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Holistic Analytical Characterization and Risk Assessment of Residual Host Cell Protein Impurities in an Active Pharmaceutical Ingredient (API) Synthesized by Biocatalysts
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  • Fengqiang Wang,
  • Xuanwen LI,
  • Michael Swanson,
  • Erik Guetschow,
  • Matthew Winston,
  • Joseph P. Smith,
  • Erik Hoyt,
  • Zhijian Liu,
  • Douglas Richardson,
  • Xiaodong Bu,
  • Vibha Jawa,
  • Narayan Variankaval
Fengqiang Wang
Merck Research Laboratories

Corresponding Author:fengqiang.wang@merck.com

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Xuanwen LI
Merck Research Laboratories
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Michael Swanson
Merck Research Laboratories
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Erik Guetschow
Merck Research Laboratories
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Matthew Winston
Merck Research Laboratories
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Joseph P. Smith
Merck Research Laboratories
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Erik Hoyt
Merck Research Laboratories
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Zhijian Liu
Merck Research Laboratories
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Douglas Richardson
Merck Research Laboratories
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Xiaodong Bu
Merck Research Laboratories
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Vibha Jawa
Merck Research Laboratories
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Narayan Variankaval
Merck Research Laboratories
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Abstract

Host cell proteins (HCPs) are a significant class of process-related impurities commonly associated with the manufacturing of biopharmaceuticals. However, due to the increased use of crude enzymes as biocatalysts for modern organic synthesis, HCPs can also be introduced as a new class of impurities in chemical drugs. In both cases, residual HCPs need to be adequately removed to ensure product purity, quality, and patient safety. Although a lot of attentions have been focused on defining a universally acceptable limit for such impurities, the risks associated with residual HCPs on product quality, safety, and efficacy often need to be determined on a case-by-case basis taken into consideration of residual HCP profile in the product, the dose, dosage form, and administration route etc. Here we describe the unique challenges for residual HCP control presented by the biocatalytic synthesis of a Merck investigational stimulator of interferon genes protein (STING) agonist, MK-1454, which is a cyclic dinucleotide synthesized using E. coli cell lysate overexpressing cyclic GMP-AMP synthase (cGAS) as a biocatalyst. In this study, a holistic characterization of residual protein impurities using a variety of analytical tools, together with in silico immunogenicity prediction of identified proteins, facilitated risk assessment and guided process development to achieve adequate removal of residual protein impurities in MK-1454 API.
27 Jan 2022Submitted to Biotechnology and Bioengineering
27 Jan 2022Submission Checks Completed
27 Jan 2022Assigned to Editor
30 Jan 2022Reviewer(s) Assigned
20 Mar 2022Review(s) Completed, Editorial Evaluation Pending
20 Mar 2022Editorial Decision: Revise Minor
04 Apr 20221st Revision Received
05 Apr 2022Submission Checks Completed
05 Apr 2022Assigned to Editor
13 Apr 2022Review(s) Completed, Editorial Evaluation Pending
13 Apr 2022Editorial Decision: Accept
Aug 2022Published in Biotechnology and Bioengineering volume 119 issue 8 on pages 2088-2104. 10.1002/bit.28112