# On-Line Tendency Control of Dissolved Oxygen Concentration during Aerobic Fed-Batch Fermentations
## 1 Introduction  
Biotechnologies have been extensively utilized in the production of agricultural products, fine chemicals, pharmaceutical products, food processing products, and several other chemical compounds over the last few years. A considerable number of these production processes are aerobic in nature, in which oxygen is necessary for microorganism growth, maintenance, and product synthesis [1; 2; 3]. During fed-batch mode, which is the most popular mode for the operation of fermentation processes, the substrate is gradually fed into the bioreactor. Although fed-batch mode is commonly preferred because it is superior at avoiding overfeeding or underfeeding of the substrate, which can inhibit microbial growth and product formation, fed-batch bioprocesses are very difficult to control due to the lack of precise models describing cellular growth, product formation, the nonlinear behaviour of the fermentation process, and the slow process response, as well as the lack of reliable on-line sensors for the quantification of key process variables [2; 4]. Microbial population dynamics in bioreactors depend on both nutrients availability and changes in the growth environment. In aerobic fermentation processes, the dissolved oxygen (DO) concentration is one of the most important operating parameters. The measurement and accurate control of the DO concentration is conducive to the calculation of the volumetric oxygen transfer coefficient (K\({}_{\text{L}}\),a), and it is also very important for the understanding of fermentation processes [5; 6]. As oxygen deficiency will lead to either cessation of aerobic growth or a decrease in the efficiency of metabolism, as well as the production of undesirable by-products, maintaining a constant DO concentration in the growth medium is required for aerobic fermentation. In addition, the DO concentration must increase asthe consumption of oxygen increases to maintain the desired level of biomass concentration and the specific growth rate [7]. Unfortunately, due to its low solubility in water, oxygen is the most limiting substrate for bacteria during fermentation and, as a result, it must be provided continuously [1,8]. Therefore, it is a difficult task to control the DO concentration, especially during fed-batch fermentation, due to strongly nonlinear, variable conditions and probe dynamics [5,9]. There are three methods that are generally used to control the DO concentration during a fermentation process. One of the most frequently employed methods is the manipulation of the agitation speed to improve mass transfer. The second method involves adjustment of the aeration rate, and the third method is based on altering the partial pressure of oxygen in the gas phase [8,10,11]. Nevertheless, increasing the oxygen partial pressure of the inlet gas is often unfeasible, as it requires either the addition of pure oxygen, which is expensive compared to using pure air, or increase of the total pressure, which increases strain on the fermentor [7]. In the last decade, a number of methods of DO control have been developed for use in fermentation processes and reported in the literature. [PERSON] et al. developed a self-tuning generalized minimum variance algorithm, the performance of which was compared to that of conventional PID (Proportion Integration Differentiation) control during a fermentation process that utilized _Saccharomyces cerevisiae NRRL Y-567_[5]. [PERSON] et al. proposed a modified mid-ranging strategy in an industrial bioproces that was used to control the DO level by manipulating the aeration rate and agitator speed [7]. In a study by [PERSON] et al., a combinational induction strategy utilizing low induction temperature and high dissolved oxygen concentration was employed for porcine interferon-\(\alpha\) production using recombinant _Pichia pastoris;_ the aeration and agitation rates were modified by manual adjustment [12].