JP5148718B2 - Bag soot removal and leak detection system, and electromagnetic stirring system for liquid storage - Google Patents

Description

  The present invention relates generally to a system for containing and manipulating fluids, and in certain embodiments, the present invention relates to a container improvement system and method including bag scum removal system, leak detection system and electromagnetic stirring system. .

  Various containers for manipulating fluids and / or various containers for performing chemical reactions, biochemical reactions and / or biological reactions are available. For example, biological materials including mammalian, plant or insect cells (eg, animal and plant cells) and microbial cultures are processed using a bioreactor. Conventional bioreactors commonly used as disposable containers or disposable are used, and many of the bioreactors use sterilized plastic containers. Reaction systems and other fluid handling systems (eg, mixing systems) are well known, but improvements to these systems are beneficial.

  The present invention relates generally to systems for containing and manipulating fluids, and in particular embodiments, the present invention is supported as used as a bioreactor for performing chemical reactions, biochemical reactions and / or biological reactions. The present invention relates to a system and method including a foldable bag. The subject matter of the present invention also includes possibly interrelated articles, alternative solutions to a particular problem, and / or the use of one or more systems and / or articles multiple times in various forms. Certain prior art systems, such as those relating to the use of disposable plastic liners or bags in support structures, are formed into a liner or bag as soon as the bag / liner is filled with liquid. It has been recognized that it suffers from problems caused by folds or other irregularities. Such folds are undesirable and create a “dead zone”, which leads to, for example, incomplete reactions, contamination or necrosis at the bottom of the bioreactor. Such particular systems suffer from the possibility of leaking from defective or damaged parts of the bag / liner. In these or other systems that provide mixing via a magnetically coupled impeller, an improvement in mixing capability or controllability is desirable and provided by certain embodiments of the present invention.

  In certain embodiments, the container of the present invention comprises a foldable bag and a reusable support structure that supports and houses the foldable bag. The container also includes a bladder or compressible material positioned between the outer wall of the foldable bag and the inner wall of the support structure, the bladder or compressible material adapting to expansion or contraction, thereby folding the bag. The body has a first configuration before expansion or contraction of the bladder or compressible material and a second configuration after expansion or contraction of the bladder or compressible material.

  In another embodiment, the container of the present invention comprises a foldable bag and a reusable support structure, the support structure having at least one wall that is inflated or deflated. By the expansion or contraction, the foldable bag body has the first configuration before the wall portion is expanded or contracted and the second configuration after the wall portion is expanded or contracted.

  In one embodiment, the method of the present invention places a foldable bag in a reusable support structure such that the reusable support structure contains and supports the foldable bag. And a step of taking liquid into the foldable bag and changing the pressure of the fluid in the region between the outer wall of the foldable bag and the inner wall of the support structure.

  In another embodiment, the container of the present invention includes a foldable bag, a reusable support structure that supports and houses the foldable bag, and fluid from the foldable bag. A detector is applied to determine if there is a leak.

  In another embodiment, the bioreactor system of the present invention comprises a support structure and a foldable bag positioned within a rigid container or support structure. The rigid container or foldable bag includes an impeller plate mounted on a lower portion of the rigid container or foldable bag, and an impeller hub attached to the impeller plate. Has at least one vane and has at least one magnet. The rigid container or foldable bag further comprises a motor having a shaft, the motor having the shaft being provided adjacent to or within the support structure, the bag further comprising a motor hub attached to the motor shaft. The motor hub comprises at least one electromagnet, and as soon as a rigid container or foldable bag is mounted inside the support structure, the motor hub aligns with the impeller plate so that the motor shaft rotates. The motor hub electromagnet drives the impeller hub. The impeller plate optionally includes a column. The bioreactor system includes one or more sensors that sense one or more parameters of any material in a rigid container or foldable bag.

  Other advantages and novel features of the invention will become apparent from the following detailed description of various non-limiting embodiments of the invention when considered in conjunction with the accompanying figures. In cases where the present specification and a document incorporated by reference include conflicting and / or inconsistent disclosure, the present specification shall control. If two or more documents incorporated by reference contain conflicting and / or inconsistent disclosure in relation to each other, the document with the closest issue date shall prevail.

FIG. 1 shows a container, which comprises a container contained within a support structure according to one embodiment of the present invention. FIG. 2 illustrates a container for performing fluid operations including biological, chemical and biochemical processes according to another embodiment of the present invention. FIG. 3 shows a bladder placed in a container according to another embodiment of the present invention. FIG. 4 illustrates various leak detection systems according to another embodiment of the present invention. FIG. 5 illustrates various leak detection systems according to another embodiment of the present invention. FIG. 6 shows a magnetically coupled impeller according to another embodiment of the present invention. FIG. 7 shows an impeller with electromagnetic drive according to another embodiment of the present invention. FIG. 8 shows a mechanically driven impeller according to another embodiment of the present invention. FIG. 9 shows an impeller magnetically coupled to an external motor according to another embodiment of the present invention.

  Non-limiting embodiments of the present invention will now be described by way of example in conjunction with the accompanying figures. The figures are schematic and are not drawn to scale. In the figure, each ideal or nearly ideal component shown is generally represented by a single numeral. For clarity, not all components are shown in all figures, and not all components of each illustrated embodiment of the invention are shown in all figures. Indeed, illustrations are not necessary for those skilled in the art to understand the invention.

  The present invention relates generally to systems for containing and operating fluids. And, in certain embodiments, the present invention relates to a system and method relating to a foldable bag or liner and a rigid container, the system and method comprising a mixing system, a storage device, a transport container or a chemical, biological Used as a reactor to carry out chemical or biological reactions. Particular embodiments of the present invention relate to continuous improvements and features of fluid containment systems, for example, by providing a container that includes a soot removal system, a leak detection system, and / or an electromagnetic stirring system. For example, the wrinkle removal system is configured to reduce or remove wrinkles in the foldable bag or liner that are formed when the bag or liner is filled with water. Soot removal is important in many cases. Because the sputum creates a “dead zone” containing undissolved solutes, cells or chemicals, reducing the speed at which it is homogenized in the mixing operation and supporting and supporting the foldable bag or liner This is because a region is generated that reduces the heat transfer efficiency due to the absence of contact with the body wall and / or produces a hypoxia or a nutritional state that traps cells and causes necrosis or the like in the cells.

  The leak detection system described herein is configured to detect leaks from the container and optionally notify the user of any leaks that are formed before or during the container fluid handling process. Leak detection is particularly useful for using foldable bags, liners or containers that contain components that contain fluid. This is because leaks between the walls of the container are difficult to detect by other methods and can lead to sudden failure or harmful drug release.

  In some containers of the present invention, including a mixing system, the system includes an electromagnetic stirring system that allows a user to easily manipulate the components as compared to a system using permanent magnets. For example, an impeller hub including an impeller and a stationary magnet is difficult to operate due to strong attraction, especially during assembly and disassembly of components. This problem is alleviated by using electromagnets that can be activated and deactivated by the user. This allows the user to control the magnitude and duration of the attractive force between the components.

  Additional advantages and a description of the above system are presented below.

  The following documents are hereby incorporated by reference: That is, US Provisional Patent Application No. 60 / 903,977 filed February 28, 2007, titled “Weight Measurements of Liquids in Flexible Containers” by PA Michell et al., “Disposable Bioreactor Systems” by G. Hodge et al. and US Patent Application No. 11 / 147,124, filed June 6, 2005, US Application Publication No. 2005/0272146, published December 8, 2005, G. Hodge et al. International Application No. PCT / US2005 / 020083 entitled “Disposable Bioreactor Systems and Methods” by WO2005 / 118771, published December 15, 2005, “System and Method for Manufacturing” by G. Hodge et al. In the international application No. PCT / US2005 / 002985 filed on February 3, 2005, titled “ WO 2005/076093, published August 18, 2005, United States of America entitled "Gas Delivery Configurations, Foam Control Systems, and Bag Molding Methods and Articles for Collapsible Bag Vessels and Bioreactors" filed June 15, 2007 Patent Application No. 11 / 818,901, US Patent Application No. 11 / 879,033 entitled “Environmental Containment Systems” filed July 13, 2007, “Continuous” filed July 30, 2007 US Patent Application No. 60 / 962,671 entitled “Perfusion Bioreactor system”, US Patent Application No. 60/962, entitled “Weight Measurements of Liquids in Flexible Containers” filed on Feb. 28, 2007 No. 903, 977, and "Information Acquisition and Management Systems and Methods in Bioreactor Systems a It is a US patent application entitled “nd Manufacturing Facilities”.

  Although much of the description herein includes typical applications of the present invention related to bioreactors (and / or biochemical and chemical reaction systems), the present invention and its uses are not limited, Furthermore, it should be noted that the present invention is equally applicable in different settings including general containment systems as well as systems for containment and / or processing of fluids in containers (eg, mixing systems). I want you to understand. Furthermore, while many of the embodiments provided herein relate to the use of a foldable bag, liner or flexible container, embodiments of the present invention provide a non-foldable bag, rigid container, and liquid containment. Can be integrated with systems with other structures.

  In certain embodiments, a container is provided that is configured to contain a predetermined volume of liquid. In certain embodiments, the container is part of a bioreactor system. For example, an unconstrained embodiment of a bioreactor system including a flexible container is shown in the schematic diagram of FIG. As shown in the embodiment of FIG. 1, the container (10) includes a reusable support structure (14) (eg, a stainless steel tank) that surrounds and houses the periphery of the container (18). . In another embodiment, the container is configured as a foldable bag or liner (polymer bag) and optionally includes a tube, a magnetically driven pump and / or a foam collapse device. Additionally or alternatively, all or a portion of the foldable bag, liner or other container may comprise a substantially rigid material such as a rigid polymer, metal, and / or glass. In other embodiments, rigid containers are used in this construction. The container is disposable and configured to be easily removed from the support structure. In certain embodiments, the container is incompletely connected to the support structure.

  When using a foldable bag, the foldable bag is constructed and arranged to contain the liquid (22), the foldable bag being a chemical, biochemical or biological reaction. Contain the reactants, media, and / or other components necessary to carry out the desired steps. Further, the foldable bag may be configured so that the liquid (22) substantially contacts only the foldable bag during use and does not contact the support structure (14). In such an embodiment, the bag is disposable and used for a single reaction or a single series of reactions and is disposed of after the reaction. Since the liquid in the foldable bag does not contact the support structure, the support structure can be reused without cleaning. That is, after a reaction has occurred in the container (18), the container can be detached from the support structure and replaced with a second (eg, disposable) container. The second reaction can be carried out in the second container without having to clean the first container or the reusable support structure. When any liquid comes into contact with the reusable support structure due to leakage from the bag, in certain embodiments, one or more leak detection systems connected to the container (10) are Appropriate measures are taken by detecting leaks and notifying the user.

  In some embodiments, the container (10) comprises one or more wrinkle removal systems that fold when pressed against the support structure by filling the bag with fluid. Reduce or remove the wrinkles that form on possible bags. For example, in the embodiment shown in FIG. 1, the wrinkle removal system comprises one or more bladders (26) that are foldable bag outer wall (28) and support structure inner wall (30). ). During or after the liquid (22) is introduced into the foldable bag, the bladder contracts (eg, squeezes), effectively stretching the foldable bag to remove any wrinkles in the bag. Or remove it. Further description of the soot removal system and additional examples are provided below.

  As shown in FIG. 1, an optional inflow port (42) and an optional exhaust port (46) can be formed in the container or reusable support structure to make liquid or gas in and out of the container more efficient. Can be done automatically. The container has an appropriate number of inflow ports and an appropriate number of exhaust ports. For example, multiple inlet ports are used to provide various gas compositions (via multiple spargers (47)) or to separate gases before they are taken into the container. The port is placed at an appropriate position with respect to the container (18). For example, in certain containers including spargers, the container has more than one gas inlet port located at the bottom. The tubes are connected to an inflow port and / or an outflow port, for example to form a delivery tube and an intake tube, each of which draws liquid in and out of the container. The container and / or support structure optionally comprises a utility tower (50), the utility tower (50) having more than one device inside the container or support structure more than one pump, controller, or electronics (e.g. , Sensor electronics, electronic interface, pressurized gas control device) or other devices. Such devices are controlled using a control system (34). The control system is used to send and receive signals from the leak detection system and the soot removal system.

  For systems including multiple spargers, the control system (34) is operably connected to each of the spargers and is configured to operate the spargers independently of each other. By the above, for example, it is possible to control while introducing a plurality of gases into the container.

