Feedback control of two supplemental feeds during fed-batch culture on a platform process using inline Raman models for glucose and phenylalanine concentration

Real‐time amino acid and glucose monitoring system for the automatic control of nutrient feeding in CHO cell culture using Raman spectroscopy

“…[ 31 ] Nevertheless, only Webster et al. [ 32 ] reported a Raman‐based automated feedback control strategy, which accomplished the adjustment of feeding rate by targeting a constant concentration of glucose and phenylalanine to establish a more consistent nutritional environment for the cells compared to bolus feeding.…”

“…[28][29][30] However, besides glucose, amino acids also play a crucial role in promoting cell growth and increasing productivity, additionally, they are the basic building blocks for the synthesis of therapeutic proteins. [31] Nevertheless, only Webster et al [32] reported a Raman-based automated feedback control strategy, which accomplished the adjustment of feeding rate by targeting a constant concentration of glucose and phenylalanine to establish a more consistent nutritional environment for the cells compared to bolus feeding.…”

The role of Raman spectroscopy in biopharmaceuticals from development to manufacturing

“…Since many of the papers report on iterative model development with several developed models, a range of model parameter values are included in the table if they were in the paper. The reader is encouraged to refer to the individual papers to learn how each study optimized the model according to the specific application needs Raman-measured parameter(s) Cell line Target molecule Preprocessing techniques Model(s) used Model figures of merit Glucose [ 75 ] CHO DG44 mAb 4, 3, 6 PLS Range: 1.02–14.46 g/L RMSEP = 0.24 g/L Glucose [ 80 ] CHO DG44 Adalimumab biosimilar 9, 6, 7 PLS Range: 0–70 mM RMSEP = 5.2 mM Glucose [ 46 ] CHO IgG1 1–7 PLS Shake flask Range: 0–60 mM RMSEP: 1.3797 mM 10 L Range: 0–60 mM RMSEP: 4.0297 mM 100 L Range: 0–60 mM RMSEP: 4.0453 mM pH [ 76 ] CHO mAb 3, 4, 6 PLS pH Range: ~ 6.6–7.3 RMSEP (full range): 0.066–0.076 RMSEP: 0–4 days: 0.020–0.039; days 4 + : 0.034–0.039 pH from lactate + pCO 2 Range: ~ 6.6–7.3 RMSEP: 0–4 days: 0.019–0.036; days 4 + : 0.030–0.034 Glucose Phenylalanine [ 73 ] CHOK1SV GS-KO® mAb 3, 4, 6 PLS Glucose Range: ~ 0–11 g/L RMSEP: 0.42 g/L Phenylalanine Range: ~ 20–580 mg/L RMSEP: 21.3 mg/L Glucose Lactate Ammonia[ 52 ] ...…”

“…The success of Raman-based glucose feed strategies supports extending the technique to amino acid feed strategies. Raman-based automated glucose and phenylalanine feed was demonstrated by Webster et al [ 73 ]. Manual-based feed control and automated feed control were performed on a fed-batch culture with two different CHOK1SV GS-KO® cell lines.…”

“…The model for methionine did not perform as well as the other three models, and the authors hypothesized that the relatively weak Raman signal of methionine and overlapping bands with cysteine were contributing factors in the model performance. Overall, the Bhatia et al [ 74 ] and Webster et al [ 73 ] studies establish the feasibility of Raman spectroscopy to quantify amino acids in-line during a cell culture bioprocess. These studies support the continuation of this research with the eventual goal of automated amino acid monitoring and control.…”