Mears Lisa, Stocks Stuart M, Albaek Mads O, Cassells Benny, Sin Gürkan, Gernaey Krist V
Department of Chemical and Biochemical Engineering, Technical University of Denmark, Kongens Lyngby 2800, Denmark.
Leo Pharma A/S, Ballerup, Denmark.
Biotechnol Bioeng. 2017 Jul;114(7):1459-1468. doi: 10.1002/bit.26274. Epub 2017 Mar 9.
A novel model-based control strategy has been developed for filamentous fungal fed-batch fermentation processes. The system of interest is a pilot scale (550 L) filamentous fungus process operating at Novozymes A/S. In such processes, it is desirable to maximize the total product achieved in a batch in a defined process time. In order to achieve this goal, it is important to maximize both the product concentration, and also the total final mass in the fed-batch system. To this end, we describe the development of a control strategy which aims to achieve maximum tank fill, while avoiding oxygen limited conditions. This requires a two stage approach: (i) calculation of the tank start fill; and (ii) on-line control in order to maximize fill subject to oxygen transfer limitations. First, a mechanistic model was applied off-line in order to determine the appropriate start fill for processes with four different sets of process operating conditions for the stirrer speed, headspace pressure, and aeration rate. The start fills were tested with eight pilot scale experiments using a reference process operation. An on-line control strategy was then developed, utilizing the mechanistic model which is recursively updated using on-line measurements. The model was applied in order to predict the current system states, including the biomass concentration, and to simulate the expected future trajectory of the system until a specified end time. In this way, the desired feed rate is updated along the progress of the batch taking into account the oxygen mass transfer conditions and the expected future trajectory of the mass. The final results show that the target fill was achieved to within 5% under the maximum fill when tested using eight pilot scale batches, and over filling was avoided. The results were reproducible, unlike the reference experiments which show over 10% variation in the final tank fill, and this also includes over filling. The variance of the final tank fill is reduced by over 74%, meaning that it is possible to target the final maximum fill reproducibly. The product concentration achieved at a given set of process conditions was unaffected by the control strategy. Biotechnol. Bioeng. 2017;114: 1459-1468. © 2017 Wiley Periodicals, Inc.
针对丝状真菌补料分批发酵过程，开发了一种基于模型的新型控制策略。所关注的系统是诺维信公司运行的中试规模（550升）丝状真菌发酵过程。在这类过程中，期望在规定的过程时间内使一批发酵中获得的总产物最大化。为实现这一目标，使补料分批系统中的产物浓度和最终总质量都最大化很重要。为此，我们描述了一种控制策略的开发，该策略旨在实现最大罐装填量，同时避免氧气受限条件。这需要分两个阶段进行：（i）计算罐起始装填量；（ii）进行在线控制，以便在氧气传递受限的情况下使装填量最大化。首先，离线应用一个机理模型，以确定搅拌器速度、顶空压力和通气速率这四种不同工艺操作条件下的合适起始装填量。使用参考工艺操作通过八个中试规模实验对起始装填量进行了测试。然后开发了一种在线控制策略，利用通过在线测量递归更新的机理模型。应用该模型来预测当前系统状态，包括生物量浓度，并模拟系统直至指定结束时间的预期未来轨迹。通过这种方式，在考虑氧气传质条件和质量的预期未来轨迹的情况下，沿着批次进程更新期望的进料速率。最终结果表明，在使用八个中试规模批次进行测试时，目标装填量在最大装填量的5%以内得以实现，并且避免了过度装填。结果具有可重复性，不像参考实验那样最终罐装填量有超过10%的变化，这还包括过度装填。最终罐装填量的方差降低了超过(74%)，这意味着可以可重复地瞄准最终最大装填量。在给定的一组工艺条件下实现的产物浓度不受控制策略的影响。《生物技术与生物工程》2017年；114：1459 - 1468。©2017威利期刊公司
