EP2029272A1

EP2029272A1 - Reactor

Info

Publication number: EP2029272A1
Application number: EP07764526A
Authority: EP
Inventors: Jörg KAULING; Helmut Brod; Sebastian Schmidt; Martin Poggel; Björn FRAHM; Reinhold Rose
Original assignee: Bayer Technology Services GmbH
Current assignee: Bayer Intellectual Property GmbH
Priority date: 2006-04-22
Filing date: 2007-04-23
Publication date: 2009-03-04
Also published as: KR20090017530A; US20140293734A1; WO2007121958A1; JP5657886B2; US20140080213A1; SG171588A1; SG147092A1; AU2007241293B2; JP2009534171A; RU2008145990A; DE102006018824A1; JP2013163183A; RU2471547C2; US8602636B2; US20090180933A1; KR101097541B1; CN101466466B; BRPI0710687A2; AU2007241293A1; CN101466466A

Abstract

The subject matter of the invention is a reactor, driven about its fixed, preferably vertical, axis in an oscillatory/rotating manner, for preferably biotechnological and pharmaceutical applications. With its process-intensifying properties for mixing, suspending, gas transport, heat transfer, irradiation and particle retention, the applicability is ensured on a commercial scale. The reactor, which does not need a shaft seal, permits especially robust production with respect to sterile requirements while dispensing with cleaning and cleaning validation if the reactor is designed as a one-way reactor.

Description

reactor

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.

In highly regulated pharmaceutical production, a great deal of time, technical and personnel costs are incurred in the provision of purified and sterilized bioreactors. In order to reliably avoid cross-contamination when changing the product in a multi-purpose system or between two product batches, a very expensive cleaning validation is required in addition to cleaning, which may need to be repeated during a process adaptation. This applies to both the upstream processing USP, i. the production of biological products in fermenters as well as for the downstream processing DSP, i. the purification of the fermentation products. Boilers are often used as stirring and reaction systems in the USP and DSP. Especially in fermentation, a germ-free environment is essential for successful cultivation. Sterilization of batch or fed-batch fermenters is usually done using SIP technology. 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.

To carry out the reactions in the USP and DSP several reaction conditions are often to be fulfilled simultaneously. For example, 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. onsflüssigkeit. Particle retention may also be required, for example, for the application of perfusion strategies.

In precipitation and crystallization, e.g. It is particularly important to a rapid mixing of the precipitant, an efficient temperature control as well as a gentle levitating the particles formed.

As a rule, low temperature gradients are required in all process steps of biotechnological production so as not to damage the products. This requirement leads, in particular in the freezing and thawing processes with increasing reactor scale, to considerably longer process times, since mixing elements can not be used in these steps. The transport of heat into the reaction medium is limited by the thermal conductivity of the ice layer and by free convection in the liquid. However, long process times can lead to significant product losses if proteolytic activity is present.

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.

The requirement of a constantly renewed boundary layer is also raised in the filtration, in order to counteract the formation of cover layers, which limit the transmembrane flow

All procedural process steps of mass and heat transport, particle separation, UV irradiation and the mixing or distribution of solids or additives or gases require sufficient movement of the reaction medium. This movement is ensured in the pharmaceutical industry in the stainless steel reactors usually used there by means of appropriately sized stirrers or by bladder gassing.

For gentle oxygenation of cell cultures membrane gassing is used. As 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]. A more than a doubling of the exchange surface and thus a significant increase in the mass transport can be achieved by a parallelization of the membrane stators.

Other 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. However, these membrane gasification systems are characterized by the fact that they can only be conditionally converted to an industrially relevant scale.

In order to meet the demand for a fast and flexible new shipment of the production plant while maintaining maximum cleanliness and sterility, there are concepts of disposable reactors of ever-increasing interest on the market.

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 Sanitisierungskonzepte must still be provided.

There are currently several commercially available mixing systems which operate on the basis of a plastic bag disposable technology. These include systems [Hyclone Laboratories, Inc. (http://www.hyclone.com)], which are equipped with blade or magnetic stirrers or umpumganganen. The systems are available up to a volume of 200 L. [Sartorius AG (http://www.sartorius.de)] offers a disposable system that works up to a volume of 500 L with a free-floating disposable magnetic stirrer, the has no contact with the disposable plastic bag and therefore also has no material wear. One-way mixing systems up to a volume of 10 liters are available from [ATMI, Ine (http: //www.atmi- lifesciences.com)]. In this system, the mix is filled into a disposable bag and mixed with rotation. For larger volumes up to 200 L [ATMI, Ine] offers 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.

