Robot control for aseptic processing

Abstract

Apparatus and methods for sampling, detecting, and / or characterizing particles, e.g., through collection, growth, and analysis of viable biological particles, such as microorganisms. The apparatus and methods include a particle sampler and an impactor, the impactor including a sampling head with one or more air intake holes, a selectively removable cover, an impactor base connected to the sampling head, and one or more permanent magnets secured to the sampling head, the selectively removable cover, and the impactor base. The one or more permanent magnets enable robotic operation of the impactor device.

Description

Background Art

[0001] [Cross - Reference to Related Applications]

[0002]

[0001] This application claims the benefit and priority of U.S. Provisional Patent Application No. 62 / 963,895, filed on January 21, 2020, which is hereby incorporated by reference in its entirety.

[0003] [Background of the Invention]

[0004]

[0002] The present invention is in the field of particle sampling, collection, and analysis. The present invention generally relates to systems and methods for robotic sampling and counting systems for sampling particles from fluids in a controlled environment.

[0005]

[0003] Cleanrooms and clean zones are commonly used in semiconductor and pharmaceutical manufacturing facilities. In the semiconductor industry, an increase in the particle concentration in the air can lead to a decrease in manufacturing efficiency because particles settling on the semiconductor wafer can affect or interfere with the manufacturing process at small length scales. For the pharmaceutical industry, which lacks this kind of real - time efficiency feedback, contamination by airborne particles and biological contaminants exposes pharmaceuticals to the risk of not meeting the cleanliness level standards established by the U.S. Food and Drug Administration (FDA) and other foreign and international health regulatory agencies.

[0006]

[0004] The presence of humans in such environments increases the risk of particulate matter and biological contamination levels. Controlled environment systems are shifting towards automated or robotic systems to limit or eliminate human interaction. However, many applications that require a controlled environment also require or utilize environmental sampling to ensure that viable and non - viable particles and / or organisms are maintained below desired levels.

[0007]

[0005] The classification criteria at the particle level in cleanrooms and the criteria for tests and monitoring to ensure compliance are defined by ISO 14664-1 and 14664-2. Aerosol optical particle counters are commonly used to determine the level of airborne particle contamination in cleanrooms and clean zones, and liquid particle counters are used to optically measure the level of particle contamination in process fluids. When microbial particles are of particular concern, such as in the pharmaceutical industry, it is not only important to quantify the number of airborne particles but also to characterize the viability and identity of microbial particles. ISO 14698-1 and 14698-2 define the evaluation criteria for cleanroom and clean zone environments for biocontaminants.

[0008]

[0006] Currently, the collection and analysis of biological particles in air are generally achieved using various techniques including settling plates, contact plates, surface swabs, fingertip sampling, and impactor-based viable air samplers. Cascade impactors have conventionally been used for particle collection and sizing. In these devices, smaller particles are successively removed from the fluid stream by a series of acceleration and inertial impacts. Each stage of the inertial impactor operates based on the principle that particles suspended in air can be collected by forcing a dramatic change in the direction of the air stream containing the particles, where the inertia of the particles separates them from the air stream streamline and allows it to impact on a surface. Biswas et al. have described the efficiency with which particles can be collected in a high-speed inertial impactor (Environ. Sci. Technol., 1984, 18(8), 611-616).

[0009]

[0007] Due to increasing quality standards and government regulatory requirements, as the requirements for lower achievable and non-achievable particle concentrations increase, it is necessary to advance sampling techniques to reduce false positives and the risk of external contamination due to human interaction in a controlled environment.

[0010]

[0008] To reduce the risk of further contamination, there remains a need for particle collection, analysis, and characterization systems that sample and collect particles and / or organisms from a controlled environment and reduce interaction with humans. These systems can include the collection of any analysis of particles within the components of a robotic restricted access barrier system or other automated controlled environment process.

Summary of the Invention

[0011]

[0009] For example, provided herein are systems and methods that enable automated sampling and / or analysis of a controlled environment to determine the presence, amount, size, concentration, viability, species, or characteristics of particles within the environment. The described systems and methods can utilize robotics or automation or 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 can be used with known particle sampling and analysis techniques and devices, including, for example, optical particle counters, impingers, and impactors.

[0012]

[0010] The provided systems and methods are useful within a controlled environment that utilizes robotic systems, such as robotic controlled restricted access barrier systems (RABS) and positive pressure isolator systems. These systems and methods enable integration with an impinger within a controlled environment to position, connect, sample, and / or analyze the environmental conditions within the controlled environment with little or no human contact, reducing the risk of contamination from particles or organisms present on the operator. Further, the described systems and methods can enable robotic sterilization of the environment or sampling components to further reduce or eliminate the risk of contamination.

[0013]

[0011] The impactor can include a sampling head having one or more suction holes, an impactor base connected to the sampling head, and a magnet fixed to the sampling head or the impactor base. The one or more suction holes can enable sampling of a fluid stream containing particles. The impactor base may be operatively connected to receive at least a portion of the fluid stream from the sampling head. The impactor base can include an impact surface for receiving at least a portion of the particles in the fluid stream. The impactor base can be provided with an outlet for discharging the fluid stream. The sampling head and the impactor base may engage to enclose the impact surface.

