Inspection system and method for closed medical containers

Abstract

The present invention relates to an inspection system (1.3) operable to inspect a medical container containing a liquid. The inspection system (1.3) comprises an actuator (1.6) operable 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 characteristics of particles in the medical container.

Description

Technical Field

[0001] The present invention relates to an inspection system and method for inspecting medical containers. The present invention relates to such inspection systems and methods, which are operable to detect and / or characterize particulate matter in a closed medical container having a liquid contained therein. The present invention relates to such inspection systems and methods, which are operable to detect, characterize and / or identify chemical particulate matter in a closed medical container using optical techniques, such as visual and / or spectroscopic techniques.

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

[0003] The present invention can be used in association with a variety of medical containers (such as vials or syringes). One and the same inspection system can be operable so that it can inspect medical containers of different types, shapes, sizes and / or different materials (such as glass, polymers, etc.). Background Art

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

[0005] Because of the potential impact of particulate matter on patients, regulatory agencies require information on the presence of particles, as well as evidence of limiting, controlling, and identifying any product-related impurities. Drug products intended for parenteral administration must be substantially free of visible particles (see, e.g., U.S. Pharmacopeia No. <1> chapter).

[0006] To meet this expectation, techniques for controlling and monitoring visible particulate matter are used. Inspection can be performed as a manual visual inspection (inspection with the naked eye under controlled conditions), a semi-automated visual inspection (which can use an additional system that provides container handling for the inspector), or an automated visual inspection. The latter uses an automated machine (e.g., a diode array sensor or a CCD camera) to detect the presence of any visible particles that may be applicable.

[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 performed in a systematic manner. Investigations into the mechanical formation and kinetics of intrinsic particles are carried out through stability studies to determine the specific profile of the product during the shelf life. This profile (which gives the expected properties and possible changes over time) should be described in the product submission documentation. As a further example, in recent years, the pharmaceutical industry has faced new challenges regarding the increasing presence of intrinsic (protein aggregates or free fatty acids) particles at the time of marketing or during storage of the final drug product. The European Pharmacopoeia Monograph 2031 "Monoclonal Antibodies for Human Use" has been revised to reflect this situation, and the clause: "No visible particles, unless otherwise justified and authorized" is included in the requirements for testing and appearance. This means that a container containing intrinsic visible particles similar to those observed and recorded during the development phase will still be considered "essentially free of visible particles".

[0008] WO 2020 / 131666 A1 discloses a system for detecting particles in a container. The system is configured so that the container rotates during a process of particle detection using optical components.

[0009] FIG. 15 is a schematic diagram of a conventional system for detecting particles in a container in which a container is rotated. A container 15.1 filled with a liquid drug product is positioned and held by a motorized sample holder 15.2 that rotates around an axis of rotation 15.3. A light ring 15.4 is placed below and centered on the sample holder so that light emitted from the light ring illuminates the entire container concurrently. A video camera 15.5, which is generally oriented orthogonal to the container, is used to acquire video of moving particles in the container as it rotates.

[0010] Various challenges are associated with the conventional setting of rotating the container during image acquisition. As shown in Figure 15, conventional automated visual inspection systems are equipped with a rotation unit to move particles so that particles can be detected by processing a series of video frames. However, the rotation of the container is the cause of bubble formation, which is one of the well-known sources of false positive detection. In addition, some biological products may be sensitive to stirring and require careful handling of the container, while other biological products tend to generate foam on the surface, which complicates sample visualization. In addition, the rapid movement of particles in the fluid is an obstacle to the precise positioning of particles that may be useful for further analysis, such as three-dimensional (3D) positioning.

[0011] If the detected particles are further characterized, this may bring additional challenges. US2020 / 0241002A1 discloses a system for analyzing particles using Raman technology. For analysis, the container must be opened and the particles must be separated using a filter.

[0012] FIG. 16 provides an overview of several steps in the chemical identification process of visible particles. The process begins with step 16.1 of imaging particles present in a closed container, followed by step 16.2 of filtering the sample on a gold-coated filter to collect particles. The next step is to transfer the gold filter to the motorized sample stage of a Fourier transform infrared spectroscopy (FTIR) or Raman microspectrometer to chemically identify the particles (steps 16.3 and 16.4). These instruments combine the visualization capabilities of a standard microscope with the analytical features of a spectrometer for component analysis. The filter view allows all separated particles to be detected and located manually or even automatically using image processing algorithms. The position of the sample stage is controlled by several motorized mechanical axes to bring the particles into focus of the microscope device one by one. The correct positioning of the particles implements step 16.3 in which FTIR or Raman spectra are acquired for each individual particle (spectral fingerprint recognition process). Then, at step 16.4, chemical identification may be performed by processing the FTIR or Raman spectrum of the test sample with the FTIR or Raman spectra in the database of known compounds using a matching algorithm.

[0013] In the process explained with reference to Figure 16, it is necessary to prepare and clean all required instruments (step 16.21) to ensure that no additional contaminants are found on the gold filter. This applies similarly to the post-filtration process, where attention needs to be paid to the cleaning and storage of the instruments (step 16.22). These two steps 16.21 and 16.22 are parallel to the chemical identification process. These steps do not increase the value of data collection and are time consuming, but are necessary to ensure sample integrity and data reliability. Conventional chemical identification processes as described with reference to Figure 16 are destructive and require a lot of time and resources due to the filtration step (step 16.2).

[0014] Therefore, there is a need for a system and method that allows for the detection, characterization, and / or chemical analysis of particles in a closed medical container using a process that mitigates at least some of the disadvantages of the conventional techniques described above. For example, there is a need for a system and method that allows for the detection, characterization, and / or chemical identification of particles in a closed medical container using optical techniques (e.g., visualization and / or spectroscopy techniques) in an efficient and reliable manner. Summary of the invention

[0015] According to the 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 subject matter of the dependent claims.

[0016] In one aspect, the present invention is a testing system operable or configured to test a medical container containing a liquid, the testing system comprising: a sample holder operable or configured to hold the medical container along an axis; at least one optical system comprising at least one light source operable or configured to output light incident on the medical container and at least one detector operable or configured to detect return light from the medical container; an evaluation system coupled to the at least one optical detector and operable or configured to detect and / or determine characteristics of particles in the medical container based at least on an output of the at least one detector; and at least one actuator operable or 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 rotationally and translationally fixed manner.

[0017] The inspection system according to the present invention is operable or configured to reliably perform efficient and reliable detection of particulate matter. Rotation of the container (which may result in increased bubble formation) does not increase the risk of false positives. By moving the light source and / or detector of the optical system about an axis, the entire container can be analyzed. The ability to locate particles is improved, such as the ability to perform three-dimensional (3D) particle location.

[0018] At least one actuator may be operable or configured to move at least one light source and at least one detector along a curved path about an axis. This facilitates the application of optical techniques to the full container volume using a simple mechanical configuration, such as a configuration with a rotating element to displace at least one light source and at least one detector.

[0019] One, several or all of the following apply: at least one segment of the path extends in a plane perpendicular to the axis; the path may include an elliptical arc; the path may include a circular arc; at least one actuator may be operable or configured to concurrently change the position and orientation of at least one light source to keep the illumination light incident on the medical container and / or the axis; at least one actuator may be operable or configured to concurrently change the position and orientation of at least one detector to cause the return light to be incident on the at least one detector. These techniques facilitate the application of optical techniques to the full container volume using simple mechanical configurations, such as configurations with rotating elements to displace at least one light source and at least one detector.

[0020] The inspection system may include a frame on which the at least one optical system is supported, wherein the sample holder is arranged in a fixed position relative to the frame. At least one actuator may be operable or configured to move at least one light source and / or at least one detector relative to the frame. By keeping the sample holder stationary during optical analysis performed by the at least one optical system, the risk of 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 a stationary container during optical analysis.

[0021] The at least one light source comprises a first light source operable or configured to output a light sheet. This allows the container volume to be analyzed in an efficient manner along a plane intersecting the container volume.

[0022] The at least one actuator may include 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 rotary actuator. This allows the container volume to be analyzed in an efficient manner and using a simple configuration, 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 incident on the medical container and an image is captured by the first detector.

[0023] The first detector may have a first detector axis arranged 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 arranged in an oblique configuration relative to the light sheet so as 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 is moved about the axis.This configuration facilitates analysis for possible optical effects that may be introduced by the cylindrical wall of the medical container.

[0025] The at least one detector includes a first detector including a photoelectric converter having a plurality of pixels. The first detector may be operable or configured to provide a first detector output in response to return light during illumination of the medical container using the light sheet. This configuration allows the use of images captured by the first detector for several angular positions of the first light source and the first detector about an axis to detect visible particles when the visible particles are within the light sheet.

[0026] The first detector may comprise a tilted objective lens. The first detector may comprise a Sham camera. This configuration facilitates an analysis that accommodates 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 the particle when it is in the light sheet, based at least on the first detector output. Thus, the inspection system may be operable or configured to receive at least a binary output indicating whether the particle is present in the container. Such determination is particularly useful for inspection during ongoing large-scale manufacturing processes.

[0028] Alternatively or additionally, the evaluation system may be operable to determine that the particle is located in the interior of the medical container based at least on the first detector output. Thus, the inspection system may be operable or configured to distinguish particles within the container from particles on the exterior of the container and / or within the container wall. This distinction is particularly useful for inspection in ongoing large-scale manufacturing processes.

[0029] Alternatively or additionally, the evaluation system may be operable to distinguish between particles and bubbles in the liquid in the medical container based at least on the first detector output. Thus, the inspection system may be operable or configured to distinguish between particles and bubbles. This distinction may be particularly useful for preventing false positives in particle detection.

[0030] Alternatively or additionally, the evaluation system may be operable to distinguish particles from impurities within the container wall of the medical container based at least on the first detector output. Thus, the inspection system may be operable or configured to distinguish particles within the container from particles within the container wall. Such distinction may be particularly useful for preventing false positives in particle detection.

[0031] Alternatively or additionally, the evaluation system may be operable to determine information about the morphology of the particle, optionally the three-dimensional surface shape of the particle, based at least on the first detector output for a number of different angular positions of the first light source and / or the first detector around the axis. Thus, the inspection system may be operable or configured to determine the geometrical properties of the particle. This determination is particularly useful for determining the possible root cause of the impurity.

[0032] Alternatively or additionally, the evaluation system may be operable to determine information about the size of the particle, optionally the three-dimensional size of the particle, based at least on the first detector output. Thus, the inspection system may be operable or configured to determine the geometric properties of the particle. Such determination may be particularly useful for determining the possible root cause of the impurity.

