A Future-proof Sample-free Production Bioreactor pH Control Strategy

This report evaluated whether routine daily offline pH sampling in 2000 L bioreactors can be safely reduced by relying on continuous inline pH monitoring. The assessment used statistical analysis of historical production data, hold-time studies, and proof-of-concept runs for two products. Most differences between inline and offline pH measurements were attributed to sample handling effects, such as temperature changes and hold time, which can account for pH shifts within the probe adjustment threshold. Inline pH probes showed stable performance with no meaningful drift beyond expected measurement error. The results support removing routine daily offline sampling after the early process phase, reducing sampling by approximately 75% without impacting product quality, while keeping existing alarms and backup procedures. It is advised to modify the sampling strategy based on process trends. It is also recommended to run stability checks on the inline probes. The evaluation also explored off-gas CO₂ as an indirect pH indicator. It was found that CO₂ alone was not a reliable predictor of pH, and further studies would be required before this approach could replace direct pH monitoring. Overall, the findings support a more efficient pH monitoring strategy without compromis-ing process control or product quality.