[{"abstract":[{"lang":"eng","text":"Biopharmaceutical quality in upstream mammalian cell culture has historically relied on Quality-by-Test (QbT) paradigm, where fixed processes are verified by end-point assays despite limited process observability and substantial biological variability. This chapter discusses how Process Analytical Technology (PAT), aligned with the Quality-by-Design (QbD) framework, enables measurement-driven process understanding and timely control by linking the trajectories of critical process parameters (CPPs) to critical quality attributes (CQAs). We review fit-for-purpose at-line, on-line, and in-line analytical technologies used in mammalian cell culture and summarize their roles across the process development and manufacturing lifecycle. Applications include multivariate process characterization, state-based monitoring and control, and trajectory-based process supervision. Finally, we outline future directions toward IIoT-enabled connectivity, soft sensors, and integrated multi-sensor PAT platforms, which are expected to support adaptive control strategies, digital twins, and ultimately autonomous biomanufacturing."}],"publication_status":"published","publisher":"Elsevier","author":[{"first_name":"Cheol-Hwan","full_name":"Park, Cheol-Hwan","last_name":"Park"},{"last_name":"Jeon","full_name":"Jeon, Yunjoo","first_name":"Yunjoo"},{"id":"85335","last_name":"Uhlendorff","first_name":"Selina","full_name":"Uhlendorff, Selina"},{"last_name":"Pein-Hackelbusch","orcid":"0000-0002-7920-0595","first_name":"Miriam","full_name":"Pein-Hackelbusch, Miriam","id":"64952"},{"full_name":"Lee, Dong-Yup","first_name":"Dong-Yup","last_name":"Lee"}],"publication":"Reference Module in Life Sciences","status":"public","title":"Process Analytical Technology in Upstream Mammalian Cell Cultures","publication_identifier":{"eisbn":["978-0-12-809633-8"]},"_id":"13712","language":[{"iso":"eng"}],"place":"[Erscheinungsort nicht ermittelbar]","doi":"10.1016/b978-0-443-24738-5.00086-0","date_updated":"2026-04-29T11:16:34Z","department":[{"_id":"DEP4028"}],"date_created":"2026-04-28T07:11:46Z","user_id":"83781","type":"book_chapter","citation":{"mla":"Park, Cheol-Hwan, et al. “Process Analytical Technology in Upstream Mammalian Cell Cultures.” <i>Reference Module in Life Sciences</i>, edited by Bernard D.  Roitberg, Elsevier, 2026, <a href=\"https://doi.org/10.1016/b978-0-443-24738-5.00086-0\">https://doi.org/10.1016/b978-0-443-24738-5.00086-0</a>.","chicago":"Park, Cheol-Hwan, Yunjoo Jeon, Selina Uhlendorff, Miriam Pein-Hackelbusch, and Dong-Yup Lee. “Process Analytical Technology in Upstream Mammalian Cell Cultures.” In <i>Reference Module in Life Sciences</i>, edited by Bernard D.  Roitberg. [Erscheinungsort nicht ermittelbar]: Elsevier, 2026. <a href=\"https://doi.org/10.1016/b978-0-443-24738-5.00086-0\">https://doi.org/10.1016/b978-0-443-24738-5.00086-0</a>.","ieee":"C.-H. Park, Y. Jeon, S. Uhlendorff, M. Pein-Hackelbusch, and D.-Y. Lee, “Process Analytical Technology in Upstream Mammalian Cell Cultures,” in <i>Reference Module in Life Sciences</i>, B. D. Roitberg, Ed. [Erscheinungsort nicht ermittelbar]: Elsevier, 2026. doi: <a href=\"https://doi.org/10.1016/b978-0-443-24738-5.00086-0\">10.1016/b978-0-443-24738-5.00086-0</a>.","van":"Park CH, Jeon Y, Uhlendorff S, Pein-Hackelbusch M, Lee DY. Process Analytical Technology in Upstream Mammalian Cell Cultures. In: Roitberg BD, editor. Reference Module in Life Sciences. [Erscheinungsort nicht ermittelbar]: Elsevier; 2026.","apa":"Park, C.