Particle sampling system and method for robotically controlled manufacturing barrier systems

Abstract

To provide novel systems and methods for detecting particles in a fluid.SOLUTION: Provided herein are systems and methods allowing for automated sampling and / or analysis of controlled environments, for example, to determine the presence, quantity, size, concentration, viability, species or characteristics of particles within the environment. The described systems and methods may utilize robotics or automation or remove some or all of the collection or analysis steps that are traditionally performed by human operators. The methods and systems described herein are versatile and may be used with known particle sampling and analysis techniques and particle detection devices including, for example, optical particle counters, impingers and impactors.SELECTED DRAWING: Figure 2

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001]

[0001] This application claims the benefit of and priority to U.S. Provisional Patent Application No. 62 / 768,365, filed November 16, 2018, and U.S. Provisional Patent Application No. 62 / 831,343, filed April 9, 2019, each of which is incorporated by reference herein to the extent not inconsistent herewith. [Technical Field]

[0002]

[0002] This invention is in the field of manufacturing barrier systems. This invention relates generally to systems and methods for robotic sampling and counting systems for sampling particles from fluids in controlled environments. [Background technology]

[0003]

[0003] Sterilization, aseptic manufacturing, and clean room environments in many industries, including pharmaceutical, biopharmaceutical, parenteral, and medical device, and microfabrication, among others, require maintaining operation under strict specifications regarding particulate matter and biological load.

[0004]

[0004] In at least some known sterile, aseptic, or clean room environments, humans must be present in the environment to perform certain operations. In the case of barrier systems, humans may be required to operate machines, manipulate objects, and otherwise interact with those placed within the barrier system. The presence of humans in such environments increases the risk of particulate and biological contamination levels. Controlled environment systems are increasingly moving toward automated or robotic systems to limit or eliminate human interaction. However, many applications requiring controlled environments also require or utilize environmental sampling to ensure that live and non-living particles and / or organisms remain below desired levels.

[0005]

[0005] As the demand for lower concentrations of viable and non-viable particles increases due to increasing quality standards and government regulatory requirements, sampling techniques need to be advanced to reduce false positives and reduce the risk of external contamination from human interaction within controlled environments.

[0006]

[0006] In view of the above, there remains a need in the art for particle collection, analysis, and characterization systems for sampling and collecting particles and / or organisms from controlled environments with reduced human interaction to reduce the risk of further contamination. These systems may include particle collection and analysis within robotic access-restricted barrier systems or other components of automated controlled environmental processes. Summary of the Invention

[0007]

[0007] Provided herein are systems and methods that enable automated sampling and / or analysis of controlled environments, for example, to determine the presence, amount, size, concentration, viability, species, or characteristics of particles within the environment. The described systems and methods may utilize robotics or automation, or may eliminate some or all of the collection or analysis steps traditionally performed by a human operator. The methods and systems described herein are versatile and may be used with known particle sampling and analysis techniques and devices, including, for example, optical particle counters, impingers, and impactors.

[0008] The provided systems and methods can be useful in controlled environments that utilize robotic systems, such as robotically controlled restricted access barrier systems (RABS) and positive pressure isolator systems. These systems and methods allow integration with samplers and / or analyzers within the controlled environment to locate, connect, sample, and / or analyze environmental conditions within the controlled environment with little or no human contact, thereby reducing the risk of contamination to operators from particles or organisms present. The described systems and methods can also enable robotic sterilization of the environment or sampling components to further reduce or eliminate the risk of contamination.

[0009] In one aspect, a system for detecting particles in a fluid is provided, the system comprising: a particle detection device and a robotic manipulator system. The particle detection device may comprise an inlet for receiving a particle-containing fluid, a sampling region for detecting particles in the fluid, and an outlet for discharging the fluid. The sampling region is in fluid communication with the inlet. The outlet is in fluid communication with the sampling region. The robotic manipulator system is configured to perform at least one of the following steps: transporting the particle detection device to a sampling location; removing the particle detection device from the sampling location; and adjusting a flow of fluid through the particle detection device.

[0010] In some embodiments, the particle detection device is an optical particle counter. In some embodiments, the optical particle counter is a scattered light particle counter, an extinction optical particle counter, or a fluorescence optical particle counter. In some embodiments, the particle detection device is an impinger or a sampling cyclone. In some embodiments, the particle detection device is an impactor.

[0011]

[0011] In some embodiments, the system may include a flow system for flowing fluid through the particle detection device. In some embodiments, the system may include a sterilization system for sterilizing all or a portion of the particle detection device. In some embodiments, the sterilization system sterilizes the particle detection device using vaporized hydrogen peroxide, chlorine dioxide, ethylene oxide, moist heat, or dry heat. In some embodiments, a robotic manipulator system is configured to transport the particle detection device to the sterilization system. In some embodiments, an impactor base having a plurality of grooves on its outer surface for engaging with a working end of the robotic manipulator system.

[0012] In some embodiments, the impactor comprises an impactor base having one or more features that allow for stacking of multiple impactors. In some embodiments, at least a portion of the impactor is transparent. In some embodiments, the robotic manipulator system comprises an optical detector or imaging device.

[0013] In some embodiments, a robotic manipulator system is configured to expose an inlet of the particle detection device to a fluid. In some embodiments, the robotic manipulator system is configured to collect particles from the particle detection device. In some embodiments, the robotic manipulator system is configured to operate the particle detection device without physical contact of the particle detection device by a user.

[0014]

[0014] In some embodiments, the impactor includes a collection surface with a growth medium for receiving biological particles in a fluid, in which case the robotic manipulator system is configured to transport the impactor in a fully assembled form to a sterilization system for sterilizing the impactor, and the growth medium is present within the impactor during its sterilization.

[0015] In some embodiments, the robotic manipulator system is configured to connect the particle detection device to the flow system. In some embodiments, the robotic manipulator system is configured to open the inlet to allow fluid to enter the particle detection device. In some embodiments, the particle detection device includes a cover to surround the inlet, and the robotic manipulator system is configured to remove the cover to allow fluid to enter the inlet. In some embodiments, the robotic manipulator system is configured to replace the cover to prevent fluid from entering the inlet. In some embodiments, the robotic manipulator system is configured to close the inlet to prevent fluid from entering the particle detection device.

[0016] In some embodiments, the flow system is located within a clean room or sterile environment, and the robotic manipulator system is configured to sample particles from the fluid without a user being physically present within the clean room or sterile environment. In some embodiments, the robotic manipulator system is located within the clean room or sterile environment. In some embodiments, the robotic manipulator system is configured to stack and unstack multiple impactors.

[0017] In one aspect, a method for detecting particles in a fluid is provided. The method may include exposing an inlet of a particle detection device to a particle-containing fluid, flowing the particle-containing fluid into the inlet, directing the fluid through a sampling region of the device, and discharging the fluid through an outlet of the device. The exposing and / or flowing steps may be performed by a robotic manipulator system. The method may include sterilizing the particle detection device via the robotic manipulator system. In some embodiments, the method may include transporting the particle detection device via the robotic manipulator system to a sterilization location for the sterilizing step. After the sterilizing step, the method may include transporting the particle detection device via the robotic manipulator system to a sampling location.

[0018] In some embodiments, the particle detection device comprises an impactor, and the sterilizing step includes sterilizing the impactor in a fully assembled form. In some embodiments, the collection surface of the impactor remains enclosed during sterilization. In some embodiments, the sterilizing step includes treating the impactor with vaporized hydrogen peroxide.

[0019] In some embodiments, at least a portion of the particles in the fluid to be sampled are biological particles, and the method includes culturing at least a portion of the biological particles received by the impactor, the culturing occurring inside the fully assembled impactor. In some embodiments, the method includes optically detecting the cultivated biological particles via a robotic manipulator system.

[0020] In some embodiments, the method includes characterizing the cultured biological particles by optical detection or imaging performed by a robotic manipulator system. In some embodiments, the method includes determining the viability, identity, or both, of microorganisms in the cultured biological particles. In some embodiments, the determining step is performed by the robotic manipulator system.

[0021] In some embodiments, the flowing step includes adjusting a flow rate of the fluid via a robotic manipulator system. In some embodiments, the method includes connecting a particle detector to the flow system prior to the flowing step. In some embodiments, the impactor is a disposable device. In some embodiments, the method includes collecting at least a portion of the particles flowing into the inlet. In some embodiments, the collecting step is performed by the robotic manipulator system.

