Patent Description:
Cell cultures are typically grown in batch processes where the biological material remains in the bioreactor until the end of the reaction time. In certain of these processes, fluid medium contained within the bioreactor can be periodically or continuously removed and resupplied in order to replenish nutrients contained within the fluid medium and for possibly removing damaging by-products that are produced during the process.

During the growth and harvesting of cell cultures, various fluids are formulated and fed to different process equipment. Such fluids, for instance, can include nutrient mediums, various different types of reagents, buffer formulations, and the like. In addition, fluids are also conveyed between different process components. For example, cell cultures are typically grown in bioreactors and then fed downstream to different purification processes. The purification processes can include chromatography skids, filtration devices, and the like. Each of these different steps of the process can also produce product and byproduct streams that are removed during the process and stored in different containers, such as bioprocess bags.

As the development of biologics continue, the ability to mass produce cell cultures in large volumes in order to produce bioproducts is imperative. The recent coronavirus pandemic, for instance, has further illustrated the need for robust processes for producing biologic products. For example, vaccines are currently being produced and tested against the coronavirus strain. Many of these vaccines are based upon biological products obtained from microorganisms, such as messenger RNA therapeutic deliveries. Once a vaccine has been tested and approved, it will be necessary to produce conceivably billions of doses of the vaccine. Thus, there is a need to produce large scale cell culture systems that operate reliably and efficiently.

During the transfer of fluids in larger scale biological processes, larger bioprocess tubes are needed in order to accommodate the volumetric flow rates of the fluids. After fluid transfer, many of these bioprocess tubes must then be disconnected from the different process equipment. Currently, the only solution for connecting and disconnecting larger bioprocess tubes is to purchase bioprocess tubes with automatic disconnects or to install disconnects on the tube. These disconnect devices, however, can form weakened areas along the bioprocess tube and are susceptible to leakage during high pressure operations. In addition, not only are the disconnect devices expensive, but they also provide no ability to make adjustments regarding the location on the bioprocess tube where a disconnection may be desired. Consequently, preassembled disconnect devices are not only impractical, but can also reduce the efficiency of the overall process.

In view of the above, a need exists for a system and method for easily disconnecting mid-scale and large scale bioprocess tubes in a biological process.

The present disclosure is generally directed to a system and method for growing, harvesting and purifying cell cultures and bioproducts produced therefrom. More particularly, the present disclosure is directed to a bioprocess system and method capable of producing relatively large batches of biological materials. The components contained within the system are all sized for high throughputs in order to produce all different types of beneficial bioproducts, including vaccines for different viruses. In accordance with the present disclosure, the bioprocess method and system include relatively large bioprocess tubes that convey fluids and connect the different components. The present disclosure is directed to a method of disconnecting the bioprocess tubes after fluid flow in an efficient and sterile manner.

For example, in one aspect, the present disclosure is directed to a bioprocess system comprising a first bioprocess device and a second bioprocess device. A bioprocess tube is in fluid communication with the first bioprocess device and the second bioprocess device. The bioprocess tube comprises a thermoplastic elastomer. The bioprocess tube defines a hollow passageway having an internal diameter, an external diameter, and an external surface. The internal diameter of the bioprocess tube is greater than about <NUM>, such as greater than about <NUM>, such as greater than about <NUM>, such as greater than about <NUM>, such as greater than about <NUM>, such as greater than about <NUM>, such as greater than about <NUM>, such as greater than about <NUM>. In accordance with the present disclosure, the system further includes a separating collar for facilitating cutting of the bioprocess tube for disconnecting the first bioprocess device from the second bioprocess device. The separating collar is slidably mounted on the exterior surface of the bioprocess tube. The separating collar has a cylindrical shape and has a length that extends from a first end to a second and opposite end. The separating collar is made from a rigid and malleable material. The separating collar defines at least one pair of adjacent separating edges that extend over the length of the collar. The pair of adjacent separating edges allow the separating collar to be installed and removed from a bioprocess tube. For instance, in one aspect, pair of adjacent separating edges form a slit that extends over the length of the collar.

The separating device can be made from various different materials, such as metallic materials, polymer materials, and the like. The separating collar can be made from a single layer of material or can be made from multiple layers of material. In one embodiment, the separating collar can be made from aluminum. During cutting of the bioprocess tube, a cutting device is used to cut the separating collar and the underlying tube. During cutting, the separating collar and bioprocess tube are compressed. The separating collar is made from a material with sufficient rigidity and malleability such that after cutting the bioprocess tube, the separating collar maintains the open ends of the bioprocess tube in a closed configuration. Consequently, the separating collar is made from a material that is able to withstand the natural biasing forces of the bioprocess tube once the clamping action of the cutting tool is released.

As described above, the separating collar can define a slit along the length of the collar. The slit can have a width, in one aspect, of greater than about <NUM>, such as greater than about <NUM>, such as greater than about <NUM>, such as greater than about <NUM>, and less than about <NUM>, such as less than about <NUM>. In another aspect, the slit can be wider. For instance, the slit can have a width of greater than about <NUM>, such as greater than about <NUM>, such as greater than about <NUM>, such as greater than about <NUM>, and generally less than about <NUM>. In general, the slit should have a width that facilitates opening the collar so as to place the collar around a bioprocess tube. The length of the separating collar can generally be from about <NUM> to about <NUM>.

In an alternative embodiment, the opposite ends of the separating collar can overlap along the slit. For example, the opposite free ends of the separating collar can overlap by greater than about <NUM>, such as greater than about <NUM>, and generally less than about <NUM>, such as less than about <NUM>.

In still another alternative embodiment, the separating collar comprises a first collar member and a separate second collar member. The first and second collar members cooperate together to form the cylindrical shape. In this embodiment, the separating collar can form two pairs of adjacent separating edges where the first collar member intersects the second collar member.

The present disclosure is also directed to a process for separating a bioprocess tube contained in a bioprocess. The method includes placing a separating collar on an exterior surface of a bioprocess tube. The bioprocess tube is made from a thermoplastic elastomer and has an internal diameter of greater than about <NUM>, such as greater than about <NUM>. The separating collar is slidably mounted on the exterior surface of the bioprocess tube. The separating collar has a cylindrical shape having a length. At least one pair of adjacent separating edges extend over the length of the separating collar. The pair of adjacent separating edges is for allowing the separating collar to be installed and removed from the bioprocess tube. The method further includes the step of cutting through the separating collar and the bioprocess tube to produce a first free end and a second free end. During cutting, the separating collar and underlying bioprocess tube are deformed, compressing the walls of the bioprocess tube together at each free end. The separating collar is made from a material with sufficient rigidity and malleability to maintain the open ends of the bioprocess tube in a closed state or condition.

In one aspect, the method can further include the step of blocking flow of fluid through the bioprocess tube upstream of the separating device using a flow stop device and blocking flow of fluids through the bioprocess tube downstream of the separating device using a second flow stop device. The flow stop devices, for instance, can comprise clamps and can be installed on each side of the separating device prior to cutting the bioprocess tube.

