At-line process analytical technology (PAT) for more efficient scale up of biopharmaceutical microfiltration unit...

Area of Science:

• Biotechnology
• Chemical Engineering
• Process Chemistry

Background:

• Tangential flow microfiltration (MF) is vital for bioprocess separation but faces scale-up challenges due to empirical methods.
• Scaling up MF processes for therapeutic protein manufacturing often involves trial-and-error, leading to inefficiencies and risks.

Purpose of the Study:

• To de-risk microfiltration (MF) scale-up by integrating at-line process analytical technology (PAT) with mass balance modeling.
• To enhance the consistency and yield of a bottleneck MF step in therapeutic protein purification.

Main Methods:

• Developed and validated a 10-minute reverse phase ultra-high performance liquid chromatography (RP-UPLC) assay for at-line protein concentration monitoring.
• Employed chromatography-based PAT to identify deviations from a mass balance model during MF scale-up.
• Adjusted process controls based on PAT data to optimize MF performance.

Main Results:

• The validated RP-UPLC assay provided reliable at-line monitoring, comparable to existing methods.
• PAT identified discrepancies between the model and actual process, pinpointing areas for improvement.
• Optimized process controls based on PAT insights led to enhanced operability and significantly increased product yield.

Conclusions:

• Integrated PAT and mass balance modeling successfully de-risked MF scale-up for therapeutic protein purification.
• This approach offers a robust strategy for improving filtration process scale-up and enabling feed-forward/feedback control.
• The methodology is broadly applicable to reduce scale-up risks in filtration processes within the biopharmaceutical industry.