Sheet illumination for particle detection in pharmaceutical containers

Abstract

To provide methods of detecting particles inside liquid-filled drug product containers, particularly containers holding highly viscous samples / products.SOLUTION: In a method for imaging a container holding a sample, the container is illuminated with a laser sheet incident on the container in a first direction corresponding to a first axis. A plane of the laser sheet is defined by the first axis and a second axis orthogonal to the first axis. The method also includes capturing an image of the container by a camera having an imaging axis that is substantially orthogonal to at least the first axis. The method further includes analyzing, by one or more processors, the image of the container to detect particles within, and / or on an exterior surface of, the container.SELECTED DRAWING: Figure 3A

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 62 / 780,542, filed December 17, 2018, the entire contents of which are incorporated herein by reference.

[0002] This application relates generally to particle detection techniques, and more particularly to particle detection techniques that can distinguish between particles within a container (e.g., a syringe, a vial, etc.) and particles on the exterior surface of the container. [Background technology]

[0003] Foreign particles in pharmaceutical containers pose serious health and safety risks to patients, especially for injectable pharmaceutical products. While automated visual inspection equipment may be able to detect particles in containers holding liquid products with acceptable accuracy, there may be many false rejects due to, for example, small particles and scratches on the exterior of the container wall, defects (e.g., cracks) on the interior of the container wall or within the container wall itself, and / or small air bubbles inside the container wall.

[0004] A conventional imaging system 100 is shown in FIG. 1. As can be seen in FIG. 1, a container 102 filled with a sample (e.g., a liquid pharmaceutical) is illuminated by two angled illuminators 104A and 104B positioned generally facing a camera 106 on the opposite side of the container 102. The illuminators 104A and 104B are directional, with most of the emitted light propagating perpendicular to the light-emitting surface shown in FIG. 1 (i.e., as indicated by the arrows in FIG. 1). This requires that the size of each illuminator 104A, 104B be large enough to evenly illuminate the entire container. Because most of the emitted light is not directed toward the lens of the camera 106, the resulting image shows a dark background against which particles, if present, are bright. FIG. 2 shows another conventional imaging system 200 commonly used for larger, opaque particles (greater than 500 μm) or fibers that may be attached to the interior walls of a container. 2, the container 202 is illuminated by a backlight 204 facing a camera 206. In this case, the camera 206 images the shadows cast by the particles, which appear as dark objects against a relatively light background.

[0005] A challenge with both of these conventional lighting techniques is that they flood the entire container, illuminating particles and surface flaws both inside and outside the container. As a result, it can be difficult to distinguish between particles inside the container and those outside the container. This difficulty increases the risk of falsely identifying good parts as defective, as particles on the outside of the container may not be relevant to quality control procedures. In rear-angle illumination configurations, such as imaging system 100, a technique known as "image subtraction" or "minimum intensity projection" (MIP) is commonly used to distinguish between small particles (approximately 100-500 μm) inside the container and those on the outside of the container. This technique involves rapidly rotating the container around its central axis (approximately 600-5000 RPM), abruptly stopping the rotation, capturing a series of images of the stopped container at intervals of approximately 10-50 ms, and then subtracting subsequent images so that only objects that have moved between images appear in the resulting difference image. This allows for the enhancement of objects suspended in and carried by the fluid within the container, while substantially negating small particles and surface imperfections that may be present on the outside of the container. However, for viscous pharmaceuticals, this technique may be inappropriate because there is little or no fluid and particle movement after the container stops rotating. Backlighting configurations such as imaging system 200 also have drawbacks because they can "bleach out" small or non-opaque particles; backlighting configurations generally rely on particles inside the container being large enough to be distinguishable from the small particles typically present on the container's exterior surface.

[0006] Some manufacturers of automated pharmaceutical inspection equipment have proposed and implemented techniques that attempt to address these challenges. For example, U.S. Patent No. 8,036,444 (Nielsen), entitled "Method and System for Irradiating and Inspecting Liquid-Carrying Containers," describes an imaging system in which two line-scan cameras generate planar images of a rotating container. One camera is aligned with the central axis of the container, and the other is offset from the central axis. This technique utilizes the basic principle that, as a container is rotated, particles outside the container move a longer distance horizontally (i.e., perpendicular to the central axis of the container) than particles inside the container. After acquiring multiple images at different rotation speeds, the images from the two line-scan cameras are compared, and the distance between the particles is calculated. This distance can, in some cases, be used to distinguish between particles inside the container and those outside the container.

[0007] As another example, European Patent No. 3,062,292 (Kwoka), entitled "Inspection Method and Inspection Device for Monitoring Production Processes," describes an imaging system that uses a single area scan camera. When a particle is detected at a location along the central axis of a container, its location is digitally shifted to a point where the particle would be located if the container were rotated exactly around the central axis of the container by a predetermined angle (approximately 45°). The container is then rotated and a new image is taken. If the particle is actually outside the container, it should overlap with the digitally shifted image. If, instead, the particle is inside the container, it will be offset by some amount from the digitally shifted particle.

