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Accelerated Upstream Process Optimization Using a QbD Approach

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APC applied its BioACHIEVE® process development technology platform to improve the process performance of a Chinese Hamster Ovary (CHO) mammalian cell bioprocess operated in a 2.5 L bench-top bioreactor, by optimising the bioreactor feed profile by moving from a traditional bolus to a PAT-enabled continuous feeding strategy in order to prevent nutrient depletion and deliver a stable macroenvironment for the cells. 

Typically, the initial phase involved advanced monitoring of the current process with appropriate PAT technologies. The nutrient, by-product and biomass concentrations in the CHO mammalian cell culture was determined online using Raman spectroscopy coupled with chemometric partial least squared (PLS) modelling. Based on the process knowledge garnered, the CPPs for the process were identified and process models which describe their trajectories and behaviours were developed. 

The model was developed to ultimately be a principal component of a model predictive control (MPC) algorithm for the closed-loop feedback control of glucose concentration in the bioreactor. Prior to implementing the process model as part of the MPC strategy, a series of process simulations were run. The simulation results gave direction to the experimental design during process development by providing a virtual environment in which to test and optimise a variety of operating conditions. 

Overall, application of the glucose set-point control strategy resulted in a 1.5 fold increase in peak viable cell density (VCD) and the integral of the viable cell density (IVC) which is directly related to increased titre.   

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Raman Spectroscopy


  • They are non-invasive and non-destructive.
  • Do not consume the analyte or require sampling.
  • No consumables.
  • Are capable of monitoring several analytes simultaneously.
  • Provide continuous real-time measurements.
  • Do not interfere with the cellular metabolism or bioreactor environment.


  • Chemometric calibration models are necessary to translate the Raman spectra into useful information.
  • Expertise in PLS model building.
  • Validated reference method.
  • Continuous verification and validation of the built PLS models
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The principal goal of process development and control under this APC paradigm is to provide: 

  • Greater Process Understanding 
  • Streamlined Optimization 
  • Process Reproducibility  
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Vials, bioreactors, wave bags, SUBs | target titers and product profiles | QbD approaches | modeling and analytics | metabolic flux, turnover, pathway | fast efficient CMC work