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Identifying and mitigating risks during biologic drug product manufacturing: A case study using computational fluid

Sheetal Pai-Wechsung1, James Morgan Harris2, Fawziya Ali3

  • 1Transformational Technology, Pfizer Research and Development, Pfizer, Inc.; Andover, MA, USA.

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|April 15, 2026
PubMed
Summary
This summary is machine-generated.

Computational fluid dynamics (CFD) modeling identified air entrainment during preservative addition as a cause of high molecular weight species (HMWS) in biologic drug manufacturing. Optimizing addition rates and location resolved the issue, ensuring product quality without process revalidation.

Keywords:
BiologicsComputational fluid dynamicsDrug product manufacturingMixingProcess riskProtein aggregationm-cresol

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Area of Science:

  • Pharmaceutical Manufacturing
  • Biotechnology
  • Process Engineering

Background:

  • Elevated high molecular weight species (HMWS) were observed in biologic drug product batches post-validation.
  • Root cause investigation was necessary to address the increased HMWS formation.

Purpose of the Study:

  • To identify the root cause of increased HMWS formation during multi-dose biologic drug product manufacturing.
  • To utilize computational fluid dynamics (CFD) modeling for risk mitigation.

Main Methods:

  • Computational fluid dynamics (CFD) modeling was employed to simulate fluid dynamics within the formulation vessel.
  • Process sampling identified the preservative addition step as critical for HMWS increase.
  • CFD simulations analyzed air entrainment and concentration gradients during m-cresol addition.

Main Results:

  • CFD simulations confirmed rapid, above-surface m-cresol addition caused air entrainment and localized hot spots, promoting protein aggregation.
  • Modeling identified optimal addition rate and J-tube location as key mitigation strategies.
  • Implementing a controlled, slow addition protocol successfully reduced HMWS levels to historical ranges.

Conclusions:

  • CFD modeling provides valuable mechanistic process understanding, especially at liquid-air interfaces.
  • Optimized preservative addition effectively mitigates HMWS formation risk in biologic drug manufacturing.
  • This approach enhances process control and ensures product quality without requiring extensive revalidation.