In [EP 1 462 155 A1], a disposable container for mixing and dispersing goods by means of a magnetic stirrer, which is enclosed in a protective cage, in order to prevent damage to the - A -

To prevent plastic bag. The contact area of the magnetic stirrer unit also consists of disposable components.

In [EP 1 512 458 A1], a solution is shown in which inflatable plastic cushions are integrated in the outer or inner region of a disposable bag system. These pillows are alternately pressurized and relaxed again. As a result, fluid movements are induced, which lead to the intensification of the mixing and the suspension in the container.

There are a variety of patents for the application of disposable technology in the field of fermentation technology. In most systems, the mixing and oxygen supply is achieved via a bubble gassing without further mixing systems being provided [US Pat. No. 5,565,015, WO 98/13469, US Pat. No. 6,432,698 B1, WO 2005/049785 A1, EP 1 602 715 A2, WO 2005 / 080544 A2]. If a higher oxygen demand of the culture is necessary, which can not be realized by blowing out the gas alone, the bubble gassing can be combined with a dispersing stirring system [WO 2005/104706 A2, WO 2005/108546 A2, WO 2005/118771 A2] or by a pumped circulation [WO 2005/067498 A2] are superimposed. The maximum process volume of a blown unit is currently up to 1000 liters. In systems with conventional stirrers, which can also be designed as one-way systems [WO 2005/104706 A2, WO 2005/108546 A2], process volumes of up to 10000 L are achieved.

In the case of bubble fumigation, foam problems may require the use and subsequent costly removal of antifoams in the DSP. The cell stress in the bubble rise, the superficial bursting of the gas bubbles and in particular in the foam destruction is problematic in cell culture systems, since the cells can be sustainably damaged by the high shear forces thereby introduced. This is all the more true if the bladder fumigation is combined with a dispersing, ie a stirring system which comminutes the gas bubbles. The destroyed cells release proteins, the removal of which can lead to significant product losses during processing. In order to maintain acceptable cell vitalities, the oxygen input into the presented bioreactors and thus also the achievable cell density must be limited. The limited cell density ultimately reduces the space-time yield of the fermenters and the capacity of the overall plant. Since the prerequisite for a safe scale-up is technically not fulfilled in most cases, 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.

Other disposable systems provide the necessary aeration rate of the culture via membrane or surface gassing. Here, the necessary exchange surface for the gas transport is provided either via a permeable to the gases to be transferred membrane or through a free interface to a gas space. Since no direct fumigation of the cell culture media takes place, the particle stress in these reactors is classified as lower.

In [US Pat. No. 5,057,429], a system is described in which an internal, cell-filled, semipermeable, flat bag is surrounded by another bag which is filled with nutrient solution and enriched with oxygen. Nutrient and oxygen transport are intensified by a tilting movement of the bags. The maximum process volume of a unit is only a few liters. The oxygen input is considerably limited by the low oxygen solubility in the master medium and the comparatively small surface area of the membrane. In comparison with standard membrane starters [WO 2005/111192 A1] with specific exchange surfaces in the order of magnitude of 30 mVm ³ in 100 L reactors, with this arrangement only a maximum of 10% of this exchange surface can be realized. In both cases, the available exchange flatness is proportional to the scale increase.

Other surface gassing systems also operate with a flat bag which is mounted on a shaker. The bag is only partially filled, so that a free O berfläche with an overlying gas space is formed. By a rocking movement or eccentric rotation movement, the culture medium is mixed, distributes the supplied nutrients, inhibits cell sedimentation and moves the surface [US 6,190,913 Bl, WO 00/66706, US 6,544,788 B2]. In this technology, the culture is supplied with oxygen via the free surface. The movement is always adjusted so that the flow is gentle and the cells are not exposed to excessive shear. The maximum process volume of a unit is currently 580 liters. Although this technology provides a gentle gassing mechanism, it is limited in industrial scale transmission. 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. To thaw the plastic bag they are cut in the frozen state and then filled into a stirred reactor. The procedure of slicing is labor intensive and adds to the pollution of the working environment. The thawing process is time-consuming because the ice blocks floating on the surface are barely reached by the hydrodynamics prevailing in the reactor. Product losses during the long thawing phases are therefore inevitable.

