Cell Culture Bioreactors: Controls, Measurements, and Scale-Down Model

Abstract

This chapter describes the types of bioreactors, bioreactor controls for process parameters, measurement of cell growth and metabolites, and a scale-down model using small- and pilot-scale culture vessels used in the biopharmaceutical industry. The major types of bioreactors used for cell culture processes in the biopharmaceutical industry today are stirred and airlift bioreactors. Recently, disposable bioreactors have been utilized for their convenience. Each type of bioreactor can be used for batch, fed-batch, and continuous cultures. Metabolites such as glucose, glutamine, lactate, ammonia, and amino acids can be monitored with an advantage of real-time measurements without sampling for in situ analysis of culture metabolites in order to maintain predetermined ranges of each metabolite in the fed-batch culture. The in situ probes will be widely used in the future due to the ease of real-time measurements and lack of sampling. Major changes in the metabolite levels are observed with lactate and ammonia, which are considered as by-products of culture, in addition to the changes in glucose, glutamine, and amino acid concentrations. The proper control of process parameters such as pH, dissolved oxygen (DO), agitation, and aeration is the most important consideration in the operation of bioreactors to consistently produce good cell growth, productivity, and quality of product. The scale-down model is also applied to the quality-by-design applications to develop a design space for process parameters to ensure predefined product quality.