Intelligent Production Process for PAT Controlled PRV Vaccine Based on Online Raman and Online Live Cell Detection
Reducing lactic acid and ammonia accumulation has long been a goal of the mammalian cell biotechnology industry,and process control is a more convenient and efficient way to achieve this.That is,the accumulation of lactic acid and ammonia is reduced by controlling lower concentrations of glucose and glutamine during culture.Based on online Raman monitoring technology and proportional-integral-derivative(PID)automatic feedback control technology,this research realized the control of low glucose concentration(about 0.5 g/L)and low glutamine concentration(about 1.5 mmol/L)during the production of BHK-21 cell PRV vaccine.Lactic acid and ammonia accumulation were reduced by 26.0％and 30.3％,respectively.The pH at virus inoculation was maintained above 6.75,and the optimal feeding,inoculation,and harvest time of the virus were determined by online live cell detection technology.After the feeding operation,the maximum specific cell growth rate was delayed for 12 h and the high cell activity state was maintained for a longer time(24-48 h).While maintaining the virus-producing ability of single cells,the cell density at virus inoculation was effectively increased.The maximum virus titer was 10 times that of the high-glucose control group and 1.4 times that of the manual feeding group.Instead of the traditional manual feeding operation,the intelligent production process of PRV vaccine controlled by BHK-21 cell reactor PAT based on low glucose and glutamine concentration as well as online Raman and online live cell detection was successfully established,which laid the foundation for the intelligent production of biological drugs.
Pseudorabies virus(PRV)Multivariate data analysisLow glucose and glutamine concentrationsProcess analysisTechnique(PAT)Online Raman detection
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