The present disclosure is also directed to a bioprocess apparatus comprising a separating collar as described above removably and slidably mounted on a bioprocess tube having an internal diameter greater than about <NUM>.

A full and enabling disclosure of the present disclosure is set forth more particularly in the remainder of the specification, including reference to the accompanying figures, in which:.

It is to be understood by one of ordinary skill in the art that the present discussion is a description of exemplary embodiments only and is not intended as limiting the broader aspects of the present disclosure.

In general, the present disclosure is directed to a system and method for propagating cell cultures, harvesting the cell cultures, purifying the cell cultures and producing a biological product. Many different types of biological products can be produced according to the present disclosure. For instance, the biological product can be a protein or any other metabolite produced by the cell culture. In one embodiment, the cell culture can be used to produce a vaccine for viruses, such as recombinant messenger RNA.

Currently, a major obstacle to the production of biologics, such as vaccines, is the ability to produce the biological products on a larger scale in a reliable manner. In particular, a need exists for bioprocess systems and methods that operate at relatively high throughputs. When over-sizing the equipment and components, various obstacles can exist that may reduce efficiencies. For example, mid-scale and large-scale bioprocess systems need bioprocess tubes that have larger sizes and diameters for connecting the different components together. The present disclosure is directed to an efficient way to disconnect larger bioprocess tubes after fluid flow in order to isolate a component in the system and/or to collect a product or a byproduct in, for instance, a bioprocess bag.

For exemplary purposes only, <FIG> illustrates one example of a bioprocess system that may incorporate the elements of the present disclosure for connecting and disconnecting the various different components and bioprocess devices. The bioreactor system includes a bioreactor <NUM>. In general, the system and process of the present disclosure can use any suitable bioreactor. The bioreactor, for instance, may comprise a fermenter, a stirred-tank reactor, an adherent bioreactor, a wave-type bioreactor, a disposable bioreactor, and the like. In the embodiment illustrated in <FIG>, the bioreactor <NUM> comprises a hollow vessel or container that includes a bioreactor volume <NUM> for receiving a cell culture within a fluid growth medium. As shown in <FIG>, the bioreactor system can further include a rotatable shaft <NUM> coupled to an agitator such as dual impellers <NUM> and <NUM> and to a motor <NUM>.

The bioreactor <NUM> can be made from various different materials. In one embodiment, for instance, the bioreactor <NUM> can be made from metal, such as stainless steel. Alternatively, the bioreactor <NUM> may comprise a single use bioreactor made from a rigid polymer or a flexible polymer film.

The bioreactor <NUM> can have any suitable volume. In general, however, the bioreactor <NUM> has a volume of greater than about <NUM>, such as greater than about <NUM>, such as greater than about <NUM>, such as greater than about <NUM>, such as greater than about <NUM>, such as greater than about <NUM>, such as greater than about <NUM>, such as greater than about <NUM>, such as greater than about <NUM>, such as greater than about <NUM>, such as greater than about <NUM>, such as greater than about <NUM>, such as greater than about <NUM>, such as greater than about <NUM>. The volume of the bioreactor <NUM> can be even greater than about <NUM>, such as greater than about <NUM>,<NUM>, such as greater than about <NUM>,<NUM>, such as greater than about <NUM>,<NUM>. The volume of the bioreactor <NUM> is generally less than about <NUM>,<NUM>, such as less than about <NUM>,<NUM>.

In addition to the impellers <NUM> and <NUM>, the bioreactor <NUM> can include various additional equipment, such as baffles, spargers, gas supplies, heat exchangers or thermal circulator ports, and the like which allow for the cultivation and propagation of biological cells. For example, in the embodiment illustrated in <FIG>, the bioreactor <NUM> includes a sparger <NUM> and a baffle <NUM>.

As shown in <FIG>, the bioreactor <NUM> also includes a plurality of ports. The ports can allow supply lines and feed lines into and out of the bioreactor <NUM> for adding and removing fluids and other materials. In addition, the one or more ports may be for connecting to one or more probes for monitoring conditions within the bioreactor <NUM>. In addition, the bioreactor <NUM> and be placed in association with a load cell for measuring the mass of the culture within the bioreactor.

In the embodiment illustrated in <FIG>, the bioreactor <NUM> includes a bottom port <NUM> connected to an effluent <NUM> for withdrawing materials from the bioreactor continuously or periodically. Materials can be withdrawn from the bioreactor <NUM> using any suitable method. For instance, in an alternative embodiment, an effluent can be removed from the bioreactor <NUM> from the top of the bioreactor using a dip tube. In addition, the bioreactor <NUM> includes a plurality of top ports, such as ports <NUM>, <NUM>, and <NUM>. Port <NUM> is in fluid communication with a first fluid feed <NUM>, port <NUM> is in fluid communication with a second feed <NUM> and port <NUM> is in fluid communication with a third feed <NUM>. The feeds <NUM>, <NUM> and <NUM> are for feeding various different materials to the bioreactor <NUM>, such as a nutrient media.

As shown in <FIG>, the bioreactor can be in communication with multiple nutrient feeds. In this manner, a nutrient media can be fed to the bioreactor containing only a single nutrient for better controlling the concentration of the nutrient in the bioreactor during the process. In addition or alternatively, the different feed lines can be used to feed gases and liquids separately to the bioreactor.

Once a cell culture has been propagated in the bioreactor <NUM>, in one embodiment, the cell culture is fed to a harvest system for harvesting a bioproduct. Not shown, for instance, the system may include a harvest tank, and a centrifuge. In many systems, the bioproduct being harvested can then be fed to downstream purification processes. For example, in <FIG>, the bioproduct harvested from the bioreactor <NUM> can be fed to a first filtration device <NUM>, a chromatography device <NUM>, and a second filtration device <NUM>. It should be understood that the system illustrated in <FIG> is merely exemplary and the system can include more than one chromatography device, less than two filtration devices or more than two filtration devices as desired.

The filtration devices <NUM> and <NUM> may include a variety of filtration mechanisms. For example, in one embodiment, one of the filtration devices may comprise a tangential flow filtration (TFF) device. A tangential flow filtration device, for instance, may enable the diafiltration of the product stream. A tangential flow filtration device may include two stages; volume reduction and diafiltration. During the volume reduction step, the bulk volume of the cell culture medias is filtered out through the permeate side of the filter until a desired product concentration is reached in the holding tank. In a diafiltration stage following the volume reduction stage, the concentrated product is washed with a fluid, such as a buffer, to remove cell culture or harvest media components that are undesired or are unacceptable. Further volume reduction may also be carried out after diafiltration to reach a desired product density.

In one embodiment, the filtration devices <NUM> and <NUM> may use ultrafiltration. During ultrafiltration, the product stream is fed through a semipermeable membrane. Suspended solids and solutes of high molecular weight are retained as a retentate, while water and low molecular weight solutes pass through the membrane as the permeate. Ultrafiltration is particularly well suited to purifying and concentrating protein solutions. In one embodiment, ultrafiltration can be used with diafiltration as described above. The chromatography device <NUM> as shown in <FIG> may use various different chromatography methods such as affinity chromatography, gel filtration chromatography, ion exchange chromatography, reversed phase chromatography, hydrophobic interaction chromatography, and the like.