  As used herein, in general, components of an advanced system that “operably connect” with one or more other components indicate the following: That is, such components are directly connected to each other in direct physical contact. The components are not connected or attached to each other or are indirectly connected to each other. Alternatively, the components can be mechanically, electrically (including via electromagnetic signals transmitted through space) or fluidically interconnected to allow sufficient connection to the components, thereby providing the desired Function can be demonstrated.

  The container optionally comprises a mixing system, such as an impeller (51), which can be rotated (eg, around a single axis) using a motor (52) disposed outside the container. In another embodiment, the impeller and motor are magnetically coupled, as described in detail below. The mixing system can be controlled by a control system (34). The mixing system is described in further detail below.

  In addition and / or as a variant, the container may comprise an antifoaming system, such as a mechanical antifoaming device. As shown in the embodiment of FIG. 1, the defoaming device may also include an impeller (61) that can be rotated (eg, magnetically) using, for example, a motor (62) disposed outside the container. It doesn't matter. The impeller may be used to disperse the foam accommodated in the upper space (63) of the container. In some embodiments, the antifoam system is in electrical connection with a sensor (43, eg, a foam sensor) via a control system (34). This sensor may, for example, determine the foam level or volume in the headspace, or the pressure in the container, thereby inducing adjustment or control of the defoaming system. In other embodiments, the antifoam system is operated independently of any sensor.

  In another embodiment, the support structure and / or container is more than one port used for specimen, analysis (eg, determining pH and / or amount of dissolved gas in a liquid), or other purposes ( 54). The support structure comprises more than one site window (60) for examining the liquid level in the container. More than one connection (64) is placed at the top of the container or other suitable location. The connection (64) includes an opening, a tube, and / or a valve for taking liquid, gas, and the like out of the container, and each of the connection (64) includes a flow sensor and / or a filter (not shown). Optional. The support structure further comprises a plurality of legs (66) and optionally has casters (68) to facilitate transport of the container.

  Not all the characteristics shown in FIG. 1 are required in all embodiments of the present invention, and the illustrated components may be exposed and configured differently. Please note. Similarly, the components described here may be added in other embodiments. For example, in some embodiments, a container or one or more container components are associated with an “identifier”. The identifiers are used to guide proper assembly of system components, and system components are correctly assembled to protect against the use of counterfeit, improper or unauthorized components. An identifier is information that is “encoded” about the component that contains the identifier (ie, such as by using information on transport, storage, generation or transport equipment such as a radio frequency identification (RFID) tag or barcode). Or any unencoded information about the component. Rather, the identifier is associated only with information contained in, for example, a database on a computer or a database on a computer-readable medium. In the latter example, information associated with the database is retrieved and used by detecting an identifier or the like. Examples and uses of additional identifiers are detailed in a US patent application filed on the same date as this application and titled “Information Acquisition and Management Systems and Methods in Bioreactor Systems and Manufacturing Facilities”. This application is hereby incorporated by reference in its entirety.

  In some embodiments, difficulties in accurately positioning the foldable bag in the reusable support structure (eg, the shape of the foldable bag is reusable, and / or The foldable bag (e.g., the presence of a seam) does not accurately fit the structure, making it difficult to properly align the foldable bag in the support structure). Relieve through the use of. For example, in some instances, the collapsible bag is composed of a flat sheet panel that is welded to form a chamber, and the reusable support structure has a curved bottom. Without a new wrinkle removal system, it is difficult to prevent folds and / or wrinkles from being formed at the bottom of the foldable bag. In the absence of a new crease removal system, once a fold or crease is formed, it tends to push up against the surface of the support structure, making it difficult or impossible to remove the crease or crease.

  As noted above, the containers described herein (eg, bioreactor systems) in certain embodiments can be one or more capable of reducing or eliminating folds and / or wrinkles in a foldable bag or liner. Includes system. In some embodiments, the wrinkle removal system includes a bladder positioned between the outer wall of the foldable bag or liner and the inner wall of the support structure. The bladder expands or contracts, for example, effectively modifying the internal volume and / or shape of the support structure with air pressure, thereby modifying the configuration of the foldable bag or liner.

  As presented in the embodiment shown in FIG. 2, the container (70) comprises one or more bladders (26) located at the bottom and sides of the foldable bag (18), the bladder comprising: Housed and supported in a reusable support structure (14). The bladder is filled with liquid or gas, thereby having the desired volume and / or shape to support the foldable bag. Thereafter, the foldable bag is partially or completely filled so that at least a portion of the wall of the foldable bag contacts or pushes up against the surface of the bladder. In some cases, when the foldable bag is filled, a portion of the wall of the foldable bag is not spread flat against the inflated bladder. This causes folds or creases formed at the wall of the foldable bag body, and has a negative impact on the material or process performed inside the container. However, when the bladder (26) is deflated, the foldable bag further expands to a configuration having fewer folds or creases in one or more walls of the foldable bag. Shrinkage occurs, for example, by removing all or part of the contents in the bladder (eg, by shrinking or flushing the contents from the bladder). This step effectively stretches the foldable bag and removes some or all of the bag folds or folds.

  The bladder has any suitable volume and shape that can be inflated and / or deflated, such that the foldable bag has a first configuration prior to inflation or deflation of the bladder and a second configuration after inflation or deflation of the bladder. Have. The bladder has a shape that is compatible with the reusable structure and / or foldable bag configuration, and in some embodiments, the bladder is reusable support structure and / or foldable. Fits the shape of the bag. For example, as shown in FIG. 2, the bladder (26) is designed to extend from the outer wall (28) of the foldable bag to the drainage groove (35) of the foldable bag and support structure. .

  The bladder (26) is placed in any suitable position relative to the foldable bag (18) and the reusable support structure (14). For example, in some embodiments, one or more bladders completely surround the outer wall (28) of the foldable bag. Alternatively, one or more bladders are completely surrounded by the inner wall (30) of the reusable support structure. In other embodiments, the one or more bladders are adjacent only to the peripheral portion of the foldable bag or the reusable support structure. For example, the bladder is adjacent to contact all or part of the bottom, top, or sides of the foldable bag or reusable support structure. In some examples, the bladder array is located around the foldable bag and within the reusable support structure.

  The bladder is positioned inside the reusable support structure using any suitable placement or attachment technique. In some embodiments, the bladder is removably or incompletely attached to the foldable bag. The bladder is reusable, for example, using an adhesive, magnetic interaction, pressure (e.g., pushes against the inner surface of the support structure as the bladder expands), etc. Removably attached to. After or before the foldable bag is introduced into the support structure, the reusable support structure is lined with a bladder. In another embodiment, the bladder is manufactured with a foldable bag (e.g., by injection molding or blow molding) so that, for example, the bladder can be folded with the foldable bag inside the fluid flow. do not do. In some embodiments, because there are fewer parts to position and align, the attachment of the incomplete bladder to the foldable bag is the introduction of the bladder and bag to the support structure and the support structure. Facilitates removal of bladders and bags from the body. In another embodiment, the foldable bladder and bladder are connected to each other prior to introducing the unit into a reusable support structure, such as with adhesive, pressure, magnetic interaction, etc. Two separate components. In yet another embodiment, the foldable bag is first inserted into the reusable support structure, and then the bladder is positioned between the foldable bag and the support structure.

  Any suitable number of bladders are connected to the foldable bag and / or support structure. If more than one bladder is used, the bladders are operated independently of each other. For example, the bladders are independently controlled so that each bladder expands depending on its position relative to the foldable bag and / or support structure, the amount of fluid and / or pressure in the foldable bag. Or it controls independently so that it may contract. The bladder in some instances self-expands / contracts, for example, by using air to inflate or deflate the bladder. In some examples, the bladder is connected to a sensor, such as a pressure sensor, which is used to measure the internal pressure of the bladder. The bladder is programmed to maintain a constant pressure or operate within a range of constant pressures. For example, the bladder has a first internal pressure before the foldable bag is filled with fluid. When the collapsible bag is filled with fluid, the pressure is applied to the bladder, thereby increasing the internal pressure of the bladder. The increase in pressure is detected by a sensor, and in response the bladder self contracts (eg, self deflates) until the internal pressure of the bladder reaches the first internal pressure. On the other hand, the configuration of the foldable bag body is changed by reducing the capacity inside the bladder. The capacity of the foldable bag is effectively increased by, for example, the collapse of the bladder and / or the number and / or size of the folds or creases in the foldable bag is reduced.

  In some examples, the bladder is particularly useful during operation of one or more other components of a foldable bag and / or support structure, such as a sensor, heater, and when opening and closing a port, etc. Adapts to expansion or contraction.

  The bladder (26) includes one or more ports (eg, port (36)) that introduce or remove substances such as gases, liquids, gels or solids from the bladder. The port is accessible from the outside of the support structure in some embodiments. The port has any suitable size and configuration and is made of any material. In some examples, the ports and / or materials used to form the bladder include a self-sealing material such as silicon.

  In some embodiments, the foldable bag is designed to have approximately the same shape and volume as the support structure. Thus, when the bladder is fully contracted or collapsed, the foldable bag is only separated from the support structure by a thin layer forming the bladder. In such an embodiment, heat is dissipated from the foldable bag to the support structure via the bladder, so that the foldable bag, the contents inside the support structure, and the outside of the support structure Used to facilitate heat exchange between different environments. All or part of the bladder is formed from a thermally conductive material to facilitate heat transport, as described in more detail below. In other embodiments, the foldable bag is designed to have a volume that does not have a bladder (eg, when the foldable bag is fully inflated) less than the capacity of the support structure. In the case of the designed configuration, it is designed to have a capacity greater than the inner capacity of the support structure with the bladder. Therefore, when the foldable bag is fully inflated, the bladder remains partially inflated. The bladder configuration prevents the bag from extending from the inner surface of the support structure. Such an embodiment is beneficial in isolating the foldable bag from the support structure.

  Certain embodiments of the present invention comprise a support structure, the support structure having at least one wall that can be inflated and / or deflated, whereby the collapsible bag is a wall. The first configuration is provided before the expansion or contraction of the portion, and the second configuration is provided after the expansion or contraction of the wall portion. For example, in one embodiment, the support structure includes one or more adaptations that can be inflated (or deflated) at least a portion of the support structure (eg, foldable). Filling or emptying the bag). Thereby, the foldable bag body can have a larger (smaller) capacity than the example without the adaptation part, and / or the effectively foldable bag body is stretched, Remove or reduce any folds and / or wrinkles. As shown in the embodiment shown in FIG. 2, the wall adaptation comprises an inflatable seam (38), which is located at a corner, end, surface (eg, face) of the support structure, Alternatively, it is arranged at any other position. The adaptation portion of the wall comprises in some embodiments a hinge, a telescoping joint or surface, a flexible material (eg, a flexible polymer), and the like. The adaptation part automatically expands or contracts, for example based on the volume of the fluid and / or the pressure inside the foldable bag, or the adaptation part is controlled manually by the user or an automatic control system.

  In certain embodiments of the present invention, the support structure comprises a compressible material that can be used to reduce or eliminate wrinkles in the foldable bag. As shown in the embodiment shown in FIG. 2, the compressible material (40) comprises, for example, an elastomeric material, a spring plate or other spring biasing component, or a composite material, which can be folded by the composite material. Can have a first configuration prior to expansion or contraction of the compressible component and a second configuration after expansion or contraction of the compressible component. In some embodiments, the compressible material (40) is a foam or other porous structure that has a greater amount of gas (eg, air) in the expanded state than in the contracted or compressed state. Can be accommodated.

  In one embodiment, the compressible material has a first configuration before introducing fluid into the foldable bag and has a second configuration after introducing fluid into the foldable bag. For example, when the foldable bag is filled, the pressure outside the fluid in the foldable bag is compressed, either all or part of the compressible material. This allows the foldable bag to be effectively stretched, thereby reducing or eliminating folds or creases in the wall of the foldable bag.

  Accordingly, in certain embodiments, the container of the present invention comprises a foldable bag and a reusable support structure that supports and houses the foldable bag. The container further comprises a bladder or compressible material and is located between the outer wall of the foldable bag and the inner wall of the support structure. When the bladder or compressible material is applied and expanded and / or contracted, the foldable bag body has the first configuration before the bladder or compressible material expands or contracts, and the bladder or compressible material expands. Or it comes to have a 2nd structure after shrinkage | contraction. In another embodiment, the container of the present invention comprises a foldable bag and a reusable support structure having at least one wall that is inflatable or compressible, thereby being foldable. The bag body has a first configuration before the wall portion is expanded or compressed, and has a second configuration after the wall portion is expanded or compressed.

