WO2009013066A1 - Procédé de fermentation de cultures cellulaires - Google Patents

Procédé de fermentation de cultures cellulaires Download PDF

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Publication number
WO2009013066A1
WO2009013066A1 PCT/EP2008/057378 EP2008057378W WO2009013066A1 WO 2009013066 A1 WO2009013066 A1 WO 2009013066A1 EP 2008057378 W EP2008057378 W EP 2008057378W WO 2009013066 A1 WO2009013066 A1 WO 2009013066A1
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Prior art keywords
metabolic
determined
cell
target
fermentation
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Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
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PCT/EP2008/057378
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German (de)
English (en)
Inventor
Werner Zang
Michelangelo Canzoneri
Rolf KRÜGER
Manfred Biselli
Rainer Fischer
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HITEC ZANG GmbH
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HITEC ZANG GmbH
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Priority to EP08760919A priority Critical patent/EP2162527A1/fr
Publication of WO2009013066A1 publication Critical patent/WO2009013066A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M41/00—Means for regulation, monitoring, measurement or control, e.g. flow regulation
    • C12M41/26—Means for regulation, monitoring, measurement or control, e.g. flow regulation of pH
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M41/00—Means for regulation, monitoring, measurement or control, e.g. flow regulation
    • C12M41/30—Means for regulation, monitoring, measurement or control, e.g. flow regulation of concentration
    • C12M41/32—Means for regulation, monitoring, measurement or control, e.g. flow regulation of concentration of substances in solution
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M41/00—Means for regulation, monitoring, measurement or control, e.g. flow regulation
    • C12M41/30—Means for regulation, monitoring, measurement or control, e.g. flow regulation of concentration
    • C12M41/34—Means for regulation, monitoring, measurement or control, e.g. flow regulation of concentration of gas
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M41/00—Means for regulation, monitoring, measurement or control, e.g. flow regulation
    • C12M41/48—Automatic or computerized control
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/0018—Culture media for cell or tissue culture
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P21/00—Preparation of peptides or proteins
    • C12P21/02—Preparation of peptides or proteins having a known sequence of two or more amino acids, e.g. glutathione