The process and system of the present disclosure, for instance, can use any suitable chromatography method.

Similar to the filtration devices <NUM> and <NUM>, the chromatography device <NUM> may also need a buffer for proper operation of the device.

As shown in <FIG>, the system can further include a buffer device <NUM> that stores and/or formulates buffers for feeding to the different components.

As shown in <FIG>, the system can further include a controller <NUM>. The controller may comprise one or more programmable devices or microprocessors. As shown, the controller <NUM> can be in communication with the one or more feeds <NUM>, <NUM> and <NUM> and with one or more effluents <NUM>.

In addition to the bioprocess devices illustrated in <FIG>, various other bioprocess devices can be incorporated into the system. For instance, the system can include membrane devices, cation exchange devices, virus reduction filtration devices, and the like.

As shown in <FIG>, each of the bioprocess devices can be in fluid communication with each other using various different bioprocess tubes <NUM>. In addition, various different bioprocess devices contained within the system can also produce a byproduct stream that can be collected in a bioprocess container or bag. A bioprocess tube can provide fluid commination between the bioprocess container and the other bioprocess device.

The present disclosure is generally directed to a bioprocess apparatus that can efficiently disconnect one bioprocess device from another bioprocess device at any location along a bioprocess tube that was previously used to connect the devices for fluid flow. The bioprocess apparatus of the present disclosure is particularly well suited to forming disconnects on bioprocess tubes that are used in mid-scale and large-scale systems. More particularly, the bioprocess apparatus is designed to form a separation along a bioprocess tube that has a relatively large internal diameter. In one aspect, the bioprocess device can be used to produce a sterile disconnect along the bioprocess tube.

Referring to <FIG>, one embodiment of a bioprocess apparatus <NUM> made in accordance with the present disclosure is shown. The bioprocess apparatus <NUM> includes a bioprocess tube <NUM> in combination with a separating collar <NUM>. Referring to <FIG>, a cross-sectional view of the bioprocess tube <NUM> is illustrated. The bioprocess tube <NUM> defines an interior passageway <NUM> that is surrounded by an interior surface <NUM>. The bioprocess tube <NUM> includes a wall thickness <NUM> that also defines an exterior surface <NUM>.

The bioprocess tube <NUM> can be made from a polymer material, particularly a thermoplastic polymer. In one aspect, the bioprocess tube <NUM> is made from a thermoplastic elastomer. For instance, the bioprocess tube <NUM> can be made from a silicone polymer. Other elastomers that may be used to produce the bioprocess tube include polyvinyl chloride polymers, polypropylene polymers, polyethylene polymers, or a polyester polymer. As used herein, a polymer can refer to a homopolymer, a copolymer, a block copolymer, a random copolymer, a terpolymer, and the like. For example, polypropylene elastomers can be used that contain a polypropylene homopolymer combined with a polypropylene random copolymer. If desired, the polymer composition used to produce the bioprocess tube <NUM> can contain a plasticizer.

As described above, the bioprocess tube <NUM> has a relatively large size capable of conveying significant fluid flow therethrough. The bioprocess tube <NUM> can have an internal diameter measured from the interior surface <NUM> and an exterior diameter measured from the exterior surface <NUM>. In general, the internal diameter of the bioprocess tube <NUM> in accordance with the present disclosure is greater than about <NUM>. For instance, the internal diameter of the bioprocess tube <NUM> can be greater than about <NUM>, such as greater than about <NUM>, such as greater than about <NUM>, such as greater than about <NUM>, such as greater than about <NUM>, such as greater than about <NUM>, such as greater than about <NUM>, such as greater than about <NUM>, such as greater than about <NUM>, such as greater than about <NUM>, such as greater than about <NUM>, such as greater than about <NUM>, such as greater than about <NUM>, such as greater than about <NUM>, such as greater than about <NUM>. The internal diameter of the bioprocess tube <NUM> is generally less than about <NUM>, such as less than about <NUM>. In one particular aspect, the internal diameter of the bioprocess tube <NUM> is from about <NUM> to about <NUM>, including all increments of <NUM> therebetween.

The wall thickness <NUM> of the bioprocess tube <NUM> can vary depending upon various factors including the type of thermoplastic polymer used to make the bioprocess tube, and the amount of pressure that may build up within the bioprocess tube <NUM> during operation. In general, the wall thickness <NUM> is generally greater than about <NUM>, such as greater than about <NUM>, such as greater than about <NUM>, and generally less than about <NUM>, such as less than about <NUM>, such as less than about <NUM>.

Referring back to <FIG>, the separating collar <NUM> of the present disclosure is shown mounted on the exterior surface <NUM> of the bioprocess tube <NUM>. The separating collar <NUM> generally has a cylindrical shape that is designed to accommodate the outside diameter of the bioprocess tube <NUM>. The separating collar <NUM> includes a pair of adjacent separating edges that define a slit <NUM> that extends along the length of the separating collar <NUM> from a first end to a second and opposite end.

In an alternative embodiment, the opposing ends of the separating collar <NUM> along the slit <NUM> can overlap. For example, as shown in <FIG>, the separating collar <NUM> defines a slit <NUM>. The opposite ends or edges of the separating collar <NUM> overlap along the slit <NUM>. The amount of overlap can depend upon various factors. In general, the opposite ends overlap greater than about <NUM>, such as greater than about <NUM>, such as greater than about <NUM>, such as greater than about <NUM>. The amount the opposite ends overlap is generally less than about <NUM>, such as less than about <NUM>, such as less than about <NUM>, such as less than about <NUM>, such as less than about <NUM>, such as less than about <NUM>.

The slit <NUM> can have various different purposes. In one aspect, for instance, the slit <NUM> allows the separating collar <NUM> to be fitted over bioprocess tubes <NUM> that have different external diameters. In addition, the slit <NUM> can be used to place the separating collar <NUM> onto the exterior surface <NUM> of the bioprocess tube <NUM>. For instance, by grasping opposite ends of the separating collar <NUM> along the slit <NUM>, one can increase the size of the slit so that the separating collar <NUM> can be placed over the bioprocess tube <NUM>. In an alternative embodiment, a device or tool made be used that can engage opposite ends of the separating collar along the slit <NUM> for providing the force necessary for the slit to open up for accommodating a bioprocess tube. In still another embodiment, the separating collar can be manufactured in an open state allowing the collar to be placed over a bioprocess tube. Once placed over the bioprocess tube, the separating collar can then be bended into a desired shape that conforms to the exterior surface of the bioprocess tube.

In addition to the above, the slit <NUM> also allows the separating device <NUM> to be slidably mounted onto the bioprocess tube <NUM>. In this manner, the separating collar <NUM> can be moved to any desired location on the bioprocess tube. The ability to slide the separating collar <NUM> over the exterior surface <NUM> of the bioprocess tube <NUM> provides significant flexibility in determining later the best location to separate the bioprocess tube after fluid flow has stopped.

