EP1373865A1 - Verfahren zur prozessüberwachung von biotechnologischen prozessen - Google Patents
Verfahren zur prozessüberwachung von biotechnologischen prozessenInfo
- Publication number
- EP1373865A1 EP1373865A1 EP02712611A EP02712611A EP1373865A1 EP 1373865 A1 EP1373865 A1 EP 1373865A1 EP 02712611 A EP02712611 A EP 02712611A EP 02712611 A EP02712611 A EP 02712611A EP 1373865 A1 EP1373865 A1 EP 1373865A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- microorganisms
- atr crystal
- atr
- process medium
- spectroscopy
- Prior art date
- 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.)
- Withdrawn
Links
- 238000000034 method Methods 0.000 title claims abstract description 97
- 238000011138 biotechnological process Methods 0.000 title claims abstract description 18
- 238000012544 monitoring process Methods 0.000 title claims abstract description 17
- 244000005700 microbiome Species 0.000 claims abstract description 70
- 239000013078 crystal Substances 0.000 claims abstract description 64
- 230000008569 process Effects 0.000 claims abstract description 61
- 230000035515 penetration Effects 0.000 claims abstract description 6
- 238000005102 attenuated total reflection Methods 0.000 claims abstract 28
- 238000004566 IR spectroscopy Methods 0.000 claims description 19
- 210000004027 cell Anatomy 0.000 claims description 18
- 238000004611 spectroscopical analysis Methods 0.000 claims description 16
- 238000001228 spectrum Methods 0.000 claims description 12
- 238000005406 washing Methods 0.000 claims description 9
- 238000004886 process control Methods 0.000 claims description 8
- 240000004808 Saccharomyces cerevisiae Species 0.000 claims description 7
- 108090000623 proteins and genes Proteins 0.000 claims description 7
- 102000004169 proteins and genes Human genes 0.000 claims description 7
- 229910003460 diamond Inorganic materials 0.000 claims description 5
- 239000010432 diamond Substances 0.000 claims description 5
- 210000003000 inclusion body Anatomy 0.000 claims description 5
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 claims description 4
- 230000015572 biosynthetic process Effects 0.000 claims description 3
- 150000002632 lipids Chemical class 0.000 claims description 3
- 241000894006 Bacteria Species 0.000 claims description 2
- 241000588724 Escherichia coli Species 0.000 claims description 2
- 241000206602 Eukaryota Species 0.000 claims description 2
- 230000003115 biocidal effect Effects 0.000 claims description 2
- 230000033001 locomotion Effects 0.000 claims description 2
- 238000012545 processing Methods 0.000 claims description 2
- 239000002609 medium Substances 0.000 description 25
- 238000005259 measurement Methods 0.000 description 19
- 238000000855 fermentation Methods 0.000 description 11
- 230000004151 fermentation Effects 0.000 description 11
- 239000000126 substance Substances 0.000 description 10
- 235000014680 Saccharomyces cerevisiae Nutrition 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 6
- 238000004458 analytical method Methods 0.000 description 5
- 239000000243 solution Substances 0.000 description 4
- 238000003860 storage Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 150000001720 carbohydrates Chemical class 0.000 description 3
- 235000014633 carbohydrates Nutrition 0.000 description 3
- 239000000470 constituent Substances 0.000 description 3
- 230000012010 growth Effects 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- XLYOFNOQVPJJNP-ZSJDYOACSA-N Heavy water Chemical compound [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 230000002238 attenuated effect Effects 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- 230000031018 biological processes and functions Effects 0.000 description 2
- 210000003850 cellular structure Anatomy 0.000 description 2
- 238000004140 cleaning Methods 0.000 description 2
- 238000011109 contamination Methods 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 238000002329 infrared spectrum Methods 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 230000002503 metabolic effect Effects 0.000 description 2
- 235000015097 nutrients Nutrition 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 1
- 238000001157 Fourier transform infrared spectrum Methods 0.000 description 1
- 229920002527 Glycogen Polymers 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 102000007056 Recombinant Fusion Proteins Human genes 0.000 description 1
- 108010008281 Recombinant Fusion Proteins Proteins 0.000 description 1
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 description 1
- WQZGKKKJIJFFOK-PHYPRBDBSA-N alpha-D-galactose Chemical compound OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-PHYPRBDBSA-N 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 239000012620 biological material Substances 0.000 description 1
- DNZWLJIKNWYXJP-UHFFFAOYSA-N butan-1-ol;propan-2-one Chemical compound CC(C)=O.CCCCO DNZWLJIKNWYXJP-UHFFFAOYSA-N 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000000356 contaminant Substances 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 230000005595 deprotonation Effects 0.000 description 1
- 238000010537 deprotonation reaction Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000005684 electric field Effects 0.000 description 1
- 238000001962 electrophoresis Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229930182830 galactose Natural products 0.000 description 1
- 229910052732 germanium Inorganic materials 0.000 description 1
- GNPVGFCGXDBREM-UHFFFAOYSA-N germanium atom Chemical compound [Ge] GNPVGFCGXDBREM-UHFFFAOYSA-N 0.000 description 1