[0014]

[0012] The impact surface can be configured to receive and capture biological particles. The sampling head and the impactor base may engage to completely enclose the impact surface, including, for example, engaging via a substantially airtight seal. The sampling head and the impactor base may each independently comprise a polymer material. The impactor base and / or the sampling head may include a magnet for effective handling of the impactor by a robotic control system. At least a portion of the impactor base, the sampling head, or both may be optically transmissive.

[0015]

[0013] The impact surface may be provided with a growth medium for receiving biological particles in the fluid. The robotic control system can be configured to expose the impactor and / or the impact surface to the fluid. The robotic control system may be further configured to collect particles from the impactor and / or the impact surface. The robotic control system may be further configured to sample particles from the fluid when the user is not physically in contact with the impactor.

[0016]

[0014] The impacter and / or impact surface may comprise a growth medium for receiving biological particles in a fluid. Thus, the impacter base may comprise a growth medium positioned to receive particles in a fluid stream, where the impact surface is the receiving surface of the growth medium. The robotic control system may further 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, where the growth medium is present in the particle sampling or counting during its sterilization. Thus, in some embodiments, the impacter is configured to be robotically sterilized on its outer surface. In some embodiments, the impacter can be configured to be sterilized in a fully assembled configuration, and the impact surface remains enclosed by the sampling head and the impacter base.

[0017]

[0015] In some embodiments, the particles collected by the impacter are microorganisms. In some embodiments, the base, sampling head, or both of the impacter are optically transmissive to enable visualization, optical detection, or imaging of particles in the growth medium without physically accessing the growth medium.

[0018]

[0016] The impacter can further comprise a removable cover that covers one or more suction holes and thereby encloses the impact surface. In some embodiments, one or more suction holes can be arranged in a radial array on the sampling head, and a magnet (sometimes referred to as a sampling head magnet) can be fixed to the sampling head at the center of the radial array.

[0019]

[0017] In some embodiments, the magnet can be fixedly attached to a selectively removable cover. In one embodiment, the magnet is fixedly attached to the underside of the selectively removable cover. For example, the magnet may be fixedly attached to a protrusion on the underside of the selectively removable cover.

[0020]

[0018] In some embodiments, the magnet is a first cover magnet fixed under a selectively removable cover, and the impactor includes a second cover magnet spaced from the first cover magnet and protruding from under the selectively removable cover.

[0021]

[0019] In embodiments where one or more permanent magnets are fixed to the cover, such magnets can be referred to as cover magnets. In such embodiments, the impactor may further include a sampling head magnet fixed to the sampling head. The sampling head magnet may be configured to cooperate with the cover magnet. Thus, in some embodiments, the selectively removable cover can hold the magnetic cover in place by magnetic attraction of the sampling head magnet to the cover magnet.

[0022]

[0020] The impactor may be configured for robotic operation via a robotic device. In one example, the robotic control system and the impactor may be configured to remove, by the robot, a selectively removable cover from the sampling head via the robotic device to expose one or more suction holes to the surrounding environment. For example, one or more permanent magnets of the impactor may be configured to engage with a robotic device magnet of the robotic device. In some embodiments, the robotic device magnet may be an electromagnet. In some embodiments, the electromagnet may be configured to exert a magnetic attraction force on the cover magnet that is greater than the magnetic attraction force exerted on the cover magnet by the sampling head magnet, thereby enabling the robotic device to remove the cover. Thus, the robotic control system and the impactor may be configured to remove the cover via engagement (e.g., magnetic attraction) of the robotic device magnet of the robotic device with the cover magnet.

[0023]

[0021] The impacter may be further configured for robotic replacement of a selectively removable cover by disengaging the robotic device magnet from the cover magnet to seal the impact surface from the surrounding environment. In one embodiment, disengaging the robotic device magnet may include reducing or cutting power to the electromagnet.

[0024]

[0022] In some embodiments, the sampling head and the selectively removable cover engage via a compressible seal member. In some embodiments, the compressible seal member is an O-ring. In some embodiments, the impacter is configured to compress the compressible seal member by magnetic attraction between the sampling head magnet and the cover magnet.

[0025]

[0023] In some embodiments, one or more permanent magnets of the impacter may be fixed to the receiving surface of the impacter via an adhesive. In some embodiments, the magnet is cast within the sampling head or the impacter base. In some embodiments, the magnet is at least partially encapsulated by a magnet chamber of the impacter.

[0026]

[0024] In one embodiment, a method for sampling biological particles from a fluid stream includes drawing a fluid stream containing biological particles into the sampling head of an impacter through one or more suction holes. At least a portion of the biological particles may be impacted against the impact surface of the impacter base. The impacter base can engage with the sampling head to enclose the impact surface. The fluid stream may be discharged from the sampling head. The impacter or its components can be operated via a magnet fixed to the impacter. Then, at least a portion of the biological particles received by the impact surface can be grown on the impact surface.

