Improvements in sterilization of fluid guide elements for bioprocess applications, and related improvements.

Abstract

To provide sterilization of fluid-guiding elements by ultra violet (UV) light, and more particularly to provide use of such fluid-guiding elements for bioprocessing applications.SOLUTION: There is disclosed an ultra-violet (UV) light sterilizable fluid-guiding element (100, 200, 300, 400, 500) configurable to form a part of a normally closed bioprocessing fluid system, at least a portion of the element being formed from a material which is transmissive to UV light, the at least one portion of the element including one or more surfaces (134) configured to contact and guide fluids within the closed system. The element further includes at least one UV light emitting diode (LED) (154) mounted in, on, or adjacent the at least one portion and has sufficient light output to sterilize at least the one or more surfaces (134).SELECTED DRAWING: Figure 1

Description

Technical Field

[0001] The present invention generally relates to the sterilization of fluid guiding elements by ultraviolet (UV) light, and more particularly to the use of such fluid guiding elements for bioprocess applications.

Background Art

[0002] As used herein, terms such as "sterile" and "aseptic" are intended to mean a bio-burden reduced to a level sufficient for the intended purpose of the element, i.e., for practical purposes, and herein, the sterilization of an element means reducing the bio-burden to a level sufficient for the element to perform its function without introducing an excessive bio-burden.

[0003] Generally, many closed fluid systems require a sterile state in order to function successfully. For example, bioprocesses, medical devices, food processing, brewing, and water treatment are some examples where closed sterilization systems are used, and closed sterilization systems are pre-sterilized and kept sealed to maintain the sterile state.

[0004] Such systems can be cleaned by chemicals such as sodium hydroxide, ethylene oxide gas, steam, or radiation such as gamma rays or UV light prior to use. Of course, not all of these methods are acceptable for every closed fluid system.

[0005] However, in many cases, there is a need to utilize other enclosed systems, for example, for the extraction or partial extraction of finished fluids or products, for sampling, for the introduction of fluids such as reagents or raw materials, or for monitoring fluids using probes or sensors. In these cases, there is always a risk of introducing contaminants into the system, such as bacteria, fungi, viruses, enzymes, and similar simple forms of living organisms, collectively referred to herein as “microorganisms.”

[0006] Therefore, even after initial sterilization of an empty system, in-process sterilization and cleaning are required in many cases. One particularly problematic system is cell culture in a bioreactor, where a constantly sealed system is kept in a state that promotes microbial growth, and many invasive procedures are performed during the cell culture process. For example, initial introduction of seed cells, introduction of oxygen and cellular nutrients, cell sampling, and harvesting of cells or cellular products such as antibodies or other proteins.

[0007] To address potential contamination, various fittings and techniques have been proposed that are supposed to maintain sterility when the system is open. However, absolute sterility can never be ensured with such mechanical fittings, even in so-called cleanroom conditions, if human activity is present.

[0008] Commercially available sterile fittings have been proposed, such as those proposed in U.S. Patent No. 6,679,529, WO2009 / 002468, and WO2013 / 147688, and are sold under the trademark name ReadyMate®, which provide one of the best ways to ensure sterility when connecting two different sterile fluid systems to each other, in which a pair of connectors, each covered by a film, is joined together, and once the connectors are joined, the film is removed, leaving the connectors connected to each other but never exposed to their surrounding environment. Many other mechanical concepts exist that use male and female parts that are exposed after mating. Their drawback is that careful manual handling is required to create a promising sterile connection.

[0009] Furthermore, one major challenge in the system design of conventional technologies when used in bioprocess applications concerns the problem of controlling microorganisms that may be trapped, for example, in the seams or stagnation zones of a bioreactor. Such systems can be difficult to keep clean during use and are required to remain sterile during use. Therefore, any stagnation zone is highly undesirable as it may trap biological substances that, after decomposition, could release pathogens or other undesirable substances into the processing batch. Thus, any such contamination may necessitate discarding the entire batch of biopharmaceutical products. [Prior art documents] [Patent Documents]

[0010] [Patent Document 1] U.S. Patent No. 6,679,529 [Patent Document 2] WO2009 / 002468 [Patent Document 3] WO2013 / 147688 [Overview of the project] [Means for solving the problem]

[0011] The inventors of this concept recognized that even with the best sterile connections, the risk of microbial contamination always exists, thus requiring different methods, and that there is a need for better methods of sterilization before, during, or after joining two fluid systems. The inventors propose using UV-transparent fluid connections or other fluid guide elements that form part of a sealed fluid system, such as pipe couplers, fluid transfer ports, valves, fluid sampling interfaces, removable sensor supports, and plugs, at any location where microorganisms can constantly enter a sealed fluid system from the external environment, or in areas that cannot be reached by conventional pre-sterilization methods, such as joints that are too narrow to allow the passage of cleaning fluid, or stagnant areas (so-called dead legs). When these fluid guide elements are exposed to UV light before and / or after they are connected to a sealed system, the UV light can be transmitted to their fluid contact surfaces, thereby sterilizing the fluid contact surfaces and adjacent areas.