- 229940096919 glycogen Drugs 0.000 description 1
- 230000005484 gravity Effects 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000010978 in-process monitoring Methods 0.000 description 1
- 239000000411 inducer Substances 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 239000011368 organic material Substances 0.000 description 1
- 229920000729 poly(L-lysine) polymer Polymers 0.000 description 1
- 239000005014 poly(hydroxyalkanoate) Substances 0.000 description 1
- 229920000903 polyhydroxyalkanoate Polymers 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000005070 ripening Effects 0.000 description 1
- 238000006748 scratching Methods 0.000 description 1
- 230000002393 scratching effect Effects 0.000 description 1
- 239000013049 sediment Substances 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 108010027322 single cell proteins Proteins 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000004114 suspension culture Methods 0.000 description 1
- 230000032258 transport Effects 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
- 210000005253 yeast cell Anatomy 0.000 description 1
Classifications
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
- G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
- G01N21/55—Specular reflectivity
- G01N21/552—Attenuated total reflection
Definitions
- the invention relates to a method for process monitoring of biotechnological processes using microorganisms.
- the IR spectroscopy of dried cells requires an enormous amount of time and preparation to bring the cells to the IR measurement in a suitable form. It can be assumed that sample preparation alone does not take less than 25 minutes (see Majara et al., Above). Furthermore, no suitable on-line equipment is available for carrying out process monitoring of biotechnological processes using microorganisms, in which the composition and the condition of microorganisms can also be monitored (Majara et al., Above).
- the Fayolle et al. The spectra obtained were measured in an optical cuvette with a 38 ⁇ m layer thickness. Such an arrangement is not suitable for a process control, since this easily clogs up during repeated measurements. Above all, the Fayalle et al. described system the measurement of the amide I band is not possible.
- Contamination of the measuring cells with polymeric or organic material is also regarded as a major disadvantage of infrared technology, especially if the optical crystals of flow lines are irreversibly coated with the contaminants and only through complex physical cleaning processes can be freed from these coatings again (US 5,604,132).
- the present invention therefore provides a method at the outset described type, which is characterized in that both the process medium and the microorganisms in the process medium are directly spectroscopically examined by means of attenuated (attenuated) total reflection (ATR) on an ATR crystal in the infrared range, the process medium containing the microorganisms being included the ATR crystal is contacted so that microorganisms reach at least a distance from the ATR crystal that corresponds to the depth of penetration of the evanescent field and during this contacting is spectroscoped in the infrared range, whereupon the process medium containing the microorganisms from the ATR -Crystal is removed, the ATR crystal is washed and, if necessary, contact is made again with the process medium containing microorganisms.
- ATR attenuated total reflection
- the method according to the invention has surprisingly been able to show that it is possible to carry out a complete and comprehensive process monitoring of biotechnological processes by means of infrared spectroscopy, wherein not only a large number of soluble compounds can be measured and monitored, but also the composition and the state of the Microorganisms are measured online and almost in "real time". According to the invention, this can be carried out without drying the microorganisms, as a result of which the entire process can be carried out so quickly that it is suitable for on-line process control.
- the soluble constituents in the culture medium can be spectroscoped in a manner known per se in the infrared range, for example in a flow cell.
- the microorganisms contained in the process medium are brought up in a special contacting step at least to a distance from the ATR crystal, which corresponds to the penetration depth of the evanescent field, and spectroscopically precisely during this contacting.
- the depth of penetration of the evanescent field is a variable which is dependent in particular on the material, wavelength, angle of incidence and media and is defined, for example, in Harrick (J. Opt * . Soc. Am. 55 (7) (1965, 851-857).
- (Depth of penetration distance from the surface of the ATR crystal at which the amplitude of the evanescent wave has dropped to half the value it has on the surface.)
- aqueous solutions and a wave number of 1000 this is about 2 ⁇ m.
- the process medium containing the microorganisms is then removed from the ATR crystal, the ATR crystal is washed with wash solutions, whereupon renewed contacting with the microorganisms containing the process medium can take place.
- Spectroscopy in infrared is preferably carried out using Fourier-transformed infrared spectroscopy (FTIR spectroscopy), which, as mentioned, has already been used in the past to monitor biotechnological processes, but only with regard to dissolved substances.