[0033] The at least one light source may include a second light source operable 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 a spectral characteristic indicative of a chemical nature of the particle. Capturing a Raman spectrum on a medical container allows 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.

[0034] The at least one actuator may include a second actuator operable or configured to move both the second light source and the second detector. This facilitates positioning the light source and detector of the Raman spectroscopy system relative to the container, making it easier to specifically target particles that have been previously positioned in 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 the Raman spectrometer to target particles that have been previously positioned in a container.

[0036] The inspection system may include a control device operable or configured to control the second actuator based at least on the first detector output. This configuration allows the first light source and the first detector to be used for 3D localization of the particle, followed by further investigation of the particle using Raman spectroscopy without opening the medical container.

[0037] The evaluation system may be operable or configured to determine the chemical characteristics of the particles based at least on 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 the spectral characteristics indicative of the chemical nature of the particles. Capturing the Raman spectrum on the medical container allows 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 particles are acceptable particles.

[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 (such as different container volumes, container lengths measured along an axis, and / or container diameters measured perpendicular to the axis). The inspection system may include at least one adjustment mechanism to accommodate containers of different types and / or sizes. The at least one adjustment mechanism may include one, several, or all of the following: a mechanism for adjusting the diameter of a receiving portion of a sample holder; a sample holder displacement mechanism for adjusting the position of a container along the axis held by the sample holder; an optical system displacement mechanism for adjusting the position of an optical system along the axis and / or perpendicular to the axis (e.g., to accommodate different refractions resulting from different container diameters). Thus, the inspection system is able to operate in association with different container types and / or sizes without requiring recalibration for each different container type and / or size.

[0039] The testing system may be operable to test a medical container selected from the group comprising or consisting of a vial and a syringe. The medical container may have a translucent, in particular transparent, circumferential wall. The circumferential wall may extend in a cylindrical manner around the axis for at least a portion of the length of the container and typically for a majority of the length of the container.

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

[0041] The evaluation system may be operable or configured to provide an output based at least on the output of the at least one detector. The inspection system may include an interface (such as a human machine interface (HMI), e.g. a graphical user interface (GUI)) for outputting information about the presence, geometrical properties and / or chemical properties of the particles based at least on the output of the at least one detector. Alternatively or additionally, the inspection system may include an interface for outputting a control signal operable or configured to control at least one component of a manufacturing system for manufacturing the medical container. Alternatively or additionally, the inspection system may include an interface for outputting a control signal operable or configured to cause the medical container to be selectively discarded based on whether the evaluation system has identified the presence of particles in the interior of the container and has identified the particles as having a size and / or chemical properties that render the medical container unacceptable.

[0042] The inspection system may be an automated inspection system. The inspection system may make a decision on the acceptability of visible particles to the medical container without human intervention.

[0043] The testing system may include a load-unload mechanism operable or configured to provide a medical container to the sample holder for analysis and to remove the medical container from the sample holder after all desired signals have been detected by the at least one detector.

[0044] The inspection system may include several optical systems operable to identify and / or characterize particles. The inspection system may be operable so as to operate several optical systems in sequence. For example, a first optical system may be operable as an imaging system that captures an image of a medical container. The first optical system may include a source of light sheets and a camera chip. The camera chip may detect an image in response to illumination of the medical container with the light sheet while a first actuator rotates the first optical system (i.e., both the source of the light sheet and the detector with the camera chip) around an axis. The 3D position of the particle in the interior of the container (i.e., within a cavity defined by the interior of the container that also contains a liquid) can thereby be determined. The Raman spectroscopy system may then be operated to specifically obtain the Raman spectrum of the previously located particle. A second actuator (which may be operable or configured to adjust the Raman probe and / or detector along at least two directions) optionally combined with the first actuator may be operated in response to the 3D position of the particle.

[0045] In one aspect, the present invention is a testing system operable or configured to test a closed medical container containing a liquid, the testing system comprising: a sample holder operable or configured to hold the closed medical container; a light source operable or configured to output a Raman detection beam incident on the closed medical container; a detector operable or configured to detect a Raman spectrum in response to the output Raman detection beam; and an evaluation system coupled to the detector and operable or configured to determine characteristics of particles in the closed medical container based at least on the Raman spectrum.

[0046] The inspection system of this aspect of the invention allows for chemical analysis of any particles located within the interior of a container that also contains a liquid, while the medical container is maintained in a sealed state. Chemical characteristics can be determined efficiently and without affecting the integrity of the container. This is particularly useful when chemical characterization is used during large-scale production, where medical containers are selectively discarded only if chemical analysis, as obtained from Raman spectroscopy, shows the presence of at least one unacceptable particle within the container.

[0047] The inspection system may comprise an actuator arrangement having at least two, for example three or more, degrees of freedom. This allows positioning of the Raman light source and / or detector relative to the sample in order to perform measurements on the positioned particles.

[0048] The actuator arrangement may include a 3-axis robotic arm. The actuator arrangement may include a first actuator operable or configured to rotate a support on which the Raman light source and detector are mounted. The actuator arrangement may include a second actuator operable or configured to displace the Raman light source and / or detector relative to the support along at least two axes. This allows the Raman light source and / or detector to be positioned relative to the sample so as to measure the positioned particles.

[0049] The sample holder can position the container so that it does not move while the Raman spectrum is measured. This facilitates measurement because the particles can be more easily targeted in an immobile container where there are no rotational forces that could easily displace the particles before the Raman spectrum is acquired.

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

[0051] Additional optional features of the testing system of this aspect of the invention, and the effects achieved thereby, correspond to the optional features discussed in connection with the testing system of the first aspect of the invention described above.

[0052] According to an embodiment of the present invention, a manufacturing system is provided, which includes: a filling device, which is operable or configured to fill at least one liquid into a medical container; a sealing device, which is operable or configured to seal the medical container containing at least one liquid; and an inspection system according to any aspect or embodiment disclosed herein, which is operable or 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 various aspects or embodiments.

[0054] The manufacturing system may include a formulation preparation system operable or configured to prepare at least one liquid. The at least one liquid may contain an active pharmaceutical ingredient (API).

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

[0056] The manufacturing system may include a discard station operable or configured to selectively discard a medical container when the inspection system determines that the medical container contains at least one particle within its interior and the at least one particle is unacceptable based on particle characteristics (such as chemical characteristics) determined by the inspection system.

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

[0058] The inspection method according to this aspect of the invention is operable or configured to reliably perform efficient and reliable detection of particulate matter. Rotation of the container (which may result in increased bubble formation) does not increase the risk of false positives. By moving the light source and / or detector of the optical system about an axis, the entire container can be analyzed. The ability to locate particles, such as the ability to perform three-dimensional (3D) particle location, is improved.

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

[0060] The optional features of the testing method and the effects obtained thereby correspond to the optional features discussed in connection with the testing system.

[0061] According to another aspect, the present invention is a method for inspecting a closed medical container containing a liquid. The method includes: positioning the closed medical container by a sample holder; irradiating the closed medical container with a Raman detection beam by a light source; detecting a Raman spectrum using a Raman spectrometer in response to irradiating the closed medical container with the Raman detection beam; and determining characteristics of particles in the closed medical container based at least on the Raman spectrum.

[0062] The inspection method according to this aspect of the invention allows for chemical analysis of any particles located within the interior of a container that also contains a liquid, while the medical container is maintained in a closed state. Chemical characteristics can be determined efficiently and without affecting the integrity of the container. This is particularly useful when chemical characterization is used during large-scale production, where medical containers are selectively discarded only if chemical analysis, as obtained from Raman spectroscopy, shows the presence of at least one unacceptable particle within 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 discussed herein.

[0064] The optional features of the testing method according to this aspect and the effects obtained thereby correspond to the optional features discussed in connection with the testing system.

[0065] According to another embodiment, the present invention is a manufacturing method comprising: filling a liquid into a medical container; sealing the medical container containing the liquid therein; 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 discussed herein.

[0067] The optional features of the manufacturing method and the effects obtained thereby correspond to the optional features discussed in connection with the manufacturing system. BRIEF DESCRIPTION OF THE DRAWINGS

[0068] The inspection system, the manufacturing system and the associated method according to the present invention are described in more detail below by means of exemplary embodiments and with reference to the accompanying drawings, in which:

[0069] Figure 1 A manufacturing system according to an embodiment is shown;

[0070] Figure 2 An inspection system according to an embodiment is shown;

[0071] Figure 3 An inspection system according to an embodiment is shown;

[0072] Figure 4 An inspection system according to an embodiment is shown;

[0073] Figure 5 An inspection system according to an embodiment is shown;

[0074] Figure 6 An inspection system according to an embodiment is shown;

[0075] Figure 7 Shows Figure 6 A plan view of the inspection system;

[0076] Figure 8 shows an image of a closed medical container obtained by an optical imaging system of an inspection system according to an embodiment;

[0077] Fig. 9 An image obtained by an optical imaging system of an inspection system according to an embodiment for different angular positions of a light sheet showing the volume of a closed medical container in which particles are present;

[0078] Fig.10 shows an image of a closed medical container and particle reconstruction obtained using an optical imaging system of an inspection system according to an embodiment;

[0079] Fig.11Components of a compact Raman video probe of an inspection system according to an embodiment are shown;

[0080] Fig.12 An inspection system according to an embodiment is shown;

[0081] Fig.13 A flow chart of a method according to an embodiment is shown;

[0082] Fig.14 An artificial intelligence (AI) model that may be executed by an inspection system according to an embodiment is shown;

[0083] FIG15 shows a schematic diagram of a prior art inspection system;

[0084] FIG. 16 shows a schematic diagram of a prior art inspection method. DETAILED DESCRIPTION

[0085] In the following description, some terms are used for convenience and are not intended to limit the present invention. The terms "right", "left", "up", "down", "below" and "above" refer to the directions in the figure. The terms include the terms and their derivatives and terms with similar meanings that are explicitly mentioned. In addition, spatial relative terms such as "below ... ", "below", "below", "above", "above", "near side", "distal side" etc. can be used to describe the relationship between an element or feature and another element or feature as shown in the figure. These spatial relative terms are intended to cover different positions and orientations of the device in use or operation in addition to the positions and orientations shown in the figure. For example, if the device in the accompanying drawings is turned over, the elements described as "below" or "below ... below" of other elements or features will be "above" or "above ... above" of other elements or features. Therefore, the exemplary term "below" can cover the position and orientation of the top and bottom. The device can be oriented (rotated 90 degrees or in other orientations) in other ways, and the spatial relative descriptors used in this article are interpreted accordingly. Similarly, the description of the movement along and around various axes includes various specific device positions and orientations.

