Artificially freeze-dried product samples for automated visual inspection systems

Abstract

An artificial lyovial is provided that includes a portion of a vial. The portion of the vial includes a vial wall having a top opening and a bottom opening. The bottom opening includes an inner diameter that is greater than the inner diameter of the top opening. At least a portion of the vial wall is translucent. The artificial lyovial includes an artificial lyocake. The artificial lyocake is secured within the portion of the vial. The artificial lyocake includes a base, an annular surface, a top surface, and a longitudinal dimension that extends from the base to at least a portion of the top surface. The outer diameter of the artificial lyocake is greater than the inner diameter of the top opening.

Description

[Technical field]

[0001] This application relates generally to the inspection of lyophilized pharmaceutical products, and more specifically to the creation and use of artificial lyophilized product samples for the purposes of training, improving, and / or qualifying automated visual inspection systems. [Background technology]

[0002] In certain situations, such as quality control procedures for manufactured pharmaceutical products, it is necessary to test samples (e.g., lyophilized product samples) for the presence of various defects (e.g., low loading, high loading, collapsed cake, meltback, foreign bodies, fibers, etc.). The acceptability of a given sample under the applicable quality standard may depend on indicators such as the condition of the lyophilized product, the presence of undesirable particles contained within the sample, etc. If the sample exhibits unacceptable indicators, it may be rejected and discarded.

[0003] To handle the volumes typically associated with commercial production of pharmaceutical products, product inspection tasks are becoming more and more automated. However, automated visual inspection (AVI) systems have struggled to overcome various barriers to achieve good product fidelity without complicating the system. For example, defect inspection of lyophilized pharmaceutical products, which are often filled and distributed in glass vials, is one of the most challenging challenges in the AVI process. One reason known AVI systems are challenging is that lyophilized pharmaceutical products deteriorate over time. Testing and calibrating AVI systems for inspection of lyophilized products presents an additional challenge in that the lyo-dried product cake ("lyo-cake") structure often has a short lifespan due to the agitation to which the lyo-cake is exposed in the AVI system. Thus, typically, a lyo-sample is passed through the AVI system only a few times before the lyo-cake sample loses its associated structure. As a result, a vial containing the lyo-dried product (i.e., a "lyo-vial") cannot be reliably and repeatedly used to test or calibrate an AVI system. Instead, new samples must be made, which adds cost and / or delays. Furthermore, the production of defective lyocakes can be expensive and can delay the development, characterization, and / or testing of AVI devices. Summary of the Invention [Means for solving the problem]

[0004] Embodiments described herein relate to artificial lyophilized product cakes and modified vials containing the artificial lyophilized product cakes.

[0005] As described herein, the artificial lyovial represents at least a portion of a freeze-dried product sample. The artificial lyovial comprises a portion of a vial. The portion of the vial comprises a vial wall having a top opening and a bottom opening. The bottom opening of the vial comprises an inner diameter greater than the inner diameter of the top opening of the vial. At least a portion of the vial wall is translucent. An artificial lyocake is secured within the portion of the vial. The artificial lyocake comprises a base, an annular surface, a top surface, and a longitudinal dimension extending from the base to at least a portion of the top surface. The outer diameter of the artificial lyocake is greater than the inner diameter of the top opening of the vial.

[0006] The method of manufacturing an artificial lyo-vial includes providing a vial including a top opening having an upper inner diameter. The method also includes forming a bottom opening by removing at least a portion of a bottom end of the vial. The bottom opening includes a bottom inner diameter that is greater than the top inner diameter. The method further includes providing an artificial lyo-cake having a base, a top surface, and an annular surface extending between the base and the top surface. The outer diameter of the artificial lyo-cake is greater than the top inner diameter of the vial. The method further includes inserting at least a portion of the artificial lyo-cake through the bottom opening of the vial.

[0007] A method for producing an artificial lyocake includes generating three-dimensional data defining a bottom surface of the lyocake, an annular surface of the lyocake, and a top surface of the lyocake. The method also includes receiving the three-dimensional data at a controller of a three-dimensional printer. The method further includes controlling material dispensing from a material dispensing device of the three-dimensional printer to dispense material based on at least a z-value of the three-dimensional data. The method further includes controlling a position of the material dispensing device relative to a platform based on at least an x-value and a y-value of the three-dimensional data.

