Shaking platform for maintaining solution homogeneity

Abstract

According to embodiments of the present disclosure, there are provided devices, systems and methods capable of maintaining the homogeneity of biomaterials during aseptic potting. In various embodiments, the device (600) for aseptic potting provided herein comprises a shaking device (601). The device also comprises a platform (609) coupled to the shaking device. The platform can rotate around a first axis. The device also comprises at least one shaft (603a, 603b) extending from the platform. The length of the shaft is adjustable. The device also comprises at least one arm (607a, 607b) extending from the shaft. The at least one arm has at least one fixing mechanism (608). The at least one fixing mechanism is configured to receive a container with a sealed compartment and to maintain the container in a substantially vertical orientation, wherein the sealed compartment accommodates biomaterials. The platform is configured to engage at least a portion of the container.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of U.S. Provisional Patent Application No. 62 / 928,115, filed on October 30, 2019, and U.S. Provisional Patent Application No. 63 / 088,782, filed on October 7, 2020, the entire contents of each of which are incorporated herein by reference. Technical Field

[0003] The present disclosure relates to apparatus, systems, and processes for aseptically fill-finishing biological materials while agitating the biological materials. Background Art

[0004] Maintaining the homogeneity of solutions or formulations under aseptic conditions is critical in bioprocessing and pharmaceutical manufacturing. Aseptic processing aims to minimize the exposure of sterile items to potential contamination hazards of manufacturing operations. Limiting the exposure time of sterile product components, providing the highest possible environmental control, optimizing processing flows, and designing equipment to prevent submicron airborne contamination in Class 100 (ISO 5 standard) clean areas are essential to ensure sterility.

[0005] A critical step in the aseptic handling of biological materials (e.g., drugs) during bioprocessing and drug manufacturing is the filling step. Importantly, once a drug or biological product is placed in a sealed sterile container, additional product transfers between containers increase the likelihood of product contamination. If the filling process is not sterile, it may pose a significant safety risk to the end user of the final product. Other adverse consequences of product contamination include damaged reputation, loss of revenue, expensive recalls, complex regulatory issues, and / or costly litigation. Therefore, aseptic filling processing is critical for pharmaceutical and bioprocess manufacturing.

[0006] In some filling / filling processes involving pharmaceutical and / or biopharmaceutical products (e.g., gene therapy, immunotherapy), maintaining product homogeneity during filling is important to achieve product homogeneity between individual units or vials. Specifically, product inhomogeneity will lead to unacceptable variation in the amount of active agent between individual vials. Such variation may result in patients receiving a dose of product that is too low (potentially leading to ineffective treatment) or too high (increasing the risk of overdose).

[0007] Traditional methods of maintaining homogeneity rely on foreign components that are in direct contact with the drug and / or biopharmaceutical product to shake and / or mix the sterilized product. For example, a magnetic shake bar can be placed in the container. The introduction of foreign components used for mixing (e.g., shake bars, magnetic shake bars, and / or impellers) into the product itself during filling / packaging increases the likelihood of product contamination or degradation due to excessive collision / friction with the structure of the foreign components. In addition, squeezing and / or kneading bags containing drug products during filling is a common practice in the industry; however, this carries the risk of puncturing the bag during filling and is not a viable solution when drug production is increased or large quantities of drug are processed. Summary of the invention

[0008] The present disclosure provides apparatus, systems and processes for aseptic filling of solutions (e.g., biological materials, including pharmaceuticals), wherein the solution is shaken without requiring any external components (e.g., shaking rods, rods or impellers). Therefore, in some embodiments, the apparatus, systems and processes described herein are particularly useful for maintaining the homogeneity of the solution during processing (e.g., aseptic filling).

[0009] Embodiments of the present disclosure generally relate to a rocking platform for mixing or rocking solutions, including biological materials, such as pharmaceuticals. In a specific embodiment, the present disclosure describes a rocking platform for rocking and / or mixing sterile biological materials (e.g., pharmaceuticals) contained in a sealed container during the filling process without introducing any foreign parts that come into contact with the sterile substance / product.

[0010] In some embodiments, a device for aseptic filling while shaking is provided. The device includes a shaking device and a platform coupled to the shaking device. The platform can rotate around a first axis. The device also includes at least one shaft extending from the platform. In some embodiments, the length of the shaft is adjustable. The device also includes at least one arm extending from the shaft, and the at least one arm has at least one fixing mechanism. The at least one fixing mechanism is configured to receive a container with a sealed compartment and maintain the container in a substantially vertical orientation, the sealed compartment containing biological material. The platform is configured to engage at least a portion of the container.

[0011] In some embodiments, the apparatus comprises at least one axis extending vertically from a midpoint of the platform and at least one arm extending vertically from the axis, and at least one fixing mechanism extends vertically from the at least one arm. In some embodiments, the at least one axis comprises a first axis disposed near a first edge of the platform and a second axis disposed near a second edge of the platform. In some embodiments, the first axis is aligned with the second axis.

[0012] In some embodiments, the platform comprises a planar surface. In other embodiments, the platform comprises a non-planar surface. In some embodiments, the platform is configured to rotate around a second axis. In certain embodiments, the platform is configured to rotate around a first axis and a second axis simultaneously. In some embodiments, the platform is configured to move in a plane defined by the first axis and the second axis. In yet other embodiments, the platform is configured to rotate along a first, second, and third axis.

[0013] In some embodiments, the container is a flexible bag. In some embodiments, the container is made of a polymer. In certain embodiments, the container comprises a biomaterial. Examples of biomaterials include, but are not limited to, medicaments, recombinant vectors (e.g., for gene and / or cell therapy), antibodies (e.g., monoclonal antibodies), therapeutic proteins (e.g., Fc fusion proteins), inhibitory nucleic acid molecules (e.g., inhibitory RNA molecules), and genetically modified cells (e.g., CAR-T cells).

[0014] In various embodiments, the apparatus described herein is not fluidly coupled to a pump, is not coupled to a second container, and / or does not include a stirring mechanism.

