System and method for inspecting sealed medical containers

Abstract

The inspection system (1.3) is operative to inspect a medical container containing a liquid. The inspection system (1.3) includes an actuator (1.6) operative to displace a light source and / or a detector of the optical system (1.5) relative to the sample holder (1.4) during data acquisition. The acquired data is analyzed to detect and / or determine the characteristics of particles in the medical container.

Description

[Technical Field]

[0001] The present invention relates to inspection systems and methods for medical containers, which are operable to detect and / or characterize particulate matter within sealed medical containers having liquids therein, and which are operable to detect, characterize, and / or identify chemical particulate matter within sealed medical containers using optical techniques, such as visual and / or spectroscopic techniques.

[0002] The inspection systems and methods can be used to detect and / or characterize visible particles. The inspection systems and methods can be used to determine in an automated manner whether a sealed medical container contains particulate matter that causes it to fail to meet industry quality standards. The inspection systems and methods can also be used to identify potential reasons for the presence of particulate matter and make it suitable for use in process control.

[0003] The present invention may be used in connection with a wide variety of medical containers, such as vials or syringes, etc. One and the same inspection system may be operable to inspect medical containers of different types, shapes, sizes, and / or materials (e.g., glass, polymer, etc.). [Background technology]

[0004] A wide variety of medical preparations are supplied in medical containers such as vials, syringes, etc. Parenteral drugs are an example.

[0005] Due to the potential impact of particulate matter on patients, regulatory agencies require information on the presence of particles, as well as evidence of the limitation, control, and identification of any product-related impurities. Pharmaceutical products for parenteral administration must be free of visible particles (e.g., as specified in the United States Pharmacopoeia <1> (see chapter).

[0006] To meet this expectation, technologies for the control and monitoring of visible particulate matter are used. Inspection can be performed as a manual visual inspection (by the naked eye under controlled conditions), a semi-automated visual inspection (which may use an additional system that provides the inspector with handling of the container), or an automated visual inspection. The latter uses automated machinery to detect the presence of any visible particles, which may apply, for example, diode array sensors or CCD cameras.

[0007] In various cases, it is desirable or necessary not only to detect the presence of particles but also to further characterize them. One example is the formulation development phase, where particle characterization and identification are systematically performed. Studies of the mechanistic formation and kinetics of intrinsic particles are conducted through stability studies to determine the product's intrinsic profile over shelf life. This profile, giving expected properties and possible changes over time, should be documented in product submission documents. As a further example, in recent years, the pharmaceutical industry has faced new challenges regarding the increasing presence of intrinsic (proteinaceous aggregates or free fatty acids) particles upon release or during storage of final drug products. To reflect this situation, the European Pharmacopoeia Monograph 2031, "Monoclonal Antibodies for Human Use," has been revised to include the condition "no visible particles unless specifically justified and permitted" in its testing and appearance requirements. This means that containers containing intrinsic visible particles similar to those observed and documented during the development phase are still considered "essentially free of visible particles."

[0008] WO 2020 / 131666 discloses a system for detecting particles in a container, where the container is configured to rotate during the process using optical components for particle detection.

[0009] Figure 15 is a schematic diagram of a conventional system for detecting particles in a rotating container. A container 15.1 filled with a liquid pharmaceutical is positioned and held by a motorized sample holder 15.2, which rotates about an axis of rotation 15.3. A light ring 15.4 is positioned below and centered on the sample holder, so that light emitted from the sample holder simultaneously illuminates the entire container. A video camera 15.5, typically oriented perpendicular to the container, is used to capture video of moving particles within the container as it rotates.

[0010] Various challenges are associated with conventional setups in which the container rotates during image acquisition. As shown in Figure 15, conventional automated visual inspection systems are equipped with a rotation unit that moves particles so that they can be detected by processing a series of video frames. However, container rotation can cause bubble formation, which is a well-known source of false-positive detections. Furthermore, some biological products are sensitive to agitation and require careful handling of the container, while others tend to generate bubbles on the surface, complicating sample visualization. Furthermore, the rapid movement of particles in a fluid is an obstacle to accurate localization of particles (e.g., three-dimensional (3D) localization), which can be useful for further analysis.

[0011] This can pose additional challenges if further characterization of the detected particles is to be performed. U.S. Patent Application Publication No. 2020 / 0241002 discloses a system that uses Raman technology to analyze particles. To perform the analysis, the container must be opened and the particles isolated using a filter.

[0012] Figure 16 provides an overview of several steps in the chemical identification process of visible particles. The process begins with step 16.1, which involves imaging particles present in a sealed container, followed by step 16.2, which involves filtering the sample on a gold-coated filter to collect the particles. The next step is to move the gold filter onto the motorized sample stage of a Fourier transform infrared spectroscopy (FTIR) or Raman microspectrometer to perform chemical identification of the particles (steps 16.3 and 16.4). These instruments combine the visualization capabilities of a standard microscope with the analytical capabilities of a spectrometer for compositional analysis. The filter view allows for the detection and localization of all isolated particles, either manually or even automated, using image processing algorithms. The position of the sample stage is controlled by several motorized mechanical axes, which introduce the particles one after the other into the focus of the microscope setup. Precise positioning of the particles enables step 16.3, in which the acquisition of FTIR or Raman spectra of each individual particle (the spectral fingerprinting process) is performed. Chemical identification is then possible in step 16.4 by processing the FTIR or Raman spectrum of the test sample with FTIR or Raman spectra in a database of known compounds using a matching algorithm.

[0013] In the process described with reference to Figure 16, all necessary equipment must be prepared and cleaned to ensure no additional contaminants are found on the gold filter (step 16.21). This equally applies to the post-filtration process, where care must be taken to clean and store the equipment (step 16.22). These two steps, 16.21 and 16.22, run parallel to the chemical identification process. They do not add value to data collection and are time-consuming, but they are necessary to ensure sample integrity and reliability of the data. The traditional chemical identification process described with reference to Figure 16 is destructive and requires a lot of time and resources due to the filtration step (step 16.2).

[0014] Therefore, there is a need for systems and methods that allow for the detection, characterization, and / or chemical analysis of particles within sealed medical containers using processes that mitigate at least some of the shortcomings of the prior art discussed above.By way of illustration, there is a need for systems and methods that allow for the detection, characterization, and / or chemical identification of particles within sealed medical containers using optical techniques, such as visualization and / or spectroscopic techniques, in an efficient and reliable manner. Summary of the Invention

[0015] According to the present invention, this need is solved by a system as defined by the features of independent claims 1 and 10 and by a method as defined by the features of independent claims 12 and 13. Preferred embodiments are the subject of the dependent claims.

[0016] In one aspect, the present invention is an inspection system operative and configured to inspect a medical container containing a liquid, the inspection system comprising: a sample holder operative and configured to hold the medical container along an axis; at least one optical system including at least one light source operative and configured to output light incident on the medical container and at least one detector operative and configured to detect return light from the medical container; an evaluation system coupled to the at least one optical detector and operative and configured to detect and / or determine characteristics of particles in the medical container based on at least an output of the at least one detector; and at least one actuator operative and configured to move the at least one light source and / or the at least one detector about the axis while the sample holder holds the medical container in a fixed, rotatable and translatable manner.

[0017] The inspection system according to the present invention is operated or configured to efficiently and reliably detect particulate matter. The risk of false positives is not increased by rotating the container, which leads to increased bubble formation. By moving the light source and / or detector of the optical system around an axis, all of the container can be analyzed. The ability to localize particles, for example, the ability to perform three-dimensional (3D) particle localization, is increased.

[0018] The at least one actuator can be operated or configured to move the at least one light source and the at least one detector along a curved path about the axis, facilitating application of optical techniques throughout the volume of the container using a simple mechanical configuration, such as a configuration having a rotating element for displacing the at least one light source and the at least one detector.

[0019] One, some, or all of the following may apply: at least a segment of the path extends in a plane perpendicular to the axis; the path may include an arc of an ellipse; the path may include an arc of a circle; the at least one actuator may be operated and configured to simultaneously change the position and orientation of the at least one light source so that the illumination light continues to be incident on the medical container and / or the axis; the at least one actuator may be operated and configured to simultaneously change the position and orientation of the at least one detector to cause the return light to be incident on the at least one detector. These techniques facilitate applying optical techniques to the entire volume of the container using a simple mechanical configuration, such as a configuration having a rotating element for displacing the at least one light source and the at least one detector.

[0020] The inspection system may include a frame on which at least one optical system is supported, the sample holder being disposed in a fixed position relative to the frame. The at least one actuator may be operable or configured to move the at least one light source and / or the at least one detector relative to the frame. By keeping the sample holder stationary during optical analysis by the at least one optical system, the risk of air bubble formation and / or damage to sensitive container contents is reduced. By moving the light source and / or detector relative to the frame, the optical system can be positioned relative to the stationary container during optical analysis.

[0021] The at least one light source comprises a first light source operative or configured to output a light sheet, which allows for efficient analysis of the volume of the container along a plane that intersects the volume of the container.

[0022] The at least one actuator may comprise a first actuator operable or configured to move the first light source and / or the first detector about an axis. The first actuator may be a rotational actuator. This allows a volume of the container to be analyzed in an efficient manner using a simple structure, such as by rotating the first light source and / or the first detector about an axis while the first light source outputs a light sheet that is incident on the medical container and an image is captured by the first detector.

[0023] The first detector may have a first detector axis positioned at a first angle relative to a central axis of the light sheet output by the first light source. The first angle may be greater than 0° and less than 180°. The first detector may be positioned in an oblique configuration relative to the light sheet to observe the light sheet as it passes through the medical container.

[0024] The first actuator may be operable or configured to move the first light source about the axis such that the light sheet remains incident on the axis as the first light source moves about the axis. This configuration facilitates analysis in terms of possible optical effects that may be introduced by the cylindrical wall of the medical container.

[0025] The at least one detector may include a first detector including an optoelectric transducer having a plurality of pixels. The first detector may be configured or operated to provide a first detector output in response to returned light while illuminating the medical container with the light sheet. This configuration enables visible particles to be detected using images captured by the first detector for several angular positions about the axes of the first light source and the first detector when the visible particles are located within the light sheet.

[0026] The first detector may include a tilted objective lens. The first detector may include a Scheimpflug camera. This configuration facilitates analysis that can account for possible optical effects that may be introduced by the cylindrical wall of the medical container.

[0027] The evaluation system may be operable or configured to detect particles when the particles are located within the light sheet based on at least the first detector output. Accordingly, the inspection system may be operable or configured to obtain at least a binary output indicative of whether a particle is present in the container. Such a determination is useful, among other things, for inspection in an ongoing mass manufacturing process.

[0028] Alternatively or additionally, the characterization system may be operative to determine that a particle is located inside the medical container based on at least the first detector output. Accordingly, the inspection system may be operative or configured to distinguish particles inside the container from particles outside the container and / or within the container wall. Such distinction may be useful, among other things, for inspection in ongoing mass manufacturing processes.

[0029] Alternatively or additionally, the evaluation system may be operative to distinguish particles from air bubbles in the liquid within the medical container based on at least the first detector output. Thus, the inspection system may be operative or configured to distinguish particles from air bubbles. Such discrimination is useful, among other things, to prevent false positives in the detection of particles.

[0030] Alternatively or additionally, the characterization system may be operative to distinguish particles from impurities within a container wall of the medical container based on at least the first detector output. Thus, the inspection system may be operative or configured to distinguish particles within the container from particles within the container wall. Such distinction is useful, among other things, to prevent false positives in particle detection.