[0008] Novel freeze-dried product cakes and modified vials containing the freeze-dried product cakes are provided. Novel methods for producing the freeze-dried product cakes and modified vials containing the freeze-dried product cakes are also provided.

[0009] Those skilled in the art will appreciate that the figures described herein are included for illustrative purposes and are not intended to limit the present disclosure. The figures are not necessarily to scale, with emphasis instead being placed on illustrating the principles of the present disclosure. It should be understood that in some instances, various aspects of the described embodiments may be shown exaggerated or enlarged to facilitate understanding of the described embodiments. In the drawings, like reference characters throughout the various figures generally refer to functionally similar and / or structurally similar components. [Brief description of the drawings]

[0010] [Figure 1] 1 shows an example of an automated visual inspection system for inspecting containers of freeze-dried products. [Figure 2A] 1 illustrates an exemplary artificial freeze-dried cake ("artificial lyocake") production system and method. [Figure 2B] 1 illustrates an exemplary artificial freeze-dried cake ("artificial lyocake") production system and method. [Figure 2C] 1 illustrates an exemplary artificial freeze-dried cake ("artificial lyocake") production system and method. [Figure 3A] 2A-C show an exemplary method for making an artificial vial ("artificial lyovial") containing the artificial lyocake of FIG. 2A-C. [Figure 3B] 2A-C show an exemplary method for making an artificial vial ("artificial lyovial") containing the artificial lyocake of FIG. 2A-C. [Figure 3C] 2A-C show an exemplary method for making an artificial vial ("artificial lyovial") containing the artificial lyocake of FIG. 2A-C. [Figure 3D] 2A-C show an exemplary method for making an artificial vial ("artificial lyovial") containing the artificial lyocake of FIG. 2A-C. [Figure 3E] 2A-C show an exemplary method for making an artificial vial ("artificial lyovial") containing the artificial lyocake of FIG. 2A-C. [Figure 4]2A-C depict an exemplary artificial lyocake produced using the systems and methods of FIG. [Diagram 5] 2A-C depict another exemplary artificial lyocake produced using the systems and methods of FIG. [Figure 6A] 1 shows a grayscale image of an exemplary vial having a defect associated with a lyophilized product. [Figure 6B] 1 shows a grayscale image of an exemplary vial having a defect associated with a lyophilized product. [Figure 6C] 1 shows a grayscale image of an exemplary vial having a defect associated with a lyophilized product. [Figure 6D] 1 shows a grayscale image of an exemplary vial having a defect associated with a lyophilized product. [Figure 6E] 1 shows a grayscale image of an exemplary vial having a defect associated with a lyophilized product. [Figure 6F] 1 shows a grayscale image of an exemplary vial having a defect associated with a lyophilized product. [Figure 6G] 1 shows a grayscale image of an exemplary vial having a defect associated with a lyophilized product. [Figure 6H] 1 shows a grayscale image of an exemplary vial having a defect associated with a lyophilized product. [Figure 6I] 1 shows a grayscale image of an exemplary vial having a defect associated with a lyophilized product. [Figure 6J] 1 shows a grayscale image of an exemplary vial having a defect associated with a lyophilized product. [Figure 6K] 1 shows a grayscale image of an exemplary vial having a defect associated with a lyophilized product. [Figure 6L] 1 shows a grayscale image of an exemplary vial having a defect associated with a lyophilized product. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0011] The various concepts introduced above and discussed in more detail below may be implemented in any of numerous ways, and the concepts described are not limited to any particular implementation. Several example implementations are provided for illustrative purposes.

[0012] As detailed herein, freeze-dried product defects such as overfilling, underfilling, and collapsed freeze-dried product cakes can be replicated using 3D printing to represent freeze-dried product cakes ("artificial lyocakes"). Freeze-dried product texture and / or color can be replicated, for example, by coating the 3D-printed artificial lyocakes with sugars and salts diluted in isopropyl alcohol. Freeze-dried product defects such as meltback, liquefaction, and / or foreign bodies can be replicated, for example, by applying particle, texture, and / or color variations to at least a portion of the top surface and / or at least a portion of the annular surface of the artificial lyocake.