[0027]

[0025] In some embodiments, the operation step is performed before the step of withdrawing the fluid. In some embodiments, the operation step occurs after the growth step. In some embodiments, the operation step includes robotic operation of the impactor or its components via a robotic device. In some embodiments, the operation step includes manual operation of the impactor or its components via a magnetic hand tool. In some embodiments, the robotic operation includes removing a selectively removable cover from the sampling head via the robotic device to expose one or more suction holes to the ambient environment. In some embodiments, the robotic operation includes engaging the magnet of the impactor via the magnet of the robotic device. In some embodiments, the robotic operation includes placing a selectively removable cover on the sampling head via the robotic device to seal the impact surface from the ambient environment. In some embodiments, the robotic operation includes sterilizing the outer surface of the impactor. In some embodiments, the robotic operation includes the step of sterilizing the impactor in a fully assembled configuration, with the impact surface remaining enclosed by the sampling head and the impactor base.

[0028]

[0026] The fluid system for connecting to the impactor may be integrated within a cleanroom or aseptic environment, where the robotic control system is further configured to sample particles from the fluid under flow when the user is not physically present within the cleanroom or aseptic environment. The robotic control system may be placed inside the cleanroom or aseptic environment, outside the cleanroom or aseptic environment, or partially inside and outside the cleanroom or aseptic environment.

[0029]

[0027] The method provided may further include the step of sterilizing the particle sampling or counting device, where the impact surface remains enclosed during sterilization to protect, for example, a growth medium for capturing biological particles such as agar.

[0030] The provided method can further include the step of sterilizing the particle sampling or counting device in a fully assembled configuration, where the impact surface remains enclosed by the sampling head and the base during sterilization. The sterilization step may be performed 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, and dry heat.

[0031] The provided method may further include the step of culturing at least a portion of the biological particles received by the growth medium. The culturing step may enable optical detection of the biological particles. The culturing step can be performed without disassembling the fully assembled particle sampling or counting device.

[0032] The provided method may further include the step of characterizing the particles performed by an imaging device. The characterization step may include, for example, the step of determining the chemical composition of the particles or the step of determining the particle size distribution.

[0033] The provided method may be performed when the user is not physically in contact with the particle sampling or counting device. The fluid may start and / or end in a clean room or a sterile environment, where the method is performed with the user not physically present in the clean room or sterile environment. Each of the providing step, the flowing step, and / or the receiving step may be performed by a system configured for robot control.

[0034] The apparatus and method of the present invention incorporate an integrated sampler and impact surface, such as the receiving surface of the growth medium, in a manner that minimizes or completely eliminates risks associated with user handling, such as the occurrence of false positive determinations due to contamination of the impact surface during particle sampling, growth, or analysis processes.

[0035]

[0033] In one aspect, the present invention provides a particle impactor device having an integrated sampler and an enclosed impact surface designed for single use and / or disposable use, thereby eliminating the costs and contamination risks associated with reuse. The particle impactor device of the present invention having an integrated sampler and an enclosed impact surface can achieve effective sampling and growth of biological particles while minimizing the occurrence of user contamination during handling and use. Further, the particle impactor device of the present invention having an integrated sampler and an enclosed impact surface can be effectively sterilized in a fully assembled configuration, where the impact surface, such as the receiving surface of the growth medium, is maintained in an enclosed configuration during the sterilization process, thereby eliminating the need for the user to access the impact surface prior to particle sampling. Further, the present invention provides an optically transmissive particle impactor that enables in situ optical and / or visual analysis of particles, such as viable biological particles, without the need for physical access or handling of the collision surface during sampling, growth, and optical characterization of viable biological particles.

[0036]

[0034] The impactor device of the present invention includes a single-use device and / or a disposable device. The impactor of the present invention is useful for monitoring biological particles in a cleanroom, aseptic, or health care advisory environment. The impactor of the present invention is useful for sampling particles within a fluid, including air or one or more process gases, for manufacturing applications. The impactor of the present invention is useful for sampling, growing, and analyzing biological particles, including viable microorganisms.

[0037]

[0035] As described above, the impactor base includes a growth medium positioned to receive particles in a fluid stream, and the impact surface is the receiving surface of the growth medium. Useful growth media include media such as agar, broth, and other substrates such as filters. In one embodiment, the growth medium is provided, for example, in a Petri dish that includes an integrated component of the impactor base, where the Petri dish is cast in a single piece with the impactor base. In one embodiment, for example, the Petri dish and the impactor base include a single unitary element such as a single cast polymer structure. In one embodiment, for example, the growth medium comprises an agar plate. In one embodiment, the sampling head and the impactor base are optionally reversibly engaged to completely enclose the impact surface, for example, providing an airtight seal around the impact surface, and thus allowing only the fluid to pass through the suction hole and interact with the impact surface.