  In some embodiments, wrinkles and / or creases in the wall of the foldable bag are removed by creating a vacuum between the outer wall of the foldable bag and the inner wall of the reusable support structure. Is done. The vacuum creates air pockets that are formed so that the folds and / or creases are removed. This allows the wall of the foldable bag to be flat against the majority or almost the entire inner wall of the reusable support structure. The exhaust is a space between the outer wall of the foldable bag and the inner wall of the reusable support structure at any suitable location along the support structure via a tube or other optimal means. And fluid flow. In some examples, the support structure has a port (not shown) that is applied to connect to the exhaust. The ports are arranged at various positions around the support structure. This can be done before, after, or during the application of vacuum, the introduction of liquid or other workpiece into the foldable bag.

  One particular method of the present invention includes positioning the foldable bag within the reusable support structure such that the reusable pointing structure contains and supports the foldable bag. Introducing the liquid into the foldable bag and changing the fluid pressure in a region between the outer wall of the foldable bag and the inner wall of the support structure. In some embodiments, the pressure change includes creating a vacuum between the outer wall of the foldable bag and the inner wall of the support structure. In another embodiment, the pressure change includes increasing or decreasing a positive pressure (eg, inflating or deflating the bladder) between the outer wall of the foldable bag and the inner wall of the support structure. .

  Certain embodiments of the present invention comprise a container having a detector that is applied to determine the presence of any liquid that leaks from a foldable bag. Leak detection is often difficult with conventional containers, particularly with containers that have a foldable bag supported by a reusable support structure. Preferably, it is desirable to detect a leak while the leak is small so that appropriate measurements can be taken before the leak increases.

  In certain embodiments, the container of the present invention has a detector configured and arranged to detect a change in electrical conduction or impedance between the fluid inside the container and the reusable support structure. If the foldable bag is not damaged and there are no leaks, no change in the electrical signal is detected. An example of such a system is the system presented in the embodiment shown in FIG. The container (72) has a conductive probe (74) that contacts the fluid (22) inside the foldable bag. For example, the probe is inserted or incorporated in the wall of the foldable bag. In one embodiment, the probe acts as a ground and is electrically isolated from the wall of the support structure (14). The measurement is performed by applying a small electric potential to the fluid contained in the foldable bag through the probe. When the foldable bag leaks, the impedance or conduction detector connected to the probe and the support structure wall will cause the conductive fluid content of the bag or the resistance between the fluid and the support structure. It is detected that the electric circuit is closed by the change of. For example, in the example shown in FIG. 3, the probe (74) is electrically connected to a detector (76) (eg, an impedance or conduction detector), which is from a foldable bag. It is configured to detect changes in electrical properties (eg, voltage, current, resistance or impedance) due to the presence of any fluid leakage. In one embodiment, the electrical signal (75) is a leaked fluid (78) (eg, a conductive material) located between the outer wall (28) of the foldable bag and the inner wall (30) of the support structure. Completed by the presence of All or some of these fluids are conductive or semiconductive. In another embodiment, the fluid (78) increases the current flow and reduces the impedance between the fluid (22) and the walls of the support structure.

  Another leak detection system is presented in the embodiment shown in FIG. The leak detection system (73) includes one or more humidity detectors (80) located between the foldable bag (18) and the inner wall (30) of the reusable support structure (14). Have As shown in FIG. 4, the humidity detector (80) is located at or near the foldable bag and / or the opening (35) of the support structure. By positioning the detector in this position, any fluid near the opening of the foldable bag or reusable support structure is detected before the fluid leaks from the system.

  The container of the present invention has one or more detectors (76) and / or (80) located at various locations in the system. The detectors (76) and (80) take measurements continuously, periodically, and / or in some instances when certain events are introduced into the container, such as liquid. The detectors (76) and / or (80) sound an alarm and send it to the control unit (34) to inform the user of the presence or absence of leaks and / or to control or remove leaks (eg, self-sealing components, etc.) ) Drive measurement. In some cases, the signal causes all or part of the system to stop.

  Detectors that determine leaks and / or humidity are known and are incorporated into the systems described herein by methods known to those skilled in the art having the art relating to the description provided herein. Examples of leak detectors include, but are not limited to, examples described in US Pat. Nos. 6,229,229, 6,873,263, and 7,292,155. Are incorporated herein. In addition, any suitable changes such as physical, electrical, optical properties, etc. are measured and used to indicate the presence of leaks and / or humidity in the containers described herein. Examples of parameters monitored to indicate leakage and / or humidity include, but are not limited to, color, absorbance, turbidity, opacity, conductivity, impedance, resistance, pressure, capacity, and temperature.

    Various aspects of the present invention are directed to a container comprising a container such as a foldable bag. As used herein, “flexible container”, “flexible bag”, and “foldable bag” mean that the container or bag is exposed to internal pressure (during operation). To maintain its shape and / or structural integrity without the benefit of the individual support structure (depending on the weight and / or hydrostatic pressure of the contained liquid and / or gas expected) It indicates that you cannot. The foldable bag is essentially made of a flexible material such as many plastics, or is usually made of what is considered a rigid material (eg glass or a specific metal), but is expected during operation. When exposed to internal pressure, the container may have an overall shape and / or structural integrity due to its thickness and / or physical properties without the benefit of individual support structures. It cannot be maintained. In another embodiment, the foldable bag comprises a combination of a flexible material and a rigid material, such as a support, such as a connection, port, mixing system and / or defoaming device. With rigid components.

  The container (eg, a foldable bag) has an appropriate size for containing the liquid. For example, containers include 0.1-5 liter, 1-40 liter, 40-100 liter, 100-200 liter, 200-300 liter, 300-500 liter, 500-750 liter, 750-1000 liter, 1000- There is a capacity of 2000 liters, 2000-5000 liters, or 5000-10000 liters. The same is possible even with a capacity of 10,000 liters or more.

  In some embodiments, the container (eg, a foldable bag) is formed from a suitable flexible material. The flexible material is one of USP Class VI certifications, for example, silicon, polycarbonate, polyethylene, and polypropylene. Non-flexible examples are polyethylene (eg linear low density polyethylene and very low density polyethylene), polypropylene, polyvinyl chloride, polyvinyl dichloride, polyvinylidene chloride, ethylene vinyl acetate, polycarbonate, polymethacrylate , Polymers such as polyvinyl alcohol, nylon, silicone rubber, other synthetic rubbers, and / or plastics. As described above, a portion of the flexible container comprises a rigid material such as a rigid polymer (eg, high density polyethylene), metal, and / or glass (eg, in the area that supports the instrument). In other embodiments, the container is a substantially rigid material. Optionally, all or a portion of the container is optically transparent so that the contents inside the container can be viewed. The material or combination thereof used to form the container is flexible, puncture, tensile, liquid and gas permeable, opaque, and blow molded, injection molded, or rotational molded (eg, seamless folding) Selected based on one or more properties, such as adaptability to a particular process (such as to form a possible bag). The container is disposable in some examples.

  The container (eg, foldable bag) has an appropriate thickness to contain the liquid and is designed to be resistant to puncture during operation or handling. For example, the container wall is 250 mils or less (1 mil is 25.4 micrometers), 200 mils or less, 100 mils or less, 70 mils or less (1 mil is 25.4 micrometers), 50 mils or less, 25 mils or less. , 15 mils or less, or 10 mils or less overall thickness. In some embodiments, the container may have more than one material layer, and the more than one material layer may be either laminated together or attached to each other to give the container certain properties. . For example, a certain layer is formed of a material that hardly penetrates oxygen. Another layer is formed of a material that provides strength to the container. Additional layers may be included to provide chemical resistance to the fluid contained within the container. One or more layers of the container have a thermally conductive material to facilitate heat transfer from the interior of the container to the environment outside the container.

  Containers, liners, or other articles described herein (eg, bladders) may be formed from any suitable combination of layers, and the invention is not limited in this respect. The article (eg, foldable bag) may have, for example, one layer, two or more layers, three or more layers, or five or more layers of material. Each layer may have a thickness of 200 mils or less, 100 mils or less, 50 mils or less, 25 mils or less, 15 mils or less, or 10 mils or less, 5 mils or less, or 3 mils or less, or combinations thereof.

  In some embodiments, the container or liner is seamless. The container is, for example, a seamless foldable bag or a seamless rigid (or semi-rigid) container. Many existing foldable pouches are constructed from two sheets of plastic material joined by thermal or chemical bonding to form a container with two longitudinal seams. The opening end of the sheet is sealed using a known technique, and the opening is formed through the wall of the container. A foldable bag having a seam may form a tear near the seam during use. In the vicinity of the seam, the fluid or reagent contained therein is not completely mixed. For example, in embodiments using foldable bags that perform chemical, biochemical, and / or biological reactions, unmixed reagents can reduce the production of the desired product. If there is a seam in the foldable bag, the foldable bag cannot conform to the shape of the reusable support structure that supports the bag. However, by using a seamless foldable bag that joins two or more flexible walls of the bag, mixing and fitting problems are avoided or reduced. The seamless foldable bag can be used with a bladder or other inventive wrinkle removal system.

  In certain embodiments, the seamless foldable bag is manufactured to be particularly compatible with a particular reusable support structure having a unique shape and structure. A foldable bag that fits almost perfectly can be used, for example, as part of a bioreactor system, or a biochemical or chemical reaction system. In some embodiments, seamless rigid or semi-rigid containers are equally effective. A further seamless container description is filed on June 15, 2007, entitled “Gas Delivery Configurations, Foam Control Systems, and Bag Molding Methods and Articles for Collapsible Bag Vessels and Bioreactors”. No. 11 / 818,901, incorporated herein by reference.

  In certain embodiments, a foldable bag without a seam joining two or more flexible walls of the foldable bag (ie, a seamless foldable bag) is Have a specific capacity to contain the liquid. The seamless foldable bag is for example at least 0.1 liter, at least 1 liter, at least 10 liter, at least 20 liter, at least 40 liter, at least 50 liter, at least 70 liter, at least 100 liter, at least 150 liter, at least It has a volume of 200 liters, at least 300 liters, at least 500 liters, at least 700 liters, or at least 1000 liters. The seamless foldable bag has a capacity of 1000 liters or more (for example, 1000-5000 liters or 5000-10000 liters) as required. In some embodiments, the foldable bag may be disposed within a reusable support structure that surrounds and houses a flexible container.

  In some embodiments, the seamless foldable bag is formed in one step. In the process, the bag liner (eg, the flexible wall of the bag) is a component of the agitator / mixer system (eg, shaft and / or support base), port, bladder, etc. As with the above components, it is cast from a continuous supply of polymer precursor material. Casting may be performed without sealing (eg, welding). Such seamless bags allow the liquid or other product inside to contact a generally flat surface, for example, there are no wrinkles, creases, tears, etc. on the surface. . In addition, in some cases, when a foldable bag is attached and filled with liquid or product, the foldable bag may be complementarily fitted into the support structure. A seamless foldable bag has a chemistry that minimizes side reactions, for example, on an essentially uniform polymer surface. A method of forming a seamless foldable bag having more than one polymer precursor material is equally feasible.

    Seamless foldable bags can be developed by various methods. In some embodiments, the seamless foldable bag is formed by introducing liquid plastic into the mold. The mold is pre-fitted into components such as ports, connections, supports, and rigid portions (eg, shafts and / or foundations) configured to support the mixing system. The rigid portion is then surrounded, obscured and / or embedded by liquid plastic. The component is a single rigid element, for example, a rigid element that can substantially maintain shape and / or structural integrity during use. Any suitable number of components (eg, at least 1, 2, 5, 10, 15, etc.) can be integrated with a container (eg, a foldable bag) using the methods described herein. The mold is designed to form a foldable bag having the shape and capacity of the mold, the mold having approximately the same shape, capacity, and / or configuration as the reusable support structure.

  In some embodiments, the container is formed using an embedded component / linear molding (ECM) technique. In one such technique, rigid elements such as tube ports, agitation bases or pre-formed components are initially placed in the mold. The polymer or polymer precursor used to form the container (e.g., a seamless foldable bag) is introduced (e.g., in a dissolved state) via the polymer making techniques described below. The component or part of the component is partially dissolved by the polymer precursor, allowing the component to continuously form an element that adheres to the container. That is, the component is a single, complete piece of material that is seamless by joining (dissolving) one or more walls of a container (eg, a flexible wall of a foldable bag). Is formed. In other examples, the component is comprised of thinner portions that can be dissolved by the polymer precursor (eg, in a dissolved state) during container formation.