- FTIR spectroscopy Fourier-transformed infrared spectroscopy
- Measurement using infrared lasers (e.g. quantum cascade laser) as an IR source is also advantageous.
- a diamond is preferably used as the ATR crystal in the process according to the invention.
- This proves to be much more stable than conventional ATR crystals, especially in the washing process, and is of particular advantage when measuring ATR.
- the ATR measurement is preferably carried out by means of a planar waveguide as an ATR crystal, in particular with that of Brai an et al., Appl. Spectrosc. 51 (4) (1997), pp. 592-597, described methodology carried out (see also WO 00/36442-A, US 5 980 831-A).
- the process medium is preferably guided to the ATR crystal with an automatic flow system from the bioreactor in which the biological process is carried out, during the time during which the biosuspension flows over the ATR crystal
- the "large” microorganism cells do not come close to the ATR surface and are therefore not or only insignificantly detected by the infrared light. These cells therefore do not make any significant contribution to the measured spectra, so that only the dissolved components, such as e.g. Sugar, alcohols, amino acids, etc., can be determined quantitatively, as in Kansiz et al. , Analytica Chimica Acta 21149
- the approach of the microorganisms to the ATR crystal can also take place in another way, for example by temporarily stopping the microorganisms in the process solution by means of suitable filters and, if appropriate, bringing them to the ATR crystal by application centrifugal force, bioelectromagnetic magnetic attachments to the ATR crystal, etc.
- the washing is preferably carried out by treating the ATR crystal with a base, for example with IM NaOH, and then rinsing with distilled water.
- a base for example with IM NaOH
- distilled water e.g., distilled water
- bases e.g., IM NaOH
- alternative washing solutions can also be used, for example Na 2 CO 3 (for example 5%), wherein washing steps with distilled water can likewise preferably be connected.
- the method according to the invention is particularly suitable for monitoring biotechnological processes using single-cell eukaryotes, in particular yeast, or bacteria, in particular E. coli, but the method is based on any suspension (submerged) cultivation, ie in which microorganisms or Aggregates of the same are in suspended form, can be used in principle.
- microorganisms are recombinant microorganisms and / or antibiotic-producing microorganisms which, because of their sensitivity and complicated metabolic processes, require extremely precise and complex process analysis.
- the method according to the invention can preferably also be used in the production of single-cell protein or for the production of feed or foodstuffs based on microorganisms, and for the measurement of microbial carbohydrates.
- the method according to the invention can be used in the entire infrared range, but the spectroscopy is particularly preferably carried out in the middle infrared range with a wave number between 4000 and 400 / cm, in particular between 1800 and 900 / cm, the so-called "fingerprint" range.
- the measurements can of course also be carried out preferably in the near infrared, that is to say at wavelengths between 2.5 p and 750 nm.
- Spectroscopy of soluble constituents in the process medium is preferably carried out before the spectroscopy of the microorganisms. After the spectroscopy of the microorganisms, the washing step can preferably be connected.
- the method is particularly preferably carried out in such a way that, after the ATR crystal has come into contact with the process medium, the movement of the medium is stopped, so that the microorganisms are deposited on the ATR crystal (which also places them at a suitable distance from the ATR Crystal can reach), whereupon the spectroscopy of the microorganisms is carried out.
- the secondary structure of proteins can be monitored in the process medium, but in particular also in the case of the microorganisms.
- the content of lipids in the process medium and / or in the microorganisms can also be monitored.
- the present invention also relates to a device for carrying out the method according to the invention, comprising an ATR element connected to an automatic flow system with an ATR crystal, an infrared spectroscopy device connected to the ATR crystal and a via automatic flow system with washing system connected to the ATR element.
- An automatic flow system is generally a device that, for example, transports and manipulates liquid or suspended samples using, for example, pumps, hoses and valves.
- the infrared spectroscopy device is preferably connected to an electronic data processing system (IR-EDP), with which the recorded spectra can be analyzed and with which preferably process devices (actuators), such as inflow devices, temperature controllers, pH controllers, etc., for the bioreactor, if they are connected to the IR EDP, can be controlled by the IR EDP, with which a change in the process parameters can be controlled.
- IR-EDP electronic data processing system
- the device according to the invention further comprises a bioreactor, which may be filled with process medium and microorganisms.
- the automatic flow system can also be used to condition the process medium or e.g. Measurement, pH value settings, temporary filtering or separation steps, separation of substances that could impair the measurement, etc., are carried out.