Definitions

  • the invention relates to a method and / or a device for an RQ-regulated feed process in cell cultures.
  • Biopharmaceutical drugs are rapidly gaining in importance.
  • Biopharmaceuticals are understood to be (recombinant) therapeutic proteins obtained by genetic engineering methods, monoclonal antibodies or nucleic acid-based drugs.
  • the volume of biopharmaceuticals produced by cell cultures has more than doubled.
  • the development has reached such a dynamic that the cell culture fermentation capacities worldwide become the limiting factor.
  • the optimization of these large-scale production processes is therefore becoming increasingly important.
  • the challenge will be to cost-effectively produce the corresponding products in competition.
  • fed-batch fermentation is currently the most widely used process control strategy.
  • other process parameters such as: As the pH, kept constant. The acidified by metabolic end product is thus neutralized and allows the culture to grow unhindered. The culture time can be extended by the fed-batch method to up to two weeks and increase the product titre in some cases up to 10-fold.
  • the maintenance of constant culture parameters is of particular importance for cell cultures. Not optimal culture parameters not only lower the productivity of the cells.
  • the aerobic degradation of nutrients leads to a decrease in the concentration of the substrate to be metabolized and to a depletion of oxygen (respiratory chain).
  • the latter can be determined by accounting for the exhaust air as the Oxygen Transfer Rate (OTR) and is a measure of the current oxygen consumption of the cell.
  • OTR Oxygen Transfer Rate
  • the direct relationship between substrate and oxygen consumption rates has been demonstrated by several groups of work (T. Anderlei, Online Respiration Activity Measurement (OTR, CTR, RQ) in shake flasks, Biochemical Engineering, 2004, 17, 187-194, Q. Feng, On -Im monitoring of oxygen uptake rate and its application in hybridoma culture, Sheng Wu Gong Cheng Xue Bao., 2003, 19 (5), 593-607; M. Canzoneri, Respiratory activity of mammalian cells, BioForum, 2006, 2).
  • the feed process or the fed-batch strategy is used as standard in various production processes (recombinant proteins, baker's yeast, antibiotics, etc.) in industry.
  • the limiting substrates are supplied after the deceleration phase.
  • the substrate is supplied to the extent that it is metabolized (quasi steady state), d. H. with the adjusted substrate concentration, a certain growth rate can be set (monodic kinetics).
  • Essential for the fed-batch technique are the instructions for the specific culture / production processes. They are based on intensive research into the course of culture and the derivation of corresponding, specific procedures / instructions.
  • a major disadvantage of conventional process control is the offline determination of the substrate consumption rates, substrate concentrations and the current cell density. As a rule, samples must be taken at regular intervals in the running process and then analyzed with external devices or with rapid tests. Based on these results, the feed rate is recalculated and then the feed rate is adjusted. The lack of online measurement of substrate concentrations makes control of the process expensive and difficult. Variations in product yield and quality are possible consequences of this type of process control.
  • the time interval between the offline analysis of the samples and the adjustment of the new process values can lead to incorrect settings of the inflow rate and thus to an unwanted nutrient limitation.
  • the aerobic metabolism of the substrates consumes oxygen and produces carbon dioxide.
  • the ratio of the amount of CO 2 released in a certain period of time to the amount of O 2 taken up in the same time unit is defined as the respiratory quotient (RQ).
  • RQ respiratory quotient
  • the measured CTR is a sum signal of cell-specific and buffer-induced carbon dioxide formation. The latter results from the effect of the buffer in acidification of the cells. In this case, the acidification causes additional CO2 to be generated chemically.
  • the determined RQ values lead to inflated values because only a part of the CO2 was produced by the metabolism of the cells and do not represent the metabolic RQ of the cells. Since the term RQ is misleading here, the term TQ (Transfer Quotient) was introduced. This represents the ratio of the total CO 2 formation to the total O 2 consumption.
  • the measured TQ does not say anything about the metabolic RQ and thus does not give any indication of the metabolic activity of the cell.
  • CER cell-specific carbon dioxide formation rate
  • Object of the present invention is to provide a method and a corresponding device for RQ-regulated supply of culture medium and / or nutrients available, which overcomes the described problems of the prior art. It is to be achieved according to the invention by determining the metabolic RQ value that the supply of culture medium and / or nutrients to a sensitive on-line control is made accessible by means of online control. At the same time an effective increase in productivity in cell culture processes should be achieved. This was not possible with the previous methods of fermentation technology. Because the methods known from culturing with microorganisms can not be transferred to the much more sensitive cell cultures. This is especially true when using animal cell cultures.
  • This object is achieved by a method for the fermentation of cell cultures in which
  • the metabolic RQ is determined online, - the metabolic RQ serves as an actual value for a regulation, - the target RQ for the desired productivity or product characteristic is determined as a setpoint for a control, and