[0015] In certain aspects, the present invention provides a method for aseptic potting while shaking. In some embodiments, the method for potting includes dispensing the biomaterial into a container (e.g., a container provided herein). In some embodiments, the container has a first end and a second end. In certain embodiments, the method includes fixing the first end of the container to a shaking device (e.g., a shaking device described herein). For example, in some embodiments, the shaking device has a platform capable of rotating around a first axis, at least one axis extending from the platform, and at least one arm extending from the axis. The first end of the container is releasably fixed to the at least one arm. In some embodiments, the method includes positioning the container in a substantially vertical orientation. In certain embodiments, the method includes engaging at least a portion of the second end of the container with the platform. In some embodiments, the method includes rotating the platform around the first axis. Examples of biomaterials include, but are not limited to, medicaments, recombinant vectors (e.g., for gene and / or cell therapy), antibodies (e.g., monoclonal antibodies), therapeutic proteins (e.g., Fc fusion proteins), inhibitory nucleic acid molecules (e.g., inhibitory RNA molecules), and genetically modified cells (e.g., CAR-T cells).

[0016] In some embodiments, the method further comprises the step of treating the biological material prior to dispensing. In some embodiments, the treating step comprises subjecting the biological material to a filtering step prior to dispensing the biological material into the container.

[0017] In various embodiments, the platform includes a planar surface or a non-planar surface.

[0018] In some embodiments, fixing the first end of the container includes adjusting the length of the shaft. In some embodiments, the rotation includes displacement of the platform around the second axis. In certain embodiments, the rotation includes displacement of the platform in a plane defined by the first axis and / or a vertical second axis. In some embodiments, the rotation includes displacement of the platform around both the first axis and the second axis. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 An exemplary system for an aseptic fill process using a pump to move a sample from one container to a second container is shown.

[0020] Figure 2A An exemplary system for an aseptic filling process that employs a recirculation loop is shown. Figure 2B Shown is an enlarged view of a recirculation loop portion of a system for aseptic filling processing.

[0021] Figure 3 An exemplary system for an aseptic filling process having a shaking device is shown.

[0022] Figure 4A-4B An exemplary shaking apparatus for an aseptic filling process according to an embodiment of the present disclosure is shown.

[0023] Figure 5 An exemplary system for aseptic filling processing with a shaking device according to an embodiment of the present disclosure is shown.

[0024] Figure 6 An exemplary shaking apparatus for an aseptic filling process according to an embodiment of the present disclosure is shown.

[0025] Figure 7 An exemplary shaking apparatus for an aseptic filling process according to an embodiment of the present disclosure is shown.

[0026] Figure 8 A method for performing a potting process using a shaking platform according to an embodiment of the present disclosure is shown.

[0027] Fig. 9 The vector genome (Vg) titer (which is a measure of viral quantification) for vials taken during final filling of Example E is shown.

[0028] Fig.10 Osmotic pressure results for vials taken during final filling of Example E are shown. DETAILED DESCRIPTION

[0029] Certain drugs and / or medical devices (including disposable systems) can be sterilized using terminal sterilization methods, such as autoclave, irradiation, ethylene oxide, or purification using vaporized hydrogen peroxide (VHP). Terminal sterilization typically involves carefully filling and sealing product containers under ambient conditions, which minimizes the microbial and particle content of the product during processing and helps ensure the success of subsequent sterilization processes. In most cases, the bioburden level of the product, container, and closure is low, but they are not sterile. The product in the final container of the product is then sterilized, such as moist heat or irradiation. Unlike terminally sterilized filled drugs and / or medical devices, the stability of aseptically filled drugs and / or biological products may be affected by traditional terminal sterilization techniques, such as steam autoclaves, dry heat sterilizers, ethylene oxide, and irradiation (e.g., cobalt 60 gamma or electron beam).

[0030] There are many global regulatory requirements for aseptic / sterile fill / fill manufacturing. For example, in the United States, these regulatory requirements can be found in the FDA's September 2004 Guidance for Industry (i.e., the "FDA Guidance"). The FDA Guidance describes that in aseptic processing, drug products, containers, and closures may first be subjected to sterilization methods individually, as appropriate, and then combined together. Since there is no process to sterilize the product in the final container, it is critical to fill and seal the container in an environment that minimizes the microbial and particulate content of the product. Aseptic processing involves more variables than terminal sterilization. Before aseptic assembly into the final product, the various parts of the final product are usually subjected to various sterilization treatments. For example, glass containers are subjected to dry heat depyrogenation methods; rubber closures are subjected to moist heat sterilization; and liquid dosage forms are subjected to sterile filtration. Each of these sterilization processes requires validation and control. Each process may introduce errors that may ultimately lead to the distribution of contaminated products. Any manual or mechanical manipulation of the sterilized drug, components, containers, or closures before or during aseptic assembly poses a risk of contamination and therefore requires careful control. On the other hand, terminally sterilized drug products are terminally sterilized in sealed containers, thus limiting the possibility of errors.

[0031] The FDA guidance further states that sterile drug manufacturers should be acutely aware of the public health impact of distributing nonsterile products. Poor “current good manufacturing practice” (CGMP) conditions in manufacturing facilities can ultimately pose life-threatening health risks to patients.

[0032] In the United States, specific rules are in place to govern aseptic processing. For example, 21CFR 211.113(b) states that appropriate written procedures designed to prevent microbial contamination of drug products claimed to be sterile shall be established and followed. Such procedures shall include validation of all sterility and aseptic processing. Another section, 21CFR 211.167(a), states that for each batch of drug product claimed to be sterile and / or pyrogen-free, appropriate laboratory tests shall be performed to determine compliance with such requirements. The testing procedures shall be in writing and shall be followed.

[0033] In some aseptic fill / fill processes involving pharmaceutical and / or biopharmaceutical products (e.g., gene therapy, immunotherapy), the product may need to be shaken or agitated during the fill / fill process to ensure homogeneity of the product in many individual units. Because the introduction of any external components (e.g., shaking bars, magnetic shaking bars, and / or impellers) into the product itself during the fill / fill process may increase the likelihood of product aggregation or contamination, as well as damage due to excessive collision / friction with the structure of the external components, it is desirable to shake such products in their respective sterile containers without exposure to external components.