- the flow system according to the invention preferably has hoses with an inner diameter of greater than 0.7 mm, that is to say larger than the standardized diameters (0.3, 0.5 and 0.7 mm), since it is the case with hoses with standard diameters due to the Microorganisms can easily become constipated.
- Tubes with inner diameters of 1 mm and above, in particular 1.2 mm and (far) above, are preferably used according to the invention.
- a dead volume of more than 5 ⁇ l, more preferably 10 ⁇ l or more, in particular 20 ⁇ l or more, is preferably provided.
- the infrared spectroscopy device is preferably a FTIR spectrometer, which is particularly well suited for optimally obtaining infrared spectra with ATR crystals. IR measurement using lasers (eg quantum cascade laser) is also advantageous.
- lasers eg quantum cascade laser
- the ATR crystal is preferably positioned horizontally with respect to the process medium to be measured or flowing past, so that the process medium can be passed over the ATR crystal.
- the microorganisms can simply sediment on the ATR crystal due to gravity and be measured there.
- the ATR crystal can also be used with a collecting device for microorganisms, e.g. a hinged filter, which - when the microorganisms are to be measured - opens and positions the "captured" microorganisms on the ATR crystal.
- microorganisms to the ATR crystal by means of suitable electrical charge induction.
- This can e.g. can be realized by an external electric field, as in "free-flow” electrophoresis (Raymond et al., Anal. Chem. 68, (15) (1996), pp. 2515-2522), or else by applying one charged surface on the ATR crystal, e.g. through a layer of poly-L-lysine.
- substances can also be provided on the ATR crystal that favorably influence the washing process or influence the adhesion of microorganisms; in particular, monolayers of these substances are provided.
- the ATR element is preferably designed as a flow cell, so that the measurement of soluble constituents / cells can be started by combining "flow on” with “stop” steps.
- the ATR crystal is preferably a diamond which, owing to its hardness properties and the resulting ease of maintenance, is particularly suitable for such a process. Crystals made of germanium, silicon or crystals of comparable hardness are also preferred.
- the device according to the invention is preferably equipped with a stopping device for stopping the flow of the process medium, which allows an IR measurement despite stopping.
- Fig. 1 the process control and growth curve of a baker's yeast production
- Fig. 4 the 2nd derivative of Fig. 3, vector normalized
- Fig. 6 Spectra on-line (in vivo), baker's yeast fermentation recorded with ATR technology
- the method according to the invention was used in the second biotechnological process.
- the spectra of the microorganisms measured during the "stopped-flow" time are very similar to those recorded in the dried state (FIGS. 6, 7 and 8).
- the comparison of the second derivatives clearly shows that the spectra recorded online contain practically the same information as that of the dried microorganisms (see FIGS. 4 and 8).
- FIGS. 9 and 10 show, information about the secondary structure of proteins as well as about the increase / decrease of lipids, RNA and the like can be derived from the spectra.
- the method according to the invention and the device according to the invention can be used for process monitoring / control of any cultivation processes of suspension cultures. It is also able to detect the degeneration of microorganisms online.
- Industrially particularly preferred areas of application for the method according to the invention are the production of recombinant proteins, in particular of proteins which are formed intracellularly, especially when Inclusion bodies, the production of antibiotics, the production of polyhydroxyalkanoates, but also in the field of basic research on bioprocesses.
Landscapes
- Physics & Mathematics (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Analytical Chemistry (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- General Physics & Mathematics (AREA)
- Immunology (AREA)
- Pathology (AREA)
- Investigating Or Analysing Materials By Optical Means (AREA)
- Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
Abstract
Description
Claims
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AT5542001 | 2001-04-05 | ||
AT0055401A AT410322B (de) | 2001-04-05 | 2001-04-05 | Verfahren zur prozessüberwachung von biotechnologischen prozessen |