[0038]

[0036] As described above, the impactor can include a selectively removable cover provided on the sampling head, which cover covers the suction hole, thereby maintaining a sterile environment for the growth medium before sampling a fluid stream containing particles, or providing a sealed environment for the growth medium after sampling a fluid stream containing particles. In one embodiment, for example, the impactor base, the sampling head, or both are optically transparent to allow visualization, optical detection, or imaging of particles in the growth medium without physically accessing the growth medium. In one embodiment, for example, the sampling head and the removable cover engage via a substantially airtight seal. In one embodiment, for example, the sampling head and the removable cover engage via a selectively removable interlocking connection. In one embodiment, for example, the sampling head and the removable cover engage via an O-ring connection (for example, provided between the bottom surface of the removable cover and the top surface of the sampling head).

[0039]

[0037] The impactor of the present invention can include a series of useful materials. In one embodiment, for example, the sampling head and the impactor base each independently include a polymeric material such as a synthetic or natural polymer. In one embodiment, for example, the sampling head and the impactor base each independently include a sterile material.

[0040]

[0038] In one embodiment, for example, the outlet of the impactor base is connected to a fan or a pump to provide a fluid flow through the impactor, and the flow changes direction after passing through the suction holes.

[0041]

[0039] The present invention includes an impactor with optically transmissive components, for example, to enable efficient use in a fully assembled configuration. In one embodiment, for example, at least a portion of the impactor base, the sampling head, or both are optically transmissive, enabling characterization of particles on the impact surface without separating the sampling head and the impactor base. In one embodiment, for example, the impactor base, the sampling head, or both are optically transmissive such that they provide a transmittance of 50% or more for at least a portion of incident light having a wavelength in the range of 400 nm to 800 nm. In one embodiment, for example, the impactor base, the sampling head, or both are optically transmissive, thereby enabling visualization, optical detection, or imaging of particles on the impact surface without separating the sampling head and the impactor base. In one embodiment, for example, the impactor base, the sampling head, or both are optically transmissive, thereby enabling determination of the amount of viable biological particles on the impact surface. In one embodiment, for example, the impactor base, the sampling head, or both are optically transmissive, thereby enabling determination of the genus or species of viable biological particles on the impact surface.

[0042]

[0040] In some embodiments, the methods and apparatus of the present invention offer the advantage of minimizing or completely eliminating the need for a user to physically access the impact surface after sterilization. In one embodiment, for example, the method does not involve a user physically contacting the medium after contacting the particles. In one embodiment, for example, the method of the present invention further includes providing a cover on the sampling head to cover the suction hole, thereby sealing the growth medium within the apparatus after the sampling step.

[0043]

[0041] In one embodiment, for example, the present invention provides a method of sampling a fluid containing particles using an impactor for single use only, and optionally a method of disposing of the impactor after use. In one embodiment, for example, the present invention provides a method of monitoring biological particles in a cleanroom or aseptic environment. In one embodiment, for example, the present invention provides a method of monitoring biological particles in air or one or more process gases. In one embodiment, for example, the method of the present invention further includes repeating the steps of the method using a new sampler.

[0044]

[0042] The apparatus and methods of the present invention are versatile and support a wide range of particle sampling, monitoring, and analysis applications. For example, the apparatus and methods of the present invention are useful in applications including the preparation, handling, manufacturing, storage, transportation, filling, and / or finishing of sterile pharmaceuticals or biological agents, pharmaceutical or biological containers, pharmaceutical or biological delivery devices, medical devices including implantable devices, blood, cells, and tissue materials. In addition, the apparatus and methods of the present invention are useful for monitoring and characterizing biological particles in a pharmacy environment such as in a hospital, operating room, surgical suite, and for providing guidance and advice regarding compounding health care. Other applications of the apparatus and methods of the present invention include the preparation, manufacturing, storage, transportation, or processing of cosmetics, personal care products, food, and beverages.

[0045] While not desiring to be bound by any particular theory, the underlying principles, beliefs, or understandings related to the devices and methods disclosed herein can be discussed herein. It is recognized that embodiments of the invention can be effective and useful nonetheless, regardless of the ultimate accuracy of any mechanical explanations or hypotheses.

Brief Description of the Drawings

[0046]

Figure 1

Figure 2

Figure 3A

Figure 3B

Figure 3C

Figure 4A

Figure 4B

Figure 4C

Figure 5

[0047]

[0053] In general, the terms and phrases used herein have their technically recognized meanings, which can be found by referring to standard texts, journal references, and contexts known to those of ordinary skill in the art. The following definitions are provided to clarify their specific use in the context of the present invention.

[0048]

[0054] "Particle" refers to a small object often regarded as a contaminant. A particle is any material that is generated by the action of friction, for example, when two surfaces are mechanically in contact and there is mechanical movement. Particles can be composed of dust, soil, smoke, ash, water, soot, metal, minerals, or any combination thereof, or aggregates of other substances or contaminants. Also, "particle" can refer to biological particles (e.g., viruses, spores, and bacteria, fungi, archaea, protists, other single-celled microorganisms). Biological particles include, but are not limited to, microorganisms having a size on the order of 0.1 - 20 μm. Biological particles include, for example, viable and reproducible biological particles when incubated in a growth medium. A particle can refer to any small object that absorbs or scatters light and is thus detectable by an optical particle counter. As used herein, "particle" is intended to exclude individual atoms or molecules of the carrier fluid, such as such gases present in air (e.g., oxygen molecules, nitrogen molecules, argon molecules, etc.) or process gases. Some embodiments of the present invention can sample, collect, detect, size, and / or count particles including aggregates of materials having a size of 50 nm, 100 nm, 1 μm or more, or 10 μm or more. Particular particles include particles having a size selected from 50 nm - 50 μm, a size selected from 100 nm - 10 μm, or a size selected from 500 nm - 5 μm.