[0034] In addition to minimizing the risk of contamination during the filling process, it is also desirable to ensure the homogeneity of the drug during filling so that each vial receives a consistent drug. However, achieving product homogeneity can be challenging because it is undesirable to introduce any foreign components for mixing or shaking the drug. The present disclosure provides apparatus, systems, and processes for ensuring the homogeneity of a drug during aseptic filling.

[0035] Without wishing to be bound by theory, it is contemplated that the devices, systems, and methods described herein may also be used in many other applications, for example, mixing or shaking any solution under sterile conditions without introducing any external components (e.g., shaking sticks, rods, impellers, etc.). In various embodiments, the devices, systems, and methods described herein may be used to mix and / or shake the biomaterial during the encapsulation step. In other embodiments, the devices, systems, and methods described herein may be used to mix and / or shake the biomaterial prior to the encapsulation step, where mixing under sterile conditions is desired.

[0036] In various embodiments, the devices described herein include a container. In some embodiments, the container is a sealable bag. In various embodiments, the bag can have one or more ports and corresponding valves for transferring drug liquids and / or biopharmaceutical liquids into or out of the container. It is contemplated that any commercially available flexible container can be used in the embodiments described herein. In various embodiments, the container can be made of a polymer. Examples include Bag or bag.

[0037] In various embodiments, shaking can be provided to the container via a shaking device operably connected to the base / platform. The terms "shaking device", "shaking equipment" and "shaking platform" can be used interchangeably in the present disclosure. In various embodiments, the shaking device is a rocker. In various embodiments, the shaking device can affect the movement of the base in the plane defined by the x-axis and the y-axis. In various embodiments, the base can be substantially planar (e.g., flat). In various embodiments, the base can be non-planar (e.g., curved). In various embodiments, the curved base can reduce the container movement caused by the shaking liquid (e.g., drug / biopharmaceutical liquid) when the liquid is mixed or shaken by the shaking device. In certain embodiments, the shaking device (e.g., rocker) can rotate along one axis, or two axes, or three axes. Any suitable commercially available rocker can be used in various embodiments described herein.

[0038] In various embodiments, shaking the drug and / or biopharmaceutical product by a shaking device during the aseptic filling / packaging process promotes drug homogeneity after downstream filtration and during the aseptic filling process. In various embodiments, shaking can include seesaw rocking, tilting, spiral rotation (i.e., the combined movement of an orbital vibrator and a rocker arm) and / or orbital mixing (e.g., 3D mixing, nutation) (in orbits / minute). In various embodiments, control of the shaking device can be achieved by a fixed tilt angle and / or via a variety of shaking modes (e.g., continuous, periodic / pulsed, progressive, sudden shaking, etc.).

[0039] Because the methods described herein eliminate the need to introduce any additional components (e.g., stirring mechanisms, such as rods, shaking bars, or impellers) that may generate particles, degrade biological materials, cause product aggregation, or entrain air into the product, the devices described herein significantly reduce the possibility of product contamination during the filling step or during any other step during bioprocess manufacturing in which the devices described herein may be used. In various embodiments, the methods described herein enhance the smooth movement of the product within its sterile container without splashing or stratified materials. In various embodiments, the methods described herein allow low-foaming shaking and / or gentle continuous shaking or stirring of the drug at variable speeds (e.g., from about 5rpm to about 60rpm) or variable speeds and tilt angles or 3D mixing.

[0040] In various embodiments, a counter-current or vortex motion that displaces the drug and / or biopharmaceutical product from one end of the container to the other opposing end may facilitate mixing or agitation with or without a shaking device.

[0041] In various embodiments, before filling the container with a drug and / or biopharmaceutical product solution, filtration can be used to sterilize the drug and / or biopharmaceutical product solution. In various embodiments, as described in the FDA guidelines for filtering drugs and / or biopharmaceutical products, such filters generally have a nominal pore size of about 0.2 μm or less. As known in the art, other suitable filter sizes can be used. In various embodiments, redundant sterilizing filters can be used. Regardless of the filter or filter combination used, validation may include microbial challenges to simulate the worst production conditions of the material to be filtered and the integrity test results of the filter used for the study. When selecting a suitable challenge microorganism to assess which microorganism represents the worst-case challenge to the filter, the product biological contamination level can be assessed. Microbial defect short wave single cell (Brevundimonas diminuta) (ATCC 19146) may be a common challenge microorganism for 0.2 μm grade filters when properly grown, harvested and used, because of its small size (average diameter 0.3 μm). Production processing control can be designed to minimize the biological contamination level of unfiltered products. The biocontamination level of non-sterile bulk solutions can be determined to approximate the characteristics of potential contaminating organisms.

[0042] In various embodiments described herein, the terms "mixing" and "shaking" are used interchangeably to describe methods used to ensure uniformity or homogeneity of a solution (e.g., a biological material). A homogeneous solution can be any liquid having components in the same proportion in any given sample of the liquid. In various embodiments, a homogeneous solution is a solution containing a drug. As described herein, mixing or shaking a solution can be used to agitate the contents of a mixture so that any solids in the mixture become completely dissolved, thereby producing a homogeneous liquid or solution. Mixing or shaking a solution as described herein can also be used in the context of a filling step of a bioprocess manufacturing process so that the drug being filled (e.g., a biologic, such as a gene therapy vector or a monoclonal antibody) has a homogeneous titer between different vials being filled.

[0043] In some filling and packaging processes, one or more pumps (e.g., peristaltic pumps) are used to pump a solution from a first container (e.g., a bag) to a second container (e.g., a bag), thereby changing the liquid flow and shaking and / or mixing the solution via small changes in the liquid flow in the two containers. In some cases, the use of a pump may produce inconsistent liquid flow throughout the transfer process, and it may be necessary to stop and start the pump (multiple pumps) to control the flow rate or filling rate. In addition, mixing may not occur when the biological material is transferred from the first bag to the second bag.