PCT/AT2002/000105 WO2002082061A1 (de) | 2001-04-05 | 2002-04-05 | Verfahren zur prozessüberwachung von biotechnologischen prozessen |
Publications (1)
Publication Number | Publication Date |
---|---|
EP1373865A1 true EP1373865A1 (de) | 2004-01-02 |
Family
ID=3676503
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP02712611A Withdrawn EP1373865A1 (de) | 2001-04-05 | 2002-04-05 | Verfahren zur prozessüberwachung von biotechnologischen prozessen |
Country Status (4)
Country | Link |
---|---|
US (1) | US20040096930A1 (de) |
EP (1) | EP1373865A1 (de) |
AT (1) | AT410322B (de) |
WO (1) | WO2002082061A1 (de) |
Families Citing this family (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7981399B2 (en) * | 2006-01-09 | 2011-07-19 | Mcgill University | Method to determine state of a cell exchanging metabolites with a fluid medium by analyzing the metabolites in the fluid medium |
US20090035807A1 (en) * | 2007-07-31 | 2009-02-05 | Wyeth | Analysis of polypeptide production |
US8629399B2 (en) | 2009-09-22 | 2014-01-14 | Bp Corporation North America Inc. | Methods and apparatuses for measuring biological processes using mid-infrared spectroscopy |
JP5723643B2 (ja) * | 2011-03-22 | 2015-05-27 | 浜松ホトニクス株式会社 | 全反射分光計測方法 |
WO2020088728A1 (en) * | 2018-10-30 | 2020-05-07 | Specshell Aps | Non-invasive continuous in line antifouling of atr-mir spectroscopic sensors |
CN115356309B (zh) * | 2022-07-29 | 2024-04-19 | 华中农业大学 | 便携式快速细菌抗生素敏感性测试方法及其装置 |
Family Cites Families (15)
Publication number | Priority date | Publication date | Assignee | Title |
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DE2164670A1 (de) * | 1971-12-24 | 1973-06-28 | Bbc Brown Boveri & Cie | Verfahren zur kontinuierlichen messung organischer substanzen in wasser und anordnung zur durchfuehrung des verfahrens |
US3911276A (en) * | 1974-10-18 | 1975-10-07 | Diax Corp | Laser spectroscopy |
JPH0776746B2 (ja) * | 1989-11-03 | 1995-08-16 | 株式会社堀場製作所 | 赤外線顕微分光測定装置 |
DE4124920C2 (de) * | 1990-07-27 | 1993-12-23 | Hitachi Ltd | Biochemischer Analysator mit einer Prismenzelle für abgeschwächte Totalreflexion und einer Kühleinrichtung |
US5777726A (en) * | 1992-05-12 | 1998-07-07 | Raytheon Company | Spectrophotometric supercritical fluid contamination monitor |
EP0624785B1 (de) * | 1992-10-07 | 1998-11-25 | Sumitomo Electric Industries, Ltd. | Optisches element für den infrarotbereich und messvorrichtung |
US5436454A (en) * | 1993-10-15 | 1995-07-25 | Nicolet Instrument Corporation | Optical probe for remote attenuated total reflectance measurements |
DE4426944A1 (de) * | 1994-07-29 | 1996-02-01 | Bayer Ag | Verfahren zur Kontrolle von Polykondensations- oder Polyadditionsreaktionen |
JP3717977B2 (ja) * | 1995-07-31 | 2005-11-16 | 株式会社ヤクルト本社 | 乳酸菌の培養管理方法 |
DE19650899A1 (de) * | 1996-12-07 | 1998-06-18 | Gunnar Dr Brink | Optische Sensoren unter der Verwendung durchstimmbarer Laserdioden |
WO1999005509A1 (en) * | 1997-07-24 | 1999-02-04 | Ecole Polytechnique Federale De Lausanne | Detection and investigation of biological molecules by fourier transform infra-red spectroscopy |
DE19805612A1 (de) * | 1998-02-12 | 1999-08-19 | Bayer Ag | Verfahren zur kontrollierten Herstellung oder Modifizierung von polymeren Produkten mittels IR-ATR-Spektroskopie |
DE69833411T2 (de) * | 1998-08-28 | 2006-09-21 | Perkin-Elmer Ltd., Beaconsfield | Spektrometrisches Zubehör zur Durchführung von Messungen abgeschwächter Totalreflexion |
CA2379823A1 (en) * | 1999-07-16 | 2001-01-25 | Human Genome Sciences, Inc. | Real-time, in situ biomanufacturing process monitoring and control in response to ir spectroscopy |
US6437082B1 (en) * | 2000-06-23 | 2002-08-20 | General Electric Company | Infrared evaluation of the stoichiometric ratio of dihydric phenol to diarylcarbonate during production of polycarbonates |
-
2001
- 2001-04-05 AT AT0055401A patent/AT410322B/de not_active IP Right Cessation
-
2002
- 2002-04-05 US US10/473,929 patent/US20040096930A1/en not_active Abandoned
- 2002-04-05 EP EP02712611A patent/EP1373865A1/de not_active Withdrawn
- 2002-04-05 WO PCT/AT2002/000105 patent/WO2002082061A1/de not_active Application Discontinuation
Non-Patent Citations (1)
Title |
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See references of WO02082061A1 * |
Also Published As
Publication number | Publication date |
---|---|
ATA5542001A (de) | 2002-08-15 |
US20040096930A1 (en) | 2004-05-20 |
AT410322B (de) | 2003-03-25 |
WO2002082061A1 (de) | 2002-10-17 |
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