-H., Jeon, Y., Uhlendorff, S., Pein-Hackelbusch, M., &#38; Lee, D.-Y. (2026). Process Analytical Technology in Upstream Mammalian Cell Cultures. In B. D. Roitberg (Ed.), <i>Reference Module in Life Sciences</i>. Elsevier. <a href=\"https://doi.org/10.1016/b978-0-443-24738-5.00086-0\">https://doi.org/10.1016/b978-0-443-24738-5.00086-0</a>","din1505-2-1":"<span style=\"font-variant:small-caps;\">Park, Cheol-Hwan</span> ; <span style=\"font-variant:small-caps;\">Jeon, Yunjoo</span> ; <span style=\"font-variant:small-caps;\">Uhlendorff, Selina</span> ; <span style=\"font-variant:small-caps;\">Pein-Hackelbusch, Miriam</span> ; <span style=\"font-variant:small-caps;\">Lee, Dong-Yup</span>: Process Analytical Technology in Upstream Mammalian Cell Cultures. In: <span style=\"font-variant:small-caps;\">Roitberg, B. D.</span> (Hrsg.): <i>Reference Module in Life Sciences</i>. [Erscheinungsort nicht ermittelbar] : Elsevier, 2026","short":"C.-H. Park, Y. Jeon, S. Uhlendorff, M. Pein-Hackelbusch, D.-Y. Lee, in: B.D. Roitberg (Ed.), Reference Module in Life Sciences, Elsevier, [Erscheinungsort nicht ermittelbar], 2026.","ama":"Park CH, Jeon Y, Uhlendorff S, Pein-Hackelbusch M, Lee DY. Process Analytical Technology in Upstream Mammalian Cell Cultures. In: Roitberg BD, ed. <i>Reference Module in Life Sciences</i>. Elsevier; 2026. doi:<a href=\"https://doi.org/10.1016/b978-0-443-24738-5.00086-0\">10.1016/b978-0-443-24738-5.00086-0</a>","chicago-de":"Park, Cheol-Hwan, Yunjoo Jeon, Selina Uhlendorff, Miriam Pein-Hackelbusch und Dong-Yup Lee. 2026. Process Analytical Technology in Upstream Mammalian Cell Cultures. In: <i>Reference Module in Life Sciences</i>, hg. von Bernard D.  Roitberg. [Erscheinungsort nicht ermittelbar]: Elsevier. doi:<a href=\"https://doi.org/10.1016/b978-0-443-24738-5.00086-0\">10.1016/b978-0-443-24738-5.00086-0</a>, .","bjps":"<b>Park C-H <i>et al.</i></b> (2026) Process Analytical Technology in Upstream Mammalian Cell Cultures. In Roitberg BD (ed.), <i>Reference Module in Life Sciences</i>. [Erscheinungsort nicht ermittelbar]: Elsevier.","ufg":"<b>Park, Cheol-Hwan u. a.</b>: Process Analytical Technology in Upstream Mammalian Cell Cultures, in: <i>Roitberg, Bernard D. (Hg.)</i>: Reference Module in Life Sciences, [Erscheinungsort nicht ermittelbar] 2026.","havard":"C.-H. Park, Y. Jeon, S. Uhlendorff, M. Pein-Hackelbusch, D.-Y. Lee, Process Analytical Technology in Upstream Mammalian Cell Cultures, in: B.D. Roitberg (Ed.), Reference Module in Life Sciences, Elsevier, [Erscheinungsort nicht ermittelbar], 2026."},"year":"2026","editor":[{"last_name":"Roitberg","full_name":"Roitberg, Bernard D. ","first_name":"Bernard D. "}]},{"has_accepted_license":"1","publication_identifier":{"eissn":["2296-4185"]},"volume":13,"intvolume":"        13","ddc":["570"],"title":"Anomaly detection and removal strategies for in-line permittivity sensor signal used in bioprocesses","article_type":"original","status":"public","publication":"Frontiers in Bioengineering and