[0044] Figure 1 A system 100 for an aseptic filling process is shown. Figure 1 In the embodiment, the container 102 (e.g., Bags) can be connected to a pump 104 (e.g., a peristaltic pump) via sterile tubing (e.g., silicon tubing of appropriate diameter). In various embodiments, container 102 includes a drug and / or biopharmaceutical product ready for filling, which can be maintained at room temperature. In various embodiments, container 102 can have any suitable capacity (e.g., 0.3L, 1L, 5L, 8L, 10L, 20L). In various embodiments, any component of system 100 can be sterilized using the above-mentioned purification techniques before contacting the drug / biopharmaceutical product. System 100 also includes a second container 106 (e.g., Bag). The first container 102 and / or the second container 106 may include a pharmaceutical and / or biopharmaceutical product 114. In various embodiments, the second container 106 may have any suitable capacity (e.g., 0.3L, 1L, 5L, 8L, 10L, 20L). In various embodiments, the second container 106 may be smaller than the first container 102. In various embodiments, the second container 106 may be the same size as the first container 102. In an exemplary embodiment, the second container 106 is filled to a predetermined limit, such as approximately 5L (e.g., in the case of a maximum capacity of 8L). In various embodiments, each container 102, 106 may have a maximum filling capacity that is less than the maximum capacity of the container to reduce the risk that the container may fail (e.g., burst). The second container 106 is connected to a rapid transfer port (RTP) and a filling assembly 108. The RTP and the filling assembly 108 are connected to an isolator 110 (e.g., any suitable commercial isolator, such as a SKAN isolator) for aseptic filling of individual product units. In various embodiments, the isolator may include a hydrogen peroxide purification system, various air filtration units (e.g., HEPA filters), pressure adjustment capabilities, filtered exhaust for aseptic filling, and / or a filling needle of a predetermined size (e.g., 3.2 mm) as known in the art. In various embodiments, the filling parameters may include a predetermined filling volume per vial (e.g., 0.1 ml, 0.2 ml, 0.3 ml, 0.4 ml, 0.5 ml, 1 ml, 2.5 ml, 5 ml, 7.5 ml, 10 ml, 20 ml, 30 ml, 40 ml, 50 ml, 60 ml, 70 ml, 80 ml, 90 ml, 100 ml, etc.), temperature control, and / or filling duration (e.g., 5 minutes, 10 minutes, 30 minutes, 1 hour, 5 hours, 10 hours, etc.). In various embodiments, the predetermined filling volume may be between 0.1 ml and 100 ml based on the target filling weight. In various embodiments, the filling duration may depend on the batch size. In various embodiments, the filling process can be performed in a sterile environment defined by good manufacturing practices (eg, Grade A, Grade B, etc.).

[0045] Figure 2A A system 200 for aseptic filling processing is shown, which employs a recirculation pump. In the system 200, a recirculation pump can be used to recirculate the product from a first container 202 (e.g., The recirculation of the drug / biopharmaceutical product 214 is performed after the bag) is transferred to the first pump 204a via a pipe and enters the recirculation loop section 220. The recirculation loop section 220 includes a second container 206, which is connected to the second pump 204b in a recirculation arrangement. The second container 206a is also connected to the RTP and filling assembly 208. In various embodiments, the pipe connecting the first pump 204a and the second container 206 can be closed after substantially all of the product 214 has been pumped out of the first container 202 and into the second container 206. In various embodiments, the recirculation loop section 220 can recirculate the product, thereby mixing or shaking the product 214 in the second container 206. In various embodiments, the recirculation can occur before any product 214 is transferred to the RTP and filler assembly 208. In various embodiments, the recirculation can occur during the transfer of the product 214 to the RTP and filling assembly. Similar to the above embodiment, the product is then transferred to the isolator 210.

[0046] In various embodiments, the recirculation loop portion 220 connecting the second container 206 and the second pump 204b can be controlled / adjusted to open and / or close via one or more valves. When closed, no recirculation occurs and the system 200 can be operated in the same manner as Figure 1 The system 100 shown in FIG. 1 operates in substantially the same manner.

[0047] In various embodiments, after the drug and / or biopharmaceutical product 214 is transferred from the first container 202, the recirculation loop portion 220 can be disconnected or isolated from the first container 202 via, for example, one or more shutoff valves.

[0048] Figure 2B An enlarged view of a recirculation loop portion 220 of the system for the potting process is shown.

[0049] In various embodiments, a shaking device can be incorporated into the aseptic filling system to further improve the mixing and / or shaking capabilities of the system. The first container and / or the second container can be placed directly on the base / platform of the shaking device to ensure proper balance and load distribution when placed thereon.

[0050] Figure 3 A system 300 for aseptic filling processing having a shaking device is shown. Figure 3 The system 300 is similar to Figure 1The system of FIG. 10 is a system of FIG. 10 but includes a shaking device 301 (e.g., a rocker arm) on which the first container 302 can be placed directly. In various embodiments, the container 302 can be a bag (e.g., a surge bag). The shaking device 301 can transfer the product 314 to the second container 306 (e.g., a pump 304). bag,

[0051] The product 314 of the first container 302 is shaken before and / or during the process of packaging (e.g., packaging bag, etc.). Figure 1 In the system, product 314 is transferred to a second container 306 via a pump 304 and then to an RTP and filling assembly 308 and an isolator 310, at which point the product 314 is transferred into individual product units (eg, vials). Figure 3 The illustrated system 300 can allow for continuous shaking and / or mixing of a drug / biopharmaceutical product 314 and its transfer to a second container 306. In some embodiments, the shaking and transfer operations can occur as discrete, step-wise operations that are performed sequentially, such that the product 314 is positioned within a container on the shaking device 301, shaken, and then transferred to the second bag 306; the process is thereafter repeated. Alternatively, the shaking and transfer operations can be performed in a temporally overlapping manner (e.g., simultaneously).