When using all of the reactors listed here, considerable sacrifices in terms of performance and scalability have to be accepted. An economic benefit can not be guaranteed in many cases, apart from the lack of performance without sufficient scalability. An increase in scale is only at the price of

Increasing the complexity and the reduction of economic benefits attainable, such. by the parallelization of several reactors or by the additional use of technically complex solutions (eg mechanical seals built into the plastic bags).

A reactor that can be scaled up to the industrial scale of 1 m ³ - 10 m ³ , the highest degree of sterility comparable to autoclaving by avoiding shaft seals and the cleaning problem guaranteed, at the same time allowing intensive and gentle liquid movement and with low technical and personnel Effort can be installed is thus a clear gap in the currently available range of technology.

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 Wärmetranspor- 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.

Through the internals distribution processes and / or mixing reactions can be carried out in a simple manner and with the same intensity as in a conventional stirred tank. On a shaft passage can be completely dispensed with this concept. The internals in turn can be supplied via the side facing away from the product with streams of material or energy, which by diffusion, convection, heat conduction and / or radiation in or out of the medium are discharged. In this way, for the first time in addition to mixing numerous basic procedural operations such as the gas distribution, the oxygen input by Membranbegasung, heat transfer, irradiation and / or particle retention in a disposable reactors are carried out gently and with a comparable efficiency to the stirred tank. The reactions and Transportvogänge take place directly on the internals. Thus, 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.

In particular, 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. Compared with the slender reactors introduced in biotechnology, such 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.

Preferably, 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. In particular, a plurality of groups of juxtaposed membranes or membrane hoses are provided, which provide an exchange surface required for membrane gassing. For example, 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.

In a preferred embodiment, 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. Preferably, 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 μm are particularly preferred because particularly fine gas bubbles are generated and an additional sterile barrier may possibly be dispensed with.

In a preferred embodiment of the gassing module, 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. As a result, a particularly large surface area can be provided for the gassing of the reactor contents with the aid of a single membrane.

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. In particular, 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.

In a particularly preferred embodiment, the gassing module is at least partially a part of the reactor vessel of the reactor according to the invention. For this purpose, 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. For example, 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. Over the sides of the frame away from the reactor contents, 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.

Preferably, 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. For this purpose, it is particularly sufficient to form only the side of the membrane facing the reactor contents through a membrane film.

Further applications for low-shear reactors are the precipitation or crystallization of proteins. These steps are z. T. in combination with the heat exchange, for example, in the plasma fractionation of animal and human blood plasma and protein purification. Both processes require a narrow particle size distribution that is shifted to particle diameters as large as possible in order to avoid clogging problems and product losses during subsequent particle separation. If the internals are used in whole or in part as distributor layers for the more even distribution of the precipitants in the reactor space, overconcentrations which contribute to nucleation and thus to the generation of very small particles can be largely avoided. In addition, it is possible to avoid the axially demanding, eccentrically arranged stirring elements in the precipitation reactors which are generally preferred for macro mixing and which have a particularly shear-intensive effect on the particles. The reactors are made on the product-contacted side of those skilled in the known, compared to solvents and dissolved substances stable materials.

Stability to solutes is also an important requirement in protein solubilization. The chemicals used for this purpose have z. T. the disadvantage of attacking the stainless steel surfaces of the standard reactors. The new reactor concept according to the invention offers the alternative of a broad range of inert materials known to the person skilled in the art.

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.

Further reactions which can be carried out in this reactor are physical, biological, biochemical and chemical reactions which take place at least partly and partly in the interior of the functionalized membranes, such as, for example, but not limited to enzymatic reactions, membrane adsorption processes or reactive extractions.

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. With the new mixing reactor 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.

Due to the process-intensifying internals, the application limits of existing one-way technologies are considerably extended, so that the new reactors can also be used in much larger scales than previously available.

The reactor is designed in particular as a disposable reactor which can be thrown away after use. For this purpose, 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. Preferably, the reactor vessel is connected to a housing which is at least partially adapted to the shell shape of the reactor. For this purpose, the preferably flexible and / or yielding reactor vessel can be positively and / or frictionally inserted and / or hooked into the container. Preferably, the reactor vessel is additionally or alternatively releasably, in particular by negative pressure, connected to the housing. For example, a trough adjacent to the reactor vessel may be provided to which a vacuum may be applied to secure the reactor vessel.

Particularly preferably, 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. Here, the cross-sectional shape can also change over the height of the housing in the axial direction. For example, the housing can be cylindrical or square in the upper region and rectangular, square, pyramidal, tetrahedral, etc. in a lower region. By a rotational movement of the reactor vessel (46) designed in this way, liquid flows (50) can be generated. Furthermore, 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. As a result, most of the components can be reused, so that only the possibly specially shaped one-way reactor must be disposed of, which in principle requires no additional mixing elements to achieve a low-shear mixture. Preferably, 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.