[0013] Correspondingly, a vial can be modified to accommodate an artificial lyocake by cutting out at least a portion of the bottom of the vial and inserting the artificial lyocake through the bottom opening. If the artificial lyocake represents a particle defect (e.g., glass particle, metal particle, fiber, etc.), the actual particle may be placed on at least a portion of the top surface and / or at least a portion of the annular surface of the artificial lyocake prior to inserting the artificial lyocake into the bottom opening of the modified vial. The artificial lyocakes and artificial lyovials of the present disclosure simplify the production of defective samples (e.g., low-filled, high-filled, collapsed cake, meltback, foreign bodies, etc.). Additionally, the artificial lyocakes are robust and can withstand shipment to facilities that require, for example, training and certification of AVI systems. The artificial lyocakes and artificial lyovials can also be used to develop new lighting and inspection techniques to detect glass particles. The artificial lyocakes and artificial lyovials may reduce costs, reduce delays, and / or improve inspection of freeze-dried products by making samples representing specific defect types available on a rapid, consistent, and reliable basis.

[0014] To provide background for the use of the lyovials of the present disclosure, FIG. 1 illustrates an automated visual inspection (AVI) system 100 for inspecting a vial 105 containing a lyophilized product 115. The exemplary vial 105 has a central axis 106 and a seal 107. The exemplary AVI system 100 also includes a profile view imager 170 having an optical axis 171 that may be oriented perpendicular to the central axis 106 of the container 105. As shown in FIG. 1, the profile view imager 170 may generate a profile view image of the vial 105, the seal 107, and the lyophilized product 115. As described in more detail herein, the profile view image of the vial 105 may be used in the AVI system 100 to detect the fill level of the lyophilized product 115 in the vial 105, the slope of the top surface of the lyophilized product 115 in the vial 105, and / or other characteristics of the lyophilized product 115.

[0015] The exemplary AVI system 100 also includes a perspective view imager 175 located above the vial 105 and having an optical axis 176 directed slightly downward toward the vial 105. As shown in FIG. 1, the perspective view imager 170 may generate a perspective view image of the vial 105, the seal 107, and the lyophilized product 115. As described in more detail herein, the perspective view image of the vial 105 may be used by the AVI system 100 to detect the shape of the top surface of the lyophilized product 115 in the vial 105, the texture of the top surface of the lyophilized product 115, the color of the top surface of the lyophilized product 115, and / or other characteristics of the top surface of the lyophilized product 115 (and possibly the surrounding area).

[0016] AVI system 100 may include angled light source 180, direct light source 185, and / or backlight light source 190. As is typical within AVI system 100, operation of angled light source 180, direct light source 185, and / or backlight light source 190 may be coordinated with image acquisition from profile view imager 170 and / or oblique view imager 175, for example, to increase contrast in the resulting image of the artificial lyovial to detect defects in the associated artificial lyovial. However, in other embodiments, AVI system 100 includes more, fewer, or differently positioned imagers (e.g., only profile view imager 170) and / or more, fewer, or differently positioned light sources (e.g., only angled light source 180).

[0017] 2A-2C illustrate an artificial freeze-dried cake ("artificial lyocake") fabrication system (FIGS. 2A and 2B) and method (FIG. 2C). Referring initially to FIG. 2A, the artificial lyocake fabrication system may include a three-dimensional (3D) printer 200a having a material dispenser 261 and a platform 262. As depicted in FIG. 2B, a controller 200b for the 3D printer 200a includes a user interface generation module 265b, a 3D artificial lyocake data receiving module 266b, and a 3D artificial lyocake fabrication module 267b. The user interface generation module 265b, the 3D artificial lyocake data receiving module 266b, and / or the 3D artificial lyocake fabrication module 267b may be computer readable instructions stored on a non-transitory computer readable medium 264, for example. Alternatively, or in addition, at least a portion of the user interface generation module 265b, the 3D artificial lyocake data receiving module 266b, and / or the 3D artificial lyocake fabrication module 267b may be configured, for example, in an application specific integrated circuit (ASIC), a field programmable gate array (FPGA), firmware, or other dedicated electronic circuitry.

