Robot control for aseptic processing

Abstract

Devices and methods for sampling, detecting, and / or characterizing particles, e.g., via collection, growth, and analysis of viable biological particles, such as microorganisms. Devices and methods of the present invention include a particle sampler and an impaction sampler, the impaction sampler including a sampling head, a selectively removable cover, an impaction sampler base connected to the sampling head, and one or more magnets secured to the sampling head, the selectively removable cover, and / or the impaction sampler base. The one or more magnets allow for robotic manipulation of the impaction sampler device.

Description

[0001] Cross-references to related applications

[0002] This application claims the benefit and priority of U.S. Provisional Patent Application No. 62 / 963,895, filed January 21, 2020, the entire contents of which are incorporated herein by reference. Background Technology

[0003] This invention belongs to the field of particle sampling, collection, and analysis. More specifically, it relates to systems and methods for robotic sampling and counting systems used to sample particles from fluids in a controlled environment.

[0004] Cleanrooms and clean areas are commonly used in semiconductor and pharmaceutical manufacturing facilities. In the semiconductor industry, increased concentrations of airborne particulate matter can lead to decreased manufacturing efficiency because particles deposited on semiconductor wafers can affect or interfere with manufacturing processes on small length scales. In the pharmaceutical industry, where this type of real-time efficiency feedback is lacking, contamination by airborne particulate matter and biological contaminants risks exposing pharmaceutical products to cleanliness standards set by the U.S. Food and Drug Administration (FDA) and other foreign and international health regulatory agencies.

[0005] The presence of humans in such environments increases the risk of particulate matter and biofouling levels. An increasing number of controlled environment systems are evolving towards automated or robotic systems to limit or eliminate human interaction. However, many applications requiring controlled environments also need to, or utilize, environmental sampling to ensure that surviving and non-surviving particles and / or organisms remain below desired levels.

[0006] ISO 14664-1 and 14664-2 provide classification standards for cleanroom particle levels, as well as standards for testing and monitoring to ensure compliance. Aerosol optical particle counters are commonly used to determine the level of particulate contamination in the air of cleanrooms and clean areas, while liquid particle counters are used for optical measurement of particulate contamination levels in process fluids. In areas where microbial particles are of particular concern, such as the pharmaceutical industry, it is important not only to quantify the number of particles in the air, but also to characterize the viability and properties of microbial particles. ISO 14698-1 and 14698-2 provide standards for assessing biocontaminants in cleanroom and clean area environments.

[0007] Currently, the collection and analysis of biological particles in the air is typically achieved using a variety of techniques, including sedimentation plates, contact plates, surface swabs, fingertip sampling, and active air samplers based on impact samplers. Traditionally, cascaded impact samplers have been used to collect particles and determine particle size. In these devices, a series of accelerated and inertial impacts continuously strip increasingly smaller particles from a fluid flow. The operating principle of each stage of an inertial impact sampler is that particles suspended in the air can be collected by forcing a significant change in the direction of the airflow containing the particles, where the inertia of the particles causes them to separate from the streamlines of the airflow and impact a surface. Biswas et al. described the efficiency of particle collection in high-speed inertial impact samplers (Environ. Sci. Technol., 1984, 18(8), 611-616).

[0008] As quality standards and government regulatory requirements become more stringent, the need for lower concentrations of both viable and non-viable particles is also increasing. Therefore, there is a need to improve sampling techniques to reduce false positives and mitigate the risk of external contamination from human interactions in controlled environments.

[0009] As can be seen from the above, there remains a need in the art for particle collection, analysis, and characterization systems to sample and collect particles and / or organisms from controlled environments with reduced human interaction, thereby mitigating the risk of further contamination. These systems could include the collection of particles for any analysis within components of robotic restricted-access barrier systems or other automated controlled environmental processes. Summary of the Invention

[0010] This paper provides systems and methods that allow for the automated sampling and / or analysis of controlled environments, for example, to determine the presence, quantity, size, concentration, viability, type, or characteristics of particles in 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 human operators. The methods and systems described herein are general and can be used with known particle sampling and analysis techniques and devices, including, for example, optical particle counters, impact samplers, and shock samplers.

[0011] The systems and methods provided can be useful in controlled environments utilizing robotic systems, such as robotically controlled restricted access barrier systems (RABS) and positive pressure isolator systems. These systems and methods allow integration with impact samplers in controlled environments 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 from particles or organisms present on operators. The described systems and methods can also allow for robotic sterilization of the environment or sampling components to further reduce or eliminate the risk of contamination.

[0012] An impact sampler may include a sampling head, an impact sampler base connected to the sampling head, and a magnet fixed to the sampling head or the impact sampler base. The sampling head includes one or more inlet holes. The one or more inlet holes may allow sampling of a fluid flow containing particles. The impact sampler base may be operatively connected to receive at least a portion of the fluid flow from the sampling head. The impact sampler base may include an impact surface for receiving at least a portion of the particles in the fluid flow. The impact sampler base may include an outlet for discharging the fluid flow. The sampling head and the impact sampler base may engage to close the impact surface.

[0013] The impact surface can be configured to receive and trap biological particles. The sampling head and impact sampler base can be joined to completely enclose the impact surface, including, for example, a substantially hermetically sealed connection. The sampling head and impact sampler base can each independently comprise a polymer material. The impact sampler base and / or sampling head can include magnets for efficiently handling the impact sampler via a robotic control system. At least a portion of the impact sampler base, sampling head, or both can be optically transparent.