[0049]

[0055] The expression "sampling particles" broadly refers to, for example, the collection of particles in a fluid stream from an environment being monitored. Sampling in this context includes moving particles in the fluid stream to an impact surface, for example, the receiving surface of 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 dimensions such as diameter, effective diameter, etc.), particle type (biological or non-biological, viable or non-viable, etc.) or particle composition. Sampling can optionally include the analysis of the collected particles, for example, via subsequent optical analysis, image analysis or visual analysis. Sampling can optionally include the growth of viable biological particles for a sample via an incubation process that includes a growth medium. A sampler refers to an apparatus for sampling particles.

[0050]

[0056] An "impactor" refers to an apparatus for sampling particles. In some embodiments, the impactor comprises a sample head that includes one or more suction holes for sampling a fluid stream containing particles, whereby at least a portion of the particles are directed towards an impact surface for collection, such as the receiving surface of a substrate such as a growth medium (e.g., an agar, broth, etc. culture medium) or a filter. The impactor of some embodiments provides a change in the direction of the flow after passing through the suction holes, where particles having a preselected characteristic (e.g., a size greater than a threshold value) do not cause a change in direction and are thus received by the impact surface.

[0051]

[0057] The expression "detecting a particle" broadly refers to sensing the presence of a particle, identifying it, and / or characterizing the particle. In some embodiments, detecting a particle refers to counting the particle. In some embodiments, detecting a particle refers to characterizing and / or measuring physical properties of the 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 volume of fluid and optionally may provide characterization of the particles, for example, based on 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 light scattering, emission, or absorbance by the particles.

[0052]

[0058] "Flow direction" refers to an axis parallel to the direction in which the majority of the fluid moves when the fluid is flowing. For a fluid flowing through a straight flow cell, the flow direction is parallel to the path taken by the majority of the fluid. For a fluid flowing through a curved flow cell, the flow direction is considered to be tangent to the path taken by the majority of the fluid.

[0053]

[0059] "Fluid communication" refers to the arrangement of two or more objects such that fluid is conveyed from one object to another, passing over, through, or from one object to another. For example, in some embodiments, when a fluid flow path is provided directly between two objects, the two objects are in fluid communication with each other. In some embodiments, the two objects are in fluid communication with each other when the fluid flow path is provided 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 intake holes, an impact surface, a fluid outlet, a flow restriction, a pressure sensor, a flow generating device. In one embodiment, two objects present within the body of a fluid are not necessarily in fluid communication with each other unless fluid from the first object is drawn to, passes over, and / or through the second object along a flow path.

[0054]

[0060] "Flow rate" refers to the amount of fluid flowing past a particular point or through a particular region, such as an intake hole or a fluid outlet of a particle impactor. In one embodiment, the flow rate refers to the mass flow rate, i.e., the mass of fluid passing through a particular point or flowing through a particular region. In one embodiment, the flow rate is the volumetric flow rate, i.e., the volume of fluid flowing past a particular point or through a particular region.

[0055]

[0061] "Pressure" refers to a measure of force 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 the pressure exerted by a gas or fluid per unit area as referenced to a perfect vacuum or volume that exerts a force of 0 per unit area. Absolute pressure is distinguished from "differential pressure" or "gauge pressure", which refers to the relative change or difference in the force per unit area exerted above or relative to a second pressure, such as ambient pressure or atmospheric pressure.

[0056]

[0062] "Polymer" refers to a macromolecule composed of repeating structural units linked by covalent chemical bonds, or often a polymerization product of one or more monomers characterized by high molecular weight. The term "polymer" includes homopolymers, or polymers consisting essentially of a single repeating monomer subunit. Also, the term polymer includes copolymers, or polymers consisting essentially of two or more monomer subunits such as random, block, alternating, segmented, grafted, tapered and other copolymers. Useful polymers include organic polymers or inorganic polymers, which may be in an amorphous, semi-amorphous, crystalline, or partially crystalline state. Cross-linked polymers having bonded monomer chains are particularly useful for some applications. Polymers that can be used in methods, devices and components include, but are not limited to, plastics, elastomers, thermoplastic elastomers, elastic plastics, thermoplastic plastics and acrylates. Typical polymers include acetal polymers, biodegradable polymers, cellulose polymers, fluoropolymers, nylons, polyacrylonitrile polymers, polyamideimide polymers, polyimides, polyarylates, polybenzimidazoles, polybutylene, polycarbonates, polyesters, polyetherimides, polyethylene, polyethylene copolymers and modified polyethylene, polyketones, poly(methyl methacrylate), polymethylpentene, polyphenylene oxides and polyphenylene sulfides, polyphthalamides, polypropylenes, polyurethanes, styrene resins, sulfone resins, vinyl resins, rubbers (including natural rubber, styrene-butadiene, polybutadiene, neoprene, ethylene-propylene, butyl, nitrile, silicone), acryl, nylon, polycarbonate, polyester, polyethylene, polypropylene, polystyrene, polyvinyl chloride, polyolefins, or any combination thereof, but are not limited thereto.

