Classifications

• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
  • B01J19/28—Moving reactors, e.g. rotary drums
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
  • B01F23/00—Mixing according to the phases to be mixed, e.g. dispersing or emulsifying
  • B01F23/20—Mixing gases with liquids
  • B01F23/23—Mixing gases with liquids by introducing gases into liquid media, e.g. for producing aerated liquids
  • B01F23/231—Mixing gases with liquids by introducing gases into liquid media, e.g. for producing aerated liquids by bubbling
  • B01F23/23105—Arrangement or manipulation of the gas bubbling devices
  • B01F23/2312—Diffusers
  • B01F23/23124—Diffusers consisting of flexible porous or perforated material, e.g. fabric
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
  • B01F27/00—Mixers with rotary stirring devices in fixed receptacles; Kneaders
  • B01F27/80—Mixers with rotary stirring devices in fixed receptacles; Kneaders with stirrers rotating about a substantially vertical axis
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
  • B01F31/00—Mixers with shaking, oscillating, or vibrating mechanisms
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
  • B01F31/00—Mixers with shaking, oscillating, or vibrating mechanisms
  • B01F31/10—Mixers with shaking, oscillating, or vibrating mechanisms with a mixing receptacle rotating alternately in opposite directions
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
  • B01F31/00—Mixers with shaking, oscillating, or vibrating mechanisms
  • B01F31/20—Mixing the contents of independent containers, e.g. test tubes
  • B01F31/201—Holders therefor
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
  • B01F33/00—Other mixers; Mixing plants; Combinations of mixers
  • B01F33/50—Movable or transportable mixing devices or plants
  • B01F33/501—Movable mixing devices, i.e. readily shifted or displaced from one place to another, e.g. portable during use
  • B01F33/5013—Movable mixing devices, i.e. readily shifted or displaced from one place to another, e.g. portable during use movable by mechanical means, e.g. hoisting systems, grippers or lift trucks
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
  • B01F35/00—Accessories for mixers; Auxiliary operations or auxiliary devices; Parts or details of general application
  • B01F35/40—Mounting or supporting mixing devices or receptacles; Clamping or holding arrangements therefor
  • B01F35/42—Clamping or holding arrangements for mounting receptacles on mixing devices
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
  • B01F35/00—Accessories for mixers; Auxiliary operations or auxiliary devices; Parts or details of general application
  • B01F35/50—Mixing receptacles
  • B01F35/513—Flexible receptacles, e.g. bags supported by rigid containers
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
  • B01F35/00—Accessories for mixers; Auxiliary operations or auxiliary devices; Parts or details of general application
  • B01F35/55—Baffles; Flow breakers
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
  • B01F35/00—Accessories for mixers; Auxiliary operations or auxiliary devices; Parts or details of general application
  • B01F35/90—Heating or cooling systems
  • B01F35/92—Heating or cooling systems for heating the outside of the receptacle, e.g. heated jackets or burners
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
  • B01F35/00—Accessories for mixers; Auxiliary operations or auxiliary devices; Parts or details of general application
  • B01F35/90—Heating or cooling systems
  • B01F35/93—Heating or cooling systems arranged inside the receptacle
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
  • B01J19/08—Processes employing the direct application of electric or wave energy, or particle radiation; Apparatus therefor
  • B01J19/12—Processes employing the direct application of electric or wave energy, or particle radiation; Apparatus therefor employing electromagnetic waves
  • B01J19/122—Incoherent waves
  • B01J19/123—Ultraviolet light
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
  • B01J19/28—Moving reactors, e.g. rotary drums
  • B01J19/285—Shaking or vibrating reactors; reactions under the influence of low-frequency vibrations or pulsations
• • 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
  • C12M23/00—Constructional details, e.g. recesses, hinges
  • C12M23/02—Form or structure of the vessel
  • C12M23/14—Bags
• • 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
  • C12M23/00—Constructional details, e.g. recesses, hinges
  • C12M23/28—Constructional details, e.g. recesses, hinges disposable or single use
• • 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
  • C12M27/00—Means for mixing, agitating or circulating fluids in the vessel
  • C12M27/02—Stirrer or mobile mixing elements
• • 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
  • C12M27/00—Means for mixing, agitating or circulating fluids in the vessel
  • C12M27/10—Rotating vessel
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
  • B01F23/00—Mixing according to the phases to be mixed, e.g. dispersing or emulsifying
  • B01F23/20—Mixing gases with liquids
  • B01F23/23—Mixing gases with liquids by introducing gases into liquid media, e.g. for producing aerated liquids
  • B01F23/231—Mixing gases with liquids by introducing gases into liquid media, e.g. for producing aerated liquids by bubbling
  • B01F23/23105—Arrangement or manipulation of the gas bubbling devices
  • B01F23/2312—Diffusers
  • B01F23/23123—Diffusers consisting of rigid porous or perforated material
  • B01F23/231231—Diffusers consisting of rigid porous or perforated material the outlets being in the form of perforations
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
  • B01F33/00—Other mixers; Mixing plants; Combinations of mixers
  • B01F33/50—Movable or transportable mixing devices or plants
  • B01F33/501—Movable mixing devices, i.e. readily shifted or displaced from one place to another, e.g. portable during use
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
  • B01J2219/00049—Controlling or regulating processes
  • B01J2219/00245—Avoiding undesirable reactions or side-effects
  • B01J2219/0025—Foam formation
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
  • B01J2219/00761—Details of the reactor
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
  • B01J2219/18—Details relating to the spatial orientation of the reactor
  • B01J2219/185—Details relating to the spatial orientation of the reactor vertical
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
  • B01J2219/19—Details relating to the geometry of the reactor
  • B01J2219/192—Details relating to the geometry of the reactor polygonal

Definitions

• the invention relates to a reactor for biotechnological and pharmaceutical applications driven by an oscillatory rotary drive about a fixed vertical axis with process-intensifying properties for mixing, suspending, oxygen transport, heat transfer, irradiation and particle retention, preferably without shaft sealing Disposable reactor can be used, thus ensuring the highest level of cleaning and sterile process safety.