[0014] The impact surface may include a growth medium for receiving biological particles in the fluid. The robot control system may be configured to expose the impact sampler and / or the impact surface to the fluid. The robot control system may also be configured to collect particles from the impact sampler and / or the impact surface. Furthermore, the robot control system may be configured to sample particles from the fluid without physical contact between the user and the impact sampler.

[0015] The impact sampler and / or impact surface may include a growth medium for receiving biological particles in the fluid. Therefore, the impact sampler base may include a growth medium positioned to receive particles in the fluid flow, wherein the impact surface is a receiving surface of the growth medium. The robotic control system may also be configured to transport the particle sampling or counting device in a fully assembled configuration to a sterilization system for sterilizing the particle sampling or counting device; and wherein the growth medium is present within the particle sampling or counting device during sterilization. Therefore, in some embodiments, the impact sampler is configured to perform robotic sterilization on its outer surface. In some embodiments, the impact sampler may be configured to be sterilized in a fully assembled configuration, wherein the impact surface remains enclosed by the sampling head and the impact sampler base.

[0016] In some embodiments, the particles collected by the impact sampler are microorganisms. In some embodiments, the impact sampler base, sampling head, or both are optically transparent to allow visualization, optical detection, or imaging of particles in the growth medium without physical contact with the growth medium.

[0017] The impact sampler may also include a selectively removable cap for covering one or more access holes and thereby sealing the impact surface. In some embodiments, one or more access holes may be arranged in a radial array on the sampling head, and a magnet, sometimes referred to as a sampling head magnet, may be fixed to the sampling head at the center of the radial array.

[0018] In some embodiments, the magnet may be attached to a selectively removable cover. In one embodiment, the magnet is attached to the underside of the selectively removable cover. For example, the magnet may be attached to a protrusion on the underside of the selectively removable cover.

[0019] In some embodiments, the magnet is a first cover magnet fixed to the underside of a selectively removable cover, wherein the impact sampler includes a second cover magnet spaced apart from the first cover magnet and protruding from the underside of the selectively removable cover.

[0020] In embodiments where one or more magnets are attached to the cover, these magnets may be referred to as one or more cover magnets. In such embodiments, the impact sampler may also include a sampling head magnet attached to a sampling head. The sampling head magnet may be configured to engage with the cover magnet. Thus, in some embodiments, a selectively removable cover may be held in place due to the magnetic attraction between the sampling head magnet and the cover magnet.

[0021] The impact sampler can be configured to be robotically manipulated via a robotic device. In one example, the robot control system and the impact sampler can be configured to robotically remove a selectively removable cap from a sampling head via the robotic device to expose one or more access holes to the surrounding environment. For example, one or more magnets of the impact sampler can be configured to engage with a robotic device magnet of the robotic device. In some embodiments, the robotic device magnet can be an electromagnet. In some embodiments, the electromagnet can be configured to apply a greater magnetic attraction to the cap magnet than the magnetic attraction applied by the sampling head magnet to the cap magnet, thereby allowing the robotic device to remove the cap. Therefore, the robot control system and the impact sampler can be configured to remove the cap via engagement (e.g., magnetic attraction) between the robotic device magnet and the cap magnet.

[0022] The impact sampler can also be configured to robotically replace a selectively removable cover via disengagement of a robotic device magnet from a cover magnet to seal and isolate the impact surface from the surrounding environment. In one embodiment, disengagement of the robotic device magnet may include reducing or cutting off the power supply to the electromagnet.

[0023] In some embodiments, the sampling head and the selectively removable cap are engaged via a compressible sealing member. In some embodiments, the compressible sealing member is an O-ring. In some embodiments, the impact sampler is configured to compress the compressible sealing member via a magnetic attraction between the sampling head magnet and the cap magnet.

[0024] In some embodiments, one or more magnets of the impact sampler may be attached to the receiving surface of the impact sampler via adhesive. In some embodiments, the magnets are cast into the sampling head or the base of the impact sampler. In some embodiments, the magnets are at least partially enclosed by the magnet chamber of the impact sampler.

[0025] In one embodiment, a method for sampling biological particles from a fluid flow includes drawing the fluid flow through one or more inlet holes and into a sampling head of an impact sampler, wherein the fluid flow contains biological particles. At least some of the biological particles may be impacted onto an impact surface of an impact sampler base. The impact sampler base may engage with the sampling head to seal the impact surface. The fluid flow may be discharged from an outlet of the impact sampler base. The impact sampler or its components may be manipulated via a magnet attached to the impact sampler. At least a portion of the biological particles received by the impact surface may then be allowed to grow on the impact surface.

[0026] In some embodiments, the manipulation step occurs before the fluid aspiration step. In some embodiments, the manipulation step occurs after the growth step. In some embodiments, the manipulation step includes robotically manipulating the impact sampler or a component thereof via a robotic device. In some embodiments, the manipulation step includes manually manipulating the impact sampler or a component thereof via a magnetic hand tool. In some embodiments, robotic manipulation includes removing a selectively removable cap from the sampling head via a robotic device to expose one or more access holes to the surrounding environment. In some embodiments, robotic manipulation includes engaging a magnet of the impact sampler via a robotic device magnet. In some embodiments, robotic manipulation includes placing a selectively removable cap on the sampling head via a robotic device to seal and isolate the impact surface from the surrounding environment. In some embodiments, robotic manipulation includes sterilizing the outer surface of the impact sampler. In some embodiments, robotic manipulation includes sterilizing the impact sampler in a fully assembled configuration, wherein the impact surface remains closed by the sampling head and the impact sampler base.