Biotechnology","author":[{"last_name":"Bolmanis","first_name":"Emils","full_name":"Bolmanis, Emils"},{"id":"85335","full_name":"Uhlendorff, Selina","first_name":"Selina","last_name":"Uhlendorff"},{"first_name":"Miriam","full_name":"Pein-Hackelbusch, Miriam","last_name":"Pein-Hackelbusch","orcid":"0000-0002-7920-0595","id":"64952"},{"last_name":"Galvanauskas","first_name":"Vytautas","full_name":"Galvanauskas, Vytautas"},{"last_name":"Grigs","full_name":"Grigs, Oskars","first_name":"Oskars"}],"publisher":"Frontiers Media SA","abstract":[{"lang":"eng","text":"Introduction: In-line sensors, which are crucial for real-time (bio-) process monitoring, can suffer from anomalies. These signal spikes and shifts compromise process control. Due to the dynamic and non-stationary nature of bioprocess signals, addressing these issues requires specialized preprocessing. However, existing anomaly detection methods often fail for real-time applications.\r\n\r\nMethods: This study addresses a common yet critical issue: developing a robust and easy-to-implement algorithm for real-time anomaly detection and removal for in-line permittivity sensor measurement. Recombinant Pichia pastoris cultivations served as a case study. Trivial approaches, such as moving average filtering, do not adequately capture the complexity of the problem. However, our method provides a structured solution through three consecutive steps: 1) Signal preprocessing to reduce noise and eliminate context dependency; 2) Anomaly detection using threshold-based identification; 3) Validation and removal of identified anomalies.\r\n\r\nResults and discussion: We demonstrate that our approach effectively detects and removes anomalies by compensating signal shift value, while remaining computationally efficient and practical for real-time use. It achieves an F1-score of 0.79 with a static threshold of 1.06 pF/cm and a double rolling aggregate transformer using window sizes w1 = 1 and w2 = 15. This flexible and scalable algorithm has the potential to bridge a crucial gap in process real-time analytics and control."}],"publication_status":"published","year":"2025","oa":"1","citation":{"din1505-2-1":"<span style=\"font-variant:small-caps;\">Bolmanis, Emils</span> ; <span style=\"font-variant:small-caps;\">Uhlendorff, Selina</span> ; <span style=\"font-variant:small-caps;\">Pein-Hackelbusch, Miriam</span> ; <span style=\"font-variant:small-caps;\">Galvanauskas, Vytautas</span> ; <span style=\"font-variant:small-caps;\">Grigs, Oskars</span>: Anomaly detection and removal strategies for in-line permittivity sensor signal used in bioprocesses. In: <i>Frontiers in Bioengineering and Biotechnology</i> Bd. 13. Lausanne, Frontiers Media SA (2025)","apa":"Bolmanis, E., Uhlendorff, S., Pein-Hackelbusch, M., Galvanauskas, V., &#38; Grigs, O. (2025). Anomaly detection and removal strategies for in-line permittivity sensor signal used in bioprocesses. <i>Frontiers in Bioengineering and Biotechnology</i>, <i>13</i>, Article 1609369. <a href=\"https://doi.org/10.3389/fbioe.2025.1609369\">https://doi.org/10.3389/fbioe.2025.1609369</a>","chicago":"Bolmanis, Emils, Selina Uhlendorff, Miriam Pein-Hackelbusch, Vytautas Galvanauskas, and Oskars Grigs. “Anomaly Detection and Removal Strategies for In-Line Permittivity Sensor Signal Used in Bioprocesses.” <i>Frontiers in Bioengineering and Biotechnology</i> 13 (2025). <a href=\"https://doi.org/10.3389/fbioe.2025.1609369\">https://doi.org/10.3389/fbioe.2025.1609369</a>.","mla":"Bolmanis, Emils, et