The width of slit <NUM> along the length of the separating collar <NUM> can vary depending upon the type of material used to produce the separating collar <NUM>, the outside diameter of the bioprocess tube <NUM>, and the like. In one aspect, for instance, the slit <NUM> can be relatively narrow. For instance, the slit can have a width of less than about <NUM>, such as less than about <NUM>, such as less than about <NUM>, such as less than about <NUM>, and generally greater than about <NUM>, such as greater than about <NUM>. Alternatively, the slit can be wider, especially when the separating collar <NUM> is to be installed on larger bioprocess tubes. For instance, the width of the slit can be greater than about <NUM>, such as greater than about <NUM>, such as greater than about <NUM>, such as greater than about <NUM>, and generally less than about <NUM>.

The length of the separating collar <NUM> and therefore the length of the slit can generally be anywhere from about <NUM> to about <NUM>,<NUM> and including all increments of <NUM> therebetween. The length of the separating collar <NUM>, for instance, should be sufficient to maintain the bioprocess tube in a closed condition after cutting as will be explained in greater detail below. The upper boundary of the length is not a factor and there may be applications where the length can be greater than about <NUM>, such as greater than about <NUM>, such as greater than about <NUM>,<NUM>, such as greater than about <NUM>,<NUM>.

In <FIG>, <FIG>, the separating collar is made from a single, integral piece of material that includes a single pair of adjacent separating edges that define a slit. In other embodiments, however, the separating collar can be made from multiple pieces of material.

For example, referring to <FIG> and <FIG>, a separating collar <NUM> is illustrated that includes a first collar member <NUM> a second collar member <NUM>. The first collar member <NUM> and the second collar member <NUM> are capable of being attached together as shown particularly in <FIG>. For instance, the separating collar <NUM> as shown in <FIG> defines a first pair of adjacent separating edges <NUM> and a second pair of adjacent separating edges <NUM>. By being made from two separate pieces of material, the separating collar <NUM> can easily be placed over a bioprocess tube.

As shown in <FIG>, the first collar member <NUM> and the second collar member <NUM> are capable of being attached together along the separating edges <NUM> and <NUM>. In general, any suitable attachment device can be used in order to connect the first collar member <NUM> to the second collar member <NUM>. In the embodiment illustrated in <FIG>, the first collar member <NUM> includes curled edges <NUM> and <NUM> that are adapted to engage curled edges <NUM> and <NUM> on the second collar member <NUM>. It should be understood, however, that any male and female connection can be made between the collar members <NUM> and <NUM> along their adjacent edges.

In an alternative embodiment, the first collar member <NUM> can be connected to the second collar member <NUM> along a hinge at a first pair of adjacent separating edges. The second pair of adjacent separating edges, on the other hand, can include a connecting device that permits the two edges to connect.

Referring to <FIG> and <FIG>, one embodiment of a disconnect process in accordance with the present disclosure is illustrated. The bioprocess tube <NUM> in <FIG> can provide fluid communication between two different bioprocess devices. The bioprocess tube <NUM> can be used for fluid transfer between the two devices. After fluid transfer has terminated, in many operations, it is desirable to disconnect the first bioprocess device from the second bioprocess device. The bioprocess apparatus of the present disclosure provides for an efficient and convenient way to disconnect the two devices from each other.

As explained above, the separating collar <NUM> is first slidably mounted onto the bioprocess tube <NUM>. The separating collar <NUM> can then be moved to any desired location where a disconnect operation can take place. Once positioned at the appropriate location, a cutting tool <NUM> as shown in <FIG> can then be used to cut through both the separating device <NUM> and the underlying bioprocess tube <NUM>. In the embodiment illustrated in <FIG>, the cutting tool <NUM> is a handheld device. In other embodiments, however, a motorized device may also be used.

A cutting device <NUM> is used that compresses the separating collar <NUM> and bioprocess tube <NUM> while simultaneously cutting through both materials. For instance, the cutting device <NUM> can deform the separating device <NUM> and compress the bioprocess tube squeezing the interior wall of the bioprocess tube together. Once the bioprocess tube <NUM> and separating collar <NUM> are compressed together, the cutting device <NUM> cuts through both materials and forms a first free end <NUM> and a second free end <NUM> as shown in <FIG>. As shown in <FIG>, the separating collar <NUM> made in accordance with the present disclosure is made from a material with sufficient malleability and rigidity to deform during cutting and then maintain each free end <NUM> and <NUM> in a closed condition. In this manner, the bioprocess apparatus of the present disclosure can produce a sterile disconnect and even an aseptic seal.

In one embodiment, in order to ensure that no fluid drips or spills from the bioprocess tube <NUM> during the cutting operation, flow stop devices can be installed upstream and downstream from the separating collar <NUM>. The flow stop device can be any suitable clamp capable of cutting off fluid flow through the bioprocess tube <NUM>.

The material used to produce the separating collar <NUM> should be selected so that the separating collar <NUM> can be fitted over a bioprocess tube, can be compressed during a cutting process, and can maintain the free ends formed during the cutting process in a closed position. The separating collar <NUM>, for instance, can be made from a polymer material, a reinforced polymer material, a metal, or mixtures thereof. The separating collar <NUM> can be made from a single layer of material or can have a multilayer design.

In one aspect, the separating collar <NUM> is made from a metal, such as an aluminum. The thickness of the separating collar <NUM> can generally be greater than about <NUM>, such as greater than about <NUM>, such as greater than about <NUM>, such as greater than about <NUM>, such as greater than about <NUM>, such as greater than about <NUM>, such as greater than about <NUM>, such as greater than about <NUM>. The thickness is generally less than about <NUM>, such as less than about <NUM>, such as less than about <NUM>, such as less than about <NUM>.

The separating device <NUM> can be used at any desired location within a bioprocess system, such as any place shown in the bioprocess system of <FIG>. In one aspect, the separating collar can be used to disconnect a bioreactor from any upstream or downstream bioprocess device. The separating collar, for instance, can be used to disconnect a bioreactor from a media supply, buffer supply, gas supply, or the like. The separating collar can also be used to disconnect a bioreactor from a downstream device, such as a filtration device.

The separating collar can also be used during harvesting and purification. For instance, the separating device can be used to separate a chromatography device from a filtration device or a filtration device from a process bag.

The devices, facilities and methods described herein are suitable for culturing any desired cell line including prokaryotic and/or eukaryotic cell lines. Further, in embodiments, the devices, facilities and methods are suitable for culturing suspension cells or anchorage-dependent (adherent) cells and are suitable for production operations configured for production of pharmaceutical and biopharmaceutical products-such as polypeptide products, nucleic acid products (for example DNA or RNA), or cells and/or viruses such as those used in cellular and/or viral therapies.

