WO2009093997A1

WO2009093997A1 - Information acquisition and management systems and methods in bioreactor systems and manufacturing facilities

Info

Publication number: WO2009093997A1
Application number: PCT/US2008/001051
Authority: WO
Inventors: Parrish M. Galliher; Michael Fisher; Richard Damren; Geoffrey Hodge
Original assignee: Xcellerex, Inc.
Priority date: 2008-01-25
Filing date: 2008-01-25
Publication date: 2009-07-30
Also published as: JP2011509685A; EP2254983A1

Abstract

The present invention relates in certain aspects to systems and methods involving the identification, tracking, determination of location of, determination of material consumption by, waste removal from, component positioning in or on, and assembly of vessels and unit operations or components of cell culture, cell containment, bioreactor, chemical manufacturing, or pharmaceutical manufacturing systems. Certain vessels, unit operations, devices, or other components of the invention may be used to perform all or part of a biological, chemical, or pharmaceutical manufacturing process therein. In some embodiments, the inventive method may be used to assemble system components, verify that the system components are correctly assembled, protect against the use of counterfeit components, etc. Other embodiments of the invention involve articles that allow for the automated assembly of bioreactor systems.

Description

INFORMATION ACQUISITION AND MANAGEMENT SYSTEMS AND METHODS IN BIOREACTOR SYSTEMS AND MANUFACTURING FACILITIES

FIELD OF INVENTION The present invention relates generally to manufacturing systems including reactors or bioreactors or components thereof, and in certain embodiments, to systems and methods involving the identification, tracking, and assembly of vessels and unit operations or components of cell culture, cell containment, bioreactor, purification, formulation, finishing, packaging, chemical manufacturing, or pharmaceutical manufacturing systems.

BACKGROUND

A variety of vessels, devices, components and unit operations for manipulating fluids or for carrying out chemical, biochemical or biological processes are available. For instance, biological materials (e.g., animal and plant cells) including, for example, mammalian, plant or insect cells and microbial cultures can be processed using bioreactors. Traditional bioreactors, which are typically designed as stationary reusable tanks or containers, or disposable bioreactors, which may utilize plastic sterile bags, may be used for such purposes. Disposable, single-use manufacturing systems can be assembled from component pieces (e.g. tubing, filters, bags, fittings, connectors, sensors, etc) into disposable assemblies. Component pieces and portable assembly capabilities, on one hand, provide advantages such as flexibility to rapidly change the configuration of the assembly. On the other hand, portable modular assemblies present the chance for human error in assembly, installation, and use. To address these specific advantages and limitations, a comprehensive system that ensures the proper use, inventory control, and anti-piracy protection on components and assemblies would be useful.

SUMMARY OF THE INVENTION

The present invention relates generally to manufacturing systems including reactors or bioreactors, purification, formulation, filling/finish and packaging operations, raw material or product handling and storage including sample handling and routing, or components thereof, and in certain embodiments, to systems and methods involving the acquisition and management of information in bioreactor systems and manufacturing facilities. Certain embodiments of the invention provide devices and methods for the identification, tracking, and assembly of unit operations, vessels, and other components of a biological, chemical, or pharmaceutical manufacturing systems. The subject matter of the present invention involves, in some cases, interrelated products, alternative solutions to a particular problem, or a plurality of different uses of one or more systems or articles.

In certain embodiments, the invention relates to a method of configuring a customizable manufacturing system. In one embodiment, the method comprises providing a first unit operation configured for performing a biological, chemical, or pharmaceutical manufacturing process or a task of such process, wherein the first unit operation comprises or is positioned in an interior of a first module and the first unit operation includes a first identifier encoded or associated with information about the unit operation. In addition, the method of this embodiment comprises providing a second unit operation configured for performing a biological, chemical, or pharmaceutical manufacturing process or a task of such process, wherein the second unit operation comprises or is positioned in an interior of a second module and the second unit operation includes a second identifier encoded or associated with information about the second unit operation. In this embodiment, at least one of the first and second module is configured to be movable. The method of this embodiment further comprises interconnecting the first and second module and obtaining information by addressing or detecting at least one of the first and second identifiers. In another embodiment, the method comprises providing a unit operation configured for performing a biological, chemical, or pharmaceutical manufacturing process or a task of such process, wherein the unit operation includes a first identifier encoded or associated with information about the unit operation. In addition, this embodiment comprises providing a module configured to be placed in operative association with the unit operation, the module including a second identifier encoded or associated with information about the module, wherein the module is configured to be movable. The method of this embodiment further comprises obtaining information by addressing or detecting at least one of the first and second identifiers. Additionally, the method comprises determining whether or not to place the unit operation and the module in an operative association or determining a configuration of association based at least in part upon the information obtained in the obtaining act.

In yet another embodiment, the method comprises providing a first module comprising or having an interior containing a first unit operation configured to perform at least one specific task of a biological, chemical, or pharmaceutical manufacturing process, wherein the first module includes a first identifier encoded or associated with information about the first module, and determining a task to be performed by the first module based upon the information encoded in or associated with the first identifier. Further, in this embodiment, the method comprises providing a second module having an interior containing a second unit operation configured to perform at least one specific task of a biological, chemical, or pharmaceutical manufacturing process, wherein the second module includes a second identifier encoded or associated with information about the second module, and determining a task to be performed by the second module based upon the information encoded in or associated with the second identifier. Moreover, in this embodiment each of the first and second unit operations include at least one connector associated therewith for interconnecting the unit operations. The method of this embodiment further comprises determining a configuration of connectivity based upon information encoded on or associated with at least one of the first and second identifiers and arranging the modules and interconnecting the first and second unit operations within the modules according to the configuration of connectivity.

In another aspect, the current invention relates to a customizable manufacturing system. In one embodiment, the system comprises at least two modules wherein each module comprises an interior space capable of being interconnected with another module interior space and contains one or more components configured to perform at least one specific task of a biological, chemical, or pharmaceutical manufacturing process, wherein at least one of the modules is configured to be movable and includes an identifier encoded or associated with information about the module. In addition, the system of this embodiment includes a control system configured to perform one or more of operation of components and process control, and further configured to access and process information obtained from or associated with the at least one identifier on at least one of the modules and to perform a function based upon the information encoded by or associated with at least one identifier on at least one of the modules.

In certain embodiments, the invention relates to a customizable manufacturing system comprising: at least two portable modules, each module having an interior including one or more unit operation components for performing at least one specific task of a biological, chemical, or pharmaceutical manufacturing process; a connection port associated with each of the modules for interconnecting the modules; and an identifier encoded with information about a component of the customizable manufacturing system, wherein upon connection, each module can be moved relative to the other without breaking the connection.

In another embodiment, the present invention comprises a vessel configured to contain a volume of liquid, the vessel comprising: an identifier encoded with information about the vessel, a collapsible bag configured to contain the liquid, and a reusable support structure surrounding and containing the collapsible bag.

In yet another embodiment, the present invention comprises a collapsible bag comprising: an identifier encoded with information about the collapsible bag, a flexible wall portion, and a rigid portion comprising a base including a shaft configured to support a magnetic impeller, wherein the rigid portion is connected to the flexible wall portion.

Other advantages and novel features of the present 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 or inconsistent disclosure, the present specification shall control. If two or more documents incorporated by reference include conflicting or inconsistent disclosure with respect to each other, then the document having the later effective date shall control.

BRIEF DESCRIPTION OF THE DRAWINGS

Non-limiting embodiments of the present invention will be described by way of example with reference to the accompanying figures, which are schematic and are not intended to be drawn to scale. In the figures, each identical or nearly identical component illustrated is typically represented by a single numeral. For purposes of clarity, not every component is labeled in every figure, nor is every component of each embodiment of the invention shown where illustration is not necessary to allow those of ordinary skill in the art to understand the invention. In the figures:

FIG. 1 is a schematic diagram showing interconnection of several modules for use in a manufacturing system, according to one embodiment of the invention. FIG. 2 is a schematic diagram showing an exemplary module for use in a manufacturing system, according to one embodiment of the invention. DETAILED DESCRIPTION

The present invention relates in certain aspects to systems and methods involving the identification, tracking, and assembly of vessels and unit operations or components of or reagents or products utilized in cell culture, cell containment, bioreactor, chemical manufacturing, or pharmaceutical manufacturing systems. Certain vessels, unit operations, devices, or other components of the systems may be used to perform all or part of a biological, chemical, or pharmaceutical manufacturing process. In some embodiments, the inventive techniques may be used to guide proper assembly of system components, verify that the system components are correctly assembled, protect against the use of counterfeit, improper or unauthorized components, etc.