  Accordingly, a method for joining together a container wall and at least a portion of a functional component during formation of the container in a mold comprises melting the portion of the functional component during the joining step. . The wall of the container has a first thickness, and some of the functional components have a second thickness, which is, for example, compared to the greater of the first and second thicknesses, Less than 100%, 80%, 60%, 40%, 20%, 10%, or 5% of each other.

  In another embodiment, the container is formed using a continuous component / linear molding (CCM) technique. In one such technique, the foldable bag or other container is freshly cast from a polymer or polymer precursor stream. The polymer or polymer precursor used to form the foldable bag is introduced by a polymer making technique as described below. The components can be introduced into flexible containers using mandrels, barriers, baffles, etc., so that functional components of the liquid containment system such as tube ports and agitation bases can be used as one continuous polymer, for example. The polymer precursor is induced to form. After fixing or removing the polymer or polymer precursor, the mandrels, barriers, etc. are recovered.

  Combinations of these techniques and other techniques may be used in other embodiments as well. For example, different polymer formulations (low molecular weight polyethylene, high molecular weight polyethylene, polypropylene, silicone, polycarbonate, polymethacrylate, combinations thereof or precursors thereof) form more rigid structures such as tubes or sensor holes, stirring systems, etc. Can be simultaneously injected into the mold area designed to do so.

  In certain embodiments, a method comprises introducing a first polymer or polymer precursor into a mold, the mold having a capacity of at least 10 milliliters, 1 liter, 40 liters, 100 liters, or 1000 liters. A shape configured to mold a possible bag. The mold further comprises a shape that is configured to mold one component of the mixing system and / or antifoam system. The component may be a shaft and / or a base configured to support the impeller. The method further comprises introducing a second polymer or polymer precursor into the mold to mold the components of the mixing system. Thus, the components of the mixing system and the foldable bag are joined without welding using the methods described herein. In some embodiments, the first and second polymers or polymer precursors are introduced simultaneously. The first and second polymers or polymer precursors may be different if they are the same in some embodiments. The method as described above can be used to form a substrate for, for example, a mixing / stirring system, an antifoam system, or other component. In another embodiment, many polymers can be introduced into a mold (eg, simultaneously) to form a container having multiple components.

    As described above, introducing a polymer or polymer precursor into a mold forms a container such as a foldable bag (eg, a seamless foldable bag) using any suitable technique. . For example, in one embodiment, the foldable bag is manufactured via a rotational molding process. For example, during rotational molding, the mold is rotated as the polymer or polymer precursor is introduced so that the mold surface is entirely coated with plastic. In other embodiments, the foldable bag is made via an injection molding process. For example, the polymer precursor is delivered to the space between the outer mold and the inner mold. In yet another embodiment, the foldable bag can be manufactured via a blow molding process. The polymer diffuses to the mold surface, for example by depositing via gas injection. In yet another embodiment, a combination of the above techniques and other techniques may be used. Those skilled in the art are familiar with polymer processing techniques such as rotational molding, injection molding, and / or blow molding, and can be used to prepare suitable foldable bags or other containers. Such techniques are used to form the bladder or other components of the present invention.

  Although many embodiments describe a seamless foldable bag, there are also examples in which a foldable bag or other container having a seam between the flexible walls of the container is made. is there. In other embodiments, a collapsible bag or other container can be made having a seam between the container components and one or more flexible walls. Joining two or more walls, or joining a wall and a part of a container may be welded (eg, heat and long wave welding), bolted, adhesive, use of fasteners, or other attachments Made by technology. It is also possible to produce a combination of joints with joints and joints without joints.

  Although many of the methods described refer to the production of a foldable bag, this method also applies to rigid containers or container components. The methods described herein used to form a container, such as a foldable bag (a seamed bag or a seamless bag), are applied to include components of various sizes. For example, the flexible wall of the foldable bag has a thickness of, for example, 100 mils or less, 70 mils or less, 50 mils or less, 25 mils or less, 15 mils or less, or 10 mils or less, The components incorporated into the for example greater than 0.5 millimeters, greater than 1 centimeter, greater than 1.5 centimeters, greater than 2 centimeters, greater than 5 centimeters, or greater than 10 centimeters thickness or height Have The size (eg, height, length, width, or diameter) of at least one cutting surface of the component is, for example, at least greater than 0.5 millimeters, greater than 1 centimeter, greater than 1.5 centimeters It may be greater than 2 centimeters, greater than 5 centimeters, greater than 10 centimeters, greater than 15 centimeters, greater than 20 centimeters, greater than 25 centimeters, or greater than 30 centimeters. In certain embodiments, the thickness of the collapsible bag (or other container) and the thickness of some of the components joined (dissolved) with the collapsible bag are compared to each other (the thicker one). And within 30%, 20%, 15%, 10%, or 5%. As described in detail below, when the thicknesses match as described above, joining of materials (melting, welding, etc.) is promoted.

  The components that integrate with the foldable bag or other container are formed of any suitable material, which may be the same as or different from the material of the bag or container. For example, in some embodiments, the container is formed of a first polymer and the component is formed of a second polymer that is different from the first polymer (such as a different composition, molecular weight, and / or chemical structure). Those skilled in the art are familiar with material processing techniques and can select appropriate materials and combinations thereof using the above techniques of the methods described herein.

  In some embodiments, a component that is integrated with a foldable bag or other container using the method described herein is formed of more than one material, which is certified as USP Class VI. For example, silicon, polycarbonate, polyethylene, and polypropylene, or alternatively, are formed from one or more non-certified materials. Non-limiting examples of materials that can be used to form the component include polymers, such as polyethylene (low density polyethylene and high density polyethylene), polypropylene, polyvinyl chloride, polyvinyl dichloride, polyvinylidene chloride. Chloride, ethylene vinyl acetate, polyvinyl alcohol, polycarbonate, polymethacrylate, nylon, silicone rubber, other synthetic rubbers, and / or plastics, and combinations thereof. It is also possible to form all or part of the components using ceramic, metal, and magnetic materials. In some embodiments, all or some of the components are rigid, while in other embodiments, all or some of the components are flexible. The material used to form the component may be, for example, affinity with a container, flexibility, tensile strength, hardness, liquid and gas permeability, puncture force, and blow molding, injection molding, or rotational molding. It is selected based on one or more characteristics such as adaptability to a particular process and / or component function.

  In certain embodiments, particularly those embodiments that comprise fluid manipulation or perform chemical, biochemical, and / or biological reactions in a container (foldable bag), the container is substantially closed. Yes. For example, in certain embodiments, the container is substantially isolated from the external environment, except for one or more inflow and / or outflow ports that add content to and / or remove content from the container. ing. When a foldable bag is used, the foldable bag substantially contracts before being filled with liquid and begins to expand as it is filled with liquid. In another embodiment, the present invention is applicable to an open container system.

  In some cases, fluid may be introduced and / or removed from the container via the inlet and / or outlet ports. The vessel may be part of a reactor system that performs biological, biochemical, or chemical reactions. A container (foldable bag) that is part of a container as described above has any suitable number of inlet and outlet ports. In some cases, a pump, such as a disposable pump, is used to introduce gas or other fluid into the container, for example via an inflow port, and / or gas or other fluid from the container, for example, via an exhaust port Remove. For example, a magnetically coupled pump is obtained by placing the top of a disposable magnetic impeller into a housing, which has an inlet port and an outlet port for pumping fluid. When flexible vanes are used, pumping is facilitated or pressure is removed. In another embodiment, fluid, gas and / or powder pumping continuously pumps the polymer tube of the electrical machine, for example, effectively “peristating” without the top of the pump and / or the pump chamber. Is achieved. The optional use of a one-way valve in the tube helps to prevent backflow.

  In some embodiments, further comprising a support structure, for example, the support structure (14) shown in FIG. The support structure may have a suitable shape and surround and / or contain the container. In some cases, the support structure is reusable. The support structure is formed of a substantially rigid material. Non-constrained embodiments of materials that can be used to form a reusable support structure include stainless steel, aluminum, glass, resin-impregnated fiberglass or carbon fiber, polymers (eg, high density polyethylene, Polyacrylate, polycarbonate, polystyrene, nylon or other polyamides, polyesters, phenolic polymers), and combinations thereof. The material is compensated for its use in the environment in which it is used. For example, a material that does not shed is used in an environment that requires the generation of minimum fine particles.

  In some embodiments, the reusable support structure is designed to have a height and diameter similar to a standard stainless steel bioreactor (or other standard reactor or vessel). Its structure can be reduced to a desktop reactor system with a small capacity. Thus, the reusable support structure has the appropriate capacity to perform the desired chemical, biochemical and / or biological reaction. In many embodiments, the reusable support structure has approximately the same capacity as the container. For example, a single reusable support structure is used to support and contain a single container having approximately the same capacity. However, in other cases, the reusable support structure is used to accommodate more than one container. Reusable support structures are, for example, 0.1-5 liters, 1-100 liters, 100-200 liters, 200-300 liters, 300-500 liters, 500-750 liters, 750-1000 liters, 1000-2000. Have a capacity of liters, 2000-5000 liters, or 5000-10000 liters. A volume greater than 10,000 liters is also possible.

  However, in other embodiments, the container does not comprise a separate container (eg, a foldable bag) and a support structure, but instead comprises a free-standing disposable container. The container may be, for example, a plastic container, optionally with a stirring system or a removable stirring system integrally attached to the container. The agitation system is disposable with the container. In certain embodiments, such a system includes an impeller welded or secured to a polymer container. Accordingly, the container configurations described herein for containers and support structures (eg, seamless containers, spreading systems, defoamers, bladders, scouring systems, leak detection systems, heat transfer systems, electromagnetic stirring systems, etc.) It should be noted that and the characteristics are also applicable to free-standing disposable containers.

In some embodiments, a container, such as the container (18) shown in FIG. 5, may include various sensors and / or for controlling and / or monitoring one or more processing parameters inside the disposable container. Provide a probe. The processing parameters include, for example, temperature, pressure, pH, dissolved oxygen (DO), dissolved carbon dioxide (DCO ₂ ), mixing ratio, and gas flow rate. The sensor may be an optical sensor in other cases.

In some embodiments, process control is performed in a manner that does not damage the sterilization barrier secured by the container (eg, a foldable bag). For example, the gas flow is monitored and / or controlled by a rotameter or mass flow meter upstream of the incoming air filter. In other embodiments, the disposable optical probe is designed to use a “part” of a material having an indicator dye. The indicator dye can be mounted on the interior surface of the container and is shown along the container wall through a window in the reusable support structure. For example, each of dissolved oxygen, pH, and / or CO ₂ is monitored and controlled by optical patches and optical sensors. The optical patch and the optical sensor are mounted on a biocompatible polymer capable of irradiating gamma rays, for example, and the polymer can be fixed, embedded, or attached to the surface of the container. .

  As shown in the embodiment illustrated in FIG. 5 as a particular embodiment of the sensor, the container (18) is operatively connected to the temperature controller (106). The temperature control device is, for example, a heat exchanger, a closed loop water jacket, an electric blanket, or a Peltier heater or cooler. Other heaters for heating the liquid inside the container are known to those skilled in the art and can be used in combination with the container (18). The heater further comprises a thermocouple and / or a resistance temperature detector (RTD) that senses the temperature of the contents in the container. The thermocouple is operatively connected to the temperature controller and controls the temperature of the contents in the container. Optionally, details are given below, but heat conductive material is used on the surface of the container, for example, heat is transferred to the surface to overcome the insulating effect of the material used to form the container part. To do.

  Cooling can be done with a closed-loop water jacket cooling system, a cooling system attached to the reactor, or a cover / jacket on a reusable support structure (eg, an electric blanket or a packaged dual unit that performs heating and cooling) This is done by standard heat exchange through a component that is configured for both cooling and cooling, but may be separated from the cooling jacket. For example, cooling is provided by a Peltier cooler. For example, a Peltier cooler is applied to the exhaust pipe to liquefy the gas in the exhaust gas and prevent the exhaust filter from getting wet.

  In certain embodiments, the reactor system comprises gas cooling that cools the headspace and / or the outlet exhaust. For example, jacket cooling, electrical and / or chemical cooling, or heat conversion is performed in the outlet air pipe and / or in the upper space of the container. As a result of the cooling, more condensate is returned to the container, which reduces clogging and deposits on the outlet exhaust filter. In some embodiments, driving the pre-cooled gas into the upper space reduces the dew point and / or reduces the burden of water vapor on the outlet air gas.

