In a continuous culture operation, nutrients essential for growth are continuously fed and a portion of the culture is continuously withdrawn. The culture volume is controlled using a level controller. A continuous culture is usually preceded by a batch or fed-batch culture. If the mass flow rates of the bioreactor feed and bioreactor effluent are identical and timeinvariant, a time-invariant (steady state) operation can be realized after sufficient time since the start of continuous culture operation. The status of the culture can be determined easily by analysis of the bioreactor effluent, thereby causing no interference with bioreactor operation, which is certainly not the case with batch and fed-batch operations. As in a fed-batch culture, the feed rate to a continuous bioreactor can be varied in a temporal sense in a predetermined fashion or using feedback control. Since the culture conditions (in a global sense) can be kept time-invariant, continuous cultures are easier to monitor and control. When culture conditions which promote biomass growth are substantially different from those which promote production of a target metabolite (on a per cell basis), a simple continuous culture operation described here may not yield the best productivity of the target metabolite. Two-staged continuous culture operations where cell growth is promoted in the first stage and synthesis of a target metabolite is promoted in the second stage have been shown to yield much higher productivity when compared to the highest productivity attainable in single-stage continuous culture. Such two-staged operations may be attained spatially in two continuous cultures in series and temporally in a single continuous culture by switching from a growth promoting medium to a production medium and vice versa. These are some of the advantages and flexibility that a continuous culture offers over batch and fed-batch cultures. Unlike the operation of continuous processes employed for production of chemicals, long-term operation of continuous cultures is subject to many operating difficulties, including risks of contamination and loss in productivity due to cell washout in case of unanticipated disturbances and substantial changes in characteristics of the biotic phase.
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