For instance, in certain embodiments, unique identifiers are used and are associated with one or more components or materials utilized in a manufacturing system. The "identifiers," as described in greater detail below, may themselves be "encoded with" information (i.e. carry or contain information, such as by use of an information carrying, storing, generating, or conveying device such as a radio frequency identification (RFID) tag or bar code) about the component including the identifier, or may not themselves be encoded with any information about the component, but rather may only be associated with information that may be contained in, for example, a database on a computer or on a computer readable medium. In the latter instance, detection of such an identifier can trigger retrieval and usage of the associated information from the database. Identifiers "encoded with" information about a component need not necessarily be encoded with a complete set of information about the component. For example, in certain embodiments, an identifier may be encoded with information merely sufficient to enable a unique identification of the unit (e.g. relating to a serial no., part no., etc.), while additional information relating to the component (e.g. type, use, ownership, location, position, connectivity, contents, etc.) may be stored remotely and be only associated with the identifier. "Information about" a unit operation, module, material or component, etc. is any information regarding the identity, positioning, or location of the unit operation, module, material or component or the identity, positioning, or location of the contents of a module, unit operation or component and may additionally include any information regarding the nature, state or composition of the unit operation, material, component or contents. "Information about" a unit operation, module or component or its contents can include information identifying the unit operation, module or component or its contents and distinguishing the unit operation, module or component or its contents from others. For example, "information about" a unit operation, module or component or its contents may refer to information indicating what the unit operation, module or component or its contents is, where it is or should be located, how it is or should be positioned, the function or purpose of the unit operation, module or component or its contents, how the unit operation, module or component or its contents is to be assembled or connected with other components of the system, the lot number, origin, destination or ownership of the unit operation, module or component or its contents, etc. In one example, a first module of an overall system including a first identifier can be connected to a second module including a second identifier. In this case, each identifier can be encoded or associated with information about the component with which it is associated. The two modules can be interconnected, and the suitability of the connectivity can be verified based at least in part upon the information encoded on or associated with the first and second identifiers. As another example, the order of connectivity can be selected based at least in part upon the information encoded on or associated with the first and second identifiers. Other embodiments of the invention involve identifiers that facilitate the automated assembly of bioreactor systems.

Although much of the description herein involves an exemplary application of the present invention related to bioreactors (or biochemical and chemical reaction systems including liquid-containing vessels), the invention and its uses are not so limited, and it should be understood that aspects of the invention can also be used in other settings, including those involving systems for containment or processing of a fluid (e.g., a liquid or a gas) in a container (e.g., mixing systems), systems related to a biological, chemical, or pharmaceutical manufacturing process (e.g., primary recovery, filtration and chromatography systems, cell culture systems, microscopy or other analytical devices, etc.), as well as other applications. It should also be understood that while many examples provided herein involve the use of vessels comprising collapsible bags or flexible containers, aspects of the invention can be integrated with vessels comprising non-collapsible or rigid containers, and other configurations involving liquid containment.

In one aspect, the invention relates to configuring a customizable manufacturing system, such as a biopharmaceutical manufacturing system. As shown in the embodiment illustrated in FIG. 1 , an exemplary customizable biopharmaceutical manufacturing system 10 includes first module 20. The module may be configured for performing a biological, chemical, or pharmaceutical manufacturing process, or a task of such a process. First module 20 includes first unit operation 21 , which may be a vessel, or other processing device or component thereof. Optionally, unit operation 21 may be surrounded by a unit operation that is a containment apparatus 24.

First unit operation 21 includes an identifier 22 which can be encoded or associated with information about the first component. In general, as used herein, the term "identifier" refers to any item capable of providing information about the unit operation (e.g. information including one or more of identity, location, or position/positioning of the unit operation or a component thereof)with which the identifier is associated or installed into, or capable of being identified or detected and the identification or detection event being associated with information about the unit operation with which the identifier is associated. Non-limiting examples of identifiers that may be used in the context of the invention include radio frequency identification (RFID) tags, bar codes, serial numbers, color tags, fluorescent or optical tags (e.g., using quantum dots), chemical compounds, radio tags, magnetic tags, among others. Non-limiting examples of unit operations of a biopharmaceutical manufacturing system that can include an identifier include a flexible container (e.g. a disposable bag or liner of a bioreactor or mixing vessel), a reusable support structure (e.g. for containing and supporting a disposable bag or liner of a bioreactor or mixing vessel), sensor(s), tubing, valve(s), reagent containers, agitation system(s) (e.g., impeller(s)), port(s), separation device(s) such as columns or centrifuges, control system components, computer hardware or software components, sparger(s), fittings, or any other functional component of the manufacturing system. In certain embodiments, described in more detail below, the identifiers may work in cooperation in such a way to verify the correct positioning of components or location of components with respect to each other to assure proper assembly. In one exemplary embodiment, a first identifier may be included on a collapsible bag and a second identifier may be included on a reusable support structure for containing and supporting the bag. The first and second identifiers when located in a certain proximity to each other or when in a certain relative position with respect to each other may indicate or be associated with information indicating proper or improper assembly. First module 20 may, in some cases, comprise only one unit operation 21 including an identifer. Alternatively, in certain embodiments, first module 20 may comprise a plurality of unit operations comprising identifiers, which may be interconnected to or otherwise operatively associated with each other. In certain embodiments, unit operation 21 can be positioned in operative association with containment apparatus 24. In general, as used herein, a unit operation of a system that is "operatively associated with" one or more other unit operations indicates that such unit operations are directly connected to each other, in direct physical contact with each other without being connected or attached to each other, or are not directly connected to each other or in contact with each other, but are mechanically, magnetically, electrically (including via electromagnetic signals transmitted through space), or fluidically interconnected or associated so as to cause or enable the unit operations so associated to perform their intended functionality. In some embodiments, containment apparatus 24 may also include an identifier 26. As described further below, the information encoded on or associated with identifiers 22 and 26 may be used to confirm the suitability of the association between unit operation 21 and containment apparatus 24.

Unit operation 21 and containment apparatus 24 may adopt a variety of configurations depending on the needs and requirements of a particular manufacturing process. In some cases, unit operation 21 may be at least partially positioned in an interior of containment apparatus 24. In one embodiment, containment apparatus 24 is an environmental containment enclosure. An "environmental containment enclosure" as used herein refers to an enclosure at least partially surrounding and creating a substantially closed or closable space (an "enclosed space") having, when in operation, a sterile, aseptic, substantially particle-free, or reduced-particle environment inside the enclosure (as compared to an environment surrounding the enclosure). The containment apparatus may be in fluid communication with a ventilation system (not shown) that helps to maintain such an environment inside the containment apparatus. The ventilation system may be external to the enclosure or could be partially or completely contained within the enclosure. Alternatively, instead of or in addition to a ventilation system, some other environmental treatment system may be used to create and maintain a sterile, aseptic, substantially particle-free, or reduced- particle environment, such as, for example, an ultraviolet or other form of radiation sterilizer, a source of steam, chlorine dioxide, ethylene oxide, hydrogen peroxide vapor or other disinfectant, etc. In certain embodiments, containment apparatus 24 is a vessel comprising a reusable support structure such as a stainless steel tank, and unit operation 21 is a disposable vessel adapted for containing a liquid (e.g., a collapsible bag). In other embodiments, other vessel(s), or other processing device(s) or component(s) thereof may be contained in module 20. In general, for simplicity and conciseness, unless prohibited by the surrounding context, the term "vessel", like the term "unit operation", may be used as a shorthand for indicating a volumetric container adapted for containing a liquid, a support structure for supporting a volumetric container, or another component, or another device or component thereof forming at least part of a cell culture, cell containment, bioreactor, chemical manufacturing, pharmaceutical manufacturing, or other manufacturing system. For example, vessel 21 may be in the form of a component configured for performing a specific step or task of a biological, chemical, or pharmaceutical manufacturing process. Non-limiting examples of unit operations that may be employed in the biological, chemical, or pharmaceutical manufacturing processes of the invention include stirred-tank bioreactors, filtration systems, seed culture expansion systems, primary recovery systems, chromatography systems, filling systems, closed media/buffer preparation/containment/supply systems, and water purification systems (e.g., water for injection (WFI) systems). Additional containment enclosures (not shown), which may be one or more environmental containment enclosures, may in certain embodiments surround and contain both containment apparatus 24 and vessel 21. In some embodiments, a second module 30 may also be provided. Second module 30 includes second unit operation 31 , configured for performing a biological, chemical, or pharmaceutical manufacturing process, or a task of such a process. Second unit operation 31 includes an identifier 32 which can be encoded or associated with information about the second unit operation. Second unit operation 31 may comprise a free-standing device, or it may be positioned in an interior of a containment apparatus 34, as described above. In some embodiments, containment apparatus 34 may also include an identifier 36.

In some cases, the first and second modules may be fluidically, electrically, physically, etc. interconnected via connector 40. Connector 40 may also include an identifier 42, which may contain or be associated with information about the connector. Connection between modules 20 and 30 can be formed before, during, or after a process has been performed in first module 20. In some embodiments, connection 40 is a fluidic connection, such as a conduit, tube, pipe, duct, etc, that allows fluid communication between the modules. Optionally, the modules can also be connected physically but without fluid communication between interiors of the modules.

Transfer of a material from module 20 to module 30 may allow the material to be further processed or manipulated in module 30, which may have a different functionality than that of module 20 (e.g., a different unit operation). For instance, while module 20 may include a unit operation in the form of a reactor for producing a biological, chemical or pharmaceutical material, module 30 may include a unit operation configured to purify the material formed in module 20.