[0031] Alternatively or additionally, the evaluation system may be operable to determine information about the particle's morphology, optionally information about the particle's three-dimensional surface shape, based at least on the first detector output for several different angular positions of the first light source and / or first detector about the axis. Thus, the inspection system may be operable or configured to determine geometric characteristics of the particle. Such determinations may be useful, among other things, for determining possible root causes of impurities.

[0032] Alternatively or additionally, the characterization system may be operable to determine information regarding the size of the particle, optionally the size of the particle in three dimensions, based on at least the first detector output. Thus, the inspection system may be operable or configured to determine geometric properties of the particle. Such determinations are useful, among other things, for determining possible root causes of impurities.

[0033] The at least one light source may include a second light source activated or configured to output a Raman probe beam. The at least one detector may include a second detector coupled to a Raman spectrometer. Thus, the inspection system may be configured to determine spectral characteristics indicative of the particle's chemical characteristics. The Raman spectrum is captured on the medical container, allowing the chemical characteristics to be determined in an efficient manner and in a manner that does not prevent the medical container from being used if the chemical characteristics indicate that the particle is an acceptable particle.

[0034] The at least one actuator may comprise a second actuator operable or configured to move both the second light source and the second detector, thereby facilitating positioning the light source and detector of the Raman spectroscopy system relative to the container and facilitating specific targeting of particles previously localized to the container.

[0035] The second actuator may have more degrees of freedom than the first actuator. The first actuator may have one degree of freedom (e.g., one rotational degree of freedom). The second actuator may have at least two degrees of freedom. The second actuator may include a multi-axis robotic arm or a multi-axis linear displacement actuator. Such a configuration allows Raman spectroscopy to target particles previously localized within the container.

[0036] The inspection system may include a control device operative or configured to control a second actuator based on at least the first detector output. Such a configuration allows the first light source and the first detector to be used for 3D localization of the particle, which can then be further investigated using Raman spectroscopy without the need to open the medical container.

[0037] The evaluation system may be operable or configured to determine a chemical characteristic of the particle based on at least the second detector output provided by the second detector or the Raman spectrum provided by the Raman spectrometer. Thus, the inspection system may be configured to determine a spectral characteristic indicative of the particle's chemical characteristic. The Raman spectrum may be captured on the medical container, allowing the chemical characteristic to be determined in an efficient manner and in a manner that does not prevent the medical container from being used if the chemical characteristic indicates that the particle is an acceptable particle.

[0038] The inspection system may be adjustable to detect and / or determine characteristics of particles in containers of different types (such as vials and syringes) and / or sizes (e.g., different container volumes, container lengths measured along an axis, and / or container diameters measured perpendicular to an axis). The inspection system may include at least one adjustment mechanism for accommodating different types and / or sizes of containers. The at least one adjustment mechanism may include one, some, or all of the following: a mechanism for adjusting the diameter of a receptacle of a sample holder; a sample holder displacement mechanism for adjusting the position at which a container is held in the sample holder along an axis; and an optical system displacement mechanism for adjusting the position of the optical system along the axis and / or perpendicular to the axis (e.g., to accommodate different refractions resulting from different container diameters). The inspection system is thereby suitable for operation in conjunction with different container types and / or sizes without requiring recalibration for all different container types and / or sizes.

[0039] The inspection system may be operable to inspect medical containers including or selected from the group consisting of vials and syringes. The medical container may have a translucent, particularly transparent, peripheral wall. The peripheral wall may extend cylindrically around an axis for at least a portion, and typically most, of the length of the container.

[0040] A system is also disclosed that includes an inspection system and a medical container.

[0041] The evaluation system may be operative or configured to provide an output based on at least the output of the at least one detector. The inspection system may include an interface (e.g., a human-machine interface (HMI), e.g., a graphical user interface (GUI)) for outputting information regarding the presence, geometric characteristics, and / or chemical characteristics of particles based on the output of the at least one detector. Alternatively or additionally, the inspection system may include an interface for outputting a control signal operative or configured to control at least one component of a manufacturing system for producing the medical container. Alternatively or additionally, the inspection system may include an interface for outputting a control signal operative or configured to selectively discard the medical container depending on whether the evaluation system identifies particles present inside the container and identifies particles having a size and / or chemical characteristics that render the medical container unacceptable.

[0042] The inspection system may be an automated inspection system that can make a determination regarding the acceptability of a medical container for visible particles without human intervention.

[0043] The testing system may include a loading-unloading mechanism that operates or is configured to provide the medical container to the sample holder for performing the analysis and to remove the medical container from the sample holder after at least one detector has detected all required signals.

[0044] The inspection system may include several optical systems operable to identify and / or characterize particles. The inspection system may operate such that several optical systems operate sequentially. To illustrate, a first optical system may operate as an imaging system capturing an image of a medical container. The first optical system may include a light source for a light sheet and a camera chip. The camera chip may detect the image in response to illumination of the medical container with a light sheet while a first actuator rotates the first optical system, i.e., both the light sheet source and the detector with the camera chip, about an axis. This may determine the 3D position of the particle within the container (i.e., within a cavity defined within the container that also contains a liquid). A Raman spectroscopy system may subsequently operate to specifically obtain a Raman spectrum of the previously localized particle. A second actuator (which may be operable or configured to adjust the Raman probe and / or detector along at least two directions) may optionally operate in combination with the first actuator in response to the 3D position of the particle.

[0045] In one aspect, the invention is an inspection system operative and configured to inspect a sealed medical container containing a liquid, the inspection system comprising: a sample holder operative and configured to hold the sealed medical container; a light source operative and configured to output a Raman probe beam incident on the sealed medical container; a detector operative and configured to detect a Raman spectrum in response to the output of the Raman probe beam; and an evaluation system coupled to the detector operative and configured to determine a characteristic of particles in the sealed medical container based on at least the Raman spectrum.

[0046] The inspection system of this aspect of the present invention allows for chemical analysis to be performed on any particles localized inside the container, including the liquid, while maintaining the medical container in a sealed state. The chemical characterization can be efficiently determined without compromising the integrity of the container. This is particularly useful when chemical characterization is used during mass production, where medical containers are selectively discarded only if the chemical analysis obtained from Raman spectroscopy indicates the presence of at least one unacceptable particle inside the container.

[0047] The inspection system may comprise an actuator device with at least two, for example three or more degrees of freedom, to position the Raman source and / or detector relative to the sample to perform measurements on local particles.

[0048] The actuator device may comprise a three-axis robotic arm. The actuator device may comprise a first actuator operable or configured to rotate a support on which the Raman source and detector are mounted. The actuator device may comprise a second actuator operable or configured to displace the Raman source and / or detector relative to the support along at least two axes, thereby positioning the Raman source and / or detector relative to the sample to perform measurements on localized particles.

[0049] The sample holder may position the container so that it is immobile while the Raman spectrum is being measured, facilitating measurement as particles can be more easily targeted in an immobile container free of rotational forces that may tend to shift particles before a Raman spectrum is obtained.

[0050] The inspection system may include an optical imaging system operative or configured to localize particles within the sealed medical container that also contains a liquid. The optical imaging system may include a tilting objective lens. The optical imaging system, the Raman light source, and / or the Raman detector may be integrated within an enclosure of the probe device.

[0051] Additional optional features of, and effects achieved by, the inspection system of this aspect of the invention correspond to any of the features described in relation to the inspection system of the first aspect of the invention above.

[0052] According to an embodiment of the present invention, there is provided a manufacturing system including a filling device operative and configured to fill at least one liquid into a medical container, a sealing device operative and configured to close the medical container containing the at least one liquid, and an inspection system of any aspect or embodiment disclosed herein operative and configured to inspect the sealed medical container for particulate matter.

[0053] The manufacturing system utilizes the effects and advantages provided by the inspection system according to an aspect or embodiment.

[0054] The manufacturing system can include a formulation preparation system operative or configured to prepare at least one liquid, which can include an active pharmaceutical ingredient (API).

[0055] The manufacturing system may include a process control system operative or configured to control at least one of the filling, sealing, and, if present, the formulation preparation system. The process control system may have an input interface coupled to the quality monitoring system and may be operative or configured to control the operation of at least one of the filling, sealing, and, if present, the formulation preparation system in response to an output of the quality monitoring system.

[0056] The manufacturing system may include a disposal station that operates or is configured to selectively discard the medical container if the inspection system determines that the medical container contains at least one particle therein and that the at least one particle is unacceptable based on particle characteristics (e.g., chemical characteristics) determined by the inspection system.

[0057] According to another aspect, the invention is a method for inspecting a medical container containing a liquid, the method including: positioning the medical container along an axis with a sample holder; illuminating the medical container with light with at least one light source; detecting return light from the medical container with at least one detector, the return light being detected in response to illuminating the medical container with light; detecting and / or determining a characteristic of the particle based on at least an output of the at least one detector with an evaluation system; and moving the at least one light source and / or the at least one detector about the axis while the sample holder holds the medical container in a fixed, rotatable and translational manner.

[0058] The inspection method according to this aspect of the invention is operable or configured to efficiently and reliably detect particulate matter. The risk of false positives is not increased by rotating the container, which leads to increased bubble formation. By moving the light source and / or detector of the optical system around an axis, all of the container can be analyzed. The ability to localize particles, for example, the ability to perform three-dimensional (3D) particle localization, is increased.

[0059] The inspection method may be performed by an inspection system or a manufacturing system according to any aspect or embodiment described herein.

[0060] Any feature of the inspection method and the effects achieved thereby correspond to any feature described in relation to the inspection system.

[0061] According to another aspect, the invention is a method for inspecting a sealed medical container containing a liquid, the method including positioning the sealed medical container with a sample holder, illuminating the sealed medical container with a Raman probe beam with a light source, detecting a Raman spectrum responsive to illuminating the sealed medical container with the Raman probe beam using a Raman spectrometer, and determining a characteristic of particles in the sealed medical container based on at least the Raman spectrum.

[0062] The inspection method according to this aspect of the present invention allows for chemical analysis to be performed on any particles localized inside the container, including the liquid, while maintaining the medical container in a sealed state. The chemical characterization can be efficiently determined without compromising the integrity of the container. This is particularly useful when using chemical characterization during mass production, where medical containers are selectively discarded only if the chemical analysis obtained from Raman spectroscopy indicates the presence of at least one unacceptable particle inside the container.

[0063] The inspection method according to this aspect may be performed by an inspection system or a manufacturing system according to any aspect or embodiment described herein.

[0064] Any feature of the inspection method according to this aspect and the effects achieved thereby correspond to any feature described in relation to the inspection system.

[0065] According to another embodiment, the invention is a method of manufacturing that includes filling a medical container with a liquid, sealing the medical container containing the liquid, and performing the inspection method of any aspect or embodiment disclosed herein to inspect the sealed medical container for particulate matter.

[0066] The manufacturing method may be performed by a manufacturing system according to any aspect or embodiment described herein.