[0052] In various embodiments, when a pliable container (e.g., a surge bag) is placed directly on a shaking device with a solution contained therein, the solution may flatten the pliable container and attenuate the force from the shaking device, resulting in less effective shaking and / or mixing of the drug and / or biopharmaceutical product solution. In various embodiments, structure may be added to the shaking device to support the container in a particular orientation, thereby allowing for improved transfer of shaking force from the shaking device to the solution.

[0053] Figure 4A-4B An exemplary shaking device 400 for aseptic filling processing according to an embodiment of the present disclosure is shown. Figure 1-Figure 3 An improvement of the embodiment described in . Figure 4AA shaking device 401 is shown, which is configured to swing from left to right in a plane defined by a first axis 407a and a second axis 407b (as shown in arcs "α" and "β"). The shaking device 401 may include a motor with an attachment member (e.g., a fulcrum) that is used to connect to a base 409 and transmit motion thereto. The shaking device 401 can operate within a certain speed and mode range (e.g., continuous, periodic pulses). In some embodiments, the shaking device 401 can operate with fine-tuning control (e.g., about 1rpm increment adjustment) within a speed range such as about 5rpm to about 50rpm. In addition, the range of motion of the device (e.g., tilt angle) can be from about 1 degree to about 20 degrees, wherein the adjustment control is performed in increments of 0.1 degree or greater. In some embodiments, monitoring shaking and / or mixing (e.g., detecting the formation of bubbles, displacement of the contents of the bag along the inner wall, etc.) to ensure that the mixing or shaking is within an acceptable level, wherein the motion mode / motion speed of the shaking device is adjusted accordingly to keep it within an acceptable range.

[0054] The rocking device 401 also includes a bracket 412 having an axis 403 that extends substantially in a vertical direction away from a base 409 of the rocking device 401. The axis 403 can be fixed to the rocking device 401 in any suitable manner known in the art, such as by welding, screws and / or adhesives. In various embodiments, the axis 403 can be adjusted in length / height via an adjustment mechanism 405. In some embodiments, the axis 403 is located at the center of the platform and extends vertically from the center. In various embodiments, the adjustment mechanism 405 can include a pin or a screw.

[0055] In various embodiments, the shaft 403 can include a first (lower) component and a second (upper) component. In various embodiments, the components can be cylindrical. In various embodiments, the outer radius of the cylindrical first (lower) component is less than the inner radius of the cylindrical second (upper) component, so that the cylindrical first component can be telescopically accommodated within the cylindrical second component. In various embodiments, the cylindrical first (lower) component has an inner radius that is larger than the outer radius of the cylindrical second (upper) component, so that the cylindrical second component can be telescopically accommodated within the cylindrical first component (not shown).

[0056] In various embodiments, the adjustment mechanism 405 includes a spring-loaded pin on a first component and a plurality of corresponding holes for receiving the pins arranged in a vertical column on a second component. In various embodiments, the shaft further includes one or more arms 407 extending laterally from the shaft 403. In the exemplary embodiment shown, the arms 407 extend bilaterally and vertically from the shaft 403, although a person of ordinary skill will understand that alternative configurations are also within the scope of the present disclosure. A fixing mechanism 408 is included along the arms 407 for releasably fixing the container. In various embodiments, the fixing mechanism may include, for example, a hook, a pin, a buckle, a clip, and / or a magnetic fastener. In the exemplary embodiment shown, the fixing mechanism 408 extends downward from the arms 407 and is evenly spaced from the shaft 403, but alternative numbers / positions of the fixing mechanisms 408 (e.g., extending upward, gathering, etc.) may be employed when desired.

[0057] In operation, the height of shaft 403 is adjusted according to the size of the bag to be placed on base 409, so as to ensure sufficient contact between the container and the surface of the base to effectively impart momentum to the contents of the container during shaking or movement of base 409. In some embodiments, the height of shaft 403 can be extended so that the container remains completely suspended above or spaced from the upper surface of the platform.

[0058] Figure 4B Shown with Figure 4A A similar rocking device 400 is shown, which has a rocking device 401 and a bracket (the bracket has an axis 403 extending from a base 409), an adjustment mechanism 405 and an arm 407. Figure 4B In the embodiment, the shaking device 401 includes an axis 407a and an axis 407b. In various embodiments, the shaking device 401 can be configured to move left / right and / or forward / backward in a plane defined by the axes 407a, 407b, so that the base 409 moves or translates in a plane defined by the axes 407a, 407b. Additionally or alternatively, the base 409 can be tilted and rotated around one or both of the axes 407a, 407b (as shown in arcs "α" and "β"). In some embodiments, a combination of tilting and rocking can provide better mixing or shaking of the product in the container fixed to the shaking device 401. In some embodiments, the mobile mode can be implemented in discrete steps; in some embodiments, the motion mode is implemented synchronously. The base 409 can be configured as a substantially planar surface to receive the bag. In some embodiments, the base 409 can include non-planar surface features to increase the surface area of ​​the platform in contact with the bag, thereby transferring greater energy and momentum to the bag to promote mixing or shaking.

[0059] Figure 5A system 500 for aseptic filling processing with a shaking device according to an embodiment of the present disclosure is shown. Figure 1-Figure 3 An improvement of the embodiment described in Figure 5 In the embodiment, the shaking device 501 is provided with a bracket 512 for placing a container 506 (e.g., Bag) is releasably fixed thereto. The support 512 depicted in this exemplary embodiment includes a base 509 and upright trapezoidal side walls, between which the container 506 is received. Those skilled in the art will recognize that the side walls may include any suitable shape, such as a rectangle or a triangle. In various embodiments, the two side walls include one or more support members 512a, 512b disposed therebetween, which are configured to support the container 506. The angle of inclination of the support side walls allows easy access to the edge of the container 506. In various embodiments, the shaking device 501 can provide gentle movement, tilting and / or rotation to the container so that the product 514 can be shaken back and forth, thereby shaking the medicine during filling. In various embodiments, any component of the shaking device 501 can be made of a polymer, such as PET, PU, ​​PE, PVC, polycarbonate and / or PMMA. As container 506 is agitated by agitation device 501 , product 514 of container 506 may be transferred (eg, discharged or pumped) into RTP and filling assembly 508 and then processed in isolator 510 .

