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Is Your Bioprocess in Control?

Dissolved carbon dioxide (DCO₂) is a critical process parameter (CPP) in biopharma production processes according to PAT guidelines. By influencing other parameters such as extracellular and intracellular pH, it has an effect on different metabolic pathways which are involved in cell growth or in product formation and quality.

WHITE PAPER: SHOULD CO₂ BE A CPP?

Introducing CO₂NTROL

Solid-state, maintenance-free, dissolved carbon dioxide sensors

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Automated Control of DCO₂ Enables:

Increased Titer

Increased Product Titer

Reproducibility

Better Batch-to-Batch Reproducibility

Consistency

More Consistency from R&D to Production Scale Reactors

Bioreactor Size Impacts CO₂

Large and small bioreactors have Mass Transfer Coefficients (KLa) that change the dissolution and stripping characteristics from reactor to reactor. As a result the same control strategy will result in different CO₂ accumulation across R&D, PD, and Production scale reactors. Only real-time control of DCO₂ to an optimized profile will result in comparable mass transfer independent of scale.

Optimizing Yield
While the small surface area to volume ratio of a typical R&D reactor means that CO₂ accumulation is minimal. Real-time control of CO₂ is critical to define the optimal set-point and optimize product yield.
Scale Up
Mimicking sparging and stripping strategies optimized for R&D will result in different conditions as the surface to volume ratio decreases. Active control of an optimal DCO₂ profile ensures consistency across scales.
Scale Down
For existing processes that were developed without DCO₂ control, the efficiency of scale-down studies can be improved by actively controlling DCO₂ to mimic the profile seen in the production reactor.

Impact of CO₂ on Process Performance

– Excessive Accumulation

During a process excess CO₂ accumulation is common as cell concentration increases and more metabolic CO₂ is produced. This accumulation reduces intracellular pH resulting in slower enzymatic activity or delayed lactate shift. The outcome is lower production quantity and quality.

– Excessive Removal

Aggressive aeration and mixing can prevent detrimental accumulation of CO₂. However, too little CO₂ can slow cell growth, metabolism, and productivity by starving cells of CO₂ needed for the formation of metabolic intermediates. Excessive removal can also reduce buffer capacity in bicarbonate systems.

– Uncontrolled CO₂ Range

Media addition and process adjustments can result in large swings in dissolved CO₂ that may go unnoticed with infrequent offline monitoring and adjustment. Continuous inline control at the optimal level yields increased viable cell density, production phase duration, and titer.

Specific Applications

  • App Note - Real-time Monitoring of DCO2 in Addition to DO

    In this application note, the utilization of a DCO2-probe in addition to a DO-probe at Ostwestfalen-Lippe University of Applied Sciences and Arts, is briefly described using cell cultivation with varying stirring speeds to demonstrate the value added of inline dissolved gas measurement.

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