[0086] To avoid repetition in the drawings and the description of the various aspects and illustrative embodiments, it should be understood that many features are common to many aspects and embodiments. The omission of an aspect in the description or drawings does not imply that the aspect is missing in the embodiment containing the aspect. On the contrary, the aspect may be omitted for clarity and to avoid lengthy descriptions. In this context, the following description applies to the rest of this specification: if a reference numeral is included in the drawings that is not explained in the directly relevant part of the specification for the purpose of illustrating the drawings, reference may be made to the previous or subsequent parts of the specification. In addition, for reasons of clarity, if a reference numeral is not provided in the drawings for all features of a certain component, reference may be made to other drawings showing the same component. Similar reference numerals in two or more drawings represent the same or similar elements.

[0087] Systems and methods according to embodiments may be operable or configured to detect and optionally further characterize visible particulate matter in the interior cavity of a medical container that also contains a liquid, such as a formulation containing an active pharmaceutical ingredient (API). The systems and methods provide automated inspection techniques. The systems and methods may be operable to detect, characterize, and / or chemically identify particles without opening the medical container and without rotating the medical container.

[0088] "Particulate matter" is a general expression that covers all forms of particles that may be found in parenteral drug products. To facilitate interpretation by manufacturers, the various regulatory agencies (European, Japanese and US Pharmacopeia) have decided to unify and share the same definition of particulate matter: "Particulate matter in injectable and parenteral dosage forms consists of extraneous mobile undissolved particles other than gas bubbles that are unintentionally present in solution".

[0089] As used herein, "visible particles" may be understood as or include particles having a diameter of 100 micrometers or greater. "Visible particles" may also encompass smaller particle diameters. The diameter may be measured along the direction along which the particle has the longest extension of the particle.

[0090] In general, particles are classified as intrinsic, extrinsic, or inherent. Intrinsic particles are generated during the manufacturing process and can include silicone oil, rubber, glass, or stainless steel. Extrinsic particles come from outside the process and can include metal, human hair and skin, or dust. Intrinsic particles, such as protein aggregates or free fatty acids, occur naturally in biologics and may be acceptable under appropriate control strategies.

[0091] Due to the potential impact of particulate matter on patients, regulatory agencies require information regarding the presence of particles, as well as evidence to limit, control, and identify any product-related impurities.The systems and methods of the present invention address the need for automated inspection of closed medical containers for particulate matter.

[0092] The inspection systems and methods according to some embodiments may also be operable or configured to provide further analysis or other characterization. In contrast to conventional techniques, this extended testing is non-destructive and can be performed while the medical container is sealed. Particle size, morphology, and chemical identification need to be determined to find the root cause of particle formation. These investigations are not routinely performed as routine testing during manufacturing and are only triggered when unexpected events and limits are violated.

[0093] However, during the formulation development phase, particle characterization and identification is performed in a systematic manner. Investigations into the mechanical formation and dynamics of the intrinsic particles are performed through stability studies to determine the product specific profile during shelf life. This profile, which gives the expected properties and possible changes over time, can be determined and recorded using the assay systems and methods disclosed herein.

[0094] In recent years, the pharmaceutical industry has faced new challenges regarding the increasing presence of inherent (protein aggregates or free fatty acids) particles in the final drug product at the time of marketing or during storage. The European Pharmacopoeia Monograph 2031 "Monoclonal Antibodies for Human Use" has been revised to reflect this situation and the clause: "absence of visible particles, unless otherwise justified and authorized" has been included in the requirements for testing and appearance. This means that containers containing inherent visible particles similar to those observed and recorded during the development phase will still be considered "essentially free of visible particles". The ability to assess inherent visible particles in closed containers is becoming increasingly important to avoid contamination and preserve samples for further analysis. In contrast to some conventional analytical techniques that rely on opening the container for further analysis (destructive testing) as previously described herein, the inspection systems and methods of some embodiments are operable or configured to address this need in an efficient manner.

[0095] The inspection systems and methods of some embodiments also allow one to obtain a more comprehensive characterization of visible particles in closed containers. This addresses the needs demonstrated by the frequent irreproducibility of manual processes performed by human inspectors, the challenges associated with bubble detection, and the lack of non-destructive automated techniques for extended visible particle characterization (counting and size) and chemical identification.

[0096] The inspection system and method of the present invention described herein provide a visual inspection device that provides robust detection, accurate size determination, quantification and 3D localization of visible particles in closed containers based on light sheet microscopy. The inspection system and method can also integrate Raman video probes into the visual inspection unit to achieve in-situ chemical identification.

[0097] The inspection system and method of the present invention are suitable for use in automated visual inspection techniques for small batches and for inspection of units in the development phase. The reliability of visible particle detection can be improved by the techniques of the present invention, and the root cause of particulate matter can be identified. The inspection system and method are not limited to these fields of use.

[0098] The inspection system and method of the present invention use one or more actuators that displace components of the optical system relative to a medical container held stationary by a sample holder during an optical measurement process. Thus, the inspection system and method address challenges encountered with techniques using rotating containers, which may be associated with particles and / or the rotating process, among other sources.

[0099] The particles that may be present in the liquid-filled container may 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, which are usually made of metal or glass, tend to have very high densities, which makes it more difficult to move or keep the particles moving for the duration of data acquisition in conventional technology. In some cases, the particles may adhere to the inner wall of the container, which makes the particles invisible to the detection algorithm in conventional technology. In addition, it may be difficult to detect the fibrous particles based on the orientation of the fibrous particles that are longer in one dimension in the container and the camera / sensor in conventional technology. The same applies to transparent particles with a refractive index close to the refractive index of the drug product solution in conventional technology. These challenges are solved by the inspection system and method of the present invention, which are designed to move the components of the optical system around the medical container during data acquisition.

[0100] Conventional automated visual inspection systems (such as the system explained with reference to FIG. 15 ) are equipped with a rotation unit to move particles so that the particles can be detected by conventional detection algorithms. However, this process is one of the main causes of bubble formation, which is one of the well-known sources of false positive detections. In addition, some biological products may be sensitive to agitation and require careful handling of the container, while other biological products tend to generate foam on the surface, which complicates sample visualization. In addition, the rapid movement of particles in the fluid is an obstacle to the accurate 3D positioning of particles that may be useful for further analysis. These challenges are solved 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 while keeping the medical container motionless during data acquisition.

[0101] The inspection system and method of the present invention can provide a binary output indicating the presence or absence of visible particles in a container.The inspection system and method of the present invention also addresses the need for better and more complete characterization of particles in closed containers.

[0102] The inspection system and method of the embodiment of the present invention uses a light sheet microscope to detect non-mobile particles in a closed container, and further analyzes the quantification, 3D size measurement and 3D position of the non-mobile particles required. Data acquisition for spectroscopy technology (especially Raman spectroscopy) can be performed to obtain a more complete characterization.

[0103] The inspection system and method of embodiments of the present invention are operable to robustly detect and accurately locate visible particles (which may be, for example, larger than 100 microns or even smaller) made of different materials in a fixed medical container filled with a liquid drug product. Compared to conventional inspection systems based on the detection of moving particles, suppressing the rotation of the sample stage (allowing extended analysis in closed containers) provides new inspection opportunities.

[0104] Figure 1 A manufacturing system 1 for manufacturing medical containers containing liquids therein is shown. The medical containers may be vials or syringes, but are not limited thereto. Each medical container may have a substantially cylindrical transparent wall extending circumferentially around the longitudinal axis of the medical container. Each medical container may be a parenteral drug product.

[0105] The manufacturing system 1 comprises a filling device 1.1. In 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 or may contain a parenteral drug. The manufacturing system may comprise a medical formulation preparation system 1.9, which in operation may prepare a liquid for filling into a medical container.

[0106] The manufacturing system 1 comprises a closure device 1.2. In operation, the closure device 1.2 closes a medical container having a liquid contained therein. The closure device 1.2 may be operable or configured to close the medical container so as to prevent the liquid from flowing out before the medical container is opened.

[0107] The manufacturing system 1 includes an inspection system 1.3 according to an embodiment. The inspection system 1.3 includes a frame that can define a housing. The inspection system 1.3 includes a sample holder 1.4. According to the present invention, the sample holder 1.4 is operable or configured to position and maintain a medical container being inspected for particulate matter in a stationary (particularly non-rotating) state when 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, in operation, irradiates a light sheet onto the medical container and uses an image sensor (such as a CCD sensor or other image sensor) to detect the resulting image of the medical container. The imaging system is rotated around the medical container by a certain angle, which can but does not need to reach or exceed a full rotation (360°). The light source and detector of the imaging system can be rotated so as to maintain their relative arrangement when 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 three-dimensional (3D) position. The optical system may include components of a Raman system, such as a source of a Raman probe beam and a Raman detector that detects light obtained by Raman scattering of the probe beam by particles in the medical container. The Raman spectrometer need not be movably mounted, but the source of the Raman probe beam and the 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 include or may be implemented as a processor, a controller, an application specific integrated circuit (ASIC), a field programmable gate array (FPGA), other integrated circuits, circuits including quantum bits (qubits) and / or quantum gates, or a combination thereof.

[0108] The manufacturing system 1 includes a process control system 1.8. The process control system 1.8 can control at least one component of the manufacturing system 1 in response to a result determined by the inspection system 1. For example, the manufacturing system 1 can control one or more of the filling device 1.1, the sealing device 1.2, and the medical preparation system 1.9 (if present) according to whether the inspection system 1.3 (i) determines that visible particles are present in the medical container, and (ii) if particles are present, determines that the particles do not have characteristics that make it acceptable to be contained in the medical container for use of the medical container. The process control system 1.8 can control an unloading device that removes the medical container from the sample holder 1.4 in order to discard the medical container when the inspection system 1.3 (i) determines that visible particles are present in the medical container, and (ii) if particles are present, determines that the particles do not have characteristics that make it acceptable to be contained in the medical container for use of the medical container.

[0109] Alternatively or additionally, the testing system 1.3 may include or may be coupled to a human machine interface (HMI), such as a graphical user interface (GUI), to output information regarding the results of the testing performed on the medical container.

[0110] Figure 2 A schematic diagram of an inspection system 2 according to an embodiment is shown. The inspection system comprises a sample holder 2.1 operable or configured to hold a medical container in an immobile state while optical measurements are being taken of it and in particular while actuators 2.6, 2.7 rotate the optical systems 2.5, 2.8 around an axis 2.2 along which the medical container extends. The medical container preferably has a transparent, substantially cylindrical wall circumferentially surrounding the axis 2.2 when held by the sample holder 2.1.