[0060] In various embodiments, such as Figure 5 As shown, system 500 does not include a pump, such as Figure 1 , Figure 2A , Figure 2B and Figure 3 In various embodiments, as shown in Figure 5 As shown, system 500 does not include a second container into which the drug and / or biopharmaceutical product is transferred. In various embodiments, the systems described herein do not include any stirring mechanism (e.g., a magnetic stirring bar) placed in direct contact with the drug and / or biopharmaceutical product, because any equipment that directly contacts the product after sterilization may contaminate and / or damage the product.

[0061] Figure 6 The shaking device 600 for aseptic filling process according to an embodiment of the present disclosure is shown. Figure 1-Figure 3 An improvement of the embodiment described in . Figure 6A shaking device 601 similar to the above-mentioned shaking device is shown. The shaking device 601 includes two shafts 603a, 603b, which are located near the opposite edges of the base 609 and aligned along the x-axis (or y-axis) and extend upward from the base 609 in a substantially vertical direction. In various embodiments, each shaft 603a, 603b may include a corresponding adjustment mechanism 605a, 605b similar to the above-mentioned adjustment mechanism. The shaking device 600 also includes arms 607a, 607b on the corresponding shafts 603a, 603b. In various embodiments, the base 609 may include one or more stabilizing beams 611 to provide additional stability to the shafts 603a, 603b. The shaking device 600 is configured to allow a container (e.g., a bag) to be fastened at a first end on a first arm 607a and a second end on a second arm 607b. In various embodiments, the container is positioned to contact the surface of the base 609 at least partially. In various embodiments, a first end of the container can be attached to the securing mechanism 608 of the first arm 607 and a second end of the container can be attached to the securing mechanism of the second arm 607b, with the middle portion of the bag hanging downwardly in a sling or hammock configuration engaged with the base 609.

[0062] Figure 7 The shaking device 700 for aseptic filling process according to an embodiment of the present disclosure is shown. Figure 1-Figure 3 An improvement of the embodiment described in . Figure 7 A shaking device 701 similar to the above-mentioned shaking device is shown. The shaking device 701 also includes four shafts 703a, 703b, 703c, 703d, which are located near the corners of the base 709 and extend upward from the base 709 in a substantially vertical direction. In various embodiments, the base 709 may include one or more stabilizing beams 711 to provide additional stability for shafts 703a to 703d. In various embodiments, each shaft 703a to 703d may include a corresponding adjustment mechanism 705a, 705b, 705c, 705d similar to the above-mentioned adjustment mechanism. The shaking device 700 also includes an arm 707a connected between shafts 703a, 703b and an arm 707b connected between shafts 703c, 703d. The shaking device 700 is constructed to allow a container (e.g., a bag) to be fastened at a first end on a first arm 707a and a second end on a second arm 707b. In various embodiments, the container all contacts the base 709.

[0063] In various embodiments, a feedback system can be implemented such that if the performance of the filling operation differs from a predetermined standard, the system described herein can stop transferring (e.g., pumping) the drug and / or biopharmaceutical product solution to the RTP and filling assembly. In various embodiments, the system can optionally or additionally stop any agitation device as described above from agitating and / or mixing the drug and / or biopharmaceutical product solution. For example, if a fill-by-weight process is implemented on the filling assembly and one or more incorrect weights are recorded for one or more vials (e.g., when excessive agitation results in undesirable bubbles in the product), the system can shut down any pumping of the drug and / or biopharmaceutical product solution and / or shut down the operation of any agitation device.

[0064] Figure 8 A method 800 for performing an encapsulation process using a shaking device according to an embodiment of the present disclosure is shown. At 802, a biological material is dispensed into a container. The container has a first end and a second end. At 804, the first end of the container is fixed to a shaking device having: a platform rotatable about at least a first axis; at least one axis extending from the platform; at least one arm extending from the axis. The first end of the container is releasably fixed to at least one arm. At 806, the container is positioned in a vertical orientation. At 808, at least a portion of the container is engaged with (e.g., in contact with) the platform. At 810, the platform moves (e.g., translates, tilts, and / or rotates) about the first axis. Moving the platform about the first axis shakes the contents of the container, thereby causing mixing or shaking of the contents (e.g., biological material). In various embodiments, the contents may be sterile. In various embodiments, the contents may be a recombinant virus, a monoclonal antibody, or a genetically modified cell. In various embodiments, the contents may be a pharmaceutical agent. In various embodiments, the contents may be subjected to a filtering step prior to the encapsulation step.

[0065] The following Examples AE describe exemplary pharmaceutical filling manufacturing processes that can be performed using the rocking platform system disclosed herein:

[0066] Example A:

[0067] A placebo (aqueous solution) with gelatin particles is prepared in a volume less than or equal to 3.0 L and shaken using a shaking platform described herein. The tilt angle of the platform can be set to 5° to 10° and can be adjusted in positive or negative increments of 1° or greater intervals as needed. For example, the positive incremental tilt can be set from 5° to 6°, or the reverse incremental tilt can be set from 10° to 5°. In various embodiments, nutation mixing can be used, that is, gentle three-dimensional (spiral rotation) shaking is used. The rocking rate is set to vary between about 15RPM and about 42RPM. The adjustment of the rocking rate can be 1RPM in positive or negative increments.

[0068] The shaking study aims to simulate the actual drug manufacturing / filling process by using the same equipment and consumables (multiple consumables) to explore the stability / robustness of the platform throughout the filling operation. The amount of alternative placebo solution relative to the sterile product bag capacity / size relative to the product bag placement height is part of the shaking study. Solution and particle displacement information is recorded based on changing the drug volume relative to the tilt angle, or the drug volume relative to the rocking rate, or a combination of these 3 parameters. Optimal shaking conditions in terms of tilt angle, rocking rate and drug volume were obtained. This information can be used as baseline data for relevant filling / manufacturing processes for drugs and / or biopharmaceutical products (e.g., gene therapy, immunotherapy), and for maintaining product homogeneity during the filling process.