al. “Anomaly Detection and Removal Strategies for In-Line Permittivity Sensor Signal Used in Bioprocesses.” <i>Frontiers in Bioengineering and Biotechnology</i>, vol. 13, 1609369, 2025, <a href=\"https://doi.org/10.3389/fbioe.2025.1609369\">https://doi.org/10.3389/fbioe.2025.1609369</a>.","van":"Bolmanis E, Uhlendorff S, Pein-Hackelbusch M, Galvanauskas V, Grigs O. Anomaly detection and removal strategies for in-line permittivity sensor signal used in bioprocesses. Frontiers in Bioengineering and Biotechnology. 2025;13.","ieee":"E. Bolmanis, S. Uhlendorff, M. Pein-Hackelbusch, V. Galvanauskas, and O. Grigs, “Anomaly detection and removal strategies for in-line permittivity sensor signal used in bioprocesses,” <i>Frontiers in Bioengineering and Biotechnology</i>, vol. 13, Art. no. 1609369, 2025, doi: <a href=\"https://doi.org/10.3389/fbioe.2025.1609369\">10.3389/fbioe.2025.1609369</a>.","havard":"E. Bolmanis, S. Uhlendorff, M. Pein-Hackelbusch, V. Galvanauskas, O. Grigs, Anomaly detection and removal strategies for in-line permittivity sensor signal used in bioprocesses, Frontiers in Bioengineering and Biotechnology. 13 (2025).","ufg":"<b>Bolmanis, Emils u. a.</b>: Anomaly detection and removal strategies for in-line permittivity sensor signal used in bioprocesses, in: <i>Frontiers in Bioengineering and Biotechnology</i> 13 (2025).","chicago-de":"Bolmanis, Emils, Selina Uhlendorff, Miriam Pein-Hackelbusch, Vytautas Galvanauskas und Oskars Grigs. 2025. Anomaly detection and removal strategies for in-line permittivity sensor signal used in bioprocesses. <i>Frontiers in Bioengineering and Biotechnology</i> 13. doi:<a href=\"https://doi.org/10.3389/fbioe.2025.1609369\">10.3389/fbioe.2025.1609369</a>, .","bjps":"<b>Bolmanis E <i>et al.</i></b> (2025) Anomaly Detection and Removal Strategies for In-Line Permittivity Sensor Signal Used in Bioprocesses. <i>Frontiers in Bioengineering and Biotechnology</i> <b>13</b>.","ama":"Bolmanis E, Uhlendorff S, Pein-Hackelbusch M, Galvanauskas V, Grigs O. Anomaly detection and removal strategies for in-line permittivity sensor signal used in bioprocesses. <i>Frontiers in Bioengineering and Biotechnology</i>. 2025;13. doi:<a href=\"https://doi.org/10.3389/fbioe.2025.1609369\">10.3389/fbioe.2025.1609369</a>","short":"E. Bolmanis, S. Uhlendorff, M. Pein-Hackelbusch, V. Galvanauskas, O. Grigs, Frontiers in Bioengineering and Biotechnology 13 (2025)."},"type":"scientific_journal_article","file_date_updated":"2025-07-31T11:35:18Z","date_updated":"2025-10-10T07:46:08Z","main_file_link":[{"open_access":"1","url":"https://doi.org/10.3389/fbioe.2025.1609369"}],"department":[{"_id":"DEP4028"},{"_id":"DEP4000"}],"date_created":"2025-07-31T09:23:31Z","user_id":"64952","doi":"10.3389/fbioe.2025.1609369","article_number":"1609369","keyword":["in-situ","permittivity","dielectric spectroscopy","signal preprocessing","dynamic threshold","static threshold","anomaly validation","Pichia pastoris"],"file":[{"access_level":"closed","creator":"f6x-0e0","date_updated":"2025-07-31T11:35:18Z","file_size":2935650,"date_created":"2025-07-31T09:24:49Z","content_type":"application/pdf","file_id":"13102","file_name":"fbioe-1-1609369.pdf","relation":"main_file"}],"place":"Lausanne","quality_controlled":"1","language":[{"iso":"eng"}],"_id":"13101"}]