  • the supply of culture medium and / or nutrients is regulated so that sets an optimal cell or product yield and / or a desired product quality or product property.
  • the process according to the invention can be carried out for the production of proteins, for example pharmaceutical proteins.
  • the process can be carried out with animal or plant cells. Both continuous cell lines and genetically engineered cells can be used in the method.
  • the target RQ can be determined in a preliminary test (eg batch operation, continuous operation or chemostat operation, continuous operation corresponds to continuous process control) or in the ongoing process. Furthermore, the target RQ can be calculated from the stoichiometry of the metabolic pathway. Online, the metabolic RQ is determined by the appropriate combination of gas analysis values and in situ measurements such as pH and temperature. The gas analysis is carried out by means of partial pressure measurement, mass and volume flow determination or any combination of two or more of said parameters.
  • the measurement of the metabolic RQ value is based on the measurement and calculation methods described in the prior art.
  • a use of the RQ value to control a fermentation of cell cultures has not yet been shown.
  • the present invention shows for the first time that it is possible in a method for fermentation of cell cultures from the measured RQ course reproducibly to close various metabolic states and that set during the fermentation various discrete RQ conditions based on the cell-specific productivity.
  • the optimal RQ value can be determined by recording a complete RQ progression of continuous cell lines and identifying and biochemically interpreting the individual RQ phases.
  • the target RQ in the course of an upstream fermentation, calculated from the stoichiometry of the metabolic pathway, but also in the ongoing process can be determined.
  • the online control and regulation of the desired RQ value thus enables an exact supply of the required culture medium and / or nutrients to achieve either a high cell yield, a high product yield, a certain product quality or product property.
  • Saccharomyces cerevisiae can produce alcohol under anaerobic conditions.
  • Crabtree effect refers to and describes aerobic alcohol formation above a critical glucose concentration of 100 mg / l, whereas below 100 mg / l, biomass production preferably proceeds.
  • the measured RQ is well over one in ethanol production. In contrast, complete oxidation of the sugar to CO2 and water has an RQ of one.
  • the process control according to the invention is completely independent of substrate offline measurements and is preferably based on the measurement of the gas exchange. Due to the exact adherence to a specific substrate concentration, the yield of biomass or ethanol can be increased many times over.
  • the respiration quotient is preferably measured by determining the appropriate combination of the gas analysis values and the measurements made in situ.
  • the gas analysis can be carried out by means of all methods available to the person skilled in the art.
  • the prerequisite is that the methods are suitable for online determination.
  • Examples of gas analysis are partial pressure measurements as well as the determination of the mass and volume flow.
  • the in situ measurement can also be measured by the usual methods known to those skilled in the art.
  • the carbon dioxide content preferably the carbon dioxide content
  • Oxygen content, the pH and the temperature determined. O 2 and CO 2 content can, for. B. be determined by means of partial pressure measurement. Possibly. can also more
  • Oxygen content and the pH, for example, conventional electrodes are considered.
  • the determination of the desired value can, according to the invention, preferably be carried out before the start of production. However, the setpoint determination can also take place at any other time points and, depending on the requirements of the operation, also be repeated as often as desired. It can be done in a separate fermenter or in the production fermenter. Preferably, the measurement is in batch mode in a separate vessel.
  • the method according to the invention can be used for plant or animal cells.
  • continuous cell lines or genetically modified cells can also be used.
  • the process according to the invention is particularly preferred for the use of animal cell cultures.
  • a particularly preferred range is the production of proteins, in particular of pharmaceutically applicable proteins.
  • the process according to the invention can be carried out in the fermenters which are known from the prior art and are suitable for preferably submersed processes. Accordingly, for example bubble columns, injector operated systems, loop reactors and stirred reactors in the form of single and multi-stage systems come into consideration. Particularly preferred are stirred reactors.
  • the reactors are regularly equipped with the state-of-the-art measuring, control and regulating systems. These include devices for online and offline measurement. Examples include pH, pÜ2-pCÜ2 measuring devices, in particular the use of appropriate sensors. Likewise, z. As the use of measurements of the supply and removal of substrate and the supply and exhaust according to the invention advantageous.
  • a device which is suitable for carrying out the method described enables the online determination of the metabolic RQ with the aid of the supply and exhaust air, as well as the pH value and the temperature.
  • the control of media and nutrient supply is automatic based on the RQ.
