A common control strategy for the production of recombinant proteins in Pichia pastoris using the alcohol oxidase 1 (AOX1) promotor is to separate the bioprocess into two main phases: biomass generation on glycerol and protein production via methanol induction. This study reports the establishment of a soft sensor for the prediction of biomass concentration that adapts automatically to these distinct phases. A hybrid approach combining mechanistic (carbon balance) and data‐driven modeling (multiple linear regression) is used for this purpose. The model parameters are dynamically adapted according to the current process phase using a multilevel phase detection algorithm. This algorithm is based on the online data of CO2 in the off‐gas (absolute value and first derivative) and cumulative base feed. The evaluation of the model resulted in a mean relative prediction error of 5.52% and R² of .96 for the entire process. The resulting model was implemented as a soft sensor for the online monitoring of the P. pastoris bioprocess. The soft sensor can be used for quality control and as input to process control systems, for example, for methanol control.
Among the greatest challenges in soft sensor development for bioprocesses are variable process lengths, multiple process phases, and erroneous model inputs due to sensor faults. This review article describes these three challenges and critically discusses the corresponding solution approaches from a data scientist’s perspective. This main part of the article is preceded by an overview of the status quo in the development and application of soft sensors. The scope of this article is mainly the upstream part of bioprocesses, although the solution approaches are in most cases also applicable to the downstream part. Variable process lengths are accounted for by data synchronization techniques such as indicator variables, curve registration, and dynamic time warping. Multiple process phases are partitioned by trajectory or correlation-based phase detection, enabling phase-adaptive modeling. Sensor faults are detected by symptom signals, pattern recognition, or by changing contributions of the corresponding sensor to a process model. According to the current state of the literature, tolerance to sensor faults remains the greatest challenge in soft sensor development, especially in the presence of variable process lengths and multiple process phases.
The accuracy and precision of soft sensors depend strongly on the reliability of underlying model inputs. These inputs (particularly readings of hardware sensors) are frequently subject to faults. This study aims to develop an adaptive soft sensor capable of reliable and robust biomass concentration predictions in the presence of faulty model inputs for a Pichia pastoris bioprocess. Hence, three soft sensor submodels were developed based on three independent model inputs (base addition, CO 2 production, and mid-infrared spectrum). An ensemble-based algorithm combined the submodels to form an ensemble model, that is, an adaptive soft sensor, to achieve fault-tolerant prediction. The algorithm's basic steps are as follows: the initial determination of submodel reliability is followed by selecting appropriate submodels to generate a reliable prediction via variance-based weighting of the submodels. The adaptive soft sensor demonstrated high robustness and accuracy in biomass prediction in the presence of multiple simulated sensor faults (RMSE = 0.43 g L −1 ) and multiple real sensor faults (RMSE = 0.70 g L −1 ).
A soft sensor concept is typically developed and calibrated for individual bioprocesses in a time-consuming manual procedure. Following that, the prediction performance of these soft sensors degrades over time, due to changes in raw materials, biological variability, and modified process strategies. Through automatic adaptation and recalibration, adaptive soft sensor concepts have the potential to generalize soft sensor principles and make them applicable across bioprocesses. In this study, a new generalized adaptation algorithm for soft sensors is developed to provide phase-dependent recalibration of soft sensors based on multiway principal component analysis, a similarity analysis, and robust, generalist phase detection in multiphase bioprocesses. This generalist soft sensor concept was evaluated in two multiphase bioprocesses with various target values, media, and microorganisms. Consequently, the soft sensor concept was tested for biomass prediction in a Pichia pastoris process, and biomass and protein prediction in a Bacillus subtilis process, where the process characteristics (cultivation media and cultivation strategy) were varied. High prediction performance was demonstrated for P. pastoris processes (relative error = 6.9%) as well as B. subtilis processes in two different media during batch and fed-batch phases (relative errors in optimized high-performance medium: biomass prediction = 12.2%, protein prediction = 7.2%; relative errors in standard medium: biomass prediction = 12.8%, protein prediction = 8.8%).
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