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While fed\u2010batch (FB) processes have been the standard, a shift toward high\u2010density perfusion processes is being driven by increased productivity, flexible facility footprints, and lower costs. Ensuring the clearance of process\u2010related impurities, such as host cell proteins (HCPs), is crucial in biologics manufacturing. Although purification processes remove most impurities, integrated strategies are being developed to enhance clearance of some\u00a0high\u2010risk HCPs. Current understanding of HCP expression dynamics in cell culture is limited. This study utilized data\u2010independent acquisition (DIA) proteomics to compare the proteomic profiles of cell culture supernatants from 14 FB clones and three perfusion clones, all expressing the same mAb from the same host cell line. Results showed that perfusion processes enhance cell growth and productivity, exhibiting distinct proteomic profiles compared to FB processes. Perfusion processes also maintain a more comparable HCP abundance profile across clones, especially for 46 problematic HCPs monitored. Cluster analysis of FB proteomics revealed distinct abundance patterns and correlations with process parameters. Differential abundance analysis identified significant protein differences between the two processes. This is the first extensive study characterizing HCPs expressed by clones under different process modes. Further research could lead to strategies for preventing or managing problematic HCPs in biologics manufacturing.<\/jats:p>","DOI":"10.1002\/biot.202400567","type":"journal-article","created":{"date-parts":[[2025,1,21]],"date-time":"2025-01-21T01:40:21Z","timestamp":1737423621000},"source":"Crossref","is-referenced-by-count":9,"title":["Proteomics Reveals Distinctive Host Cell Protein Expression Patterns in Fed\u2010Batch and Perfusion Cell Culture Processes"],"prefix":"10.1002","volume":"20","author":[{"given":"Ansuman","family":"Sahoo","sequence":"first","affiliation":[{"name":"Biologics Process Research &amp; Development Merck &amp; Co., Inc.  Rahway New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taku","family":"Tsukiadate","sequence":"additional","affiliation":[{"name":"Analytical Research &amp; Development Mass Spectrometry Merck &amp; Co., Inc.  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