• the autoclaving technique In order to ensure sufficient long-term sterility during continuous process control, the autoclaving technique is also used, which, however, requires cumbersome transport of the reactors to the autoclave and can only be used in comparatively small reactor yardsticks.
• the risk of contamination during fermentation is particularly critical during sampling and on agitated stirrer shafts.
• the latter are usually equipped with elaborate sealing systems (eg mechanical seals). Technologies that do not require such penetrations of the fermentation casing are preferred because of their greater process robustness.
• the loss of use of the reactors due to the provisioning procedures may be on the order of the reactor availability, in particular in the case of short periods of use and frequent product changes.
• Affected in the USP of biotechnological production are the process steps of media production and fermentation and DSP solubilization, freezing, thawing, pH adjustment, precipitation, crystallization, rebuffering and virus inactivation.
• the fermentation requires, in addition to the oxygen supply and CO 2 removal, a gentle suspension of the cells, a rapid mixing of the media and neutralizing agents to avoid overconcentration as well as a temperature control of the reactants. onswashkeit. Particle retention may also be required, for example, for the application of perfusion strategies.
• a gentle sterilization and virus inactivation of starting materials and product solutions can be achieved by UVC irradiation with a wavelength of 254 nm.
• the radiation damages the DNA and RNA of the viruses and germs lying in the absorption maximum and thus prevents their further propagation, while the proteins located in the absorption minimum of the UVC radiation are largely retained.
• a major problem is the penetration depth of UVC radiation in biological media, which is often limited to just a few tenths of a millimeter. This requires an efficient exchange of the film in the active irradiation zone in order, on the one hand, to irradiate all viruses with the required radiation dose and, on the other hand, to minimize the radiation exposure of the products.
• membrane gassing For gentle oxygenation of cell cultures membrane gassing is used.
• membranes gas-permeable silicone tubes are wound on a cylindrical membrane stator, which are flown by a radially-promoting anchor stirrer [WO 2005/111192 Al].
• membrane gasification systems [WO 85/02195 and DE 10 2004 029 709 B4 and DE3428758] focus on agitators or baskets which are obtained with membrane tubes and are oscillating in the fermentation solution or on membrane stacks [US Pat. No. 6,708,957 B2] Panning fermentation solution.
• these membrane gasification systems are characterized by the fact that they can only be conditionally converted to an industrially relevant scale.
• Disposable filtration technologies have been known for a long time. More recently, a disposable technology has also been available on the market for UVC treatment [WO02 / 038191 WO02 / 0385502, EP1464342]. Concepts for disposable heat exchangers are only available for small scales [EP 1464342]. All technologies are operated in the flow, so that in addition to a storage tank, the use of pumps and lines is necessary, for which cleaning and Sanitmaschinesshede must still be provided.
• the mix is filled into a disposable bag and mixed with rotation.
• a disposable bag agitator system which is characterized by the fact that the agitator is inserted into the bag. Mixing is achieved in this case not by a rotational movement about a fixed axis but by a stirring-tilting movement.
• the contact area of the magnetic stirrer unit also consists of disposable components.
• the volume increase in the blast-agitated one-way reactors must be achieved by an elaborate parallelization of the systems. If the fermenters are operated with standard stirring systems as proposed, the volume that can be processed increases to the area of the permanently installed ones However, equipment, the risk of contamination can then be controlled only with comparable technical effort, eg by using damped mechanical seals. However, the great technical and personnel expense of such installations largely removes the advantages of the disposable concept.
• the height of the bag must be kept approximately constant, so that an increase in volume at a constant surface to volume ratio can be done only in the two horizontal spatial directions.
• the scale-up can therefore only be achieved via a technically complex parallelization.
• the technologies available on the market use large stainless steel reactors supplied with cooling liquids for freezing, or small flat plastic bags which are secondarily frozen over heat-conducting surfaces or by means of convective cold air. In both cases there is no possibility to move the product during the freezing process, which considerably slows down the cooling and freezing process.
• the metal vessels are expensive and take up large storage areas during temporary storage. The thawing is tedious, since the liquid movement between the block of ice and the container wall is comparable to the freezing only by free convection.
• the object of the present invention was to produce a reactor, in particular for pharmaceutical applications, which has very good reaction properties for carrying out biological, biochemical and / or chemical reactions with respect to mixing, dispersing, suspending, solubilizing, mass transfer, and even in large reactor scale réelletranspor- tes, the filtration and irradiation has, or their combinations, and which is preferably easy to handle, the high cleansing and sterile technical requirements of the pharmaceutical industry is fair and to increase the process robustness and to increase the Space-time yield contributes.
• the object has been achieved by a reactor comprising a reactor vessel and a drive unit, characterized in that the reactor contents, which may be received by the reactor vessel, are set in oscillatory-rotary motion by the drive unit about the stationary, preferably vertical, axis of the reactor, wherein the power input into the reactor contents is made possible by a suitable jacket shape of the reactor or of the reactor vessel and / or by internals installed statically in the reactor or in the reactor vessel.
• the reactor is preferably designed as a one-way reactor.
• the locations of the largest hydrodynamic energy density and the greatest responsiveness are identical or spatially at least close in reactions within the membranes. No further installations (e.g., stirrers or pumps) are needed to deliver the fluids to the reaction site. Since only the amount of energy is added to the liquid, which is actually required to carry out the reaction, these reactions can therefore be carried out particularly low shear.
• the latter is particularly important in shear-sensitive cultures with animal or plant cells of crucial importance, for example, must be supplied with oxygen during a fermentation. Because of the high shear forces here a bubble fumigation often can not be used, so that usually the low-shear membrane gassing is applied. If the static mixing elements in the reactor according to the invention are designed as hose modules, as described below, a very high oxygen input or CO 2 removal can be achieved with a significantly increased specific hose or exchange area of more than 30 m 2 / m compared to the prior art 3 in a disposable reactor without rotating sealing elements are ensured even in large reactor scale.
• the reactor has a ratio of height to average diameter of 0.2-2.0, preferably 0.6-1.2, and particularly preferably 0.8-1.0. This can eg by Imbalance caused tilting moments can be reduced and it is guaranteed despite an even on a large scale easily realizable installation space requirement from the top.