Some embodiments of the invention involve the use of a control system 50. The control system can be configured or programmed to be capable of performing a variety of functions including directing assembly, electronic gathering and recordation of data, process control, diagnostics, among others described in detail below. The control system may include one or more computers optionally running control software, one or more alarms, as well as other components. In some embodiments, the control system is configured to address or detect the identifiers in the system and to obtain information about the unit operations associated with the identifiers from the identifiers or to associate information contained externally of the identifiers (e.g. in a database stored in a computer of the control system or elsewhere) about the unit operations associated with the identifiers upon detection or sensing the identifiers. The identifiers may be activated or addressed and information may be obtained from the identifiers via communication pathways (indicated by the dotted lines originating at the identifiers in FIG. 1) using detectors or readers 54. Activation, reading, detection, etc. of identifiers can be accomplished by a variety of methods known to those of ordinary skill in the art depending upon the nature of the particular identifiers employed. Non-limiting examples of detectors include RFID readers, bar code scanners, chemical detectors, cameras, radiation detectors, magnetic or electric field detectors, microphones, among others. The method of detection and appropriate type of detector depends on the particular identifier utilized and can include, for example, optical imaging, fluorescence excitation and detection, mass spectrometry, nuclear magnetic resonance, sequencing, hybridization, electrophoresis, spectroscopy, microscopy, etc. In some embodiments, the detectors may be mounted or pre- embedded in specific locations, while in other embodiments, the detectors may be portable. In some cases, the detectors may be integrated with control system 50 via communication pathways (illustrated by dash-dot lines in FIG. 1). Communication between the detectors and the control system may occur along a hard-wired network or may be transmitted wirelessly.

The functions performed by control system 50 may be dependent, at least in part, upon the information encoded on or associated with the identifier of one or more of the system components. Non-limiting examples of such control system functions that may be associated with or use such information include, directing the detachment or attachment of components, directing the moving of components, commencing, interrupting, continuing or selecting a particular process, adjusting environmental parameters (e.g. temperature, pressure), adjusting chemical levels, setting off one or more alarms, adding data to or extracting data from a database or automated report, verifying identity, ownership or authenticity of components or materials, among many others.

In some cases, the information encoded on or associated with an identifier can be used, at least in part, to verify the identity or function of a unit operation, module, connector, or other system component. An identifier may also be used, for example, to determine the location of a unit operation, module, connector, or other system component. In some cases, determining the location or identity or function of a component is performed as part of an inventory control process or regulatory compliance process. Information regarding the identity or function of components can be used simultaneously, in some embodiments, with the information regarding location or connectivity to assist in the assembly, disassembly, or operation of a biopharmaceutical manufacturing system. In some cases, the aforementioned tasks can be automated when performed in tandem with control system 50.

In some embodiments, information obtained from or associated with at least one identifier may be used to verify the suitability of the operative association (e.g. to avoid connecting the wrong tubing and mixing product a A with a batch B incorrectly) between unit operations, between a unit operation and a module, between two modules, between a connector and a unit operation or module, or between any two components of the system. In some cases, the operative association to be verified comprises connectivity between two components. If the two components are determined to be suitable, they can be placed in operative association with each other. If the two components are determined to be unsuitable, an alarm or lock-out condition may be triggered preventing their interconnection or, if already connected, a lock-out condition preventing operation may be triggered or the components may be automatically disconnected. As an example, a control system of the bioreactor system can be programmed to recognize an identifier of a particular component (e.g., carrying or associated with information relating to model, manufacturer, size, etc.) as indicating the component may be suitably connected with another component of the system. In some embodiments, the suitability of connectivity of two components may involve determining the order of connectivity of the components. Verifying the suitability of connectivity of two components may also involve determining whether the material within a first component is biologically or chemically compatible with the material within a second component or with the material from which the second component is manufactured. Such recognition of the identity of components may be useful, for example, for systems that require assembly of many different parts, for systems that require assembly of parts in specific configurations, for systems that are designed to be assembled and disassembled (e.g., portable systems), or for aiding assembly of systems by persons unfamiliar with the system. Identifiers associated with one or more components of a bioreactor system are especially useful for systems that are designed specifically for a customer at a first location, disassembled (partially or fully), and then shipped to the customer at a second location, where the bioreactor system must be reassembled (partially or fully) prior to use.

In another example, the identifier of a bioreactor system or components of the system can be associated with predetermined or programmed information contained in a database regarding the use of the system or component for a particular purpose, user or product, or with particular reaction conditions, reagents, users, and the like. If an incorrect match is detected or an identifier has been deactivated, the process may be halted or the system may be rendered not operable until the user has been notified, or upon acknowledgement by a user. Information encoded on or associated with an identifier may also be used, for example, to determine whether the component associated with the identifier is authentic or counterfeit. In some embodiments of the invention, the determination of the presence of a counterfeit component causes system lockout. In one example, the identifier may contain a unique identity code. In this example, the process control software or the module would not permit system startup (e.g., the system may be disabled) if a foreign or mismatched identity code (or no identity code) was detected. If the identifiers are RFID tags, verification could be achieved, for example (but not limited to), via radio frequency identification (RFID) or other proximity readers that are positioned in specific locations within the system, for example adjacent to on or within a module or in a vessel wall. In certain embodiments, RFID identifiers connected to the components would trigger the appropriate proximity readers and signal that the proper units, assembly, materials, etc. was in place. Similarly, RFID identifiers embedded in a liner could interact with a reader in a support vessel to signal that the liner was properly seated in a support vessel prior to engagement of an external agitator drive motor (see discussion of Fig. 2 below). In cases where the manufacturing system is operated with a control system 50, system lockout may be automated.

In certain embodiments, the information obtained from or associated with an identifier can be used to verify the identity of a customer to whom the component is sold or for whom a biological, chemical, or pharmaceutical process is to be performed. In some cases, the information obtained from or associated with an identifier is used as part of a process of gathering data for troubleshooting a system. The identifier may also contain or be associated with information such as batch histories, assembly process and instrumentation diagrams (P and IDs), troubleshooting histories, among others. Troubleshooting a system may be accomplished, in some cases, via remote access or include the use of diagnostic software. Control system 50 may be used as part of the troubleshooting process.

The information encoded on or associated with the identifiers may also be used to ensure that the biopharmaceutical manufacturing system is operating properly. In some cases, the information encoded on or associated with the identifiers may be used to verify that the unit operations, modules, connectors, or other system components are functioning properly. Information from or associated with the identifiers may also be used to determine whether unit operations, modules, connectors, or other system components are properly assembled. In still other embodiments, detecting or obtaining information from the identifiers can be performed to verify that proper reagents are being used for the biological, chemical, or pharmaceutical manufacturing process. In some cases, control system 50 may be used to automatically shut down the system in response to abnormalities in the system based on information encoded on or associated with the identifiers. In addition, control system 50 may be used, in some cases, to facilitate or guide correction of the improper assembly of system components or the use of improper reagents.

In some cases, the information encoded on or associated with the identifiers may be used to track unit operations, modules, connectors, or other system components to one or more product lot(s) that are manufactured using the system components. In one embodiment, tracking may comprise establishing cross-link connections between process data and raw material bar codes or RFID tags. In some cases, such tracking system can be constructed to ensure prevention of cross-mixing and confusion of components or raw material use for multiple products, for example by setting off alarm conditions or causing lock-out if detection of improper or unauthorized components or raw materials occurs. The information from or associated with an identifier can, in some embodiments, be stored, for example in computer memory or on a computer readable medium, for future reference and record-keeping purposes. For example, certain control systems may employ information from or associated with identifiers to identify which components or type of components were used in a particular chemical or biological reaction, the date, time, and duration of use, the conditions of use, etc. Such information may be used, for example, to determine whether the component should be cleaned or replaced. An identifier may also report or record the location or identity of a component (or sets of components) at any point in time. Optionally, the manufacturing system could generate a report from gathered information, including information encoded by or associated with the identifiers, that may be used in providing proof of compliance with regulatory standards or verification of quality control.

Control systems of the invention may be configured to produce a change in a first environmental factor associated with one or more of the components of the manufacturing system responsive to a change in a second environmental factor associated with one or more of the components of the manufacturing system. An environmental factor may include a measurable property within a system component including, but not limited to temperature, pressure, pH, flow field, a concentration of a dissolved gas, molarity, osmolarity, glucose concentration, glutamine concentration, pyruvate concentration, apatite concentration, color, turbidity, viscosity, a concentration of an amino acid, a concentration of a vitamin, a concentration of a hormone, serum concentration, a concentration of an ion, shear rate, and degree of agitation. In some embodiments, an environmental factor may include external factors such as the position or identity of a component (e.g., module, unit operation, connector, etc.), the presence of a counterfeit component, the presence of incorrectly assembled components, etc.

In some cases, the manufacturing systems of the invention may also include actuators operatively associated with components of the system. In one set of embodiments, a sensor or identifier may be in operative association with an actuator or a microprocessor able to produce an appropriate change in an environmental factor within a module. In one particular example, the actuator is connected to an external pump, and the actuator causes the release of a substance from a reservoir. In another example, the actuator may produce energy to heat a component or contents thereof or selectively kill a type of cell susceptible to a particular type or intensity of energy produced by the actuator. It is to be understood that any control system and technique disclosed herein can be provided in combination in any combination with other control systems and techniques.