[0018] The controller 200b may execute at least a portion of the user interface generation module 265b, the 3D artificial lyocake data receiving module 266b, and / or the 3D artificial lyocake fabrication module 267b to perform the method 200c. The controller 200b may execute the user interface generation module 265b to cause the controller 200b to generate a user interface (block 265 of FIG. 2C). The user interface may enable a user to configure, control, and / or interact with the artificial lyocake fabrication system.

[0019] The controller 200b may execute the 3D artificial lyocake data receiving module 266b to cause the controller 200b to receive the 3D artificial lyocake data (block 266c in FIG. 2C). The 3D artificial lyocake data may be formatted, for example, as a stereolithography (STL) file. The 3D artificial lyocake data may include Cartesian coordinates that define the bottom, annular, and top surfaces of the artificial lyocake 205. The 3D artificial lyocake data may be generated using a 3D laser scanner (i.e., scanning the freeze-dried product using a 3D laser scanner). Alternatively, the 3D artificial lyocake data may be generated using computer-aided design (CAD) software and may include special coordinates based on the internal dimensions of each container, along with coordinates that define the top surface of the artificial lyocake.

[0020] The controller 200b may execute the 3D artificial lyocake fabrication module 267b to cause the artificial lyocake fabrication system to fabricate an artificial lyocake (block 267c in FIG. 2C). For example, the 3D printer may fabricate an artificial lyocake based on the 3D artificial lyocake data. The controller 200b may control the discharge of material from the material discharger 261 of the artificial lyocake fabrication system to discharge material based on at least the z value of the three-dimensional data. The control device 263 controls the position of the material discharger 261 relative to the platform 262 based on at least the x value and the y value of the three-dimensional data.

[0021] At least a portion of the top surface and / or annular surface of the artificial lyocake may be coated with sugar and salt diluted in isopropyl alcohol, for example. The artificial lyocake may be coated manually. Alternatively, the controller 200b may further execute the 3D artificial lyocake fabrication module 267b to cause the artificial lyocake fabrication system to coat the artificial lyocake (block 267c) or (if the resolution is sufficient) fabricate the artificial lyocake in a manner that accurately reflects the desired surface texture / characteristics without coating.

[0022] Labels may be added manually, for example, to the artificial lyocakes and / or associated artificial lyocake packaging to identify respective defects. Additionally or alternatively, the controller 200b may further execute the artificial lyocake creation module 267b to add label data to the 3D artificial lyocake data (block 267c). The artificial lyocake labels and / or label data may identify respective artificial lyocakes as acceptable, reject, low fill, high fill, meltback, collapsed lyocake, tampered lyocake, etc. The artificial lyocake label data may be used to test and / or train (with supervised learning) the associated AVI system 100.

[0023] The artificial lyocake can be made, for example, from a semi-flexible material (e.g., thermoplastic polyurethane (TPU) or the like). Artificial lyocake defects, such as high-filled, low-filled, and collapsed cakes, may be produced by 3D printing (e.g., using the 3D printer 200a and controller 200b as described above). Other defects, such as artificial lyocakes containing meltbacks and foreign bodies, can be produced, for example, by coating the 3D printed artificial lyocake with sugar and / or salt diluted in isopropyl alcohol. When making particle defects, the respective particles can be placed on the top surface and / or annular surface of the artificial lyocake.

[0024] As an alternative to 3D printing, the artificial lyocake may be manufactured using a computerized manufacturing process implementing computer numerical control (CNC). As another alternative, the artificial lyocake may be manufactured using molding and / or co-molding techniques. An associated mold may be mold designed based on the 3D artificial lyocake data. As another alternative, the artificial lyocake may be machined from a block of material. Relatedly, the controller may cause an associated machining device to automatically machine the artificial lyocake based on the 3D artificial lyocake data.

[0025] 3A-3D show an example sequence of steps 300a-e for making an artificial vial containing an artificial lyocake ("artificial lyovial"), corresponding to method 334 of FIG. 3E. Step 300a includes providing a vial 305 (block 338 of FIG. 3E). Vial 305 may include a top opening 309 (optionally covered by a cap) having an inner diameter 310, a translucent wall 308 having an inner diameter 311, and a bottom 312. Wall 308 and bottom 312 may be integrally formed of the same material (e.g., glass), for example.