• a broad reactor design offers the opportunity to dispense with expensive high-rise buildings in favor of installation in less expensive, hall-shaped installations when accommodating the reactors.
• installed internals are provided in the reactor vessel, which provide oscillating moving functionalized surfaces relative to the drive unit for performing physical, biological, biochemical and / or chemical reactions on and / or in membranes.
• the functionalized surfaces may in particular be provided for gassing via semipermeable membranes, for gas distribution, for liquid distribution, for irradiation, for filtration, for absorption, for adsorption, for analysis as well as for cooling and / or heating ,
• the invention further relates to a gassing module suitable for such a reactor, in particular a gas distributor or a membrane module, which are in particular a part of the inventive reactor and are described below by way of example in the installed state.
• the membrane module which is preferably configured as a hose module, has in particular substantially vertically arranged permeable, in particular tubular membranes, through which gases such as oxygen and carbon dioxide but no liquid can penetrate, so that the reactor can be sparingly sparged with oxygen and / or other gases.
• the membranes may be fixed or movable in the reactor and are particularly preferably designed so that they can be moved relative to the inert fluid, so that not only a gassing, gas distribution but also a mixed flow can be induced.
• a plurality of groups of juxtaposed membranes or membrane hoses are provided, which provide an exchange surface required for membrane gassing.
• configured as a hose module membrane module and the flat membranes are substantially immobile at least relative to the reactor, executed and only the reactor is driven by the drive unit, so that the gassing module without design effort, especially as an optional additional unit can be provided if necessary.
• the membranes are microporous and allow the uniform low-shear distribution of gas bubbles, in particular of microbubbles, over the reactor cross section or in the reactor volume without the need for additional stirring elements.
• the microporous membranes are designed with pore sizes of 0.05-500 microns, which can be provided via indentations in the bottom of the reactors. On this simple This way, bladder coalescence is successfully prevented. Membranes below 0.5 ⁇ m are particularly preferred because particularly fine gas bubbles are generated and an additional sterile barrier may possibly be dispensed with.
• a first holding profile and a second holding profile is provided between which an elongate, in particular tubular membrane can be arranged back and forth guided.
• the membrane may in this case be arranged zigzag-shaped or meandering.
• the membrane of the gassing module preferably has a membrane film which is comparatively thin relative to the total thickness of the membrane.
• the membrane film is preferably flat with an open-pore material, such as foam, connected.
• the open-pored material is at least largely enveloped by the at least one membrane film.
• the open-pore material allows for uniform convective gas transport through the membrane so that substantially all of the membrane sheet can be gas-charged. Since the membrane film is connected to the open-pored material, it is avoided at the same time that the membrane film can inflate at elevated pressures. As a result, such a further developed membrane of the gassing module can be operated without problems even at high pressures, so that a comparatively low use of material, a high volume flow for the fumigation of the reactor contents can be provided.
• the gassing module is at least partially a part of the reactor vessel of the reactor according to the invention.
• the reactor vessel may have at least two, in particular exactly two, sections, while the gassing module has a frame with the aid of which the membranes can be fastened.
• the sections can be connected to the frame, for example by gluing, in order to be able to form the reactor vessel of the reactor together with the frame of the gassing module.
• two shell-shaped sections are provided, which can be glued to two mutually remote end faces of a substantially rectangular shaped frame with the frame.
• the reactor contents facing sides of the frame form part of the lateral surface of the reactor vessel.
• the membranes of the gassing module can be filled with gas, e.g. Oxygen are supplied without having to provide for passageways that would have to be passed through the sections.
• the reactor vessel is lined on an inner side at least partially with a permeable membrane for fumigation of the reactor, in order to improve the fumigation and Totwas- areas or laminar boundary layers to avoid the flow.
• a permeable membrane for fumigation of the reactor, in order to improve the fumigation and Totwas- areas or laminar boundary layers to avoid the flow.
• it is particularly sufficient to form only the side of the membrane facing the reactor contents through a membrane film.
• Another reaction that can be carried out in the new mixing reactors is the irradiation of the reactor contents for the purpose of sterilization and virus inactivation.
• the irradiation takes place within the disposable reactor, for example by means of UV lamps, which are positioned in the container wall and / or in the installation elements.
• Retaining walls and bags are known from the skilled transparent transparent, permeable to UV radiation materials, the support walls preferably made of quartz glass, PMMA or Makrolon and the bag can be made of fluoroelastomers, PMMA or Makrolon, depending on the application, for example.
• a problem with the UV irradiation of biological media is the often extremely limited penetration depth of the UV rays, which, depending on the turbidity, can penetrate only a few tenths of a millimeter of the medium. Due to the good mixing movement and the permanent intensive exchange of the media-side boundary layers it is achieved that the boundary layer-far reactor zones are also covered by the irradiation, without the products being unduly damaged in the reactive zones if the residence time is too long. In this way, the sterilization and inactivation with large germ depletion levels and small For the first time, product losses can be carried out in single-use large-scale reactors under sterile conditions.
• Another reaction that can be carried out with the mixing reactors is the freezing and thawing required at various points in a biopharmaceutical process, e.g. Expecting a release analysis to avoid product loss due to time decay.
• whole product lumps can be frozen, stored space-saving and thawed in the same reactor. Freezing and thawing processes take place in the moving state and thus allow the application of higher temperature differences between tempering medium and product solution for intensification and time reduction of the processes. A portioning on several bags and the manual removal of the bag by cutting and the resulting pollution of the working environment eliminated.
• the reactor is designed in particular as a disposable reactor which can be thrown away after use.
• the reactor vessel can be made of a stable, preferably multi-layered, or of a polymer material applied to stabilizing network structures and supporting the intended basic procedural operation.
• the reactor vessel is connected to a housing which is at least partially adapted to the shell shape of the reactor.
• the preferably flexible and / or yielding reactor vessel can be positively and / or frictionally inserted and / or hooked into the container.
• the reactor vessel is additionally or alternatively releasably, in particular by negative pressure, connected to the housing.
• a trough adjacent to the reactor vessel may be provided to which a vacuum may be applied to secure the reactor vessel.
• the container and the reactor at least partially an angular, preferably two- to octagonal, more preferably three- to quadrangular cross-section and with flat (45), pyramidal (41) or tetrahedral bottom.