Control systems described herein can be implemented in numerous ways, such as with dedicated hardware or firmware, using a processor that is programmed using microcode or software to perform the functions recited above or any suitable combination of the foregoing. A control system may control one or more operations of a single unit operation for a biological, biochemical or chemical reaction, or of multiple (separate or interconnected) unit operations. Each of the systems described herein, and components thereof, may be implemented using any of a variety of technologies, including software (e.g., C, C#, C++, Java, or a combination thereof), hardware (e.g., one or more application-specific integrated circuits), firmware (e.g., electrically-programmed memory) or any combination thereof.

Various embodiments according to the invention may be implemented on one or more computer systems. These computer systems, may be, for example, general-purpose computers such as those based on Intel PENTIUM-type and XScale-type processors, Motorola PowerPC, Motorola DragonBall, IBM HPC, Sun UltraSPARC, Hewlett-Packard PA-RISC processors, any of a variety of processors available from Advanced Micro Devices (AMD) or any other type of processor. It should be appreciated that one or more of any type of computer system may be used to implement various embodiments of the invention. The computer system may include specially-programmed, special-purpose hardware, for example, an application-specific integrated circuit (ASIC). Aspects of the invention may be implemented in software, hardware or firmware, or any combination thereof. Further, such methods, acts, systems, system elements and components thereof may be implemented as part of the computer system described above or as an independent component.

In one embodiment, a control system operatively associated with a module or vessel described herein is portable. The control system may include, for example, all or some of the necessary controls and functions required to address or detect identifiers and retrieve information from or associate information with particular identifiers and take action based upon such information, perform a fluidic manipulation (e.g., mixing and reactions), measure and control process parameters in the manufacturing system, etc. Such a movable/portable control system may include a support and wheels for facilitating transport and may, optionally, be physically connected to, e.g. mounted upon, a module or vessel with which the control system is operatively associated.. Advantageously, such a portable control system can be programmed with set instructions, if desired, transported (optionally with the vessel), and hooked up to a vessel, ready to perform process control in a shorter amount of time than conventional control systems (e.g., less than 1 week, 3 days, 1 day, 12 hours, 6 hours, 3 hours, or even less than 1 hour). In certain embodiments in which manufacturing systems include multiple modules including separate control systems associated therewith, such control systems may be placed in operative and cooperative association with each other upon assembly of a manufacturing system from the modules to facilitate integration and global control of the manufacturing system. In certain such embodiments, the individual control systems of the modules may communicate with and be controlled by a higher level master control system.

Any of the modules may be configured to be movable/portable. Wheels (not shown in FIG. 1) or any other components for facilitating movement/portability of the modules can be included in any of the modules illustrated in FIG. 1. Identifiers can be mounted on the modules, in certain embodiments, to identify module location or passage through a facility or storage locations. Advantageously, modules that are configured to be individually movable/portable can be reconfigured after use to, for example, perform a different biological, chemical, or pharmaceutical process within the module from that performed with the modules in a different configuration.. For instance, after a material within module 20 has been transferred to module 30, modules 20 and 30 may be disconnected and module 20 may be used to perform a different process. In some cases, a second process is unrelated to the first process performed using the module; for example, the first process may involve synthesizing a drug and the second process may involve harvesting cells. An identifier may be encoded or associated with information regarding the compatibility of module 20 with alternative process steps, and the identifier may be used as part of a system to ensure proper re-assembly of module 20 into a second system set-up. In other cases, the second process is related to the first process. For example, the first process may be forming a drug precursor and the second process may be reacting the drug precursor with a compound to form a drug.

The use of disposable components within the modules can facilitate reconfiguration of the modules. For example, after a first process has been performed in a disposable bag bioreactor (e.g. unit operation 21 in this case), and the material has been transferred from module 20 to module 30, the disposable bag can be removed from module 20 and a new disposable bag can be inserted therein. This arrangement can allow a second process to be performed within module 20 while the transferred material is processed in module 30. Likewise, after the second process within module 20 has been accomplished, the material within the module can be transferred to module 30. Alternatively or additionally, module 20 can be interconnected with a third module 60 via connection 70, described in more detail below. In certain embodiments, one or more processes can be performed simultaneously using system 10, saving the user time and space.

The system described herein may be self-sufficient and independently customized to perform a specific biological, chemical, or pharmaceutical process. This can allow, for example, system 10 to be customized to perform a particular process at a first location, disassembled, and then shipped to a second location to perform the same process at the second location. Because the modules and other components in certain embodiments include identifiers that can facilitate assembly, the time and expertise required to disassemble the modules at the first location and assemble the modules at the second location may be reduced. The use of identifiers and a control system to provide automation can also facilitate easier operation of the modules, especially when users are untrained or unfamiliar with the system. This characteristic may be especially advantageous when operating the system in remote locations. In one embodiment, at least one identifier encoded with information used in the manufacturing system comprises an RFID tag. The RFID tag may include an integrated circuit (e.g., for storing and processing information, modulating and demodulating a radio frequency (RF) signal, etc.) and an antenna for receiving and transmitting a signal. The RFID tag may be passive, semi-passive (e.g., battery-assisted), or active. RFID tags, generally, are known in the art and any suitable RFID tag can potentially be used in the context of the present invention as described above. An identifier of the invention may be connected to a component by any suitable method, either directly or indirectly. Methods for attaching an identifier to a system component are discussed in more detail below. Identifiers can be used to confirm that all disposables/product contact materials have been cleared from modules or facility before introduction of disposables/product contact materials designated for a second product. As previously mentioned, the customizable biopharmaceutical manufacturing system shown in FIG. 1 may be configured to include more than two modules or unit operations. Referencing FIG. 1, a third module 60 may be provided and configured for performing a biological, chemical, or pharmaceutical manufacturing process, or a task of such a process. Third module 60 includes third unit operation 61, which may be a vessel containing a liquid, separation device, or other processing device or component thereof. Third module 60 may be desired, for example, if further processing or manipulation of the material within second module 30 is required, in which case, module 60 may be interconnected with module 30 (not shown). In certain embodiments, third module 60 may be advantageous when running more than one process in parallel, as previously described. The third module may be designed and configured to perform a different process than that of the first or second modules. For instance, third unit operation 61 may include a vessel comprising an ultra filtration system for separation of desired products produced in a bioreactor comprising unit operation 21 of module 20, while unit operation 31 of module 30 may comprise a medium supply/storage/preparation device or system. The third unit operation 61 as illustrated includes an identifier 62 which is encoded or associated with information about the third unit operation. The third unit operation may stand alone and itself comprise a module, or it may be positioned in an interior of containment apparatus 64. Identifier 62 can be used in the performance of any of the functions previously described. In some embodiments, containment apparatus 64 may also include identifier 66. Connector 70, interconnects modules 20 and 60 and may also include an identifier 72, which may contain information about the connector or the connectivity of the modules, etc.. In other embodiments of the invention, additional modules or unit operations may be added in a similar manner for performing further processing functions. As previously mentioned, a unit operation, module, or other component may be at least partially surrounded by an environmental containment enclosure which is part of an environmental containment system configured to maintain a sterile, aseptic, substantially particle-free, or reduced-particle environment within the enclosure. In certain embodiments, access to material contained within a module or unit operation is achieved without subjecting the material to an external atmosphere surrounding the environmental containment enclosure(s). Accordingly, such environmental containment systems can prevent or decrease the amount of contamination, e.g., from personnel, equipment, and ambient air, of a material contained in the vessel or the degree of exposure of a user to the material. These systems may be particularly useful for producing or isolating toxins or other infectious materials within the vessel with improved safety. Furthermore, the use of modules having an environmental containment enclosure can allow the modules to be used in non-sterile or non- clean room environments for processes requiring such environments, since the enclosed space(s) formed by the environmental containment enclosure(s) can be operated under sterile, aseptic, particle-free, or reduced-particle conditions. This feature can substantially save costs as clean room or other facilities may not be required. Environmental containment systems and methods associated therewith are described in more detail in commonly owned U.S. Patent Application Serial No. 11/879,033, filed July 13, 2007, entitled "Environmental Containment Systems," which is incorporated herein by reference.

Connection between modules may take place through a variety of means such as, for example, a rigid or flexible tube, a latch, electrical wiring, or the like. Connectors may include identifiers which may aid in the assembly of a manufacturing system. In certain embodiments, connector tubing contains embedded wire connecting to identifiers in both of the modules or unit operations being connected by the tubing. In some instances, a flexible connection between the modules is formed, allowing each of the modules to be moved in different orientations with respect to one another even when interconnected. This feature is particularly useful in systems where module movement is automated. Interconnection between modules and methods associated therewith are described in more detail in commonly owned U.S. Patent Application Publication No. 2005/0226794 incorporated herein by reference.