  • dosing devices gaseous, liquid or solid media
  • a regulation of the oxygen or. NaOH / CO 2 supply to maintain a desired oxygen concentration or pH in the fermenter are performed.
  • the apparatus for carrying out the method may include a) a fermenter; b) a gas mixing system; c) supply air ducts for gas; d) exhaust ducts; e) measuring devices for determining the oxygen and CO 2 concentration and the mass flow in the supply air and in the exhaust air for determining the oxygen consumption rate OTR and the carbon dioxide formation rate CTR; f) device for measuring the pH and the temperature; g) Apparatus for determining CER and metabolic RQ from the temperature, pH, oxygen concentration and carbon dioxide concentration values; h) contain an RQ regulator for RQ-based control of the supply of culture medium and / or nutrients.
  • P1 corresponds to phase 1; P2 of phase 2; Phase 3 P3; Phase 4 P4; Phase 5 P5 and Phase 6 P6.
  • FIG. 1 Course of the RQ in a batch fermentation of the hybridoma cell line CF-10H5. Continuous line: glutamine; dashed line: glucose; continuous line in gray: RQ.
  • Fig. 2 Course of the cell-specific productivity. Dashed line: cell-specific productivity; continuous line in gray: RQ.
  • FIG. 4 Dependence of the RQ on the glutamine concentration in the chemostatic mode of operation. Continuous line: glutamine; continuous line in gray: RQ.
  • Fig. 5 Glutamine course in the RQ-regulated fed-batch (nominal value RQ 0.66). Continuous line: glutamine; continuous line in gray: RQ. The arrow marks the start of the RQ-controlled Fed-Batch process.
  • Fig. 6 Productivity course in the RQ-regulated Fed-Batch. Dashed line: cell-specific productivity; continuous line in gray: RQ.
  • FIG. 7 Process flow diagram of the RQ-controlled fed-batch process.
  • FIG. 1 fermenter; 2: stirrer; 3: supply air; 4: exhaust air; 5 and 22: pH and p ⁇ 2 electrodes; 7: device for the exhaust gas analysis; 8: device for determining the metabolic RQ; 9: nutrient container; 10: nutrient pump; 11: supply line.
  • FIG. 8 shows an apparatus for carrying out the RQ-controlled fed-batch process.
  • 1 fermenter; 2: stirrer; 3: supply air for gas; 4: exhaust ducts; 5: pH electrode; 6-7: Measuring devices for determining the oxygen and CO 2 concentration and the mass flow in the incoming air; 8: device for determining the metabolic RQ; 9: nutrient container; 10: nutrient pump; 11: supply line; 12: device for measuring the pH value; 13: device for measuring the temperature; 14-15: measuring devices for determining the oxygen and CO 2 concentration and the mass flow in the exhaust air; 16: Device for determining the oxygen consumption rate OTR; 17: device for determining the carbon dioxide formation rate CTR; 18: device for determining the CER; 19: predetermined target RQ; 20: RQ controller; 21: gas mixing system;
  • FIG. 1 shows the course of the RQ in a batch fermentation of the hybridoma cell line CF-10H5.
  • FIG. 1 shows the RQ curve and the decrease in the glucose and glutamine concentration during the batch cultivation of the hybridoma cell line CF-10H5 in the fermenter.
  • the glutamine concentration decreases continuously over the course of the culture until it is completely exhausted after about 60 hours.
  • Glucose concentration decreases throughout the culture but never limits culture until the end of fermentation.
  • various discrete RQ states (phases 1 to 6) occur during the fermentation.
  • FIG. 2 shows the course of the cell-specific productivity in the batch.
  • FIG. 4 shows the dependence of the RQ on the glutamine concentration in the chemostatic mode of operation.
  • This type of process control reflects the continuous operation of a fermentation without cell retention.
  • This system is characterized by the continuous feed of fresh culture medium and the effluent of spent culture medium including cells.
  • the flow equilibrium taking into account the flow rate (D ⁇ ma ⁇ ) allows the setting of defined growth rates, substrate, product and cell concentrations in the fermenter.
  • FIG. 5 shows the glutamine profile in the RQ-regulated fed-batch (nominal value RQ 0.66).
  • FIG. 6 shows the productivity profile in the RQ-regulated fed batch (nominal value RQ 0.66).
  • the RQ is regulated by the controlled addition of culture medium and / or nutrients (here: fed-batch medium, quadruple-concentrate of nutrients).
  • Factor four be increased. From an initial productivity of approximately 1 E-7 ⁇ g / N / h, productivity was increased to approximately 4E-7 ⁇ g / N / h.
  • FIG. 7 shows a process flow diagram with an example of the application of the RQ control according to the invention.
  • the production takes place in a fermenter 1 with a stirrer 2.
  • the fermenter is equipped with a supply air 3 and an exhaust air 4.
  • the electrodes 5 and 22 are provided for the measurement of the pH and the pÜ2.
  • the exhaust 4 a device for the exhaust gas analysis 7 is still arranged.
  • the RQ can be determined as a function of the OTR, CTR, pH and the temperature.
  • the regulation of the inflow of culture media and / or nutrients 9 then takes place.
  • the RQ regulator actuates the valve of the nutrient pump 10 for the supply line 11. 7.
  • FIG. 8 shows a process flow diagram of the device for carrying out the method.
  • the gas composition and the gas flow is determined.
  • the composite through the gas mixing system 21 supply air 3 is first passed through the device to determine the oxygen and carbon dioxide content 6-7 of the supply air.
  • OTR oxygen consumption rate
  • the measurement pH 5 and the temperature 13 in the fermenter in combination with the calculation of the CTR allows the determination of the CER 18 and thus of the metabolic RQ 8.