[0022] In some embodiments, the robotic manipulator system includes an imaging device and the characterizing step is performed by the imaging device. In some embodiments, the fluid originates and / or terminates in a clean room or sterile environment and the method is performed without a user being physically present in the clean room or sterile environment. In some embodiments, the exposing and flowing steps are performed by the robotic manipulator system.

[0023] In one aspect, a system for detecting particles in a fluid is provided, the system comprising: i) an optical particle counter comprising: a) a flow chamber for flowing a particle-containing fluid along a flow direction through a beam of electromagnetic radiation; b) a light source in optical communication with the flow chamber for providing the beam of electromagnetic radiation; c) an optical collection system for collecting and directing at least a portion of the electromagnetic radiation to a photodetector, the photodetector generating an electrical signal characteristic of the number and / or size of the detected particles; ii) a flow system for flowing at least a portion of the fluid through the flow chamber of the optical particle counter so as to interact with the beam of electromagnetic radiation; and iii) a robotic control system configured to direct movements for at least one of positioning the optical particle counter at a sampling location, transporting the optical particle counter to and from the sampling location, and adjusting the flow rate of the fluid through the flow chamber of the optical particle counter. The optical particle counter may be a scattered light particle counter, an extinction optical particle counter, or a fluorescence optical particle counter.

[0024]

[0024] In one aspect, a system for sampling particles from a fluid is provided, the system comprising: i) an impinger or sampling cyclone; ii) a flow system for channeling at least a portion of the fluid through the impinger or sampling cyclone to facilitate acceptance of at least a portion of the particles in the fluid by the impinger or sampling cyclone; and iii) a robotic control system configured to direct at least one of the following actions: positioning the impinger or sampling cyclone at a sampling location; transporting the impinger or sampling cyclone to and from the sampling location; and adjusting the flow rate of the fluid passing through the impinger or sampling cyclone.

[0025]

[0025] In one aspect, there is provided a system for sampling particles from a fluid, the system comprising: i) an impactor, comprising: a) a sampling head having one or more inlet openings for sampling a fluid stream containing particles; and b) an impactor base operatively connected to receive at least a portion of the fluid stream from the sampling head, the impactor base comprising an impact or collection surface for receiving at least a portion of the particles in the fluid stream and an outlet for discharging the fluid stream, the sampling head and impactor base being integral components that engage to surround the impact surface; The impactor comprises: ii) an impactor that causes sampling of particles and growth of biological particles received on the impact surface without detachment of the sampling head and impactor base; ii) a flow system for circulating at least a portion of the fluid through the impactor to facilitate acceptance of at least a portion of the particles in the fluid by the impactor; and iii) a robotic control system configured to direct at least one of the following actions: positioning the impactor at a sampling position; transporting the impactor to and from the sampling position; and adjusting the flow rate of the fluid passing through the impactor device.

[0026] The systems described herein may further include a sterilization system for sterilizing the optical particle counter, impactor, impinger, or sampling cyclone. The sterilization system may utilize vaporized hydrogen peroxide, chlorine dioxide, ethylene oxide, moist heat, and dry heat. The robotic control system may be further configured to transport the optical particle counter, impactor, impinger, or sampling cyclone to the sterilization system.

[0027] The impactor collection surface may be configured to receive and capture biological particles. The sampling head and impactor base may engage to completely surround the collection surface, including, for example, by engaging via a substantially airtight seal. The sampling head and impactor base may each independently comprise a polymeric material. The impactor base may have multiple grooves on its outer surface to enable effective handling of the impactor by a robotic control system. The impactor base may have one or more features to enable effective stacking of multiple impactors. At least a portion of the impactor base, the sampling head, or both may be optically transparent.

[0028] The collection surface may comprise a growth medium for receiving biological particles in the fluid. The robotic control system may further comprise an optical detector or imaging device. The robotic control system may be further configured to expose the optical particle counter, impactor, impinger, sampling cyclone, and / or collection surface to the fluid. The robotic control system may be further configured to collect particles from the optical particle counter, impactor, impinger, sampling cyclone, and / or collection surface. The robotic control system may be further configured to sample particles from the fluid without a user having physical contact with the optical particle counter, impactor, impinger, or sampling cyclone.

[0029]

[0029] The impactor and / or collection surface may be provided with a growth medium for receiving biological particles in the fluid, in which case the robotic control system is further configured to transport the particle sampling or counting device in a fully assembled form to a sterilization system for sterilizing the particle sampling or counting device, and the growth medium is present within the particle sampling or counting device during its sterilization.

[0030] The robotic control system may be further configured to connect the optical particle counter, impactor, impinger, or sampling cyclone to the flow system. The optical particle counter, impactor, impinger, or sampling cyclone may further include an inlet for receiving at least a portion of the fluid under flow, in which case the robotic control system is further configured to open the inlet to allow the fluid to enter the optical particle counter, impactor, impinger, or sampling cyclone.

[0031]

[0031] The optical particle counter, impactor, impinger, or sampling cyclone may further include a cover for enclosing the optical particle counter, impactor, impinger, or sampling cyclone, in which case the robotic control system may be further configured to remove the cover to allow fluid to contact the optical particle counter, impactor, impinger, or sampling cyclone. The robotic control system may be further configured to close the inlet to prevent fluid from flowing into the optical particle counter, impactor, impinger, or sampling cyclone. The robotic control system may be further configured to replace the cover to prevent fluid from contacting the optical particle counter, impactor, impinger, or sampling cyclone.

[0032] The flow system may be incorporated within a clean room or sterile environment, and in this case the robotic control system is configured to sample particles from the flowing fluid without a user being physically present within the clean room or sterile environment. The robotic control system may be located inside the clean room or sterile environment, outside the clean room or sterile environment, or partially located both inside and outside the clean room or sterile environment. The systems described herein may further include multiple impactors or impingers, and in this case the robotic controller is further configured to direct the movement of the robot for stacking and unstacking the impactors or impingers.

[0033]

[0033] In one aspect, a method for detecting particles in a fluid is provided, the method comprising the steps of: i) providing an optical particle counter, the optical particle counter comprising: a) a flow chamber for flowing a fluid containing particles along a flow direction through a beam of electromagnetic radiation; b) a light source in optical communication with the flow chamber for providing the beam of electromagnetic radiation; and c) an optical collection system for collecting and directing at least a portion of the electromagnetic radiation to an optical detector, the optical detector generating an electrical signal characteristic of the number and / or size of the detected particles; ii) flowing at least a portion of the fluid through the flow chamber of the optical particle counter; and iii) determining the number and / or size of the detected particles based on the electrical signal, wherein at least one of the providing or flowing steps is performed by a system configured for robotic control.

[0034]

[0034] In one aspect, a method for sampling particles from a fluid is provided, the method comprising the steps of: i) providing an impinger or sampling cyclone; ii) flowing at least a portion of the fluid through the impinger or sampling cyclone; and iii) receiving at least a portion of the particles in the fluid in the impinger or sampling cyclone, wherein at least one of the providing, flowing, and receiving steps is performed by a system configured for robotic control.

[0035]

[0035] In one aspect, there is provided a system for sampling particles from a fluid, the method comprising the steps of: i) providing an impactor comprising: a) a sampling head having one or more intake openings for sampling a fluid stream containing particles; and b) an impactor base operatively connected to receive at least a portion of the fluid stream from the sampling head, the impactor base having an impact or collection surface for receiving at least a portion of the particles in the fluid stream and an outlet for discharging the fluid stream, wherein the sampling head and impactor base are integral components that engage to surround the impact surface, and the impactor provides particle sampling and growth of biological particles received on the impact surface without disengagement of the sampling head and impactor base; ii) flowing at least a portion of the fluid through the sampling head of the impactor; and iii) receiving at least a portion of the particles in the fluid on the impactor base impact surface, wherein at least one of the providing, flowing and receiving steps is performed by a system configured for robotic control.

[0036] In one aspect, a method for sampling particles from a fluid is provided, the method comprising: i) providing a particle sampling or counting device; ii) flowing at least a portion of the fluid through the particle sampling or counting device; and iii) receiving at least a portion of the particles (4) in the fluid (6) within the particle sampling or counting device, wherein at least one of the providing, flowing, and receiving steps is performed by a system configured for robotic control. The fluid may be a gas in a controlled environment, such as air or an inert gas. The particle sampling or counting device may comprise an impactor, impinger, sampling cyclone, and / or an optical particle counter.

