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Achieving a manufacturing process that is sufficiently productive with the requisite product quality is critically important for commercialization success. Mammalian producer cell lines (PCLs) are stably transfected to integrate AAV structural and non\u2010structural genes and are frequently combined with infection by wild\u2010type adenovirus (Ad5) to provide helper elements. Within the PCL, both Ad5 amplification and rAAV production occur. During AAV manufacturing with PCLs, the upstream process targets the generation of high rAAV titers and full\u2010capsid percentages. This is followed by a downstream process designed to effectively clear Ad5 and other process\u2010related impurities, while further enriching full rAAV capsids. To explore potential improvements at the cellular level, we developed a mechanistic model based on empirical cell culture data, capturing intracellular dynamics of rAAV assembly and Ad5 amplification. Sensitivity analysis using this model identified cellular processes associated with rAAV yield and full\u2010particle percentage. Notably, the analysis confirmed the critical influence of Ad5 amplification on both rAAV yield and quality. Further analysis, including nonlinear optimization, identified additional targets for cell line and helper virus engineering to evaluate process performance.<\/jats:p>","DOI":"10.1002\/btpr.88524","type":"journal-article","created":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T06:01:36Z","timestamp":1780639296000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A mechanistic model for recombinant adeno\u2010associated virus production dynamics in a helper virus\u2010assisted producer cell line"],"prefix":"10.1002","volume":"42","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4514-5671","authenticated-orcid":false,"given":"Sha","family":"Sha","sequence":"first","affiliation":[{"name":"Ultragenyx Pharmaceutical Inc., Global CMC Development  Woburn Massachusetts 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