• the cross-sectional shape can also change over the height of the housing in the axial direction.
• the housing can be cylindrical or square in the upper region and rectangular, square, pyramidal, tetrahedral, etc. in a lower region.
• the container can form internals within an outer wall of the container, by means of which the reactor can be received in a non-slip manner and which at the same time have a flow-breaking action in order to improve the mixing of the reactor contents.
• the housing can be set by the drive unit about the stationary, preferably vertical, axis of the reactor oscillatory - rotating in motion, so that a direct coupling of the drive unit with the reactor vessel itself is not required.
• the housing is movable in a substantially vertical direction, in particular hanging, rotatably mounted.
• the housing can thereby be used, for example, from above with the aid of a crane or from below by means of a lift simply in a holder or a thrust bearing, so that the same drive unit and / or the same measuring technology are used for different types of housing or reactor vessel can.
• the reactor is positively coupled to the drive unit such that accelerating and decelerating the reactor rotation occurs at a substantially constant angular acceleration or deceleration.
• the rotational speed of the reactor changes linearly with time in each phase of the rotational oscillation.
• Intermediate control modules are not required in this simple reactor movement, so that, for example, according to a preferred embodiment for the realization of the oscillatory reactor movement, a pendulum gear can be used.
• the constant angular acceleration in each phase of the oscillatory-rotating reactor movement keeps peak momenta of the hydrodynamic shear forces on suspended particles (for example animal cells) comparatively lower than in other forms of movement of the reactor.
• the reactor can perform an oscillatory - rotating motion in which the angular amplitude ⁇ is in the range of 2 ° ⁇
• 45 ° or
• 90 °, whereby deviations of + 5 ° may be present.
• the oscillating motion thus covers an angle of 2 [ ⁇
• the foam is gentle by re-sucking under the liquid surface without applying shear forces, i. under strict avoidance of gas bubble bursting, again dissolved.
• a wave flow can be established by which a portion of the surface of the reactor contents is conveyed into the interior of the Reaktiorinhalts.
• Foaming can thus be largely suppressed in this preferred type of reactor and a particularly gentle and effective surface gassing can be realized at the same time.
• the use of the oscillating foam destroyer is by no means limited to surface-aided reactors. sengerasten advantageous bring reactors used.
• the intensity of the oscillatory-rotating movement can be adjusted such that a wave flow can be generated on the surface of the reactor contents which conveys a portion of the reactor contents located on the surface into the interior of the reactor contents
• the reactor vessel has at least one elongated im
• a pH and / or an oxygen concentration of the reactor contents can be detected.
• a non-contact detection is a to the reactor vessel spaced optical detection device provided, for example, gives off a flash of light in order to determine the reaction of the fluorescence sensor on the flash of light the desired reading.
• the detection rate and the oscillatory-rotating movement are selected such that the fluorescence sensor is optically detected at different partial areas. It is therefore possible to irradiate the fluorescence sensor at different positions, so that a fading of the fluorescence sensor is prevented by "photo-Bleeching" and significantly increases the life.
• the invention further relates to a blow-treated reactor with a reactor vessel which has a polygonal cross-section at least in the region of a liquid surface of a reactor contents taken from the Reaktorgefbus reactor, which is acted upon via the surface or porous membranes with gas bubbles and for the purpose of foam destruction in an oscillatory - rotating Movement is added such that foam is required on the surface of the reactor contents in the interior of the reactor contents.
• the blow-blasted reactor can in particular be formed and developed further as described above.
• the bubbled-together reactor is thus designed so constructively that it can additionally or alternatively be a foam destroyer.
• a method is provided in which a reactor or blast-added reactor is used, which may be formed and further developed as described above.
• the reactor is most preferably used to suspend bioreactive materials. It is thus possible to provide biological material, such as, for example, animal and / or plant cells and / or microorganisms, which are to be suspended in a liquid substrate in order, in particular, to chemically convert substances contained in the substrate with the continuous addition of oxygen.
• the oscillatory-rotating movement of the reactor or the power input can in particular be set such that foaming on the surface of a reactor contents is minimized. For this purpose, it is already sufficient oscillatory oscillating the reactor by a relatively small angle amplitude
• the reactor or the bladder-blown reactor is used in particular for preferably low-shear destruction of foam, which can occur during mixing and / or gassing.
• the destruction of the foam takes place in particular by solubilizing the foam, which can be soaked into the interior of the reactor contents by the flow induced in the reactor vessel. That is, the soaked foam can collapse sheared inside the reactor contents.
• FIG. 1a is a schematic simplified side view of a built-in reactor
• FIG. 1b is a schematic perspective view of the reactor of FIG. 1a, FIG.
• Fig. 2b a schematic diagram for comparing the O 2 entry at various conditions
• FIG. 3 a shows a schematic sectional view of the reactor from FIG. 1 a
• FIG. 3b is a schematic plan view of the reactor of Fig. 3a
• FIG. 3c is a schematic sectional detail view of the reactor of Fig. 3a
• FIG. 4a shows a schematic simplified side view of the installed reactor in a further embodiment.
• FIG. 4b is a schematic perspective view of the reactor of Figure 4a. 5
• FIG. 5c shows a schematic perspective top view of the reactor from FIG. 5a or FIG.
• FIG. 5d is a schematic sectional detail view of the reactor of FIG. 5a at high speeds;
• FIG. 5e a schematic top view of the reactor from FIG. 5a at high speeds, FIG.
• FIG. 5f a schematic sectional view of the reactor from FIG. 5a in a further embodiment, FIG.
• FIG. 5g is a schematic plan view of the reactor of FIG. 5f;
• FIG. 6a a schematic sectional view of the reactor in the installed state in a further embodiment,
• FIG. 6b shows a schematic plan view of the reactor from FIG. 6a, FIG.
• FIG. 7b shows a schematic sectional view of a silicone tube suitable for the reactor.
• FIG. 7c shows a schematic sectional view of a module with the silicone tubes of FIG.
• FIG. 7d shows a schematic sectional view of the reactor from FIG. 7a in a further embodiment
• FIG. 8b a schematic sectional view of the reactor from FIG. 8a, FIG.