[0067] Any feature of the manufacturing method and the effects achieved thereby correspond to any feature described in relation to the manufacturing system. [Brief explanation of the drawings]

[0068] Exemplary embodiments of the inspection system, manufacturing system, and associated methods according to the present invention are described in more detail below with reference to the accompanying drawings. [Figure 1] 1 illustrates a manufacturing system according to an embodiment. [Figure 2] 1 illustrates an inspection system according to an embodiment. [Figure 3] 1 illustrates an inspection system according to an embodiment. [Figure 4] 1 illustrates an inspection system according to an embodiment. [Figure 5] 1 illustrates an inspection system according to an embodiment. [Figure 6] 1 illustrates an inspection system according to an embodiment. [Figure 7] 7 shows a plan view of the inspection system of FIG. 6. [Figure 8] 1 shows an image of a sealed medical container obtained by an optical imaging system of an inspection system, according to an embodiment. [Figure 9] 10A-10C show images of a volume of a sealed medical container with particles present, obtained for different angular positions of a light sheet by an optical imaging system of an inspection system, according to an embodiment. [Figure 10] 1 shows an image of a sealed medical container and particle reconstruction obtained using an optical imaging system of an inspection system, according to an embodiment. [Figure 11] 1 illustrates components of a miniature Raman imaging probe of an inspection system, according to an embodiment. [Figure 12] 1 illustrates an inspection system according to an embodiment. [Figure 13] 1 shows a flowchart of a method according to an embodiment. [Figure 14] 1 illustrates an artificial intelligence (AI) model that may be executed by an inspection system, according to an embodiment. [Figure 15]1 shows a schematic diagram of a prior art inspection system; [Figure 16] 1 shows a schematic diagram of a prior art inspection method. DETAILED DESCRIPTION OF THE INVENTION

[0069] In the following description, certain terminology is used for convenience and is not intended to limit the invention. The terms "right," "left," "up," "down," "under," and "above" refer to directions in the figures. The terms include those explicitly mentioned, their derivatives, and terms of similar meaning. Spatially relative terms, such as "beneath," "below," "lower," "above," "upper," "proximal," and "distal," may also be used to describe the relationship of one element or feature shown in the figures to another. These spatially relative terms are intended to encompass various positions and orientations of the device during use or operation in addition to the positions and orientations shown in the figures. For example, if a device in the figures were inverted, elements described as "below" or "below" other elements or features would become "above" or "above" the other elements or features. Thus, the exemplary term "downward" can encompass both upward and downward positions and orientations. The device may be otherwise oriented (rotated 90 degrees or at other orientations), and the spatially relative descriptors used herein may be interpreted accordingly. Similarly, descriptions of movement along and about various axes include various particular device positions and orientations.

[0070] To avoid repetition in the figures and descriptions of various aspects and exemplary embodiments, it should be understood that many features are common to many aspects and embodiments. If an aspect is omitted from a description or figure, this does not mean that the aspect is missing from an embodiment incorporating that aspect. Rather, the aspect may be omitted for purposes of clarity and to avoid redundant description. In this context, the following applies to the remainder of this description: For clarity of the drawings, if a figure includes a reference sign that is not described in the directly relevant part of the specification, reference is made to the preceding or subsequent part of the specification. Furthermore, for clarity, if not all features of a part in a drawing are labeled with a reference sign, reference is made to another drawing showing the same part. Like numbers in two or more figures represent the same or similar elements.

[0071] Systems and methods according to embodiments operate or are configured to detect and, optionally, further characterize visible particulate matter in an interior cavity of a medical container that also contains a liquid, such as a formulation including an active pharmaceutical ingredient (API). The systems and methods provide an automated inspection technique. The systems and methods operate without requiring the medical container to be opened or rotated for particle detection, characterization, and / or chemical identification.

[0072] "Particulate matter" is a general expression that covers all forms of particles that may be found in parenteral pharmaceutical products. To facilitate interpretation for manufacturers, various regulatory authorities (European Pharmacopoeia, Japanese Pharmacopoeia, and United States Pharmacopoeia) have decided to align and share the same definition of particulate matter as "particulate matter in injections and parenteral infusions consisting of extraneous mobile, undissolved particles other than gas bubbles unintentionally present in solution."

[0073] As used herein, a "visible particle" may be understood to be or include a particle having a diameter of 100 microns or greater. A "visible particle" may also encompass smaller particle sizes. The diameter may be measured along the direction in which the particle has its longest extension.

[0074] Generally, particles are classified as endogenous, exogenous, or intrinsic. Intrinsic particles are generated within the manufacturing process and may include silicone oil, rubber, glass, or stainless steel. Extrinsic particles originate from outside the process and may include metals, human hair and skin, or dust. Intrinsic particles, such as protein aggregates or free fatty acids, are naturally present in biologics and can be tolerated with appropriate control strategies.

[0075] Due to the potential impact of particulate matter on patients, regulatory agencies require information regarding the presence of particles, as well as evidence of the limitation, control, and identification of any product-related impurities. The systems and methods of the present invention address the need for automated inspection of sealed medical containers for particulate matter.

[0076] Inspection systems and methods according to some embodiments are also operable or configured to provide further analysis or other characterization. In contrast to conventional techniques, this extended inspection is non-destructive and can be performed with the medical container sealed. Determination of particle size, morphology, and chemical identity is necessary to find the root cause of particle formation. These investigations have traditionally not been performed as routine testing in the manufacturing process, but only when unexpected events and limit violations occur.

[0077] However, during the formulation development phase, particle characterization and identification are systematically performed. Studies of the mechanistic formation and kinetics of specific particles are performed through stability studies to determine the product's specific profile over shelf life. This profile, which provides expected properties and possible changes over time, can be determined and documented using the testing systems and methods disclosed herein.

[0078] In recent years, the pharmaceutical industry has faced new challenges related to the increasing presence of intrinsic (proteinaceous aggregates or free fatty acids) particles during the release or storage of final drug products. To reflect this situation, the European Pharmacopoeia Monograph 2031, "Monoclonal Antibodies for Human Use," was revised to include the condition "no visible particles unless specifically justified and permitted" in its testing and appearance requirements. This means that containers containing intrinsic visible particles similar to those observed and documented during the development phase are still considered "essentially free of visible particles." The ability to assess intrinsic visible particles in sealed containers is becoming increasingly important to avoid contamination and preserve samples for further analysis. Some embodiment inspection systems and methods operate or are configured to efficiently address this need, as opposed to some conventional analytical techniques that rely on opening the container for further analysis (destructive testing), as described herein.

[0079] The inspection system and method of some embodiments also enable obtaining a more comprehensive characterization of visible particles within a sealed container, addressing the need evidenced by the lack of repeatability frequently encountered in manual processes by human inspectors, challenges associated with detecting air bubbles, and the lack of non-destructive automated techniques for extended visible particle characterization (counting and sizing) and chemical identification.

[0080] The inventive inspection system and method described herein provides a visual inspection setup that provides robust detection, accurate sizing, quantification, and 3D localization of visible particles in sealed containers based on light sheet microscopy. The inspection system and method may also integrate a Raman video probe into the visual inspection unit to achieve in situ chemical identification.

[0081] The inspection system and method of the present invention are suitable for use as an automated visual inspection technique for smaller batches and for inspecting units in the development phase. The reliability of visible particle detection can be improved by the technique of the present invention, and the root cause of particulate matter can be identified. The inspection system and method are not limited to these areas of use.

[0082] The inspection system and method of the present invention uses one or more actuators to displace components of an optical system during an optical measurement process relative to a medical container held stationary by a sample holder. Thus, the inspection system and method address challenges encountered in techniques using rotating containers that may be associated with particles and / or rotation processes, as well as other sources.

[0083] Particles that can be present in a liquid-filled container can originate from different sources and have different sizes, shapes, compositions, physical properties (such as density), and optical properties (such as refractive index or transparency). Some particles, usually made of metal or glass, tend to have very high densities, which makes it more difficult to move or keep them moving during data acquisition with conventional techniques. In some cases, particles can adhere to the interior walls of the container, making them invisible to conventional technology detection algorithms. Furthermore, fiber-like particles that are longer in one dimension can be difficult to detect with conventional techniques, depending on their orientation within the container and the camera / sensor. The same applies to transparent particles with refractive indices close to those of pharmaceutical solutions in conventional techniques. These challenges are addressed by the inspection system and method of the present invention, which is designed to move components of the optical system around the medical container during data acquisition.

[0084] Conventional automated visual inspection systems (such as those described with reference to FIG. 15 ) include a rotation unit to move particles so they can be detected by conventional detection algorithms. However, this process is one of the main causes of bubble formation, which is a well-known source of false-positive detections. Furthermore, some biological products are sensitive to agitation and may require careful handling of the container, while others tend to generate bubbles on the surface, complicating sample visualization. Furthermore, the rapid movement of particles in a fluid hinders accurate 3D localization of the particles, which may be useful for further analysis. These challenges are addressed by the inspection system and method of the present invention, which are designed to move components of the optical system around the medical container during data acquisition while keeping the medical container stationary during data acquisition.

[0085] The inspection system and method of the present invention can provide a binary output indicating the presence or absence of visible particles within the container. The inspection system and method of the present invention also addresses the need for better and more complete characterization of particles within sealed containers.

[0086] The inspection system and method of the present invention uses light sheet microscopy to detect non-moving particles in sealed containers and to perform their quantification, 3D size measurement, and 3D location required for further analysis. Data acquisition of spectroscopic techniques (particularly Raman spectroscopy) can be performed for even more complete characterization.

[0087] The inspection system and method of the present invention operates to perform robust detection and precise localization of visible particles (which may be larger or smaller than 100 microns, for example) made of different materials within a stationary medical container filled with a liquid pharmaceutical. Rotation of the sample stage can be suppressed, allowing for extended analysis within the sealed container, offering new detection opportunities compared to conventional detection systems based on the detection of moving particles.

[0088] FIG. 1 illustrates a manufacturing system 1 for manufacturing medical containers containing a liquid therein. The medical containers may be, but are not limited to, vials or syringes. Each medical container may have a substantially cylindrical, transparent wall extending circumferentially around the longitudinal axis of the intermediate container. Each medical container may be a parenteral pharmaceutical product.

[0089] The manufacturing system 1 includes a filling device 1.1. During operation, the filling device 1.1 fills a liquid into a cavity of a medical container. The liquid may be a formulation containing one or several active ingredients. The liquid may be a parenteral drug or may contain a parenteral drug. The manufacturing system may include a medical formulation preparation system 1.9 that can prepare the liquid for filling the medical container during operation.

[0090] The manufacturing system 1 includes a sealing device 1.2. In operation, the sealing device 1.2 closes a medical container containing a liquid. The sealing device 1.2 may be operated or configured to close the medical container in a manner that prevents the liquid from spilling out until the medical container is opened.

[0091] The manufacturing system 1 includes an inspection system 1.3 according to an embodiment. The inspection system 1.3 includes a frame that may define an enclosure. The inspection system 1.3 includes a sample holder 1.4. According to the present invention, the sample holder 1.4 is operative or configured to position and hold a medical container being inspected for particulate matter in an immobile, particularly non-rotating, state while the medical container is inspected using optical techniques. The inspection system 1.3 includes one or more optical systems. The optical system may include an imaging system (also referred to herein as a first optical system) that, during operation, illuminates a light sheet on the medical container and detects the resulting image of the medical container using an image sensor (such as a CCD sensor or other image sensor). The imaging system rotates around the medical container through an angle that may, but need not, reach or exceed a full rotation (360°). The light source and detector of the imaging system may be rotated to maintain their relative alignment while being rotated. Image information recorded for several angular positions is evaluated to detect particles, distinguish particles from bubbles, infer particle size information, infer particle morphology information, and / or infer particle position in three dimensions (3D). The optical system may include components of a Raman system, such as a Raman probe beam source and a Raman detector that detects light obtained by Raman scattering of the probe beam from particles in the medical container. The Raman spectrometer need not be movably mounted, but the Raman probe beam source and Raman detector are movably mounted relative to the sample holder. One or more actuators 1.6 of the inspection system 1.3 displace the optical system relative to the sample holder 1.4. Evaluation circuitry 1.7 may evaluate the detector output, including advanced processing such as comparison with a library of Raman spectra for chemical analysis. Evaluation circuitry 1.8 may comprise or be implemented as a processor, controller, application-specific integrated circuit (ASIC), field-programmable gate array (FPGA), other integrated circuit, circuitry comprising quantum bits (qubits) and / or quantum gates, or a combination thereof.