[0026] Stage 300b includes removing the bottom 312 of the vial 305 to create a modified vial 306 having a bottom opening 313 (block 334 of FIG. 3E). The modified vial 306 includes a bottom rim 314. In embodiments in which the bottom 312 comprises the entire bottom of the vial 305, the bottom rim 314 may be a portion of the wall 308 where the vial sides are vertical (when the modified vial 305 is in an upright position). Although the bottom opening 313 is shown to have the same dimension as the vial inner diameter 311, if the vial 305 is instead a container of a non-uniform shape, the bottom opening 313 may have a different diameter than the vial inner diameter 311. In any case, the inner diameter of the bottom opening 313 is larger than the inner diameter 310 of the top opening 309.

[0027] Stage 300c includes providing an artificial lyocake 315 (block 336 of FIG. 3E). The artificial lyocake 315 may be similar to the artificial lyocake 215 of FIG. 2, for example, and providing the artificial lyocake 315 may include fabricating the artificial lyocake 315 using a 3D printer 200a. The artificial lyocake 315 includes a base portion 321, an annular surface 324, a top surface 322, a longitudinal dimension 323 extending from the base portion 321 to at least a portion of the top surface 322, and an outer diameter 316 that is substantially larger than the inner diameter 310 of the top opening 309. The artificial lyocake 315 may include an optional flange having an outer diameter 318, a height 319, and a width 320. If the artificial lyocake 315 includes the optional flange, the artificial lyocake 315 may include an additional longitudinal dimension 317. The flange may be formed integrally with the remainder of the artificial lyocake 315 (e.g., formed by the 3D printer 200a as well) or may be added at a later stage (e.g., a rubber or plastic cap that fits and / or is glued to the bottom edge of the artificial lyocake 315).

[0028] Stage 300d includes inserting the artificial lyocake 315 into the modified vial 306 through the bottom end opening 313 (block 338 of FIG. 3E). If the artificial lyocake 315 includes a flange, when the artificial lyocake 315 is inserted into the bottom end opening 313, the bottom rim 314 is adjacent to the flange width 320. If the artificial lyocake 315 does not include the optional flange, the bottom rim 314 may be flush with the base portion 321.

[0029] In embodiments with or without the optional flange, the artificial lyocake 315 can fit snugly within the modified vial 306 such that friction helps to hold the artificial lyocake 315 within the wall 308. That is, the means for fixing the artificial lyocake 315 within the modified vial 306 can be the annular surface 324 and the artificial lyocake 315 itself, the latter being dimensioned to fit snugly (by friction fit) within the modified vial 306, i.e. the inner diameter 311 of the vial 305 (at least at the bottom end opening 313) is slightly smaller (e.g., 0.1-5% smaller) than the diameter of the artificial lyocake 315, and the artificial lyocake is made of a compressible material. The artificial lyocake 315 can then exert an outward / expansive pressure to remain fixed within the modified vial 306.

[0030] Although not shown in Figures 3C and 3D, the artificial lyocake 315 may include alternative means for securing the artificial lyocake 315 within the modified vial 306. For example, the means for securing the artificial lyocake 315 within the modified vial 306 may be a separate cap that fits over both the artificial lyocake 315 and the bottom rim 314. Alternatively, the securing means may include flexible ribs, as will be discussed in more detail below with reference to Figure 5.

[0031] In some embodiments, the artificial lyovials are labeled, for example manually (block 340 in FIG. 3E). The label may, for example, identify each artificial lyovial as a particular type of defect (e.g., low-fill, high-fill, meltback, collapsed lyovial, lyovial with foreign material, etc.) or as a non-defective sample. The label may be a physical label (e.g., for storage or packaging if the artificial lyovial is shipped) or may be a data label corresponding to the artificial lyovial. For example, the label may be used for supervised training of a neural network (e.g., when a system similar to the AVI system 100 captures an image of the artificial lyovial and the image along with the label is used to train the neural network) or for testing / certification of an already trained neural network (or computer vision system, etc.).

[0032] 4 depicts another artificial lyocake 400 having a body portion 415, a base portion 421, and a top surface 422, where the body portion 415 has an annular surface 424 extending from the periphery of the base portion 421 to the periphery of the top surface 422. The top surface 422 may, for example, define a concave shape. The concave shape defined by the top surface 422 may, for example, resemble a lyocake having a meltback defect. Otherwise, the artificial lyocake 400 may, for example, resemble the artificial lyocake 215 of FIG. 2 or the artificial lyocake 315 of FIG. 3C.