[0027] The flow system for connection to the impactor sampler can be integrated into a cleanroom or sterile environment, wherein the robot control system is also configured to sample particles from the flowing fluid without the physical presence of a user in the cleanroom or sterile environment. The robot control system can be located inside, outside, or partially inside and outside the cleanroom or sterile environment.

[0028] The provided method may also include a step of sterilizing the particle sampling or counting device, wherein the impact surface remains closed during sterilization, for example, to protect the growth medium (such as agar) used to capture biological particles.

[0029] The provided method may further include a step of sterilizing a fully assembled particle sampling or counting device, wherein the impact surface remains sealed by the sampling head and base during sterilization. The sterilization step can be performed by treating the fully assembled and sealed particle sampling or counting device using at least one of the following: vaporized hydrogen peroxide, chlorine dioxide, ethylene oxide, moist heat, and dry heat.

[0030] The provided method may also include a step of culturing at least a portion of the biological particles received by the growth medium. This culturing step may allow for optical detection of the biological particles. The culturing step can be performed without disassembling the fully assembled particle sampling or counting device.

[0031] The provided method may also include a step of characterizing the particles performed by an imaging device. This characterization step may include, for example, determining the chemical composition of the particles or determining the particle size distribution.

[0032] The provided method can be performed without physical contact between a user and the particle sampling or counting device. Fluid can be generated and / or terminated in a cleanroom or sterile environment; and the method is performed without the physical presence of a user in the cleanroom or sterile environment. Each of the providing, flowing, and / or receiving steps can be performed by a system configured for robot control.

[0033] The apparatus and method of the present invention combine an integrated sampler and an impact surface (such as a receiving surface of a growth medium) in a manner that minimizes or completely eliminates risks associated with user handling, such as false positive determinations due to contamination of the impact surface during particle sampling, growth, or analysis processes.

[0034] In some aspects, the present invention provides a particle impact sampler device having an integrated sampler and a closed impact surface, designed for single-use and / or disposable use, thereby eliminating the costs and contamination risks associated with reuse. The particle impact sampler device of the present invention with an integrated sampler and a closed impact surface enables efficient sampling and growth of biological particles while minimizing the incidence of user contamination during handling and use. The particle impact sampler device of the present invention with an integrated sampler and a closed impact surface also enables efficient sterilization in a fully assembled configuration, wherein the impact surface, such as the receiving surface of the growth medium, remains in a closed configuration during the sterilization process, thereby eliminating the need for the user to contact the impact surface before particle sampling. The present invention also provides an optically transparent particle impact sampler that enables in-situ optical and / or visual analysis of particles, such as live biological particles, during sampling, growth, and optical characterization of live biological particles without requiring physical contact with or handling of the impact surface.

[0035] The impact sampler device of the present invention includes single-use devices and / or disposable devices. The impact sampler of the present invention can be used to monitor biological particles in cleanrooms, sterile environments, or medical environments. The impact sampler of the present invention can be used to sample particles within a range of fluids, including air or one or more process gases used in the manufacturing application. The impact sampler of the present invention can be used to sample, grow, and analyze biological particles, including viable microorganisms.

[0036] As described above, the impact sampler base includes a growth medium positioned to receive particles in a fluid flow, wherein the impact surface is the receiving surface of the growth medium. Useful growth media include culture media such as agar, broth, and other substrates such as filters. In embodiments, the growth medium is provided in a petri dish that includes an integrated component of the impact sampler base, for example, wherein the petri dish and the impact sampler base are cast as a single piece. For example, in embodiments, the petri dish and the impact sampler base comprise a single integral element, such as an integral component comprising a single cast polymer structure. For example, in embodiments, the growth medium comprises an agar plate. In embodiments, the sampling head and the impact sampler base are engaged, optionally reversibly engaged, to completely contain the impact surface, for example, by providing an hermetically sealed area around the impact surface, thus allowing fluid to pass through the inlet orifice and interact with the impact surface only.

[0037] As described above, the impact sampler may include a selectively removable cap disposed on the sampling head to cover the access port, thereby maintaining a sterile environment for the growth medium before sampling a particle-containing fluid flow, or providing an hermetically sealed environment for the growth medium after sampling a particle-containing fluid flow. For example, in embodiments, the impact sampler base, sampling head, or both are optically transparent to allow visualization, optical detection, or imaging of particles in the growth medium without physical contact with the growth medium. For example, in embodiments, the sampling head and the removable cap are joined via a substantially hermetically sealed connection. For example, in embodiments, the sampling head and the removable cap are joined via a selectively removable interlocking connection. For example, in embodiments, the sampling head and the removable cap are joined via an O-ring connection, such as an O-ring connection disposed between the bottom surface of the removable cap and the top surface of the sampling head.

[0038] The impact sampler of the present invention may include a range of useful materials. For example, in embodiments, the sampling head and the impact sampler base each independently comprise a polymeric material, such as a synthetic polymer or a natural polymer. For example, in embodiments, the sampling head and the impact sampler base each independently comprise a sterile material.

[0039] For example, in one embodiment, the outlet of the impact sampler base is connected to a fan or pump to provide a fluid flow through the impact sampler, wherein the flow changes direction after passing through the inlet orifice.