[0037] The provided method may further include sterilizing at least a portion of the system configured for robotic control, including, for example, sterilizing the particle sampling or counting device. The particle sampling or counting device may be sterilized in fully assembled form. The providing step may include positioning the particle sampling or counting device in a position for the sterilization step by the system configured for robotic control. The providing step may include positioning the particle sampling or counting device to receive particles after the sterilization step by the system configured for robotic control.

[0038]

[0038] The described particle sampling or counting device may comprise: a) a collection surface configured to receive at least a portion of the particles in the fluid; b) a sampling head having one or more inlets for receiving at least a portion of the fluid under flow; and c) a base operably connected to the sampling head for receiving at least a portion of the sampled fluid from the sampling head, wherein the base has the collection surface and a fluid outlet, the sampling head and base being integral components that engage to surround the collection surface, and wherein the flowing step comprises a step of contacting at least a portion of the fluid with the collection surface.

[0039] The sampling head and base may, for example, engage to completely surround the collection surface via a substantially airtight seal. The sampling head and base may each independently comprise a polymeric material. The base may have a plurality of grooves provided on its exterior surface to enable effective handling of the particle sampling or counting device by a system configured for robotic control. The base may have one or more features that enable effective stacking of multiple particle sampling or counting devices.

[0040] At least a portion of the base, the sampling head, or both may be optically transparent. The provided method may further include sterilizing the particle sampling or counting device, wherein the collection surface remains enclosed during sterilization to protect a growth medium, such as agar, for capturing biological particles. The collection surface may comprise a growth medium for receiving the biological particles.

[0041] The provided method may further include the step of sterilizing the particle sampling or counting device in fully assembled form, wherein the collection surface remains enclosed by the sampling head and base during sterilization. The sterilization step may be carried out by treating the fully assembled and enclosed particle sampling or counting device with at least one of vaporized hydrogen peroxide, chlorine dioxide, ethylene oxide, moist heat, dry heat, and radiation.

[0042] The provided method may further include culturing at least a portion of the biological particles received by the growth medium. The culturing step may allow for optical detection of the biological particles. The culturing step may be performed without disassembly of the fully assembled particle sampling or counting device.

[0043] The provided methods may further include characterizing at least a portion of the grown biological particles by visualization, optical detection, molecular detection (e.g., techniques utilizing polymerase chain reaction (PCR) for biological materials), and / or imaging. The culturing step, the characterization step, or both may be performed by a system configured for robotic control. The provided methods may further include determining the presence, viability, identity, or both, of microorganisms in the grown biological particles. The determining step may be performed by a system configured for robotic control.

[0044] The recited providing step may include exposing a particle collection or sampling device to the fluid using a system configured for robotic control. The providing step may include exposing a collection surface of the particle collection or sampling device to the fluid using a system configured for robotic control. The distributing step may include adjusting a flow rate of the fluid by a system configured for robotic control.

[0045] The provided method may further include the step of removing a cover of the particle sampling or counting device or opening an inlet of the particle counting or sampling device by a system configured for robotic control. The provided method may further include the step of connecting the particle sampling or counting device to a flow system to enable fluid flow by a system configured for robotic control.

[0046] The provided method may further include replacing a cover of the particle sampling or counting device or closing an inlet of the particle counting or sampling device by a system configured for robotic control. The provided method may further include removing the particle sampling or counting device from the flow system and stopping the fluid flow by a system configured for robotic control. The particle sampling or counting device may be a single-use (e.g., disposable) particle counting or sampling device.

[0047] The provided method may further include collecting at least a portion of the particles received by the particle sampling or counting device and / or the collection surface. The described collecting step may be performed by a system configured for robotic control. The system configured for robotic control may include an imaging device.

[0048]

[0048] The provided method may further comprise a step of characterising the particles carried out by the imaging device, which may comprise, for example, determining the chemical composition of the particles or determining the particle size distribution of the particles.

[0049] The provided methods may be performed without a user having physical contact with the particle sampling or counting device. The fluid may originate and / or terminate in a clean room or sterile environment, and in this case the methods are performed without a user being physically present in the clean room or sterile environment. Each of the providing, distributing, and / or receiving steps may be performed by a system configured for robotic control.

[0050]

[0050] In one aspect, a system for sampling particles from a fluid is provided, the system comprising: a) a particle sampling or counting device; b) a flow system for channeling at least a portion of the fluid through the particle sampling or counting device to facilitate acceptance of at least a portion of the particles in the fluid by the particle sampling or counting device; c) a robot; and d) a robot controller for controlling the robot, the robot controller configured to direct movement of the robot for at least one of: i) positioning the particle sampling or counting device at a sampling location; ii) transporting the particle sampling or counting device to and from the sampling location; and iii) adjusting the flow rate of the fluid through the particle sampling or counting device.

[0051] The particle sampling or counting device may be an impactor, impinger, sampling cyclone, and / or optical particle counter. The provided system may further include a sterilization system for sterilizing the particle sampling or counting device. The sterilization system may utilize at least one of vaporized hydrogen peroxide, chlorine dioxide, ethylene dioxide, moist heat, and dry heat. The robot controller may be further configured to direct movement of the robot to transport the particle sampling or counting device to and from the sterilization system.

[0052]

[0052] The described particle sampling or counting device may comprise: A) a collection surface configured to receive at least a portion of the particles in a fluid; B) a sampling head having one or more inlets for sampling at least a portion of the fluid under flow; and C) a base operably connected to the sampling head for receiving at least a portion of the fluid sampled from the sampling head, wherein the base has the collection surface and a fluid outlet, the sampling head and base being integral components that engage to surround the collection surface, and the flow system configured to bring at least a portion of the fluid into contact with the collection surface.

[0053] The sampling head and base may engage to completely surround the collection surface. The sampling head and base may engage via a substantially airtight seal. The sampling head and base may each independently comprise a polymeric material. The sampling head or base may have multiple grooves on its outer surface to enable effective handling of the particle sampling or counting device by a robot. The sampling head or base may have one or more features that enable effective stacking of multiple particle sampling or counting devices. At least a portion of each of the base, the sampling head, or both may be optically transparent.

[0054] The collection surface may comprise a growth medium (e.g., agar) for receiving biological particles in the flowing fluid. The robot may further comprise an optical detector or imaging device. The robot controller may be further configured to direct movement of the robot to expose the particle sampling or counting device and / or the collection surface to the fluid. The robot controller may be further configured to direct movement of the robot to collect particles from the particle sampling or counting device and / or the collection surface. The robot controller may be further configured to direct movement of the robot to sample particles from the fluid without a user having physical contact with the particle sampling or counting device.

[0055]

[0055] The provided system may be configured such that the particle sampling or counting device and / or collection surface comprises a growth medium for receiving biological particles in the fluid, in which case the robotic controller is further configured to transport the particle sampling or counting device in fully assembled form to a sterilization system for sterilizing the particle sampling or counting device, and the growth medium is present within the particle sampling or counting device during its sterilization.

[0056] The robot controller may be further configured to direct movement of the robot to connect the particle sampling or counting device to the flow system. The particle sampling or counting device may further include a fluid inlet for receiving at least a portion of the fluid under flow, in which case the robot controller is further configured to direct movement of the robot to open the inlet to allow fluid to enter the particle sampling or counting device. The particle sampling or counting device may further include a cover for enclosing the particle counting or sampling device, in which case the robot controller is further configured to direct movement of the robot to remove the cover to allow fluid to contact the particle sampling or counting device.

[0057] The robot controller may be further configured to direct movement of the robot to close the inlet to stop fluid flow to the particle sampling or counting device. The robot controller may be further configured to direct movement of the robot to replace the cover to prevent fluid from contacting the particle sampling or counting device.

[0058] The flow system may be incorporated within a clean room or sterile environment, and in this case the robot controller is further configured to direct the movement of the robot to sample particles from the flowing fluid without a user being physically present within the clean room or sterile environment. The robot is located inside the clean room or sterile environment, and the robot controller is located outside the clean room or sterile environment. The provided system may further comprise a plurality of particle sampling or counting devices, and in this case the robot controller is further configured to direct the movement of the robot to stack and de-stacking the particle sampling or counting devices.