A non-limiting example of a bioreactor system that may comprise a module or unit operation of a module is illustrated in FIG. 2. Module 100 includes container 1 18, which can be, for example, a flexible container. Container 1 18 includes identifier 119. Identifier 119 may be associated with container 118 in a variety of ways, for example it may be embedded in or otherwise attached to a wall of the container, printed on a wall of the container (e.g. as a bar code), suspended in the liquid contained within the container, etc. Module 100 further comprises a reusable support structure 1 14 (e.g., a stainless steel tank) that surrounds, supports and contains container 1 18. In some cases, support structure 1 14 may include an identifier 115. In some embodiments, the container is configured as a collapsible bag (e.g., a polymeric bag). In other embodiments, the container may be a rigid container, such as a rigid plastic carboy. Additionally or alternatively, all or portions of a collapsible bag or other container may comprise a substantially rigid material such as a rigid polymer, metal, or glass. In some of these embodiments, container 118 comprises a collapsible bag with a flexible wall portion and a rigid portion comprising a base. In some embodiments, the rigid portion of the collapsible bag comprising a base is sealed to the flexible wall portion. In some cases, the rigid portion comprising the base may include a shaft or other receiver configured to support a means for stirring (e.g., impeller). The container may be disposable and may be configured to be easily removable from the support structure. In some cases, the container is irreversibly connected to the support structure.

If a collapsible bag is used, the collapsible bag may be constructed and arranged for containing a liquid 122, which may contain reactants, media, organisms or other components for carrying out a desired process such as a chemical, biochemical or biological reaction. The collapsible bag may also be configured such that liquid 122 remains substantially in contact only with the collapsible bag during use and is not in contact with support structure 114. In such embodiments, the bag may be disposable and used for a single reaction or a single series of reactions, after which the bag is discarded. Because the liquid in the collapsible bag does not come into contact with the support structure, the support structure can be reused without cleaning. That is, after a reaction takes place in container 1 18, the container can be removed from the support structure and replaced by a second (e.g., disposable) container. A second reaction can be carried out in the second container without having to clean either the first container or the reusable support structure. Identifiers can be used to track inventory passage in and out of a module to verify that the module is stocked with all appropriate reagents, components, etc. before enclosing and onset of operations. Inventory data can be recorded to track inventory and to verify usage of each component in the performance of a batch. Identifiers can also be configured and employed to cooperate with or act as leak detection sensors to indicate a condition of leakage from a unit operation or component. For example, use of identifiers in the context of leak detection is particularly advantageous for identifiers incorporated into or associated with collapsible bag containers of the inventive systems or identifiers incorporated into or associated with reusable support structures containing or supporting the collapsible bag containers of the inventive systems.

Module 100 may optionally include a mixing means such as one or more impeller(s) 151 positioned within the container 1 18, which can be rotated (e.g., about a single axis) using a motor 152 that can be external to the container. In one embodiment, an identifier 153 may be included on any part of the impeller (e.g., the base, blades, etc.). In some embodiments, the impeller and motor are magnetically coupled. The mixing system or other module components can be controlled by control system 134, which may also be programmed or configured for addressing or detecting the identifiers and receiving information from the identifiers and processing, storing and acting upon the information. Control system 150 may communicate, in some embodiments, with the mixing means or other components in order to provide process control. In some cases, control of the mixing means is aided by the identifier(s) associated with the mixing means or container.

An identifier may be connected to the unit operation, module, impeller, or any other portion of the system (or any component of manufacturing system 10 in FIG. 1) by any suitable method, either directly or indirectly. For instance, an identifier may be embedded into to a wall of a flexible container, vessel, or other component. Attachment may occur reversibly or irreversibly, but in many instances, an identifier is irreversibly attached to a component (e.g., by bonding, embedding, use of adhesives, lamination, encapsulation, fastening, or any other suitable method of attaching components).

In some embodiments, an identifier (such as an RPID tag) may be placed in the bioprocessing fluid 122. The identifier may be used, for example, to measure and, optionally, store the value of, at least one property of the liquid in the unit operation. Non-limiting examples of properties that may be recorded and optionally tracked using an identifier placed in the liquid include, for example, pH, temperature, pressure, fluid flow pattern, oxygen level, CO₂ level, reagent level, product level, metabolite level, conductivity, or any other reactor or processing parameter. The support structure or the container may also include, in some embodiments, one or more ports 154 that can be used for sampling, analyzing (e.g., determining pH or amount of dissolved gases in the liquid), or for other purposes. In some cases, identifiers are incorporated to work in concert with the sampling or analyzing tools. Parameters can also be measured upstream or downstream from the reaction site. In some instances, one or more identifiers is added to the fluid and remotely sensed and analyzed (e.g., continuously or periodically) during or after the bioprocessing operation has been performed. In still other embodiments, the identifier does not itself carry information about the unit operation, but rather comprises a detectable material or article suspended or dissolved in the process fluid, wherein detection of the material or article is associated with information about the unit operation/process fluid by a control system.

In some cases, a product of a chemical or biological reaction, or a container or unit operation containing such product, can be labeled with an identifier that includes stored information contained therein so that the components, conditions, or sequence of conditions used to form the product can be quickly and easily identified if needed. An identifier associated with a package of a product can also enable authentication of the product.

Also shown in FIG. 2 are an optional inlet port 142 and optional outlet port 146, which can be formed in the container 1 18 and, optionally, reusable support structure and can facilitate convenient introduction and removal of a liquid or gas from the container. The container may have any suitable number of inlet ports and any suitable number of outlet ports. For example, a plurality of inlet ports may be used to supply different gas compositions (e.g., via a plurality of spargers 147), or to allow separation of gases prior to their introduction into the container. These ports may be positioned in any suitable location with respect to container 118. For instance, for certain vessels including spargers, the container may include one or more gas inlet ports located at a bottom portion of the container. Tubing may be connected to the inlet and outlet ports to form, e.g., delivery and harvest lines, respectively, for introducing and removing liquid from the container. The ports optionally can include identifiers (not shown) which may be used for such functions as identifying the port type, identifying proper ports to associate with appropriate connectors, etc. Optionally, the container or support structure includes a utility tower 150, which may be provided to facilitate interconnection of one or more devices internal to the container or support structure with one or more pumps, controllers, or electronics (e.g., sensor electronics, electronic interfaces, and pressurized gas controllers) or other devices. Such devices may be controlled using control system 134. Control system 134 may be the same unit used to control the assembly and operation of a manufacturing system (e.g. control system 50 in FIG. 1), or it may be a separate unit dedicated to control of module 100. In general, the various identifiers and control system of module 100 may be configured and operated to perform any of functions of identification, authentication, inventory/source/destination management, assembly and compatibility verification, correlation of product lots to use of particular components (e.g. particular disposable bag containers), data collection and regulatory compliance management, etc. described previously for the identifiers of the modules of system 10 of Fig. 1. For systems including multiple spargers, control system 134 may be operatively associated with each of the spargers and configured to operate the spargers independently of each other. This can allow, for example, control of multiple gases being introduced into the container. Spargers may include identifiers, in some embodiments, that may enable the control system to ensure proper gas identity, supply and connectivity (e.g. my assuring compatibility between identifiers on the sparger and other identifiers on gas supply cylinders connected thereto), facilitate automated control of the spargers, or perform other functions in addition to or in the alternative to these.

Additionally or alternatively, module 100 may include an antifoaming system such as a mechanical antifoaming device. As shown in the embodiment illustrated in Fig. 2, an antifoaming device may include, for example, an impeller 161 that can be rotated (e.g., magnetically) using a motor 162, which may be external to the container. The impeller can be used to collapse a foam contained in a head space 163 of the container. In some embodiments, the antifoaming system is in electrical communication with a sensor 143 (e.g., a foam sensor) via control system 134. In certain embodiments, the antifoaming device or portion thereof or foam sensor may include one or more identifiers encoded or associated with information about the component with which they are associated. The sensor 143 may determine, for instance, the level or amount of foam in the head space or the pressure in the container, which can trigger regulation or control of the antifoaming system. In other embodiments, the antifoaming system is operated independently of any sensors. Antifoaming systems are described in more detail in commonly owned U.S. patent application serial no. 1 1/818,901 , filed: June 15, 2007, entitled: GAS DELIVERY CONFIGURATIONS, FOAM CONTROL SYSTEMS, AND BAG MOLDING METHODS AND ARTICLES FOR COLLAPSIBLE BAG VESSELS AND BIOREACTORS, which is incorporated herein by reference. The support structure 1 14 may also include one or more sight windows 160 for viewing a level of liquid within the container 1 18. In some embodiments, an level sensor is incorporated with the sight window. The level sensor may allow for communication of the liquid level to control system 134. One or more connections 164 may be positioned at a top portion of the container or at any other suitable location. Connections 164 may include openings, tubes, or valves for adding or withdrawing liquids, gases, and the like from the container, each of which may optionally include a flow sensor or filter (not shown). As mentioned previously, these connections may include identifiers that may aid in ensuring the proper assembly or function of the module. The support structure may further include a plurality of legs 166, optionally with wheels 168 for facilitating transport of the vessel.

It should be understood that not all of the features shown in Fig. 2 need be present in all embodiments of the invention and that the illustrated elements may be otherwise positioned or configured. Also, additional elements may be present in other embodiments, such as the elements described herein.