Preferably, 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. As a result, 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. Thereby, e.g. the release of electromagnetic radiation, e.g. Disturbances of sensors can be drastically reduced. In particular, 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.

It has surprisingly been found that a comparatively small angle amplitude is sufficient for the oscillatory-rotating movement of the reactor in order to achieve a good mixing and / or a sufficient intensification of transport processes. In particular, it is hardly necessary to turn 3600 ° revolutions, which corresponds to 10 revolutions, of the reactor to real life. so that structurally complex solutions for the connection of the oscillatory - rotating reactor to the static environment (eg for the supply and removal of media and gases, electrical energy and electrical signals) are hardly required. The reactor can perform an oscillatory - rotating motion in which the angular amplitude α is in the range of 2 ° <| α | <3600 °, preferably 20 ° <| α | <180 °, more preferably 45 ° <| α | <90 °. In particular, approximately | α | = 45 ° or | α | = 90 °, whereby deviations of + 5 ° may be present. In total, the oscillating motion thus covers an angle of 2 [α |

Experiments have shown that when the power input is increased, states of motion can occur in this reactor, in which gas bubbles are introduced into the reactor. For the cells, which are not damaged by a bubble gassing, in this way a very simple gas distribution in a preferred polygonal, particularly preferred 2-4 angular embodiment of the reactor according to the invention can be realized without expensive internals. Surprisingly, it has been shown that an undesirable foaming initially increases as expected with increasing reactor movement, but then fall back to well controllable foam heights of a few centimeters after passing through a maximum foam height. The cause of this very astonishing phenomenon of this foam destruction is that in these states of motion of the liquid not only the gas in the headspace, but also the foam itself is sucked in from the surface. 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. In particular, 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. However, the use of the oscillating foam destroyer is by no means limited to surface-aided reactors. sengerasten advantageous bring reactors used. Therefore, in the case of the reactor according to the invention, in particular 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

In a preferred embodiment, the reactor vessel has at least one elongated im

Essentially in the circumferential direction to the axis of the reactor extending fluorescence sensor, with the help of which in particular a pH and / or an oxygen concentration of the reactor contents can be detected. For 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. In particular, 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 Reaktorgefaß 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.

Preferably, 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 | a | <3600 ° to move in and counterclockwise. 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.

The invention with reference to the accompanying drawings with reference to preferred embodiments, to which the invention is not limited, explained in more detail.

Show it: FIG. 1a is a schematic simplified side view of a built-in reactor, FIG.

FIG. 1b is a schematic perspective view of the reactor of FIG. 1a, FIG.

2a shows a schematic diagram with rotational vibrations suitable for the reactor,

Fig. 2b: a schematic diagram for comparing the O ₂ entry at various

fumigation,

3 a shows a schematic sectional view of the reactor from FIG. 1 a,

3b is a schematic plan view of the reactor of Fig. 3a,

3c is a schematic sectional detail view of the reactor of Fig. 3a,

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

5a shows a schematic perspective view of the reactor in a further embodiment,

5b shows a schematic perspective view of the reactor in a further embodiment,

5c shows a schematic perspective top view of the reactor from FIG. 5a or FIG.

5b

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.

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.

7a: a schematic sectional view of the reactor in the installed state in a further embodiment,

FIG. 7b shows a schematic sectional view of a silicone tube suitable for the reactor. FIG

FIG. 7c shows a schematic sectional view of a module with the silicone tubes of FIG.

7b

7d shows a schematic sectional view of the reactor from FIG. 7a in a further embodiment,

8a: a schematic sectional view of the reactor in the installed state in a further embodiment,

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.

9a: a schematic sectional view of the reactor in the installed state in a further embodiment,

9b: a schematic sectional view of the reactor from FIG. 9a, FIG.

9c shows a schematic plan view of the reactor from FIG. 9b, FIG.

10 shows a schematic sectional view of the reactor in the installed state in a further embodiment,

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.

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

Status,

12a: a schematic sectional view of the reactor in the installed state in a further embodiment,

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; FIG.

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.

14a: a schematic exploded perspective view of the reactor 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.

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. FIG. 15e is a schematic perspective view of the reactor of FIG

installation,

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.