[0008] While the techniques of U.S. Pat. No. 8,036,444 (Nielsen) and European Patent No. 3,062,292 (Kwoka) may offer some improvements over the traditional image subtraction methods described above, each technique has significant drawbacks of its own. One drawback is that both techniques introduce significant errors when the container vibrates even slightly between images. Furthermore, particles inside the container may "slip" during rotation and not be in the expected position to be properly detected. Furthermore, the spatial resolution limitations of the imager may make these techniques inadequate for identifying small scratches on the inside of the glass, which can be a significant source of false positives. [Prior art documents] [Patent documents]

[0009] [Patent Document 1] U.S. Patent No. 8,036,444 [Patent Document 2] European Patent No. 3,062,292 Summary of the Invention [Problem to be solved by the invention]

[0010] Additionally, promising 3D imaging techniques have been developed that offer the ability to measure particle size and morphology from images, but such techniques are computationally prohibitive and may not operate at typical manufacturing line speeds (e.g., 300-600 containers per minute).Therefore, there is a need for improved methods to detect particles inside liquid-filled pharmaceutical containers, especially (but not limited to) those holding highly viscous samples / products. [Means for solving the problem]

[0011]

[0003] Embodiments described herein relate to systems and methods that improve upon conventional automated visual inspection techniques. In particular, an imaging system illuminates a container with a relatively thin sheet of laser light, which is incident on the container from a direction substantially perpendicular to the camera's imaging axis. The laser sheet may, for example, pass through the central axis of the container. With this illumination configuration, particles are visible in the resulting image only if they are within the thickness of the laser sheet (or are visible only at a particular intensity level, etc.). In this manner, by utilizing the laser sheet and the orthogonal camera orientation, it is easily possible to determine whether a particle visible in the image is inside or outside the container; i.e., an imaged particle that is outside the container will be outside the container walls in the image, and an imaged particle that is inside the container will be between the container walls in the image.

[0012] In some embodiments, to inspect the entire volume of a pharmaceutical (or other sample) contained within a container, the container is rotated several times around its central axis, and the laser sheet remains illuminated and is imaged after each rotation. While a large number of rotations may be required, the image processing and computational load can be significantly lighter, and the probability of false positives can be significantly lower. Furthermore, this technique has the unexpected advantage that some of the laser light is scattered within the sample or refracted at the container / sample (e.g., glass / liquid) interface and travels around the inner periphery of the container (e.g., if the container is cylindrical). This scattered or refracted light can illuminate bubbles anywhere inside the container, even bubbles that do not intersect with the laser sheet. This phenomenon, driven by the large refractive index difference at surfaces (which results in substantial reflection and refraction), can be exploited to distinguish between bubbles and particles (e.g., debris, protein aggregates, etc.) with greater accuracy than other techniques that rely solely on differences in bubble and particle morphology. Being able to better distinguish between air bubbles (which are usually harmless) and other particles can be important, as air bubbles are typically a significant cause of false positives (e.g., when using traditional image subtraction methods).

[0013] While laser sheet technology is not essential, other, more complex configurations may be used. For example, to compensate for the fact that the optical scattering of a laser sheet is different where it enters the container than where it exits, two laser sheets (both orthogonal to a single camera) facing each other at 180 degrees may be used. This reduces the number of rotations / images required by a factor of two. As another example, to better image a specific area of ​​the container (e.g., the shoulder or bung area), one or more additional laser sheets may be directed at an oblique angle relative to the first laser sheet. As yet another example, an imaging system may include a first laser source generating a laser sheet of one color (e.g., red) and a second laser source generating a laser sheet of another color (e.g., blue), with some angular offset between the two laser sheets relative to the central axis of the container. In this situation, two cameras (each tuned to a different one of the two colors) can capture images simultaneously. Alternatively, a single camera (e.g., with one or more mirrors, prisms, and / or other optical components) can be used to capture images that preserve the visual information provided by the illumination of each of the different color laser sheets (e.g., using a camera implemented with a Bayer filter or using a camera with optics and filters to map the different colors of the two laser sheets to different portions of the camera sensor). Whether one or two cameras are used, this approach can reduce the number of required rotations / images by a factor of two (or by a factor of three if three different color laser sheets are used). As yet another example, an imaging system may include a laser source that generates a laser sheet of one color (e.g., red) and an illumination source that generates light of another color (e.g., blue) that substantially illuminates the entire volume of the container. By using cameras tuned to different colors, particles inside and outside the container can be distinguished in one plane (within the laser sheet) while simultaneously capturing a snapshot of the entire volume (using the other illumination source).

[0014] The techniques described above and elsewhere herein may provide several advantages, such as enabling automated detection of fibers and other particles in high-viscosity products, enabling accurate automated detection of small particles stuck to the interior walls of containers, improving differentiation between air bubbles and particles inside the container, avoiding false positives or other problems resulting from small scratches on the interior walls of the container, reducing the risk of non-compliance due to particles that are not actually inside the container or due to air bubbles (i.e., reducing false positives that could result in the entire batch of pharmaceutical product being discarded), reducing the need for costly manual inspection to avoid false positives, and / or reducing patient risk. Furthermore, the techniques can be implemented by retrofitting current automated inspection equipment with minimal hardware modifications (e.g., by simply adding one or more laser sources).