In embodiments, the cells express or produce a product, such as a recombinant therapeutic or diagnostic product. As described in more detail below, examples of products produced by cells include, but are not limited to, antibody molecules (e.g., monoclonal antibodies, bispecific antibodies), antibody mimetics (polypeptide molecules that bind specifically to antigens but that are not structurally related to antibodies such as e.g. DARPins, affibodies, adnectins, or IgNARs), fusion proteins (e.g., Fc fusion proteins, chimeric cytokines), other recombinant proteins (e.g., glycosylated proteins, enzymes, hormones), viral therapeutics (e.g., anti-cancer oncolytic viruses, viral vectors for gene therapy and viral immunotherapy), cell therapeutics (e.g., pluripotent stem cells, mesenchymal stem cells and adult stem cells), vaccines or lipid-encapsulated particles (e.g., exosomes, virus-like particles), RNA (such as e.g. siRNA) or DNA (such as e.g. plasmid DNA), antibiotics or amino acids. In embodiments, the devices, facilities and methods can be used for producing biosimilars.

As mentioned, in embodiments, devices, facilities and methods allow for the production of eukaryotic cells, e.g., mammalian cells or lower eukaryotic cells such as for example yeast cells or filamentous fungi cells, or prokaryotic cells such as Gram-positive or Gram-negative cells and/or products of the eukaryotic or prokaryotic cells, e.g., proteins, peptides, antibiotics, amino acids, nucleic acids (such as DNA or RNA), synthesised by the eukaryotic cells in a large-scale manner. Unless stated otherwise herein, the devices, facilities, and methods can include any desired volume or production capacity including but not limited to bench-scale, pilot-scale, and full production scale capacities.

Moreover and unless stated otherwise herein, the devices, facilities, and methods can include any suitable reactor(s) including but not limited to stirred tank, airlift, fiber, microfiber, hollow fiber, ceramic matrix, fluidized bed, fixed bed, and/or spouted bed bioreactors. As used herein, "reactor" can include a fermentor or fermentation unit, or any other reaction vessel and the term "reactor" is used interchangeably with "fermentor. " For example, in some aspects, an example bioreactor unit can perform one or more, or all, of the following: feeding of nutrients and/or carbon sources, injection of suitable gas (e.g., oxygen), inlet and outlet flow of fermentation or cell culture medium, separation of gas and liquid phases, maintenance of temperature, maintenance of oxygen and CO2 levels, maintenance of pH level, agitation (e.g., stirring), and/or cleaning/sterilizing. Example reactor units, such as a fermentation unit, may contain multiple reactors within the unit, for example the unit can have <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, or <NUM>, or more bioreactors in each unit and/or a facility may contain multiple units having a single or multiple reactors within the facility. In various embodiments, the bioreactor can be suitable for batch, semi fed-batch, fed-batch, perfusion, and/or a continuous fermentation processes. Any suitable reactor diameter can be used. In embodiments, the bioreactor can have a volume between about <NUM> and about <NUM>,<NUM>. Non-limiting examples include a volume of <NUM>, <NUM>, <NUM>, <NUM>, <NUM> liter, <NUM> liters, <NUM> liters, <NUM> liters, <NUM> liters, <NUM> liters, <NUM> liters, <NUM> liters, <NUM> liters, <NUM> liters, <NUM> liters, <NUM> liters, <NUM> liters, <NUM> liters, <NUM> liters, <NUM> liters, <NUM> liters, <NUM> liters, <NUM> liters, <NUM> liters, <NUM> liters, <NUM> liters, <NUM> liters, <NUM> liters, <NUM> liters, <NUM> liters, <NUM> liters, <NUM> liters, <NUM> liters, <NUM> liters, <NUM> liters, <NUM> liters, <NUM> liters, <NUM> liters, <NUM> liters, <NUM> liters, <NUM> liters, <NUM> liters, <NUM> liters, <NUM> liters, <NUM> liters, <NUM> liters, <NUM> liters, <NUM> liters, <NUM> liters, <NUM> liters, <NUM> liters, <NUM> liters, <NUM> liters, <NUM> liters, <NUM> liters, <NUM>,<NUM> liters, <NUM>,<NUM> liters, <NUM>,<NUM> liters, and/or <NUM>,<NUM> liters. Additionally, suitable reactors can be multi-use, single-use, disposable, or non-disposable and can be formed of any suitable material including metal alloys such as stainless steel (e.g., <NUM> or any other suitable stainless steel) and Inconel, plastics, and/or glass.

In embodiments and unless stated otherwise herein, the devices, facilities, and methods described herein can also include any suitable unit operation and/or equipment not otherwise mentioned, such as operations and/or equipment for separation, purification, and isolation of such products. Any suitable facility and environment can be used, such as traditional stick-built facilities, modular, mobile and temporary facilities, or any other suitable construction, facility, and/or layout. For example, in some embodiments modular clean-rooms can be used. Additionally and unless otherwise stated, the devices, systems, and methods described herein can be housed and/or performed in a single location or facility or alternatively be housed and/or performed at separate or multiple locations and/or facilities.

By way of non-limiting examples and without limitation, <CIT>; <CIT>; <CIT>; <CIT>; and <CIT>; <CIT>; and <CIT> describe example facilities, equipment, and/or systems that may be suitable.

In embodiments, the cells are eukaryotic cells, e.g., mammalian cells. The mammalian cells can be for example human or rodent or bovine cell lines or cell strains. Examples of such cells, cell lines or cell strains are e.g. mouse myeloma (NSO)-cell lines, Chinese hamster ovary (CHO)-cell lines, HT1080, H9, HepG2, MCF7, MDBK Jurkat, NIH3T3, PC12, BHK (baby hamster kidney cell), VERO, SP2/<NUM>, YB2/<NUM>, Y0, C127, L cell, COS, e.g., COS1 and COS7, QC1-<NUM>,HEK-<NUM>, VERO, PER. C6, HeLA, EBI, EB2, EB3, oncolytic or hybridoma-cell lines. Preferably the mammalian cells are CHO-cell lines. In one embodiment, the cell is a CHO cell. In one embodiment, the cell is a CHO-K1 cell, a CHO-K1 SV cell, a DG44 CHO cell, a DUXB11 CHO cell, a CHOS, a CHO GS knock-out cell, a CHO FUT8 GS knock-out cell, a CHOZN, or a CHO-derived cell. The CHO GS knock-out cell (e.g., GSKO cell) is, for example, a CHO-K1 SV GS knockout cell. The CHO FUT8 knockout cell is, for example, the Potelligent® CHOK1 SV (Lonza Biologics, Inc. Eukaryotic cells can also be avian cells, cell lines or cell strains, such as for example, EBx® cells, EB14, EB24, EB26, EB66, or EBvl3.

In one embodiment, the eukaryotic cells are stem cells. The stem cells can be, for example, pluripotent stem cells, including embryonic stem cells (ESCs), adult stem cells, induced pluripotent stem cells (iPSCs), tissue specific stem cells (e.g., hematopoietic stem cells) and mesenchymal stem cells (MSCs).

In one embodiment, the cells are for cell therapy.

In one embodiment, the cells may include T cells, or immune cells. For instance, the cells can include B cells, natural killer cells, dendritic cells, tumor infiltrating lymphocytes, monocytes, megakaryocytes, or the like.