[0033] 5 depicts an artificial lyocake 500 having an annular surface 515 and a flexible rib 527 near the bottom of the artificial lyocake 500 and above the base portion 521. The annular surface 515 has an upper surface 522 and extends at least to the flexible rib 527. The flexible rib 527 may be formed of a resilient and / or compressible material (e.g., rubber), has an outer diameter 528 larger than the diameter of the annular surface 515, and is generally configured to secure the artificial lyocake 500 within an associated modified vial (modified vial 306 of FIG. 3B). The artificial lyocake 500 may be similar to, for example, the artificial lyocake 215 of FIG. 2, the artificial lyocake 315 of FIG. 3C, or the artificial lyocake 400 of FIG. 4. Between the ribs 527, the artificial lyocake 500 may have a diameter 526 that is smaller than the rib diameter 528 but slightly larger than the diameter of the annular surface 515 (e.g., where the region 525 and the ribs 527 collectively form a rubber cap that is placed over the remainder of the artificial lyocake 500).

[0034] 6A-6L show grayscale images of exemplary vials having freeze-dried product defects 600a-l. The vials illustrated in images 600a-l (except for image 600a) are conventional vials containing actual freeze-dried product. However, images 600b-l provide examples of what may be artificially recreated using the systems and techniques described above.

[0035] Referring first to image 600a, vial 605 (which may be similar to lyovial 305, or may be modified to become a vial similar to modified vial 306) includes a seal 617 (eg, similar to seal 107).

[0036] Referring to image 600b, vial 605 includes a freeze-dried product 615b having a top surface 622b and an annular surface 624b that reflect the "collapsed cake" defect. An artificial collapsed freeze-dried product cake may be created to replicate freeze-dried product 615b using 3D printing. Optionally, the artificial lyocake may be coated with sugar and / or salt diluted in isopropyl alcohol. When creating a replica of a collapsed cake such as freeze-dried product 615b, it may be desirable to exceed a certain threshold slope of the top surface of the cake (e.g., a threshold slope above which the AVI system should reject the sample). Thus, the angle of at least a portion of the top surface of the artificial lyocake (e.g., an angle relative to the central axis 106 of FIG. 1) may be set to be greater than the slope threshold of the collapsed cake.

[0037] Referring to image 600c, vial 605 contains lyophilized product 615c having top surface 622c and annular surface 624c that reflect "liquefied product" defects. An artificial liquefied lyophilized product cake can be created using 3D printing and a translucent material. Alternatively, the liquefied lyophilized product cake may be replicated to replicate lyophilized product 615c using 3D printing. When creating a replica of a liquefied product such as lyophilized product 615c, it may be desirable to coat at least a portion of the 3D printed material with a high gloss material.

[0038] Referring to image 600d, vial 605 includes a lyophilized product 615d having a top surface 622d and an annular surface 624d that reflect a "high-fill" defect. An artificial high-fill lyophilized product cake may be created to replicate the lyophilized product 615d using 3D printing. When replicating a high-fill defect such as lyophilized product 615b, it may be desirable to exceed a certain threshold cake height (e.g., a threshold cake height above which the AVI system should reject the sample). Thus, the longitudinal dimension of the artificial lyophilized cake may be set larger than the high product fill threshold.

[0039] Referring to image 600e, vial 605 contains lyophilized product 615e, which has a top surface 622e and an annular surface 624e that reflect the "underfill" defect. An artificial underfilled lyophilized product cake may be created to replicate lyophilized product 615e using 3D printing. When replicating an underfilled defect such as lyophilized product 615b, it may be desirable to be below a certain threshold cake height (e.g., a threshold cake height below which the AVI system should reject the sample). Thus, the longitudinal dimension of the artificial lyophilized cake may be set below the underfilled product threshold.