[0015] Those skilled in the art will understand that the drawings described herein are included for illustrative purposes and are not intended to limit the present disclosure. The drawings are not necessarily to scale, emphasis instead being placed upon illustrating the principles of the present disclosure. It should be understood that in some instances, various aspects of the described embodiments may be shown exaggerated or enlarged to facilitate understanding of the described embodiments. In the drawings, like reference numerals generally refer to functionally similar and / or structurally similar components throughout the various views. [Brief explanation of the drawings]

[0016] [Figure 1] 1 and 2 show a conventional imaging system for particle detection. [Figure 2] 1 and 2 show a conventional imaging system for particle detection. [Figure 3A] 3A and 3B show different views of a first embodiment of an exemplary imaging system that operates according to the principles described herein. [Figure 3B]3A and 3B show different views of a first embodiment of an exemplary imaging system that operates according to the principles described herein. [Figure 4] FIG. 4 shows an exemplary image of a container illuminated by an imaging system similar to that of FIGS. 3A and 3B. [Figure 5] FIG. 5 illustrates a second embodiment of an exemplary imaging system that operates according to the principles described herein. [Figure 6] FIG. 6 illustrates a third embodiment of an exemplary imaging system that operates according to the principles described herein. [Figure 7] FIG. 7 illustrates a fourth embodiment of an exemplary imaging system that operates according to the principles described herein. [Figure 8] FIG. 8 is a schematic block diagram of an exemplary automated inspection system that may be used with the imaging system of FIG. 3, 5, 6, or 7. [Figure 9] FIG. 9 is a flow diagram of an exemplary method for imaging a vessel containing a specimen. DETAILED DESCRIPTION OF THE INVENTION

[0017] The various concepts described introductory above and in more detail below can be implemented in any of many ways, and the described concepts are not limited to any particular implementation manner. Example embodiments are provided for illustrative purposes.

[0018] A first embodiment is shown in FIGS. 3A and 3B. FIGS. 3A and 3B present an exemplary imaging system 300 from different perspectives. Specifically, FIG. 3A is an off-axis perspective view, and FIG. 3B is a top view. In FIGS. 3A and 3B, one or more images of a container 302 (in a holder 303) are captured by an imager 304 while the container 302 is illuminated by a laser source 306. While the container 302 is depicted as a syringe in FIGS. 3A and 3B, it should be understood that the container 302 may instead be another suitable type of container and may have any suitable size and shape. For example, the container 302 may instead be a vial, test tube, cartridge, etc. The container 302 may be made from glass, plastic, or other suitable material (or combination of materials) that is at least partially transparent or translucent to allow light from the laser source 306 to pass through and to the imager 304 to pass through. During operation, the container 302 may hold a liquid sample. However, in some applications, the container 302 may also hold a non-liquid sample, such as a lyophilized or frozen sample.

[0019] The holder 303 may include any hardware necessary to maintain the container 302 in a desired position and to rotate the container 302 so that the imager 304 can capture images from other perspectives. The holder 303 may simply be part of any suitable means for positioning the container 302 in one or more desired positions and / or orientations. The positioning means may include any suitable combination of hardware, firmware, and / or software, depending on the requirements of the imaging system 300. For example, the positioning means may simply comprise a platform (e.g., a flat base component) on which the holder 303 may be positioned in a fixed orientation or from which it may protrude vertically so that the holder 303 can be rotated. However, in other embodiments, the positioning means may include automated / robotic hardware (e.g., a robotic arm with another suitable holding means, such as "fingers" that can grasp / pinch the holder 303 or the container 302). In these latter embodiments, the positioning means may also include a processing unit (e.g., a microprocessor and / or an application specific integrated circuit (ASIC) or field programmable gate array (FPGA), etc.) and memory (e.g., solid state memory or hard drive memory) that stores instructions that the processing unit can execute to grip / hold / fix, shift, and / or rotate the container 302. Of course, other positioning means are possible.

[0020] Imager 304 may be, for example, a camera including one or more charge-coupled device (CCD) sensors. Alternatively, imager 304 may include one or more complementary metal-oxide semiconductor (CMOS) sensors and / or any other suitable type of imaging device / sensor. Imager 304 may include, for example, a telecentric lens or any other suitable lens (or combination of lenses). In various embodiments, imager 304 may include any suitable combination of hardware and / or software, such as an image sensor, an optical stabilizer, an image buffer, a frame buffer, a frame grabber, etc. More generally, imaging system 300 may include any suitable means for capturing one or more images of container 302 (or another suitable container), where the imaging means includes imager 304 and / or one or more any other suitable imaging devices (e.g., imager 304 plus one or more mirrors, additional lenses, etc.).

[0021] Laser source 306 generates laser sheet 310, which generally conforms to a plane. While laser sheet 310 is referred to herein as a "sheet," it should be understood that practical limitations imposed by the laser source 306 and the medium through which laser sheet 310 passes (i.e., air or other gas, the walls of container 302, and the liquid or other sample within container 302) may prevent laser sheet 310 from forming a uniformly flat sheet. For example, laser sheet 310 undergoes some diffusion as it enters and exits container 302. In some embodiments, laser source 306 is a diode laser with a power output of 1-5 mW, a line beam angle of 30-60 degrees, and a line width (thickness) of 1-1.5 mm. In one embodiment, laser source 306 is a Micro VLM™ Laser Diode Line, manufactured by Edmund Optics, product code #52-267, with a power output of 3.5 mW, a wavelength of 670 nm, and a line beam angle of 60 degrees. In another embodiment, laser source 306 is an Edmund Optics Micro VLM™ Laser Diode Line, product code #52-268, with a power output of 1.6 mW, a wavelength of 670 nm, and a line emission angle of 30 degrees. More generally, imaging system 300 may include any suitable means for generating laser sheet 310, such as laser source 306 or another suitable laser source. In some embodiments (e.g., when container 302 is dark brown to block visible light), laser source 306 generates laser sheet 310 using infrared laser light. As used herein, the term "light" does not necessarily refer to the portion of the electromagnetic spectrum that is visible to humans.

