{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T10:06:29Z","timestamp":1790762789691,"version":"4.1.0"},"reference-count":44,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T00:00:00Z","timestamp":1790726400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T00:00:00Z","timestamp":1790726400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100000046","name":"National Research Council Canada","doi-asserted-by":"publisher","award":["AI4D\u2010103\u20101"],"award-info":[{"award-number":["AI4D\u2010103\u20101"]}],"id":[{"id":"10.13039\/501100000046","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["analyticalsciencejournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Biotech &amp;amp; Bioengineering"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Adenoviral vectors are a critical vaccine platform, with billions of vaccine doses administered during the COVID\u201019 pandemic. In addition, they are promising therapeutics for cancer treatment. To advance their manufacturing, real\u2010time monitoring of adenovirus production is essential for process optimization, yield improvement, and product quality assurance. However, despite modern bioreactors being equipped with advanced sensors, comprehensive monitoring of viral production in real\u2010time remains limited. In this work, we investigated potential indicators of the cell density effect (CDE), which imposes a trade\u2010off between high cell density and specific productivity, thereby hindering process optimization. Glucose availability (expressed as glucose per cell) at time of infection was identified as the most effective proxy indicator. We developed an age\u2010structured mechanistic model linking measurable process variables, such as glucose and viable cell density to viral production while capturing the CDE. This framework enables the prediction of viral particle titers in both batch and fed\u2010batch operation modes, achieving an RMSE of 0.39 in log\n                    <jats:sub>10<\/jats:sub>\n                    IVP\/mL for infectious viral particles and 0.20 in log\n                    <jats:sub>10<\/jats:sub>\n                    VP\/mL for total viral particles, corresponding to approximately 2.6 and 2.0 times the measurement standard deviation of the respective assays. The proposed model and calibration method lay the foundation for a digital twin of adenovirus production, bridging real\u2010time sensing with model\u2010based simulation to support adaptive control and accelerate the transition toward Biopharma 4.0.\n                  <\/jats:p>","DOI":"10.1002\/bit.70395","type":"journal-article","created":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T09:48:21Z","timestamp":1790761701000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Mechanistic Digital Model for Real\u2010Time Monitoring and Optimization of Adenovirus Production"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-6839-779X","authenticated-orcid":false,"given":"Xingge","family":"Xu","sequence":"first","affiliation":[{"name":"Department of Bioengineering McGill University Montreal Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7817-1884","authenticated-orcid":false,"given":"Daniel","family":"R\u00fcdiger","sequence":"additional","affiliation":[{"name":"Department of Bioprocess Engineering Max Planck Institute for Dynamics of Complex Technical Systems Magdeburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-7939-6163","authenticated-orcid":false,"given":"Jeongbin","family":"Shin","sequence":"additional","affiliation":[{"name":"Department of Bioengineering McGill University Montreal Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0627-8006","authenticated-orcid":false,"given":"Shawninder","family":"Chahal","sequence":"additional","affiliation":[{"name":"Department of Chemical and Biological Engineering University of Ottawa Ottawa Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9110-8815","authenticated-orcid":false,"given":"Amine","family":"Kamen","sequence":"additional","affiliation":[{"name":"Department of Bioengineering McGill University Montreal Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,30]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"crossref","unstructured":"Altaras N. E. J. F.Aunins R. K.Evans et al.2005.Production and Formulation of Adenovirus Vectors 0724\u20136145.","DOI":"10.1007\/10_008"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/btpr.2035"},{"issue":"2","key":"e_1_2_9_4_1","doi-asserted-by":"crossref","DOI":"10.3390\/vaccines11020432","article-title":"Adenoviral Vector\u2010Based Vaccine Platform for COVID\u201019: Current Status","volume":"11","author":"Chavda V.","year":"2023","journal-title":"Vaccines"},{"key":"e_1_2_9_5_1","unstructured":"ClinicalTrials.gov.2026.https:\/\/clinicaltrials.gov\/search?cond=cancer&intr=adenovirus."},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1021\/bp034237l"},{"key":"e_1_2_9_7_1","doi-asserted-by":"crossref","unstructured":"Efron B.1979. Bootstrap Methods: Another Look at the Jackknife. The Annals of Statistics 7(1) 1\u201026.http:\/\/www.jstor.org\/stable\/2958830.","DOI":"10.1214\/aos\/1176344552"},{"key":"e_1_2_9_8_1","doi-asserted-by":"crossref","unstructured":"Farn\u00f3s O. B. C.Martins Fernandes Paes B.Getachew et al.2024. Intranasally Delivered Adenoviral Vector Protects Chickens against Newcastle Disease Virus: Vaccine Manufacturing and Stability Assessments for Liquid and Lyophilized Formulations. Vaccines 12(1) 41.https:\/\/www.mdpi.com\/2076-393X\/12\/1\/41.","DOI":"10.3390\/vaccines12010041"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.gt.3302618"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/btpr.64"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1177\/1947601910392989"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1023\/A:1005672410905"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2025.03.062"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1003372"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/bit.20074"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymben.2005.08.002"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/0042-6822(69)90273-6"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM195412302512701"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.3390\/pr10112180"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1002\/bit.27945"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1002\/jgm.503"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0378-4347(00)00597-1"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1007\/10_2020_136"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40265-023-01846-z"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1021\/bp025638o"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.2174\/1568009618666171129221503"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1002\/bit.26858"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1002\/bit.10128"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1002\/biot.201900172"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10529-022-03302-6"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbiotec.2016.11.010"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.vaccine.2015.05.097"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1002\/1873-3468.13690"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2003.08.016"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.3181\/00379727-84-20714"},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1006819"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.1099\/0022-1317-36-1-59"},{"key":"e_1_2_9_38_1","doi-asserted-by":"crossref","unstructured":"Shen C. F. A.Rodenbrock S.Lanthier E.Burney andM.Loignon.2024. Optimization of Culture Media and Feeding Strategy for High Titer Production of an Adenoviral Vector in HEK 293 Fed\u2010Batch Culture. Vaccines 12(5) 524.https:\/\/www.mdpi.com\/2076-393X\/12\/5\/524.","DOI":"10.3390\/vaccines12050524"},{"key":"e_1_2_9_39_1","doi-asserted-by":"publisher","DOI":"10.1002\/btpr.286"},{"key":"e_1_2_9_40_1","doi-asserted-by":"publisher","DOI":"10.1021\/bp990077v"},{"key":"e_1_2_9_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2020.01.006"},{"key":"e_1_2_9_42_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymben.2005.07.002"},{"key":"e_1_2_9_43_1","doi-asserted-by":"publisher","DOI":"10.1002\/bit.28712"},{"key":"e_1_2_9_44_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.copbio.2013.04.016"},{"key":"e_1_2_9_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.enzmictec.2006.03.021"}],"container-title":["Biotechnology and Bioengineering"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/analyticalsciencejournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/bit.70395","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/analyticalsciencejournals.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/bit.70395","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/analyticalsciencejournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/bit.70395","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T09:48:24Z","timestamp":1790761704000},"score":1,"resource":{"primary":{"URL":"https:\/\/analyticalsciencejournals.onlinelibrary.wiley.com\/doi\/10.1002\/bit.70395"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,30]]},"references-count":44,"alternative-id":["10.1002\/bit.70395"],"URL":"https:\/\/doi.org\/10.1002\/bit.70395","archive":["Portico"],"relation":{},"ISSN":["0006-3592","1097-0290"],"issn-type":[{"value":"0006-3592","type":"print"},{"value":"1097-0290","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,30]]},"assertion":[{"value":"2025-12-03","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-16","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-30","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"bit.70395"}}