[0069] Example B:

[0070] A virus-based retroviral replication vector is prepared in a volume of less than or equal to 5.0 L and shaken using a shaking platform as described herein. The resulting vials are filled to approximately 4 mL per vial. The tilt angle of the platform can be set to 5° to 10° and can be adjusted in a forward or reverse direction in increments of 5° or greater. For example, the forward incremental tilt can be set from 5° to 10°, or the reverse incremental tilt can be set from 10° to 5°. The rocking rate is set to vary between approximately 10 RPM and approximately 25 RPM. The rocking rate can be adjusted in forward or reverse increments of 5 RPM. This shaking study is intended to study the physical stability of the drug based on manual visual inspection of the filled drug vials.

[0071] Visual inspection standards can follow USP <788> 、USP <790> The contents outlined in , which are incorporated herein by reference regarding visual inspection. Intrinsic, intrinsic and extrinsic particulates (regardless of their solubility, configuration or construction) followed standard visual inspection guidelines. Material aggregation or agglomeration was the focus of this study by varying the volume of the drug relative to the tilt angle, or the volume of the drug relative to the rocking rate, or a combination of these three parameters. No sedimentation or aggregation / agglomeration tendency of the drug was observed. The product vials passed the quality defined based on manual visual inspection and the acceptable quality level (AQL).

[0072] Example C:

[0073] Virus-based retroviral replication vectors were prepared in a volume of less than or equal to 5.0 L and shaken using the shaking platform described herein. The resulting vials were filled to approximately 5 mL per vial. The tilt angle of the platform was set to a fixed angle of 5°. This study was designed to investigate the physical stability of the drug product by manual visual inspection of the filled finished vials. The visual inspection criteria followed USP <788> 、USP <790> The contents of the present invention are incorporated herein by reference with respect to visual inspection. No material aggregation or clumping was observed. The product vials passed the quality defined based on manual visual inspection and acceptable quality level (AQL). A specific number of vials were randomly selected for quality control (QC) release testing, such regulatory QC testing includes but is not limited to concentration curves (titer Vg / mL), pH, osmotic pressure, and other tests that meet defined release standards.

[0074] Example D:

[0075] A recombinant adeno-associated virus (rAAV) gene therapy drug having a weight of about 800 g in solution was prepared and shaken using the shaking platform described herein. The resulting vials were filled to about 1.0 mL per vial. The platform's tilt angle ranged from 5° to 10°, with a target angle of about 7°. It can be adjusted in positive or negative increments of 1° or 2°. For example, the positive incremental tilt can be set from 5° to 6°, or the reverse incremental tilt can be set from 7° to 5°. The rocking rate ranges from about 5RPM to about 25RPM, with a target of about 20RPM set. The rocking rate can be adjusted in positive or negative increments of 1RPM. This shaking study aims to explore the optimal shaking conditions for rAAV gene therapy drugs during the final filling process. The number of drugs relative to the capacity / size of the sterile product bag relative to the drug placement height is part of the shaking study. The product vials passed the quality defined based on manual visual inspection and the acceptable quality level (AQL). A specific number of vials (randomly selected vials) sampled during the manufacturing process after filling meet predefined release criteria and / or quality qualities.

[0076] Example E:

[0077] An rAAV gene therapy drug product having a weight of about 600 g in solution was prepared and shaken using the shaking platform described herein. The resulting vials were filled to about 1.0 mL per vial. The platform's tilt angle ranged from 5° to 10°, with a target angle of about 7°. Adjustments can be made in forward or reverse increments of 1° or 2°. The rocking rate ranged from about 5 RPM to about 25 RPM, with a target of about 10 RPM. Adjustments to the rocking rate can be made in forward or reverse increments of 1 RPM. This study was designed to investigate the physical stability of the drug based on manual visual inspection of filled drug vials. Visual inspection criteria followed USP <788> 、USP <790> The contents of , which are incorporated herein by reference regarding visual inspection. No material aggregation or clumping was observed. The product vials passed the defined quality based on manual visual inspection and acceptable quality level (AQL). A specific number of vials were randomly selected for quality control (QC) release testing, such regulatory QC testing includes but is not limited to concentration curve (AAV capsid titer Vg / mL), pH, osmotic pressure, appearance, sub-visible particles and other tests that meet defined release criteria.

[0078] Fig. 9 The vector genome (Vg) titer (which is a measure of viral quantification) of the vials taken during final filling for Example E is shown. In particular, Fig. 9 Shown are Vg titers through final fill vials (top, blue line) and Vg titer data from randomly sampled vials (bottom, red line). Fig. 9 The data shown include minimum Vg titer concentration requirements. Fig. 9 The data shown in indicate that the concentration curve (titer Vg / mL) is within the release criteria.

[0079] Fig.10 The osmotic pressure results of vials taken during final filling for Example E are shown. In particular, Fig.10 The predefined osmotic pressure range for the drug product (middle, blue line) through the final fill osmotic pressure (top and bottom, red lines) is shown. Fig.10 The data shown include osmotic pressure data from randomly sampled vials. Fig.10 The data shown in indicate that the osmotic pressure profile (mOsm / kg) is within the release criteria.

[0080] In various embodiments, vector genome concentration information, Vg titer is a key batch release assay for AAV vector formulations and is used as a measure for dosing purposes. In various embodiments, methods for quantifying AAV vectors can include quantitative PCR (qPCR) methods. In various embodiments, osmolality is a measure of the total number of active ions or particles dissolved in a given volume of solution given in osmol / kg. In various embodiments, osmolality measurements can be made using an osmometer, such as an Orion TM Versa Star Pro TM pH / ISE / Conductivity / Dissolved Oxygen Multi-Parameter Benchtop Meter. In various embodiments, osmotic pressure may be routinely performed in the pharmaceutical industry and clinical or research laboratories to establish the isotonicity of a solution.