[0059] While not wishing to be bound by any particular theory, beliefs or understandings of underlying principles related to the devices and methods disclosed herein may be discussed herein. It is recognized that regardless of the ultimate correctness of any mechanistic explanation or hypothesis, embodiments of the present invention may nevertheless be operable and useful. [Brief explanation of the drawings]

[0060] [Figure 1] 1 is a flowchart of a method for sampling particles from a fluid according to one embodiment of the present disclosure. [Figure 2] FIG. 2 is a schematic diagram of a system for sampling particles from a fluid that can be used to perform the method of FIG. 1 according to one embodiment of the present disclosure. [Figure 3] FIG. 3 is a schematic diagram of a typical impinger in use in the system of FIG. 2. [Figure 4] 2 is a flowchart of an example of the method shown in FIG. 1 according to another embodiment of the present disclosure. [Figure 5] 1 shows a perspective view of an exemplary impactor of the present invention. [Figure 6] A cross-sectional view of the impactor in Figure 2 is shown. [Figure 7] FIG. 7 is an exploded view of the impactor of FIGS. 5 and 6, with components of the device spatially separated for clarity. [Figure 8] 1 shows a perspective view of an impactor of the present invention. [Figure 9] 2 is a flowchart of an example of the method shown in FIG. 1 according to yet another embodiment of the present disclosure. [Figure 10] 2 is a flowchart of an example of the method shown in FIG. 1 according to yet another embodiment of the present disclosure. [Figure 11] 2 is a flowchart of an example of the method shown in FIG. 1 according to another embodiment of the present disclosure. [Figure 12] 2 is a flowchart of an example of the method shown in FIG. 1 according to yet another embodiment of the present disclosure. [Figure 13] 2 is a flowchart of an example of the method shown in FIG. 1 according to yet another embodiment of the present disclosure. [Figure 14] 1 provides an example of an optical particle counter that may be used in some embodiments of the present invention. [Figure 15] FIG. 1 illustrates an example of a robot manipulator according to one embodiment of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0061]

[0075] In the following description, numerous specific details of the devices, device components, and methods of the present invention are set forth in order to provide a thorough explanation of the precise nature of the invention. However, it will be understood by those skilled in the art that the present invention may be practiced without these specific details.

[0062]

[0076] Generally, the terms and phrases used herein have their art-recognized meanings, which can be found by reference to standard texts, journal sources, and context known to those skilled in the art. The following definitions are provided to clarify their specific use in the context of the present invention.

[0063]

[0077] "Operably connected," "operably coupled," "operably connected," and "operably coupled" refer to a form of element in which the action or reaction of one element affects other elements in a manner that maintains the functionality of each element. The connection may be by direct physical contact between the elements. The connection may be indirect, with other elements indirectly connecting the operably connected elements. The term also refers to two or more functionally related components being coupled to one another for the flow of electrical current and / or data signals. This coupling of two or more components may be a wired and / or wireless connection. Two or more components so coupled via a wired and / or wireless connection may be in close proximity to one another (e.g., in the same room or in the same residence) or may be separated by a distance in physical space (e.g., in different buildings).

[0064]

[0078] "Particle" refers to small objects often considered contaminants. A particle may be any substance created by the action of friction, for example, when two surfaces come into mechanical contact and mechanical movement is present. A particle may consist of aggregates of materials such as dust, dirt, smoke, ash, water, soot, metals, minerals, or any combination thereof, or other materials and contaminants. "Particle" may also refer to biological particles, such as bacteria, fungi, archaea, protists, viruses, prions, spores, and microorganisms, including other single-celled microorganisms, particularly those with sizes on the order of 1-15 μm or less. A particle may refer to any small object that absorbs, blocks, or scatters light and is therefore detectable by an optical particle counter. As used herein, "particle" refers to the exclusion of individual atoms or molecules of a carrier fluid, such as water molecules, process chemical molecules, oxygen molecules, helium atoms, and nitrogen molecules. Some embodiments of the present invention can detect, size, and / or count particles comprising agglomerates of material having sizes greater than or equal to 10 nm, 20 nm, 30 nm, 50 nm, 100 nm, 500 nm, 1 μm, or greater than 10 μm. Specific particles include particles having a size selected from 20 nm to 50 nm, 50 nm to 50 μm, 100 nm to 10 μm, or 500 nm to 5 μm.

[0065]

[0079] The phrase "sampling particles" broadly refers to the collection of particles in a fluid stream, for example, from an environment being monitored. In this context, sampling can include moving particles in the fluid stream to an impact surface, such as a surface receiving a growth medium. Alternatively, sampling can refer to passing particles in a fluid through a particle analysis region, for example, for optical detection and / or characterization. Sampling can refer to the collection of particles having one or more preselected characteristics, such as size (e.g., cross-sectional dimension, such as diameter or effective diameter), particle type (biological or non-biological, viable or non-viable, etc.), or particle composition. Sampling can optionally include analysis of the collected particles, for example, by subsequent optical analysis, image analysis, or visual analysis. Sampling can optionally include growing viable biological particles for the sample through a culture process involving a growth medium. A sampler refers to a device for sampling particles.

[0066]

[0080] "Impactor" refers to a device for sampling particles. In some embodiments, the impactor includes an inlet, e.g., a sample head including one or more intake openings, for sampling a particle-containing fluid stream, such that at least a portion of the particles in the sampling region of the impactor are directed onto an impaction surface for collection, such as a receiving surface of a growth medium (e.g., agar, broth, or other medium) or a substrate such as a filter. Some impactor embodiments effect a change in direction of the flow after passing through the intake opening, where particles having a preselected characteristic (e.g., size greater than a threshold) do not change direction and are therefore received by the impaction surface.

[0067]

[0081] "Impinger" refers to a closed sampling device designed to contain a fluid for capturing particles from an environmental fluid due to interaction between the particles and the impinger fluid. An impinger may include an inlet, a sampling region where particles interact with the fluid, and an outlet. For example, an impinger may contain a liquid that allows particles in the vapor to become suspended in the liquid due to the flow of the vapor over a surface or through a liquid medium. Impingers may use water, condensates, polar fluids, non-polar fluids, and solvents.

[0068]

[0082] "Cyclone sampler" refers to a sampling device that directs the flow of fluid passing through an inlet into a vortex or cyclone within the sampling region of the sampler, forcing particles in the flow toward the outside of the sampler where they are captured, for example, due to the force of the fluid flow or forces within the sampling medium or filtration system.

[0069]

[0083] The phrase "detecting particles" broadly refers to sensing particles, identifying the presence of particles, and / or characterizing particles. In some embodiments, detecting particles refers to counting particles. In some embodiments, detecting particles refers to characterizing and / or measuring a physical property of a particle, such as diameter, cross-sectional dimension, shape, size, aerodynamic size, or any combination thereof. A particle counter is a device for counting the number of particles in a fluid or the volume of a fluid, and optionally characterizing particles based on, for example, size (e.g., cross-sectional dimension such as diameter or effective diameter), particle type (e.g., biological or non-biological), or particle composition. An optical particle counter is a device that detects particles by measuring the scattering, emission, extinction, or absorbance of light by the particles.

[0070]

[0084] "Flow direction" refers to the axis parallel to the direction in which the majority of the fluid is moving as the fluid flows. For fluid flowing through a straight flow cell, the flow direction is parallel to the path taken by the majority of the fluid. For fluid flowing through a curved flow cell, the flow direction may be considered to be tangential to the path taken by the majority of the fluid.

[0071]

[0085] "Optical communication" refers to an orientation of components such that they are positioned in a manner that allows light or electromagnetic radiation to be transmitted between them.

[0072]

[0086] "Fluid communication" refers to the arrangement of two or more objects such that a fluid can be transported past, through, or from one object to another. For example, in some embodiments, two objects are in fluid communication with each other if a fluid flow path is directly between the two objects. In some embodiments, two objects are in fluid communication with each other if a fluid flow path is indirectly between the two objects, such as by including one or more other objects or flow paths between the two objects. For example, in one embodiment, the following components of a particle impactor are in fluid communication with each other: one or more inlet openings, impact surfaces, fluid outlets, flow restrictions, pressure sensors, and flow generators. In one embodiment, two objects present in the body of a fluid are not necessarily in fluid communication with each other unless fluid from the first object is attracted to, past, and / or via the second object, such as along a flow path.

[0073]

[0087] "Flow rate" refers to the amount of fluid flowing past a particular point or through a particular area, such as through an inlet opening or fluid outlet of a particle impactor. In one embodiment, flow rate refers to mass flow rate, i.e., the mass of fluid flowing past a particular point or through a particular area. In one embodiment, flow rate refers to volumetric flow rate, i.e., the volume of fluid flowing past a particular point or through a particular area.