[0040] This invention includes an impact sampler comprising optically transparent components, for example, to allow effective use in a fully assembled configuration. For example, in an embodiment, at least a portion of the impact sampler base, sampling head, or both is optically transparent to allow characterization of particles on an impact surface without disengaging the sampling head and impact sampler base. For example, in an embodiment, the impact sampler base, sampling head, or both are optically transparent to provide a transmittance of greater than or equal to 50% for at least a portion of incident light having wavelengths in the range of 400 nm to 800 nm. For example, in an embodiment, the impact sampler base, sampling head, or both are optically transparent to allow visualization, optical detection, or imaging of particles on an impact surface without disengaging the sampling head and impact sampler base. For example, in an embodiment, the impact sampler base, sampling head, or both are optically transparent to allow determination of the amount of biological particles surviving on the impact surface. For example, in an embodiment, the impact sampler base, sampling head, or both are optically transparent to allow determination of the genus or species of biological particles surviving on the impact surface.

[0041] In some embodiments, the methods and apparatus of the present invention provide the benefit of minimizing or completely eliminating the need for a user to physically contact the impact surface after sterilization. For example, in an embodiment, the method does not require the user to physically contact the growth medium after the growth medium has come into contact with the particles. For example, in an embodiment, the method of the present invention further includes the step of providing a cap on the sampling head to cover the access port, thereby sealing the growth medium within the apparatus after the sampling step.

[0042] For example, in one embodiment, the present invention provides a method for sampling a particle-containing fluid using an impactor sampler, the impactor sampler being used only once and optionally discarded after use. For example, in one embodiment, the present invention provides a method for monitoring biological particles in a cleanroom or sterile environment. For example, in one embodiment, the present invention provides a method for monitoring biological particles in air or one or more process gases. For example, in one embodiment, the method of the present invention further includes repeating the steps of the method using a new sampler.

[0043] The apparatus and method of the present invention are general-purpose and support a range of particle sampling, monitoring, and analysis applications. For example, the apparatus and method can be used in applications involving the preparation, processing, manufacturing, storage, transfer, filling, and / or completion of sterile pharmaceuticals or biological agents, pharmaceutical or biocontainers, pharmaceutical or biodelivery devices, medical devices including implantable devices, and blood, cell, and tissue materials. Furthermore, the apparatus and method can be used to monitor and characterize biological particles in medical settings such as hospitals, operating rooms, surgical rooms, and pharmacies. Other applications of the apparatus and method include the preparation, manufacturing, storage, transfer, or processing of cosmetics, personal care products, and food and beverages.

[0044] Not intended to be bound by any particular theory, this document may be a discussion of beliefs or understandings of the fundamental principles relating to the apparatuses and methods disclosed herein. It should be recognized that, regardless of the ultimate correctness of any mechanistic explanation or assumption, embodiments of the invention may still be operable and useful. Attached Figure Description

[0045] Figure 1 This is an exploded perspective view of the impact sampler of the present invention, wherein the components of the device are spatially separated for clarity.

[0046] Figure 2 It shows Figure 1 An exploded side view of the impact sampler.

[0047] Figure 3A A perspective view of the selectively removable cover of the impact sampler of the present invention is shown.

[0048] Figure 3B It shows Figure 3A A bottom view of the optional removable cover.

[0049] Figure 3C It shows Figures 3A to 3B Cross-sectional view of the selectively removable lid.

[0050] Figure 4A A perspective view of the sampling head of the impact sampler of the present invention is shown.

[0051] Figure 4B It shows Figure 4A A top view of the sampling head.

[0052] Figure 4C It shows Figures 4A to 4B A cross-sectional view of the sampling head.

[0053] Figure 5 yes Figure 1 Different exploded three-dimensional views of the impact sampler. Detailed Implementation

[0054] Generally, the terms and phrases used herein have their generally accepted meanings in the art, which can be found by referring to standard texts, journal references, and context known to those skilled in the art. The following definitions are provided to clarify their specific use in the context of this invention.

[0055] “Particle” refers to small objects that are generally considered contaminants. Particles can be any material generated by friction, for example, when two surfaces come into mechanical contact and there is mechanical motion. Particles can consist of aggregates of materials, such as dust, dirt, smoke, ash, water, soot, metals, minerals, or any combination of aggregates of these materials, or any combination of other materials or contaminants. “Particle” can also refer to biological particles, such as viruses, spores, and microorganisms, including bacteria, fungi, archaea, protozoa, and other single-celled microorganisms. Biological particles include, but are not limited to, microorganisms having a size on the order of 0.1 μm–20 μm. Biological particles include viable biological particles capable of reproduction, for example, those that reproduce when incubated in a growth medium. Particle can refer to any small object that absorbs or scatters light and is therefore detectable by an optical particle counter. As used herein, “particle” is intended to exclude individual atoms or molecules of a carrier fluid, such as those present in the air (e.g., oxygen molecules, nitrogen molecules, argon molecules, etc.) or those present in process gases. Some embodiments of the present invention are capable of sampling, collecting, detecting, determining the size and / or counting particles comprising material polymers having a size greater than 50 nm, 100 nm, 1 μm or larger, or greater than 10 μm or larger. Specific particles include particles having a size selected from 50 nm to 50 μm, from 100 nm to 10 μm, or from 500 nm to 5 μm.