FIG. 16e is a schematic sectional plan view of the diaphragm of FIG. 16d; FIG.

17a: a schematic sectional view of the reactor in a further embodiment,

FIG. 17b is a schematic plan view of the reactor of FIG. 17a; FIG.

17c shows a schematic perspective view of a part of the gassing module for the reactor from FIG. 17a, FIG.

18 shows a schematic sectional view of the reactor in a further embodiment,

Fig. 19: a schematic plan view of the reactor in a further embodiment and

Fig. 20 is a schematically illustrated qualitative test result for Schaumer¬

Generation due to the gas bubble entry through the liquid surface at the same time

Foam destruction taking place as a result of foaming in the liquid.

INDEX

1 potential

2 O ₂ transport with hose stators + anchor stirrer

3 O ₂ transport in membrane modules

4 reactor contents 5 reactor

6 Moving housing

7 door

8 bearings frame

10 drive table

11 oscillating fluid movement

12 drive shaft moving housing 14 drive

15 rotational vibration

16 angles of the oscillating motion

17 reactor width

18 heat exchanger 20 floor

21 Arched ground

24 Eccentric connection piece

25 Welding Axial passage

26 Centric connection piece 27 Axial feedthrough

28 Connecting piece with extension 30 Inlet and outlet of the tempering medium 32 Receptacle heat exchanger 34 Recess Bottom 36 Horizontal opening in the floor

38 Centric hose connection (bag)

40 Arched Ground (Bag)

41 Pyramidal Soil (Bag)

42 Drainage bag (bag) 43 Rectangular reactor

44 harvesting valve (bag)

45 gas bubbles

46 Accelerated movement

47 Flow vortices 48 Relative movement of the liquid

49 foam

50 Radial secondary vortex 52 Stirring blade, foil elements 54 Upper clamping element 56 Lower clamping element 58 Ground support 59 pins for transmitting the torque to 58

60 Distributor below 62 Distributor above 64 Tie rod 65 Connecting element 66 Suction base

68 tensioning device tie rod

69 Counter connection tie rod

70 holding device 72 hose module

74 silicone hose

76 module holding and supply device

78 potting compound

79 Basic body 80 Module holder

82 Fastening pipe for gas supply

84 Fastening pipe for gas discharge

86 Distribution room Gas supply

88 Distribution room Gas discharge 90 Tie rod and supply line Gas supply

92 Tie rod and supply line Gas removal

94 gas stream addition

96 gas discharge

97 Width of the side pocket 98 Depth of the side pocket

99 Lateral support element

100 invagination in the head or bottom

102 Cylindrical support element

103 Side pocket 104 Angle of attack Support element to the horizontal

105 angle of the lateral pocket

106 Cone-shaped invagination

107 taper angle of the support element

108 Cone-shaped support element 110 Pyramidal invagination

112 Pyramidal support element 114 Radiolucent cone-shaped support element

116 radiation source

117 radiation jacket

118 Radiation-permeable conical indentation 120 Temperature control inlet

122 Inlet line for temperature control 124 Distribution channel

126 exhaust pipe

127 Temperable support element 128 Temperiermantel

129 deflection device

130 collecting channel

132 drain line temperature control

134 Temperature Control Process 136 Support ring with eyelets

138 Frozen fluid

140 carrying pieces

142 intermediate floor

144 Procedure 146 Extended support element

147 Transport

148 Liquid distributing support element

149 O-ring

150 filtering layer 151 cylindrical projection element 152 time axis

154 speed in left direction

155 speed in the right direction

156 Sinusoidal Velocity Profile 157 Linear Velocity Profile

158 Stepped velocity profile 160 Time interval per movement cycle 162 Amplitude

170 Foam development to be expected in the surface-treated system without foam destruction 175 Foam development due to surface fumigation with simultaneous foam destruction 180 first turning point 185 second turning point 190 maximum 200 bag half 201 frame

202 groove in the moving housing

203 circumferential connecting edge of the bag half

204 Frame-based bag

205 Distance between frame and blade element 250 Lid

300 membrane film

301 Porous layer

302 parallel membrane extruded membrane tube

303 distribution room 304 collection room

305 connecting webs between membrane hoses

320 through-flow element made of flat membranes

321 lower holder

322 upper holder 330 element through which can be flowed through from tube membranes 340 membrane stack

342 delimiter element

343 spacer element

350 Meander-shaped membrane element 360 membrane element integrated in the bag wall

401 sensor layer 1

402 Sensor layer 2 420 Holder for optical fibers

411 Light guide for sensor layer 1 412 Light guide for sensor layer 2

In Fig. Ia and Ib 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 mass of the filled reactor 5, the strength-related limited tensile and shear loads can be expected, is collected in the vertical direction from the bottom 20 of a surrounding container and in the lateral direction on the jacket 6. For easy installation of the reactor 5, the jacket 6 via a door 7 will be opened. During the process, 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. By an easy-to-achieve sizing of jacket 6 and reactor 5 20 small reactors can be operated on the same floor, which increases the flexibility of production, especially with frequent product changes.