[0074]

[0088] "Pressure" refers to a measure of force exerted per unit area. In one embodiment, pressure refers to the force exerted by a gas or fluid per unit area. "Absolute pressure" refers to a measure of pressure exerted by a gas or fluid per unit area referenced to a perfect vacuum or volume that exerts zero force per unit area. Absolute pressure is distinguished from "differential pressure" or "gauge pressure," which refers to the relative change or difference in force exerted per unit area over or relative to a second pressure, such as ambient or atmospheric pressure.

[0075]

[0089] "Polymer" refers to a macromolecule composed of repeating structural units or the polymerization product of one or more monomers connected by covalent chemical bonds, and is often characterized by a high molecular weight. The term polymer includes homopolymers, or polymers consisting essentially of a single repeating monomer subunit. The term polymer also includes copolymers, or polymers consisting essentially of two or more monomer subunits, such as random, block, alternating, segmented, graft, tapered, and other copolymers. Useful polymers include organic or inorganic polymers that may be amorphous, semi-amorphous, crystalline, or partially crystalline. Crosslinked polymers, having linked monomer chains, are particularly useful in some applications. Polymers that can be used in the methods, devices, and components include, but are not limited to, plastics, elastomers, thermoplastic elastomers, elastoplastics, thermoplastics, and acrylates. Exemplary polymers include, but are not limited to, acetal polymers, biodegradable polymers, cellulosic polymers, fluoropolymers, nylon, polyacrylonitrile polymers, polyamideimide polymers, polyimides, polyarylates, polybenzimidazoles, polybutylenes, polycarbonates, polyesters, polyetherimides, polyethylene, polyethylene copolymers and modified polyethylenes, polyketones, poly(methyl methacrylate), polymethylpentene, polyphenylene oxide and polyphenylene sulfide, polyphthalamides, polypropylenes, polyurethanes, styrenics, sulfones, vinyls, rubbers (including natural rubber, styrene butadiene, polybutadiene, neoprene, ethylene-propylene, butyl, nitrile, silicone), acrylics, nylons, polycarbonates, polyesters, polyethylene, polypropylene, polystyrene, polyvinyl chloride, polyolefins, or any combination thereof.

[0076]

[0090] Figure 1 is a flow chart of a method 2 for sampling particles 4 from a fluid 6 according to one embodiment of the present disclosure. Figure 2 shows a schematic diagram of one embodiment of an example robotic sampling and counting system 8 for sampling particles 4 from a fluid 6. In one example, method 2 is implemented and performed, at least in part, by system 8.

[0077]

[0091] 1, 2, and 15, a method (2) includes a step (10) of providing a particle sampling or counting device (12). The method (2) includes a step (14) of flowing at least a portion of a fluid (6) through the particle sampling or counting device (12) and a step (16) of receiving at least a portion of the particles (4) in the fluid (6) with the particle counting or sampling device (12). At least one of the providing step (10), flowing step (14), and receiving step (16) is performed by a system configured for robotic control (18) (e.g., a robotic manipulator (20)). Alternatively, any combination of the providing step (10), flowing step (14), and receiving step (16) is performed by a system configured for robotic control (18). In another example, each of the providing step (10), distributing step (14), and receiving step (16) is performed by a system configured for robotic control (18).

[0078]

[0092] 2 and 15, a system 8 includes one or more particle sampling or counting devices 12. The system 8 includes a flow system 22 for flowing at least a portion of a fluid 6 into and / or through the particle sampling or counting device 12 to facilitate receipt of at least a portion of the particles 4 in the fluid 6 by the particle sampling or counting device 12. The flow system 22 includes a flow control valve 3. The flow system 22 includes a sampling port 5 configured to be in fluid communication with the particle sampling or counting device 12. The system 8 includes a robotic manipulator 20 and a robot controller 24 for controlling the robotic manipulator 20. The robot controller 24 is operably connected to the robotic manipulator 20. The robotic manipulator 20 includes at least one robotic arm 21 having one or more degrees of freedom of movement. The robotic arm (21) includes at least one working end (27) configured to at least one of grasp, move, and / or otherwise manipulate objects disposed within the system (8). The robotic controller (24) is configured to direct the movement (25) of the robotic manipulator (20) for at least one of positioning the particle sampling or counting device (12) at a sampling location (26), transporting the particle sampling or counting device (12) to and from the sampling location (26), and regulating the flow rate of the fluid (6) to and / or through the particle sampling or counting device (12).

[0079]

[0093] In the example shown in FIGS. 2 and 15, the system 8 is located inside a sterile or clean room environment 13 (9). The sterile or clean room environment 13 includes a heating, ventilation, and air conditioning (HVAC) system 11. The HVAC system 11 may include components located either inside the sterile or clean room environment 13 (9) or outside the sterile or clean room environment 13 (15), or both. The HVAC system 11 receives a supply fluid 17 (e.g., air 15 from outside) through at least one supply duct 19. The HVAC system 11 processes the supply fluid 17, for example, to adjust its temperature and / or flow rate and / or reduce particulate matter present in the supply fluid 17. The fluid 6 exits the HVAC system 11 and flows into the clean room or sterile environment 13 (9) through at least one interior duct 29. Internal ducts (29) deliver the fluid (6) to various processing equipment (23) located within the clean room or sterile environment (13).

[0080]

[0094] Example 1 - Particle and Biological Contaminant Sampling or Counting Device, or Viable / Non-viable Particle Sampling Device In one example, the particle sampling or counting device 12 is an impactor 28. The impactor 28 may be any of the devices disclosed in U.S. Patent Application No. 14 / 338,615, which is incorporated herein by reference in its entirety. In another example, the particle sampling or counting device 12 is an impinger 30. In yet another example, the particle sampling or counting device 12 is configured for use with a cyclone-based method. In yet another embodiment, the particle sampling or counting device 12 is an optical particle counter 32. In yet another embodiment, the particle sampling or counting device 12 includes any combination of an impactor 28, an impinger 30, an optical particle counter 32, and a device 12 configured for use with a cyclone-based method. In yet another embodiment, the particle sampling or counting device (12) includes an impactor (28), an impinger (30), an optical particle counter (32), and a device (12) each configured for use in a cyclone-based method.

[0081]

[0095] FIG. 3 is a schematic diagram of a typical impinger 30 in use in system 8. The impinger 30 is at least partially filled with a liquid 31, which may be a liquid growth medium 72. The end of the impinger 30 is configured to fit over the end of the sampling port 5 (e.g., by the robotic arm 21 of the robotic manipulator 20). A fluid 6 to be sampled by the impinger 30 flows into the impinger 30. The liquid 31 contained within the impinger 30 captures particles 4 present in the fluid 6 for subsequent characterization and / or analysis. After capturing particles 4 from the inlet fluid 6 entering the impinger 30 through the sampling port 5, the fluid 6 continues to flow out of the impinger 30 via the fluid outlet 54. Impinger (30) includes cover (86) and seal (56) that provides an airtight and / or sealingly operable coupling of cover (86) to impinger (30) (e.g., to prevent contamination of liquid (31)).

[0082]

[0096] automatic sterilization 4 is a flowchart of an example method (2) for sampling particles (4) from a fluid (6) according to another embodiment of the present disclosure. In this example, method (2) includes a step (34) of sterilizing at least a portion of a system configured for robotic control (18). In this example, method (2) includes a step (36) of sterilizing particle sampling or counting device (12). In method (2), sterilization step (36) includes sterilizing particle sampling or counting device (12) in its fully assembled form.

[0083]

[0097] 2, system 8 includes a sterilization system 38 for sterilizing particle sampling or counting device 12. In one example, sterilization system 38 utilizes at least one of vaporized hydrogen peroxide, chlorine dioxide, ethylene dioxide, radiation, moist heat, and dry heat. Robotic controller 24 is configured to direct movement 25 of robotic manipulator 20 to transport particle sampling or counting device 12 to sterilization system 38.

[0084]

[0098] In this example, the providing step (10) of method (2) includes a step (40) of positioning the particle sampling or counting device (12) in position (42) for the sterilization steps (34 and / or 36) by a system configured for robotic control (18) (including, for example, without limitation, a robotic manipulator (20)). In this example, the positioning step (40) is performed in method (2) prior to the providing step (10). Alternatively, the positioning step (40) is performed in method (2) after the providing step (10). In another example, the positioning step (40) is performed in method (2) simultaneously with the providing step (10). In this example, the positioning step (40) is performed in method (2) prior to the sterilization steps (34 and / or 36). Alternatively, the positioning step (40) is performed in method (2) simultaneously with the sterilization steps (34 and / or 36). In one example, the providing step (10) of the method (2) includes positioning (44) a particle sampling or counting device (12) to receive (16) particles (4) from the sterilization steps (34 and / or 36) by a system configured for robotic control (18).