[0081] In various embodiments, for both Vg titer and osmotic pressure measurements, random vials are selected, for example, approximately every 200th vial in the entire batch, where some vials are used for Vg titer measurements and other vials are used for osmotic pressure measurements. For example, vials No. 1, No. 200, No. 300 ... are selected for Vg titer, and vials No. 2, No. 201, No. 301 ... are selected for osmotic pressure. Fig. 9 and Fig.10 The results shown in the batch show that the Vg titer and osmotic pressure of different vials in the batch are consistent (ie, ≥1E12 Vg / mL and 300-400mOsm / Kg), thus demonstrating the stability of the product throughout the batch. In various embodiments, Fig. 9 and Fig.10 The Vg titer and osmotic pressure results shown in indicate that the custom-made shaking platform can provide adequate shaking for homogenized rAAV gene therapy products in filled vials using a tilt angle of approximately 7° and a rocking rate of 10 rpm.

[0082] The flowcharts and block diagrams in the figures illustrate the possible architectures, functions and operations of the systems, methods and devices according to various embodiments of the present disclosure. In various alternative implementations, the functions marked in the blocks may not appear in the order marked in the figures. For example, two blocks shown in succession may actually be executed substantially simultaneously, or the blocks may sometimes be executed in reverse order, depending on the functions involved. It should also be noted that each block in the block diagram and / or flow chart and the combination of blocks in the block diagram and / or flow chart diagram may be implemented by a dedicated hardware-based system that performs a specified function or action or executes a combination of dedicated hardware and computer instructions.

[0083] The description of various embodiments of the present disclosure has been presented for illustrative purposes, but the description is not intended to be exhaustive or limited to the disclosed embodiments. Many modifications and variations will be apparent to those of ordinary skill in the art without departing from the scope and spirit of the described embodiments. The terms used herein are selected to best explain the principles of the embodiments, practical applications, or technical improvements to technologies found in the marketplace, or to enable other persons of ordinary skill in the art to understand the embodiments disclosed herein.

Claims

1. A system for aseptic filling, comprising: Isolator; a quick transfer port and filling assembly connected to the isolator; A device for aseptic filling while shaking, the device being connected to the rapid transfer port and the filling assembly, the device comprising: shaking device; a platform coupled to the rocking device, the platform being rotatable about a first axis; at least one shaft extending from the platform, the shaft being adjustable in length, wherein the shaft comprises a first cylindrical member and a second cylindrical member, wherein an outer radius of the first cylindrical member is smaller than an inner radius of the second cylindrical member such that the first cylindrical member is telescopically received within the second cylindrical member; at least one arm extending from the shaft, the at least one arm having at least one securing mechanism; wherein the at least one securing mechanism is configured to receive a container having a sealed compartment containing a biological material and to hold the container in a substantially vertical orientation; and wherein the platform is configured to engage at least a portion of the container; wherein the apparatus shakes the container during filling.

2. The system according to claim 1, wherein: The shaft extends perpendicularly from a midpoint of the platform, the at least one arm extends perpendicularly from the shaft, and the at least one securing mechanism extends perpendicularly from the at least one arm.

3. The system according to claim 1, wherein: The platform includes a planar surface.

4. The system according to claim 1, wherein: The platform includes a non-planar surface.

5. The system according to claim 1, wherein: The at least one axis includes a first axis and a second axis, the first axis being disposed proximate a first edge of the platform and the second axis being disposed proximate a second edge of the platform.

6. The system according to claim 5, wherein: The first axis is aligned with the second axis.

7. The system according to claim 1, wherein: The rocking device displaces the platform at a variable speed.

8. The system according to claim 1, wherein: The platform is configured to rotate about a second axis.

9. The system according to claim 1, wherein: The platform is configured to rotate simultaneously about a first axis and a second axis.

10. The system according to claim 1, wherein: The platform is configured to move in a plane defined by the first axis and the second axis.

11. The system according to claim 1, wherein: The container is a flexible bag.

12. The system according to claim 1, wherein: The container comprises a polymer.

13. The system of claim 1, wherein: The biological material is selected from the group consisting of recombinant viruses, monoclonal antibodies, pharmaceutical agents and genetically modified cells.

14. The system according to claim 1, wherein: The container is not fluidly connected to the pump.

15. The system of claim 1, wherein: The container does not include a stirring mechanism.

16. The system of claim 1, wherein: The container is not fluidly connected to a second container.

17. A method for aseptic filling, the method comprising: dispensing a biological material into a container having a first end and a second end; securing the first end of the container to a shaking device having: a platform capable of rotating about a first axis, at least one shaft extending from the platform, wherein the shaft comprises a first cylindrical member and a second cylindrical member, wherein an outer radius of the first cylindrical member is smaller than an inner radius of the second cylindrical member such that the first cylindrical member is telescopically received within the second cylindrical member, at least one arm extending from the shaft, wherein the first end of the container is releasably secured to the at least one arm; positioning the container in a substantially vertical orientation; engaging at least a portion of the second end of the container with the platform; and The platform is rotated about the first axis during filling of the biological material from the container into the isolator via the rapid transfer port and filling assembly.

18. The method of claim 17, further comprising processing the biological material prior to dispensing.

19. The method of claim 17, further comprising subjecting the biological material to a filtration step prior to dispensing.

20. The method according to claim 17, wherein The platform includes a planar surface.

21. The method according to claim 17, wherein The platform includes a non-planar surface.

22. The method according to claim 17, wherein Securing the first end of the container includes adjusting a length of the shaft.

23. The method according to claim 17, wherein Rotation comprises displacement of the platform about a second axis.

24. The method according to claim 17, wherein Rotation comprises displacement of the platform in a plane defined by the first axis and a perpendicular second axis.

25. The method according to claim 17, wherein Rotation includes displacement of the platform about both the first and second axes.

26. The method according to claim 17, wherein The biological material is selected from the group consisting of recombinant viruses, monoclonal antibodies, pharmaceutical agents and genetically modified cells.

27. The method according to claim 17, wherein The biological material is sterile.

28. The method according to claim 17, wherein The container is not fluidly connected to the pump.

29. The method according to claim 17, wherein The container does not include a stirring mechanism.

30. The method of claim 17, wherein: The container is not fluidly coupled to a second container.

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