[0056] The expression "sampling particles" broadly refers to, for example, collecting particles from a fluid flow in a monitored environment. Sampling as used herein includes transferring particles from a fluid flow to an impact surface, such as a receiving surface of a growth medium. Alternatively, sampling may refer to passing particles in a fluid through a particle analysis region, for example, for optical detection and / or characterization. Sampling may refer to collecting particles having one or more preselected characteristics, such as size (e.g., cross-sectional size, such as diameter, effective diameter, etc.), particle type (biological or non-biological, viable or non-viable, etc.), or particle composition. Sampling may optionally include analyzing the collected particles, for example, via subsequent optical analysis, imaging analysis, or visual analysis. Sampling may optionally include, for example, growing viable biological particles via an incubation process involving a growth medium. A sampler refers to a device used for sampling particles.

[0057] "Impact sampler" refers to a device for sampling particles. In some embodiments, an impact sampler includes a sampling head with one or more inlet orifices for sampling a fluid flow containing particles, thereby directing at least a portion of the particles to an impact surface for collection. This impact surface is, for example, a receiving surface of a growth medium (e.g., a culture medium such as agar, broth, etc.) or a matrix such as a filter. Some embodiments of the impact sampler provide a change in flow direction after passing through the inlet orifice, wherein particles having preselected characteristics (e.g., a size greater than a threshold) do not undergo a change in direction and are thus received by the impact surface.

[0058] The term "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 the physical properties of particles, such as diameter, cross-sectional size, shape, dimensions, aerodynamic dimensions, or any combination of these properties. A particle counter is a device for counting the number of particles in a fluid or a volume of fluid, and optionally may also provide particle characterization, for example, based on size (e.g., cross-sectional size, such as diameter or effective diameter), particle type (e.g., biological or non-biological), or particle composition. An optical particle counter is a device for detecting particles by measuring the scattering, emission, or absorption of light by the particles.

[0059] "Flow direction" refers to the axis parallel to the direction in which the fluid mass moves as it flows. For fluid flowing through a straight flow cell, the flow direction is parallel to the path taken by the fluid mass. For fluid flowing through a tortuous flow cell, the flow direction can be considered tangent to the path taken by the fluid mass.

[0060] "Fluid communication" refers to the arrangement of two or more objects such that fluid can be transported to, through, or from one object to another. For example, in some embodiments, two objects are fluidly connected if a fluid flow path is provided directly between them. In some embodiments, two objects are fluidly connected if a fluid flow path is provided indirectly between them, such as by including one or more other objects or flow paths between them. For example, in one embodiment, the following components of a particle impact sampler are fluidly connected to each other: one or more inlets, impact surfaces, fluid outlets, flow restrictors, pressure sensors, and flow generation devices. In one embodiment, two objects present in the bulk of a fluid are not necessarily fluidly connected to each other unless fluid from the first object is drawn to, through, and / or through the second object, such as along a flow path.

[0061] "Flow rate" refers to the amount of fluid flowing through a specified point or through a specified area (such as flowing through the inlet or outlet of a particle impact sampler). In one embodiment, flow rate refers to mass flow rate, that is, the mass of fluid flowing through a specified point or through a specified area. In one embodiment, flow rate is volumetric flow rate, that is, the volume of fluid flowing through a specified point or through a specified area.

[0062] "Pressure" refers to a measure of the force exerted per unit area. In this embodiment, pressure refers to the force exerted by a gas or fluid per unit area. "Absolute pressure" refers to a measure of the force exerted by a gas or fluid per unit area, relative to a perfect vacuum or a volume where zero force is exerted 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 relative to or exceeding a second pressure, such as ambient pressure or atmospheric pressure.

[0063] "Polymer" refers to a macromolecule or polymer of one or more monomers composed of repeating structural units linked by covalent chemical bonds, typically characterized by a high molecular weight. The term polymer includes homopolymers, or polymers consisting essentially of a single repeating monomer subunit. It also includes copolymers, or polymers consisting essentially of two or more monomer subunits, such as random copolymers, block copolymers, alternating copolymers, segment copolymers, graft copolymers, graded copolymers, and other copolymers. Useful polymers include organic or inorganic polymers that can be in an amorphous, semi-amorphous, crystalline, or partially crystalline state. Crosslinked polymers with linked monomer chains are particularly useful for some applications. Polymers that can be used in methods, apparatus, and components include, but are not limited to, plastics, elastomers, thermoplastic elastomers, elastic plastics, thermoplastics, and acrylates. Exemplary polymers include, but are not limited to, acetal polymers, biodegradable polymers, cellulose polymers, fluoropolymers, nylon, polyacrylonitrile polymers, polyamide-imide polymers, polyimides, polyarylates, polybenzimidazoles, polybutene, polycarbonates, polyesters, polyetherimides, polyethylene, polyethylene copolymers and modified polyethylene, polyketones, poly(methyl methacrylate), polymethylpentene, polyphenylene ethers and polyphenylene sulfides, polyphthalamides, polypropylene, polyurethanes, styrene resins, sulfone resins, vinyl resins, rubbers (including natural rubber, styrene-butadiene, polybutadiene, chloroprene rubber, ethylene-propylene, butyl rubber, nitrile, silicone), acrylic acid, nylon, polycarbonate, polyesters, polyethylene, polypropylene, polystyrene, polyvinyl chloride, polyolefins, or any combination of these polymers.