Fig. 2a shows suitable rotational vibrations 15, z. With rectangular 158, 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. To achieve this, 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. As far as the torque of the drive used allows high angular acceleration of the reactor, rectangular pulses 158 can be approximately realized. However, these lead to a significantly greater width of the velocity distribution in the reactor and thus with a comparable mechanical power input to an increase in the shear stress of suspended particles. This mode of drive will usually be avoided in the cultivation of shear-sensitive animal cells. By contrast, when suspending sedimented particles or mixing in additives, these additional mixing effects may well be desirable. In the case of membrane gassing, high specific exchange surfaces of significantly more than 30 m ² / m ³ can be ensured in a disposable reactor without rotating sealing elements and even in very large reactor dimensions. 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. To generate this plot, the volumetric mass transfer coefficient ka for oxygen was measured by the dynamic method and plotted as ordinate. On the abscissa 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. ). The Vergeichsflockendurchmesser is a measure of the hydrodynamic shear of small suspended particles, with small Vergleichflockendurchmesser indicate large shear forces and vice versa. According to this study, 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. As an alternative to tube modules 72, with which very large specific exchange surfaces can be realized in bioreactors, z. B. also cheaper durchströmbare 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.

In the case of producing coarse or fine gas bubbles across membranes, e.g. the oscillating motion of microporous fillets 150 are utilized to evenly distribute gas bubbles across the reactor cross-section in the liquid 11.

In Fig. 3a, but by way of example, 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. For tempering the medium 4, 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. To improve the heat transfer, it is advisable to fill the cavity 32 with 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. In eccentric addition, 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 Schaubverbindung on the neck and sealed on the inner edges of the bushings by means of an O-ring. Furthermore, preference is given to sensors based on fluorescent reactive dyes which are simply applied to the reactor wall in order to interact with the medium. 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. However, it has surprisingly been found that 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.

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. 5b) bottom is used instead of a reactor with a cylindrical cross section 5, one obtains the in Fig These are a reaction to the relative to the accelerated rotational movement 46 of the rectangular reactor 43 counteracting caused by the inertia of the medium 4 relative movement 48. With the help of these secondary flows 50 mixing operations can be excited. Due to the movement of the liquid surface, the reactor is also suitable for the oxygen input through the surface gassing. However, since the reactor height would have to be kept constant during the scale-up, this aeration method is only suitable for small reactor volumes, depending on the desired cell number, because of the considerable space requirement. 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. Depending on the selection of the fermentation medium, 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 By suitably adjusted wave motion, 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). This is illustrated 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. It is shown schematically how the foam height h / D, related to the reactor diameter, initially increases strongly with increasing fluid movement due to the increase of the mechanical power input P / V as a result of the introduction of gas bubbles, but with a further increase of the line entry to drop again. Compared to a surface-treated reactor without foam-destroying properties (curve 170), in which a continued increase the foam heights can be assumed with increasing power input, thus resulting in a much wider range of applications. In the reactor according to the invention, flow movements take place with a foam-destroying effect, so that the foam development 175 decreases again after passing through a maximum 190 arranged between a first inflection point 180 and a second inflection point 185. 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.

In the embodiment of the reactor shown in Fig. 5f, 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. In addition to the outflow 42, circumferentially extending fluorescence sensors 401, 402 are provided which can measure the pH value or the O ₂ concentration ratio. For each sensor 401, 402, 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).

A significant increase in the mixing movement is possible with the help of internals. FIGS. 6a and 6b show an example of a cylindrical reactor 5 with a built-in Blartrührer. 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. With the help of the recessed into the bottom 20 drive dome 59, depending on the drive torque z. B. may be designed as a gear or simple key head, 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. When used as a disposable reactor, 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. 6 in the container 4 filled with medium. Otherwise, a static connection between bottom bearing 60 and drive pin 59 must be ensured. 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. For this purpose, 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.

In 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. In the indentations 100, 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. To improve the axial mixing, 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. In this case, 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.