Various embodiments described herein include a container such as a collapsible bag. "Flexible container", "flexible bag", or "collapsible bag" as used herein, indicates that the container or bag is unable to maintain its shape or structural integrity when subjected to the internal pressures (e.g., due to the weight or hydrostatic pressure of liquids or gases contained therein expected during operation) without the benefit of a separate support structure. The collapsible bag may be made out of inherently flexible materials, such as many plastics, or may be made out of what are normally considered rigid materials (e.g., glass or certain metals) but having a thickness or physical properties rendering the container as a whole unable to maintain its shape or structural integrity when subjected to the internal pressures expected during operation without the benefit of a separate support structure. In some embodiments, collapsible bags include a combination of flexible and rigid materials; for example, the bag may include rigid components such as connections, ports, identifiers, such as one or more RFID tags, supports for a mixing or antifoaming system, etc. The container (e.g., collapsible bag) may have any suitable size for containing a liquid. For example, the container may have a volume between 0.1-40 L, 40-100 L, 100-200 L, 200-300 L, 300-500 L, 500-750 L, 750-1 ,000 L, 1,000-2,000 L, 2,000-5,000 L, or 5,000- 10,000 L. In some instances, the container has a volume greater than 1 L, or in other instances, greater than 10 L, 20 L, 40 L, 100 L, 200 L, 500 L, or 1 ,000 L. Volumes greater than 10,000 L are also possible.

In some embodiments, the collapsible bag is disposable and is formed of a suitable flexible material. The flexible material may be one that is USP Class VI certified, e.g., silicone, polycarbonate, polyethylene, and polypropylene or not certified for pharmaceutical use. Non-limiting examples of flexible materials include polymers such as polyethylene (e.g., linear low density polyethylene and ultra low density polyethylene), polypropylene, polyvinylchloride, polyvinyldichloride, polyvinylidene chloride, ethylene vinyl acetate, polycarbonate, polymethacrylate, polyvinyl alcohol, nylon, silicone rubber, other synthetic rubbers or plastics. As noted above, portions of the flexible container may comprise a substantially rigid material such as a rigid polymer (e.g., high density polyethylene), metal, or glass (e.g., in areas for supporting fittings, etc.). In other embodiments, the container is made of a substantially rigid material. All or portions of the container may be optically transparent to allow viewing of contents inside the container. The materials or combination of materials used to form the container may be chosen based on one or more properties such as flexibility, puncture strength, tensile strength, liquid and gas permeabilities, opacity, and adaptability to certain processes such as blow molding, injection molding, or spin cast molding (e.g., for forming seamless collapsible bags). The container (e.g., collapsible bag) may have any suitable thickness for holding a liquid and may be designed to have a certain resistance to puncturing during operation or while being handled. For instance, the walls of a container may have a total thickness of less than or equal to 250 mils (1 mil is 25.4 micrometers), less than or equal to 200 mils, less than or equal to 100 mils, less than or equal to 70 mils (1 mil is 25.4 micrometers), less than or equal to 50 mils, less than or equal to 25 mils, less than or equal to 15 mils, or less than or equal to 10 mils. In some embodiments, the container includes more than one layer of material that may be laminated together or otherwise attached to one another to impart certain properties to the container. For instance, one layer may be formed of a material that is substantially oxygen impermeable. Another layer may be formed of a material to impart strength to the container. Yet another layer may be included to impart chemical resistance to fluid that may be contained in the container. It should be understood that a container may be formed of any suitable combinations of layers. The container (e.g., collapsible bag) may include, for example, 1 layer, greater than or equal to 2 layers, greater than or equal to 3 layers, or greater than equal to 5 layers of material(s). Each layer may have a thickness of, for example, less than or equal to 200 mils, less than or equal to 100 mils, less than or equal to 50 mils, less than or equal to 25 mils, less than or equal to 15 mils, less than or equal to 10 mils, less than or equal to 5 mils, or less than or equal to 3 mils, or combinations thereof. As previously mentioned, in certain embodiments, module 24 may be in the form of a support structure, as shown in FIG. 2, which can surround and contain unit operation 20. The support structure may have any suitable shape able to surround or contain the container. In some cases, the support structure is reusable. The support structure may be formed of a substantially rigid material. Non-limiting examples of materials that can be used to form the reusable support structure include stainless steel, aluminum, glass, resin-impregnated fiberglass or carbon fiber, polymers (e.g., high-density polyethylene, polyacrylate, polycarbonate, polystyrene, nylon or other polyamides, polyesters, phenolic polymers, and combinations thereof. The materials may be certified for use in the environment in which it is used. For example, non-shedding materials may be used in environments where minimal particulate generation is required.

In some embodiments, the reusable support structure may be designed to have a height and diameter similar to standard industrial size stainless steel bioreactors (or other standard reactors or vessels). The design may also be scaleable down to small volume bench reactor systems. Accordingly, the reusable support structure may have any suitable volume for carrying out a desired chemical, biochemical or biological reaction. In many instances, the reusable support structure has a volume substantially similar to that of the container. For instance, a single reusable support structure may be used to support and contain and single container having a substantially similar volume. In other cases, however, a reusable support structure is used to contain more than one container. The reusable support structure may have a volume between, for example, 0.1-100 L, 100-200 L, 200-300 L, 300-500 L, 500-750 L, 750-1,000 L, 1,000-2,000 L, 2,000-5,000 L, or 5,000-10,000 L. In some instances, the reusable support structure has a volume greater than 1 L, or in other instances, greater than 10 L, 20 L, 40 L, 100 L, 200 L, 500 L, or 1,000 L. Volumes greater than 10,000 L are also possible.

In other embodiments, however, a unit operation of the present invention does not include a separate container (e.g., collapsible bag) and module, but instead comprises a self- supporting disposable or reusable container. The container may be, for example, a plastic vessel and, in some cases, may include an agitation system integrally or removably attached thereto. The agitation system may be disposable along with the container. In one particular embodiment, such a system includes an impeller welded or bolted to a polymeric container. It should therefore be understood that many of the aspects and features of the vessels described herein with reference to a container and a support structure (for example, a seamless container, a sparging system, an antifoaming device, etc.), are also applicable to a self-supporting disposable container.

The following commonly owned patent applications and publications describe in more detail various components described above that may be useful in practicing certain embodiments of the present invention. Each of the following are incorporated herein by reference in their entirety: U.S. Provisional Patent Application Serial No. 60/903,977, filed February 28, 2007, entitled "Weight Measurements of Liquids in Flexible Containers," by P.A. Mitchell, et al; U.S. Provisional Patent Application Serial No. 60/830,997, filed July 14, 2006, entitled "Stirred Tank Bioreactor Having Environmental Containment," by G. Hodge, et al; U.S. Patent Application Serial No. 11/147,124, filed June 6, 2005, entitled "Disposable Bioreactor Systems and Methods," by G. Hodge, et al, published as U.S. Patent Application Publication No. 2005/0272146 on December 8, 2005; International Patent Application No. PCT/US2005/020083, filed June 6, 2005, entitled "Disposable Bioreactor Systems and Methods," by G. Hodge, et al, published as WO 2005/118771 on December 15, 2005; U.S. Patent Application Serial No. 1 1/050,133, filed February 3, 2005, entitled "System and Method for Manufacturing," by G. Hodge, et al, published as U.S. Patent Application Publication No. 2005/0226794 on October 13, 2005; International Patent Application No. PCT/US2005/002985, filed February 3, 2005, entitled "System and Method for Manufacturing," by G. Hodge, et al , published as WO 2005/076093 on August 18, 2005; U.S. Patent Application Serial No. 11/147,124, filed June 6, 2005, entitled "Disposable Bioreactor Systems and Methods," by G. Hodge, et al, published as U.S. Patent Application Publication No. 2005/0272146 on December 8, 2005, U.S. Application Serial No. 60/962,671, filed July 30, 2007, entitled, "Continuous Perfusion Bioreactor System," and a U.S. Patent Application filed on even date herewith, entitled, "Bag Wrinkle Remover, Leak Detection Systems, and Electromagnetic Agitation for Liquid Containment Systems." While several embodiments of the present invention have been described and illustrated herein, those of ordinary skill in the art will readily envision a variety of other means or structures for performing the functions or obtaining the results or one or more of the advantages described herein, and each of such variations or modifications is deemed to be within the scope of the present invention. More generally, those skilled in the art will readily appreciate that all parameters, dimensions, materials, and configurations described herein are meant to be exemplary and that the actual parameters, dimensions, materials, or configurations will depend upon the specific application or applications for which the teachings of the present invention is/are used. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. It is, therefore, to be understood that the foregoing embodiments are presented by way of example only and that, within the scope of the appended claims and equivalents thereto, the invention may be practiced otherwise than as specifically described and claimed. The present invention is directed to each individual feature, system, article, material, kit, or method described herein. In addition, any combination of two or more such features, systems, articles, materials, kits, or methods, if such features, systems, articles, materials, kits, or methods are not mutually inconsistent, is included within the scope of the present invention.

All definitions, as defined and used herein, should be understood to control over dictionary definitions, definitions in documents incorporated by reference, or ordinary meanings of the defined terms.

The indefinite articles "a" and "an," as used herein in the specification and in the claims, unless clearly indicated to the contrary, should be understood to mean "at least one."

It should also be understood that, unless clearly indicated to the contrary, in any methods claimed herein that include more than one step or act, the order of the steps or acts of the method is not necessarily limited to the order in which the steps or acts of the method are recited.