• FIG. 8c is a schematic plan view of the reactor of FIG. 8b; FIG.
• FIG. 9b a schematic sectional view of the reactor from FIG. 9a, FIG.
• FIG. 9c shows a schematic plan view of the reactor from FIG. 9b, FIG.
• FIG. 1 a shows a schematic sectional view of the reactor in the installed state in a further embodiment in a first state
• FIG. IIb shows a schematic sectional view of the reactor from FIG. IIa in a second state
• FIG. 11c shows a schematic sectional view of the reactor from FIG. 11a in a third state
• FIG. FIG. Hd is a schematic sectional view of the reactor from FIG. 11a in a fourth state
• FIG. 1 is a schematic sectional view of the reactor from FIG. 11a in a fifth state, FIG.
• Fig. 1 If: is a schematic sectional view of the reactor of Fig. I Ia in a sixth
• FIG. 12b is a schematic sectional detail view of the reactor of FIG. 12a in a first state
• FIG. 12c is a schematic sectional detail view of the reactor of FIG. 12a in a second state
• 13a is a schematic sectional view and a schematic plan view of the reactor in the installed state in a further embodiment
• 13b shows a schematic sectional view and a schematic plan view of the reactor in the installed state in a further embodiment.
• FIG. 14b is a schematic sectional view of the reactor of FIG. 14a; FIG.
• FIG. 14c is a schematic plan view of the reactor of FIG. 14a; FIG.
• FIG. 15a is a schematic exploded perspective view of the reactor of FIG. 14a in another embodiment
• FIG. 15b a schematic sectional view of the reactor from FIG. 15a, FIG.
• FIG. 15c is a schematic plan view of the reactor of FIG. 15a; FIG.
• FIG. 15d is a schematic perspective view of the reactor of FIG. 15a prior to installation;
• FIG. 15e is a schematic perspective view of the reactor of FIG. 15d
• 16a shows a schematic sectional view of a membrane suitable for the gassing module
• FIG. 16b shows a schematic sectional view of a membrane suitable for the gassing module in a further embodiment
• FIG. 16c shows a schematic sectional side view of the membrane from FIG. 16a, FIG.
• FIG. 16d shows a schematic sectional view of a membrane suitable for the gassing module in a further embodiment
• FIG. 16e is a schematic sectional plan view of the diaphragm of FIG. 16d; FIG.
• FIG. 17b is a schematic plan view of the reactor of FIG. 17a; FIG.
• FIG. 17c shows a schematic perspective view of a part of the gassing module for the reactor from FIG. 17a, FIG.
• Fig. 19 a schematic plan view of the reactor in a further embodiment
• Fig. 20 is a schematically illustrated qualitative test result for Schaumer ⁇
• Stepped velocity profile 160 Time interval per movement cycle 162 Amplitude
• a reactor vessel 5 referred to reactor vessel of the reactor according to the invention is shown with drive unit without process-intensive internals.
• the medium 4 a substrate or buffer solution, a fermentation solution or a product solution, is contained in the reactor 5, which in the particularly preferred use as a disposable reactor for stability improvement is produced from stable, preferably multilayer plastic films known to the person skilled in the art. is presented.
• the base 20, which is mounted so as to rotate on the bearing 8, is set into rotation 15 via the drive table 10 in an oscillating manner.
• the position of the drive axle is preferably stationary in order to avoid lateral forces caused by eccentricity on the reactor 5, or the system consisting of casing 6, floor 20 and drive table 10. Transverse forces pose considerable problems in scale transmission.
• the angle of the drive axle is in principle arbitrary between 0 and 90 ° to the horizontal selectable. Angles at 90 ° to the horizontal belong to the particularly preferred embodiments, because thereby a comparatively simple storage of the reactor and the drive unit is made possible. In this type of storage remains at the top of the reactor 5 is largely unloaded and allows easy access to the reactor interior through connecting lines and sensors.
• Fig. 2a shows suitable rotational vibrations 15, z.
• linear 157 or sinusoidal 156 course of angular velocity over time.
• the period 160 and amplitude 162 of the rotational vibration 15 depend on the geometry and size of the reactor 5 and its internals and the desired mechanical power input, which is required to carry out the process step.
• a shear-poor motion can be induced if the flow-through losses of the installation elements and thus the relative speed between the installation elements and the fluid are kept as constant as possible.
• the fluid is advantageously first accelerated in one direction with a sinusoidal velocity pulse 156 of the mounting element and later decelerated so as to be accelerated and decelerated in the opposite direction at the zero crossing of the rotational speed.
• FIG. 2 b shows the gentle application of the membrane gasification 3 according to the invention using hose modules 72 in comparison with a membrane stator system 2 which has been flown in with a stirring element according to the prior art.
• the volumetric mass transfer coefficient ka for oxygen was measured by the dynamic method and plotted as ordinate.
• the so-called comparative flock diameter is applied, determined according to the method described by Henzler and Biedermann (Henzler, H.-J., Biedermann, A., Stressing of particles in stirred reactors, Chemie-Ingenieur-Technik 68 (1996) 1546 ff. ).
• Vergeichsflocken tomesser is a measure of the hydrodynamic shear of small suspended particles, with smalldemandflocken oncemesser indicate large shear forces and vice versa.
• the potential 1 of the increase in power of the ka value is more than 10-fold with the same particle load, if one bases on sensitive cell cultures in the turbulent flow range of comparative flake diameter of 150 micrometers. This tremendous potential 1 allows scope for scale-up and for the design of cost-effective membrane aerators.
• tube modules 72 with which very large specific exchange surfaces can be realized in bioreactors, z. B. also cheaper Oberströmbare elements of flat membranes 320 or parallel extruded tubular membranes 330 with slightly reduced specific exchange surfaces in the order of about 10 m 2 / m 3 are used.
• microporous fillets 150 are utilized to evenly distribute gas bubbles across the reactor cross-section in the liquid 11.
• the invention is not restrictively shown, in which way the rotatably mounted on the bearing 8 floor 20 by means of a built-in drive table 10 electric drive 14 via a gear 12 can be driven.
• Alternative drive options for electric drives 14 could be provided via magnetic forces, induction forces, pneumatics or hydraulics.