[0092] Manufacturing system 1 includes process control system 1.8. Process control system 1.8 may control at least one component of manufacturing system 1 in response to the results determined by inspection system 1. By way of example, manufacturing system 1 may control one or more of filling device 1.1, sealing device 1.2, and, if present, medical preparation system 1.9, depending on whether inspection system 1.3 (i) determines visible particles present in the medical container and (ii) determines, if present, that the particles do not have properties that make the medical container acceptable for use. Process control system 1.8 may control an ejection device that removes the medical container from sample holder 1.4 so that the medical container is discarded if inspection system 1.3 (i) determines that visible particles are present in the medical container and (ii) determines, if present, that the particles do not have properties that make the medical container acceptable for use.

[0093] Alternatively or additionally, the inspection system 1.3 may include or be coupled to a human machine interface (HMI), such as a graphical user interface (GUI), to output information regarding the results of the inspection performed on the medical container.

[0094] 2 shows a schematic diagram of an inspection system 2 according to an embodiment. The inspection system comprises a sample holder 2.1 operative or configured to hold a medical container immobile while optical measurements are performed thereon, in particular while actuators 2.6, 2.7 rotate optical systems 2.5, 2.8 about an axis 2.2 along which the medical container extends. The medical container preferably has a transparent, substantially cylindrical wall that circumferentially surrounds axis 2.2 when held by sample holder 2.1.

[0095] The sample holder 2.1 may be stationary relative to the frame 2.3 of the inspection system 2. The first actuator 2.6 may be operable or configured to displace at least the first optical system 2.5 (such as an imaging system) relative to the axis 2.2. The first actuator 2.6 may be operable or configured to rotate the support 2.4 on which the first optical system 2.5 is disposed. The first optical system 2.5 may comprise components (such as a first light source and a first detector) that are circumferentially offset from one another by an angle that may be fixed when the first optical system 2.5 rotates about the axis 2.2.

[0096] The second actuator 2.7 can displace at least the second light source and / or second detector of the second optical system 2.8 (and optionally additional components such as an interferometer beam path) relative to axis 2.2. The second actuator 2.7 can be operated or configured to provide translational displacement along axis 2.2 and transverse to axis 2.2. The second actuator 2.7, alone or in combination with the first actuator 2.6, can enable the second light source and / or second detector of the second optical system 2.8 to be positioned in 3D relative to the sample holder 2.1. In use, the second actuator 2.7 can be controlled to cause the second optical system 2.8 to sequentially probe any particles identified as located within the interior cavity of the vessel using the first optical system 2.5.

[0097] In one embodiment, the second actuator 2.7 may comprise a multi-axis robotic arm, such as a three-axis robotic arm. In another embodiment, the second actuator 2.7 may be operable in combination with the first actuator 2.6. The first actuator 2.6 may be operable, under the control of a control device (which may be implemented as a computer), to adjust a desired angular position about axis 2.2 of the second light source and / or second detector of the second optical system 2.8. The second actuator 2.7 may be operable, under the control of the control device, to provide linear displacement along one or two axes, thereby targeting particles to a desired location along axis 2.2 and / or a desired radial location (measured transversely to axis 2.2) within the medical container.

[0098] The inspection system and method are described in further detail below. The embodiment inspection system and method includes a novel lighting and camera / lens configuration that rotates around a stationary container filled with a liquid pharmaceutical. A visual inspection system is positioned to point on the container's axis of symmetry and is operated or configured to output a laser light sheet that is used to illuminate particles within the sealed container. Additionally, a video camera fitted with an oblique (Scheimpflug) objective lens is positioned at a predetermined distance and angle from the light sheet to ensure its field of view is adjusted to the illuminated portion of the sample. A motorized mechanical system is then used to hold the light sheet and video camera and enable their rotation around the static sample to ensure inspection of the entire volume.

[0099] Figure 3 illustrates an inspection system according to one embodiment. Container 3.1 (represented here by a vial; it is understood that the container can have different containers and can be a syringe or other type of container capable of holding a liquid pharmaceutical) is held stationary in the center of the setup by a sample holder. Laser 3.2, which generates a light sheet of sufficient height to illuminate the entire height of the sample, can be directed and focused onto the central axis of the container. Video camera 3.4, fitted with tilted objective lens 3.3, is positioned accordingly with respect to the container and light sheet to acquire images of the sample. The representation of tilted laser 3.21, camera 3.31, and lens 3.41, after rotation has been added, represents the scanning of the setup around stationary container 3.1. The motorized mechanical system enabling the rotation of laser 3.2, camera 3.3, and objective lens 3.4 is not shown in Figure 3 but is shown and described in more detail elsewhere herein.

[0100] Rotation of the optical imaging system in Figure 1 scans the entire volume of the container, allowing for easy detection of visible particles inside, if present. If a particle is located within the width of the light sheet, it emits a clearly distinguishable reflection on the image acquired by the camera. Particles larger than the width of the light sheet can be seen on more than one frame. The image acquisition increment (in degrees) is defined by the diameter of the container and the width of the light sheet to acquire frames of the entire volume and even reconstruct it in three dimensions. The interior and exterior walls of the container are also visible on the collected images, allowing the evaluation circuitry (not shown) to easily distinguish particles inside or outside the internal cavity of the medical container. For illustration, particles located within the internal cavity can be distinguished from particles within the wall thickness and particles outside the container wall.

[0101] The tilted objective lens 3.4 makes it possible to overcome challenges related to the sample configuration. The cylindrical shape of the container filled with the liquid pharmaceutical results in a lens effect, causing blind spots that prevent a complete examination of the sample. Furthermore, this imaging setup provides a very sensitive imaging system. The positioning between the camera and the direction of the illumination generated by the laser light sheet is set to reduce / eliminate unwanted reflections. An aperture laser with a light trap can also be used to prevent the light emitted by the light sheet from being reflected by the setup components.

[0102] Analyzing particles suspended in a liquid solution using this newly proposed inspection system and method can be difficult if the particles are moving too quickly within the container. To avoid this, the medical container 3.1 is maintained for several seconds before and during analysis. In addition, the visual inspection components and machine / robotic axes are selected to allow for rapid scanning of the sample. One way to reduce analysis time is to add one or more light sheets and cameras, which increases the scanning area that can be simultaneously illuminated at any given time during data acquisition.

[0103] The complete setup can be adjusted depending on the needs of the analysis. For example, to provide robust detection in a short time, two wide light sheets and two cameras that scan the sample very quickly can be used, if desired. A single light sheet with a narrow width and one camera that scans the sample in finer increments can be used, allowing for robust detection, but also increasing the accuracy of the 3D localization of the detected particles and the resolution of the 3D reconstruction.

[0104] As explained above, inspection systems for particle inspection in liquid-filled containers face many challenges that stem from different sources. Maintaining a stationary sample and detecting non-moving visible particles offers significant advantages over conventional inspection systems.

[0105] One of the most pervasive challenges in conventional systems is the generation of air bubbles due to sample movement. These air bubbles are detected as visible particles by the inspection system and are one of the main causes of false positives. The inspection system and method according to the present invention are not subject to this challenge and provide more reliable and robust detection.

[0106] Non-moving particle detection provides a solution for particles that are too dense to move during the rotation process or particles stuck to interior walls that cannot be detected by conventional systems. The same is true for visible particles present in highly viscous products or low fill volume samples that are not moving adequately enough to be detected.

[0107] Another important advantage of this inspection system and method is that it can be used for several types of containers (vials or syringes) and different sample configurations. In fact, it is robust enough to inspect containers with small or large diameters and small or large fill volumes without the need to modify its components. The scanning performed by the light sheet and camera with tilted lenses is not affected by challenges associated with the sample meniscus or large depth of field caused by changes in liquid fill level.

[0108] Inspecting freeze-dried or emulsion / suspension products for the presence of visible particles is challenging due to the constraints of visually inspecting their contents. Traditional methods typically require additional testing, including reconstitution, dissolution, or destruction of a small number of samples, to ensure batch quality. The proposed new inspection system and method offers new capabilities for inspecting these difficult-to-inspect products. One new possibility is visually inspecting samples before the freeze-drying process. Indeed, freeze-drying processes requiring uncapped containers do not allow for sample transfer, making it impossible to inspect samples using traditional methods. Another interesting possibility for emulsion / suspension products is the increased sensitivity of visible particle detection offered by illumination generated by a light sheet.

[0109] The use of a light sheet and camera with tilted lenses to scan a static sample for the detection of visible particles offers various effects and advantages over conventional systems, providing more robust detection and opening up new applications. A more comprehensive characterization of detected particles is achieved. Slicing the sample and particles with a light sheet allows for 3D reconstruction, which is not possible with conventional systems. This provides highly accurate 3D localization of each detected particle, useful for chemical identification using spectroscopic techniques (such as Raman spectroscopy) in a second step. 3D imaging of particles enables more advanced characterization by providing 3D visualization of morphology and 3D sizing. Furthermore, inspection systems and methods can use image classification algorithms using machine learning applied to the 3D images to identify detected particles.

[0110] Inspection systems and methods according to embodiments of the present invention may include a Raman video probe integrated into the inspection system.

[0111] In contrast to conventional particle chemical identification procedures, which involve analyzing particles trapped on a filter, the inspection system and method can be operated or configured to perform data acquisition for Raman spectroscopy in a sealed container filled with a liquid pharmaceutical. The inspection system and method address the challenge of analyzing particles in a liquid medium, which prevents the use of some conventional identification methods. Raman spectroscopy is a suitable method for analysis in a sealed container due to its low interference with water and glass walls. Furthermore, the Raman backscattering process facilitates in situ analysis because it does not require sample preparation.

[0112] Particles are not immobilized or trapped and can be located anywhere in the sample. This represents a major challenge, as chemical identification of particles requires sufficiently long data acquisition; that is, the particle must remain in the focus of the Raman instrument for a minimum time, which can be several seconds (to capture sufficient scattered light). Therefore, inspection systems and methods use probes that offer better mobility and can control their position in response to the 3D particle position determined using a light sheet and camera with a tilting objective lens.

[0113] The visual inspection system described above and in some detail with reference to Figure 3 is designed to facilitate the integration of a motorized Raman probe. Indeed, by keeping the medical container stationary, particles can remain as immobile as possible, improving the 3D localization precision required for focusing the Raman probe. The data collected by visual inspection can be used by a control device to control the 3D position of the Raman probe around the sample and focus it on each particle in turn.

[0114] Probe motorization can be achieved using a robotic arm or a combination of mechanically motorized axes. Sufficient degrees of freedom must be provided to position the probe, allowing it to aim and focus regardless of the particle's position within the sample. The Raman probe must be able to at least rotate around the sample (by aiming at the vessel's axis of symmetry) and change its height and focus. Mounting the probe on the same rotational system as the laser light sheet and camera (as shown schematically in Figure 2 and in more detail, e.g., in Figure 12) facilitates calibration and improves positioning accuracy.

[0115] Incorporating a video camera into the Raman probe allows for a live stream to add additional capabilities to the overall setup. This makes it easier to calibrate the system, as the images acquired by the camera can be used to control the precise positioning of the probe. Additionally, acquiring images during analysis makes it easier to ensure that the system is well-focused during measurements. This live stream can be used to track particles and correct the position of the probe during data acquisition to ensure that particles remain within the Raman focal plane during measurements.

[0116] Furthermore, the acquisition of in situ images of particles with higher resolution can then be used to better characterize the particles. These images provide information about morphology, allow for more accurate sizing, and can be processed by machine learning-based image classifiers to perform particle classification. The integrated light unit can also be thought of as illuminating the particles being analyzed.