[0064] Figure 1 and Figure 5 This is a three-dimensional exploded view of the particle impact sampler 10. Figure 2This is an exploded side view of the particle impact sampler 10. As shown in these figures, the particle impact sampler 10 includes a sampling head 200, a selectively removable cover 100, and an impact sampler base 300. The sampling head 200 includes a sampling head magnet 250, which is fixed to the underside of the sampling head 200. The selectively removable cover 100 includes a first cover magnet 155 and a second cover magnet 150, which are fixed to the underside of the cover and spaced apart by a spacer 158. The sampling head magnet 250 engages with the second cover magnet 150 to secure the cover 100 to the impact sampler. The sampling head 200 and the selectively removable cover 100 are engaged via a compressible sealing member 110. The impact sampler 10 is configured to compress the compressible sealing member 110 via a magnetic attraction between the sampling head magnet 250 and the second cover magnet 150. The sampling head 200 and the impact sampler base 300 are engaged via a compressible sealing member 210. The first cover magnet 155 can be configured to engage with a robotic device.

[0065] The sampling head 200 includes multiple inlet holes 220 for sampling a fluid flow containing particles. The impact sampler base 300 includes an outlet 320 and an impact surface 350. In operation, a gas flow is guided through the inlet holes 220 of the sampling head 100, where it is accelerated toward the impact surface 350 and flows out of the outlet 320, forcing the gas to change direction rapidly. Due to the momentum of the particles, the particles entrained in the gas flow cannot change direction rapidly and impact the impact surface 350.

[0066] In an embodiment, the impact surface 350 includes a receiving surface for a growth medium (such as agar) provided in the impact sampler base 300. For example, surviving biological particles collected on the impact surface can then be grown and evaluated to provide analysis of the composition of the sampled fluid flow. To collect biological particles on the impact surface, controlling the distance between the inlet 220 and the impact surface 350 is important. For example, if this distance is too large, the particles may be able to follow the fluid path, thus avoiding impact with the impact surface 350. However, if the distance is too small, the particles may impact the impact surface 350 with a force sufficient to kill them, thus preventing them from multiplying.

[0067] Figure 3A A perspective view of the selectively removable cover 100 is shown. Figure 3B A bottom view of the selectively removable cover 100 is shown. Figure 3C A cross-sectional view of a selectively removable cover 100 is shown. The selectively removable cover 100 includes a first cover magnet 155 and a second cover magnet 150, which are fixed to the lower center of the cover 100 and separated by a spacer 158.

[0068] The selectively removable cover 100 also includes an O-ring groove 120 located on the underside of the cover 100 near its outer edge. The O-ring groove 120 is configured to receive an O-ring 110. A second cover magnet 150 magnetically engages with a sampling head magnet 250 to compress the O-ring 110. Thus, the cover 100 can form an hermetically sealed connection with the sampling head 200.

[0069] Figure 4A A three-dimensional view of the sampling head 200 is shown. Figure 4B A bottom view of the sampling head 200 is shown. Figure 4C A cross-sectional view of the sampling head 200 is shown. The sampling head 200 includes an aperture 220 and a sampling head magnet 250. As shown, the aperture 220 can be arranged radially around the sampling head magnet 250 at the center of the sampling head 200.

[0070] This invention provides an air sampler, including an impactor sampler, for analyzing surviving biological particles in monitored environments, such as aseptic manufacturing environments. One aspect of the invention is to provide an impactor sampler device that integrates an agar medium plate with the air sampler in an integrated, single-use and / or disposable package. The impactor sampler of this invention is well-suited for cleanroom environments, particularly aseptic environments, where medical products, such as sterile pharmaceutical products (e.g., drugs, biological products, diagnostics, medical devices, medical implants, etc.), are manufactured. For example, in one embodiment, a connector on the side of the device supports connection to a vacuum source (e.g., a portable vacuum source (e.g., a pump or fan) or a house vacuum line) that draws air into a slit-like air inlet (e.g., 20 slits, 0.1 mm nominal width), where particles are subsequently impacted onto a receiving surface of a growth medium (e.g., agar medium). After sampling cleanroom air, the device is transferred to a laboratory for sustained incubation over several days to promote the growth of the sampled surviving microorganisms. Then, laboratory technicians count the number of CFUs (colony forming units) and, if present, determine the genus or species of the microorganism present.

[0071] The impact sampler of the present invention provides many technical benefits, including the following.

[0072] Eliminating false positive contamination

[0073] Traditional methods of airborne microbial sampling involve operators loading agar plates into a stainless steel sampling head device. During this process, the operator must have direct contact with the plate to load and unload it. When this process is performed carefully and correctly, the operator should not contaminate the medium. However, it frequently occurs that operators may contaminate the plate, resulting in a "false positive" (i.e., microbial growth not originating from the environment during the production batch, but from handling by the operator before or after the production batch). When positive microbial growth is observed, the manufacturer's quality department must conduct an investigation to determine the risk level of the finished pharmaceutical product and decide whether to discard the batch or continue shipping it. These investigations must be very thorough and costly (e.g., a quality investigation like this can cost the company between $5,000 and $18,000 per investigation). If the batch is discarded, it could result in losses ranging from thousands to millions of dollars, depending on the product's market value and the material and production costs. Furthermore, false positives can endanger the final patient. Human error can occur in any investigation. Sometimes, a manufacturer's quality department may determine that a contamination event is a false positive when it is actually a genuine contamination. This could impair the purity of the pharmaceutical product and expose consumers / patients to the risk of illness, injury, or death.