In one embodiment, the cell is a differentiated form of any of the cells described herein. In one embodiment, the cell is a cell derived from any primary cell in culture.

In embodiments, the cell is a hepatocyte such as a human hepatocyte, animal hepatocyte, or a non-parenchymal cell. For example, the cell can be a plateable metabolism qualified human hepatocyte, a plateable induction qualified human hepatocyte, plateable Qualyst Transporter CertifiedTM human hepatocyte, suspension qualified human hepatocyte (including <NUM>-donor and <NUM>-donor pooled hepatocytes), human hepatic kupffer cells, human hepatic stellate cells, dog hepatocytes (including single and pooled Beagle hepatocytes), mouse hepatocytes (including CD-<NUM> and C57BI/<NUM> hepatocytes), rat hepatocytes (including Sprague-Dawley, Wistar Han, and Wistar hepatocytes), monkey hepatocytes (including Cynomolgus or Rhesus monkey hepatocytes), cat hepatocytes (including Domestic Shorthair hepatocytes), and rabbit hepatocytes (including New Zealand White hepatocytes). Example hepatocytes are commercially available from Triangle Research Labs, LLC, <NUM> Davis Drive Research Triangle Park, North Carolina, USA <NUM>.

In one embodiment, the eukaryotic cell is a lower eukaryotic cell such as e.g. a yeast cell (e.g., Pichia genus (e.g. Pichia pastoris, Pichia methanolica, Pichia kluyveri, and Pichia angusta), Komagataella genus (e.g. Komagataella pastoris, Komagataella pseudopastoris or Komagataella phaffii), Saccharomyces genus (e.g. Saccharomyces cerevisae, cerevisiae, Saccharomyces kluyveri, Saccharomyces uvarum), Kluyveromyces genus (e.g. Kluyveromyces lactis, Kluyveromyces marxianus), the Candida genus (e.g. Candida utilis, Candida cacaoi, Candida boidinii,), the Geotrichum genus (e.g. Geotrichum fermentans), Hansenula polymorpha, Yarrowia lipolytica, or Schizosaccharomyces pombe,. Preferred is the species Pichia pastoris. Examples for Pichia pastoris strains are X33, GS115, KM71, KM71H; and CBS7435.

In one embodiment, the eukaryotic cell is a fungal cell (e.g. Aspergillus (such as A. fumigatus, A. nidula), Acremonium (such as A. thermophilum), Chaetomium (such as C. thermophilum), Chrysosporium (such as C. thermophile), Cordyceps (such as C. militaris), Corynascus, Ctenomyces, Fusarium (such as F. oxysporum), Glomerella (such as G. graminicola), Hypocrea (such as H. jecorina), Magnaporthe (such as M. orzyae), Myceliophthora (such as M. thermophile), Nectria (such as N. heamatococca), Neurospora (such as N. crassa), Penicillium, Sporotrichum (such as S. thermophile), Thielavia (such as T. terrestris, T. heterothallica), Trichoderma (such as T. reesei), or Verticillium (such as V.

In one embodiment, the eukaryotic cell is an insect cell (e.g., Sf9, Mimic™ Sf9, Sf21, High FiveTM (BT1-TN-5B1-<NUM>), or BT1-Ea88 cells), an algae cell (e.g., of the genus Amphora, Bacillariophyceae, Dunaliella, Chlorella, Chlamydomonas, Cyanophyta (cyanobacteria), Nannochloropsis, Spirulina,or Ochromonas), or a plant cell (e.g., cells from monocotyledonous plants (e.g., maize, rice, wheat, or Setaria), or from a dicotyledonous plants (e.g., cassava, potato, soybean, tomato, tobacco, alfalfa, Physcomitrella patens or Arabidopsis).

In one embodiment, the cell is a bacterial or prokaryotic cell.

In embodiments, the prokaryotic cell is a Gram-positive cells such as Bacillus, Streptomyces Streptococcus, Staphylococcus or Lactobacillus. Bacillus that can be used is, e.g. the B. subtilis, B. amyloliquefaciens, B. licheniformis, B. natto, or B. megaterium. In embodiments, the cell is B. subtilis, such as B. subtilis 3NA and B. subtilis <NUM>. Bacillus is obtainable from, e.g., the Bacillus Genetic Stock Center , Biological Sciences <NUM>, <NUM> West 12th Avenue, Columbus OH <NUM>-<NUM>.

In one embodiment, the prokaryotic cell is a Gram-negative cell, such as Salmonella spp. or Escherichia coli, such as e.g., TG1, TG2, W3110, DH1, DHB4, DH5a, HMS <NUM>, HMS174 (DE3), NM533, C600, HB101, JM109, MC4100, XL1-Blue and Origami, as well as those derived from E. coli B-strains, such as for example BL-<NUM> or BL21 (DE3), all of which are commercially available.

Suitable host cells are commercially available, for example, from culture collections such as the DSMZ (Deutsche Sammlung von Mikroorganismen and Zellkulturen GmbH, Braunschweig, Germany) or the American Type Culture Collection (ATCC).

In embodiments, the cultured cells are used to produce proteins e.g., antibodies, e.g., monoclonal antibodies, and/or recombinant proteins, for therapeutic use. In embodiments, the cultured cells produce peptides, amino acids, fatty acids or other useful biochemical intermediates or metabolites. For example, in embodiments, molecules having a molecular weight of about <NUM> daltons to greater than about <NUM>,<NUM> daltons can be produced. In embodiments, these molecules can have a range of complexity and can include posttranslational modifications including glycosylation.