[0111] 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 arranged. The first optical system 2.5 may include components (such as a first light source and a first detector) that are offset from each other by a certain angle around the circumferential direction, which angle may be fixed when rotating the first optical system 2.5 around the axis 2.2.

[0112] The second actuator 2.7 can displace at least a second light source and / or a second detector of the second optical system 2.8 (and optionally additional components, such as an interferometer beam path) relative to the axis 2.2. The second actuator 2.7 can be operable or configured to produce a translational displacement along the axis 2.2 and transverse to the axis 2.2. The second actuator 2.7 can allow the second light source and / or the second detector of the second optical system 2.8 to be positioned in 3D relative to the sample holder 2.1 alone or in combination with the first actuator 2.6. In use, the second actuator 2.7 can be controlled so that the second optical system 2.8 sequentially detects any particles that have been identified as being located in the internal cavity of the container using the first optical system 2.5.

[0113] In one embodiment, the second actuator 2.7 may comprise a multi-axis robotic arm, such as a 3-axis robotic arm. In another embodiment, the second actuator 2.7 may be operated in combination with the first actuator 2.6. The first actuator 2.6 may be operated under the control of a control device (which may be implemented as a computer) to adjust the desired angular position of the second light source and / or the second detector of the second optical system 2.8 around the axis 2.2. The second actuator 2.7 may be operated under the control of the control device to provide a linear displacement along one or two axes so as to thereby target particles in the medical container at a desired position along the axis 2.2 and / or at a desired radial position (measured transversely to the axis 2.2).

[0114] The inspection system and method will be described in more detail below. The inspection system and method of an embodiment relate to a novel lighting and camera / lens configuration that rotates around a stationary container filled with a liquid drug product. The visual inspection system is operable or configured to output a laser light sheet for illuminating particles in a closed container, the laser light sheet being positioned to aim at the axis of symmetry of the container. In addition, a video camera having a tilted (Sham) objective lens mounted thereon is positioned at a defined distance and angle from the light sheet to ensure that the field of view of the video camera is adjusted to the illuminated portion of the sample. A motorized mechanical system is then used to hold the light sheet and the video camera and to enable their rotation around the static sample to ensure inspection of the entire volume.

[0115] Figure 3An inspection system according to an embodiment is shown. A container 3.1 (here represented by a vial, it should be understood that the container can have different containers and can be a syringe or other type of container that can hold a liquid drug product) is held stationary in the center of the device by a sample holder. A laser 3.2 that generates a light sheet that is high enough to illuminate the entire height of the sample is guided and can be focused on the central axis of the container. A video camera 3.4 equipped with a tilted objective lens 3.3 is positioned accordingly relative to the container and the light sheet to obtain an image of the sample. A representation of the laser 3.21, camera 3.31 and lens 3.41 tilted after rotation has been added to represent the scanning of the device around the stationary container 3.1. The motorized mechanical system that enables the rotation of the laser 3.2, camera 3.3 and objective lens 3.4 is not shown. Figure 3 , but are shown and explained in more detail elsewhere herein.

[0116] Figure 1 The rotation of the optical imaging system enables scanning of the entire volume of the container and easily detects visible particles on the inside (if present). If a particle is positioned in the width of the light sheet, the particle will emit a reflection that is clearly discernible on the image acquired by the camera. Particles larger than the width of the light sheet can be found 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 the entire volume in three dimensions. The inner and outer walls of the container are also visible on the collected images, which allows the evaluation circuit (not shown) to easily distinguish particles inside or outside the internal cavity of the medical container. For example, particles located in the internal cavity can be distinguished from particles within the wall thickness and particles on the outside of the container wall.

[0117] The tilted objective 3.4 enables overcoming challenges associated with sample configuration. The cylindrical shape of the container filled with liquid pharmaceutical product creates a lens effect that results in blind areas preventing complete inspection of the sample. Furthermore, the imaging device 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 so as 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 device components.

[0118] Analyzing particles suspended in a liquid solution using this newly proposed inspection system and method can become challenging if the particles move too fast within the container. To avoid this, the medical container 3.1 is maintained for several seconds before and during the analysis. In addition to this, the visual inspection components and mechanical / robotic axes are selected so as to enable rapid scanning of the sample. One way to reduce the analysis time is to add one or more light sheets and cameras, which increases the scan area that can be concurrently illuminated at any given time during data acquisition.

[0119] The complete device can be adjusted according to the needs of the analysis. For example, when desired, two light sheets with larger widths and two cameras that scan the sample very quickly can be used to provide robust detection in a reduced time. A single light sheet with a smaller width and one camera that scans the sample in finer increments can be used to achieve robust detection while also improving the accuracy of the 3D localization of the detected particles and the resolution of the 3D reconstruction.

[0120] As explained above, inspection systems for particle inspection in liquid-filled containers face many challenges that stem from different sources. Maintaining the sample stationary and detecting non-moving visible particles provides significant advantages over conventional inspection systems:

[0121] One of the most common challenges of conventional systems is the generation of bubbles due to sample motion. These bubbles are detected as visible particles by the inspection system and represent one of the main causes of false detections (false positives). The inspection system and method according to the present invention does not encounter this challenge and instead provides more reliable and robust detection.

[0122] The detection of non-moving particles provides a solution for particles that are too dense to move during the rotation process or particles that adhere to the inner walls and cannot be detected using conventional systems. The same applies to visible particles present in high viscosity products or low fill volume samples, which are not put into adequate enough motion to be detected.

[0123] Another important advantage of the inspection system and method is that the inspection system and method can be used for several types of containers (vials or syringes) and different sample configurations. In fact, the inspection system and method are robust enough to inspect containers of small or large diameter and with small or large fill volumes without changing their components. The scanning done by the light sheet and the camera with tilted lens is not affected by the challenges related to the meniscus of the sample or the large depth of field triggered by changes in the liquid fill level.

[0124] It is challenging to inspect freeze-dried or emulsion / suspension products for the presence of visible particles because visual inspection of the product contents is constrained. Using conventional methods, it is usually necessary to perform additional tests involving the reconstitution, dissolution or disintegration of a few samples to ensure the quality of the batch. The proposed new inspection system and method provide new capabilities for inspecting these difficult-to-inspect products. One of the new possibilities is to visually inspect the samples before the freeze-drying process. In fact, the freeze-drying process (which requires containers with non-sealed lids) does not allow the samples to be moved, making it impossible to use conventional methods to inspect these samples. Another interesting possibility for emulsion / suspension products is increased sensitivity for visible particle detection provided by the illumination generated by the light sheet.

[0125] Scanning a static sample using a light sheet and a camera with a tilted lens to detect visible particles provides various effects and benefits compared to conventional systems, providing more robust detection and opening up new applications for the future. A more comprehensive characterization of the detected particles is achieved. Slicing the sample and particles with the aid of a light sheet allows for 3D reconstruction that is not possible with conventional systems. This provides very accurate 3D positioning of each individual particle detected, which can be used, for example, 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 size determination. In addition, the inspection system and method can use an image classification algorithm using machine learning that is applied to these 3D images to identify the detected particles.

[0126] Inspection systems and methods according to embodiments of the present invention may include a Raman video probe integrated into the inspection system.

[0127] In contrast to conventional procedures for chemical identification of particles consisting of analyzing particles captured on a filter, the inspection system and method may be operable or configured to perform data acquisition for Raman spectroscopy in a closed container filled with a liquid pharmaceutical product. The inspection system and method address the challenge of analyzing particles in a liquid medium, which prevents the use of several conventional identification methods. Raman spectroscopy is a suitable method for analysis in a closed container due to lower interference with water and glass walls. In addition, the Raman backscattering process is conducive to in-situ analysis because it does not require sample preparation.

[0128] The particles are not fixed or trapped and can be located anywhere in the sample. This represents a huge challenge, since chemical identification of the particles requires data acquisition for a sufficiently long time, i.e. the particles must remain in the focus of the Raman instrument for a minimum time of several seconds (to capture enough scattered light). Therefore, the inspection system and method use a probe that provides better mobility and can be controlled in place in response to the 3D particle position determined using a light sheet and a camera with a tilted objective.

[0129] Described above and with reference to Figure 3 The visual inspection system explained in a little more detail is designed to facilitate the integration of a motorized Raman probe. In fact, maintaining the medical container stationary allows the particles to remain as immobile as possible and increases the 3D positioning accuracy necessary for the focusing of the Raman probe. The data collected by the visual inspection can be used by the control device to control the 3D position of the Raman probe around the sample and focus the Raman probe on each particle one by one.

[0130] Motorization of the probe can be achieved using a robotic arm or a combination of mechanical motorized axes. Sufficient degrees of freedom must be given for positioning the probe to allow the probe to be aimed and focused regardless of the position of the particles within the sample. The Raman probe must at least be able to rotate around the sample (by aiming at the axis of symmetry of the container), changing its height as well as its focus. Mounting the probe on the same rotation system as the laser light sheet and camera (e.g. Figure 2 It is shown schematically, and as in e.g. Fig.12 ) makes calibration easier and increases positioning accuracy.

[0131] Incorporating a video camera into the Raman probe enables live streaming, adding additional capabilities to the entire device. This makes it easier to calibrate the system, as the image obtained by the camera can be used to control the correct positioning of the probe. In addition, obtaining images during analysis makes it easier to ensure that the system is well focused during measurement. This live stream can be used to track particles and correct the position of the probe during data acquisition to ensure that the particles remain in the Raman focal plane during measurement.

[0132] Furthermore, the acquisition of in situ images of the particles at higher resolution can subsequently be used to better characterize the particles. These images provide information on morphology, enable more accurate size determination, and can be processed by machine learning-based image classifiers for particle classification. It is also possible to consider integrating light units to illuminate the particles to be analyzed.

[0133] Figure 4 A second optical system 4 of the inspection system is shown. The second optical system 4 is operable or configured to perform data acquisition for Raman spectroscopy of particles in a medical container 4.1. A probe 4.2 of the second optical system 4. The probe 4.2 combines a light unit 4.5, a video camera unit 4.4 and a Raman probe 4.6. The probe 4.2 is operable 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 light unit 4.5. The image obtained by the video camera 4.4 passes through the same optical path when leaving / entering the microscope objective 4.3.

[0134] Figure 4 A representation of the application of this probe for chemical identification of visible particles present in a static sample 4.1 is provided. The Raman video probe 4.2 is mounted on a mechanical / robotic motorized assembly allowing control of its 3D position around the sample. Note that Figure 4 The motorization system of the probe is not shown above.