• the bottom 20 can be equipped with a cavity 32 in which an electrical (eg a heating mat) or a heat exchanger 18 through which a temperature control medium can be accommodated.
• a heat transfer medium which is a good heat conductor, eg water or oil.
• the heat exchanger is supplied via the centric line 30, which is connected via hoses or cables to the energy supply, ie to a temperature control circuit or to electricity.
• a Addition or removal to or from the reactor 5 can take place via centric 26 or eccentric 24, 28 feedthroughs through the head of the reactor 5. With the help of the lance 28, the addition can be made in the reactor 5 in the depth.
• the lance 28 acts as a flow resistance to the surrounding medium 4, so that at the point of introduction according to the selected intensity of the rotational vibration 15, a mixing-promoting liquid inflow can be produced.
• Feedthroughs 24, 26 and 28 are also suitable commercially available sampling systems and sensors for the measurement of temperature, gas content, ion concentrations, optical properties, particle concentration and cell vitality for process control purposes with the medium 4 and the gas space, respectively to bring into contact.
• the introduction of thermally or chemically pre-sterilized and calibrated systems can be done at the beginning of the process under a safety cabinet.
• the sensors are usually mounted with a Schaubtagen on the neck and sealed on the inner edges of the bushings by means of an O-ring.
• Stimulation and measurement of the layers can be done non-invasively from the outside, which eliminates the risk of introducing a sensor into the sterile environment.
• the load capacity of the plastic-made reactors can be increased in the area of the bushings by means of welding or adhesive reinforcements 25 (see also FIG. 3c). It is expedient to limit the angle 16 (see FIG. 3 b) between the two reversal points of the rotational oscillation 15. In this way, an excessive rotational stress of the connected to the reactor 5, flexible supply lines, such as hoses or electrical cables, prevented. Angle 16 to 3600 ° is technically still manageable.
• the reactors can be operated with comparatively low shear and with good hydrodynamic surface inflow of the built-in elements intended for process intensification even at substantially smaller angles 16.
• the scale transmission can be done depending on the task by keeping the mechanical power input P / V or the particle stresses or the distance traveled by the flow fixtures. It follows that, depending on the criterion used, the angular velocity and / or the angle 16 on scale-up decrease with increasing reactor size 17.
• FIG. 4a and b A favorable, non-limiting embodiment of the disposable reactor is shown in Fig. 4a and b.
• This disposable reactors have a curved bottom 40 and a central outlet 38. This ensures that after opening a valve 44 complete removal of the medium 4 via a hose 42 is possible.
• the tubing 42 is laid out of the conical recess 34 over a bottom gap 36 of the arched executed bottom 21 to the outside.
• a particularly simple and yet effective method for transmitting the rotational vibration 15 from the reactor walls to the medium 4 can already be done without fluidic installations by the choice of a suitable reactor geometry. If, as shown in Fig. 5 ac, a rectangular reactor 43 with flat (see Fig. 5a) or pyramidal 41 (see Fig.
• Improvement of the oxygen input, if tolerated by the cells, is achieved by bubble gassing, which occurs in this reactor above certain reactor-scale-related states of motion by drawing gas bubbles below the liquid surface.
• bubble gassing which occurs in this reactor above certain reactor-scale-related states of motion by drawing gas bubbles below the liquid surface.
• a more or less large foam problem can be generated by introducing the gas bubbles. It must absolutely be prevented that the foam is led through exhaust pipes to connected sterile filters and wets them, thus causing a contamination risk or a clogging problem
• the foam 49 formed on the surface can be sucked into the interior of the medium 4 via flow vortices 47, 50, so that bursting of the gas bubbles 45 is largely avoided (FIG. 5 d).
• the foam 49 can thereby be absorbed to a shearing extent to an extent such that the foam thickness is very low or even at least partially the surface is foam-free (FIG. 5e).
• FIG. 20 illustrates by way of example in FIG. 20, in which the foam height h formed in the reactor vessel 5 is plotted relative to the average diameter D in the region of the surface of the reactor contents 4, the average diameter being formed from a round comparison cross section with the same area as the actual area Cross section of the reactor vessel 5 in the region of the surface of the reactor contents 4 results.
• the foam height h related to the average diameter D is sketched as a function of the mechanical power input P related to the volume V of the reactor contents 4.
• the reactor 5, which is at least surface-aided, can therefore preferably be operated at a specific mechanical power input P / V, which is chosen to be greater in relation to the second inflection point 185, so that a good mixing performance is possible with surprisingly low foaming.
• the housing 6 is rotatably suspended via a bearing 8 driven by drive 14.
• the rectangular one-way reactor 43 provided with a large lid 250 has a pyramidal bottom 41 at the bottom of which a drain 42 is provided.
• circumferentially extending fluorescence sensors 401, 402 are provided which can measure the pH value or the O 2 concentration ratio.
• a respective light guide 411, 412 is provided in order to flash the sensors 401, 402 for a measurement with light. Since the sensors 401, 402 are arranged at the bottom in the vicinity of the outlet 42 in the illustrated exemplary embodiment, it makes sense to design the sensors 401, 402 as semi-annular sensor layers (FIG. 5g).
• FIGS. 6a and 6b show an example of a cylindrical reactor 5 with a built-in Blartrrocker.
• the blade stirrer can be formed by stirring blade foil elements 52, which are clamped between the two clamping elements 54 and 56 at the time the reactor is used.
• the stirring blade foil elements 52 which are distributed uniformly on the circumference in a manner analogous to conventional stirred containers of between 1 and 50, preferably 1-8, particularly preferably 1-4, are anchored in the central internals 60 and 62.
• the bottom bearing 60 is firmly connected to the bottom of the reactor 5 by means of welding or adhesive technology via the bearing ring 58.
• the driving forces are transmitted to the ground camp, without transmitting torsional forces on the sensitive in disposable reactors wall of the reactor 5.
• the stretching of the stirring blade foil elements 52 takes place in the case of disposable reactors in the medium 4 filled state of the reactor 5, in which the tie rod 64 connected to the headstock 62 in the holder 70 z. B. by means of a countered screw 66 and 68 torsionally stiff clamped.