[0057]

[0063] FIG. 1 is a perspective exploded view of the particle impactor 10, and FIG. 2 is a side exploded view of the particle impactor 10. As shown in these figures, the particle impactor 10 includes a sampling head 200, a selectively removable cover 100, and an impactor base 300. The sampling head 200 includes a sampling head magnet 250 fixed to the lower side of the sampling head 200. The selectively removable cover 100 includes a first cover magnet 155 and a second cover magnet 150 fixed to the lower surface of the cover 100 and spaced apart via a spacer 158. The sampling head magnet 250 engages with the second cover magnet 150 to fix the cover 100 to the impactor. The sampling head 200 and the selectively removable cover 100 engage via a compressible seal member 110. The impactor 10 is configured to compress the compressible seal member 110 by magnetic attraction between the sampling head magnet 250 and the second cover magnet 150. The sampling head 200 and the impactor base 300 engage via a compressible seal member 210. The first cover magnet 155 may be configured to engage with a robotic device.

[0058]

[0064] The sampling head 200 includes a plurality of suction holes 220 for sampling a fluid stream containing particles. The impactor base 300 includes an outlet 320 and an impact surface 350. During operation, the gas stream is guided through the suction holes 220 of the sampling head 100, where it is accelerated towards the impact surface 350 and exits from the outlet 320 that forces the gas to rapidly change direction. Due to their momentum, the particles entrained in the gas stream cannot cause a rapid change in direction and impact on the impact surface 350.

[0059]

[0065] In an embodiment, the impact surface 350 includes a receiving surface for a growth medium such as agar provided on the impactor base 300. For example, viable biological particles collected on the impact surface can then be grown, evaluated, and provide an analysis of the composition of the sampled fluid stream. For the collection of biological particles on the impact surface, it is important to control the distance between the suction hole 220 and the impact surface 350. If the distance is too large, for example, the particles may sufficiently follow the fluid path to avoid collision with the collision surface 350. However, if the distance is too small, the particles may collide with the collision surface 350 with sufficient force to render the particles non-viable and thus may not be able to regenerate.

[0060]

[0066] FIG. 3A shows a perspective view of the selectively removable cover 100. FIG. 3B is a bottom view showing the selectively removable cover 100. FIG. 3C shows a cross-sectional view of the selectively removable cover 100. The selectively removable cover 100 includes first and second cover permanent magnets 155, 150 that are fixed to the lower center of the cover 100 and separated by a spacer 158.

[0061]

[0067] Also, the selectively removable cover 100 includes an O-ring groove 120 on the lower side of the cover 100 proximate to the outer edge. The O-ring groove 120 is configured to receive an O-ring 110. The second cover magnet 150 magnetically engages with the sampling head magnet 250 to compress the O-ring 110. Accordingly, the cover 100 can form an airtight seal with the sampling head 200.

[0062]

[0068] FIG. 4A shows a perspective view of the sampling head 200. FIG. 4B shows a bottom view of the sampling head 200. FIG. 4C shows a cross-sectional view of the sampling head 200. The sampling head 200 includes a hole 220 and a sampling head magnet 250. The hole 220 may be radially arranged around the sampling head magnet 250 at the center of the sampling head 200 as shown.

[0063]

[0069] The present invention provides an air sampler including an impactor for the analysis of viable biological particles in an environment under surveillance such as a sterile manufacturing environment. One aspect of the present invention is an impactor device that integrates an agar plate and an air sampler into an integrated single-use and / or disposable package. The impactor of the present invention is well-suited for use in a cleanroom environment, particularly a sterile environment, in which pharmaceuticals such as sterile pharmaceuticals (e.g., medical agents, biologics, diagnostics, medical devices, medical implants, etc.) are manufactured. In one embodiment, for example, 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 a fan) or a house vacuum line) that draws air into a slit-shaped air inlet (e.g., 20 slits with a nominal width of 0.1 mm), where the particles are then impacted onto a receiving surface of a growth medium such as an agar plate. After sampling the cleanroom air, the device is transferred to a laboratory and incubated for several days to promote the growth of the sampled viable microorganisms. Next, a technician counts the number of CFUs (colony forming units) and, if present, identifies the genus or species of the microorganisms present.

[0064]

[0070] The impactor of the present invention provides a number of technical advantages including the following.