[0022] As can be seen in the exemplary embodiment of FIG. 3A , the laser sheet 310 is incident on the container 302 in a direction 322 that corresponds to (i.e., aligns with) a first axis 330 and generally coincides with a plane defined by the first axis 330 and an orthogonal second axis 332. In the illustrated embodiment, the second axis 332 is parallel to a central axis 320 of the container 302. Furthermore, as more clearly shown in FIG. 3B , in the illustrated embodiment, the imaging axis 324 of the imager 304 passes through the center of the container 302 (i.e., through the central axis 320). The imaging axis 324 of the imager 304 is substantially parallel to a third axis 334, which is orthogonal to both the first axis 330 and the second axis 332. The term “substantially” is used in this context to reflect the fact that part alignment is never completely perfect and to indicate that small deviations can be tolerated without destroying the primary benefits provided by the techniques described herein. For example, in some applications, imaging axis 324 may be within 5 degrees, or within 3 degrees, or within 2 degrees, or within 1 degree, etc., of being perfectly perpendicular to axes 330 and 332 .

[0023] Laser sheet 310 has a finite thickness 340 that covers a small range of third axis 334. Thickness 340 may represent, for example, three times the beam width of laser sheet 310 along third axis 334. Because laser source 306 is not ideal (theoretically perfect), thickness 340 is not precisely uniform at all points along axis 334. However, at least at the location where laser sheet 310 enters container 302, thickness 340 is substantially smaller than the diameter of container 302. Thickness 340 may be set as a design parameter based on both the size (e.g., diameter) of container 302 and the desired (or, e.g., maximum allowable) number of rotations / images. In particular, thickness 340 may be set such that when container 302 is rotated a certain number of times (to allow imager 304 to capture images from those perspectives) with a certain angular offset per rotation, all portions (or most of them) of the volume of container 302 are ultimately illuminated. This may also require consideration of whether laser sheet 310 will adequately illuminate both sides of container 302 (i.e., both where laser sheet 310 enters container 302 and where laser sheet 310 exits container 302) at any rotational position of container 302. For example, if container 302 is rotated / imaged 90 times to achieve complete coverage, and if laser sheet 310 adequately illuminates both the entrance and exit sides of container 302, thickness 340 may be set so that laser sheet 310 covers 1 / 90 (or just over 1 / 90) of the circumference of container 302, with half of the coverage corresponding to where laser sheet 310 enters container 302 and half of the coverage corresponding to where laser sheet 310 exits container 302. On the other hand, if laser sheet 310 does not sufficiently illuminate the exit side of container 302, thickness 340 can be set so that laser sheet 310 still covers approximately 1 / 90 of the circumference of container 302, but this time all of this coverage occurs where laser sheet 310 enters container 302.Thus, for example, if the diameter of container 302 is 100 mm and laser sheet 310 adequately illuminates both sides of the container, thickness 340 may be set to approximately 2 mm, i.e., the coverage by laser sheet 310 is 100 mm * π / (90 revolutions) = 3.49 mm / revolution (where half the coverage occurs on both sides of container 302 so that thickness 340 is 3.49 mm / 2 = 1.74 mm, allowing for an extra 0.26 mm of thickness to ensure full coverage). Conversely, if laser sheet 310 does not adequately illuminate the exit side of container 302, thickness 340 may be set to approximately 4 mm (alternatively, the number of revolutions may be increased from 90 to 180).

[0024] The thickness 340 may be constrained on the lower end by what is necessary for complete coverage / illumination, while the thickness 340 may be constrained on the upper end by the need to avoid over-illuminating the walls of the container 302 for any given rotation / image. In particular, if the laser sheet 310 illuminates particles that are outside the container 302 but that nevertheless appear (from the perspective of the imager 304) to be between the outermost boundaries of the container 302, the improved discrimination provided by the imaging system 300 begins to diminish. In various embodiments, the thickness 340 is greater than zero, less than 1 mm, less than 2 mm, less than 3 mm, less than 4 mm, less than 5 mm, etc. Stated as a range, in various embodiments, the thickness 340 may be in the range of 1-3 mm, 1-5 mm, 0.5-5 mm, etc.

[0025] In some embodiments, the distance of the laser source 306 from the container 302 and the beam angle of the laser sheet 310 along the second axis 332 may be fixed so that the laser sheet 310 illuminates the entire cross-section of the container 302 in the plane defined by the axes 330, 332. However, in other embodiments, the laser sheet 310 illuminates only a smaller cross-section of the container 302 (e.g., excluding the shoulder or bung area as shown in FIG. 3A and / or including only areas known to hold samples). Furthermore, in some embodiments, the laser sheet 310 does not extend at a particular beam angle. For example, the laser source 306 may instead generate a more collimated sheet (e.g., a laser sheet covering a substantially fixed / constant range of the second axis 332), such as by illuminating a series of cylindrical lenses with a conventional Gaussian laser beam.