• the torques are transmitted via the holding device 70 on the jacket 6 of the support container. In this case, a power transmission to the walls of the reactor 5 is avoided.
• the filling of the reactor 5 is a prerequisite for the tensioning of the stirring blade foil elements 52, if for the sake of simplicity an additional attachment between the bottom bearing 60 the drive pin 59 should be dispensed with.
• FIGS. 7a to 7c show, by way of example of the cylindrical reactor 5, not restricting the invention that tube modules 72 can be accommodated in a reactor 5 in a manner comparable to the mixing device shown in FIGS. 6a to 6c to improve the introduction of oxygen.
• the module 72 consists, as shown in FIG. 7b, of silicone tubes 74, which are glued in a base body 79 with an FDA-approved silicone grout 78.
• the main body 79 may be connected to the module support 80, e.g. be connected gas-tight by means of screw or snap-in connections as shown, wherein the silicone casting compound 78 at the same time acts as a sealing surface.
• the two channels of the module holder 80 supply the preferably in multiple layers laid in two parallel silicone tubes 74 with oxygen-containing gas 94 or provide for the discharge of the spent gas stream 96.
• Both channels of the module holder 80 are connected via connecting elements 82 and 84 with the distribution element 76, the to supply a plurality of modules, a distribution chamber 82 for the gas supply and a distribution chamber 88 for the exhaust gas provides.
• the two distribution chambers 82 and 88 are supplied via the coaxial lines 90 for the gas supply and 92 for the gas discharge.
• the anchoring of the looped laid silicone tubing 74 on the reactor floor is carried out with the help of a laid inside the loop clamping element 56.
• the clamping of the silicone tubing is carried out as in the mixing reactor in Fig.
• the gassing module 72 can be firmly sucked by a bottom support 58 on the bottom 20, in particular pneumatically by an applied negative pressure, whereby sufficient stability can be achieved in order to ensure a relative movement of the silicone hoses 74 to the medium 4.
• the bottom support 58 may rest against a suction foot 66, wherein the suction foot 66 may be formed as a recess of the housing 6 which can be connected to a vacuum source.
• FIGS. 8 a to c an alternative reactor concept which is particularly advantageous compared to the mixing reactor in FIGS. 6 a to c, using the example of a cylindrical reactor 5, is not shown restricting the invention to this reactor.
• the transmission of the rotational vibration 15 to the medium 4 is no longer carried out by tightly exciting blade sheets 52, but by means of pocket-shaped, welded-in or glued-in invaginations 100, which are preferably in the ground but also in the head (not shown in the picture), as shown. or in the sides (see Fig. 13) of the reactor 5 can be used.
• the static support members 102 are mounted, which are mounted on the floor 20.
• the clamping of the indentations 100 to mixing elements can be done in this way even with empty reactors 5 by simply mounting.
• Reactor and reactor frame consisting of jacket 6 and bottom 20 can thus be significantly simplified structurally, since with a sufficient number of indentations a power transmission can take place directly on the reactor 5 without strength problems.
• An anchoring of the floor storage is eliminated.
• a holding device 70 analogous to Fig. 6a is only necessary if indentations 100 and support member 102 are to be used in the head of the bag.
• the angle 104 of the support elements can be changed.
• a better axial mixing is achieved with angles of attack 104 ⁇ 90 °, preferably 30 ° to 70 °, particularly preferably 45 ° to 60 ° to the horizontal. If at angles of incidence ⁇ 90 °, the distance to the reactor wall to be kept constant, a curved profile for the support member 102 is selected.
• FIG. 9 shows the conical design of the support elements that is particularly preferred for simplified installation.
• the shape of the support elements may be pyramidal 110 or conical 108. Since the conical support members 108 and indentations 106 are easier to manufacture, these are considered a preferred solution. Angles 107 between 0 ° and 45 ° lead to technically meaningful solutions, and the range between 2 and 15 ° is to be regarded as a particularly preferred embodiment.
• the invention is illustrated by the example of a cylindrical reactor 5, but not limited to this reactor, as sterilization or virus inactivation of a medium 4 in a reactor 5 can be carried out by UVC irradiation.
• both the reactor 5 and the indentations 106, as well as the support elements 117 and the irradiation jacket 114, are manufactured from materials which are permeable to UVC radiation. Suitable materials for the bags are known to those skilled in UVC-transparent films into consideration. Some absorption by the plastic material can easily be compensated for by the very large irradiation area that can be realized in this reactor.
• the transparent support elements 117 and the transparent double-walled, outwardly radiation-insulated irradiation jacket 114 which are made of known in the art stable, UV-radiolucent materials, preferably made of quartz glass, Makrolon or PMMA, can from the interior with UVC radiation sources 116th be equipped, for example be supplied via the floor 20 with electrical energy.
• FIGS. 1 a to e using the example of a rectangular reactor 43, the invention is not presented as restricting preferred embodiments and methods of a novel one-way freezing and thawing concept to this reactor.
• the temperature control 120 is fed via the flexible connection 122 close to the center in a distribution channel 124 of the moving floor 20 and then in the flow-through support members 127 and the container shell 128.
• the in the container casing 128 installed cylindrical deflection device 129 ensures a targeted upward flow over the available heat exchange surface of the tempering 128.
• the removal of the downward flowing in the countercurrent temperature control from the tempering 128 takes place on the outside of the tempering 128.
• the collection channel 130th connected, via which also from the support members 127 via the exhaust pipes 126 taken Temperierffenströme be removed.
• the collecting channel 130 is connected to the center of the flexible drain line 132 via which the calorically modified temperature control 134 is withdrawn and returned, for example, in a heat cycle.
• FIG. 10 b shows the rectangular reactor 43 with indentations 106 for receiving the supporting elements 127.
• the reactor 43 has in the head area a glued or welded stable support ring 136, to which a plurality of eyes for receiving traction devices 140 (see Fig. L lc) are attached. With the help of the support ring 136 and the pulling device 140, the rectangular reactor 43 can be removed with the frozen product for temporary storage or returned to the reactor for thawing. In order to prevent damage to the inner flanks of the indentations 106 in particular when introducing the frozen products into larger containers, the use of a carrying structure shown in FIG. Hd is recommended.
