Quality-by-Design approach to monitor the operation of a batch bioreactor in an industrial avian vaccine manufacturing process

tMonitoring batch bioreactors is a complex task, due to the fact that several sources of variability can affecta running batch and impact on the final product quality. Additionally, the product quality itself may notbe measurable on line, but requires sampling and lab analysis taking several days to be completed. Inthis study we show that, by using appropriate process analytical technology tools, the operation of anindustrial batch bioreactor used in avian vaccine manufacturing can be effectively monitored as thebatch progresses. Multivariate statistical models are built from historical databases of batches alreadycompleted, and they are used to enable the real time identification of the variability sources, to reliablypredict the final product quality, and to improve process understanding, paving the way to a reductionof final product rejections, as well as to a reduction of the product cycle time. It is also shown thatthe product quality “builds up” mainly during the first half of a batch, suggesting on the one side thatreducing the variability during this period is crucial, and on the other side that the batch length canpossibly be shortened. Overall, the study demonstrates that, by using a Quality-by-Design approachcentered on the appropriate use of mathematical modeling, quality can indeed be built “by design” intothe final product, whereas the role of end-point product testing can progressively reduce its importancein product manufacturing.