[0026] In some embodiments, imaging system 300 is configured differently than that shown in FIGS. 3A and 3B . For example, imager 304 may be positioned such that imaging axis 324 is parallel to (e.g., aligned with) central axis 320 of container 302. As another example, imaging axis 324 of imager 304 may be angled slightly above or below a plane defined by axes 330, 334. As yet another example, direction 322 of laser sheet 310 may be angled slightly above or below a plane defined by axes 330, 334 (e.g., to better illuminate a shoulder or bung region). As yet another example, imaging system 300 may include one or more additional imagers and / or illumination sources (e.g., as described below with reference to FIGS. 5-7 ).

[0027] Figure 4 shows an exemplary image 400 of a container illuminated by an imaging system, such as imaging system 300 of Figures 3A and 3B. The container being imaged may be, for example, container 302 as it is illuminated by laser sheet 310. In particular, Figure 4 corresponds to a scenario in which the laser sheet is incident on the container from the left of the area shown in image 400, and an embodiment in which the laser sheet does not adequately illuminate the exit side of the container (i.e., to the right of the area shown in image 400).

[0028] Because the thickness of the laser sheet (e.g., thickness 340 in FIGS. 3A and 3B ) only illuminates a small “slice” of the container per time / rotation, particles (e.g., dust or fibers) outside the container are only illuminated (at least to a level sufficient for clear imaging) along the portion of the container wall facing the laser sheet source (e.g., the portion of a curved container wall with a surface normal vector substantially perpendicular to the imaging axis). Thus, particles outside the container wall are only visible (or clearly visible) when the image indicates that they are clearly outside the container. In the exemplary image 400, this means that particles outside the container only appear immediately to the left of (and touching) the container wall. In embodiments where the laser sheet also adequately illuminates the exit (right) side of the container, the image can also show external particles as being immediately to the right of (and touching) the container. However, external particles located in other parts of the container wall (i.e., parts of the wall closer to the center of image 400) are not illuminated or are at most very faintly illuminated by scattered / refracted light. Thus, particles shown between the left and right boundaries of the container in image 400 are clearly inside the container (i.e., within the portion / slice of the sample illuminated by the laser sheet as it passes through the container's interior).

[0029] As can be seen in Figure 4, the laser sheet illuminates several small, dust-like particles on the outside left side of the container, as well as larger particles (fibers) just inside the left wall of the container. Also visible in image 400 is a small particle inside the container slightly to the right of the fibers. As used herein, the term "particle" refers to any object that is small relative to the container and is a solid (e.g., fiber or other debris, or protein aggregates, etc.), or possibly in some use cases a microemulsion.

[0030] A secondary benefit of imaging with a laser sheet is that bubbles can be illuminated anywhere within the container, even when they do not intersect the laser sheet. This is due to the highly reflective nature of bubbles and the fact that some of the laser light is scattered and / or refracted at the container / sample interface and / or due to interactions with objects within the sample. One such bubble is shown in Figure 4. As a result, it may be easier to distinguish between bubbles and particles. For example, automated image analysis / processing may initially count an object that appears between the container walls as a "candidate" particle, but then determine that the object is a bubble rather than an actual particle if other images at other rotation points continue to show the object in the expected location based on the initial object's location and the known rotation angle. Conversely, automated image analysis / processing may identify the object (candidate particle) as an actual particle if the object does not reappear in the corresponding location in other images at other rotations.

[0031] FIG. 5 illustrates an alternative embodiment in which imaging system 500 images container 502 using imager 504, first laser source 506A, and second laser source 506B, with laser sources 506A and 506B pointing in 180-degree opposed directions. Referring to FIGS. 3A and 3B, for example, container 502 may be similar to container 302, imager 504 may be similar to imager 304, and each of laser sources 506A and 506B may be similar to laser source 306. Laser sources 506A and 506B generate laser sheets 510A and 510B, respectively, which may be similar to laser sheet 310 of FIGS. 3A and 3B. However, in imaging system 500, laser sheet 510A is incident on container 502 in direction 522A, and laser sheet 510B is incident on container 502 in the opposite direction 522B. An imaging axis 524 of imager 504 is substantially perpendicular to directions 522A and 522B.

[0032] By using a second, opposing laser source, imaging system 500 can better illuminate both sides of container 502 (i.e., the "left" and "right" sides from the perspective of imager 504) during each rotation of container 502, thereby reducing the amount of rotations and images required by half. Alternatively, if the number of rotations / images is not reduced, the second laser source can allow laser sheets 510A and 510B to each have approximately half the thickness (relative to thickness 340 of laser sheet 310), which can help ensure that illuminated particles outside container 502 do not appear to be just inside the walls of container 502 (e.g., near but between the left and right edges of container 400 in FIG. 4).

[0033] 6 illustrates another alternative embodiment in which imaging system 600 images container 602 using a first imager 604A, a second imager 604B, a first laser source 606A, and a second laser source 606B. Referring to FIGS. 3A and 3B, for example, container 602 may be similar to container 302, each of imagers 604A and 604B may be similar to imager 304, and each of laser sources 606A and 606B may be similar to laser source 306. In the embodiment of FIG. 6, a laser sheet 610A (e.g., similar to laser sheet 310) generated by laser source 606A is incident on container 602 in a first direction 622A, and a laser sheet 610B (e.g., also similar to laser sheet 310) generated by laser source 606B is incident on container 602 in a second direction 622B that is neither parallel nor orthogonal to first direction 622A. For example, there may be an angular displacement of 135 degrees (or 150 degrees, 120 degrees, 60 degrees, 30 degrees, etc.) between directions 622A and 622B. The imaging axis 624A of imager 604A is substantially orthogonal to the first direction 622A, and the imaging axis 624B of imager 604B is substantially orthogonal to the second direction 622B.

