title: Quality-by-Design approach to monitor the operation of a batch bioreactor in an industrial avian vaccine manufacturing process.
abstract: Monitoring batch bioreactors is a complex task, due to the fact that several sources of variability can affect a running batch and impact on the final product quality. Additionally, the product quality itself may not be measurable on line, but requires sampling and lab analysis taking several days to be completed. In this study we show that, by using appropriate process analytical technology tools, the operation of an industrial batch bioreactor used in avian vaccine manufacturing can be effectively monitored as the batch progresses. Multivariate statistical models are built from historical databases of batches already completed, and they are used to enable the real time identification of the variability sources, to reliably predict the final product quality, and to improve process understanding, paving the way to a reduction of final product rejections, as well as to a reduction of the product cycle time. It is also shown that the product quality "builds up" mainly during the first half of a batch, suggesting on the one side that reducing the variability during this period is crucial, and on the other side that the batch length can possibly be shortened. Overall, the study demonstrates that, by using a Quality-by-Design approach centered on the appropriate use of mathematical modeling, quality can indeed be built "by design" into the final product, whereas the role of end-point product testing can progressively reduce its importance in product manufacturing.
authors.affiliation: CAPE-Lab-Computer-Aided Process Engineering Laboratory, Department of Industrial Engineering, University of Padova, via Marzolo 9, 35131 Padova PD, Italy.
authors.forename: Martina
authors.initials: M
authors.lastname: Largoni
authors.affiliation: CAPE-Lab-Computer-Aided Process Engineering Laboratory, Department of Industrial Engineering, University of Padova, via Marzolo 9, 35131 Padova PD, Italy.
authors.forename: Pierantonio
authors.initials: P
authors.lastname: Facco
authors.affiliation: Merial-A Sanofi Company, via Baviera 9, 35027 Noventa Padovana PD, Italy.
authors.forename: Donatella
authors.initials: D
authors.lastname: Bernini
authors.affiliation: CAPE-Lab-Computer-Aided Process Engineering Laboratory, Department of Industrial Engineering, University of Padova, via Marzolo 9, 35131 Padova PD, Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Bezzo
authors.affiliation: CAPE-Lab-Computer-Aided Process Engineering Laboratory, Department of Industrial Engineering, University of Padova, via Marzolo 9, 35131 Padova PD, Italy. Electronic address: max.barolo@unipd.it.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Barolo
mesh_terms: D000818:Animals; D061249:Batch Cell Culture Techniques / Q000295:instrumentation*; D019149:Bioreactors; D002138:Calibration; D002645:Chickens; D004867:Equipment Design; D007221:Industry; D016018:Least-Squares Analysis; D013997:Time Factors; D014612:Vaccines / Q000138:chemical synthesis*
chemical_list: D014612:Vaccines
keywords: Batch process monitoring; Bioreactors; PAT; Process analytical technology; Quality by design; Vaccine manufacturing