[0040] Referring to image 600f, vial 605 contains a lyophilized product 615f, which has a top surface 622f and an annular surface 624f, one or both of which may reflect a "collapsed cake" and / or a "meltback" defect 623f. An artificial collapsed lyophilized product may be created to replicate the lyophilized product 615f using 3D printing. When replicating a collapsed cake or meltback such as the lyophilized product 615f, it may be desirable to coat at least a portion of the 3D printed artificial lyocake with sugar and / or salt, for example, diluted in isopropyl alcohol. It may also be desirable to create one or more discontinuities (e.g., gaps) that are greater than a threshold distance (e.g., a threshold discontinuity length or other distance above which the AVI system should reject the sample). Thus, the discontinuities 623f in at least a portion of the top surface 622f or at least a portion of the annular surface 624f of the artificial lyocake may be set greater than the meltback discontinuity threshold distance.

[0041] As another alternative, or in addition, the color discontinuity 623f of the top surface 622f and / or the annular surface 624f of the artificial lyocake 615f may be set to be greater than the collapsed cake color threshold and / or the meltback color threshold. In the context of the grayscale image 600f of Figure 6F, the collapsed cake color threshold and / or the meltback color threshold may be based, for example, on the grayscale value of pixels associated with the image 600f of the discontinuity 623f relative to the grayscale values ​​of pixels associated with the remainder of the top surface 622f or the annular surface 624f in the image 600f.

[0042] Referring to image 600g, vial 605 contains lyophilized product 615g, which has a top surface 622g and annular surface 624g, one or both of which may reflect a "color cake" defect 623g (the uneven color is not evident in the grayscale image of FIG. 6G). An artificial colored lyophilized product cake may be created to replicate lyophilized product 615g using 3D printing by applying color (e.g., dye) to certain areas of the artificial lyophilized product cake after printing.

[0043] Referring to image 600h, vial 605 contains freeze-dried product 615h, which has a top surface 622h and annular surface 624h that reflects "fiber particle" (e.g., 100um, 200um, 300um, 400um, 500um, 750um, 1000um, and / or 2000um fiber particle) defect 623h. An artificial freeze-dried product cake having fiber particles visually similar to fiber particles 623h may be created to replicate freeze-dried product 615h using 3D printing by applying fiber particles visually similar to fiber particles 623h to a 3D printed artificial lyocake prior to inserting the artificial lyocake into the bottom opening of a modified vial.

[0044] Referring to image 600i, vial 605 includes a freeze-dried product 615i having a top surface 622i and an annular surface 624i that reflect a "foreign body" (e.g., unknown foreign body) defect 623i. An artificial freeze-dried product cake having a material visually similar to the foreign body 623i can be fabricated to replicate the freeze-dried product 615i by using 3D printing to apply a material visually similar to the foreign body 623i prior to inserting the artificial lyocake into the bottom opening of the modified vial. To more accurately replicate the defect of FIG. 6i (where the defect is partially above the level of the cake), the material may be applied to the interior surface of the modified vial rather than the artificial lyocake.

[0045] Referring to image 600j, vial 605 contains a freeze-dried product 615j, which has a top surface 622j and an annular surface 624j, one or both of which reflect a "glass particle" (e.g., 100um, 200um, 300um, 400um, 500um, 750um, and / or 1000um glass particle) defect 623j. An artificial freeze-dried product cake having glass particles visually similar to glass particle 623j may be created to replicate freeze-dried product 615j by using 3D printing to apply glass particles to the artificial freeze-dried product cake prior to inserting the artificial freeze-dried product cake into the bottom opening of a modified vial.

[0046] Referring to image 600k, vial 605 includes a freeze-dried product 615k having a top surface 622k and annular surface 624k that reflect a "metal particle" (e.g., 100um, 200um, 300um, 400um, 500um, 750um, and / or 1000um metal particle) defect 623k. An artificial freeze-dried product cake having metal particles visually similar to metal particles 623k may be created to replicate freeze-dried product 615k by using 3D printing and applying the metal particles to the 3D printed artificial freeze-dried product cake prior to inserting the artificial freeze-dried product cake into the bottom opening of the modified vial.

[0047] Referring to image 600l, vial 605 contains lyophilized product 615l, which has top surface 622l and annular surface 624l, either or both of which may reflect an "abnormal appearance" defect. An artificial lyophilized product cake having an abnormal appearance may be created to replicate lyophilized product 615l using 3D printing by coating at least a portion of the 3D printed artificial lyophilized cake with, for example, sugar and / or salt diluted in isopropyl alcohol or with a high gloss coating.