  Although the methods described above are used to heat or cool the contents inside the container, the heat exchange rate using such methods is not as desirable as in certain examples. In some examples, the heat exchange rate is limited to below a desired level or below an optimum level, depending on the material used to form the container. For example, systems for the use of stirring containers and / or containers used for biological, chemical and / or pharmaceutical reactions, particularly disposable liners in the form of foldable bags, are generally polyethylene, poly, It is made of a material having low thermal conductivity such as tetrafluoroethylene (PTFE) or ethylene vinyl acetate. The chemical / biochemical / physical processes performed in the container generate heat, and the heat transfer is low, for example if it is removed for the purpose of maintaining a suitable growth environment or controlling the reaction By using a material, heat removal is suppressed or slowed to an undesirable degree from the container. For example, if not controlled, a highly exothermic chemical reaction can produce uncontrolled heat generation, creating excessive pressure and / or excessive temperature beyond the safe state, which is dangerous. Further, if the biological reaction is fast and active, it is desirable to remove heat to maintain the culture within the operating temperature range of optimal conditions for cell growth and / or product production. In a particular embodiment for the recombinant organism, product production is controlled by a heat sensitive promoter activated by a sudden temperature change. In these and other examples, the rate of heat removal from the container is important in controlling the amount of product produced. Rapid cooling of the heat is required to cool the culture taken after the product production process.

  As the container size increases, the ratio of the container surface area to the container liquid volume decreases. This reduces the amount of effective cooling capacity of the container and makes it more difficult to control the temperature in large containers. To address this problem, the containers described herein, such as foldable bags or rigid containers, have one or more thermally conductive materials used therein. In some embodiments, a thermally conductive material incorporated into at least a portion of the container wall. Additionally or alternatively, the thermally conductive material lines the inside of the container wall. For example, the thermally conductive material and the container wall form a laminated structure. In containers that include one or more bladders, the thermally conductive material is used to form all or part of the bladder, facilitating heat transport. Other configurations are also possible, as detailed below.

  Preferably, the container (and / or bladder) is used by a thermally conductive material to conduct heat from the inside of the container to the outside environment of the container, or to conduct heat from the outside environment of the container to the container. It is done. In embodiments of a support structure in which the container is reusable (eg, a stainless steel tank), heat transfer from or to the container is facilitated by the support structure. For example, heat from the contents inside the container is dissipated to the thermally conductive support structure via the thermally conductive material of the container. The support structure is optionally cooled using a suitable cooling system to increase the heat dissipation rate.

  In some embodiments, the thermally conductive material is in the form of a plurality of particles. The particles are in the form of nanoparticles, microparticles, powders and the like. The thermally conductive material is in the form of nanotubes, nanowires, nanorods, fibers, meshes or other elements. The thermally conductive material is incorporated into the material used to form the container, for example, whereby all or part of each element is wrapped or surrounded by the material used to form the container .

  In some embodiments, the incorporated thermally conductive material is substantially uniformly distributed in the main material used to form the container. In this context, “substantially uniformly distributed” means that when checking the cross-sections of any of the above-mentioned materials, if the material has an average configuration of any number of cross-sections, for example, approximately grain. Alternatively, investigations regarding the selection of the material size of the atom have revealed that the heat conductive material is basically uniformly distributed in the main part. The number of optional cross-sectional portions used to determine the average is, for example, at least 3, at least 5, at least 10, at least 20. In some examples, the number of arbitrary cross-sectional portions is selected such that adding more than one cross-sectional portion only changes the average by 5%. In other embodiments, the average changes by only 1%. Micrographs, scanning electron micrographs, or other similar microscale or nanoscale investigation processes have revealed that the dispersion is essentially uniform. The “main part” of the material includes at least 50% of the cross-sectional dimension of the material. In certain embodiments, the major portion is at least 60%, 70%, 80%, 90% or 95% of the cross-sectional dimension of the material. Those skilled in the art will clearly understand the meaning of these terms from this description.

  In other embodiments, the thermally conductive material is not uniformly distributed throughout the major portion of the material that forms the container (and / or bladder). For example, the particle gradient is formed across the container cross section. In another example, the thermally conductive material forms a film or layer adjacent to the layer of material used to form the container. In such an embodiment, the film or layer of thermally conductive material is uniformly positioned across the width or height of the container. For example, the heat conductive material is configured such that a part of the container includes the heat conductive material, and the adjacent portion of the container includes the heat conductive material. Alternatively, the thermally conductive material may be presented as a strip, wire, or have other configurations so that a portion of the container comprises a thermally conductive material, and the adjacent portion of the container may be thermally conductive Does not have a sex material.

  The thermally conductive material is encapsulated between two polymer sheets in certain embodiments. Alternative thermally conductive material layers and polymer layers are also possible. Alternatively, in some embodiments, the outer surface of the container has a layer of thermally conductive material, while the inner surface of the container does not have a thermally conductive material. This arrangement allows heat to be conducted from the container contents (or to the container contents) if any reactivity between the container contents and the thermally conductive material is not avoided or limited. It is possible to conduct heat). For example, silver has a high thermal conductivity and is used as a thermal conductive material, however, it is known to have an antibacterial effect. By placing silver on the outer surface of the container (or incorporated between two polymer layers) but not in contact with any contents inside the container. The heat transfer of the container is increased without adversely affecting the contents inside the container.

  The thermally conductive material has any suitable size or dimension. By selecting the size of the thermally conductive element, for example, a specific distribution (eg, a gradient or a substantially uniform distribution) is achieved in the main members used to form the container, leading to the container portion. By the way, the protrusion of the element is prevented, or it has a specific surface area or a ratio of the thermally conductive material to the container capacity. In some examples, the thermally conductive material is less than 500 microns, less than 250 microns, less than 100 microns, less than 50 microns, less than 10 microns, less than 1 micron, less than 100 nanometers, less than 50 nanometers, less than 25 nanometers, Less than 10 nanometers, less than 5 nanometers, or less than 1 nanometer.

  Any suitable thermally conductive material is used as the thermally conductive material. Thermally conductive materials are used to form containers, thermal conductivity, particle size, magnetic properties, compatibility with specific processing techniques (eg ability to be deposited by specific deposition techniques) Compatibility with the main components to be used, compatibility with any material contained in the container (eg, cells, nutrients, gas, etc.), any treatment or pre-treatment (eg disinfection) that is relevant to the execution of reactions inside the container ) Is selected based on factors such as compatibility with other factors as well.

  In one particular set of embodiments, the thermally conductive material comprises a metal. In one embodiment, the thermally conductive material is a metal. In other examples, the thermally conductive material comprises a semiconductor. Suitable uses as a thermally conductive material include, for example, elements from Group 1 to Group 17. For example, elements of Group 2 to Group 14 or elements of Group 2, Group 10, Group 11, Group 12, Group 13, Group 14 and Group 15 are particularly preferable. Potentially suitable elements from group 2 of the periodic table include beryllium, magnesium, calcium, strontium and barium. Potentially suitable elements from group 10 include, for example, nickel, palladium or platinum. Potentially suitable elements from group 11 include, for example, copper, silver or gold. Potentially suitable elements from group 12 include, for example, zinc, cadmium or mercury. Suitable elements from group 13 include, for example, boron, aluminum, gallium, indium or thallium. Suitable elements from group 14 include, for example, carbon, silicon, germanium, tin or lead. Suitable elements from group 15 include, for example, nitrogen, phosphorus or bismuth. In some examples, the thermally conductive material is Al, Cu, Fe, or Sn.

  It should be understood that if the thermally conductive material includes a metal, one or more metals are used. Similarly, if the thermally conductive material comprises a semiconductor, one or more semiconductor materials are used. Therefore, metal and semiconductor are mixed. That is, the thermally conductive material is a single metal, a single semiconductor, or one or more mixed metals or one or more semiconductors (eg, alloys). Without limitation, suitable metals are indicated above, and appropriate components of the semiconductor are indicated above. It is well known to those skilled in the art that semiconductors are formed from one or more of the elements described above, or other elements.

  In certain embodiments, the thermally conductive material is non-metallic. For example, the thermally conductive material includes carbon. The thermally conductive material is, for example, in the form of a conductive polymer. Without limitation, conductive polymers include polypyrrole, polyaniline, polyphenylene, polythiophene, and polyacetylene.

  One skilled in the art can readily select a suitable metal, semiconductor and / or non-metal from the materials described above or other materials known in the art. In addition, from the description herein, one of ordinary skill in the art can select materials without undue burden or experimentation for proper use with the embodiments shown herein.

  Optionally, the thermally conductive material is covered or treated, eg chemically and / or physically, to increase certain chemical and / or physical properties of the material. For example, the surface of a thermally conductive material is treated with a surfactant, oxide or any other suitable material, so that it is more hydrophilic / hydrophobic, less reactive, has a specific pH, etc. . These and other processes allow the thermally conductive material to be compatible with the material used to form the container and / or a specific processing technique. For example, it is possible to adhere the material used to form the container to a desired degree by the treatment of the heat conductive material, it can be dissolved by a specific solvent, or a specific dispersibility It is possible to achieve this level.

  As described herein, in some embodiments, a container (eg, a rigid container or a foldable bag) and / or a bladder comprises a polymer material (eg, a primary member). The polymer material as described herein may have appropriate physical / mechanical properties, for example, by adjusting the amount of constituents of the polymer blend or adjusting the degree of crosslinking. Selected or formulated. For example, those skilled in the art will understand the thermal conductivity of polymers, compatibility with specific processing techniques (eg, the ability to be deposited by specific deposition techniques), compatibility with thermally conductive materials, any material contained in a container. Containers based on factors such as compatibility with (e.g., cells, nutrients, gas, etc.) and compatibility with any treatment or pre-treatment (e.g. disinfection) that has relevance to performing reactions inside the container It is possible to select a suitable polymer to be used within the.

  Containers and / or bladders with thermally conductive materials are formed by any suitable method. In certain embodiments, the thermally conductive material is physically mixed with the material used to form the container (eg, the primary material) and optionally with reactants, solvents, gases, and surfactants. The thermally conductive material can be injected into the main member, for example. The resulting mixture is in the form of a solution, emulsion or suspension.

  The mixture can be made into a container (or bladder), or a container (or bladder) precursor, by methods such as blow molding, injection molding, rotational molding and extrusion, such as those described above and / or methods known to those skilled in the art. Molded. For example, in one embodiment, the thermally conductive material and the material used to form the container can be simultaneously extruded at a sufficiently high temperature that the material is easy to mold. The material is molded into a container precursor such as a container or sheet. Containers that include a thermally conductive material have no seams or have seams that are welded to form the containers. In some examples, a more controlled welding is achieved by heating the thermally conductive material with an energy source such as a microwave source or a laser.

  In some embodiments, the thermally conductive material is applied to all or a portion of the material used to form the container or bladder, the application comprising a physical deposition method, Chemical vapor deposition methods, plasma enhanced chemical vapor deposition techniques, thermal evaporation (eg resistance heating, induction heating, radiation heating and electron beam heating) sputtering (eg diode sputtering, DC magnetron) Sputtering, RF sputtering, RF magnetron sputtering, pulse sputtering, dual magnetron sputtering, AC sputtering, FM sputtering and reactive sputtering) jet vapor deposition, electrophoretic deposition, magnetic deposition (magnetophorectic deposition), rotation Coating, dip coating, spray , Brushing, screen printing, ink jet printing, toner printing, sintering, laser ablation, electroplating, ion plating, cathodic arc, and combinations thereof. Such a method is performed in a vacuum or an inert atmosphere.

  In particular, in embodiments where the material is incorporated into the main material, the thermally conductive material is aligned using magnetic interaction, electrostatic interaction, or the like.

  The container (or bladder or other article) is provided with an appropriate amount of thermally conductive material. For example, based on the total weight of the container, the container may be, for example, at least 0.1 wt%, at least 1 wt%, at least 2 wt%, at least 5 wt%, at least 10 wt%, at least 15 wt%, at least 20 wt%, at least 30 wt% of the thermally conductive material. %, At least 50 wt%. In some examples, these percentages are based on the total weight of the flexible portion (eg, wall).