[0065]

[0071] Elimination of false positive contamination

[0066]

[0072] In conventional microbial air sampling methods, an operator places an agar plate into a stainless-steel sampling head device. In this process, the operator directly contacts the plate to insert and remove the agar plate. If this process is carried out carefully and appropriately, the operator should not contaminate the medium. However, it occurs daily that an operator can contaminate the plate and cause "false positives" (i.e., the growth of microorganisms resulting from operator handling before or after the production batch rather than from the environment during the production batch). When microbial growth is observed, the manufacturer's quality department conducts an investigation to determine the level of risk to the final formulation and decides whether to discard the batch or continue to ship the product. These investigations are very thorough and very costly (for example, in such quality inspections, a company incurs costs of $5K to $18K per investigation). If the batch is discarded, losses of thousands to millions of dollars can occur depending on the market price of the product and the material and production costs of the product. Furthermore, false positives can also pose a risk to the end patient. Human error can occur in any investigation. Sometimes, the manufacturer's quality department may determine that a contamination event is a false positive, but in reality, it is a true contamination, which can reduce the purity of the formulation and expose consumers / patients to the risk of illness, injury, or death.

[0067]

[0073] The device of the present invention reduces or essentially eliminates the possibility of false-positive contaminants from operator handling. The configuration of the device enables robotic operations including sterilization, sampling, incubation, and / or analysis processes.

[0068] Statement regarding incorporation by reference and modification

[0069]

[0074] All citations through this application, for example, patent documents including issued or granted patents or equivalents; patent application publications; and non-patent literature or other materials; are individually incorporated by reference to the extent that each citation does not conflict at least partially with the disclosure of this application (for example, partially conflicting citations are incorporated by reference except for the partially conflicting parts of the citation).

[0070]

[0075] The terms and expressions used in this specification are used as terms of explanation and not of limitation, and in the use of such terms and expressions, there is no intention to exclude equivalents of the features shown and described or parts thereof, but it is recognized that various modifications are possible within the scope of the claimed invention. Accordingly, although the present invention is specifically disclosed by preferred embodiments, typical embodiments and any features, modifications and variations of the concepts disclosed herein may be utilized by those skilled in the art, and it should be understood that such modifications and variations are considered to be within the scope of the present invention as defined by the appended claims. The specific embodiments provided herein are examples of useful embodiments of the present invention, and it will be apparent to those skilled in the art that the present invention can be implemented using numerous variations of the devices, components of the devices, and method steps described herein. As will be apparent to those skilled in the art, the methods and devices useful in the methods of the present invention can include any number of compositions and processing elements and steps.

[0071]

[0076] When a group of substituents is disclosed herein, it is understood that all individual members and all subgroups of that group are disclosed separately. When Markush groups or other groups are used in this specification, all individual members of the group, and all possible combinations and subcombinations of the group are intended to be individually included in the disclosure.

[0072]

[0077] As used in this specification and the appended claims, it should be noted that the singular forms "a", "an", and "the" include plural references unless the context clearly indicates otherwise. Thus, for example, reference to "a cell" includes a plurality of such cells known to those skilled in the art and their equivalents. 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 expression "any of claims XX-YY" (where XX and YY refer to claim numbers) is intended to provide alternative forms of multiple dependent claims and, in some embodiments, is interchangeable with the expression "any one of claims XX-YY".

[0073]

[0078] 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 belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are described herein. No provision of this specification should be construed as an admission that the present invention is not entitled to antedate such disclosure by virtue of prior invention.

[0074]

[0079] Any combination of the components described or exemplified herein can be used to practice the invention unless otherwise stated.

[0075]

[0080] Whenever a range is recited in the specification, such as a range of integers, a temperature range, a time range, a composition range, or a concentration range, all intermediate ranges and subranges, as well as all individual values included in the recited range, are intended to be included in the disclosure. The ranges used herein specifically include the values provided as the end point values of the range. When used herein, a range specifically includes all integer values within the range. For example, the range of 1 to 100 specifically includes the end point values of 1 and 100. It will be understood that any subranges or individual values within the ranges or subranges included in the description herein can be excluded from the claims herein.

[0076]

[0081] All patents and publications referred to herein are indicative of the level of skill of those of ordinary skill in the art to which the invention pertains. The references cited herein are hereby incorporated by reference in their entirety and are indicative of the state of the art as of their publication or filing date, and it is intended that this information can be used herein, if necessary, to exclude specific embodiments in the prior art. For example, when a composition of matter is claimed, it should be understood that compounds known and available in the art prior to the applicant's invention, including compounds for which enabling disclosures are provided in the references cited herein, are not intended to be included in the composition of the claimed matter herein.

[0077]

[0082] As used herein, "comprising" is synonymous with "including", "containing", or "characterized by", is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. As used herein, "consisting of" excludes any element, step, or ingredient not specified in the claim. As used herein, "consisting essentially of" does not exclude materials or steps that do not substantially affect the basic and novel characteristics of the claim. In each instance herein, any of the terms "comprising", "consisting essentially of", and "consisting of" may be replaced with either of the other two terms. The invention illustratively described herein can be practiced appropriately where no element, limitation, or restriction not specifically disclosed herein is present.

