Multi-sample fermentor and method of using same

Details Multi-sample fermentor and method of using same Multi-sample fermentor and method of using same

2001-02-08

2003-10-21

Tate, Christopher R. (Department: 1651)

Chemistry: molecular biology and microbiology

Micro-organism, tissue cell culture or enzyme using process...

C435S027000, C435S029000, C435S283100, C435S287100, C435S288200, C435S289100, C435S294100, C435S299100, C435S299200, C435S300100, C435S304100, C435S305100, C435S305300, C435S325000, C435S808000, C435S802000, C435S813000

Reexamination Certificate

active

06635441

ABSTRACT:

FIELD OF THE INVENTION
The field of the present invention is fermentation systems. More specifically, the present invention relates to an apparatus and method for simultaneously fermenting multiple samples as part of a multiple process system.
BACKGROUND OF THE INVENTION
Fermentation is a key technology in many fields and industries and is performed both on a mass production scale and on an experimental, bench top scale. For example, fermentation systems are used for the production of a large number of products such as antibiotics, vaccines, synthetic biopolymers, synthetic amino acids, and proteins. Fermentation technology is integral in the production of recombinant proteins using biological organisms such as
E. coli
and many other cell cultures. For example, production of commercial pharmaceuticals such as recombinant insulin (Eli Lilly), erythropoietin (Amgen), and interferon (Roche) all involve fermentation as an essential step.
Fermentation may be conducted on a production scale in order to make commercial quantities of pharmaceuticals or other products. Production scale processes emphasize limited human intervention and automation to increase output and efficiency. In an assembly line fashion, automated equipment enables high throughput processing of production scale amounts of material without disrupting the assembling, testing, or synthesizing process at each individual processing step. For example, automated liquid dispensers, aspirators, and specimen plate handlers facilitate the handling and testing of hundreds of thousands of samples per day, with limited human interaction with the actual sample from start to finish of the entire analysis process. In a further example, sample materials are automatically dispensed into multiple well specimen plates, reagents are added and removed via automated liquid dispensers and aspirators, and the specimen plates are transferred to each successive processing station by automated plate handlers. This increased production efficiency is premised in part on the viability of conducting the entire production process in the specimen plate. Similarly, automated procedures enable the synthesis of commercial pharmaceuticals from starting reagents to finished product without disrupting the production process with cumbersome, inefficient steps such as changing a sample vessel or transferring the sample materials manually to new sample vessels.
Rapid advances in biotechnology have enabled the development of high throughput alternatives to traditional laboratory bench top processes. Unfortunately, fermentation methods have not been amenable to automation because limits in current fermentation technology prevent the uninterrupted processing flow that characterizes automated high throughput systems. Existing fermentation systems typically involve multiple handling steps by either a batch processing method or a continuous processing method.
Current production scale batch processes involve first fermenting in large scale, bulk fermentation vessels, then processing the fermentation medium to isolate the desired fermentation product, followed by transferring this product into the production stream for further processing, and finally cleaning the fermentation apparatus for the next batch. In a large scale batch culture, it is generally necessary to provide a high initial concentration of nutrients in order to sustain cell growth over an extended time. As a result, substrate inhibition may occur in the early stages of cell growth and then may be followed by a nutrient deficiency in the late stages of fermentation. These disadvantages result in sub-optimal cell growth rates and fermentation yields. Another disadvantage of this method lies in the need to individually dispense the fermentation products from the bulk fermentation apparatus into separate sample vessels for further processing. Thus, by producing the fermentation product on a bulk scale, the fermentation product is not immediately available for automated processing. Further disadvantages include the decreased efficiency of both transferring the material to another sample vessel, as well as cleaning and sterilizing the fermentation apparatus for the next batch. These disadvantages result in increased production costs, inefficient production times and decreased yields.
Continuous batch processes involve siphoning off the fermentation product from the bulk fermentation vessel and continuously adding nutrients to the fermentation medium according to a calculated exponential growth curve. This curve, however, is merely an approximation that does not accurately predict cell growth in large, industrial scale quantities of fermentation medium. Consequently, due to the unpredictable nature of large scale fermentation environments, experienced personnel are required to monitor the feeding rate very closely. Changes in the fermentation environment may result in either poisoned fermentation products being siphoned off into the production stream or sub-optimal production yields due to starved fermentation mediums. As a further disadvantage, unpredictable fermentation product yields affect the accuracy of subsequent processing steps. For example, when the fermentation yield decreases, the amount of aspirating, the amount of reagent dispensed, or the centrifuge time is no longer optimized, or even predictable. Frequent or continuous monitoring of the fermentation process and adjustment of the fermentation conditions is often not practicable or efficient in a production scale process.
Fermentation remains a key processing step in a number of industries, particularly in biotechnology industries, and thus a need exists for incorporating fermentation processes into current multiple process systems, such as automated high throughput systems. A process that produces a precise, known, and repeatable amount of unpoisoned fermentation product with limited human interaction or sample vessel transfer is essential to integrating fermentation into modem production processes.
SUMMARY OF THE INVENTION
The present invention greatly alleviates the disadvantages of known fermentation systems by providing a fermentation apparatus that may be incorporated into high throughput processing systems.
Briefly, the fermentation apparatus is constructed to produce a known and repeatable amount of unpoisoned fermentation product using multiple fermentation vessels. To facilitate further processing and to be compatible with other product processing steps, the fermentation apparatus preferably has an array of sample vessels arranged in a container frame. The container frame may be configured to hold the sample vessels during fermentation and to transport the vessel array to or from another processing station.
The sample vessels may be arranged in the container frame in an array format to facilitate tracking of the sample vessels during the production process and to make the format of sample vessels compatible with other processing steps. In a preferred embodiment, a total of 96 sample vessels are arranged in an 8×12 format. An arrayed 96-member sample format is compatible with other methods for sample handling such as a 96-well microtiter plate. An 8×12 arrayed format is similarly compatible with sample handling formats designed for greater numbers of sample vessels, such as 384- and 1536-member sample formats, which are multiples of the 96-member sample format.
In a preferred embodiment a cannula array, having a number of cannula corresponding to the number of sample vessels in the sample vessel array, is configured such that each cannula may be placed inside a sample vessel. The cannula array may be attached to a gas distributor that delivers gases from a gas source through the cannula into the sample vessel. Depending on the gas delivered, either aerobic fermentation with agitation or oxygenation or anaerobic fermentation, i.e., with a nitrogen bubbler, for example, can be performed with the present invention. Because the fermentation volume for each individual sample vessel is smaller than a bulk fermentation appara

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