[0074] The device of the present invention reduces or substantially eliminates the possibility of false-positive contaminants from operator handling. The device configuration allows for robotic handling, including sterilization, sampling, incubation, and / or analysis processes.

[0075] Declarations regarding incorporation and changes via reference

[0076] All references in this application, such as patent documents (including published or granted patents or equivalents, patent application publications) and non-patent documents or other original sources, are incorporated herein by reference in their entirety as if they were individually incorporated by reference: each reference is at least partially inconsistent with the disclosure in this application (e.g., partially inconsistent references are incorporated by reference except for the partially inconsistent parts of the reference).

[0077] The terms and expressions used herein are used as descriptive rather than restrictive terms and are not intended to exclude any equivalents of the features shown and described or portions thereof. However, it should be recognized that various modifications can be made within the scope of the claimed invention. Therefore, it should be understood that although the invention has been specifically disclosed through preferred embodiments, exemplary embodiments, and optional features, modifications and variations of the concepts disclosed herein can be taken by those skilled in the art, and 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 it will be apparent to those skilled in the art that the invention can be practiced using a large number of variations of the apparatus, apparatus components, and method steps set forth in this specification. As will be apparent to those skilled in the art, the methods and apparatus that can be used in this method may include a large number of optional components and processing elements and steps.

[0078] When a set of substitutes is disclosed herein, it should be understood that all individual members of that set and all its subgroups are disclosed separately. When the Markush set or other groupings are used herein, all individual members of that set, as well as all possible combinations and subcombinations of that set, are intended to be included separately in this disclosure.

[0079] It should be noted that, as used herein and in the appended claims, the singular forms “a,” “an,” and “the” include references in the plural forms unless the context clearly specifies otherwise. Thus, for example, a reference to “a cell” includes multiple such cells and their equivalents known to those skilled in the art, etc. Similarly, the terms “a” (or “an”), “one or more,” and “at least one” are used interchangeably herein. It should also be noted that the terms “comprising,” “including,” and “having” are used interchangeably. The expression “any one of claims XX-YY” (where XX and YY refer to claim numbers) is intended to provide multiple dependent claims in an alternative form and, in some embodiments, may be interchanged with the expression “any one of claims XX-YY.”

[0080] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. While any methods and materials similar to or equivalent to those described herein may be used in the practice or testing of this invention, preferred methods and materials are described here. Nothing herein should be construed as an admission that this invention is not entitled to bring this disclosure forward by virtue of a prior invention.

[0081] Unless otherwise stated, every combination of the components described or exemplified herein can be used to practice the invention.

[0082] Whenever a range is given in the specification, such as an integer range, temperature range, time range, composition range, or concentration range, all intermediate ranges and subranges, as well as all individual values ​​included within a given range, are intended to be included in this disclosure. As used herein, a range specifically includes values ​​provided as endpoint values ​​of the range. As used herein, a range specifically includes all integer values ​​of the range. For example, a range of 1 to 100 specifically includes the endpoint values ​​of 1 and 100. It should be understood that any subrange or individual value of a range or subrange included in this specification may be excluded from the claims herein.

[0083] All patents and disclosures mentioned in this specification demonstrate the skill of a person skilled in the art to which this invention pertains. The entire contents of all references cited herein are incorporated by reference to indicate prior art up to the date of their publication or filing, and such information may be used herein to exclude specific embodiments of the prior art if necessary. For example, when a composition of a claimed substance is claimed, it should be understood that compounds known and available in the art prior to the applicant's invention, including compounds that are effectively disclosed in the references cited herein, are not intended to be included in the composition of the substance claimed herein.

[0084] As used herein, “comprising” is synonymous with “including,” “comprising,” or “characterized in,” and is inclusive or open-ended, and does not exclude additional, unrecorded elements or method steps. As used herein, “consisting of” excludes any element, step, or component not specified in the elements of the claim. As used herein, “substantially constitutes” does not exclude materials or steps that do not substantially affect the essential and novel features of the claim. In each instance herein, any one of the terms “comprising,” “substantially constitutes,” and “consisting of” may be replaced by any of the other two terms. The invention exemplarily described herein can be suitably practiced in the absence of any elements or elements, limitations, or limitations not specifically disclosed herein.

[0085] Those skilled in the art will understand that, in the practice of this invention, starting materials, biological materials, reagents, synthetic methods, purification methods, analytical methods, assay methods, and biological methods other than those specifically exemplified can be employed without excessive experimentation. All functional equivalents known in the art of any such material and method are intended to be included in this invention. The terminology and expressions used are used as descriptive rather than restrictive terms, and their use is not intended to exclude any equivalents of the features or portions thereof shown and described, but it should be recognized that various modifications can be made within the scope of the claimed invention. Therefore, it should be understood that although the invention has been specifically disclosed by way of preferred embodiments and optional features, modifications and variations of the concepts disclosed herein can be taken by those skilled in the art, and such modifications and variations are considered to be within the scope of the invention as defined by the appended claims.