[0012] The ultraviolet (UV) light spectrum exists between 200 and 400 nanometers. The so-called UV-C portion (wavelengths around 254 nanometers) is particularly suitable for sterilization because it is known to kill microorganisms or at least damage their DNA, thereby preventing, for example, viruses or spores from infecting cells. UV light emitted from commercially available LEDs, around 255-265 nanometers, for example, around 260 nanometers, is UV-C radiation and generates very little heat, making it particularly suitable. This means such LEDs can be placed near sensitive components or liquids without the risk of thermal damage. The size of the LED also makes it suitable for placement within, on, or near fluid guide elements to provide localized sterilizing UV light.

[0013] It should be understood that the above summary is provided to briefly introduce selected concepts from those further described in the detailed description below. The detailed description is not intended to identify any important or essential features of the claimed subject matter, and the scope of the claimed subject matter is uniquely defined by the claims that follow the detailed description. Furthermore, the claimed subject matter is not limited to an implementation that solves any of the defects described above or in any part of this specification. The above advantages and other advantages and features of this specification will become readily apparent when modes for carrying out the invention below are considered alone or in combination with the accompanying drawings. The present invention extends to any combination of the features disclosed herein, whether such combinations are explicitly stated herein or not. Furthermore, if two or more features are described in combination in the same paragraph, for example, it is intended that such features may be claimed separately without broadening the scope of the invention. Features from the various embodiments described below may be combined in any claim.

[0014] In its broadest form, the present invention provides a fluid guide element according to claim 1, having the preferred features defined by the claims dependent on claim 1.

[0015] The present invention also provides a method as defined by claim 12.

[0016] The present invention can be implemented in various ways, and non-limiting embodiments that are helpful in illustrating this are described below with reference to the drawings. [Brief explanation of the drawing]

[0017] [Figure 1] This figure shows a first embodiment of a fluid guide element that takes the form of a pipe joint. [Figure 2] This figure shows a second embodiment of a fluid guide element forming a modified pipe fitting. [Figure 3a]It is a figure showing the operating position of a third embodiment of a fluid guiding element. [Figure 3b] It is a figure showing the operating position of a third embodiment of a fluid guiding element. [Figure 3c] It is a figure showing the operating position of a third embodiment of a fluid guiding element. [Figure 4] It is a figure showing a further embodiment of a fluid guiding element. [Figure 5] It is a figure showing a further embodiment of a fluid guiding element. **Embodiments for Carrying out the Invention**

[0018] The present invention, together with its objects and advantages, can be better understood by reference to the following description in conjunction with the accompanying drawings in which like reference numerals identify like elements in each of the figures.

[0019] Referring to FIG. 1, a fluid guiding element in the form of a fluid fitting 100 is shown. The fitting 100 includes a body 130 having a barb 132 for receiving a plastic tube 120 clamped to the barb by a clamp 122, and a mating surface 110. The fitting 100 is intended to fit a complementary fitting (not shown) at its mating surface 110. In use, the inner surface 134 of the body 130 and the mating surface 110 are in contact with the fluid. In use, the mating surface 110 is extended to the complementary surface, and when their respective ring seals 112 come into contact, their respective sealing films 114 are pulled out together from the gap between the surfaces provided by the ring seals. The complementary fittings can be held together by a ring clamp (not shown) that holds their respective outer flanges 136 together. The system allows for a good guarantee of maintaining the sterilized state of the pre-sterilized fittings, but once damaged, the fittings can be contaminated and may contaminate the fluid system.

[0020] In this embodiment, a sterilization UV LED circuit 150 including a push button switch 152, a UV LED 154, a battery 156, and a current limiting resistor 158 is provided within an extension portion 140 of a housing 130. The LED provides UV sterilization light as required, and this UV sterilization light can internally reflect to every corner of the housing 130, and even into any void or tight joint that can harbor microorganisms, such as the void 138 on the outer surface of the barb, over the area indicated by the slashes.

[0021] In use, the fluid contact surfaces 134 and 110 of the fitting can be sterilized before and / or after coupling to another similar fitting. If the connected tube 120 or equivalent component is also made permeable, the UV light will also propagate along the tube over at least a short distance by internal reflection, and thus they will also be partially sterilized. In a refinement, the outer surface 144 of the body 130 has UV light reflection characteristics, such as a polished and metal-plated surface, or a surface with a mirror-finished inner surface, to better reflect light back to the fluid contact surface 134.

