用于红霉素生产的500m3生物反应器的理性设计

Rational design of a 500 m3 fermenter for erythromycin production by Saccharopolyspora erythraea

摘要:

红霉素(erythromycin)是由绛红色糖多胞菌(Saccharopolyspora erythraea)发酵生产的次级代谢产物，其生产水平不仅受发酵工艺的影响，也受反应器结构影响。为解决红霉素发酵过程放大问题，本研究采用时间常数法和计算流体力学(computational fluid dynamics,CFD)数值模拟验证相结合的方法设计了500m³超大规模红霉素耗氧发酵生物反应器。首先，通过对50L反应器红霉素发酵过程研究，发现溶氧是关键性限制因素，通过氧消耗速率(oxygen uptake rate,OUR)等参数分析计算得到设备的氧供应时间常数t_mt需小于6.25s。然后，基于时间常数法和经验关联式理性设计500m³反应器搅拌桨叶组合方式，即底层BDT8桨叶+两层MSX4桨叶的搅拌桨组合，并通过经验公式及CFD方法对设计结果进行了模拟验证。两种验证方法结果均表明500m³反应器采取底层BDT8桨叶+两层MSX4桨叶的组合方式时设备的氧供应时间常数小于6.25s，且反应器内流场特性(如持气率、剪切率和速度矢量等)均能满足红霉素大规模发酵的需要。经实际发酵验证，设计的生物反应器能够满足红霉素的工业规模发酵应用。

关键词:红霉素发酵;生物反应器设计;计算流体力学模拟;耗氧速率;时间常数法

Abstract:

Erythromycin is a macrolide antibiotic produced by Saccharopolyspora erythraea. Its yield is greatly affected by the fermentation conditions and the bioreactor configurations. In this study, a novel scale-up method for erythromycin fermentation was developed based on computational fluid dynamics (CFD) and time constant analysis. Firstly, the dissolved oxygen (DO) was determined as a key parameter according to the physiological properties of S.erythraea cultivated in a 50 L bioreactor. It was found that the time constant of oxygen supply (t_mt) in a 500 m³ bioreactor should be less than 6.25 s in order to satisfy the organism's oxygen uptake rate (OUR). Subsequently, a 500 m³ bioreactor was designed using the time constant method combined with empirical correlations. The impeller combination with one BDT8 impeller at bottom and two MSX4 impellers at upper part was determined, and then validated by numerical simulation. The results indicated that the t_mt of the bioreactor (<6.25 s) and the fluid properties, including gas hold-up, shear stress and fluid vector, met the requirements of erythromycin fermentation. Finally, the industrial production of erythromycin in the 500 m³ showed the design method was applicable in large scale fermentation.

Key words:erythromycin fermentation;stirred tank bioreactor;computational fluid dynamics;oxygen uptake rate;time constant analysis