[0135] The Raman probe of the inspection system and method also considers another challenge regarding the physical condition of the sample. The cylindrical glass container filled with the liquid drug product acts as a cylindrical lens. Therefore, strong astigmatism may occur. Even if the probe is positioned to aim at the central axis of the container, the acquired image may be distorted and will not allow correct focus on the particles. The same challenge occurs for emitted and backscattered Raman light. Therefore, the probe 4.2 of the inspection system and method has a compensation lens located between the Raman probe 4.5 and the medical container 4.1 to correct the lens effect. The compensation lens can take into account the parameters of the Raman video probe component, the Raman spectrometer and the sample. The lens can be container-specific and can have a configuration according to the diameter of each container.

[0136] The complete Raman system can be divided between the probe 4.2 and the spectrometer. These two parts can be connected by two optical fibers, one for the emitted light to excite the sample and the other for the backscattered light collection. These components and their parameters are selected to meet various purposes. For example, the microscope objective 4.3 to be mounted on the probe 4.2 is selected so that the working length is sufficient to reach all particles present in the sample while maximizing the numerical aperture (NA) to ensure proper collection of backscattered light. In addition, the laser wavelength is selected so as to enhance the Raman scattering process and reduce the fluorescence background.

[0137] The interpretation and processing of the collected raw Raman spectra may include data processing, such as background correction prior to spectral analysis. Due to the sampling conditions, the Raman spectra that will be collected may consist of backscattered light from the particles to be identified and from the surrounding environment (from the glass of the container and the protein formulation). A database of reference spectra under similar analysis conditions can be used to improve the results of the matching algorithm and facilitate the identification of particles.

[0138] Integrating a complete Raman system into a visual inspection device will provide new measurement capabilities. Eliminating the filtering step (Figure 16) will save time and resources, avoid product consumption and potential contamination of the sample, and most importantly, it will automate the entire process of particle identification. Therefore, applying spectroscopic methods to analyze directly in a closed container is believed to increase productivity and reliability of results. The combination of motorized probes will provide a fully automated system to ensure high efficiency and throughput (if desired). The inspection system and method disclosed herein solves the following challenges: combining Raman spectroscopy with a visual inspection system to perform in situ chemical identification of one or more visible particles.

[0139] Inspection systems and methods address the need to obtain a more comprehensive characterization of visible particles in closed containers. The combination of a new inspection system and method for non-mobile visible particle detection in closed containers and in situ Raman spectroscopy for chemical identification provides a complete system for visible particle analysis in closed containers.

[0140] Figure 5 An inspection system 5 is shown, which combines a visual inspection system (for particle detection, localization and / or size determination) with a light sheet source 5.2 and a camera 5.3 with a tilted objective lens with a Raman video probe 5.4. A medical container 5.1, represented here as a vial, is placed in the center of the system and is kept stationary. The axis of symmetry of the medical container is placed along the axis 5.1 by a sample holder (not shown), wherein the axis 5.1 is used as a reference for the positioning and movement of system components. The laser light sheet source 5.2 and the camera 5.3 are mounted on a motorized rotation system, allowing scanning to achieve detection, characterization and 3D localization of visible particles that may be present in the container 5.1. The collected 3D position data is then used to control the position of the motorized Raman video probe 5.4, allowing the motorized Raman video probe to aim and focus on each detected particle one by one in order to perform chemical identification of the particles. The system is designed in such a way that all possible containers and configurations can be analyzed with only a few hardware adaptations (such as replacing the objective lens and / or compensation lens of the Raman video probe 5.4).

[0141] The inspection system and method provide robust detection of visible particles while reducing the variation of the manual visual inspection process, thereby meeting industry requirements. By performing visible particle quantification, accurate particle size measurement, and high-resolution image capture for morphological information, the inspection system and method provide various effects that are superior to conventional fluid imaging systems while being non-destructive. Finally, the integration of Raman spectroscopy (which enables chemical identification of particles) can replace conventional methods involving filtration of samples. The inspection system and method provide the possibility of characterizing visible particles present in parenteral drug products in a non-destructive and fully automated manner. The inspection system and method provide a connection between the morphology, size, and chemical identification of each particle present in the sample.

[0142] The ability to perform extended characterization in situ is a major advantage over conventional methods. In situ analysis reduces the risk of losing and damaging samples containing atypical particles, which are often available in limited quantities. In the early stages of developing a drug product, only small amounts of sample are available for testing, so any method that allows analysis without sample loss is recommended. In addition, conventional methods require opening the sample and must be performed in special "particle-free" laboratories, which can represent a challenge.

[0143] Application of the novel assay systems and methods disclosed herein provides an opportunity to improve formulation development by enabling new methods to study the mechanical formation and kinetics of particles. Analysis of particles in closed containers at regular time points will provide indications to better understand protein aggregation pathways and possible factors that influence or control the protein aggregation process.

[0144] The data collected by the visual inspection sections 5.2, 5.3 provide the following benefits: The images are measured in real time and while the particles remain suspended, which is an advantage over conventional techniques. This allows excellent imaging of highly irregularly shaped particles, as well as monitoring the dynamic behavior of particles where the size distribution changes over time.

[0145] For products containing large or various particle counts, chemical identification is key to assessing the underlying mechanism and impact on product quality. The presence of foreign particles (such as fragments of glass and / or rubber) and silicone oil droplets may act as "nucleation sites" that promote aggregation of biologics. The materials of the components of foreign particles often have unique Raman spectra. Therefore, the inspection systems and methods disclosed herein can be used to identify the source of foreign particle contamination. This feature is valuable for finding the root cause of particles that appear in development and manufacturing.

[0146] The inspection system can be integrated into the existing capabilities of a production site for parenteral drug products. No special environment is required for the operation of the installation of the inspection system. Providing an inspection system that performs extensive particle analysis in a fully automated manner allows more reliable results to be obtained in a short period of time, which is conducive to investigations in response to the detection of atypical particles in a sample. Although the more thorough analysis may result in longer analysis times 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, re-inspecting all ejected containers in which at least visible particles were detected will allow a double check to be performed, giving important information about the potential particles present in the product and the performance of the process implemented.

[0147] Figure 6 An inspection system 6 according to an embodiment is shown. The inspection system is operable or configured to detect and characterize particles in the interior of a medical container 6.1. The inspection system 6 comprises a sample holder 6.2, a laser 6.3 operable 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 mounted with a tilting objective 6.7, and a motorized mechanical structure 6.8.

[0148] The sample to be tested for the presence of visible particles therein may be a liquid drug product filled in a cylindrical container. The testing system 6 is operable or configured to test samples having various different properties of the liquid drug product, such as viscosity, density, turbidity, opacity, fill volume, etc. The cylindrical container may be made of different materials, such as, for example, glass or a polymer, and may have any of a variety of heights and diameters. Figure 6 A vial is shown in FIG, but the medical container may be represented by any type of cylindrical container such as a syringe.

[0149] For the sample to be analyzed, the laser light sheet must illuminate the target area of ​​the sample, and the image must be captured by the video camera 6.6. The container is sealed by making the closed system (stopper for vials and plunger for syringes) in its final position. The inspection system 6 does not require the sample to be in motion. 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 liquids in the container can be inspected. For containers with stoppers (such as vials), an upright position is preferred, i.e., the stopper is upward. This also applies to containers with needles (such as syringes).

[0150] The sample holder 6.2 is used to ensure the proper positioning and orientation of the sample in the novel visual inspection system 6. The axis 6.11 along which the axis of symmetry of the medical container 6.2 is arranged represents the reference axis of the complete 6 system, which is used to orient the rotation of the laser light sheet, the video camera 6.4 and the motorized mechanical structure 6.8. The selection of the components constituting the sample holder 6.2 (which realizes the positioning and orientation of the sample holder) can depend on the accuracy requirements of the inspection system 6. The sample holder 6.2 may include a flat platform with a cylindrical shape and a footprint of the diameter of the sample to be analyzed (small enough to ensure visibility of the bottom of the sample). The proposal will be container-specific and modified according to the diameter of the sample to be analyzed. A more complex design of the sample holder 6.2 may include a mechanical / robotic motorized axis that can be used for any type of sample and will provide better positioning accuracy. In addition, this configuration of the sample holder 6.2 realizes the automation of sampling of the complete system.

[0151] Unlike conventional inspection systems, the inspection system 6 detects non-moving particles. The medical container table does not need to be rotated and must remain stationary during the analysis. In addition, the syringe can be filled with different volumes, which means that the position of the plunger can be changed. The height of the laser light sheet generated by the laser 6.3 and imaged by the camera 6.4 can be kept fixed in the inspection system 6 to facilitate their calibration. Therefore, it is preferred that the sample holder 6.2 is motorized to control the height of the sample holder according to the sample to be inspected.

[0152] The inspection system and method operate based on scanning of a fixed sample. The laser 6.3 can generate a light sheet. Another light source capable of illuminating a thin area comparable to a plane can be used. The light sheet generated by the laser 6.3 (oriented to pass through the axis 6.11) passes through the sample and illuminates the area within the container and the outer wall of the container. If a particle is located within the thickness of the light sheet, strong light will be reflected and / or scattered from the particle, which will allow the particle to be detected. The contrast between the light reflected by the particle and the surrounding area within the sample is very strong, which makes it a very sensitive system.

[0153] The light sheet passes through various optical media and some diffusion may occur. Therefore, the shape and width of the light sheet may not be exactly the same at all points of the light sheet. To compensate for this, the light sheet generated by the laser 6.3 can be focused by the optical components within the laser. One method is to focus on the area captured by the video camera 6.6 to obtain a clear plane and ensure optimal illumination of the target area.

[0154] In an exemplary embodiment, the laser light sheet may be manufactured by a laser optics manufacturer available from Laser Components. MW nanolasers are generated with thicknesses of a few microns to a few millimeters, output powers up to 100 mW, and wavelengths ranging from 635 nm to 785 nm (red), 405 to 450 nm (violet), and / or 520 to 532 (green). In one embodiment, the laser light sheet can be obtained from Laser Components MW nanolaser generation 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 (green).

[0155] Figure 7 A top view of the first optical system 7 of the inspection system is shown. Figure 7 The arrangement and characteristics may be applied to a first light source outputting a light sheet and to a first detector detecting light reflected and / or scattered when the light sheet passes through the medical container 7 . 1 .

[0156] The width 7.22 of the light sheet is a parameter chosen to ensure detection of particles starting at, for example, 100 microns in size (particles with a size greater than 100 microns are also detectable). An adjustment ring may be provided, which may be integrated into the laser 7.2, to provide the possibility of adjusting the width 7.22 of the light sheet using a special optical system. The width 7.22 of the light sheet is used to calculate the increment of the scan (which also depends on the diameter of the sample) in order to cover the entire volume of the medical container 7.1 and to acquire images using a video camera 7.3 equipped with a tilting objective 7.4.