The amount and type of thermally conductive material, the material used to form the container, the arrangement of the thermally conductive material relative to the material used to form the container, the thickness of the container, the specific overall that the container is thermally conductive Selected to achieve the level. The overall thermal conductivity of the container is, for example, at least 0.1 Watts-m ⁻¹ -K ⁻¹ , at least 0.2 Watts-m ⁻¹ -K ⁻¹ , at least 0.5 Watts-m ⁻¹ -K ⁻¹ , At least ¹ Watts-m ^-1 -K ^-1 , at least 2 Watts-m ^-1 -K ^-1 , at least 3 Watts-m ^-1 -K ^-1 , at least 5 Watts-m ^-1 -K ^-1 , at least 10 Watts-m ^-1 -K ^-1 , at least 15 Watts-m ^-1 -K ^-1 . In some examples, the thermal conductivity of a container that includes a thermally conductive material is at least 1.5 times, at least twice, at least twice that of a container that does not have thermal conductivity (all other factors are the same). 5 times, at least 10 times, or at least 50 times larger. Thermal conductivity is measured by those skilled in the art by determining the amount of heat transferred over a period of time via the thickness of the container perpendicular to the container surface. The amount of heat transferred is due to the difference in temperature under steady state, and thermal conductivity is measured by those skilled in the art when the heat transfer depends only on the temperature gradient.

  In addition to the advantage of increasing thermal conductivity using containers and / or bladders with thermally conductive materials, such articles also have increased sensing capabilities. For example, containers are used to determine temperature, conductivity, impedance as well as electrostatic charge dissipation and control. In some embodiments, it is used to detect any leakage of material from the inside to the outside of the container. Such measurements are made, for example, by determining changes in the thermal and / or electrical conductivity of one or more container parts.

  Referring to FIG. 5, in some cases, a sensor and / or probe (eg, probe 106) is connected to the sensor's electronic module (132), which outputs the terminal board (130) and / or relay box (128). Sent to. The result of the sensor operation is input to a control system (115, for example, a computer) executed by a computer. The control system calculates and controls various parameters (temperature and weight / capacity measurements) and displays and controls user interaction. The control system as described above comprises an electrical, mechanical and / or pneumatic system so that heat, air delivered to the disposable container in response to the need for stabilization or control of environmental parameters of the process operation And / or liquid is controlled or heat, air, and / or liquid is recovered from the disposable container. It should be appreciated that the control system performs other functions and that the control system is not limited to having any particular function or set of functions.

  More than one control system can be implemented in many ways. The approach uses dedicated hardware and / or firmware, or a processor programmed to perform the functions listed above or any suitable combination of the foregoing using microcode or software. There is something to do. The control system controls one or more operations of a single reactor of biological, biochemical or chemical reactions, or more than one operation of multiple (separate or interconnected) reactors.

  Each of the described systems (eg, in connection with FIG. 5), and their components, include software (eg, C, C #, C ++, Java, or combinations thereof) hardware (eg, 1 (Or more application-specific integrated circuits), firmware (eg, electrically programmed memory), or any combination thereof may be used to implement.

  Various embodiments described herein are implemented on one or more computer systems. These computer systems include, for example, Intel's PENTIUM®-type and XScale-type processors, Motorola's Power PC, Motorola's DragonBall, IBM's HPC, Sun's UltraSPARC, Hewlett-Packard's PA-RISC processor, Advanced Micro A general purpose computer based on various processors available in Devices (AMD) or any other type of processor. It should be appreciated that one or more of any type of computer system can be used to implement various embodiments of the invention. Computer systems include specially programmed, special purpose hardware such as application specific integrated circuits (ASICs). Various components may be implemented in software, hardware, or firmware, or any combination thereof. Further, the methods, acts, systems, system elements and components described above may be implemented as part of the described computer system or as independent components.

  In certain embodiments, the control system operably connected to the container described herein is portable. The control system includes, for example, all or many of the controls and functions necessary to perform fluid operations (eg, mixing and reaction) within the control system. The control system includes one support and a caster that facilitates transport of the container. A portable control system such as the one described above is programmed with programmed commands, transported as needed (optionally with the container) and attached to the container, allowing fluid operation in a shorter time than conventional fluid operation control systems. It is possible to be ready to do (eg, less than 1 week, less than 3 days, less than 1 day, less than 12 hours, less than 6 hours, less than 3 hours, or less than 1 hour).

  The container may in some embodiments be connected to a source of one or more gases, such as air, oxygen, carbon dioxide, nitrogen, ammonia, or a mixture. Gas is compressed or pumped in. The use of the gas provides growth conditions and / or reaction conditions suitable for the production of the product inside the container. By using gas, the gas is sprinkled on the contents inside the container, for example for mixing or other purposes. For example, in certain embodiments using a sparger, the bubble size and distribution can be controlled when the gas flow at the inlet port passes through a highly permeable surface prior to being applied to the container. . Furthermore, the dispersed surface may be used as a single cell separation device by alternately applying pressure and reduced pressure on the outer surface of the porous surface, or by any other suitable method.

  As a specific embodiment, FIG. 5 shows the sources of gas (118) and (124). The gas at the inlet port optionally passes through a filter (120) and / or a flow meter and / or valve (122). The gas is controlled by the control system (115) before entering the container. Valve (122) is a pneumatic actuator (compressed air and / or carbon dioxide or other gas (124)) and is controlled by electromagnetic valve (126). These solenoid valves are controlled by a relay (128) connected to a terminal board (130), which is connected to a control system (115). The terminal board includes, for example, a PCI terminal board, a USB / parallel, or a fire port terminal board of a connection portion. In other embodiments, flush closure valves are used for additional ports, intake valves and sampling valves. An advanced tubular pinch valve that accurately measures flow may be used. In some cases, the valve is a flush closure valve (eg, for an inflow port, an exhaust port, a sampling port, etc.). The incoming gas is connected to any suitable inlet of the vessel. In some embodiments, the incoming gas is connected to one or more spargers, which can be independently controlled as described in detail below.

  As shown in the specific embodiment of FIG. 5, the container and support structure shown in FIG. 1 are operatively connected with various components as part of the overall bioreactor system (100). Therefore, the container and / or the support structure is not only connected to a pipe supplying a reagent such as a liquid medium or gas, but also to a plurality of functional components such as a filter, a sensor, and a mixer. A connection fitting is provided. Containers and fittings are sterilized before use to provide a “sterilization membrane” and protect the contents inside the container from airborne contaminants. In some embodiments, the contents inside the container do not contact the reusable support structure. Thus, while the container and / or fittings connected to the container can be discarded, the reusable support structure provides certain chemical, biochemical, and / or biological reactions that do not sterilize. Can be reused after In other embodiments, the containers, fittings, and / or reusable support structures are reusable (eg, after cleaning and sterilization).

  In another aspect, the container also includes a mixing system that mixes the contents of the container. In some cases, more than one agitator or mixer is used, and the agitator and / or mixer may be the same or different. More than one agitation system is used, for example, to increase mixing capacity. In some cases, if the height of the stirrer is adjustable, the draft shaft raises the impeller or stirrer above the bottom of the tank and / or allows the use of multiple impellers or stirrers. The container mixing system may be disposable or may be intended for a single use (eg, with the container).

  Various methods of mixing fluids are performed in the container. For example, mixers based on magnetic drive, spraying and / or bubble pumps can also be used. It is also possible to use a direct shaft driven mixer that is not hermetically sealed. In one particular embodiment, US Patent Application No. 11 / 147,124, filed June 6, 2005, entitled “Disposable Bioreactor Systems and Methods” by G. Hodge et al., December 2005. US Publication No. 2005/0272146, published 8 days, is incorporated into the present invention by reference, and a mixing system as disclosed in that application is used with the described embodiments. For example, the mixing system comprises a motor (112), which may be an impeller (or other component used for mixing), a power regulator (114), and / or a motor controller (e.g. 116) is driven.

  In some cases, multiple (eg, more than 1, 2, or 3) mixers or impellers are used to mix the contents in the container. Additionally and / or as a variant, the mixing system comprises an adjustable impeller and / or impeller in the form of various impeller vanes. For example, the mixer has an extended drive shaft that allows the impeller to be raised to different heights relative to the bottom of the container. It is also possible to integrate a plurality of impellers by the extended shaft. In other embodiments, the bioreactor system comprises more than one agitation drive per container, which can increase the mixing capacity.

  In order to increase the mixing efficiency, the container is provided with a baffle such as an inner membrane or a protrusion. The inner membrane or protrusion is, for example, arranged across the interior of the container or extends from the inner surface of the container at various heights and at various angles. The baffle may be formed of any suitable material such as a polymer, metal, or ceramic as long as it can be integrated with the container.

  In some embodiments, a direct drive stirrer is also used. Generally, the agitator comprises a direct drive shaft that can be inserted into a container. In certain embodiments, the location where the shaft exits the container is maintained in a sterilized condition. For example, internal and / or external rotating seals can be used to maintain a sterilization seal and / or fresh hot steam can be used to help maintain the sterilization seal. By maintaining a sterilization seal as described above, contaminants introduced by the shaft from, for example, the external environment, exhausted gas, etc. are reduced or avoided.

  In certain embodiments, a magnetic stirrer is used. The magnetic stirrer rotates or moves a stirrer such as an impeller, a blade plate, a blade, a thick plate, or a cone by using a magnet of a fixed magnet, a permanent magnet, or an electromagnet. In some cases, the magnet inside the magnetic stirrer is fixed and activated or sequentially activated, thereby accelerating or decelerating the stirrer via the internal magnetic impeller hub. Since the shaft does not penetrate the container, it is not necessary to maintain the agitator in a sterilized condition using internal and / or external rotary seals, fresh hot steam, and the like.

  In yet another embodiment, an electromechanical polymer agitator is used. The electromechanical polymer stirrer is, for example, a stirrer that includes an impeller of an electromechanical polymer substrate and rotates by “paddling”, that is, the stirrer moves mechanically up and down to Advance while rotating.

  Specific non-limiting examples of devices that can be used in particular embodiments as mixing and / or antifoaming systems are shown in FIGS. Although the illustrated device includes a magnetically driven impeller, other arrangements are possible. In some of these magnetic structures, the motor may not be directly connected to the impeller. The magnet that connects to the drive head may be aligned with the magnet that connects to the hub of the impeller. Therefore, the drive head can rotate the impeller by magnetic interaction. In some cases, the motor portion (and other motors that connect to the elements) may be mounted on a support structure.

  As shown in FIG. 6, the example system includes an impeller support (300). The impeller support is attached to a part of the container wall (302), but is preferably attached to the lower part of the container wall. The system also includes an impeller hub (304), a motor (306), a motor shaft (308), and a drive head (310). The impeller support may be attached to the container wall using any suitable technique. For example, two pieces of impeller supports can be heat welded in two places, the container wall can be sandwiched between impeller supports or overlaid, or other methods described herein can be used. . As an example, the opening of the container wall may be used to extend the center of the impeller plate from the outside to the inside of the container (or vice versa). And the seal ring (not shown) may be glued, or the container may be glued directly to the outer periphery of the impeller support to glue the container wall between them. As another example, a small opening in the container wall may be used to form the seal. This seal is formed at the outer peripheral edge of the impeller support and is slightly larger than the opening. In other embodiments, at least a portion of the impeller support is embedded in the wall of the container and / or the impeller support and the container are manufactured simultaneously (eg, rotational molding, injection molding, or blow molding). .

  One feature according to some embodiments described herein is that it includes one or more spargers that connect to the impeller support. This sparger directs air or other gas into the container. In some cases, the sparger may comprise a porous, superporous, or ultrafiltration element (301) (eg, a spreading element). The sparger spargs gas or moves fluid into and / or out of the container. This is possible because the sparger is sized to connect with the gas supply. This connection is made through a tube (306). In some cases, such sparging and / or liquid addition or removal may be used in conjunction with a mixing system (eg, rotation of an impeller hub). Details of the spraying system are described below.

  In the embodiment shown in FIG. 6, the inside of the impeller support comprises a shaft or column (312). This shaft or column (312) is accommodated in the central opening of the impeller hub (304). The impeller hub may be slightly spaced (305) on the impeller support surface (e.g., using a physically spaced spacer) to prevent friction occurring therebetween. Low friction materials may be used in the manufacture of the impeller hub, thereby minimizing friction between the impeller hub and column. In other embodiments, one or more bearing portions are provided for friction reduction. That is, the impeller hub may be a bearing (323) (eg, a roller bearing, a ball bearing (eg, a radial shaft ball bearing), a thrust bearing, a race bearing, a double race bearing, a rotary bearing, or other bearings depending on circumstances. Any suitable bearing) may be provided to reduce or prevent friction between the impeller support and the column. The drive head further includes a spacer (324) that reduces or prevents friction between the physically spaced drive head and the impeller support.

  The impeller hub also has one or more vanes (318). In some examples, a magnet incorporated into an impeller is used to remove iron or magnet particles from a solution, slurry, or powder.

