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These biomolecules are produced in cell-based expression systems that generate thousands of impurities, which must be removed through a sequence of chromatographic and filtration steps to ensure drug efficacy and patient safety. Host cell proteins (HCPs) are among the most concerning impurities, due to quantification challenges, their physicochemical diversity, and their potential to affect drug stability and increase immunogenicity. Tracking and removing HCPs remains a perpetual industrial goal and a growing topic of discussion in the biotechnology industry and amongst regulators. In this review, we provide a comprehensive overview of the research about HCPs in biopharmaceutical processes, highlighting gaps in process analytics, process design, and impurity risk assessment. We summarise the challenges and recent progress in HCP detection and quantification, with extensive focus on LC-MS workflows. We next examine methods to reduce HCPs in the upstream process, followed by an overview of emerging purification technologies. Finally, we review some experimental and computational tools for predicting product immunogenicity and optimising manufacturing processes. This review focuses on advances made in the past five years and is intended to support decision-making in therapeutic protein manufacturing.<\/jats:p>","DOI":"10.1186\/s13036-026-00685-2","type":"journal-article","created":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T11:44:04Z","timestamp":1779191044000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Host cell protein impurities in therapeutic proteins: overview of advances in detection, nonconventional removal technologies and immunogenicity assessment"],"prefix":"10.1186","volume":"20","author":[{"given":"Sakhr","family":"Alhuthali","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Syazana Mohamad","family":"Pauzi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cleo","family":"Kontoravdi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,5,19]]},"reference":[{"key":"685_CR1","doi-asserted-by":"publisher","first-page":"107552","DOI":"10.1016\/j.biotechadv.2020.107552","volume":"43","author":"R O\u2019Flaherty","year":"2020","unstructured":"O\u2019Flaherty R, Bergin A, Flampouri E, Mota LM, Obaidi I, Quigley A, et al. 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