[0034] Laser sources 606A and 606B may generate light of different wavelengths / colors. For example, laser sheet 610A may be red, while laser sheet 610B may be blue or green, etc. Additionally, optical filters of imagers 604A and 604B may pass only the color of the corresponding laser source (e.g., imager 604A may be configured to image red light but not blue light, and imager 604B may be configured to image blue light but not red light). By utilizing different colors, imaging system 600 enables simultaneous imaging by imagers 604A and 604B, which may have one or more advantages. For example, imaging two “slices” of the sample at once may reduce the number of required rotations of container 602 by half compared to using a single laser sheet and imager, or may reduce the thickness of the laser sheet, as discussed above in connection with FIG. 5 .

[0035] In an alternative embodiment, imaging system 600 includes imager 604A but omits imager 604B. In such an embodiment, imaging system 600 includes appropriate optics (e.g., one or more mirrors, prisms, and / or other optical components) to ensure that the optical path of imager 604A has both a first component aligned with direction 624A and a second component aligned with direction 624B. Imager 604A may include, for example, a Bayer filter (e.g., a conventional color CCD or CMOS chip) to capture, distinguish, and store the visual information provided by the illumination from each of laser sheets 610A and 610B. That is, a single imager 604A can capture a composite image with sufficient information to recreate a first image corresponding to the color of laser sheet 610A (e.g., red) and a second image corresponding to the color of laser sheet 610B (e.g., green) for each rotation of container 602. Alternatively, imager 604A may comprise a camera with appropriate optics and filters to map visual information corresponding to different colors onto different parts of the camera sensor.

[0036] 7 illustrates yet another alternative embodiment in which imaging system 700 images container 702 using a first imager 704A, a second imager 704B, a laser source 706 that generates a laser sheet 710, and an additional illumination source 712. With reference to FIGS. 3A and 3B , for example, container 702 may be similar to container 302, one or both of imagers 704A and 704B may be similar to imager 304, and laser source 706 may be similar to laser source 306. However, illumination source 712 may not generate a laser sheet, or indeed may not generate a laser at all. For example, illumination source 712 may include one or more light-emitting diodes (LEDs) and / or another suitable light source that illuminates substantially the entire volume of container 702 at once. Laser sheet 710 (e.g., similar to laser sheet 310) is incident on container 702 in direction 722, with an imaging axis 724A of imager 704A substantially perpendicular to direction 722 and an imaging axis 724B of imager 704B being neither parallel nor perpendicular to direction 722. While illumination source 712 is shown in FIG. 7 in a backlight configuration (relative to imager 704B), it should be understood that in some embodiments, illumination source 712 may be offset from imaging axis 724B. For example, illumination source 712 may comprise one or more light sources positioned above and / or below imaging axis 724B and angled downward and / or upward to illuminate container 702 without providing direct backlighting.

[0037] Laser source 706 and illumination source 712 generate light of different wavelengths / colors. For example, laser sheet 710 may be red, and the light generated by illumination source 712 may be blue. Additionally, the optical filters of imagers 704A and 704B may be configured to pass the color of the corresponding illumination source (e.g., imager 704A may be configured to image red light but not blue light, and imager 704B may be configured to image blue light but not red light). By utilizing different colors, imaging system 700 enables simultaneous imaging by imagers 704A and 704B, which may have one or more advantages. For example, the image generated by imager 704B may be used to identify particles anywhere in or on container 702 for movement tracking purposes, while the image generated by imager 704A may be used to determine which of those particles are outside of container 702.

[0038] In an alternative embodiment, imaging system 700 includes imager 704A but omits imager 704B. Similar to the configuration described above in connection with FIG. 6 , for example, imager 704A may implement a Bayer filter (or optics / filters that map different colors to different regions of the camera sensor), and imaging system 700 may include appropriate additional optical components (e.g., mirrors and / or prisms) to provide imager 704A with optical path components along both directions 724A and 724B. In this manner, imager 704A can capture images that preserve visual information provided by illumination from laser source 706 and illumination from light source 712, respectively.

[0039] Figure 8 is a schematic block diagram of an exemplary automated inspection system 800 that may be used with any one of the imaging systems described above in connection with Figures 3, 5, 6, or 7. The automated inspection system 800 includes a computer system 802 that receives images from an imager 804 (e.g., similar to imager 304). The imager 804 generates one or more images of a container holding a sample while the container and the sample are illuminated by a laser sheet, as described in any of the various embodiments above.

[0040] Computer system 802 may be a general-purpose computer specifically programmed to perform the operations described herein, or it may be a special-purpose computing device (e.g., part of an imaging unit that includes imager 804). As can be seen in Figure 8, computer system 802 includes a processing unit 810 and a memory unit 812. However, in some embodiments, computer system 802 includes two or more computers that are co-located or remote from each other. In these distributed embodiments, the operations described herein related to processing unit 810 and / or memory unit 812 may be divided among multiple processing units and / or memory units, respectively.