  The impeller hub has one or more magnets (314) that are arranged around the hub or in any other suitable location, the magnets being provided on the drive head (310). Corresponds to the position of the magnet (316). The magnetic poles are aligned to increase the magnitude of the magnetic force between the impeller hub magnet and the drive head magnet. Magnets (314) and / or (316) are permanent magnets, electromagnets, superconducting magnets, or combinations thereof. For example, in one embodiment, magnet (314) is a permanent magnet and magnet (316) is an electromagnet. In another embodiment, magnet (314) is an electromagnet and magnet (316) is a permanent magnet. In some examples, the system comprises manually or electrically (eg, solid state relays). Other combinations are possible.

  The drive head (310) is attached to the center of the shaft (308) of the motor (306). In a mixing system that includes an electromagnet, the drive head (310) is powered by a signal generator. The signal generator is programmed to operate the electromagnet at a specific frequency and / or current, thereby controlling the strength of the magnetic field, the coupling interaction with the impeller, and the degree of mixing in the container.

  Not all the characteristics shown in FIG. 6 are required in all embodiments of the present invention, and the illustrated components may be exposed and configured differently. Please note. For example, in some embodiments relating to electromagnets, the shaft (308) and / or the motor (306) may be used because the electromagnet is operated continuously, eg, using a signal generator, to provide a rotating magnetic force. Not needed. Further elements are also presented in other embodiments, such as the elements described herein.

  The advantage is that the magnetic force between the impeller and the drive head can be controlled by a mixing system including electromagnets. For example, the components of the mixing system can be easily inserted and / or removed by moving the electromagnet away, such as removing the drive head from the impeller support (300).

  Another example of an electromagnetically driven impeller is presented in the embodiment shown in FIG. The mixing system (350) includes an impeller (318) that is rotatable about a post or shaft (312). The column or shaft is connected to the impeller support (300), which is attached to the container wall (302). Housed and / or supported on impeller support and / or container wall (356). As shown, the wall (356) of the support structure does not have an opening exposing the impeller support (300). This arrangement prevents any fluid leaking from the container from leaking from the support structure. This configuration can also reduce or eliminate friction problems associated with the rotating hub. However, there is an opening in the wall of the support structure, which allows direct access to the impeller support (300).

  The electromagnet (352) is located outside the wall of the support structure. In an embodiment, the electromagnet is arranged in the form of an annulus and is operated continuously to give a rotating magnetic force to the impeller. The electromagnet is electrically connected to a control system (34) that includes a signal generator and / or other controls for operating the electromagnet.

  In some embodiments, electromagnetic force is not used to stop the impeller. That is, since the impeller is attached to a fixed bearing and does not need to be stopped, almost all of the generated electromagnetic force is used to provide rotational motion. This feature prevents the impeller from accidentally contacting and damaging the container (eg, a foldable bag).

  Further examples of mixing systems and components used in such systems are described by G. Hodge et al. In US patent application Ser. No. 11/147, filed Jun. 6, 2005, entitled “Disposable Bioreactor Systems and Methods”. No. 124, U.S. Application Publication No. 2005/0272146, published Dec. 8, 2005, and U.S. Application Publication No. 200201818594, filed Feb. 27, 2002, under the title "Apparatus and method for mixing small volumes of liquid". Which are incorporated herein by reference.

  FIG. 8 shows another embodiment with a mechanically driven impeller. As shown, the present embodiment comprises an impeller support (400), an impeller hub (404) having a shaft (405), and an external motor (406) having a shaft (408). The shaft connection between the impeller hub shaft and the motor shaft may be accomplished by methods well known to those skilled in the art (eg, gearbox, hex drive, etc.).

  For example, the impeller support is attached to the bottom of the side of the bioreactor wall (402). The impeller support may be attached to the bioreactor wall using any of the methods described herein. Porous, ultraporous, or ultrafiltration elements (401) may also be included in the present invention so that the sparger can sparg gas or move fluid into and out of the bioreactor. This is described in detail below. In the embodiment shown in FIG. 8, the shaft of the impeller hub is housed in a seal portion (412) (the seal portion also optionally comprises a bearing). This seal is located at the center of the impeller support (400). By using the seal, it is ensured that the contents of the container are not contaminated. The impeller hub can also prevent friction between them by allowing a slight clearance above the surface of the impeller support. The impeller hub may comprise one or more impeller vanes (418), or other suitable mixing structures (eg, vanes, plates, cones, etc.).

  FIG. 9 schematically illustrates an embodiment of a drive head that is magnetically coupled to an impeller. In FIG. 9, the impeller support (501) shown in cross section comprises a horizontal portion (504) from which a substantially vertical impeller shaft (508) extends upwardly and the vane Supports the car (509) (the impeller (509) comprises a central part (510) and a vane plate (511)). The impeller (509) may rotate around the shaft (508). Furthermore, this rotation may be prompted by a bearing (507). The bearing (507) may be any suitable bearing, such as a roller bearing, a ball bearing (eg, radial shaft ball bearing), a thrust bearing, a race bearing, a double race bearing, a rotary bearing, and the like.

  The impeller support (501) comprises a drive head arrangement element (512). In the illustrated portable embodiment, the drive head arrangement element is a generally vertical downward ridge, forming a circular recess. At least a part of the drive head (516) is inserted into the recess. By arranging the guide element (512), the drive head can be arranged at a predetermined desired position with respect to the impeller (509) when meshing with the impeller support. In one arrangement, the guide element (512) places the drive head in a central position relative to the impeller (509) when engaged with the impeller support.

  As a further embodiment, a physically spaced spacer (520) is disposed between the drive head (516) and the bottom surface (524) of the impeller support. The bottom surface (524) of the impeller support is aligned with a portion of the top surface (526) of the drive head. In that position, the drive head is ideally arranged with respect to the impeller support. A physically spaced spacer (520) physically separates the bottom surface (524) of the impeller support and the top surface (526) of the drive head at a desired distance. However, at least a portion between the top surface of the drive head and the bottom surface of the impeller support may form a continuous, physical connection (no gaps, etc.) between the drive head and the impeller support. This allows a more precise tolerance of the drive head than was understood in many conventional arrangements using the impeller support, and allows the engagement of the drive head and the impeller support to be reproducible and reliable. Make things. In some cases, the drive head includes a recess (528). At least a part of the spacer (520) having a physical interval is inserted into the recess (528). With this arrangement, the engagement of the drive head with the spacer that is physically spaced is reproducible and reliable.

    The bottom of the impeller support and the top surface of the drive head are separated by a spacing (521) (eg, using a physically spaced spacer). In some embodiments, the spacing (521) is only about 50% of the average thickness (530) of the generally horizontal portion (504) of the impeller support. In other embodiments, this spacing is only 40%, 30%, 20%, 10%, or 5% of the thickness of the impeller support.

  In some embodiments, the physically spaced spacers (520) are only about 50% of the average thickness (530) of the generally horizontal portion (504) of the impeller support. In other embodiments, this thickness is only 40%, 30%, 20%, 10%, or 5% of the thickness of the impeller support.

  In some embodiments, the physically spaced spacer (520) is a bearing that facilitates rotation of the drive head relative to the impeller support. If the physically spaced spacer (520) is a bearing, any suitable bearing may be selected, such as a roller bearing, a ball bearing (eg, radial shaft ball bearing), a thrust bearing, a race bearing, two Examples include heavy race bearings and rotary bearings.

  In the embodiment shown in FIG. 9, the drive head can be repositioned relative to the shaft (508). This change is only 5 millimeters in normal operation. Alternatively, in other embodiments, the change is only 4, 3, 2, 1 millimeter (0.5 or 0.25 millimeter in normal operation). The drive head can also be varied in distance to the bottom surface (524) of the impeller support. This change is only 10 millimeters, 1 millimeter, 0.5 millimeters, 0.25 millimeters, 0.1 millimeters, or 0.005 millimeters in certain embodiments using the arrangement shown in FIG.

  In an embodiment, in particular where physically spaced spacers (520) are used, the arrangement of FIG. 9 is in addition to any other physical support that impeller support (501) receives, ) With physical support. Providing support in this manner is very useful for the arrangement of foldable bags including impellers (eg, mixing devices and / or antifoaming devices).

  The impeller hub and drive head comprise one or more magnets (314) (316) as described above, which magnets comprise fixed magnets, permanent magnets, electromagnets, superconducting magnets or combinations thereof. Although the magnets are shown to be located around the hub, the magnets (314) and (316) have any suitable size and configuration and are placed in any suitable position with respect to the impeller and drive head. . As described above, the magnetic force between the impeller and the drive head can be controlled by the use of an electromagnet, whereby the drive head (516) is formed in the recess (512) formed by the drive head arrangement element (512). To facilitate insertion and / or removal from

  Optionally, the impeller support (501) comprises a sparger (540). The sparger (540) is disposed under the impeller vane. The sparger is sized to be connected to one or more gas sources. For example, the sparger is connected to the tube (542) and includes a port capable of fluid communication with one or more gas sources.

  In many of the figures described herein, an impeller is disposed at or near the container bottom, but in other embodiments the impeller may be at any suitable location within the container, such as the container. It can be arranged near the center or at the top of the container. This is possible by extending the length of the shaft that supports the impeller, or by any other suitable arrangement. The position of the impeller in the container depends on the work performed in the container. That is, in an embodiment in which spraying is required, the impeller may be arranged near the sparger. This allows the impeller to remove and / or limit the foam introduced into the container. Furthermore, although the figures described herein show one impeller connected to the shaft, in some cases more than one impeller may be used. For example, the first impeller connected to the shaft may be arranged at the bottom of the container. The second impeller connected to the shaft may be arranged near the center of the container. The first impeller can appropriately remove the dispersed gas, and the second impeller can appropriately mix the contents in the container.

  In some embodiments, the impeller support is uniquely designed to allow a foldable bag to be easily secured. Certain known arrangements of impellers attached to a foldable bag have the following disadvantages. The disadvantage is that the bag is non-ideally attached to the impeller support and / or such attachment is done in a non-ideal manner. As shown in the embodiment of FIG. 9, this embodiment comprises an impeller support having a base. This base is substantially perpendicular to the shaft and the impeller rotates on the shaft. The impeller support also has a first portion (534) having an average thickness sufficient to properly support the shaft of the impeller and a second thinner than the first portion that facilitates attachment to the bag. It has a peripheral part (536) of the part. The thickness of the first portion is formed as a cross section of the entire thickness determined by the first portion at an arbitrary location. Also, when the first portion has a raised structure or other structure having various thicknesses, the thickness in this case is defined as the thickest portion. In some embodiments, the periphery of the second portion forms a structure similar to or substantially identical to the structure of the foldable bag. Further, the peripheral portion of the second portion has a thickness similar to the thickness of the foldable bag body. In another embodiment, the periphery of the second portion is formed of a composition that is different from the composition of the foldable bag. That is, in some embodiments, the first portion is formed from low density polyethylene and the second portion is formed from high density polyethylene, polypropylene, silicone, polycarbonate, and / or polymethacrylic acid.

  The thickness of the periphery of the support and the wall of the foldable bag (540) does not exceed 100% before attachment. Alternatively, in other embodiments, it does not exceed 80%, 60%, 40%, 20%, or 10% (eg, this percentage is expressed as a percentage of the greater thickness between the wall and the periphery of the bag) ). The thickness of the periphery of the impeller support and the thickness of the foldable bag (at least a part that can be attached to the impeller support) are made of the same (or compatible) material and the same thickness. , And joining one to the other is easily reproducible and can be performed using a product. This product does not have significant irregularities and thickness at the joints. Thus, one embodiment includes an article of attachment of each of the foldable bag and impeller support as defined above, and in another embodiment, an embodiment comprises an impeller support prior to attachment. The kit includes a body and a foldable bag. As described herein, the bonding of the bag and the support is performed by any suitable method. Suitable methods include, for example, molding and welding (eg, ultrasonic or thermal welding). In one aspect, the impeller (in some embodiments through magnetic coupling of the drive head to the impeller) is driven by a motor that can reverse the direction of rotation and fine-tune the rotational speed. Reversing the direction of the spin has provided significant advantages in achieving a variety of aeration / dispersion characteristics. Fine adjustments to the speed of the impeller are made so that the degree and / or balance of aeration / dispersion, shear, etc. is accurate and controllable. This degree and / or balance is determined to be very beneficial in connection with the mixing of a large number of media, particularly media containing cells. According to this embodiment, the rotational speed of the impeller can be adjusted to be reproducible and controllable. The rotational speed of the impeller is plus or minus 5% or less in the rotational speed range between 10% and 90% of the maximum impeller rotational speed. In other embodiments, a 4%, 3%, 2% or 1% rotation adjustment of this speed is facilitated. In some devices, these aspects are realized by using servo motors.