[0117] FIG. 4 shows a second optical system 4 of the inspection system. The second optical system 4 is operative or configured to perform data acquisition for Raman spectroscopy on particles in a medical container 4.1. The second optical system 4 is a probe 4.2. The probe 4.2 combines an optical unit 4.5, a video camera unit 4.4, and a Raman probe 4.6. The probe 4.2 is operative to mount various microscope objectives 4.3, providing different measurement possibilities. The emitted and backscattered Raman light is received and processed by the Raman probe 4.6. The illumination (probe beam) is generated by the optical unit 4.5. The image acquired by the video camera 4.4 follows the same optical path as it exits / enters the microscope objective 4.3.

[0118] Figure 4 provides a representation of the application of this probe for the chemical identification of visible particles present in a static sample 4.1. The Raman video probe 4.2 is mounted on a mechanical / robot motorized assembly that allows controlling its position in 3D around the sample. Note that the motorized system of the probe is not shown in Figure 4.

[0119] The Raman probe of the inspection system and method also considers another challenge related to the physical state of the sample. A cylindrical glass container filled with a liquid pharmaceutical acts as a cylindrical lens. This can result in strong astigmatism. Even if the probe is positioned to face the central axis of the container, the acquired image can be distorted and unable to properly focus on the particle. The same challenge arises for the emitted and backscattered Raman light. Therefore, the probe 4.2 of the inspection system and method includes a compensation lens between the Raman probe 4.5 and the medical container 4.1 to correct for this lens effect. The compensation lens may take into account parameters of the Raman video probe components, the Raman spectrometer, and the sample. The lens may be container-specific or may have a configuration depending on the diameter of each container.

[0120] The complete Raman system can be split between the probe 4.2 and the spectrometer. The two parts can be connected by two optical fibers, one for emitted light to excite the sample and the other for backscattered light collection. These components and their parameters are selected to serve various purposes. For example, the microscope objective lens 4.3 attached to the probe 4.2 is selected to have a sufficient working length to reach all particles present in the sample while maximizing the numerical aperture (NA) to ensure proper collection of backscattered light. Also, the laser wavelength is selected to emphasize the Raman scattering process and reduce the fluorescence background.

[0121] Interpretation and processing of collected raw Raman spectra may include data processing such as background correction before spectral analysis. Due to sampling conditions, the collected Raman spectrum will likely be composed of backscattered light from the surrounding environment (glass from the container and protein formulation) as well as from the particle being identified. A reference spectral database under similar analytical conditions can be used to improve the results of the matching algorithm and facilitate particle identification.

[0122] The integration of a complete Raman system into a visual inspection setup opens up new capabilities for measurement. Eliminating the filtration step (Figure 16) saves time and resources, avoids product waste and potential sample contamination, and, above all, allows for automation of the entire particle identification process. Therefore, analyzing and applying spectroscopy directly in a sealed container is expected to increase productivity and reliability of results. The incorporation of a motorized probe results in a fully automated system, ensuring high efficiency and, where necessary, throughput. The inspection system and method disclosed herein address the challenge of combining Raman spectroscopy with a visual inspection system to perform in situ chemical identification of visible particle(s).

[0123] The inspection system and method addresses the need for obtaining a more comprehensive characterization of visible particles in sealed containers. The combination of a new inspection system and method for non-migrating visible particle detection in sealed containers with in situ Raman spectroscopy for chemical identification provides a complete system for visible particle analysis in sealed containers.

[0124] Figure 5 shows an inspection system 5 that combines a visual inspection system with a light sheet source 5.2, a camera 5.3 with a tilting objective lens (for particle detection, localization, and / or sizing), and a Raman video probe 5.4. A medical container 5.1, here represented by a vial, is positioned at the center of the system and held immobile. Its axis of symmetry is aligned along axis 5.1 by a sample holder (not shown), which serves as a reference for positioning and moving the system components. The laser light sheet source 5.2 and camera 5.3 are mounted on a motorized rotation system that enables scanning for the detection, characterization, and 3D localization of visible particles that may be present within the container 5.1. The collected 3D position data is then used to control the positioning of the motorized Raman video probe 5.4, allowing it to aim and focus on each detected particle individually to perform chemical identification of each particle. The system is designed to be able to analyze all possible vessels and configurations, requiring only minor hardware adaptations (such as changing the objective and / or compensation lenses of the Raman Video Probe 5.4).

[0125] The inspection system and method provide robust detection of visible particles while reducing the process variability of manual visual inspection, thereby meeting industry requirements. By performing visible particle quantification of morphological information, accurate particle size measurement, and high-resolution image capture, the inspection system and method offers various advantages over conventional fluid imaging systems while remaining non-destructive. Finally, the integration of Raman spectroscopy, which enables chemical identification of particles, can replace traditional methods involving sample filtration. The inspection system and method offers the possibility of characterizing visible particles present in parenteral pharmaceuticals in a non-destructive and fully automated manner. The inspection system and method provides a link between the morphology, size, and chemical identity of each particle present in a sample.

[0126] The ability to perform extended characterization in situ is a significant advantage over traditional methods. In situ analysis reduces the risk of loss and damage to samples containing atypical particles, which are often available in limited numbers. In the early stages of drug development, only small amounts of sample are available for testing, so any method that allows analysis without sample loss is recommended. Furthermore, traditional methods require the opening of samples and must be performed in special "particle-free" laboratories, which can present challenges.

[0127] The application of the novel testing systems and methods disclosed herein offers an opportunity to improve formulation development by enabling new approaches to study the mechanistic formation and kinetics of particles. Analysis of particles in sealed containers at periodic time points provides insights into better understanding protein aggregation pathways and factors that may influence or control the protein aggregation process.

[0128] The data collected by visual inspection sections 5.2 and 5.3 offers the advantage of measuring images in real time under conditions where particles remain suspended, an advantage over conventional techniques. This allows for superior imaging of highly irregularly shaped particles and monitoring of particle dynamic behavior as the size distribution changes over time.

[0129] For products containing high or variable particle counts, chemical identification is important in assessing potential mechanisms and impacts on product quality. The presence of extraneous particles, such as glass and / or rubber pieces and silicone oil droplets, can act as "nucleation sites" in promoting biologic aggregation. Materials that comprise extraneous particles typically have unique Raman spectra. Therefore, the inspection system and method disclosed herein can be used to identify the source of extraneous particle contamination. This feature can help identify the root cause of particles seen in development and manufacturing.

[0130] The inspection system can be integrated into the existing capabilities of parenteral pharmaceutical manufacturing sites. The installation of the inspection system does not require a special environment for operation. Providing an inspection system that performs extensive particle analysis in a fully automated manner allows for more reliable results in a shorter time and facilitates investigation upon detection of unusual particles in samples. While a more thorough analysis may result in a longer analysis time compared to conventional inspection systems, several inspection systems according to the present invention can be installed and operated in parallel to provide the desired throughput. For example, reinspection of all discharged containers in which at least visible particles were detected allows for a double check, which provides important information not only about particles that may be present in the product, but also about the performance of the implemented process.

[0131] 6 illustrates an inspection system 6 according to an embodiment. The inspection system is operative or configured to detect and characterize particles inside a medical container 6.1. The inspection system 6 includes a sample holder 6.2, a laser 6.3 operative or configured to generate a light sheet, laser apertures 6.4.1, 6.4.2, a laser trap 6.5, a video camera 6.6 attached to a tilting objective lens 6.7, and a motorized mechanical structure 6.8.

[0132] The sample to be tested for the presence of visible particles therein may be a liquid pharmaceutical product filled in a cylindrical container. The testing system 6 is operative or configured to perform testing on samples having a variety of different liquid pharmaceutical characteristics, such as viscosity, density, turbidity, opacity, and fill volume. The cylindrical container may be made of different materials (e.g., glass or polymer) and may have any one of a variety of heights and diameters. While a vial is shown in FIG. 6, the medical container may be represented by any type of cylindrical container, such as a syringe.

[0133] For a sample to be analyzed, the laser light sheet must illuminate the region of interest of the sample and the image must be captured by the video camera 6.6. The container is sealed by ensuring that the closure system is in its final position (stopper for vials, and plunger for syringes). The inspection system 6 does not require the sample to be moving. Therefore, the inspection system 6 can be used to inspect the sample before the freeze-drying process. The orientation of the sample, set by the sample holder 6.2, is set so that all the liquid in the container can be inspected. For containers with stoppers (such as vials), an upright position, i.e., the stopper is at the top, is preferred. The same applies to containers with needles (such as syringes).

[0134] The sample holder 6.2 is used to ensure proper positioning and orientation of the sample onto the 6-well innovative visual inspection system. Axis 6.11, along which the axis of symmetry of the medical container 6.2 is located, represents the reference axis of the complete 6-well system, used to orient the rotation of the laser light sheet, video camera 6.4, and motorized mechanical structure 6.8. The selection of components that make up the sample holder 6.2 allows for its positioning and orientation and may depend on the precision requirements of the inspection system 6. The sample holder 6.2 may include a flat platform with a cylindrical shape and diameter footprint of the sample being analyzed (small enough to ensure visibility of the sample's bottom). This proposal is container-specific and will vary depending on the diameter of the sample being analyzed. More complex designs of the sample holder 6.2 can be used for any type of sample and may include mechanical / robotic motorized axes, which provide better positioning accuracy. Furthermore, this configuration of the sample holder 6.2 allows for the automation of sampling in the complete system.

[0135] Unlike conventional inspection systems, inspection system 6 detects particles that do not move. The medical container stage does not need to be rotated but must remain stationary during the analysis. Furthermore, syringes can be filled with different volumes, which means that the position of the plunger can change. The height of the laser light sheet generated by laser 6.3 and imaged by camera 6.4 can remain fixed within inspection system 6 to facilitate their calibration. Therefore, sample holder 6.2 is preferably motorized to control its height depending on the sample being inspected.

[0136] The inspection system and method operate based on scanning an immobilized sample. Laser 6.3 can generate a light sheet. Another light source can be used, capable of illuminating a thin area comparable to a plane. The light sheet generated by laser 6.3, oriented along axis 6.11, passes through the sample, illuminating the interior area of ​​the container and the exterior wall of the container. If a particle is located within the thickness of this light sheet, intense light is reflected and / or scattered, allowing the particle to be detected. The contrast between the light reflected by the particle and the surrounding area within the sample is very strong, resulting in a very sensitive system.

[0137] The sheet of light passes through various optical media and may be subject to some diffusion. Therefore, its shape and width may not be perfectly uniform at all points. To compensate for this, the light sheet generated by the laser 6.3 may be focused by an optical assembly inside the laser. One approach is to focus the area captured by the video camera 6.6 to obtain a sharp plane, ensuring the best illumination of the area of ​​interest.

[0138] In an exemplary embodiment, the laser light sheet can be produced by a FLEXPOINT® MW nanolaser available from Laser Components, with a thickness of a few microns to a few millimeters, an output power of up to 100 mW, and wavelengths ranging from 635 nm to 785 nm (red), 405 to 450 nm (violet), and / or 520 to 532 nm (green). In one embodiment, the laser light sheet can be produced by a FLEXPOINT® MW nanolaser from Laser Components, with a thickness of 10 to 330 microns, a focal length of 0 to 1000 mm, an output power of 30 mW, and a wavelength of 520 to 532 nm (green).

[0139] Figure 7 shows a top view of a first optical system 7 of an inspection system. The arrangement and characteristics of Figure 7 can be applied to a first light source that outputs a light sheet and a first detector that detects reflected and / or scattered light as the light sheet passes through a medical container 7.1.

[0140] The width 7.22 of the light sheet is a parameter selected to ensure the detection of particles with sizes starting from, for example, 100 microns (although particles with sizes larger than 100 microns can also be detected). To provide the possibility to adjust the width 7.22 of the light sheet using a special optical system, an adjustment ring may be provided that may be integrated into the laser 7.2. The width 7.22 of the light sheet is used to calculate the scanning increment (which also depends on the diameter of the sample) to cover the entire volume of the medical container 7.1 and to acquire the image with a video camera 7.3 equipped with a tilting objective lens 7.4.

