium contained therein in such a way as to reduce the deviation, wherein the automatic steps include in particular a change in the quantity and/or a change in the composition of the culture medium.