With the aid of the arrangement in FIG. 10, 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. In this case, 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.

In 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 drive and energy supply part of the new reactor Fig. I Ia. 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. This is with the collection channel 130th connected, via which also from the support members 127 via the exhaust pipes 126 taken Temperiermittelströme 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. 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). To use the support structure, it is necessary to carry out the reactor 43 in the center with a passage 144 instead of an indentation 106. 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.

In Fig. 13 a and b, the invention is not restrictive preferred reactors 5 with lateral, integrated into the reactor wall pockets 103 shown. In this form, 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. In pure mixing tasks, 1 to 8 pockets appear to be adequate, analogous to wall-mounted stirring systems, with 2 pockets being regarded as the preferred number because of the comparatively low installation effort. 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. By 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 °.

In the exemplary embodiment of the reactor illustrated in FIG. 14 a, 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. In the exemplary embodiment of the reactor shown in FIG. 15a, instead of the blade stirrer 52, 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 aufzusannen 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.

In the alternative embodiment of the membrane 74 shown in FIG. 16a, 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. In order to pressurize the membrane 74 with a gas pressure, 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. In particular, 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). Thereby, 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). By limiting elements 342, the membrane stack 340 can vaπabel on an upper holder 321 and / or a lower holder 322 are fixed.

In the embodiment of the reactor shown in FIG. 18, 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. In the bag wall of the reactor vessel 5, 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.

By means of the process-intensifying internals and thus the physical, biological, biochemical and chemical reactions which can be carried out in and on membranes, e.g. for gassing, gas distribution, liquid distribution, particle retention, irradiation and / or heat supply and removal, the application limits of existing one-way technologies are greatly expanded, so that the new reactors are also applied at much larger scales than previously available can.

Claims

claims

1. Reactor, comprising a reactor vessel (5) and a drive unit (14), characterized in that the reactor contents (4) by the drive unit (14) about the stationary, preferably vertical, axis of the reactor oscillating - is set in rotation, wherein the mechanical power input into the reactor contents (4) by a suitable shell shape of the reactor and / or the reactor vessel (5) and / or by static in the reactor and / or in the reactor vessel (5) installed internals is made possible.

2. Reactor according to claim 1, comprising a reactor vessel and a drive unit, characterized in that the reactor contents by the drive unit to the stationary, preferably vertical, axis of the reactor is oscillatory - rotating in motion, wherein the power input into the reactor contents by a suitable Sheath shape of the reactor and / or statically installed in the reactor internals is made possible.

3. Reactor according to claim 1 or 2, characterized in that the movement in a non-round, preferably rectangular reactor (43) with flat (45) or pyramidal

(41) Ground generated by a rotational movement (46) secondary flows (50).

4. Reactor according to one of claims 1 to 3, characterized in that in a reactor vessel (43) with polygonal, preferably two- to octagonal, more preferably three- to quadrangular cross-section and with flat (45), pyramidal (41) or tetraedri - See bottom by a rotational movement (46) liquid flows (50) can be generated.

5. Reactor according to one of claims 1 to 4, characterized in that the reactor vessel (5) has a ratio of height to average diameter of 0.2 to 2.0, preferably 0.6 to 1.2 and particularly preferably 0.8 to 1.0.

6. Reactor according to one of claims 1 to 5, characterized in that in the reactor vessel (5) installed internals are provided, the relative to the drive unit oscillating moving functionalized surfaces for performing physical, biological, biochemical and / or chemical reactions and / or in membranes, eg for gassing via 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.

7. Reactor according to one of claims 1 to 6 comprising, a container with clamping elements, a base, a blade stirrer, formed by Rührblattelemente (52), which are spanned at the time of reactor use between the two clamping elements (54) and (56), at least a bottom bearing (60), which is welded or adhesive technically fixedly connected to the bottom of the reactor (5) via the support ring (58), a driving mandrel (59) embedded in the rotatable bottom (20) and depending on the drive torque Gear or simple key head can be designed, a connected to the head bearing (62) tie rod (64) and a holding device (70).

8. Reactor according to one of claims 1 to 7, comprising, a container with chucking elements, a subframe, a blade stirrer, formed by stirring blade foil elements (52), which at the time of reactor use between the two clamping elements (54) and (56 ) are clamped, at least one bottom bearing (60), which is welding or adhesive technically fixedly connected via the support ring (58) to the bottom of the reactor (5), a in the rotatable bottom (20) embedded drive mandrel (59) depending after driving torque can be designed as a gear or simple key head, a tie rod (64) connected to the head bearing (62) and a holding device (70).