The phrase "or," as used herein in the specification and in the claims, should be understood to mean "either or both" of the elements so conjoined, i.e., elements that are conjunctively present in some cases and disjunctively present in other cases. Other elements may optionally be present other than the elements specifically identified by the "or" term, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, a reference to "A or B" can refer, in one embodiment, to A only (optionally including elements other than B); in another embodiment, to B only (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements); etc. For example, when separating items in a list, "or" shall be interpreted as being inclusive, i.e., the inclusion of at least one, but also including more than one, of a number or list of elements, and, optionally, additional unlisted items. Only terms clearly indicated to the contrary, such as "only one of or "exactly one of," will refer to the inclusion of exactly one element of a number or list of elements. In general, the term "or" as used herein shall only be interpreted as indicating exclusive alternatives (i.e. "one or the other but not both") when preceded by terms of exclusivity, such as "either," "one of," "only one of," or "exactly one of."

In the claims, as well as in the specification above, all transitional phrases such as "comprising," "including," "carrying," "having," "containing," "involving," "holding," "composed of," and the like are to be understood to be open-ended, i.e., to mean including but not limited to. Only the transitional phrases "consisting of and "consisting essentially of shall be closed or semi-closed transitional phrases, respectively.

What is claimed is:

Claims

1. A method of configuring a customizable manufacturing system, comprising: providing a first unit operation configured for performing a biological, chemical, or pharmaceutical manufacturing process or a task of such process, wherein the first unit operation comprises or is positioned in an interior of a first module and the first unit operation includes a first identifier encoded or associated with information about the unit operation; providing a second unit operation configured for performing a biological, chemical, or pharmaceutical manufacturing process or a task of such process, wherein the second unit operation comprises or is positioned in an interior of a second module and the second unit operation includes a second identifier encoded or associated with information about the second unit operation, wherein at least one of the first and second module is configured to be movable; interconnecting the first and second module; and obtaining information by addressing or detecting at least one of the first and second identifiers.

2. The method as in claim 1 , wherein the obtaining information act further comprises verifying the suitability of the connectivity of the first and second unit operations based at least in part upon the information encoded on or associated with the first and second identifiers.

3. The method as in claim 2, wherein verifying the suitability of the connectivity of the first and second unit operations comprises verifying the order of assembly of the unit operations.

4. The method as in claim 1, wherein the obtaining information act further comprises verifying the identity or functions of the unit operations.

5. The method as in claim 1, wherein the obtaining information act further comprises verifying the identity of a customer to whom the unit operations are sold or for whom the biological, chemical, or pharmaceutical manufacturing process is being performed.

6. The method as in claim 1, wherein the obtaining information act further comprises gathering information from at least one of the first and second identifiers for troubleshooting the system.

7. The method as in claim 1, wherein the obtaining information act further comprises determining a location of the unit operations based at least in part upon the information encoded on or associated with the first and second identifiers.

8. The method as in claim 7, wherein the obtaining information act is performed as part of an inventory control process.

9. The method as in claim 1, wherein the obtaining information act further comprises verifying that the unit operations are functioning properly based at least in part upon the information encoded on or associated with the first and second identifiers.

10. The method as in claim 1 , wherein the obtaining information act further comprises determining whether the unit operations are counterfeit based at least in part upon the information encoded on or associated with the first and second identifiers.

1 1. The method as in claim 10, wherein a determination of the presence of a counterfeit component causes system lockout.

12. The method as in claim 1 , wherein the obtaining information act further comprises tracing the unit operations to product lots that are manufactured using the unit operations based at least in part upon the information encoded on or associated with the first and second identifiers.

13. The method as in claim 1 , wherein the obtaining information act further comprises determining whether at least one of the unit operations is properly assembled based at least in part upon the information encoded on or associated with the first and second identifiers.

14. The method as in claim 1, wherein the obtaining information act further comprises verifying that a reagent or product of a first batch of material manufactured with the system is cleared from the system before manufacture of a second batch of material manufactured with the system.

15. The method as in claim 1 , wherein the obtaining information act further comprises verifying that proper reagents are being used for the biological, chemical, or pharmaceutical manufacturing process based at least in part upon the information encoded on or associated with the first and second identifiers.

16. The method as in claim 1 , wherein the first unit operation comprises a vessel.

17. The method as in claim 16, wherein the vessel comprises a collapsible bag and support.

18. The method as in claim 17, wherein the collapsible bag includes an identifier encoded or associated with information about the collapsible bag, tubing connected to the collapsible bag, filter associated with the collapsible bag, connector connected to the collapsible bag, or contents of the collapsible bag.

19. The method as in claim 18, wherein the collapsible bag comprises an impeller.

20. The method as in claim 19, wherein the impeller includes an identifier encoded or associated with information about the impeller.

21. The method as in claim 1 , wherein at least one identifier comprises a radio frequency identification (RFID) tag.

22. The method as in claim 1 , wherein at least one identifier comprises a bar code.

23. The method as in claim 1, wherein at least one identifier comprises a detectable article or material contained in a process fluid in at least one unit operation.

24. A method of configuring a customizable manufacturing system, comprising: providing a unit operation configured for performing a biological, chemical, or pharmaceutical manufacturing process or a task of such process, wherein the unit operation includes a first identifier encoded or associated with information about the unit operation; providing a module configured to be placed in operative association with the unit operation, the module including a second identifier encoded or associated with information about the module, wherein the module is configured to be movable; obtaining information by addressing or detecting at least one of the first and second identifiers; and determining whether or not to place the unit operation and the module in an operative association or determining a configuration of association based at least in part upon the information obtained in the obtaining act.

25. The method of claim 24, further comprising placing the unit operation and the module in operative association with each other.

26. The method of claim 25, wherein placing the unit operation and the module in operative association with each other comprises connecting the unit operation to the module.

27. The method of claim 25, wherein placing the unit operation and the module in operative association with each other comprises placing the unit operation within an interior of the module.

28. The method of claim 27, wherein the unit operation comprises a collapsible bag, and the module comprises a support vessel.

29. The method of claim 24, wherein information encoded within or associated with at least one of the first and second identifiers is utilized to verify that the unit operation and the module are compatible or correctly matched or assembled.

30. The method of claim 24, wherein the information encoded within or associated with at least one of the first and second identifiers is utilized to verify that the unit operation is functioning properly.

31. The method of claim 24, wherein the module comprises a vessel and the unit operation comprises a collapsible bag.

32. The method of claim 24, wherein the module comprises a bioreactor and the unit operation comprises a reagent or media supply container.

33. The method as in claim 24, wherein at least one identifier comprises an RFID tag.

34. The method as in claim 24, wherein at least one identifier comprises a bar code.

35. The method as in claim 24, wherein at least one identifier comprises a detectable article or material contained in a process fluid in the unit operation.

36. The method as in claim 24, wherein two or more modules are connected together.

37. The method as in claim 24, wherein the module comprises an environmental containment enclosure.

38. The method as in claim 37, wherein the unit operation comprises a bioreactor, at least a portion of the bioreactor being contained within the environmental containment enclosure.

39. The method as in claim 37, wherein the unit operation comprises a separation system.

40. The method as in claim 39, wherein the separation system comprises a chromatography column.

41. The method as in claim 39, wherein the separation system comprises a centrifuge.

42. The method as in claim 37, wherein the unit operation comprises a media storage container.

43. A method for configuring a customizable manufacturing system, comprising: providing a first module comprising or having an interior containing a first unit operation configured to perform at least one specific task of a biological, chemical, or pharmaceutical manufacturing process; wherein the first module includes a first identifier encoded or associated with information about the first module; determining a task to be performed by the first module based upon the information encoded in or associated with the first identifier; providing a second module having an interior containing a second unit operation configured to perform at least one specific task of a biological, chemical, or pharmaceutical manufacturing process, wherein the second module includes a second identifier encoded or associated with information about the second module; determining a task to be performed by the second module based upon the information encoded in or associated with the second identifier; wherein each of the first and second unit operations include at least one connector associated therewith for interconnecting the unit operations; determining a configuration of connectivity based upon information encoded on at least one of the first and second identifiers; and arranging the modules and interconnecting the first and second unit operations within the modules according to the configuration of connectivity.

44. The method of claim 43, wherein the determining act comprises determining a first order of connectivity configured to create a manufacturing system configured to produce a first product or perform a first series of specific tasks of a biological, chemical, or pharmaceutical manufacturing process based at least in part upon information encoded on or associated with at least one of the first and second identifiers.

45. The method of claim 44, wherein the arranging act comprises arranging the modules and interconnecting the first and second unit operations within the modules in the first order of connectivity.

46. The method as in claim 43, wherein the determining act further comprises verifying the suitability of the connectivity of the first and second unit operations based at least in part upon the information encoded on or associated with the first and second identifiers.

47. The method as in claim 44, wherein verifying the suitability of the connectivity of the first and second unit operations comprises verifying the order of the unit operations.

48. The method as in claim 43, wherein the determining act further comprises verifying the identity or functions of the unit operations based at least in part upon the information encoded on or associated with the first and second identifiers.

49. The method as in claim 43, wherein the determining act further comprises verifying the identity of a customer to whom the unit operations are sold or for whom the biopharmaceutical manufacturing process is being performed based at least in part upon the information encoded on or associated with the first and second identifiers.

50. The method as in claim 43, wherein the determining act further comprises determining the location of the module.

51. The method as in claim 43, wherein the determining act further comprises gathering information from at least one of the first and second identifiers for troubleshooting the system.