[0022] In various alternative embodiments, a remotely controllable, non-contact power supply, and / or transistor switch-operated UV LED circuit can be provided. Such a UV LED circuit is provided for a plurality of bioprocess system components and can be batch-operated, for example, by a remote computer system. Thus, it can enable the provision of an automated bioprocess system that can operate cooperatively to enhance sterilization efficiency.

[0023] Figure 2 shows another fluid guide element 200 that takes the form of a fluid coupling similar to coupling 100, and the similar component has the same last two digits. In this embodiment, the fluid contact surfaces 234 and 210 are sterilized in use by light internally reflected from the UV LED circuit 250 as described above, as in the previous case. In this case, the extension 240 housing the LED circuit 250 also includes a shroud 242 which fits snugly onto the body 230 and has a highly reflective surface 244, such as polished metal or electroplated metallized finish, on the surface adjacent to the body 230, except for an area 256 adjacent to the LED 254 to allow light to enter the transmissive body 230. This configuration is more efficient than the embodiment in Figure 1 because more LED light is reused by the reflective surface and can be incorporated into existing couplings that do not have equipment for the LED circuit. Alternatively, the main body 230 may have high reflectivity by having a window equivalent to the window 256, for example, a mirrored outer surface, instead of the reflective shroud 242, in which case the shroud 242 functions solely as a removable mount for the UV circuit 250, including the adjacent LED light source 254.

[0024] Figure 3a shows another fluid guide element 300 in the form of a fluid tube 320 and a two-part tube clamp 330 / 340. Here, the outer tube clamp 340 is intended to house an LED circuit 350 in order to provide sterilizing light to the inner tube clamp 330. If the tube 320 is also transparent to UV light, the propagation of UV light passing through the inner tube clamp 330 will sterilize the inner surface 334 of the tube 320 and the tube joint 338 between the tube 320 and its insert portion 30 that fits inside the tube 320 by internal reflection.

[0025] Referring further to Figures 3b and 3c, it can be seen that the inner clamp 330 is axially slid over the insertion portion 30 during use, and then the outer clamp 340 is axially slid over the inner clamp 330, tightening the inner clamp 330 around the pipe 320 and holding the pipe 320 in place on the insertion portion 30. During the clamping process, a UV LED may be irradiated to provide a certain period of time and some relative motion of the LED in order to provide complete sterilization of the fitting 300.

[0026] Figure 4 shows a fluid guide element in the form of a port 400 suitable for accessing a bioprocess container 40, for example, for supplying fluid, withdrawing fluid, taking samples, or inserting a probe or sensor into the container. When not in use, the port is sealed using, for example, a screw cap (not shown). The port 400 includes a body 430 that is transparent to UV light and has a fluid access opening 420, and a body extension 440 that houses a UV LED circuit 450. The body is transparent and allows UV light to propagate to the fluid contact surface 434 of the opening 420 before, during, and / or after use of the port. In this example, the port may be used adjacent to cells or other biomaterials, and therefore the walls 42 of the container 40 are made of UV LED-impermeable plastic to prevent damage to the contents of the container by stray UV light.

[0027] Figure 5 shows a fluid guide element in the form of a ball valve 500, comprising a valve body 530 housing a UV LED circuit 550 containing multiple LEDs. The body 530 is transparent to UV light and includes a fluid passage 520 and a rotary valve mechanism 538, each of which can be sterilized by allowing light to propagate to the passage 520 and to the valve joint between the body 530 and the mechanism 538 through internal reflection around the body. Thus, various passages of the valve, and any joints or dead legs, can be sterilized before and after use of the valve. Alternative valve devices can also be sterilized in this manner.

[0028] It will become apparent that other configurations similar to those described above may be used so that the fluid guide elements can be sterilized by UV light for subsequent use in fluid systems that are normally sealed.

[0029] Sterilization can be performed using weakly UV-transmitting materials, i.e., materials that do not transmit light particularly well, or materials that absorb UV light. Effective sterilization can be guaranteed if at least 5% of UV light is transmitted per 1 mm of thickness of the element (5% / mm).

[0030] Many materials are useful for transmitting UV light, such as glass, specifically quartz glass. However, for disposable products typically used in bioprocesses and medical applications, plastic is often more economical. In this regard, it is common practice to pre-sterilize plastic components with gamma rays before use, although this can reduce the UV light transmission properties of some plastics. Suitable plastics include polypropylene (PP), polymethyl methacrylate (PMMA), polydimethylsiloxane (PDMS), and polyimide (PI). However, polypropylene (PP) suffers from UV degradation over time, polymethyl methacrylate (PMMA) has little UV transmission, especially for wavelengths shorter than 250 nm, but its transmission is acceptable at wavelengths around 260 nm, i.e., about 50% / mm, polydimethylsiloxane (PDMS) is not easily injection molded, and polyimide (PI), such as fluorinated PI, is colorless, stable when manufactured, and transmits all UV light.

