Lovastatin biosynthesis depends on the carbon–nitrogen proportion: Model development and controller design

Abstract

Lovastatin biosynthesis depends on the relative concentrations of dissolved oxygen and the carbon and nitrogen resources. An elucidation of the underlying relationship would facilitate the derivation of a controller for the improvement of lovastatin yield in bioprocesses. To achieve this goal, batch submerged cultivation experiments of lovastatin production by Aspergillus flavipus BICC 5174, using both lactose and glucose as carbon sources, were performed in a 7‐L bioreactor and the data used to determine how the relative concentrations of lactose, glucose, glutamine, and oxygen affected lovastatin yield. A model was developed based on these results and its prediction was validated using an independent set of batch data obtained from a 15‐L bioreactor using five statistical measures, including the Willmott index of agreement. A non‐linear controller was designed considering that dissolved oxygen and lactose concentrations could be measured online, and using the lactose feed rate and airflow rate as process inputs. Simulation experiments were performed to demonstrate that a practical implementation of the non‐linear controller would result in satisfactory outcomes. This is the first model that correlates lovastatin biosynthesis to carbon–nitrogen proportion and possesses a structure suitable for implementing a strategy for controlling lovastatin production.