[0141] A very thin light sheet improves scanning resolution, but requires acquiring more images to cover the entire volume of the medical container 7.1. A larger light sheet can shorten the scanning time with larger increments, but reduces the scanning resolution. Therefore, it is necessary to find a good compromise between the width and increment value of the light sheet to ensure robust detection (even for smaller particles) while optimizing the image volume acquired by the video camera 7.3. The width 7.2 can be kept constant, and the increment value can be adjusted according to the diameter of the medical container 7.1. This can be done automatically depending on the medical container being analyzed.

[0142] The laser light sheet is oriented parallel and impinges on axis 6.11, which can act as a lens to reduce the reflection of the light sheet passing through the cylindrical wall of the liquid-filled medical container 7.1. Furthermore, the laser light sheet is mounted on a rotation system (e.g., system 6.8) whose sample holder has axis 6.11 as its rotation axis, which positions the axis of symmetry of the medical container 7.1, making slicing of the medical container 7.1 easier. Proper optical alignment is required, even though slight misalignments may be tolerable.

[0143] The laser is positioned at a distance 7.21 and height that ensures that the entire liquid-filled height of the container is illuminated by the light sheet. Both the top and bottom of the container are illuminated. In some configurations, particularly in the case of syringes, the bottom of the sample is not necessarily perfectly flat (conical plunger). Therefore, the laser 7.2 is positioned close enough so that the angle of illumination can overcome this obstacle and illuminate the entire bottom of the sample. After optimizing the distance between the laser light sheet 7.2 and the medical container 7.1, the focus of the light sheet can be adjusted on the region of interest captured by the video camera 7.3. The laser 7.2 generating the light sheet is mounted on a rotating mechanical structure (e.g., support 6.8) so that the laser's orientation and its distance 7.21 can be locked. The same applies to its height relative to the sample 6.1. The only possible movement of the light sheet generated by the laser 7.2 is performed by the rotating mechanical structure (e.g., support 6.8), which allows for illumination and therefore scanning of the complete sample.

[0144] The visual inspection system 7 is highly sensitive. Therefore, it is desirable to reduce and / or identify reflections from physical elements other than particles that may be present in the sample. Laser apertures 6.4.1 and 6.4.2, located above and below the laser light sheet, can capture light that is not useful for illuminating the sample and prevent its transmission to the video camera 6.6. Laser apertures 6.4.1 and 6.4.2 can be combined with one or several laser traps 6.5 to further reduce unwanted artifacts. To achieve a fully automated system, the positions of the laser apertures 6.4.1 and 6.4.2 can be independently controlled by two motorized mechanical axes. Their position is adapted depending on the height of the container and the filled volume of the sample. The illuminated volume represents the portion of the sample filled with pharmaceutical liquid. It may also be possible to illuminate the unfilled portion (located at the top) to check for particles that may be attached to the container walls.

[0145] The light trap 6.5 can be sized (e.g., wide enough and tall enough) to cover the light sheet. The light trap 6.5 can be attached to the exit of the sample to interrupt the propagation of light in the setup. The light trap is oriented parallel to the light sheet generated by the laser 6.3 and is positioned approximately at the same height as the sample.

[0146] A housing (not shown) covering the entire setup can reduce the risk of light from the environment being reflected off the cameras 6.6, 7.3. At the same time, this housing can be useful for safety issues related to the laser light sheet. The housing is large enough to cover the imaging system and the motorized mechanical system that enables its rotation.

[0147] At least one video camera 6.6 equipped with a charge-coupled device (CCD) sensor is used to capture images of the sample area illuminated by the laser light sheet. A high-definition camera is used to ensure that pixel size is below the minimum particle size target for detection. The camera's field of view (FOV) is large enough to capture a complete image of the sample 6.1. Image acquisition is defined by incremental values ​​that allow slicing of the entire volume of the sample. The acquisition of each image can be triggered by a mechanical rotation system 6.8. The mechanical rotation system 6.8 may have an angle sensor. Image acquisition may also be triggered by the output of the angle sensor. A low exposure time for the video camera 6.6 is useful because the light reflected by particles present in the sample is strong compared to other features present in the image (Figure 8). Such a setting allows for better characterization of the particles by avoiding overexposure of pixels illuminated by the presence of particles. If the color information of the particles is not important, separating the color channels (e.g., RGB) and selecting a single channel that can match the wavelength or color of the laser light sheet reduces the amount of data collected.

[0148] The sample's configuration, a cylindrical object filled with liquid, acts as a lens, creating blind spots when inspecting the sample with conventional optical systems. The use of tiltable lenses 6, 7, and 7.4 offers a highly effective solution to this challenge by providing a non-perpendicular viewing angle for the light sheet to avoid these blind spots. The tiltable mount can be compatible with any C-mount camera. A precise built-in adjustment mechanism allows for precise Scheimpflug conditions and imaging of tilted surfaces in good (e.g., perfect) focus. This lens offers a wide range of magnification and viewing angles. Because the Scheimpflug adjustment tilts around the horizontal axis of the detector plane, image sharpness is maintained even when the lens is tilted to a wide angle. This tilting objective lens allows for adjustment of the tilt angle as well as the focus, which offers several analytical possibilities. For illustrative purposes, we will use the Stemmer Imaging tilting objective MCSM1-01X.

[0149] The positioning of the video camera 7.3, assembled with the tilted objective lens 7.4, relative to the laser 7.2 or light sheet affects the ability to obtain a proper image of the illuminated particles. To avoid blind spots, the camera is positioned at an angle 7.31 relative to the central axis of the laser light sheet. Then, during calibration, the angle 7.31 of the tilted lens is adjusted to obtain a clear image of the area illuminated by the laser light sheet. The angle 7.31 can have different values, allowing for several angles of view. Therefore, optimization can be performed to determine the value that provides the best image quality of the detected particles. The distance 7.32 of the camera 7.3 from the sample and the height between the camera and the sample are set so that the entire area of ​​the sample illuminated by the laser light sheet is present in the image acquired by the video camera 7.3. The focusing of the tilted objective lens 7.4 can be ensured by an adjustment ring.

[0150] Figure 8 shows an image 8 recorded by video cameras 6.6 and 7.3. As can be seen in Figures 7 and 8, video camera 7.3 is positioned so that the entrance 8.1 of the laser light sheet 6.3 in the liquid is on the right side of the image 8 captured by the camera. However, the video camera can also be positioned so that the entrance 8.1 of the light sheet is on the left side of the image. Both configurations were tested and it was concluded that the configuration shown in Figure 7 allows for proper illumination of the sample while mitigating reflections of the laser light sheet into the sample container.

[0151] The video cameras 6.6, 7.3 and tilting objectives 6.7, 7.4, fastened to one another, are mounted on a rotating mechanical structure 6.8, which allows locking their relative orientation, their distance and their height with respect to the medical containers 6.1, 7.1 and the laser light sheet. The only movement of the video cameras and tilting objectives is brought about by the rotating mechanical structure 6.8, which allows for the acquisition of an image of the complete sample.

[0152] To scan the entire sample volume, a motorized rotating mechanical system 6.8 can be used, to which the imaging optics can be attached. This system is represented in Figure 6 by a disk placed under the setup. Its rotation axis is coaxial with the axis of symmetry of the stationary sample, which is placed along axis 6.11. The system configuration takes into account the position and movement of the components of the first optical system, which may be the imaging system. Any combination of structures and motorized mechanical axes that allow for the mounting of the imaging system and its automatic rotation can be used. This structure is attached to a fixed base (which serves as a frame) that can be attached, for example, to a laboratory bench. One implementation uses a circular optical table 12.1 (Figure 12) with a diameter large enough to allow the fixation of the components of the visual imaging system 6 and their rotation by a motorized rotating table 12.2. A laser 6.3 generating a light sheet, laser apertures 6.4.1 and 6.4.2, a laser trap 6.5, a camera 6.6 with a tilting objective 6.7, and a Raman video probe 12.6 are attached to this circular optical table 12.1 (Figure 12).

[0153] Figure 8 shows an example of an image 8 acquired by the inspection system 6. This image was acquired with a sufficiently high exposure time to allow complete visualization of the sample 6.1. The shape of the container can be easily recognized, as can the entrance 8.1 and exit 8.2 of the light sheet through the medical container. The inner and outer walls of the container reflect light, which makes it possible to easily recognize them and use them as references for defining the region of interest 8.3 in the raw image. In a second step, these boundaries can even be used to implement a mask based on an imaging algorithm that allows cropping the region of interest 8.3 and removing the rest of the image. In this image, a particle 8.4 located within the beam of the light sheet can be seen. The light reflected by this particle is very intense and provides a strong contrast with the rest of the sample. The quality of the raw image is high enough to be processed with image processing algorithms that allow automatic detection of particles present in the sample. Processing can be performed by an evaluation circuit, which can be implemented by a computer programmed to process the image data.

[0154] To perform a complete inspection of the sample, the laser light sheet and video camera must be rotated around the static medical container. This process allows the entire sample to be scanned. Small particles are captured in only a few frames, while larger particles can be captured in several frames.

[0155] Figure 9 shows an example of a portion of an image (enlarged scale) that provides an overview of nine images a-i acquired one after the other after completing nine successive increments. From frame a to frame c, despite the rotation of the imaging system, the particle is not yet within the width of the light sheet, and no light is reflected. In frames d and e, the intensity of the first pixels begins to increase, indicating that the particle is close to the light sheet. In frame f, a very bright area is visible, indicating that part of the particle is within the light sheet (as well as within the focal plane of the camera). In images g and h, the particle (which is larger than the width of the light sheet, even after the rotation of the imaging system) is located within the width of the light sheet, resulting in the appearance of many bright pixels. In image i, the light sheet has passed through most of the particle, and only a few pixels remain bright, indicating reflections from the part of the particle that still overlaps with the light sheet.

[0156] A preliminary correction of the raw images can be applied to correct for possible variations associated with the random placement of particles within the sample. Processing of the raw images with image processing algorithms can be used to perform particle detection, characterization, and 3D localization. As captured particles are reflected in several frames, 3D clustering algorithms can be used. For example, the DBScan algorithm, which uses pixel intensity values ​​and 3D particle volume, can be applied. Such algorithms can operate based on three parameters to be optimized: Image threshold: the intensity at which a pixel must be considered to belong to a particle - Epsilon: the distance in 3D between pixels above the threshold to be considered part of the same particle -Minimum Neighborhood: The minimum size of a pixel in a cluster (3D). (Values ​​are in pixels)

[0157] Furthermore, slicing of the entire volume of the sample by the inspection system 6 offers the possibility to perform a 3D reconstruction of the detected particles.

[0158] Figure 10 provides examples of 3D reconstructions 10.1 of the complete sample shown in Figure 9 and reconstructions 10.2 of single particles. 3D imaging of particles in a sealed container allows for more advanced characterization by providing 3D visualization of morphology and 3D sizing. Furthermore, more precise localization of particle centers can be achieved.

[0159] Integrating a Raman probe into an inspection system allows for chemical characterization of detected visible particles (e.g., identification based on spectroscopic fingerprinting). The probe configuration (e.g., as described with reference to Figure 4) allows the source of the Raman probe beam and the Raman detector to be moved in 3D around the sample and adjust their position according to the position of the particles (which remain stationary during acquisition). The size and weight of the probe are implemented to ensure proper motorization and integration into the inspection system. The addition of an optical unit and a video camera to the miniature Raman probe can be considered to illuminate the sampling area, which makes it possible to visualize the particles to be identified in order to acquire an image and facilitate focusing.