In embodiments, the protein is, e.g., BOTOX, Myobloc, Neurobloc, Dysport (or other serotypes of botulinum neurotoxins), alglucosidase alpha, daptomycin, YH-<NUM>, choriogonadotropin alpha, filgrastim, cetrorelix, interleukin-<NUM>, aldesleukin, teceleulin, denileukin diftitox, interferon alpha-n3 (injection), interferon alpha-nl, DL-<NUM>, interferon, Suntory (gamma-1a), interferon gamma, thymosin alpha <NUM>, tasonermin, DigiFab, ViperaTAb, EchiTAb, CroFab, nesiritide, abatacept, alefacept, Rebif, eptoterminalfa, teriparatide (osteoporosis), calcitonin injectable (bone disease), calcitonin (nasal, osteoporosis), etanercept, hemoglobin glutamer <NUM> (bovine), drotrecogin alpha, collagenase, carperitide, recombinant human epidermal growth factor (topical gel, wound healing), DWP401, darbepoetin alpha, epoetin omega, epoetin beta, epoetin alpha, desirudin, lepirudin, bivalirudin, nonacog alpha, Mononine, eptacog alpha (activated), recombinant Factor VIII+VWF, Recombinate, recombinant Factor VIII, Factor VIII (recombinant), Alphnmate, octocog alpha, Factor VIII, palifermin,Indikinase, tenecteplase, alteplase, pamiteplase, reteplase, nateplase, monteplase, follitropin alpha, rFSH, hpFSH, micafungin, pegfilgrastim, lenograstim, nartograstim, sermorelin, glucagon, exenatide, pramlintide, iniglucerase, galsulfase, Leucotropin, molgramostirn, triptorelin acetate, histrelin (subcutaneous implant, Hydron), deslorelin, histrelin, nafarelin, leuprolide sustained release depot (ATRIGEL), leuprolide implant (DUROS), goserelin, Eutropin, KP-<NUM> program, somatropin, mecasermin (growth failure), enlfavirtide, Org-<NUM>, insulin glargine, insulin glulisine, insulin (inhaled), insulin lispro, insulin deternir, insulin (buccal, RapidMist), mecasermin rinfabate, anakinra, celmoleukin, <NUM> mTc-apcitide injection, myelopid, Betaseron, glatiramer acetate, Gepon, sargramostim, oprelvekin, human leukocyte-derived alpha interferons, Bilive, insulin (recombinant), recombinant human insulin, insulin aspart, mecasenin, Roferon-A, interferon-alpha <NUM>, Alfaferone, interferon alfacon-<NUM>, interferon alpha, Avonex' recombinant human luteinizing hormone, dornase alpha, trafermin, ziconotide, taltirelin, diboterminalfa, atosiban, becaplermin, eptifibatide, Zemaira, CTC-<NUM>, Shanvac-B, HPV vaccine (quadrivalent), octreotide, lanreotide, ancestirn, agalsidase beta, agalsidase alpha, laronidase, prezatide copper acetate (topical gel), rasburicase, ranibizumab, Actimmune, PEG-Intron, Tricomin, recombinant house dust mite allergy desensitization injection, recombinant human parathyroid hormone (PTH) <NUM>-<NUM> (sc, osteoporosis), epoetin delta, transgenic antithrombin III, Granditropin, Vitrase, recombinant insulin, interferon-alpha (oral lozenge), GEM-<NUM>, vapreotide, idursulfase, omnapatrilat, recombinant serum albumin, certolizumab pegol, glucarpidase, human recombinant C1 esterase inhibitor (angioedema), lanoteplase, recombinant human growth hormone, enfuvirtide (needle-free injection, Biojector <NUM>), VGV-<NUM>, interferon (alpha), lucinactant, aviptadil (inhaled, pulmonary disease), icatibant, ecallantide, omiganan, Aurograb, pexigananacetate, ADI-PEG-<NUM>, LDI-<NUM>, degarelix, cintredelinbesudotox, Favld, MDX-<NUM>, ISAtx-<NUM>, liraglutide, teriparatide (osteoporosis), tifacogin, AA4500, T4N5 liposome lotion, catumaxomab, DWP413, ART-<NUM>, Chrysalin, desmoteplase, amediplase, corifollitropinalpha, TH-<NUM>, teduglutide, Diamyd, DWP-<NUM>, growth hormone (sustained release injection), recombinant G-CSF, insulin (inhaled, AIR), insulin (inhaled, Technosphere), insulin (inhaled, AERx), RGN-<NUM>, DiaPep277, interferon beta (hepatitis C viral infection (HCV)), interferon alpha-n3 (oral), belatacept, transdermal insulin patches, AMG-<NUM>, MBP-<NUM>, Xerecept, opebacan, AIDSVAX, GV-<NUM>, LymphoScan, ranpirnase, Lipoxysan, lusupultide, MP52 (beta-tricalciumphosphate carrier, bone regeneration), melanoma vaccine, sipuleucel-T, CTP-<NUM>, Insegia, vitespen, human thrombin (frozen, surgical bleeding), thrombin, TransMID, alfimeprase, Puricase, terlipressin (intravenous, hepatorenal syndrome), EUR-<NUM>, recombinant FGF-I (injectable, vascular disease), BDM-E, rotigaptide, ETC-<NUM>, P-<NUM>, MBI-594AN, duramycin (inhaled, cystic fibrosis), SCV-<NUM>, OPI-<NUM>, Endostatin, Angiostatin, ABT-<NUM>, Bowman Birk Inhibitor Concentrate, XMP-<NUM>, <NUM> mTc-Hynic-Annexin V, kahalalide F, CTCE-<NUM>, teverelix (extended release), ozarelix, rornidepsin, BAY-<NUM>, interleukin4, PRX-<NUM>, Pepscan, iboctadekin, rhlactoferrin, TRU-<NUM>, IL-<NUM>, ATN-<NUM>, cilengitide, Albuferon, Biphasix, IRX-<NUM>, omega interferon, PCK-<NUM>, CAP-<NUM>, pasireotide, huN901-DMI, ovarian cancer immunotherapeutic vaccine, SB-<NUM>, Oncovax-CL, OncoVax-P, BLP-<NUM>, CerVax-<NUM>, multi-epitope peptide melanoma vaccine (MART-<NUM>, gp100, tyrosinase), nemifitide, rAAT (inhaled), rAAT (dermatological), CGRP (inhaled, asthma), pegsunercept, thymosinbeta4, plitidepsin, GTP-<NUM>, ramoplanin, GRASPA, OBI-<NUM>, AC-<NUM>, salmon calcitonin (oral, eligen), calcitonin (oral, osteoporosis), examorelin, capromorelin, Cardeva, velafermin, 131I-TM-<NUM>, KK-<NUM>, T-<NUM>, ularitide, depelestat, hematide, Chrysalin (topical), rNAPc2, recombinant Factor V111 (PEGylated liposomal), bFGF, PEGylated recombinant staphylokinase variant, V-<NUM>, SonoLysis Prolyse, NeuroVax, CZEN-<NUM>, islet cell neogenesis therapy, rGLP-<NUM>, BIM-<NUM>, LY-<NUM>, exenatide (controlled release, Medisorb), AVE-<NUM>, GA-GCB, avorelin, ACM-<NUM>, linaclotid eacetate, CETi-<NUM>, Hemospan, VAL (injectable), fast-acting insulin (injectable, Viadel), intranasal insulin, insulin (inhaled), insulin (oral, eligen), recombinant methionyl human leptin, pitrakinra subcutancous injection, eczema), pitrakinra (inhaled dry powder, asthma), Multikine, RG-<NUM>, MM-<NUM>, NBI-<NUM>, AT-<NUM>, PI-<NUM>, Org-<NUM>, Cpn10 (autoimmune diseases/inflammation), talactoferrin (topical), rEV-<NUM> (ophthalmic), rEV-<NUM> (respiratory disease), oral recombinant human insulin (diabetes), RPI-<NUM>, oprelvekin (oral), CYT-<NUM> CTLA4-Ig, DTY-<NUM>, valategrast, interferon alpha-n3 (topical), IRX-<NUM>, RDP-<NUM>, Tauferon, bile salt stimulated lipase, Merispase, alaline phosphatase, EP-2104R, Melanotan-II, bremelanotide, ATL-<NUM>, recombinant human microplasmin, AX-<NUM>, SEMAX, ACV-<NUM>, Xen-<NUM>, CJC-<NUM>, dynorphin A, SI-<NUM>, LAB GHRH, AER-<NUM>, BGC-<NUM>, malaria vaccine (virosomes, PeviPRO), ALTU-<NUM>, parvovirus B19 vaccine, influenza vaccine (recombinant neuraminidase), malaria/HBV vaccine, anthrax vaccine, Vacc-5q, Vacc-4x, HIV vaccine (oral), HPV vaccine, Tat Toxoid, YSPSL, CHS-<NUM>, PTH(<NUM>-<NUM>) liposomal cream (Novasome), Ostabolin-C, PTH analog (topical, psoriasis), MBRI-<NUM>, MTB72F vaccine (tuberculosis), MVA-Ag85A vaccine (tuberculosis), FARA04, BA-<NUM>, recombinant plague FIV vaccine, AG-<NUM>, OxSODrol, rBetV1, Der-p1/Der-p2/Der-p7 allergen-targeting vaccine (dust mite allergy), PR1 peptide antigen (leukemia), mutant ras vaccine, HPV-<NUM> E7 lipopeptide vaccine, labyrinthin vaccine (adenocarcinoma), CML vaccine, WT1-peptide vaccine (cancer), IDD-<NUM>, CDX-<NUM>, Pentrys, Norelin, CytoFab, P-<NUM>, VT-<NUM>, icrocaptide, telbermin (dermatological, diabetic foot ulcer), rupintrivir, reticulose, rGRF, HA, alpha-galactosidase A, ACE-<NUM>, ALTU-<NUM>, CGX-<NUM>, angiotensin therapeutic vaccine, D-4F, ETC-<NUM>, APP-<NUM>, rhMBL, SCV-<NUM> (oral, tuberculosis), DRF-<NUM>, ABT-<NUM>, ErbB2-specific immunotoxin (anticancer), DT3SSIL-<NUM>, TST-<NUM>, PRO-<NUM>, Combotox, cholecystokinin-B/gastrin-receptor binding peptides, 111In-hEGF, AE-<NUM>, trasnizumab-DM1, Antagonist G, IL-<NUM> (recombinant), PM-<NUM>, IMP-<NUM>, rhIGF-BP3, BLX-<NUM>, CUV-<NUM> (topical), L-<NUM> based radioimmunotherapeutics (cancer), Re-<NUM>-P-<NUM>, AMG-<NUM>, DC/<NUM>/KLH vaccine (cancer), VX-<NUM>, AVE-<NUM>, AC-<NUM>, NY-ESO-<NUM> vaccine (peptides), NA17. A2 peptides, melanoma vaccine (pulsed antigen therapeutic), prostate cancer vaccine, CBP-<NUM>, recombinant human lactoferrin (dry eye), FX-<NUM>, AP-<NUM>, WAP-8294A (injectable), ACP-HIP, SUN-<NUM>, peptide YY [<NUM>-<NUM>] (obesity, intranasal), FGLL, atacicept, BR3-Fc, BN-<NUM>, BA-<NUM>, human parathyroid hormone <NUM>-<NUM> (nasal, osteoporosis), F-<NUM>-CCR1, AT-<NUM> (celiac disease/diabetes), JPD-<NUM>, PTH(<NUM>-<NUM>) liposomal cream (Novasome), duramycin (ophthalmic, dry eye), CAB-<NUM>, CTCE-<NUM>, GlycoPEGylated erythropoietin, EPO-Fc, CNTO-<NUM>, AMG-<NUM>, JR-<NUM>, Factor XIII, aminocandin, PN-<NUM>, <NUM>, SUN-E7001, TH-<NUM>, BAY-<NUM>-<NUM>, teverelix (immediate release), EP-<NUM>, hGH (controlled release, Biosphere), OGP-I, sifuvirtide, TV4710, ALG-<NUM>, Org-<NUM>, rhCC10, F-<NUM>, thymopentin (pulmonary diseases), r(m)CRP, hepatoselective insulin, subalin, L19-IL-<NUM> fusion protein, elafin, NMK-<NUM>, ALTU-<NUM>, EN-<NUM>, rhTPO, thrombopoietin receptor agonist (thrombocytopenic disorders), AL-<NUM>, AL-<NUM>, nerve growth factor antagonists (pain), SLV-<NUM>, CGX-<NUM>, INNO-<NUM>, oral teriparatide (eligen), GEM-OS1, AC-<NUM>, PRX-<NUM>, LFn-p24 fusion vaccine (Therapore), EP-<NUM>, S pneumoniae pediatric vaccine, malaria vaccine, Neisseria meningitidis Group B vaccine, neonatal group B streptococcal vaccine, anthrax vaccine, HCV vaccine (gpE1+gpE2+MF-<NUM>), otitis media therapy, HCV vaccine (core antigen+ISCOMATRIX), hPTH(<NUM>-<NUM>) (transdermal, ViaDerm), <NUM>, SYN-<NUM>, PGN-<NUM>, aviscumnine, BIM-<NUM>, tuberculosis vaccine, multi-epitope tyrosinase peptide, cancer vaccine, enkastim, APC-<NUM>, GI-<NUM>, ACC-<NUM>, TTS-CD3, vascular-targeted TNF (solid tumors), desmopressin (buccal controlled-release), onercept, and TP-<NUM>.