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Abstract

La présente invention concerne un procédé et un dispositif correspondant de fermentation de cultures cellulaires, le procédé comprenant les opérations suivantes : détermination du quotient respiratoire (QR) métabolique en tant que valeur réelle pour permettre une régulation en ligne; détermination expérimentale ou par calcul du QR cible permettant l'obtention d'une productivité ou caractéristique de production cible, en tant que valeur théorique permettant une régulation; sur la base de ces valeurs théorique et réelle, obtention par commande d'un ou de plusieurs dispositifs de dosage, d'une rendement cellulaire élevée, d'un rendement de production optimal et/ou d'une qualité de produit optimale ou d'une caractéristique de production souhaitée, par ex. une quantité réduite en produits secondaires.
PCT/EP2008/057378 2007-06-15 2008-06-12 Procédé de fermentation de cultures cellulaires Ceased WO2009013066A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP08760919A EP2162527A1 (fr) 2007-06-15 2008-06-12 Procédé de fermentation de cultures cellulaires

Applications Claiming Priority (2)

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DE102007028355.7 2007-06-15
DE102007028355 2007-06-15

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103869091A (zh) * 2014-03-28 2014-06-18 南京工业大学 一种在线检测生物发酵尾气中氧气和二氧化碳的装置及方法
WO2014152145A1 (fr) 2013-03-15 2014-09-25 Bristol-Myers Squibb Company Procédés de production d'anticorps
WO2014151645A1 (fr) * 2013-03-15 2014-09-25 Butamax Advanced Biofuels Llc Procédé de maximisation de croissance de biomasse et de rendement en butanol par rétrocontrôle

Citations (1)

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US4891310A (en) * 1985-03-25 1990-01-02 Hitachi, Ltd. Method of controlling culture

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US4891310A (en) * 1985-03-25 1990-01-02 Hitachi, Ltd. Method of controlling culture

Non-Patent Citations (10)

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Title
AIBA S ET AL: "FED BATCH CULTURE OF SACCHAROMYCES-CEREVISIAE A PERSPECTIVE OF COMPUTER CONTROL TO ENHANCE THE PRODUCTIVITY IN BAKERS YEAST CULTIVATION", BIOTECHNOLOGY AND BIOENGINEERING, vol. 18, no. 7, 1976, pages 1001 - 1016, XP002507590, ISSN: 0006-3592 *
BIDEAUX CARINE ET AL: "Minimization of glycerol production during the high-performance fed-batch ethanolic fermentation process in Saccharomyces cerevisiae, using a metabolic model as a prediction tool", APPLIED AND ENVIRONMENTAL MICROBIOLOGY, vol. 72, no. 3, March 2006 (2006-03-01), pages 2134 - 2140, XP002507587, ISSN: 0099-2240 *
BURKE PATRICIA V ET AL: "A fermentor system for regulating oxygen at low concentrations in cultures of Saccharomyces cerevisiae", APPLIED AND ENVIRONMENTAL MICROBIOLOGY, vol. 64, no. 3, March 1998 (1998-03-01), pages 1040 - 1044, XP002507591, ISSN: 0099-2240 *
CANZONERI M ET AL: "Atmungsaktivität von Säugerzellen: Kontinuierliche Onlineermittlung im Schüttelkolben", BIOFORUM, GIT VERLAG, DARMSTADT, DE, vol. 3, 1 January 2006 (2006-01-01), pages 45 - 47, XP009109694 *
HITEC ZANG GMBH: "Bioprozessoptimierung im Schüttelkolben", INTERNET ARTICLE, 4 May 2007 (2007-05-04), XP002507588, Retrieved from the Internet <URL:http://web.archive.org/web/20070504033731/www.hitec-zang.de/de/fermentationstechnik/ramos.html> [retrieved on 20081209] *
KARIN KOLLER: "Fermentation im Griff", CAV.DE CHEMIE-ANLAGEN + VERFAHREN, June 2008 (2008-06-01), pages 20, XP002507593, Retrieved from the Internet <URL:http://www.cav.de/cav/live/cav_infopool/ha_artikel/detail/31487743.html> [retrieved on 20081209] *
METTLER TOLEDO: "Echtzeitmessung im Fermenter", PHARMACEUTICAL NEWSLETTER 15, December 2006 (2006-12-01), pages 1 - 7, XP002507592, Retrieved from the Internet <URL:http://ch.mt.com/mt_ext_files/Editorial/Generic/0/PROcess_Pharma_Newsletters_2007_Editorial-Generic_1169470590318_files/Pharmaceutical_Newsletter_15_g_MTD.pdf> [retrieved on 20081209] *
PROF. DR.-ING. WERNER ZANG: "Es ist angerichtet", CAV.DE CHEMIE-ANLAGEN + VERFAHREN, October 2007 (2007-10-01), pages 62, XP002507594, Retrieved from the Internet <URL:http://www.cav.de/cav/live/cav_infopool/ha_artikel/detail/31208462.html> [retrieved on 20081209] *
See also references of EP2162527A1 *
WANG H Y ET AL: "COMPUTER AIDED BAKERS YEAST FERMENTATIONS", BIOTECHNOLOGY AND BIOENGINEERING, vol. 19, no. 1, 1977, pages 69 - 86, XP002507589, ISSN: 0006-3592 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014152145A1 (fr) 2013-03-15 2014-09-25 Bristol-Myers Squibb Company Procédés de production d'anticorps
WO2014151645A1 (fr) * 2013-03-15 2014-09-25 Butamax Advanced Biofuels Llc Procédé de maximisation de croissance de biomasse et de rendement en butanol par rétrocontrôle
CN103869091A (zh) * 2014-03-28 2014-06-18 南京工业大学 一种在线检测生物发酵尾气中氧气和二氧化碳的装置及方法

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