[0041] The processing unit 810 comprises processing means for analyzing images of the container to detect particles within the container and / or on the exterior surface of the container. The processing unit 810 comprises one or more processors, each of which may be a programmable microprocessor that executes software instructions stored in the memory unit 812 to perform some or all of the functions of the computer system 802 described herein. The processing unit 810 may include, for example, one or more graphics processing units (GPUs) and / or one or more central processing units (CPUs). Alternatively or additionally, some of the processors in the processing unit 810 may be other types of processors (e.g., ASICs, FPGAs, etc.), and some of the functions of the computer system 802 described herein may instead be implemented in hardware. The memory unit 812 may comprise one or more volatile and / or non-volatile memories. It may include one or more suitable memory types, such as read-only memory (ROM), random-access memory (RAM), flash memory, solid-state drive (SSD), hard disk drive (HDD), etc. Collectively, memory unit 812 may store instructions for one or more software applications, data received / used by those applications, and data output / generated by those applications.

[0042] One such software application stored in memory unit 812 is particle detection application 814 that, when executed by processing unit 810, processes images generated by imager 804 (and possibly images generated by one or more other imagers, such as imager 604B of FIG. 6 or imager 704B of FIG. 7) to detect particles within a sample (e.g., measure the number of particles within the sample) and / or determine characteristics of those particles (e.g., particle size, type, etc.). Particle detection application 814 may also perform other operations, such as evaluating a particular sample based on particle number, size, type, and / or other factors to determine whether the sample is acceptable or should be discarded.

[0043] In a relatively simple embodiment, the particle detection application 814 may analyze all “slice” images for a particular container / sample (e.g., 90 images corresponding to a 90-degree rotation of the container with a fixed laser sheet orientation) and classify those that appear between the container walls as particles inside the container and those that appear outside the container walls as particles outside the container. However, as described above, more complex algorithms can also be used. For example, the particle detection application 814 may classify those that appear between the container walls in any image as “candidate particles” and then use a classifier (e.g., a trained neural network) to determine whether each candidate is actually a particle or, instead, an air bubble (and / or, if not, classify the type of particle, e.g.,). As another example, the particle detection application 814 may also analyze images from one or more additional imagers (e.g., imager 604B of FIG. 6 or imager 704B of FIG. 7) to more accurately detect, classify, and / or locate particles within the container. For example, images from two imagers can be used to better determine the three-dimensional position of a particle within a container at a single time corresponding to a single rotation / position of the container (this may be necessary if the sample is not very viscous and the particle / bubble moves somewhat as the container rotates from one position to the next). The particle detection application 814 may additionally or alternatively utilize any other suitable techniques to detect, classify, and / or locate particles within the container and sample.

[0044] 9 is a flow diagram of an exemplary method 900 for imaging a container holding a specimen. Method 900 may be performed by one or more portions of imaging systems 300, 500, 600, or 700 and / or by one or more portions of automated inspection system 800. For example, block 902 may be performed by one of laser sources 306, 506A, 606A, and 706, block 904 may be performed by one of imagers 304, 504, 604A, and 704A, and block 906 may be performed by computer system 802 (e.g., by processing unit 810 when executing instructions of particle detection application 814 stored in memory unit 812).

[0045] In block 902, the container is illuminated by a laser sheet incident on the container in a first direction corresponding to a first axis (e.g., direction 322 corresponding / aligned with first axis 330 in FIG. 3A). The plane of the laser sheet is defined by the first axis and an orthogonal second axis (e.g., second axis 332 in FIG. 3A). The laser sheet may, for example, pass through the central axis of the container (e.g., central axis 320 in FIG. 3A). The laser sheet is associated with a particular thickness along a third axis (e.g., third axis 334 in FIG. 3A) orthogonal to the first and second axes. Where the laser sheet enters the container, the thickness of the laser sheet is greater than zero, but may be less than 1 mm, less than 2 mm, less than 3 mm, less than 4 mm, less than 5 mm, etc. As a range, in various embodiments, the thickness is in a range of 1-3 mm, 1-5 mm, 0.5-10 mm, etc. In some embodiments, the thickness is 1 / 360 to 1 / 30 of the outer perimeter (e.g., circumference) of the container. The laser sheet may, for example, include white light or may be constrained to a narrower portion of the visible spectrum (e.g., a red laser sheet).

[0046] In block 904, an image of the container is captured by an imager (e.g., imager 304, 504, 604A, or 704A) while illuminated by the laser sheet. The imager has an imaging axis (e.g., imaging axis 324 of FIG. 3A) that is substantially orthogonal to at least a first axis (and possibly a second axis).

[0047] In block 906, the image captured in block 904 is analyzed to detect particles within the container and / or on the exterior surface of the container. In some embodiments, particles on the outside are "detected" only for purposes of subtracting them (e.g., for quality control procedures where particles on the outside of the container are not of interest). Block 904 may also include classifying particles inside the container (by type, size, etc.), counting particles inside the container, and / or one or more other operations.

[0048] 9. For example, method 900 may include a first additional block in which the container is moved through multiple rotations about the central axis of the container while the laser sheet illuminates the container. Method 900 may also include a second additional block in which an imager captures multiple images of the container (each image corresponding to a respective one of the multiple rotations), and a third additional block in which each of the multiple images is analyzed to detect particles within the container and / or on the exterior surface of the container.