In some embodiments, the polypeptide is adalimumab (HUMIRA), infliximab (REMICADE™), rituximab (RITUXAN™/MAB THERA™) etanercept (ENBREL™), bevacizumab (AVASTIN™), trastuzumab (HERCEPTIN™), pegrilgrastim (NEULASTA™), or any other suitable polypeptide including biosimilars and biobetters.

Other suitable polypeptides are those listed below and in Table <NUM> of <CIT> :.

In embodiments, the polypeptide is a hormone, blood clotting/coagulation factor, cytokine/growth factor, antibody molelcule, fusion protein, protein vaccine, or peptide as shown in Table <NUM>.

In embodiments, the protein is multispecific protein, e.g., a bispecific antibody as shown in Table <NUM>.

Claim 1:
A bioprocess system comprising:
a first bioprocess device;
a second bioprocess device;
a bioprocess tube in fluid communication with the first bioprocess device and the second bioprocess device, the bioprocess tube comprising a thermoplastic elastomer, the bioprocess tube defining a hollow passageway and having an internal diameter, an external diameter, and an external surface, the internal diameter being greater than about <NUM>; and
a separating collar for facilitating cutting the bioprocess tube for disconnecting the first bioprocess device from the second bioprocess device, the separating collar being slidably mounted on the exterior surface of the bioprocess tube, the separating collar having a cylindrical shape and having a length that extends from a first end to a second and opposite end, the separating collar defining at least one pair of adjacent separating edges that extend over the length of the collar, the pair of adjacent separating edges allowing the separating collar to be installed and removed from a bioprocess tube, characterized in that the separating collar is made from a material that is sufficiently rigid and malleable such that when the separating collar is cut with a cutting tool to form cut ends, the cut ends of the separating collar maintain cut ends of the bioprocess tube in a closed configuration.