52. The method as in claim 43, wherein the determining act further comprises determining a location of the modules based at least in part upon the information encoded on or associated with the first and second identifiers.

53. The method as in claim 52, wherein the determining act is performed as part of an inventory control process.

54. The method as in claim 43, wherein the determining act further comprises verifying that the unit operations are functioning properly based at least in part upon the information encoded on or associated with the first and second identifiers.

55. The method as in claim 43, wherein the determining act further comprises determining whether the unit operations are counterfeit based at least in part upon the information encoded on or associated with the first and second identifiers.

56. The method as in claim 55, wherein the determination of the presence of a counterfeit component causes system lockout.

57. The method as in claim 43, wherein the determining act further comprises determining a lack of presence of an identifier where the presence of one is expected, the presence of an incorrect identifier, or a condition of misalignment or mispositioning of one or more modules or components of the system.

58. The method as in claim 55, wherein the determination of the lack of presence of an identifier where the presence of one is expected, the presence of an incorrect identifier, or the condition of misalignment or mispositioning of one or more modules or components of the system causes system lockout.

59. The method as in claim 43, wherein the determining act further comprises tracing the unit operations to product lots that are manufactured using the unit operations based at least in part upon the information encoded on or associated with the first and second identifiers.

60. The method as in claim 43, wherein the determining act further comprises determining whether at least one of the unit operations is properly assembled based at least in part upon the information encoded on or associated with the first and second identifiers.

61. The method as in claim 43, wherein the determining act further comprises verifying that proper reagents are being used for the biopharmaceutical manufacturing process based at least in part upon the information encoded on or associated with the first and second identifiers.

62. The method as in claim 43, wherein at least one of the modules comprises a collapsible bag housed within a support.

63. The method as in claim 62, wherein the collapsible bag includes an impeller.

64. The method asjn claim 63, wherein the impeller includes an identifier encoded on or associated with information about the impeller.

65. The method as in claim 62, wherein the collapsible bag includes an identifier encoded on or associated with information about the collapsible bag, tubing connected to the collapsible bag, filter associated with the collapsible bag, connector connected to the collapsible bag, or contents of the collapsible bag.

66. The method as in claim 43, wherein at least one identifier comprises an RFID tag.

67. The method as in claim 43, wherein at least one identifier comprises a bar code.

68. The method as in claim 43, wherein at least one identifier comprises a detectable article or material contained in a process fluid in at least one unit operation.

69. A customizable manufacturing system comprising: at least two modules wherein each module comprises an interior space capable of being interconnected with another module interior space and contains one or more components configured to perform at least one specific task of a biological, chemical, or pharmaceutical manufacturing process; wherein at least one of the modules is configured to be movable and includes an identifier encoded on or associated with information about the module; and a control system configured to perform one or more of operation of components and process control, and further configured to access and process information obtained from or associated with the at least one identifier on at least one of the modules and to perform a function based upon the information encoded by or associated with the at least one identifier on at least one of the modules.

70. The customizable manufacturing system of claim 69, wherein at least one of the modules includes an environmental control system for controlling an environment within the module.

71. The customizable manufacturing system of claim 69, wherein the control system comprises a computer configured and programmed to generate quality control verification reports based at least in part on information encoded by or associated with the at least one identifier.

72. The customizable manufacturing system of claim 69, wherein the control system function performed based upon the information encoded by or associated with the at least one identifier comprises verifying the suitability of the connectivity of the at least two modules.

73. The customizable manufacturing system of claim 69, wherein the control system function performed based upon the information encoded by or associated with the at least one identifier comprises verifying the identity or functions of the at least two modules.

74. The customizable manufacturing system of claim 69, wherein the control system function performed based upon the information encoded by or associated with the at least one identifier comprises determining the location or relative position of at least one of the at least two modules.

75. The customizable manufacturing system of claim 69, wherein the control system function performed based upon the information encoded by or associated with the at least one identifier comprises verifying that the vessels are functioning properly.

76. The customizable manufacturing system of claim 69, wherein the control system function performed based upon the information encoded by or associated with the at least one identifier comprises determining whether at least one of the modules is counterfeit or comprises a counterfeit component.

77. The customizable manufacturing system of claim 76, wherein the determination of the presence of a counterfeit module or component thereof causes system lockout.

78. The customizable manufacturing system of claim 69, wherein the control system function performed based upon the information encoded by or associated with the at least one identifier comprises tracing the module to a product lot that is manufactured using the module.

79. The customizable manufacturing system of claim 69, wherein the control system function performed based upon the information encoded by or associated with the at least one identifier comprises determining whether at least one of the unit operations is properly assembled.

80. The customizable manufacturing system of claim 69, wherein the control system function performed based upon the information encoded by or associated with the at least one identifier comprises verifying that proper reagents are being used for the biological, chemical, or pharmaceutical manufacturing process.

81. The customizable manufacturing system of claim 69, wherein at least one of the modules comprises a vessel.

82. The customizable manufacturing system of claim 81, wherein the vessel comprises a collapsible bag and support structure.

83. The customizable manufacturing system of claim 82, wherein the collapsible bag includes an impeller.

84. The customizable manufacturing system of claim 83, wherein the impeller includes an identifier encoded or associated with information.

85. The customizable manufacturing system of claim 81, wherein the collapsible bag includes an identifier encoded or associated with information.

86. The customizable manufacturing system of claim 69, wherein the at least one identifier comprises an RFID tag.

87. The customizable manufacturing system of claim 69, wherein the at least one identifier comprises a bar code.

88. The customizable manufacturing system of claim 69, wherein the at least one identifier comprises a detectable article or material contained in a process fluid in at least one unit operation.

89. A vessel configured to contain a volume of liquid, the vessel comprising: an identifier encoded with information about the vessel; a collapsible bag configured to contain the liquid; and a reusable support structure surrounding and containing the collapsible bag.

90. The vessel of claim 89, wherein the vessel is part of a reactor in a biological, biochemical or a chemical reaction system.

91. The vessel of claim 89, wherein the identifier is embedded into the wall of the vessel.

92. The vessel of claim 89, wherein the information about the vessel comprises information regarding at least one property of the liquid contained within the collapsible bag.

93. The vessel of claim 92, wherein the at least one property of the liquid is at least one of the following: pH, temperature, pressure, fluid flow pattern, oxygen level, CO₂ level, reagent level, product level, metabolite level, or conductivity.

94. The vessel of claim 89, wherein the information encoded on the identifier comprises information regarding the compatibility of the vessel with other components of a manufacturing system.

95. The vessel of claim 89, wherein the information encoded on the identifier comprises information regarding the identity or functions of the vessel.

96. The vessel of claim 89, wherein the information encoded on the identifier comprises information regarding the location or positioning of the vessel.

97. The vessel of claim 89, wherein the information encoded on the identifier comprises information regarding verification that the vessel is functioning properly.

98. The vessel of claim 89, wherein the information encoded on the identifier comprises information regarding authenticity verification.

99. The vessel of claim 89, wherein the information encoded on the identifier comprises information linking the vessel to a product lot that is manufactured using the vessel.

100. The vessel of claim 89, wherein the collapsible bag includes an impeller.

101. The vessel of claim 89, wherein the identifier comprises a detectable material or article suspended or dissolved in process fluid contained in the vessel.

102. The vessel of claim 101, wherein the information about the vessel comprises information about the process fluid contained in the vessel.

103. A collapsible bag comprising: an identifier encoded with information about the collapsible bag; a flexible wall portion; and a rigid portion comprising a base including a shaft configured to support a magnetic impeller, wherein the rigid portion is connected to the flexible wall portion.

104. The collapsible bag of claim 103, wherein the collapsible bag is part of a reactor in a biological, biochemical or a chemical reaction system.

105. The collapsible bag of claim 103, wherein the identifier is embedded into the wall portion of the collapsible bag.

106. The collapsible bag of claim 103, wherein the information about the collapsible bag comprises information regarding at least one property of a liquid contained within the collapsible bag.

107. The collapsible of claim 106, wherein the at least one property of the liquid is at least one of the following: pH, temperature, pressure, fluid flow pattern, oxygen level, CO₂ level, reagent level, product level, metabolite level, or conductivity.

108. The collapsible of claim 103, wherein the information encoded on the identifier comprises information regarding the compatibility of the collapsible bag with other components of a manufacturing system in which the collapsible bag is utilized.

109. The collapsible of claim 103, wherein the information encoded on the identifier comprises information regarding the identity of the owner of the collapsible bag.

110. The collapsible of claim 103, wherein the information encoded on the identifier comprises information regarding verification that the collapsible bag is functioning properly.

111. The collapsible of claim 103, wherein the information encoded on the identifier comprises information regarding authenticity verification.

112. The collapsible of claim 103, wherein the information encoded on the identifier comprises information linking the collapsible bag to a product lot that is manufactured using the collapsible bag.

1 13. A customizable manufacturing system comprising: at least two portable modules, each module having an interior including one or more unit operation components for performing at least one specific task of a biological, chemical, or pharmaceutical manufacturing process; a connection port associated with each of the modules for interconnecting the modules; and an identifier encoded with information about a component of the customizable manufacturing system, wherein upon connection, each module can be moved relative to the other without breaking the connection.