[0157] A very thin light sheet increases the scanning resolution, but requires a large number of images to be acquired to cover the entire volume of the medical container 7.1. While a larger light sheet can reduce the scanning time with larger increments, a larger light sheet reduces the scanning resolution. Therefore, it is necessary to find the right compromise between the width of the light sheet, the increment value, to ensure robust detection (even of 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 depending on the diameter of the medical container 7.1. Depending on the medical container to be analyzed, this can be done automatically.

[0158] The laser light sheet is oriented parallel and impinges on the axis 6.11 to reduce reflections of the light sheet, which passes through the cylindrical wall of the liquid-filled medical container 7.1, which can act as a lens. In addition, the laser light sheet facilitates the sectioning of the medical container 7.1, because the laser light sheet is mounted on a rotating system (e.g., system 6.8) having the axis 6.11 as the axis of rotation, along which the sample holder is positioned the axis of symmetry of the medical container 7.1. Even small deviations may be acceptable, but proper optical alignment is required.

[0159] The laser is positioned at a distance 7.21 and height that ensures that the entire height filled with liquid in the container is illuminated by the light sheet. The top and bottom of the liquid in the container are illuminated. In some configurations, especially for syringes, the bottom of the sample is not always completely flat (tapered plunger). Therefore, the laser 7.2 is positioned close enough so that the illumination angle 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 to the target area to be captured by the video camera 7.3. The laser 7.2 that generates the light sheet is mounted on a rotating mechanical structure (such as a support 6.8) so that the orientation of the laser and its distance 7.21 can be locked. The same applies to the height of the laser relative to the sample 6.1. The only possible movement of the light sheet generated by the laser 7.2 is generated by the rotating mechanical structure (such as a support 6.8), which realizes the illumination and thus the scanning of the entire sample.

[0160] The visual inspection system 7 is sensitive. Therefore, it is desirable to reduce and / or identify reflections from any other physical elements other than particles that may be present in the sample. The laser apertures 6.4.1, 6.4.2 placed above and below the laser light sheet can capture light that is useless for illumination of the sample and avoid its propagation into the video camera 6.6. The laser apertures 6.4.1, 6.4.2 can be combined with one or several laser traps 6.5 to further reduce undesirable artifacts. In order to have a fully automated system, the positions of the laser apertures 6.4.1, 6.4.2 can be independently controlled by two motorized mechanical axes. The position of the laser aperture will be adapted according to the height of the container and the filling volume of the sample. The target volume to be illuminated represents the portion of the sample filled with the drug product liquid. The unfilled portion (located at the top) can also be illuminated to inspect for particles that may adhere to the wall of the container.

[0161] The light trap 6.5 may be sized (e.g. may be wide enough and high enough) to cover the light sheet. The light trap 6.5 may be attached to the sample outlet to interrupt the propagation of light in the device. The light trap is oriented parallel to the light sheet generated by the laser 6.3 and is positioned at approximately the same height as the sample.

[0162] A housing (not shown) covering the entire device can mitigate the risk of light from the environment being reflected onto the cameras 6.6, 7.3. At the same time, the housing can be useful for safety issues related to laser light sheets. The housing is large enough to cover the imaging system and the motorized mechanical system that allows the imaging system to rotate.

[0163] At least one video camera 6.6 comprising a charge coupled device (CCD) sensor is used to acquire images of the area illuminated by the laser light sheet. A high definition camera is used to ensure that the pixel size is less than or equal to the minimum particle size target to be detected. The field of view (FOV) of the camera is large enough to capture a complete image of the sample 6.1. The acquisition of the images 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 can have an angle sensor. Image acquisition can be triggered by the output of the angle sensor. The low exposure time of the video camera 6.6 is useful because the light reflected by the particles present in the sample is strong compared to other features present on the image ( Figure 8 ). This setting allows for better characterization of the particles by avoiding overexposure of pixels illuminated by the presence of the particles. If the color information of the particles is not important, separating the color channels (such as RGB) and selecting a single channel that can match the wavelength or color of the laser light sheet will reduce the amount of data collected.

[0164] The configuration of the sample (cylindrical object filled with liquid) acts as a lens, which produces blind spots when inspecting the sample using a conventional optical system. The use of tiltable lenses 6.7 and 7.4 provides a very effective solution to this challenge by providing a non-vertical viewing angle to the light sheet to avoid these blind spots. The tiltable mount can be compatible with any C-mount camera. The precise built-in adjustment mechanism allows the Sham conditions to be accurately met and the tilted plane to be imaged with good (e.g., perfect) focus. The lens provides a range of magnifications and viewing angles. Even when the lens is tilted at a wide angle, image clarity is maintained because the Sham adjustment piece tilts around the horizontal axis of the detector plane. The tilt angle and the focus of the tilted objective lens can be adjusted, which provides several analysis possibilities. For example, the tilted objective lens MCSM1-01X obtained from StemmerImaging can be used.

[0165] The positioning of the video camera 7.3 assembled with the tilting objective 7.4 relative to the laser 7.2 or the light sheet affects the ability to obtain a proper image of the illuminated particles. In order to avoid blind spots, the camera is positioned at a certain angle 7.31 to the central axis of the laser light sheet. Adjustment of the angle 7.31 of the tilting lens is then performed during calibration in order to obtain a clear image of the area illuminated by the laser light sheet. The angle 7.31 can have different values, achieving several viewing angles. Therefore, an optimization can be performed to define the value of the angle 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 presented on the image acquired by the video camera 7.3. The focusing of the tilting objective 7.4 can be ensured with the help of an adjustment ring.

[0166] Figure 8 An image 8 recorded by video cameras 6.6, 7.3 is shown. Figure 7 and Figure 8 As can be seen in FIG. 7 , the video camera 7.3 is positioned so that the inlet 8.1 of the laser light sheet 6.3 in the liquid is located on the right side of the image 8 captured by the camera. However, the video camera can also be positioned so that the inlet 8.1 of the light sheet is located in the left part of the image. Both configurations were tested and it was concluded that Figure 7 The configuration shown is one that allows for proper illumination of the sample while reducing reflections of the laser light sheet into the sample container.

[0167] The video camera 6.6, 7.3 and the tilting objective lens 6.7, 7.4, which are fastened to each other, are mounted on a rotating mechanical structure 6.8, allowing to lock their relative orientation, distance and height relative to the medical container 6.1, 7.1 and the laser light sheet. The only movement of the video camera and the tilting objective lens is generated by the rotating mechanical structure 6.8, allowing to acquire images of the complete sample.

[0168] In order to scan the entire sample volume, a motorized rotary mechanical system 6.8 can be used, on which the imaging optics can be mounted. Figure 6 6.11. The system configuration takes into account the position and movement of components of a first optical system, which can be an imaging system. Any combination of structures and motorized mechanical axes can be used, which allows the mounting of an imaging system and its automated rotation. The structure is attached to a fixed base (serving as a frame) which can be mounted on a laboratory table, for example. One implementation uses a circular optical table 12.1 ( Fig.12 ), where the diameter is large enough to allow the fixing of the components of the visual imaging system 6 and the rotation of the visual imaging system by means of a motorized rotating table 12.2. The laser 6.3 generating the light sheet, the laser apertures 6.4.1, 6.4.2, the laser trap 6.5, the camera 6.6 mounted with a tilting objective 6.7 and the Raman video probe 12.6 are mounted on this circular optical table 12.1 ( Fig.12 )superior.

[0169] Figure 8 An example of an image 8 acquired by an inspection system 6 is shown. The image is acquired with a sufficiently long exposure time to allow full visualization of the sample 6.1. The shape of the container and the entrance 8.1 and exit 8.2 of the light sheet through the medical container can be easily identified. The inner and outer walls of the container reflect light, which allows the inner and outer walls to be easily identified and these walls to be used as references to define the target area 8.3 of the original image. In a second step, these boundaries can even be used for the realization of a mask based on an imaging algorithm, allowing the target area 8.3 to be cropped and the rest of the image to be removed. On this image, a particle 8.4 located in the beam of the light sheet can be seen. The light reflected by the particle is so intense that the light provides a strong contrast with the rest of the sample. The quality of the original image is high enough to be processed using an image processing algorithm to achieve automated detection of particles present in the sample. This processing can be completed by an evaluation circuit, which can be implemented by a computer programmed to process image data.

[0170] In order to fully inspect the sample, it is necessary to rotate the laser light sheet and video camera around the static medical container. This process allows the entire sample to be scanned. Small particles will be captured in only a few frames, while larger particles can be captured in several frames.

[0171] Fig. 9An example of a portion of an image is shown (in magnified proportions), providing an overview of nine images a to i acquired one by one after completing nine consecutive increments. From frame a to frame c, although the imaging system rotates, 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 pixel begins to increase, indicating that the particle is close to the light sheet. On frame f, a very bright portion is visible, indicating that a portion of the particle is located in the light sheet (and in the focal plane of the camera). On images g and h, the particle (which is larger than the width of the light sheet even after the imaging system is rotated) is located in the width of the light sheet, resulting in the appearance of many high-brightness pixels. On image i, the light sheet has passed over most of the particle, and only a few pixels remain bright, indicating that the portion of the particle that still overlaps the light sheet is reflected.

[0172] A preliminary correction can be applied to the raw images to correct for possible variations associated with the random positioning of particles within the sample. Treatment of the raw images by an imaging processing algorithm can be used for detection, characterization and 3D localization of particles. Since the captured particles are reflected on several frames, a 3D clustering algorithm can be used. For example, a DBScan algorithm using pixel intensity values ​​and 3D particle volumes can be applied. Such an algorithm can work on the basis of three parameters to be optimized:

[0173] -Image threshold: The intensity a pixel must have to be considered as belonging to a particle

[0174] -ε: 3D distance (in pixels) between pixels that exceed the threshold to be considered part of the same particle

[0175] -Minimum Neighbors: Minimum size of pixels within a cluster (in 3D). (Values ​​are in pixels)

[0176] Furthermore, slicing of the entire volume of the sample by the inspection system 6 provides the possibility to perform a 3D reconstruction of the detected particles.

[0177] Fig.10 An example of a 3D reconstruction of the complete sample 10.1 is provided as well Fig. 9 Reconstruction of a single particle is shown in Figure 10.2. 3D imaging of particles in closed containers will enable more advanced characterization by providing 3D visualization of morphology and 3D size determination. In addition, more precise localization of the center of the particle can be achieved.