[0048] Although the systems, methods, devices, and components thereof have been described in terms of exemplary embodiments, they are not limited to these exemplary embodiments. The detailed description is to be construed as an example only and does not describe all possible embodiments of the invention, since describing all possible embodiments of the invention would be impractical, if not impossible. Many alternative embodiments can be implemented using either current technology or technology developed after the filing date of this patent, and still fall within the scope of the claims that define the invention.

[0049] It should be understood by those skilled in the art that various modifications, variations, and combinations can be made to the above-described embodiments without departing from the scope of the present invention, and such modifications, variations, and combinations should be construed as being within the scope of the concept of the present invention.

Claims

1. An artificial lyovial representing at least a portion of a freeze-dried product sample, wherein the artificial lyovial is A part of a vial, the part of the vial having a vial wall with an upper end opening and a bottom end opening, the bottom end opening having an inner diameter larger than the inner diameter of the upper end opening, and at least a portion of the vial wall being semi-transparent, An artificial lion cake fixed within a portion of a vial by means for fixing the artificial lion cake within a portion of the vial, wherein the artificial lion cake has a base portion, an annular surface, a top surface, a longitudinal dimension extending from the base portion to at least a portion of the top surface, and an outer diameter larger than the inner diameter of the upper end opening. Artificial lyovial containing [unclear].

2. The artificial lyo-vial according to claim 1, wherein the means for fixing the artificial lyo-cake within the portion of the vial includes a separate cap that fits over the artificial lyo-cake and the bottom rim of the portion of the vial.

3. The artificial lyo vial according to claim 1, wherein the means for fixing the artificial lyo cake within the portion of the vial includes friction fitting between the artificial lyo cake and the portion of the vial.

4. The artificial lyo vial according to claim 3, wherein the friction fitting is achieved by the outer diameter of the artificial lyo cake being larger than the inner diameter of the bottom opening of a portion of the vial.

5. The artificial lion vial according to claim 3 or 4, wherein the artificial lion cake is formed from a compressible material.

6. The artificial lyo vial according to claim 1, wherein the means for fixing the artificial lyo cake within the portion of the vial includes at least one circumferentially extending flexible rib above the base portion.

7. A method for manufacturing an artificial lion vial, wherein the method is To provide a vial, wherein the vial includes an upper end opening having an upper inner diameter. The bottom opening is formed by removing at least a portion of the bottom end of the vial, wherein the bottom opening has a bottom inner diameter larger than the upper inner diameter. To provide an artificial lion cake having a base portion, an upper surface, an annular surface extending between the base portion and the upper surface, and an outer diameter larger than the upper inner diameter, Inserting at least a portion of the artificial lion cake through the bottom opening, To provide a means for fixing the artificial lyocake inside the vial. A method that includes this.

8. The method according to claim 7, wherein providing the means for fixing the artificial lyocake inside the modified vial includes fitting a separate cap onto the artificial lyocake and the bottom rim of the vial.

9. The method according to claim 7, wherein the outer diameter of the artificial lion cake is larger than the inner diameter of the bottom.

10. The method according to claim 9, wherein providing the artificial lion cake comprises forming the artificial lion cake from a compressible material.

11. The method according to claim 7, wherein the means for fixing the artificial lyocake within the portion of the vial includes at least one circumferentially extending flexible rib above the base portion.

12. The method according to any one of claims 7 to 11, wherein providing the artificial lion cake includes printing the artificial lion cake using a three-dimensional printer.

13. After coating at least a portion of the artificial lion cake, insert at least the portion of the artificial lion cake through the bottom opening. The method according to any one of claims 7 to 11, further comprising:

14. The method according to claim 13, wherein coating at least a portion of the artificial lyo cake includes coating at least a portion of the artificial lyo cake with a sugar diluted with isopropyl alcohol or a salt diluted with isopropyl alcohol.

15. Before inserting at least a portion of the artificial lion cake through the bottom opening, apply at least one foreign object to the artificial lion cake. It further includes, The method according to any one of claims 7 to 11, wherein applying the foreign matter to at least a portion of the artificial lyo cake includes applying at least one of fibrous particles, metal particles, or glass particles.

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