[0160] 11 is a diagram of a probe 11 including a Raman probe, an optical unit, and a video camera. The probe 11 is designed to provide good performance while maintaining flexibility in the choice of camera and objective lens used. The probe 11 is operable or configured to perform in situ Raman spectroscopic analysis of visible particles present in a liquid-filled container and collect high-resolution particle images and Raman spectra.

[0161] The probe 11 includes a Raman probe 11.1. The Raman probe 11.1 is connected to a spectrometer (not shown in Figure 11) using two optical fibers: one allows excitation of the sample area and the other allows collection of Raman backscattered light. The selected inner diameter of these optical fibers is chosen based on the size of the desired excitation spot and the volume to be collected. Furthermore, the measurement settings of the spectrometer are set to allow good identification of detected particles without damaging the particles or the formulation in the container. Strong laser exposure over a long period of time can cause damage to the sample area. On the other hand, too low power and exposure do not allow scattering and therefore make identification impossible.

[0162] The excitation wavelength affects Raman intensity, spatial resolution, background fluorescence, and acquisition time. The context and surrounding environment of the sample being identified are important considerations. First, particles may be made of different materials that may be more sensitive to different excitation wavelengths. Second, the laser must pass through several media. A wavelength that minimizes the appearance of data from the vessel or solution within the vessel is preferred. The use of a 785 nm wavelength offers a good compromise between Raman scattering intensity and fluorescence suppression for various use cases. To provide further flexibility to the system, a second Raman probe with a different wavelength can be provided.

[0163] The addition of an illumination mechanism is achieved by the presence of a fiber optic lens collimator 11.2 connected to a light source (not shown in Figure 11). Illumination of the sample area makes it easier to visualize the detected particles and focus on them. The use of additional optical elements allows the use of the same light path as the Raman probe.

[0164] The integration of a video camera on the probe 11 provides visualization capabilities over the sampling area. This integration is made possible by using a camera mount with an external C-mount thread 11.3. The acquired image allows for calibration of the probe placement, performed by the 3D particle localization data collected by the visual inspection system 6. Furthermore, this acquired image is used as a readout to check the accuracy of the probe positioning. Additional optical components allow visualization via the same optical path. It is also possible to visualize the laser beam on the particle during the measurement, which ensures the reliability of the acquired data. If the particle is moving slightly, the acquired image can be used to track and correct the position of the probe 11 in real time to keep the particle within the focal plane of the probe 11 during data acquisition.

[0165] The optical output of this probe 11 has an objective lens mount 11.4 that allows the attachment of a conventional microscope objective. The sample characteristics as well as the type of data to be acquired by this probe are taken into consideration when selecting the microscope objective. Furthermore, to reach all particles, the working distance is kept greater than the radius of the largest container, since particles can be positioned at any point within the sealed container. To maximize Raman backscatter collection, the numerical aperture is increased (e.g., maximized). Corrected near-infrared (NIR) objectives can also be used.

[0166] The medical container to be analyzed is mainly cylindrical in shape and filled with a liquid, which acts as a lens. To compensate for the light distortion and obtain a clear image, a compensating lens is inserted between the sample and the microscope objective of the miniature probe 11. The shape and material used to make this probe depend on the properties of the sample (liquid solution and the container in which it is contained). Correction lenses dedicated to a particular container type and / or size (e.g., diameter) can be used.

[0167] The probe 11 has an enclosure 11.5 to hold the different components of the probe in place and to maintain the integrity of the optical components. The arrangement and configuration of the components can be carried out to provide a compact design and low weight for ease of positioning while also facilitating integration into the inspection system.

[0168] At least a portion of the beam path may be shared by various components, such as a video camera and a Raman probe 11.4 integrated into the probe 11. The probe 11 may be provided with various optical components, which may include reflectors (such as mirrors 11.9), focusing, collimating, or other beam conditioning components such as tube lenses 11.8, components that provide beam splitting and / or interference settings, such as beam splitters 11.7 (which may have, but are not limited to, 80% transmission and 20% reflection), and dichroic filters 11.6.

[0169] The visual imaging system 6 performs detection and 3D localization of particles present in a liquid-filled, sealed container. These particles can be located anywhere within the sealed container. An automated mechanical or robotic system is used to enable movement of the probe 11 around the sample. To minimize optical effects created by the cylindrical shape of the container, the probe 11 is oriented toward the sample's axis of symmetry, which is aligned with axis 6.11 by the sample holder. A mechanical structure or automated robotic actuator can provide at least three degrees of movement for the probe 11 to enable focusing of the entire sample. The actuator device used to displace the probe 11 can provide a first degree of freedom that allows rotational movement around the sample while maintaining its orientation toward axis 6.11, along which the container's axis of symmetry is aligned. The actuator device used to displace the probe 11 can provide second and third degrees of freedom that allow the inspection system 6 to adjust its height 5.41 (in the same direction as the axis of symmetry) as well as its distance to the interior of the sample 5.42 (perpendicular to the direction of the axis of symmetry). It is also conceivable to add an additional degree of rotation that allows the probe to be tilted up or down in case some particles float on the surface of the liquid or are at the bottom of the sample.

[0170] In one embodiment, the probe 11 is mounted on a circular motorized structure 6.8, 12.2 that rotates the optical imaging setup. This reduces the number of motorized axes and facilitates calibration between the two optical systems because they are mounted on the same moving structure 6.8, 12.2. The addition of two motorized linear axes allows the probe 11 to change height over an amplitude large enough to cover large samples, while the second motorized linear axis allows its focus to be varied over an amplitude of at least the radius of the largest sample. An additional rotational axis can be incorporated into the motorized structure to allow tilting of the probe. This complete motorized structure 12.5, which holds and motorizes the miniature probe 11, is shown in Figure 12.

[0171] FIG. 12 shows a perspective view of the inspection system 12, which includes a sample holder 12.1 for stationary positioning of a medical container during data acquisition, a first light source 12.3 for outputting a light sheet, a first detector 12.4 for detecting an image of the container illuminated by the light sheet, and a probe 12.5 for performing data acquisition for Raman spectroscopy. The first light source 12.3, the first detector 12.4, and the probe 12.5 are mounted on a rotatable support 12.2. A central opening in the support 12.2 allows for the fixation and vertical movement of the sample holder 12.1. The optical table may have a set of threaded holes arranged in a grid pattern to allow for easy fixation of the system components. The optical table may be fixed to a motorized rotary table driven by a motor 12.6 using a shaft 12.7, which may be a hollow tube through which the stationary sample holder 12.1 passes. The inner diameter of this tube must be large enough to allow for the passage of the sample holder, and long enough to allow for the implementation of a rotating cable protection system. In one embodiment, a motorized rotary table DMT 200N-D90-HiDS from Owis is implemented, providing very accurate rotational positioning with no angular limitations.

[0172] The probe 12.5 can be mounted in several positions on the support 12.2 so that it does not obstruct the visual imaging setup. Positioning the probe 12.5 away from the illumination generated by the laser 12.3 is preferred to avoid generating additional reflections. The probe 12.5 is positioned to ensure no obstruction to the camera 12.4. Furthermore, it is preferred to mount the probe 12.5 close enough to the sample so that its movement towards the detected particle requires as little time as possible.

[0173] In one embodiment, the probe 12.5 and its actuator (also referred to as the second actuator) can be mounted as close as possible to the region of interest 8.3 visualized by the camera 12.4, avoiding any interference with the visual inspection setup. Knowing that the rotary table 12.1 rotates clockwise, the positioning of the probe 12.5 and its motorized structure as shown in FIG. 12 allows the probe to be targeted as quickly as possible (with the smallest possible angle of rotation) over the region to be inspected. The lateral position of the probe 12.5 relative to the sample is then defined by the amplitude of the motorized axis, which allows the miniature probe 12.5 to be focused at least to the center of the vessel.

[0174] In one embodiment, the sample holder 12.1 and the sample are positioned at the center of the system. The sample remains stationary throughout the entire analysis. A motorized linear axis fixed to the frame (not shown in Figure 12) allows the vertical position of the sample holder 12.1 to be adjusted before the start of the analysis according to the sample's loading volume. A circular support, such as the optical table 12.2, serves as a base for fixing the components of the visual inspection system: the laser light sheet 12.3 and camera 12.4, as well as the miniature Raman probe and its motorized structure 12.5. This optical table 12.2 is rotated around the sample 12.1 (which remains stationary) by a motorized rotary table driven by a motor 12.6, which allows the scanning of the sample and the aiming of the miniature probe in the second step. The connection between these two components is made by a spacer tube 12.7, which is hollow and allows the passage of the motorized axis attached to the sample holder 12.1.

[0175] The axis of symmetry of the sample is coaxial with the axis of rotation of the rotary table. Manual mechanical axes can be used to facilitate placement and alignment between the different components.

[0176] In the configuration shown in Figure 12, the rotational motion produced by the rotary table is clockwise. However, counterclockwise rotation can be used. In this case, it may be preferable to reposition the probe 12.5 and its motorized structure.

[0177] The 3D particle position data detected by the visual imaging system is used to control the position of the miniature Raman probe 12.5. The different elements are calibrated to ensure accurate positioning.

[0178] The inspection system may include an electrical control cabinet (not shown in FIG. 12) that provides monitoring and power supply for the various components of the inspection system 12. Additionally, the inspection system 12 may be provided with a control device, such as a computer running specialized software, to perform various tasks for automated control of the entire system and processing of detector outputs.

[0179] 13 is a flow chart of method 13. Method 13 may be performed automatically by an inspection system according to the present invention.

[0180] In step 13.1, a sample holder receives the medical container. The sample holder positions the medical container so that its axis of symmetry is aligned with and oriented along the axis. The sample holder positions the medical container and holds it immobile or stationary during data acquisition for analysis.

[0181] In step 13.2, the vertical position of the sample holder and laser aperture can be adjusted according to the configuration of the medical container. This can be done automatically in response to container detection (e.g., using a container identifier such as a barcode) or in response to user input specifying the container type and / or size and / or fill level. In step 13.2, the laser light sheet can be turned on.

[0182] In step 13.3, the actuator (e.g., a motorized mechanical structure) begins its rotation, allowing the entire sample to be scanned. Images are acquired as a function of the increment value adjusted according to the sample configuration in step 13.2. The Raman probe system can remain inoperative during this scan.

[0183] In step 13.4, the image captured in step 13.3 is processed by imaging algorithms that allow for the detection, characterization and / or 3D localization of particles present in the sample, if any.

[0184] In step 13.5, the 3D localization data is processed by the control unit to perform control of the movement of the Raman video probe.

[0185] In step 13.3, an actuator device responsible for displacing the probe in the Raman probe is controlled. This actuator device may comprise a motorized mechanical structure that provides rotation of a motorized shaft dedicated to the support 12.2 and the probe 12.5. The probe 12.5 is adjusted to aim and focus on the detected particle.

[0186] In step 13.7, a Raman measurement is triggered by the control unit to perform chemical identification of the particles. Additional images can be acquired by a camera integrated into the probe.

[0187] Steps 13.6 and 13.7 are repeated for previously identified particles within the medical container.

[0188] Processing of visual image data and / or spectroscopic data (such as Raman spectra) captured in response to illumination of a medical container with a light sheet may use an artificial intelligence (AI) model. The AI ​​model may be trained on impurities of known characteristics (such as size and / or chemical properties), preferably for various types of containers (vials, syringes, or other), walls (glass or plastic), and liquids. Supervised learning may also be used, in which the parameters of the AI ​​model are adjusted using techniques such as gradient descent.