[0178] Integration of Raman probes into inspection systems allows chemical characterization of detected visible particles (e.g., identification based on spectral fingerprinting). Probe configuration (e.g., as in reference Figure 4The Raman probe head (described in detail) allows the source of the Raman detection beam and the Raman detector to be moved in 3D around the sample and their position to be adjusted according to the position of the particles (which remain stationary during acquisition). The size and weight of the probe head are implemented to ensure adequate motorization and integration into the inspection system. It is contemplated to add a light unit and a video camera to the compact Raman probe head to illuminate the sampling area, which would allow visualization of the particles to be identified to obtain an image and facilitate focusing.

[0179] Fig.11 is a representation of a probe 11 comprising a Raman probe, an optical unit and a video camera. The probe 11 is designed to provide good capabilities while maintaining flexibility in selecting the camera and objective to be used. The probe 11 is operable or configured to perform in situ Raman spectroscopy of visible particles present in a liquid-filled container, collecting high-resolution particle images and Raman spectra.

[0180] The probe 11 includes a Raman probe 11.1. The Raman probe 11.1 is connected to a spectrometer using two optical fibers ( Fig.11 In the embodiment of the present invention, one optical fiber allows the excitation of the sampling area, while the other allows the collection of the Raman backscattered light. The selected inner diameter of these optical fibers is selected based on the desired excitation area size and the collection volume. In addition, the measurement settings of the spectrometer are set to allow a good identification of the detected particles without damaging the particles and without damaging the formulation in the container. Continuous long-term strong laser exposure may cause damage to the sample area. On the other hand, too low power and exposure will not allow scattering and therefore no identification.

[0181] The excitation wavelength has an impact on the Raman intensity, spatial resolution, background fluorescence, and acquisition time. The condition of the sample to be identified and the surrounding environment are taken into account. First, the particles can be made of different materials that may be sensitive to different excitation wavelengths. Second, the laser must pass through several media. A wavelength that minimizes the appearance of data from a container or solution in a container would be preferred. The use of a 785nm wavelength provides a good compromise between Raman scattering intensity and fluorescence suppression for a variety of use cases. A second Raman probe with another wavelength can be provided to provide greater flexibility to the system.

[0182] Lighting features are added by connecting to a light source ( Fig.11 This is achieved by the presence of a fiber lens collimator 11.2 (not shown in FIG. 1 ). The illumination of the sample area makes it easier to visualize the detected particles and focus on them. The use of additional optical components allows the use of the same optical path as the Raman probe.

[0183] Integrating a video camera on the probe 11 provides the ability to visualize the sampling area. This integration can be achieved by using a camera mount 11.3 with an external C-thread. The acquired image allows calibration of the probe placement, which is accomplished thanks to the 3D positioning data of the particles collected by the visual inspection system 6. In addition, this acquired image is used as a reading to check the accuracy of the probe positioning. Additional optical components allow visualization through the same optical path. Visualization of the laser beam can also be achieved on the particles during measurement, which ensures the reliability of the acquired data. In the case of slightly moving particles, the acquired image can be used to track and correct the position of the probe 11 in real time to keep the particles in the focal plane of the probe 11 during data acquisition.

[0184] At the optical output end of the probe 11 is an objective mount 11.4 that allows attachment of a conventional microscope objective. The characteristics of the sample and the type of data acquired by the probe are taken into account to select the microscope objective. In addition, in order to reach all particles, the working distance is maintained greater than the radius of the largest container, since particles can be located at any point within a closed container. The numerical aperture is made larger (e.g., maximized) in order to maximize Raman backscatter collection. Corrected near-infrared (NIR) objectives can also be used.

[0185] The medical container to be analyzed (which is mainly cylindrical in shape and filled with liquid) acts as a lens. A compensating lens is inserted between the sample and the microscope objective of the compact probe 11 to compensate for light distortion and obtain a clear image. The shape and material used to make the probe depend on the characteristics of the sample (liquid solution and the container in which the liquid solution is contained). Corrective lenses dedicated to specific container types and / or sizes (e.g., diameters) can be used.

[0186] The probe 11 has a housing 11.5 to hold the different components of the probe in place and maintain the integrity of the optical components. The placement and configuration of the components may be achieved so as to produce a compact design and light weight to facilitate integration of the components into an inspection system while giving ease of locatability.

[0187] At least part 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. Various optical components may be provided in the probe 11. These optical components may include reflectors such as a mirror 11.9, focusing, collimating or other beam conditioning components such as a tubular lens 11.8, components providing beam splitting and / or interference settings such as a beam splitter 11.7 (which may have a transmittance of 80% and a reflectance of 20%, but is not limited thereto), and a dichroic filter 11.6.

[0188] The visual imaging system 6 detects and locates particles present in a closed container filled with liquid in 3D. These particles can be located at any position within the closed container. An automated mechanical or robotic system is used to allow the probe 11 to move around the sample. In order to minimize the optical effect caused by the cylindrical shape of the container, the probe 11 is aimed at the axis of symmetry of the sample, which is aligned with the axis 6.11 through the sample holder. A mechanical structure or automated robotic actuator can provide at least three degrees of movement to the probe 11 to allow focusing on the entire sample. The actuator arrangement for displacing the probe 11 can provide a first degree of freedom that allows rotational movement around the sample while maintaining the probe toward the axis 6.11 along which the axis of symmetry of the container is positioned. The actuator arrangement for displacing the probe 11 can provide a second and third degree of freedom that allows the inspection system 6 to adapt its height 5.41 (in the same direction as the axis of symmetry) and its distance 5.42 (perpendicular to the direction of the axis of symmetry) into the sample. It is also possible to consider adding an additional degree of rotation that allows the probe to be tilted up or down in the event that some particles float on the surface of the liquid or are located at the bottom of the sample.

[0189] In one embodiment, the probe 11 is mounted on a circular motorized structure 6.8, 12.2 that rotates the visual imaging device. This reduces the number of motorized axes and facilitates the calibration between the two optical systems, since they are mounted on the same mobile structure 6.8, 12.2. Adding two motorized linear axes allows, for the first motorized linear axis, the height of the probe 11 to be varied within an amplitude large enough to cover large samples, and for the second motorized linear axis, the focus of the probe to be varied within an amplitude of at least the radius of the largest sample. An additional rotation axis allowing the probe to be tilted can be integrated in the motorized structure. Fig.12 The complete motorized structure 12.5 that holds and motorizes the compact probe 11 is shown in FIG.

[0190] Fig.12A perspective view of an inspection system 12 is shown, which includes a sample holder 12.1 for positioning a medical container in a stationary manner during data acquisition, a first light source 12.3 outputting a light sheet, a first detector 12.4 detecting an image of the container illuminated by the light sheet, and a probe 12.5 operable to perform 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. An opening in the center of the support 12.2 allows the fixation of the sample holder 12.1 and its vertical movement. The optical table can have a set of threaded holes placed like a grid to allow simplified fixation of the components of the system. A shaft 12.7 (which can be a hollow tube through which the fixture of the sample holder 12.1 passes) can be used to fix the optical table on a motorized rotating table driven by a motor 12.6. The inner diameter of the tube must be large enough to allow the fixture of the sample holder to pass through and long enough to allow the implementation of a rotating cable protection system. In one embodiment, a motorized rotation table DMT 200N-D90-HiDS available from Owis is implemented, providing very precise rotational positioning without angular limitations.

[0191] The probe 12.5 can be placed at several positions on the support 12.2 so that the probe 12.5 does not disturb the visual imaging device. The probe 12.5 is preferably placed outside the illumination generated by the laser 12.3 to avoid generating additional reflections. The probe 12.5 is positioned to ensure that there is no obstruction to the camera 12.4. In addition, the probe 12.5 is preferably placed close enough to the sample so that the movement of the probe towards the detected particles requires as little time as possible.

[0192] 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 target area 8.3 visualized by the camera 12.4, avoiding any interference with the visual inspection equipment. Fig.12 The positioning of the probe 12.5 shown and its motorized structure allow the probe to target the inspected area as quickly as possible (rotating as small an angle as possible). The lateral position of the probe 12.5 relative to the sample is then defined by the amplitude of the motorized axis, allowing the compact probe 12.5 to be focused at least to the middle of the container.

[0193] In one embodiment, the sample holder 12.1 and the sample are placed in the center of the system. The sample remains stationary during the entire analysis. The motorized linear axis ( Fig.1212.1 ) allows the vertical position of the sample holder 12.1 to be adjusted according to the filling volume of the sample before the analysis starts. A circular support such as an optical table 12.2 is used as a base to fix the components of the visual inspection system: the laser light sheet 12.3 and the camera 12.4, as well as the compact 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 rotating table driven by a motor 12.6, which allows in a second step the scanning of the sample and the aiming of the compact probe. The coupling between these two parts is realized by a spacer tube 12.7, which is hollow and allows the passage of a motorized shaft attached to the sample holder 12.1.

[0194] The sample's axis of symmetry is coaxial with the rotation axis of the rotating table. Manual mechanical axes can be used to facilitate placement and alignment between different components.

[0195] exist Fig.12 In the configuration shown, the rotational movement produced by the rotating table is in a clockwise direction. However, a counterclockwise rotation may be used. In this case, it may be preferable to reposition the probe 12.5 and its motorized structure.

[0196] The 3D particle position data detected by the vision imaging system is used to control the position of the Compact Raman Probe 12.5. The different components are calibrated to ensure accurate positioning.

[0197] The inspection system may include an electrical control cabinet ( Fig.12 ), which provides monitoring and power supply to various components of the inspection system 12. In addition, a control device (such as a computer running dedicated software) can be set in the inspection system 12 to perform various tasks to automatically control the entire system and process the detector output.

[0198] Fig.13 is a flow chart of method 13. Method 13 can be automatically performed by the inspection system according to the present invention.

[0199] At step 13.1, the sample holder receives the medical container. The sample holder positions the medical container so that the axis of symmetry of the medical container is aligned with the axis and oriented along the axis. The sample holder positions the medical container and holds the medical container in a motionless or stationary state during data acquisition for analysis.

[0200] At step 13.2, the vertical position of the sample holder and the laser aperture may be adjusted according to the configuration of the medical container. This may be done automatically in response to detection of the container (using, for example, a container identifier such as a barcode) or in response to user input specifying the container type and / or size and / or fill level. At step 13.2, the laser light sheet may be turned on.

[0201] At step 13.3, the actuator (such as a motorized mechanical structure) starts its rotation, allowing the entire sample to be scanned. Images are acquired at incremental values ​​that have been adjusted according to the sample configuration at step 13.2. During this scan, the Raman probe system can remain inactive.