9. Reactor according to one of claims 1 to 8, characterized in that the substances to be mixed by other internals simultaneously UV-irradiated, and / or are gassed with oxygen, and / or filtered, and / or heat is discharged.

10. Reactor according to one of the claims 1 to 9, characterized in that it is the reactor is a disposable reactor.

11. Reactor according to claim 10, characterized in that the reactor vessel (5) is made of stable, preferably multi-layered or of a polymer material applied to stabilizing network structures.

12. Reactor according to any one of the claims 10 to 11, characterized in that it is made of stable, preferably multilayer plastic films.

13. Reactor according to any one of claims 10 to 12, characterized in that the reactor vessel (5) is connected to a housing (6) which is at least partially adapted to the shell shape of the reactor vessel (5), the housing (6) passing through the housing Drive unit (14) about the stationary, preferably vertical axis of the reactor (5) oscillatory - is set to rotate in motion.

14. Reactor according to claim 13, characterized in that the reactor vessel (5) releasably, in particular by negative pressure, with the housing (6) is connected.

15. Reactor according to claim 13 or 14, characterized in that the housing (6) in a substantially vertical direction movable, in particular hanging, is rotatably mounted.

16. Reactor according to one of claims 1 to 15, characterized in that the reactor (5) is forcibly coupled to the drive unit (14) such that the acceleration and deceleration of the reactor rotation takes place with a substantially constant angular acceleration or deceleration.

17. Reactor according to one of claims 1 to 16, characterized in that the ozillatoric-rotating movement of the reactor (5) has an angle amplitude α in the range of 2 °

<| α | <3600 °, preferably 20 ° <| α | <180 °, more preferably 45 ° <| α | <90 °.

18. A reactor according to any one of claims 1 to 17, characterized in that a gassing module (72) is provided with substantially vertically arranged permeable in particular tubular membranes (74) for gassing of the reactor (5).

19. Reactor according to claim 18, characterized in that the reactor vessel (5) has at least two, in particular exactly two, sections (200) and the gassing module (72) has a frame (201) for fastening the membranes (74), wherein the sections (200) are each connected to the frame (201), in particular by gluing.

20. Reactor according to claim 18 or 19, characterized in that the membrane (74) has a membrane with an open-pore material, in particular foam, connected membrane film.

21. Reactor according to one of claims 18 to 20, characterized in that the gassing module (72) has a first holding profile (321) and a second holding profile (322) and at least one elongated diaphragm (74) is provided, which is between the first holding profile (321) and the second Halteprofϊl (322) back and forth, in particular zigzag-shaped or meandering, is arranged.

22. Reactor according to one of claims 1 to 21, characterized in that the reactor (5) is lined on an inner side at least partially with a permeable membrane (360) for gassing the reactor (5).

23. Reactor according to one of claims 1 to 22, characterized in that the reactor vessel (5) has an elongated substantially in the circumferential direction to the axis of the reactor extending fluorescence sensor (401, 402), in particular for the detection of a pH value and / or an oxygen concentration, and a to the reactor vessel (5) objectionable optical detection device (411, 412) is provided, in particular, the detection rate and the Oscillatory-rotating movement are chosen such that the fluorescence sensor (401, 402) is optically detected at different partial surfaces.

24. Reactor according to one of claims 1 to 23, characterized in that the oscillatory-rotating movement, in particular the acceleration value of the oscillatory rotating movement, is adjustable such that on the surface of the reactor contents (4) a wave flow can be generated, which is a part promotes the surface of the reactor (4) to the interior of the reactor contents (4).

25. Blister gasified reactor, in particular according to one of claims 1 to 24, with a reactor vessel (5) which has a polygonal cross-section at least in the region of a liquid surface of the reactor vessel (5) received reactor contents (4), which over the surface or porous membranes is subjected to gas bubbles and is added for the purpose of foam destruction in an oscillatory - rotating movement such that foam (49) on the surface of the reactor contents (4) in the interior of the reactor contents (4) is promoted.

26. A method for mixing and / or dispersing of substances using a reactor according to any one of claims 1 to 25, in particular for the purpose of preferably low-sparing foam destruction.

27. A process for mixing substances using a reactor according to one of claims 1 to 26.

28. Use of a reactor according to any one of claims 1 to 27 as a foam destroyer for particular low-shear solubilization of the reactor vessel (5) resulting foam (49).