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Novel Application of Pourbaix Diagrams to Model Precipitation in Upstream Biomanufacturing Process Solutions
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  • Timothy Brantley,
  • Brandon Moore,
  • Chris Grinnell,
  • Sarwat Khattak
Timothy Brantley
Biogen Inc
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Brandon Moore
Biogen
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Chris Grinnell
Biogen Inc
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Sarwat Khattak
Biogen Inc
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Abstract

Commercial production of therapeutic proteins using mammalian cells requires complex process solutions, and consistency of these process solutions is critical to maintaining product titer and quality between batches. Inconsistencies between process solutions prepared at bench and commercial scale may be due to differences in mixing time, temperature, and pH which can lead to precipitation and subsequent removal via filtration of critical solution components such as trace metals. Pourbaix diagrams provide a useful tool to model the solubility of trace metals and were applied to troubleshoot the scale-up of nutrient feed preparation after inconsistencies in product titer were observed between bench- and manufacturing-scale batches. Pourbaix diagrams modeled the solubility of key metals in solution at various stages of the nutrient feed preparation and identified copper precipitation as the likely root cause of inconsistent media stability at commercial scale. Copper precipitation increased proportionally with temperature in bench-scale preparations of nutrient feed and temperature was identified as the root cause of copper precipitation at the commercial scale. Additionally, cell culture copper titration studies performed in bench-scale bioreactors linked copper-deficient mammalian cell culture to inconsistent titers at the commercial scale. Pourbaix diagrams can predict when trace metals are at risk of precipitating and can be used to mitigate risk during the scale-up of complex media preparations.

Peer review status:ACCEPTED

25 Mar 2021Submitted to Biotechnology and Bioengineering
26 Mar 2021Submission Checks Completed
26 Mar 2021Assigned to Editor
03 Apr 2021Reviewer(s) Assigned
27 Apr 2021Review(s) Completed, Editorial Evaluation Pending
27 Apr 2021Editorial Decision: Revise Major
28 May 20211st Revision Received
29 May 2021Submission Checks Completed
29 May 2021Assigned to Editor
30 May 2021Reviewer(s) Assigned
12 Jun 2021Review(s) Completed, Editorial Evaluation Pending
12 Jun 2021Editorial Decision: Accept