[0031] When materials with low permeability are used, or when faster sterilization is required, two or more LEDs may be used, for example, a ring of LEDs may be used in any of the embodiments described above.

[0032] While exemplary embodiments have been described and illustrated, it will be apparent to those skilled in the art that additions, deletions, and modifications can be made to these embodiments without departing from the claimed scope of the invention. For example, circuits 150, 250, 350, 450, and 550 are intended, for convenience, to have a local power supply, for example, by a battery. Their configuration is suitable for disposable fluid guide elements such as disposable fluid connectors, but if reusable elements are required, a remote power supply, for example, a plug-in DC supply, may be used. Only the embodiment in Figure 1 has been described as optionally including a back-reflective outer surface, but other embodiments may also include such a surface. [Explanation of symbols]

[0033] 30 Insertion part 40 Bioprocess containers 42 Wall 100 Fluid couplings 110 Mating surface, fluid contact surface 112 Ring Seals 114 Sealing film 120 Plastic Tubes 122 Clamp 130 Main unit, housing 132 barbs 134 Internal surfaces, fluid contact surfaces 136 Outer flange 138 void 140 Expansion section 144 Outer surface 150 Sterile UV LED Circuit 152 Push button switch 154 UV LED 156 Batteries 158 Current limiting resistor 200 Fluid guide elements 210 Fluid contact surfaces 230 Main Unit 234 Fluid contact surfaces 240 Expansion section 242 Shroud 244 Highly reflective surface 250 UV LED circuit, UV circuit 254 LED, LED light source 256 areas, windows 300 Fluid guide elements, fittings 320 Fluid pipe 330 2-piece pipe clamp, inner pipe clamp, inner clamp 334 Inner surface 338 Pipe joint 340 2-part pipe clamp, outer pipe clamp, outer clamp 350 LED Circuit 400 ports 420 Fluid access opening 430 Main Unit 434 Fluid contact surfaces 440 Main Unit Expansion Unit 450 UV LED circuit 500 Ball valve 520 Fluid passage 530 Valve body 538 Rotary valve mechanism 550 UV LED circuit

Claims

1. A UV-sterilizable fluid guide element (300) for bioprocess applications, which can be configured to form part of a permanently sealed fluid system, wherein at least a portion of the element is formed from a material transparent to UV light, and the at least portion of the element includes one or more surfaces (134) configured to contact and guide the fluid in the sealed system during use, and the element further includes at least one UV light-emitting diode (LED) (154) mounted in, on, or adjacent to the at least portion and having sufficient light output to sterilize at least one or more surfaces (134), The UV light-sterilizable fluid guide element comprises a fluid tube, an inner tube clamp, and an outer tube clamp. The outer tube clamp houses the LED circuit. The outer pipe clamp tightens the inner clamp around the fluid pipe. The inner tube clamp is transparent to UV light, The internal clamp is configured to reflect UV light into at least one void (138) or joint into which microorganisms may parasitize, and is a fluid guide element (300).

2. The fluid guide element (300) according to claim 1, wherein the LED (154) emits light with a wavelength of 100 nanometers to 280 nanometers.

3. The fluid guide element (300) according to claim 1 or 2, wherein the material transmits 5% or more of the UV light per 1 mm of light propagation distance.

4. The fluid guide element (300) according to any one of claims 1 to 3, wherein the material is glass, or polypropylene (PP), or polymethyl methacrylate (PMMA), or polydimethylsiloxane (PDMS), or polyimide (PI), or a combination of the materials.

5. A fluid guide element (300) according to any one of claims 1 to 4, which is one or more of a fluid connector, a pipe coupler, a removable fluid transfer port, a valve, a fluid sampling interface, a removable sensor support, a plug, or an element at a location where microorganisms can enter the permanently sealed fluid system from the external environment.

6. A method for maintaining the sterile state of a fluid system that is normally sealed for bioprocess applications, a) A step of opening the fluid system in the fluid guide element (300) according to any one of claims 1 to 5, wherein at least a portion of the fluid is in contact with the fluid, b) The step of closing the fluid system in the element, c) Sterilizing the portion of the element by UV light transmitted to the portion in fluid contact by propagation within the element before, and / or while, and / or after closing, A method that includes this.

7. The method according to claim 6, wherein the UV light is light from an LED (154) having an output wavelength of 100 nanometers to 280 nanometers.

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