[0085]

[0099] Particle collection form In one example, the particle sampling or counting device 12 of the system 8 is an impactor 28. Figure 5 shows a perspective view of an exemplary impactor 28 of the present invention. Figure 6 shows a cross-sectional view of the impactor 28 of Figure 2. Figure 7 shows an exploded view of the impactor 28 of Figures 5 and 6, with the components of the device spatially separated for clarity. Figure 8 shows a perspective view of the impactor 28 of the present invention.

[0086]

[0100] In the embodiment of the particle counting or sampling device (12) shown in Figures 5-8, the impactor (28) includes a base (52) portion, a dispensing portion (47), and a protective portion (49). Furthermore, the impactor (28) as a whole is disposable or usable for a single sampling of the air to be sampled and / or analyzed. In particular, the base (52) includes a support (53) suitable for containing a growth (e.g., culture) medium (72) for the growth of microorganisms. Preferably, the support (53) may be a Petri dish. In a preferred embodiment of the invention, the support (53) has a height h and an area A that are smaller than the height h1 and area A1 of the base (52).

[0087]

[0101] By way of example and not limitation, the height h of the support 53 may range from 17 mm to 19 mm, and the area A of the support 53 may range from 5,930 mm to 5,940 mm. Additionally, the height h1 of the base 52 may range from 22 mm to 24 mm, and the area A1 of the base 52 may range from 10,730 mm to 10,760 mm.

[0088]

[0102] As previously mentioned, the support 53 is adapted to receive a growth medium 72 suitable for microbial growth, for example, when the impactor 28 is placed under temperature and O2 / CO2 conditions favorable for colony-forming unit (CFU) growth. Depending on the type of microorganism whose presence in the ambient air is to be analyzed, a technician using basic knowledge can identify known growth media that best suit their needs. By way of example and not limitation, the growth medium 72 may be selected from TSA (tryptone soy agar) or SDA (Sabouraud dextrose agar). For purposes of the present invention, the amount of growth medium 72 present in the support 53 is such that it ensures the growth of microbial colonies on the medium 72. In this regard, the support 53 is preferably adapted to receive a medium volume of 20 to 40 mL. The base 52 includes a fluid conduit 51 adapted to connect the interior region of the base 52 to the outside, for example, via a sampling port 5, as can be seen in FIGS. 5-8. Preferably, conduit 51 is closed by a cap disposed on its free end when impactor 28 is not sampling fluid 6, such as during transport or storage of impactor 28. Conversely, when impactor 28 is sampling fluid 6, conduit 51 is adapted to be connected to a vacuum source (not shown) to promote deposition onto growth medium 72 of microorganisms present in the fluid 6 (e.g., air) sample.

[0089]

[0103] The distribution section (47) of the impactor (28) includes one or more openings (55) for ensuring the passage of airborne microorganisms onto the growth medium (72). For this purpose, as shown in FIGS. 6 and 7, when the distribution section (47) is connected to the base (52), one or more openings (55) are disposed adjacent to the growth medium (72). The openings (55) may have any type of shape deemed suitable by those skilled in the art for the purposes of the present invention. Preferably, the openings (55) are rectangular in shape and are distributed over the entire area (A) of the support (53). In one embodiment, the openings (55) are distributed in a substantially uniform manner over the entire area (A) of the support (53). This uniform distribution can be, for example, a radial pattern, as shown by way of example in FIGS. 5-8. The uniform placement of the openings (55) on the growth medium (72) is particularly advantageous as it allows for the identification of possible false positives during the air sample contamination assessment phase, for example if microorganisms are not detected as being uniformly distributed throughout the growth medium (72).

[0090]

[0104] As previously described, impactor 28 operates in a manner similar to impactors for microbial air sampling. Accordingly, impactor 28 is shaped to define a fluid 6 (e.g., air) connecting path between one or more openings 55 and conduit 51. Dispensing portion 47 and base 52 portions may be connected to one another in a sealing manner, for example, without limitation, by an interlocking mechanism, so that passage of microorganisms preferably occurs only through openings 55.

[0091]

[0105] The impactor 28 also includes a protective portion 49 that may be positioned over the dispensing portion 47 to block one or more openings 55, for example, when the impactor 28 is not performing fluid 6 sampling. In one embodiment of the present invention, the protective portion 49, the base 52, and / or the dispensing portion 47 may be formed from a transparent material. Preferably, the transparent material may be plastic and / or glass. Impactor 28 embodiments in which the dispensing portion 47, the protective portion 49, and / or the base 52 are formed from a transparent material are particularly advantageous. Indeed, once the impactor 28 is placed in temperature, O2, or CO2 conditions suitable for microbial growth, colony-forming unit (CFU) counts and / or other characterizations and / or analyses may be performed without the need to remove the dispensing portion 47, the protective portion 49, and / or the base 52 to access and examine the growth medium 72. Enumeration of colony forming units present in growth medium 72 provides a quantitative estimate of contamination of the fluid 6 sample and, subsequently, for example, of the air in the environment of interest (e.g., environment 13). Regarding the mode of operation of impactor 28, the impactor operates by promoting sedimentation of microorganisms present in sampled fluid 6 by impacting fluid 6 into opening 55 in growth medium 72.

[0092]

[0106] The impactor 28 includes a collection surface 46 configured to receive at least a portion of the particles 4 in the fluid 6. In this example, the particle sampling or counting device 12 (e.g., the impactor 28) includes a sampling head 48 having one or more inlets 48 for receiving at least a portion of the flowing fluid 6. In this example, the particle sampling or counting device 12 (e.g., the impactor 28) includes a base 52 operably connected to the sampling head 48 to receive at least a portion of the sampled fluid 6 from the sampling head 48. The base 52 includes the collection surface 46 and a fluid outlet 54. In this example, the sampling head 48 and the base 52 are integral components that circumferentially engage the collection surface 46. In this example, the flow system (22) is configured to bring at least a portion of the flowing fluid (6) (via the sampling port (5)) into contact with the collection surface (46).

[0093]

[0107] In one example, the sampling head 48 and the base 52 engage to completely surround the collection surface 46. The sampling head 48 and the base 52 may engage via a substantially airtight seal 56. The sampling head 48 and the base 52 may each be independently formed from a polymeric material. At least a portion of the base 52, the sampling head 48, or both may be optically transparent. The base 52 may have multiple grooves 58 formed in its outer surface 60 to enable effective handling of the particle sampling or counting device 12 (e.g., impactor 28) by the robotic manipulator 20. The base 52 may have one or more mechanisms to enable effective stacking and / or de-stacking of multiple particle sampling or counting devices 12 (e.g., multiple impactors 28), for example, including without limitation, by the robotic manipulator 20. Any of the particle sampling or counting devices (12) described herein may be a disposable particle counting or sampling device (12).

[0094]

[0108] 9 is a flowchart of an example method 2 for sampling particles 4 from a fluid 6 according to yet another embodiment of the present disclosure. In this example, the flowing step 14 of the method 2 includes contacting at least a portion of the fluid 6 with a collection surface 46 (step 62). The providing step 10 of the method 2 includes engaging a sampling head 48 and a base 52 (step 64) to completely surround the collection surface 46 of a particle sampling or counting device 12 (e.g., impactor 28). The engaging step 64 may include sealing the engaged sampling head 48 and base 52 (step 66) via a substantially airtight seal 56. The providing step 10 of the method 2 may include stacking 68 and / or unstacking 70 the particle sampling or counting device 12. Referring again to FIG. 4, in method (2), with respect to the step (36) of sterilizing the particle sampling or counting device (12) of method (2), the collection surface (46) remains enclosed during sterilization.

[0095]

[0109] System for detecting and characterizing biological particles In one example, in system 8, collection surface 46 of particle sampling or counting device 12 (e.g., impactor 28) of system 8 includes growth medium 72 for receiving biological particles 4 in flowing fluid 6. In this example, a system (e.g., robotic manipulator 20) configured for robotic control 18 includes an optical detector 74 for detecting biological particles 4 in or on growth medium 72. In another example, a system configured for robotic control 18 includes an imaging device 76 for detecting biological particles 4 in or on growth medium 72. In yet another example, a system configured for robotic control 18 includes an optical detector 74 and an imaging device 76 for detecting biological particles 4 in or on growth medium 72.

