Enhancing real‐time cell culture monitoring: Automated Raman model optimization with Taguchi method

Abstract Raman spectroscopy has found widespread usage in monitoring cell culture processes both in research and practical applications. However, commonly, preprocessing methods, spectral regions, and modeling parameters have been chosen based on experience or trial‐and‐error strategies. These choices can significantly impact the performance of the models. There is an urgent need for a simple, effective, and automated approach to determine a suitable procedure for constructing accurate models. This paper introduces the adoption of a design of experiment (DoE) method to optimize partial least squares models for measuring the concentration of different components in cell culture bioreactors. The experimental implementation utilized the orthogonal test table L 25 (5 6 ). Within this framework, five factors were identified as control variables for the DoE method: the window width of Savitzky–Golay smoothing, the baseline correction method, the order of preprocessing steps, spectral regions, and the number of latent variables. The evaluation method for the model was considered as a factor subject to noise. The optimal combination of levels was determined through the signal‐to‐noise ratio response table employing Taguchi analysis. The effectiveness of this approach was validated through two cases, involving different cultivation scales, different Raman spectrometers, and different analytical components. The results consistently demonstrated that the proposed approach closely approximated the global optimum, regardless of data set size, predictive components, or the brand of Raman spectrometer. The performance of models recommended by the DoE strategy consistently surpassed those built using raw data, underscoring the reliability of models generated through this approach. When compared to exhaustive all‐combination experiments, the DoE approach significantly reduces calculation times, making it highly practical for the implementation of Raman spectroscopy in bioprocess monitoring.