[0202] At step 13.4, the image captured at step 13.3 is processed by an imaging algorithm, enabling detection, characterization and / or 3D localization of particles, if any, present in the sample.

[0203] At step 13.5, the 3D positioning data is processed by a control unit to perform motion control of the Raman video probe.

[0204] At step 13.3, the actuator arrangement responsible for displacing the probe with the Raman probe is controlled. The actuator arrangement may include a motorized mechanical structure that produces a rotation of the support 12.2 and a motorized axis dedicated to the probe 12.5. The probe 12.5 is adjusted to aim and focus on the detected particle.

[0205] At step 13.7, a Raman measurement is triggered by the control unit for chemical identification of the particles. Additional images may be acquired by a camera integrated in the probe.

[0206] Repeat steps 13.6 and 13.7 for the previously identified particles in the medical container.

[0207] Artificial intelligence (AI) models may be used for processing visual image data captured in response to illumination of the medical container with the light sheet and / or spectral data (such as Raman spectra). The AI ​​model may be trained for impurities with known characteristics (such as size and / or chemical characteristics), preferably for containers of various types (vials, syringes, etc.), walls (glass or plastic), and liquids. Supervised learning may be used, while adjusting the parameters of the AI ​​model using techniques such as gradient descent.

[0208] Fig.14An example of an AI model 14 is shown, which after training can be executed by a computer of an inspection system to process acquired data. The AI ​​model 14 includes an input layer 14.1, which is operable or configured to receive pixel values ​​or quantities derived therefrom (such as particle size data or portions of a spectrum). The AI ​​model 14 includes an output layer 14.2. The output layer 14.2 can output a binary output indicating whether a particle makes a medical container unacceptable. The output layer 14.2 can output an output indicating which type of particle is present. Thus, the AI ​​model 14 can operate as a classifier that processes information obtained using the optical system of the inspection system into information about the particles. The AI ​​model 14 can include a hidden layer 14.3, which can include a convolutional layer, a recursive layer, or other artificial neural network (ANN) configuration.

[0209] This description and drawings illustrating aspects and embodiments of the invention should not be construed as limiting the claims defining the protected invention. In other words, although the invention has been illustrated and described in detail in the drawings and the foregoing description, such illustration and description are considered to be illustrative or exemplary rather than restrictive. Various mechanical, compositional, structural, electrical and operational changes may be made without departing from the spirit and scope of the present specification and claims. In some cases, well-known circuits, structures and techniques are not shown in detail so as not to confuse the invention. Therefore, it should be understood that changes and modifications may be made by a person of ordinary skill in the art within the scope and spirit of the appended 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 may be operated in an embodiment in which:

[0210] The medical container is not sealed and contains a lyophilized product;

[0211] The inspection system includes more than one visual imaging system, wherein each of the visual imaging systems uses a light sheet;

[0212] The inspection system includes more than one spectroscopy system.

[0213] The present disclosure also encompasses all additional features shown in the figures. Although they may not be described in the preceding or following description, they are separate. In addition, single alternatives to the embodiments described in the drawings and description and single alternatives to their features may be excluded from the subject matter of the present invention or from the disclosed subject matter. The present disclosure includes subject matter consisting of features defined in the claims or exemplary embodiments as well as subject matter including said features.

[0214] Furthermore, in the claims, the term "comprises / includes" does not exclude other elements or steps, and the indefinite article "a / an" does not exclude a plurality. A single unit or step may perform the functions of several features listed in the claims. The mere fact that certain measures are listed in mutually different dependent claims does not indicate that the combination of these measures cannot be advantageous. The terms "substantially", "about", "approximately", etc., which are related to attributes or values, also accurately define the attributes or accurate values, respectively. In the context of a given value or range, the term "about" refers to a value or range within 20%, 10%, 5% or 2% of a given value or range, for example. Components described as coupled or connected may be directly coupled electrically or mechanically, or they may be indirectly coupled via one or more intermediate components. Any figure marks in the claims should not be interpreted as limiting the scope.

[0215] The computer program may be stored / distributed on a suitable medium (such as an optical storage medium or solid-state medium provided 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 a computer executable program code adapted to be executed to implement a specific method such as the method according to the present invention. In addition, the computer program may also be a data structure product or signal for embodying a specific method such as the method according to the present invention.

Claims

1. A testing system (1.3; 12), which is operable to test a medical container containing a liquid, the testing system (1.3; 12) comprising: a sample holder (1.4; 2.1; 12.1) operable 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) having: at least one light source (3.2; 4.6; 5.2; 6.3; 7.2; 11) operable to output light incident on the medical container; and at least one detector (3.4; 4.6; 5.3; 6.6, 6.7; 7.3, 7.4; 11) operable to detect return light from the medical container, wherein the at least one detector comprises a first detector (3.4; 4.6; 5.3; 6.6, 6.7; 7.3, 7.4) comprising a photoelectric converter having a plurality of pixels; and an evaluation system (1.7) coupled to at least one optical detector and operable to detect and / or determine a characteristic of particles in the medical container based at least on an output of the at least one detector; at least one actuator (1.6; 2.6, 2.7; 12.6) operable 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 rotationally and translationally fixed manner; It is characterized in that The at least one light source comprises a first light source (3.2; 4.6; 5.2; 6.3; 7.2) operable to output a light sheet, and The first detector (3.4; 4.6; 5.3; 6.6, 6.7; 7.3, 7.4) comprises a tilting objective lens (6.7; 7.4).

2. An inspection system (1.3; 12) according to claim 1, wherein the at least one actuator (1.6; 2.6, 2.7; 12.6) is operable to move the at least one light source and the at least one detector along a curved path around the axis (2.2; 6.11), Optionally, one, some or all of the following apply: At least one section of the path extends in a plane perpendicular to the axis (2.2; 6.11); The path comprises an elliptical arc; The path comprises an arc; The at least one actuator (1.6; 2.6, 2.7; 12.6) is operable to concurrently change the position and orientation of the at least one light source (3.2; 4.6; 5.2; 6.3; 7.2; 11) to maintain illumination light incident on the medical container and / or the axis (2.2; 6.11); The at least one actuator is operable to concurrently 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) so that the return light is incident on the at least one detector.

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

4. The inspection system (1.3; 12) according to any one of the preceding claims, wherein 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) operable 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 operable to move the first light source (3.2; 4.6; 5.2; 6.3; 7.2) around the axis (2.2; 6.11) so that as the first light source (3.2; 4.6; 5.2; 6.3; 7.2) is moved around the axis (2.2; 6.11), the light sheet remains incident on the axis (2.2; 6.11).

5. An inspection system (1.3; 12) according to claim 4, wherein the first detector (3.4; 4.6; 5.3; 6.6, 6.7; 7.3, 7.4) is operable to provide a first detector output in response to the return light during illumination of the medical container using the light sheet, optionally wherein the first detector comprises a Sham camera.

6. The inspection system (1.3; 12) of claim 5, wherein the evaluation system (1.7) is operable to perform at least one of the following: detecting the particle when the particle is located in the light sheet based at least on the first detector output; determining that the particle is located within the interior of the medical container based at least on the first detector output; distinguishing the particles from bubbles in a liquid within the medical container based at least on the first detector output; distinguishing the particles from impurities within a container wall of the medical container based at least on the first detector output; At least based on the first light source and / or the first detector around the axis (2.2; 6.11) to determine information about the morphology of the particle, optionally the three-dimensional surface shape of the particle; Information about the size of the particle, optionally the three-dimensional size of the particle, is determined based at least on the first detector output.

7. An inspection system (1.3; 12) according to any of the preceding claims, wherein the at least one light source comprises a second light source (11) operable to output a Raman detection beam, and the at least one detector comprises a second detector (11) coupled to a Raman spectrometer.

8. Inspection system (1.3; 12) according to claim 7 when dependent on claim 6, wherein 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), wherein the second actuator has more degrees of freedom than the first actuator, optionally wherein the first actuator (2.6; 12.6) has one degree of freedom and the second actuator (2.7) has at least two degrees of freedom (5.41, 5.42), and / or optionally wherein 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) comprises control means operable to control the second actuator (2.7) based at least on the first detector output.

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

10. A testing system (1.3; 12), which is operable to test a closed medical container containing a liquid, the testing system (1.3; 12) comprising: a sample holder (1.4; 2.1; 12.1) operable to hold said closed medical container; and a light source (11) operable to output a Raman detection beam incident on the sealed medical container; Features: a detector (11) operable to detect a Raman spectrum in response to outputting the Raman probe beam; and An evaluation system (1.7) coupled to the detector and operable to determine characteristics of particles in the closed medical container based at least on the Raman spectrum.

11. A manufacturing system (1), comprising: a filling device (1.1) operable to fill at least one liquid into the medical container; a sealing device (1.2) operable to seal said medical container containing said at least one liquid therein; as well as A testing system (1.3; 12) according to any one of the preceding claims, operable to test closed medical containers for particulate matter.

12. A method for inspecting a medical container containing a liquid, the method comprising: Through the sample holder (1.4; 2.1； 12.1) along the axis (2.2; 6.11) Positioning the medical container; illuminating the medical container with light via at least one light source; detecting, by 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 means of an evaluation system, a property of the particle at least based on an output of the at least one detector, wherein the at least one detector comprises a first detector (3.4; 4.6; 5.3; 6.6, 6.7; 7.3, 7.4) comprising a photoelectric converter having a plurality of pixels; as well as orienting the at least one light source and / or the at least one detector about the axis (2.2; 6.11) moves, while the sample holder (1.4; 2.1; 12.1) holds the medical container in a rotationally and translationally fixed manner, Features: The at least one light source comprises a first light source (3.2; 4.6; 5.2; 6.3; 7.2) operable to output a light sheet, and The first detector (3.4; 4.6; 5.3; 6.6, 6.7; 7.3, 7.4) comprises a tilting objective lens (6.7; 7.4).

13. A method for inspecting a closed medical container containing a liquid, the method comprising: Through the sample holder (1.4; 2.1; 12.1) positioning the sealed medical container; irradiating the sealed medical container with a Raman detection beam via a light source; Features: detecting a Raman spectrum using a Raman spectrometer in response to illuminating the sealed medical container with the Raman probe beam; and A characteristic of particles in the closed medical container is determined based at least on the Raman spectrum.

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

15. A manufacturing method, comprising: Filling liquids into medical containers; sealing the medical container containing the liquid therein; as well as The testing method according to any one of claims 12 to 14 is carried out to test closed medical containers for particulate matter.

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