[0096]

[0110] In this example, the robotic controller 24 is configured to direct the movement 25 of the robotic manipulator 20 to expose the particle sampling or counting device 12 (e.g., impactor 28) and / or the collection surface 46 to the fluid 6. The robotic controller 24 is configured to direct the movement 25 of the robotic manipulator 20 to collect particles 4 from the particle sampling or counting device 12 (e.g., impactor 28) and / or the collection surface 46. The robotic controller 24 is further configured to direct the movement 25 of the robotic manipulator 20 to sample particles 4 from the fluid 6 without the user 78 physically contacting the particle sampling or counting device 12 (e.g., impactor 28).

[0097]

[0111] In this example, the particle sampling or counting device 12 (e.g., impactor 28) and / or collection surface 46 includes a growth medium 72 for receiving biological particles 4 in fluid 6. The robotic controller 24 is configured to direct the movement 25 of the robotic manipulator 20 to transport the particle sampling or counting device 12 (e.g., impactor 28) in a fully assembled form to a sterilization system 38 for sterilization of the particle sampling or counting device 12. The growth medium 72 is present within the particle sampling or counting device 12 during its sterilization.

[0098]

[0112] 10 is a flowchart of an example method 2 for sampling particles 4 from a fluid 6 according to yet another embodiment of the present disclosure. In some embodiments, the method 2 includes a step 80 of incubating at least a portion of the biological particles 4 received in a growth medium 72. The incubation step 80 enables and allows optical detection (e.g., by an optical detector 74 and / or an imaging device 76) of the grown biological particles 4. In this example, the incubation step 80 may be performed without disassembly of the fully assembled particle sampling or counting device 12.

[0099]

[0113] In this example, method 2 includes characterizing (82) at least a portion of grown biological particles 4 by at least one of visualization (e.g., by user 78), optical detection (e.g., by optical detector 74), imaging (e.g., by imaging device 76), and polymerization chain reaction (PCR). In this example, culturing (80), characterizing (82), or both, may be performed by a system configured for robotic control 18 (e.g., robotic manipulator 20). In this example, method 2 includes determining (84) at least one of the presence, viability, and identity of microorganisms in grown biological particles 4. In this example, determining (84) may be performed by a system configured for robotic control 18.

[0100]

[0114] 4, the sterilization step (36) of method (2) includes sterilizing (36) the particle sampling or counting device (12) (e.g., impactor (28)) in a fully assembled form with the collection surface (46) remaining enclosed by the sampling head (48) and base (52) during sterilization. In this example, the sterilization step (36) may be performed by treating the fully assembled and enclosed particle sampling or counting device (12) with at least one of vaporized hydrogen peroxide, chlorine dioxide, ethylene dioxide, moist heat, dry heat, and radiation.

[0101]

[0115] Robot Control and Positioning In one example, the robotic controller 24 of the system 8 is configured to direct the movement 25 of the robotic manipulator 20 to connect the particle sampling or counting device 12 (e.g., via the sampling port 5) to the flow system 22. In this example, the particle sampling or counting device 12 (e.g., the impactor 28) includes an inlet 50 for receiving at least a portion of the fluid 6 under flow. The robotic controller 24 is configured to direct the movement 25 of the robotic manipulator 20 to open the inlet 50 to allow the fluid 6 to enter the particle sampling or counting device 12.

[0102]

[0116] In this example, particle sampling or counting device 12 includes a cover 86 for enclosing particle counting or sampling device 12. Robotic controller 24 is configured to direct movement 25 of robotic manipulator 20 to remove cover 86 to allow fluid 6 to contact particle sampling or counting device 12. In this example, robotic controller 24 is configured to direct movement 25 of robotic manipulator 20 to close inlet 50 to stop the flow of fluid 6 into particle sampling or counting device 12. Robotic controller 24 is configured to direct movement 25 of robotic manipulator 20 to replace cover 86 to prevent fluid 6 from contacting particle sampling or counting device 12.

[0103]

[0117] 11 is a flowchart of an example method 2 for sampling particles 4 from a fluid 6 according to yet another embodiment of the present disclosure. In this example, the providing step 10 of the method 2 includes exposing the particle sampling or counting device 12 to the fluid 6 using a system (e.g., a robotic manipulator 20) configured for robotic control 18. In this example, the flowing step 14 includes regulating (e.g., via a regulator valve 3) the flow rate of the fluid 6 (e.g., entering the device 12 via inlet 50) using the system (e.g., the robotic manipulator 20) configured for robotic control 18.

[0104]

[0118] In this example, method 2 includes removing 92 cover 86 of particle sampling or counting device 12 with a system (e.g., robotic manipulator 20) configured for robotic control 18. Method 2 includes opening 94 inlet 50 of particle counting or sampling device 12 with a system (e.g., robotic manipulator 20) configured for robotic control 18. Method 2 includes connecting 96 particle sampling or counting device 12 to flow system 22 to allow fluid 6 to flow with the system (e.g., robotic manipulator 20) configured for robotic control 18.

[0105]

[0119] In this example, method 2 includes replacing 98 the cover 86 of the particle sampling or counting device 12 with a system (e.g., robotic manipulator 20) configured for robotic control 18. Method 2 includes closing 100 the inlet 50 of the particle counting or sampling device 12 with a system (e.g., robotic manipulator 20) configured for robotic control 18. Method 2 includes removing 102 the particle sampling or counting device 12 from the flow system 22 to stop the flow of fluid 6 with a system (e.g., robotic manipulator 20) configured for robotic control 18.

[0106]

[0120] Particle collection and characterization 12 is a flowchart of an example method 2 for sampling particles 4 from a fluid 6 according to yet another embodiment of the present disclosure. In this example, the method 2 includes a step 104 of collecting at least a portion of the particles 4 received by the particle sampling or counting device 12 and / or collection surface 46. In this example, the collecting step 104 is performed by a system (e.g., a robotic manipulator 20) configured for robotic control 18. In this example, the system configured for robotic control 18 includes an imaging device 76.

[0107]

[0121] In this example, method 2 includes characterizing 106 particles 4 performed by imaging device 76. Characterizing 106 may include determining 108 the chemical composition of particles 4. Characterizing 106 may include determining 110 the particle size distribution of particles 4.

[0108]

[0122] In one example, method 2 includes a synchronization step 107. For example, based on a predetermined schedule of user 78, system 8 performs synchronized sampling of fluid 6 by robotic manipulator 20 for particles 4 based on a particular cycle (mode) being performed in environment 13 (e.g., vial filling, vial capping, among other cycles, in a pharmaceutical manufacturing facility). Any step in any of the embodiments of method 2 disclosed herein may be synchronized in a similar manner.

[0109]

[0123] Lack of user interaction In one example, the flow system 22 of the system 8 is integrated into the clean room or sterile environment 13. In this example, the robotic controller 24 is configured to direct the movement 25 of the robotic manipulator 20 to sample particles 4 from the flowing fluid 6 without the physical presence of a user 78 within the clean room or sterile environment 13. In this example, the robotic manipulator 20 is located inside the clean room or sterile environment 13, and the robotic controller 24 is located outside the clean room or sterile environment 13. Alternatively, both the robotic manipulator 20 and the robotic controller 24 are located within the clean room or sterile environment 13. In this example, the fluid 6 originates within the clean room or sterile environment 13. The fluid 6 terminates in the clean room or sterile environment 13. Alternatively, fluid 6 originates in clean room or sterile environment 13 and fluid 6 terminates outside clean room or sterile environment 13. In other examples, fluid 6 originates outside clean room or sterile environment 13 and fluid 6 terminates inside clean room or sterile environment 13.

[0110]

[0124] 13 is a flowchart of an example method 2 for sampling particles 4 from a fluid 6 according to yet another embodiment of the present disclosure. In this example, method 2 is performed without a user 78 having physical contact 114 with the particle sampling or counting device 12. In this example, method 2 may be performed without a user 78 having physical contact 116 with the clean room or sterile environment 13. Alternatively, method 2 may be performed without a user 78 having physical contact 114 with the particle sampling or counting device 12 and without a user 78 having physical contact 116 with the clean room or sterile environment 13.