[0049] In some embodiments, the laser sheet is a first color (e.g., red), and the imager is configured to filter out colors other than the first color. In one such embodiment, method 900 includes a first additional block in which the container is illuminated by a second laser sheet of a different color (e.g., blue) simultaneously with illuminating the container with the laser sheet. The second laser sheet may be incident on the container in a second direction that is not parallel to the first axis (i.e., not parallel to the direction of the other laser sheet), and the plane of the second laser sheet may be defined by the second direction and a third direction that is substantially parallel to the second axis. Method 900 may also include a second additional block in which additional images of the container are captured by an additional imager, the additional imager being configured to filter out colors other than the color of the second laser sheet and having an imaging axis that is substantially orthogonal to at least the second (or possibly third) direction. The additional image may be captured, for example, simultaneously with the image captured in block 904. Block 906 then may include analyzing both images of the container to detect particles.

[0050] In yet another embodiment, as in the example above, the laser sheet is a first color (e.g., red) and the imager is configured to filter out colors other than the first color. However, in this embodiment, method 900 includes a first additional block that, simultaneously with illuminating the container with the laser sheet, illuminates the container with light of a different color (e.g., blue) that illuminates all or at least a majority of the volume / contents of the container. Method 900 may also include a second additional block in which an additional image of the container is captured by an additional imager, the additional imager configured to filter out colors other than the color of the additional (e.g., non-laser) light source. The additional image may, for example, be captured simultaneously with the image captured in block 904. Block 906 then may include analyzing both images of the container to detect particles.

[0051] Although the systems, methods, devices, and components thereof have been described in terms of exemplary embodiments, the systems, methods, devices, and components thereof are not limited thereto. The detailed description is to be construed as an example only and does not describe every possible embodiment of the invention, as describing every possible embodiment would be impractical, if not impossible. Many alternative embodiments can be implemented using either current technology or technology developed after the filing date of this patent, and such embodiments will still fall within the scope of the claims that define the invention.

[0052] Those skilled in the art will understand that numerous modifications, changes, and combinations can be made to the above-described embodiments without departing from the scope of the present invention, and that such modifications, changes, and combinations are to be construed as being within the scope of the inventive concept.

Claims

1. 1. A method for imaging a container holding a specimen, the method comprising: illuminating the container with a laser sheet of a first color; capturing one or more images of the container with a first imager configured to filter out colors other than the first color; illuminating the container with light of a second color different from the first color simultaneously with illuminating the container with the laser sheet of the first color, wherein the light of the second color illuminates at least a majority of the entire volume of the container; capturing one or more additional images of the container with a second imager configured to filter out colors other than the second color; analyzing, by one or more processors, the one or more images and the additional one or more images to detect particles within the container and / or on the exterior surface of the container; Including, illuminating the container with the laser sheet includes illuminating the container with a laser sheet that passes through a central axis of the container; the laser sheet is incident on the container in a first direction corresponding to a first axis, the plane of the laser sheet being defined by the first axis and a second axis orthogonal to the first axis; The method, wherein the first imager has an imaging axis that is substantially orthogonal to the first axis and the second axis.

2. 10. The method of claim 1, wherein the laser sheet has a thickness of less than 3 millimeters where the laser sheet enters the container along a third axis orthogonal to the first and second axes.

3. 2. The method of claim 1, wherein the thickness of the laser sheet covers 1 / 360 to 1 / 30 of the circumference of the container.

4. The method of claim 1 , wherein the first direction is substantially perpendicular to a central axis of the container.

5. Analyzing the one or more images and the additional one or more images includes: determining that a candidate particle is present; using a classifier to determine whether the candidate particle is a particular type of particle; The method of claim 1 , comprising:

6. The method of claim 5 , wherein the classifier is a trained machine learning model.

7. Analyzing the one or more images and the additional one or more images includes: determining that a candidate particle is present; using a classifier to determine whether the candidate particle is a bubble; The method of claim 1 , comprising:

8. 1. An imaging system, comprising: a first illumination source configured to illuminate the container with a laser sheet of a first color; a first imager configured to (i) filter out colors other than the first color, and (ii) capture one or more images of the container; a second illumination source configured to illuminate the container with light of a second color different from the first color, the second illumination source illuminating at least a majority of the entire volume of the container; a second imager configured to (i) filter out colors other than the second color, and (ii) capture one or more additional images of the container; one or more processors configured to analyze the one or more images and the additional one or more images to detect particles within the container and / or on an exterior surface of the container; Equipped with The laser sheet passes through the central axis of the container, the laser sheet is incident on the container in a first direction corresponding to a first axis, the plane of the laser sheet being defined by the first axis and a second axis orthogonal to the first axis; The imaging system, wherein the first imager has an imaging axis that is substantially orthogonal to the first axis and the second axis.

9. 9. The imaging system of claim 8, wherein the laser sheet has a thickness of less than 3 millimeters where the laser sheet enters the container along a third axis that is orthogonal to the first and second axes.

10. The imaging system of claim 8 , wherein the thickness of the laser sheet covers 1 / 360 to 1 / 30 of the circumference of the container.

11. The imaging system of claim 8 , wherein the first direction is substantially perpendicular to a central axis of the container.

12. The one or more processors include at least: determining that a candidate particle is present; using a classifier to determine whether the candidate particle is a particular type of particle; 9. The imaging system of claim 8, configured to analyze the one or more images and the additional one or more images by:

13. The imaging system of claim 12 , wherein the classifier is a trained machine learning model.

14. The one or more processors include at least: determining that a candidate particle is present; using a classifier to determine whether the candidate particle is a bubble; 9. The imaging system of claim 8, configured to analyze the one or more images and the additional one or more images by:

Images