[0078]

[0083] One skilled in the art will appreciate that starting materials, biological materials, reagents, synthetic methods, purification methods, analytical methods, assay methods, and biological methods other than those specifically exemplified can be used in the practice of the invention without undue experimentation. All functional equivalents known in the art for any such materials and methods are intended to be included in the invention. The terms and expressions used have been used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the claimed invention. Accordingly, although the invention has been specifically disclosed by preferred embodiments and optional features, modifications and variations of the concepts disclosed herein may be resorted to 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. A sampling head comprising one or more intake holes for sampling a fluid stream containing particles, 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 surface for receiving at least a portion of the particles in the fluid stream and an outlet for discharging the fluid stream, A magnet fixed to the sampling head or the impactor base, An impactor comprising, The magnet is configured to engage with a magnet for a robotic device of a robotic device, The sampling head and the impactor base engage to enclose the impact surface, Impactor.

2. The impactor according to claim 1, wherein the sampling head comprises a selectively removable cover for covering the one or more intake holes.

3. The impactor according to claim 2, wherein the magnet is fixed to the selectively removable cover.

4. The impactor according to claim 3, wherein the magnet is fixed to the underside of the selectively removable cover.

5. The magnet is a first cover magnet fixed to the underside of the selectively removable cover, and the impactor comprises a second cover magnet spaced from the first cover magnet and protruding from the underside of the selectively removable cover. The impactor according to claim 4.

6. The impactor according to claim 5, comprising a sampling head magnet fixed to the sampling head and configured to fit with the second cover magnet.

7. The one or more intake 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. The impactor according to claim 6.

8. The impactor according to any one of claims 1 to 7, wherein the magnet is fixed to the impactor base.

9. The magnet is a sampling head magnet fixed to the sampling head, and the impactor comprises an impactor base magnet fixed to the impactor base. The impactor according to any one of claims 1 to 8.

10. The sampling head and the selectively removable cover engage via a compressible seal member, the impactor according to any one of claims 2 to 9.

11. The impactor is configured to compress the compressible seal member via magnetic attraction between the sampling head magnet and the cover magnet, the impactor according to claim 10.

12. The compressible seal member is an O-ring, the impactor according to claim 11.

13. The magnet is fixed to the receiving surface of the impactor via an adhesive, the impactor according to any one of claims 1 to 12.

14. The magnet is cast into the sampling head or the impactor base, the impactor according to any one of claims 1 to 13.

15. The magnet is at least partially enclosed by the magnet chamber of the impactor, the impactor according to any one of claims 1 to 14.

16. The impactor is configured for robotic operation via a robotic device, the impactor according to any one of claims 1 to 15.

17. The impactor is configured to robotically remove the selectively removable cover from the sampling head via a robotic device and expose the one or more intake holes to the ambient environment, the impactor according to any one of claims 2 to 16.

18. The impactor is configured to robotically replace the selectively removable cover on the sampling head via a robotic device to seal the impact surface from the ambient environment, the impactor according to any one of claims 2 to 17.

19. The outer surface of the impactor is configured to be sterilized by a robot, the impactor according to any one of claims 1 to 18.

20. The particles are microorganisms, the impactor according to any one of claims 1 to 19.

21. The impactor base further comprises a growth medium positioned to receive particles in the fluid stream, and the impact surface is the receiving surface of the growth medium, the impactor according to any one of claims 1 to 20.

22. The impactor base, sampling head, or both are optically transmissive so as to enable visualization, optical detection, or imaging of particles in the growth medium without physically accessing the growth medium, the impactor according to claim 21.

23. The impactor according to any one of claims 1 to 22, wherein the impactor is configured to be sterilized in a fully assembled configuration in which the impact surface remains enclosed by the sampling head and the impactor base.

24. A sampling head comprising one or more intake holes for sampling a fluid stream containing particles and a selectively removable cover for covering the one or more intake holes, 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 surface for receiving at least a portion of the particles in the fluid stream and an outlet for discharging the fluid stream, A magnet fixed to the sampling head or the impactor base, A magnet fixed to the selectively removable cover, An impactor comprising: An impactor in which the sampling head and the impactor base engage to enclose the impact surface.

25. A sampling head comprising one or more intake holes for sampling a fluid stream containing particles and a selectively removable cover for covering the one or more intake holes, 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 surface for receiving at least a portion of the particles in the fluid stream and an outlet for discharging the fluid stream, A magnet fixed to the sampling head or the impactor base, A magnet fixed to the selectively removable cover, An impactor comprising: An impactor in which the sampling head and the impactor base engage to enclose the impact surface via the compressible seal member, The impactor is configured to compress the compressible seal member via magnetic attraction between the sampling head magnet and the cover magnet.

26. A sampling head comprising one or more intake holes for sampling a fluid stream containing particles and a selectively removable cover for covering the one or more intake holes, 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 surface for receiving at least a portion of the particles in the fluid stream and an outlet for discharging the fluid stream, A magnet fixed to the sampling head or the impactor base, An impactor comprising, The sampling head and the impactor base engage to enclose the impact surface, The impactor is configured to robotically remove the selectively removable cover from the sampling head via a robotic device to expose the one or more intake holes to the ambient environment, or, The impactor is configured to robotically replace the selectively removable cover on the sampling head via a robotic device to seal the impact surface from the ambient environment.

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