[0111]

[0125] Example 2 - Robot-Controlled Optical Particle Counter The systems and methods described herein may incorporate an optical particle counter system used in combination with a robotic control system to, for example, position the optical particle counter to receive a fluid to characterize the fluid, including determining the number, size, or other properties of particles contained in the fluid.

[0112]

[0126] Optical particle counters are known in the art, for example, in U.S. Pat. No. 7,745,469, U.S. Pat. No. 7,916,299, and U.S. Pat. No. 8,154,724, each of which is incorporated by reference in its entirety herein, particularly with respect to optical particle detection systems and methods.

[0113]

[0127] 14 provides an example of an optical particle counter system. Fluid flows through flow system 150 into flow chamber 210. Light source 220 projects a beam of electromagnetic radiation 221 (e.g., a laser) into flow chamber 210, where the electromagnetic radiation 221 interacts with any particles in the fluid. Electromagnetic radiation 221 is then collected by collection system 230 and directed toward photodetector 240, which generates an electrical signal characteristic of the number and / or size of the particles to be detected. In some embodiments, processor or analyzer 100 may be operably connected to the particle detection system.

[0114]

[0128] Statement of Incorporation by Reference and Modification All references cited throughout this application, e.g., patent literature, including issued or allowed patents or their equivalents, patent application publications, and non-patent literature, or other materials, are incorporated by reference in their entirety herein, as if each reference were individually incorporated by reference to the extent not inconsistent with the disclosure in this application (e.g., a partially conflicting reference is incorporated by reference except for the partially conflicting portion of the reference).

[0115]

[0129] The terms and expressions used herein are used as terms of description and not as terms of limitation, and the use of such terms and expressions is not intended to exclude any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the invention as defined by the appended claims. Thus, while the present invention has been specifically disclosed in terms of preferred embodiments, exemplary embodiments, and optional features, it should be understood that modifications and variations of the concepts disclosed herein may be made by those skilled in the art, and that such modifications and variations are considered to be within the scope of the invention as defined by the appended claims. The specific embodiments provided herein are examples of useful embodiments of the invention, and those skilled in the art will recognize that the invention may be practiced using numerous variations of the apparatus, apparatus components, and method steps described herein. As will be apparent to those skilled in the art, the methods and apparatus useful therefor may include numerous optional compositions and processing elements and steps.

[0116]

[0130] As used herein and in the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, a reference to a "cell" includes a plurality of such cells and equivalents thereof known to those skilled in the art. Similarly, the terms "a" (or "an"), "one or more," and "at least one" can be used interchangeably herein. It should also be noted that the terms "comprising," "including," and "having" can be used interchangeably. The phrase "as defined in any of claims XX-YY" (XX and YY refer to claim numbers) is intended to provide multiple dependent claims in the alternative and, in some embodiments, can be replaced with the phrase "as defined in any one of claims XX-YY."

[0117]

[0131] Any device, system, combination of components, or method described or illustrated herein can be used to practice the invention, unless stated otherwise.

[0118]

[0132] Whenever a range is given in the specification, such as a temperature range, a time range, or a composition or concentration range, all intermediate ranges and subranges, as well as all individual values ​​that fall within the given range, are intended to be included within the disclosure. Of course, any subrange or individual value within a range or subrange that is included in the description herein may be excluded from the claims.

[0119]

[0133] All patents and publications mentioned in this specification are indicative of the level of skill of those skilled in the art to which this invention pertains. The references cited herein are incorporated by reference in their entirety to indicate the state of the art as of their publication or filing date, and it is intended that this information may be used herein, if necessary, to exclude certain embodiments that are in the prior art. For example, if a composition of matter is claimed, it should be understood that compounds known and available in the art prior to Applicant's invention, including compounds for which enabling disclosure is provided in the references cited herein, are not intended to be included in the composition of matter claims herein.

[0120]

[0134] As used herein, "comprising" is synonymous with "including," "including," or "characterized by," and is inclusive or open-ended, not excluding additional, unrecited elements or method steps. As used herein, "consisting of" excludes any element, step, or ingredient not specified in the claimed element. As used herein, "consisting essentially of" does not exclude materials or steps that do not materially affect the basic and novel characteristics of the claim. In each case, the terms "comprising," "essentially consisting of," and "consisting of" may be substituted for either of the other two terms. The inventions illustratively described herein may be practiced in the absence of any element or elements, or limitation or limitations not specifically disclosed herein.

[0121]

[0135] Those skilled in the art will recognize that devices, systems, and methods other than those specifically exemplified can be used in the practice of the present invention without undue experimentation. All art-known functional equivalents of any such devices and methods are intended to be encompassed by this invention. The terms and expressions that have been used are used as terms of description and not of limitation, and there is no intention in their use to exclude any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the invention as defined by the appended claims. Thus, while the present invention has been specifically disclosed in terms of preferred embodiments and optional features, it should be understood that modifications and variations of the concepts disclosed herein may be made by those skilled in the art, and that such modifications and variations are deemed to be within the scope of this invention as defined by the appended claims. [Explanation of symbols]

[0122] 4...particle, 6...fluid, 8...system, 12...particle sampling or counting device, 20...robotic manipulator, 21...robotic arm, 22...flow system, 24...robot controller, 26...sampling location.

Claims

1. A system for detecting particles in a particle-containing fluid in a clean room or sterile environment, comprising:

1. A particle detection device, comprising: an inlet for receiving the particle-laden fluid; a sampling region for detecting particles in the fluid, the sampling region being in fluid communication with the inlet; an outlet for discharging the fluid, the outlet being in fluid communication with the sampling region; a particle detection device comprising: a flow system configured to deliver at least a portion of the particle-containing fluid along a fluid path that originates within the clean room or sterile environment and terminates at the inlet of the particle detection device outside the clean room or sterile environment; a robotic manipulator system configured to perform the step of adjusting a flow of fluid through the particle detection device; A system comprising:

2. The system of claim 1 , wherein the particle detection device is an optical particle counter.

3. The system of claim 2 , wherein the optical particle counter is a scattered light particle counter, an extinction optical particle counter, or a fluorescence optical particle counter.

4. The system of any one of claims 1 to 3, comprising a sterilization system for sterilizing all or part of the particle detection device.

5. 5. The system of claim 4, wherein the sterilization system utilizes vaporized hydrogen peroxide, chlorine dioxide, ethylene oxide, moist heat, or dry heat to sterilize the particle detection device.

6. The system of claim 4 , wherein the robotic manipulator system is configured to transport the particle detection device to the sterilization system.

7. The system of any one of claims 1 to 6, wherein the robotic manipulator system is configured to open the inlet to allow fluid to flow into the particle detection device.

8. the particle detection device comprising a cover for surrounding the inlet; and The system of any preceding claim, wherein the robotic manipulator system is configured to remove the cover to allow fluid to enter the inlet.

9. The system of claim 8 , wherein the robotic manipulator system is configured to replace the cover to prevent the fluid from entering the inlet.

10. The system of any one of claims 1 to 9, wherein the robotic manipulator system is configured to close the inlet to prevent the fluid from flowing into the particle detection device.

11. A method for detecting particles in a particle-containing fluid in a clean room or sterile environment, comprising: exposing an inlet of a particle detection device to the particle-containing fluid; flowing at least a portion of the particle-containing fluid from the clean room or sterile environment into the inlet, wherein the particle detection device is located outside the clean room or sterile environment; directing the fluid through a sampling region of the device; Discharging the fluid through an outlet of the device; Including, A method wherein the exposing step is performed by a robotic manipulator system.

12. The method of claim 11 , comprising sterilizing the particle detection device via the robotic manipulator system.

13. 13. The method of claim 11 or 12, comprising transporting the particle detection device via the robotic manipulator system to a sterilization location for the sterilizing step.

14. 14. The method of claim 12 or 13, comprising transporting the particle detection device to a sampling location via the robotic manipulator system after the sterilizing step.

15. optically detecting the cultured biological particles via said robotic manipulator system.

15. The method of claim 14, comprising:

16. characterizing the cultured biological particles by optical detection or imaging performed by the robotic manipulator system.

16. The method of claim 15, comprising:

17. determining the viability, identity, or both, of the microorganisms in the cultured biological particles.

17. The method of claim 15 or 16, comprising:

18. The method of claim 17 , wherein the determining step is performed by the robotic manipulator system.

19. The method, wherein the method is performed without a user being physically present within the clean room or sterile environment. The method according to any one of claims 11 to 18.

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