[0189] FIG. 14 shows an example of an AI model 14 that, after training, may be executed by the inspection system's computer to process acquired data. The AI ​​model 14 includes an input layer 14.1 that operates or is configured to receive pixel values ​​or quantities derived therefrom (such as particle size data or spectral portions). The AI ​​model 14 includes an output layer 14.2. The output layer 14.2 may output a binary output indicating whether a particle renders a medical container unacceptable. The output layer 14.2 may output an output indicating what type of particle is present. Thus, the AI ​​model 14 may operate as a classifier, processing information obtained using the inspection system's optical system into information about particles. The AI ​​model 14 may include a hidden layer 14.3, which may include a convolutional layer, a recurrent layer, or other artificial neural network (ANN) configuration.

[0190] The present specification and the accompanying drawings, which illustrate aspects and embodiments of the present invention, should not be construed as limiting the scope of the claims, which define the protected invention. In other words, while the present invention has been illustrated and described in detail in the drawings and the foregoing description, such illustration and description should be considered illustrative or exemplary, rather than limiting. Various mechanical, compositional, structural, electrical, and operational changes may be made without departing from the spirit and scope of the specification and claims. In some instances, well-known circuits, structures, and techniques have not been shown in detail so as not to obscure the invention. Accordingly, it will be understood that those skilled in the art can make changes and modifications within the scope and spirit of the following claims. In particular, the present invention encompasses further embodiments having any combination of features from the different embodiments described above and below. For example, the present invention can be operated in the following embodiments: Medical containers are not sealed and contain freeze-dried products The inspection system includes two or more visual imaging systems, each of which uses a light sheet. The inspection system includes multiple spectroscopic systems

[0191] Furthermore, the present disclosure encompasses all additional features that may not be described in the above or following description but are individually illustrated in the drawings. Also, individual alternatives to the embodiments and individual alternatives to those features described in the drawings and specification may be discarded from the subject matter of the present invention or disclosed subject matter. The present disclosure includes subject matter consisting of, and comprising, the features defined in the claims or exemplary embodiments.

[0192] Furthermore, in the claims, the word "comprising" does not exclude other elements or steps, and the indefinite articles "a" or "an" do not exclude a plurality. A single unit or step may fulfill the functions of several features recited in a claim. The fact that certain means are recited in mutually different dependent claims does not mean that a combination of these means cannot be advantageously used. The terms "essentially," "about," "approximately," and the like, in connection with an attribute or value, specifically define that very attribute or exactly that value as well. The term "about" in the context of a given numerical value or range refers, for example, to a value or range that is within 20%, within 10%, within 5%, or within 2% of the given value or range. Components described as being coupled or connected may be directly coupled electrically or mechanically or indirectly coupled via one or more intermediate components. Any reference signs in the claims should not be construed as limiting the scope.

[0193] The computer program may be stored / distributed on a suitable medium, such as an optical storage medium or a solid-state medium, supplied together with or as part of other hardware, but may also be distributed in other forms, such as via the Internet or other wired or wireless telecommunications systems. In particular, for example, the computer program may be a computer program product stored on a computer-readable medium, which may have computer-executable program code adapted to be executed to perform a particular method, such as the method according to the present invention. Furthermore, the computer program may also be a data structure product or a signal for embodying a particular method, such as the method according to the present invention.

Claims

1. An inspection system (1.3; 12) operative to inspect a medical container containing a liquid, said inspection system (1.3; 12) comprising: a sample holder (1.4; 2.1; 12.1) operative to hold said medical container along an axis (2.2; 6.11); at least one optical system (1.5; 2.5, 2.8; 3; 4; 5; 6; 7; 11; 12.3, 12.4, 12.5), At least one light source (3.2; 4.6; 5.2; 6.3; 7.2; 11) operative to output light incident on said medical container; and at least one optical system (1.5; 2.5, 2.8; 3; 4; 5; 6; 7; 11; 12.3, 12.4, 12.5) having at least one detector (3.4; 4.6; 5.3; 6.6, 6.7; 7.3, 7.4; 11) operative to detect return light from the medical container, the at least one detector (3.4; 4.6; 5.3; 6.6, 6.7; 7.3, 7.4; 11) comprising a first detector (3.4; 4.6; 5.3; 6.6, 6.7; 7.3, 7.4) comprising an opto-electrical transducer having a plurality of pixels; and an evaluation system (1.7) coupled to the at least one optical detector and operative to detect and / or determine characteristics of particles in the medical container based on at least an output of the at least one detector; at least one actuator (1.6; 2.6, 2.7; 12.6) operative to move the at least one light source (3.2; 4.6; 5.2; 6.3; 7.2; 11) and / or the at least one detector (3.4; 4.6; 5.3; 6.6, 6.7; 7.3, 7.4; 11) about the axis (2.2; 6.11) while the sample holder (1.4; 2.1; 12.1) holds the medical container in a rotatable and translatable fixed manner, the at least one light source comprises a first light source (3.2; 4.6; 5.2; 6.3; 7.2) operative to output a light sheet; 1. An inspection system (1.3; 12), characterized in that the first detector (3.4; 4.6; 5.3; 6.6, 6.7; 7.3, 7.4) comprises an inclined objective lens (6.7; 7.4).

2. said at least one actuator (1.6; 2.6, 2.7; 12.6) is operative to move said at least one light source and said at least one detector along a curved path around said axis (2.2; 6.11); Optionally, the following: at least a segment of said path extends in a plane perpendicular to said axis (2.2; 6.11); the path comprises an arc of an ellipse; the path includes a circular arc; said at least one actuator (1.6; 2.6, 2.7; 12.6) operates to simultaneously change the position and orientation of said at least one light source (3.2; 4.6; 5.2; 6.3; 7.2; 11) so that said illumination light remains incident on said medical container and / or said shaft (2.2; 6.11); The inspection system (1.3; 12) of claim 1, wherein one, some, or all of the following are applied: the at least one actuator operates to simultaneously change the position and orientation of the at least one detector (3.4; 4.6; 5.3; 6.6, 6.7; 7.3, 7.4; 11) to cause the returned light to be incident on the at least one detector.

3. 3. The inspection system (1.3; 12) of claim 1 or claim 2, further comprising a frame (2.3) on which the at least one optical system is supported, the sample holder (1.4; 2.1; 12.1) being arranged in a fixed position relative to the frame (2.4), and the at least one actuator (1.6; 2.6, 2.7; 12.6) being operable to move the at least one light source and / or the at least one detector relative to the frame (2.3).

4. the at least one actuator (1.6; 2.6, 2.7; 12.6) comprises a first actuator (1.6; 2.6, 2.7; 12.6) operative to move the first light source (3.2; 4.6; 5.2; 6.3; 7.2) about the axis (2.2; 6.11); Optionally, the first actuator (1.6; 2.6, 2.7; 12.6) is operative to move the first light source (3.2; 4.6; 5.2; 6.3; 7.2) about the axis (2.2; 6.11) such that the light sheet remains incident on the axis (2.2; 6.11) as the first light source (3.2; 4.6; 5.2; 6.3; 7.2) moves about the axis (2.2; 6.11).

5. 5. The inspection system (1.3; 12) of claim 4, wherein the first detector (3.4; 4.6; 5.3; 6.6, 6.7; 7.3, 7.4) operates to provide a first detector output in response to the returned light while illuminating the medical container with the light sheet, and optionally the first detector includes a Scheimpflug camera.

6. The evaluation system (1.7) detecting the particle when the particle is located in the light sheet based on at least the first detector output; determining that the particle is located within the medical container based on at least the first detector output; distinguishing the particles from gas bubbles in the liquid within the medical container based on at least the first detector output; distinguishing the particles from impurities within a container wall of the medical container based on at least the first detector output; - determining information about the particle's morphology, optionally a three-dimensional surface shape of the particle, based at least on the first detector output for several different angular positions of the first light source and / or the first detector about the axis (2.2; 6.11), 6. The inspection system (1.3; 12) of claim 5, which is operable to at least one of determine information about the size of the particle, and optionally about the three-dimensional size of the particle, based on at least the first detector output.

7. 7. The inspection system (1.3; 12) of claim 1, wherein the at least one light source comprises a second light source (11) operative to output a Raman probe beam, and the at least one detector comprises a second detector (11) coupled to a Raman spectrometer.

8. the at least one actuator comprises a second actuator (2.7) operable to move both the second light source (11) and the second detector (11), the second actuator having more degrees of freedom than the first actuator, optionally the first actuator (2.6; 12.6) having one degree of freedom and the second actuator (2.7) having at least two degrees of freedom (5.41, 5.42), and / or optionally the second actuator comprises a multi-axis robot arm or a multi-axis (5.41, 5.42) linear displacement actuator, and / or The inspection system (1.3; 12) of claim 7 when dependent on claim 6, wherein the inspection system (1.3; 12) comprises a control device operative to control a second actuator (2.7) based on at least the first detector output.

9. An inspection system (1.3; 12) as described in claim 7 or claim 8, wherein the evaluation system (1.7) operates to determine chemical properties of the particles based on at least a second detector output provided by the second detector or a Raman spectrum provided by the Raman spectrometer.

10. An inspection system (1.3; 12) operative to inspect a sealed medical container containing a liquid, said inspection system (1.3; 12) comprising: a sample holder (1.4; 2.1; 12.1) operative to hold said sealed medical container; and a light source (11) operable to output a Raman probe beam incident on the sealed medical container; a detector (11) operative to detect a Raman spectrum in response to the output of the Raman probe beam; and An inspection system (1.3; 12), characterized by an evaluation system (1.7) coupled to said detector and operative to determine a characteristic of particles in said sealed medical container based on at least said Raman spectrum.

11. A manufacturing system (1), comprising: a filling device (1.1) operable to fill at least one liquid into a medical container; a sealing device (1.2) operable to close the medical container containing the at least one liquid; and A manufacturing system (1) comprising an inspection system (1.3; 12) according to any one of claims 1 to 10, operative to inspect the sealed medical container for particulate matter.

12. 1. A method for inspecting a medical container containing a liquid, comprising: positioning said medical container along an axis (2.2; 6.11) by means of a sample holder (1.4; 2.1; 12.1), illuminating the medical container with light by at least one light source; detecting, with at least one detector, return light from the medical container, the return light being detected in response to illuminating the medical container with the light; Detecting and / or determining by an evaluation system a characteristic of the particle based on at least an output of the at least one detector, the at least one detector including a first detector (3.4; 4.6; 5.3; 6.6, 6.7; 7.3, 7.4) including a photoelectric converter having a plurality of pixels; and and moving the at least one light source and / or the at least one detector around the axis (2.2; 6.11) while the sample holder (1.4; 2.1; 12.1) holds the medical container in a rotatably and translatably fixed manner, the at least one light source comprises a first light source (3.2; 4.6; 5.2; 6.3; 7.2) operative to output a light sheet; 10. The inspection method according to claim 9, wherein the first detector (3.4; 4.6; 5.3; 6.6, 6.7; 7.3, 7.4) comprises an inclined objective lens (6.7; 7.4).

13. 1. A method for inspecting a sealed medical container containing a liquid, comprising: positioning said sealed medical container by means of a sample holder (1.4; 2.1; 12.1), irradiating the sealed medical container with a Raman probe beam by a light source; detecting a Raman spectrum responsive to irradiating the sealed medical container with the Raman probe beam using a Raman spectrometer; and determining a characteristic of particles in the sealed medical container based on at least the Raman spectrum.

14. An inspection method according to claim 12 or 13, performed by an inspection system (1.3; 12) according to any one of claims 1 to 10 or by a manufacturing system according to claim 11.

15. A manufacturing method comprising: Filling liquids into medical containers; sealing the medical container containing the liquid; and A manufacturing method comprising carrying out the inspection method of any one of claims 12 to 14 to inspect the sealed medical container for particulate matter.

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