  The impeller system described herein may mix any type of fluid, solid, or foam. For example, mixing the liquid inside the container provides nutrients and provides dissolved gas for cell growth applications. Similar disposable containers are used to mix buffers and media, or other solutions. For other solutions, disposable product contact surfaces are desirable. This includes that the container need not be sterile or sterile. Further, in the embodiments described herein, containers with liquid / mixture / gas can be removed and disposed of from a reusable support structure. Thereby, the reusable support structure is not contaminated by the fluid mixed in the container. Thus, the reusable support structure need not be cleaned or sterilized after each use.

  In some embodiments, the plurality of spargers (including the spreading elements) are sized to connect with different gas sources and / or are independently controlled. The type of gas used in the bioreactor system or biochemical / chemical reaction system, the number of spargers, and the type and structure of the spargers are specific to the specific process being performed (eg aerobic versus anaerobic reactions), liquid Depending in part on the removal of any toxic by-products from the control, pH control of the reaction, etc. For more details, see US patent application Ser. No. 11/818, entitled “Gas Delivery Configurations, Foam Control Systems, and Bag Molding Methods and Articles for Collapsible Bag Vessels and Bioreactors,” filed June 15, 2007. No. 901, which is incorporated herein by reference, and the system is used for different gases having different functions in performing, for example, chemical, biochemical, biological reactions. It has a separate sparger. For example, a bioreactor system for cell culture uses a “dissolved oxygen control gas” that controls the amount of dissolved oxygen in the culture solution, a “strip gas” that controls the amount of toxic by-products in the culture solution, and a pH in the culture solution. Various types of gases such as “pH control gas” to be controlled may be included. Each type of gas is introduced into the culture using various spargers. This sparger can be operated and controlled independently. Advantageously, such a system provides variability of high speed process control and low speed process control (high speed and low speed means, for example, one oxygen gas, strip gas, and pH control gas introduced into the reactor). As compared to a specific system coupled to a gas stream). Chemical, biochemical and / or biological reactions performed within the bioreactor system described herein can also reduce gas costs due to low gas consumption and / or ( Since the total amount of gas flow (for example, strip gas) is small, this can reduce foam formation and / or reduce the size of the required inlet gas sterilization filter.

In certain embodiments, the container (eg, as part of a reactor system that performs a biological, biochemical or chemical reaction) is configured to contain a volume of liquid and is at least 0. A container (eg, a foldable bag) having a capacity of 01 liters and at least 2 liters (or any other capacity) is included. The container optionally includes a support structure for enclosing and containing the container. Further, the container has a first sparger, and the sparger is connected to the first gas composition source so as to allow fluid flow, or is sized so that the fluid can flow. In addition, the container has a second sparger, and the sparger is connected to a supply source of a second gas composition different from the first gas composition so that the fluid can flow, or has a size that allows the fluid to flow. Is done. The container further comprises a control system that is operably connected to the first and second spargers and configured to operate the spargers independently of each other. Of course, for example, depending on the size of the container, a third, fourth, fifth or more number of spargers can be included (more than 10 or more than 20 spargers). Many). In some embodiments, the container further comprises a mixing system comprising an impeller and a base, and the first and / or second sparger is connected to the base. In certain embodiments, the first gas composition comprises air and the second gas composition comprises air supplemented with O ₂ and N ₂ . If it contains more spargers, the spargers are connected to a source of N _2, CO _2, NH ₃ and / or any other suitable gas.

  The opening connected to the sparger may be formed of any suitable material. That is, in one embodiment, a porous polymer material is used as a spreading element, allowing gas to move from one of the materials to the other. The openings may also be formed of other materials such as metals, ceramics, polymers, and / or combinations thereof. The material having the holes and openings may have any suitable shape. For example, the material can be used to form knitted, woven, or mesh or other porous elements. The elements can be, for example, sheet-like, film-like and block-like, and can be of any suitable size. In some cases, such elements are incorporated into an impeller or impeller support, as shown in FIG. The elements are arranged firmly and fixed in the area of the impeller or impeller support for preferred use. This fixing can be done by any number of different techniques. Examples of this technology include friction fitting, press fitting, detent mechanism, clipping and clip release mechanism, fixing with screws, piles, clamps, etc., welding (eg thermal and ultrasonic welding), and using adhesives There is. In other embodiments, the impeller and / or part of the impeller support is fabricated directly into a hole or opening through which fluid can flow.

The container may include one or more sensors in electrical communication with the control system. This control system determines the amount or concentration of gas (eg, O ₂ , N ₂ , CO ₂ , NH ₃ , reaction byproducts) in the container. Additionally and / or alternatively, the container comprises a sensor in electrical communication with the control system to determine the pH of the liquid in the container or the amount or level of foam in the bag.

  In another aspect, a bubble tower or bubble pump system (which utilizes air bubbles or other gas bubbles) is used with a disposable bioreactor bag. Such a system provides mixing energy by adding a gas (eg, air) near the bottom of the reactor. Here, the rising gas bubbles and the low density gas saturated liquid rise and replace the falling gas deficient liquid, resulting in up and down circulation. The path of the rising liquid is guided, for example, using a partition in the bag chamber. For example, a plastic sheet that cuts the inside of the bioreactor bag body, for example, vertically using a gap between the top and bottom is used. When gas is added to one side of the partition, the gas and the liquid rich in gas are raised to one side, descending to the other side so as to cross the upper surface of the barrier sheet, and passing under the partition to add gas Return to point. Further, such bubble column / bubble pump mixing systems and methods may be combined with any other mixing system described herein.

  In certain embodiments, the bioreactor system described herein is a closed resin loading / filling system. While the resin slurry is extruded onto the column, the filling is usually done in a sterile room and a carboy with an open lid that contains the resin is used. This resin is mixed manually. However, in certain embodiments, a container, such as a flexible container, is filled with a chromatographic resin. The chromatographic resin is slurried with a stirrer while the slurry is pushed into the column.

  In certain chemical, biochemical, and / or biological processes that require light, the bioreactor system described herein can be directly, indirectly, and / or implanted in-tube (eg, any suitable A simple optical fiber). Any suitable light source can be used. Such a bioreactor system is useful in activation of, for example, photosynthesis of plant cells. In certain embodiments, flexible fluorescent containers are used to provide light, for example, for plant cell growth.

While several embodiments of the present invention are described and depicted, those having ordinary skill in the art will perform the function and / or result and / or one or more described herein. Other means and / or structures for obtaining the effect can be easily conceived. Such variations and / or modifications are also considered to be within the scope of the present invention. Further, it will be appreciated by those skilled in the art that all parameters, dimensions, materials and forms described herein are exemplified, and that actual parameters, dimensions, materials and / or forms are specific to a particular application or invention. We recognize that the teachings of are based on the application used. Those skilled in the art will understand or understand without using routine experimentation and many equivalents of the specific examples described herein. Accordingly, the foregoing embodiments are presented as examples only. Also, within the scope of the appended claims and their equivalents, the present invention may be practiced otherwise than as specifically described in the description and claims. The present invention is directed to each individual feature, system, article, material, kit, and / or method described herein. Further, combinations of two or more such features, systems, articles, materials, kits and / or methods are within the scope of the present invention. It is only if the features, systems, articles, materials, kits and / or methods are not inconsistent with each other.
All definitions defined and used herein will, of course, use the dictionary definition, the definitions in the literature incorporated herein by reference, and / or the ordinary meaning of the term. The indefinite articles "a" and "an" used in the specification and claims of this invention naturally mean "at least one" unless explicitly stated.
Also, unless explicitly stated, the number of steps or actions of the method claimed herein or the order of the steps or actions of the method need not necessarily be limited.
In the claims as in the above specification, all transitional phrases are used in a non-limiting manner. Transition phrases include, for example, “comprising”, “including”, “carrying”, “having”, “containing”, “involving”, “holding” "" Composed of ". Non-limiting means that it includes, but is not limited to. Only the transitional phrases “consisting of” and “consisting essentially of” are respectively limited or semi-limiting transitional phrases.

Claims (23)

A foldable bag,
A reusable support structure that supports and houses the foldable bag; and
Comprising a bladder or compressible material is disposed between the outer wall and the inner wall of the support structure of the collapsible bag, the collapsible bag, the bladder or the expansion or pre-shrinkage of the compressible material the first has a configuration, the bladder or to have a second configuration after the expansion or contraction of the compressible material, the bladder or the compressible material is applied to the expansion and / or contraction, the
The container according to claim 1, wherein the first configuration has more folds on the inner wall of the foldable bag, and the second configuration has fewer folds on the inner wall of the foldable bag. The container of claim 1 , wherein the bladder includes a fluid selected from a liquid and a gas . The first configuration includes the foldable bag having a first capacity, the second configuration includes the foldable bag having a second capacity, and the first capacity is the second capacity. The container according to claim 1, wherein the container is less than. The container according to claim 2, wherein the bladder contains a gas. The container according to claim 2, wherein the bladder contains a liquid. The container according to claim 1, wherein the bladder or the compressible material does not fluidly flow with any contents in the foldable bag. The container according to claim 1, wherein the bladder or the compressible material is disposed around a side wall of the foldable bag. The container according to claim 1, wherein the bladder or the compressible material is disposed at a bottom portion of the foldable bag body. The container according to claim 1, further comprising a mixer. A container comprising a foldable bag and a reusable support structure,
  The reusable support structure comprises at least one wall that can be inflated or compressed, so that the foldable bag has a first configuration before the wall is inflated or compressed, The wall has a second configuration after expansion or compression, the first configuration has more folds on the inner wall of the foldable bag body, and the second configuration has an inner wall of the foldable bag body. A container characterized by having a small number of folds. 11. A container according to claim 10, wherein the at least one wall of the reusable support structure comprises a compressible material that lines the wall. 12. A container according to claim 11, wherein the compressible material comprises an elastomer. Positioning the foldable bag in the reusable support structure such that the reusable support structure contains and supports the foldable bag;
  Introducing liquid into the foldable bag;
  Changing the pressure of the fluid in the region between the outer wall of the foldable bag and the inner wall of the support structure;
  Changing the pressure comprises generating a vacuum between the outer wall of the foldable bag and the inner wall of the support structure. 11. A detector used to determine the presence of a fluid leak from the foldable bag by sensing a change in impedance or conductivity. Container. A bioreactor system comprising the container according to claim 1 and a foldable bag,
  The foldable bag is an impeller plate attached to a lower portion of the foldable bag;
  An impeller hub attached to the impeller plate, the impeller hub having at least one impeller vane plate and at least one magnet;
  The foldable bag further includes:
  A motor having a shaft, the motor having the shaft being disposed adjacent to or within the support structure;
  The foldable bag further includes:
  A motor hub attached to the motor shaft, the motor hub comprising at least one electromagnet, and as soon as the foldable bag is attached within the support structure, the motor hub is aligned with the plate of the impeller. Thus, when the motor shaft rotates, the electromagnet of the motor hub drives the hub of the impeller,
  The bioreactor system further comprises:
  A bioreactor system comprising one or more sensors, the sensors detecting one or more parameters of any material in the foldable bag. 16. The bioreactor system of claim 15, wherein the impeller vane is disposed on at least one porous element and extends across the width of the at least one porous element. The bioreactor system according to claim 15, further comprising a thermally conductive material incorporated in at least a part of a rigid container or a wall portion of the foldable bag. 15. A container according to claim 14, characterized in that the detector is used to determine the presence of fluid in a region between the outer wall of the foldable bag and the inner wall of the support structure. 15. A container according to claim 14, wherein the detector is used to determine the presence of a fluid located at an opening of the reusable support structure. An identifier associated with the container or one or more components of the container, the identifier included in the database or encoded with information on a computer readable medium, or included in the database 11. A container according to claim 1 or claim 10, wherein the container is associated with information on a computer readable medium. 21. A container according to claim 20, wherein the identifier is capable of retrieving and using associated information on a medium contained in the database or readable by a computer. 22. A container according to claim 20 or claim 21, wherein the identifier is capable of accurately positioning the foldable bag in the reusable support structure. The identifier retrieves information for use selected from confirming the correct assembly of system components and protecting against the use of counterfeit, improper or unauthorized components. 23. Container according to claim 22, characterized in that it can be made.