• This consists of a thin-walled, made of good thermal conductivity materials intermediate bottom 142 and thin-walled as possible, good thermal conductivity, conical intermediate elements 148, which are placed between the indentations 106 and the temperature-controlled support members 127.
• an elongate support member 146 In the center of the bottom plate is an elongate support member 146 with a carrying eye, with the aid of which the reactor, e.g. after the freezing process by means of a pulling device can be removed (see Fig. 1 Ie).
• the rectangular shape of the reactor 43 favors a space-saving storage and therefore belongs to the particularly preferred embodiment.
• the support structure moreover enables damage-free transport (see Fig. 1 Id) of the reactors 43 on a transport base 147, e.g. to a storage room space and a simple and safe stacking of the reactors 43 on shelves.
• FIGS. 12 a to c show a preferred embodiment of the mixing reactor with process-intensifying properties for particle retention which does not limit the invention.
• the indentations 150 made, for example, from woven fabrics, nonwovens, perforated films, porous layers and / or filter membranes are mounted on liquid-distributing supporting elements 148, for example gap sieves, or perforated sheets.
• the seal can be made in the region of the cylindrical, made of impermeable materials necking elements 151 of the indentation, by means of O-ring 149.
• the removal of the filtrate can take place through the bottom 20.
• the device is in a similar embodiment also suitable for the liquid distribution, the bubbling of the bubbles and the implementation of reactive process steps on and / or in permeable, semipermeable or non-permeable membranes 150.
• the invention is not restrictive preferred reactors 5 with lateral, integrated into the reactor wall pockets 103 shown.
• the reactor preferably supported by the lateral support elements 99 in the outer wall 6, can transmit the rotational movement to the reactor contents analogously to conventional stirring systems.
• Support members 99 and pockets 103 may also be used for process intensification as in the previous examples.
• the number, width 97 and depth 98, as well as the desired material properties (radiolucent, filtering, gas or heat-permeable) and thus the material of the lateral pockets 103 and the lateral support members 99 are by the required boundary conditions, e.g. fixed to the required exchange surface.
• the depth 98 of the pockets 103 is, in analogy to stirring systems, preferably between 0.02-0.4, preferably 0.05-0.2, more preferably 0.1-0.15 times the reactor diameter.
• the preferred shape of the pockets ranges from cuboid over frustoconical to roof-like.
• the preferred opening angles 97 of the pockets 103 to the support element 99 can vary between 0 ° and 45 °, wherein the opening angles between 2 ° and 20 ° to count among the preferred angles.
• the angle of attack 105 of the pockets 103 to the vertical the intensity of the axial mixing can be influenced.
• Favorable angles of attack are between 0 ° and 75 ° and particularly preferred between 0 ° and 45 °.
• the reactor vessel 5 designed as a disposable bag has two bag halves 200 which can be glued to a frame 201 arranged between the bag halves 200. Since the bag halves 200 are flexible and the frame 201 is rigid, it is obvious that the housing 6 has grooves 202 into which the part of the frame 201 projecting between the bag halves 200 can be inserted (FIG. 14c). , A movement of the housing 6 can be transferred directly to the reactor vessel 5, without significant relative movement with friction being able to occur. Furthermore, at least one in particular foil-like or more stable blade guide 52, possibly fabricated from the material of the frame 201, may be provided between an upper holding profile and a lower holding profile of the frame 201 (FIG. 14b).
• the distance 205 between the blade stirrer 52 and the vertical parts of the frame 201 is particularly chosen such that slots result, which additionally increase turbulence of the medium 4.
• the distance 205 preferably ranges from 0 to 30% of the reactor diameter.
• a gassing module configured as a hose module 72 is provided, wherein the frame 201 can be part of the hose module 72, for example, as permeable silicone hoses 74 réellesannen trained diaphragm.
• the gas stream addition 94 and / or the gas stream discharge line 96 can be sealed before installation of the reactor vessel 5 (FIG. 15d), and a gas supply can easily be connected after installation (FIG. 15e).
• the supply lines of the gas flow addition 94 and / or the gas flow discharge line 96 can each be arranged completely within a bag half 200 assigned to them so as not to impair the connection of the bag halves 200 to the frame 201 (FIG. 15c) it is possible to limit the number of connections to be led outwards from the Emweg reactor and to position them in the vicinity of the vertical axis for gentle handling of the connection lines.
• a membrane envelope 300 is provided, which is connected in a planar manner to a porous layer 301, wherein the porous layer may comprise an open-pore material, such as foam.
• the gas stream addition 94 and / or the gas stream discharge line 96 from the end face of the membrane 72 (Fig. 16a) and / or from the longitudinal side of the membrane 72 (Fig. 16b) through the membrane film 300 into the porous layer 301 hm- a.
• the membrane 72 has two membrane sheaths 300 which overlap the porous layer 301, so that the membrane sheaths 300 can be connected to one another at the overlapping regions and the porous layer can be completely enveloped (FIG. 16c).
• a flat membrane 72 can be provided which does not inflate under pressure and as a flat membrane element 320 may be part of a membrane stack 340, preferably all flat membrane elements 320 of the membrane stack 340 with exactly one gas flow addition 94 and / or exactly one gas flow discharge
• the flat membrane elements 320 can be spaced apart by spacer elements 343 and, as part of the membrane stack 340, can be part of the gassing module 72 (FIG. 17 a).
• the membrane stack 340 can va ⁇ abel on an upper holder 321 and / or a lower holder 322 are fixed.
• the flat membrane 72 is designed to be particularly long and guided back and forth in a meandering manner between the lower holder 321 and the upper holder 322, resulting in a meander-shaped membrane element 350.
• the reactor shown in FIG. 19 has a reactor vessel 5 designed as a disposable bag, which conforms to an inner wall of a moving housing 6.
• a membrane element 360 is integrated, so that the inside of the reactor vessel 5 is at least partially lined with the membrane element 360 in order to be able to gas the medium 4 from radially outside.
• the gas stream addition 94 and / or the gas stream outlet 96 for the membrane elements 360 may be guided over the frame 201, so that further membranes 72 for gassing the medium 4 can be connected to the frame 201 without difficulty.

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