Claims

1. An impact sampler, comprising: A sampling head, the sampling head including one or more inlet holes for sampling a fluid flow containing particles, and the sampling head including a selectively removable cap for covering the one or more inlet holes; as well as An impact sampler base is operatively connected to receive at least a portion of the fluid flow from the sampling head; the impact sampler base includes an impact surface for receiving at least a portion of particles in the fluid flow, and an outlet for discharging the fluid flow. A magnet, fixed to the sampling head or the impact sampler base, the magnet comprising: a first cover magnet fixed to the underside of the selectively removable cover; and a second cover magnet spaced apart from the first cover magnet and protruding from the underside of the selectively removable cover; The sampling head and the impact sampler base are engaged to seal the impact surface.

2. The impact sampler according to claim 1, wherein the magnet comprises: A sampling head magnet, the sampling head magnet being fixed to the sampling head, the sampling head magnet being configured to cooperate with the second cover magnet.

3. The impact sampler according to claim 2, wherein, The one or more inlet holes are arranged in a radial array on the sampling head, and the sampling head magnet is fixed to the sampling head at the center of the radial array.

4. The impact sampler according to claim 1, wherein, The magnet includes: Impact sampler base magnet, the impact sampler base magnet is fixed to the impact sampler base.

5. The impact sampler according to claim 1, wherein, The magnet includes: A sampling head magnet, the sampling head magnet being fixed to the sampling head, and Impact sampler base magnet, the impact sampler base magnet is fixed to the impact sampler base.

6. The impact sampler according to claim 2, wherein, The sampling head and the selectively removable cap are engaged via a compressible sealing member.

7. The impact sampler according to claim 6, wherein, The impact sampler is configured to compress the compressible sealing member via the magnetic attraction between the sampling head magnet and the second cover magnet.

8. The impact sampler according to claim 7, wherein, The compressible sealing component is an O-ring.

9. The impact sampler according to any one of claims 1-8, wherein, The magnet is fixed to the receiving surface of the impact sampler by an adhesive.

10. The impact sampler according to any one of claims 1-8, wherein, The magnet is cast into the sampling head or the impact sampler base.

11. The impact sampler according to any one of claims 1-8, wherein, The magnet is at least partially enclosed by the magnet chamber of the impact sampler.

12. The impact sampler according to any one of claims 1-8, wherein, The impact sampler is configured to be robotically manipulated via a robotic device.

13. The impact sampler according to any one of claims 1-8, wherein, The magnet is configured to engage with the robotic device magnet of the robotic device.

14. The impact sampler according to any one of claims 1-8, wherein, The impact sampler is configured to robotically remove the selectively removable cover from the sampling head via a robotic device to expose the one or more access holes to the surrounding environment.

15. The impact sampler according to any one of claims 1-8, wherein, The impact sampler is configured to robotically replace the selectively removable cover onto the sampling head via a robotic device to seal and isolate the impact surface from the surrounding environment.

16. The impact sampler according to any one of claims 1-8, wherein, The impact sampler is configured to perform robotic sterilization on the outer surface of the impact sampler.

17. The impact sampler according to any one of claims 1-8, wherein, The particles are microorganisms.

18. The impact sampler according to any one of claims 1-8, wherein, The bottom of the impact sampler also includes a growth medium positioned to receive the particles in the fluid flow, wherein the impact surface is the receiving surface of the growth medium.

19. The impact sampler according to claim 18, wherein, The impact sampler base, the sampling head, or both are optically transparent to allow visualization, optical detection, or imaging of particles in the growth medium without physical contact with the growth medium.

20. The impact sampler according to any one of claims 1-8, wherein, The impact sampler is configured to be sterilized in a fully assembled configuration, wherein the impact surface remains enclosed by the sampling head and the impact sampler base.

21. A method for sampling biological particles from a fluid flow, the method being performed using an impactor sampler according to any one of claims 1-20, the method comprising: - Aspiration fluid flow step: Aspirate a fluid flow through one or more inlet holes and into the sampling head of the impact sampler, wherein the fluid flow contains biological particles; - Impaction step: At least some biological particles are impacted onto the impact surface of the impact sampler base, which engages with the sampling head to seal the impact surface; - Fluid discharge step: Discharge the fluid flow from the outlet of the impact sampler base; - Manipulation steps: Manipulate the impact sampler or its components via a magnet fixed to the impact sampler; as well as - Growth step: to grow at least a portion of the biological particles received by the impact surface.

22. The method according to claim 21, wherein, The manipulation step occurs before the suction fluid flow step.

23. The method according to claim 21, wherein, The manipulation step occurs after the growth step.

24. The method according to claim 21, wherein, The manipulation steps include: The impact sampler or its components are robotically manipulated via a robotic device.

25. The method according to claim 21, wherein, The manipulation steps include: The impact sampler or its components are manually manipulated using a magnetic hand tool.

26. The method of claim 24, wherein, The manipulation of the robot includes: A selectively removable cap is removed from the sampling head via a robotic device to expose the one or more access holes to the surrounding environment.

27. The method according to claim 24, wherein, The manipulation of the robot includes: The robotic device magnet engages with the magnet of the impact sampler via the robotic device.

28. The method according to claim 24, wherein, The manipulation of the robot includes: A selectively removable cap is placed on the sampling head via a robotic device to seal and isolate the impact surface from the surrounding environment.

29. The method according to claim 24, wherein, The manipulation of the robot includes: The outer surface of the impact sampler is sterilized.

30. The method according to any one of claims 24-29, the method comprising: The impact sampler is sterilized in a fully assembled configuration, wherein the impact surface remains enclosed by the sampling head and the impact sampler base.

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