Systems and methods for drug delivery

Abstract

An approach is provided for determining material compatibility for components of a drug delivery system that involves using surface zeta potential analysis to evaluate the surface interaction of a desired molecule with at least one material present in a given IV bag system.

Description

Technical Field

[0001] Cross - Reference to Related Applications This application claims priority to U.S. Patent Application No. 62 / 925,685, filed on October 24, 2019. This priority application is hereby incorporated by reference in its entirety.

[0002] The present disclosure generally relates to drug delivery systems, and more particularly to drug therapies, drug delivery devices, and / or material compatibility and component compatibility for drug delivery systems.

Background Art

[0003] Drugs are administered to treat various conditions and diseases. Intravenous (IV) therapy is a drug administration process that delivers drugs directly into a patient's vein using a drip solution contained in a delivery container (e.g., a soft bag). These drug administrations may be performed in a medical facility or, in some cases, at a remote location such as the patient's home. For certain applications, drug products may be shipped in powder or lyophilized form to medical facilities (e.g., inpatient facilities, outpatient facilities, and / or pharmacies).

[0004] When reconstituting these drugs for administration, it is particularly important to maintain a sterile environment so as not to degrade or otherwise compromise the quality of the drug. Additionally, some classes of drugs, such as bispecific T cell engagers, may require extremely precise amounts of the drug product and / or other fluids for administration to prevent the drug product from becoming toxic. In many cases, healthcare professionals must prepare the drug by strictly following a set of procedures to ensure that a sterile environment is maintained and the correct amounts of the components are added to the delivery container. When reconstituting these drugs for administration, it may be desirable or necessary to utilize diluents, such as by adding a diluent to the drug product vial. As a result of these various procedures and requirements, the reconstitution process can be time-consuming, cumbersome, and can result in an unacceptable or undesirable error rate.

[0005] The current process for reconstituting lyophilized oncology products is often performed by an authorized pharmacist either in a hospital or a specialty compounding pharmacy. The use of a hood is often required to perform the reconstitution process, which can provide a sterile working environment that may be cumbersome for the pharmacist considering the complexity of the process. Additionally, this addition and mixing process involves the use of multiple needles for withdrawing / adding water for injection (WFI), saline, and / or intravenous solution stabilizer (IVSS) solutions. Typically, for relatively complex oncology products such as bispecific T cell engagers (BiTE®) particle (e.g., Blincyto®), a specific amount of WFI is added to reconstitute the lyophilized drug product contained in the vial by using a needle and syringe system. Next, appropriate amounts of saline and IVSS solution are added to an empty IV bag before the reconstituted final drug product is introduced.

[0006] It can also be particularly important to utilize materials for devices and system components that are compatible with components for drug therapy, e.g., materials that do not degrade, inactivate, contaminate, or otherwise adversely affect components for drug therapy. For each particle or particle group, it may be desirable to evaluate the compatibility of the major types of plastics used worldwide in their chemical structures. However, since materials are constantly changing, it is resource-intensive and unsustainable to inspect all materials. There are few technologies that can determine compatibility and ultimately adjust and particle optimize IVSS for all of the

[0007] In addition, current regulatory requirements implemented by the National Institute for Occupational Safety and Health (NIOSH) include certain oncology products in a list of hazardous drugs that require the use of additional engineering controls such as closed drug transfer systems (CSTDs) as an additional means of protection. Also, regardless of whether a drug is on the NIOSH list, it may be advantageous to utilize a CSTD and / or other components / systems to minimize or prevent undesirable emissions of fumes or other exposures into the air.

[0008] As will be described in more detail below, the present disclosure describes a system and method for drug delivery device reconfiguration that embodies advantageous alternatives to existing systems and methods, addresses one or more of the problems or needs described herein, and can also provide other benefits and advantages. SUMMARY OF THE INVENTION MEANS FOR SOLVING THE PROBLEM

[0009] According to a first aspect, surface zeta potential analysis is used to determine the desired particle (molecule)A method is provided for determining the material compatibility of components of a drug delivery system, including evaluating surface interactions with at least one material present within a given IV bag system. In some examples, the method includes providing a double-gap flow cell having an upper layer, a bottom layer, and a flow path for a desired particle to flow between the upper and bottom layers, and measuring a first zeta potential when the desired particle flows through a first potential material. The upper and bottom layers are constructed from the first potential material.

[0010] In some examples, the method further includes replacing the first potential material with a second potential material. Further, a second zeta potential of the desired particle is measured while flowing through the second potential material. The first zeta potential is compared to the second zeta potential.

[0011] In some of these examples, the desired particle includes a drug product for intravenous delivery. In some examples, the solution is formed of a drug product and an intravenous solution stabilizer. Then, the zeta potential of the solution may be measured.

[0012] According to a second aspect, a drug delivery system for delivering a medicament includes a drug container that houses a B cell maturation antigen bispecific T cell engager (BiTE®), a fluid path that receives a drug product from the drug product container, and a drug delivery device positioned along and / or adjacent to the fluid path. The drug delivery device includes a housing, a fluid displacement assembly at least partially supported by and / or surrounded by the housing, and a drive component at least partially supported by and / or surrounded by the housing. The drive component pushes the medicament through the fluid displacement assembly. The drug product container is constructed from at least one of ethyl vinyl acetate (“EVA”) or polyolefin, and the fluid path is constructed from at least one of polyethylene, polyurethane, or polyvinyl chloride (“PVC”).

[0013] According to a third aspect, a drug delivery system for delivering a medicament includes a drug container, a fluid pathway for receiving a drug product from a drug product container, and a drug delivery device positioned along and / or adjacent to the fluid pathway. The drug container houses a humanized bispecific XmAb T cell mobilizing antibody. The drug delivery device includes a housing, a fluid displacement assembly at least partially supported by and / or surrounded by the housing, and a drive component at least partially supported by and / or surrounded by the housing. The drive component extrudes the medicament through the fluid displacement assembly. The drug product container and the fluid pathway are constructed from at least one of EVA or a polyolefin.

[0014] According to a fourth aspect, a drug delivery system for delivering a medicament includes a drug container, a fluid pathway for receiving a drug product from a drug product container, and a drug delivery device positioned along and / or adjacent to the fluid pathway. The drug container houses a prostate-specific membrane antigen bispecific T cell engager (BiTE®). In some examples, the BiTE® is a half-life extended (HLE) BiTE®. The drug delivery device includes a housing, a fluid displacement assembly at least partially supported by and / or surrounded by the housing, and a drive component at least partially supported by and / or surrounded by the housing. The drive component extrudes the medicament through the fluid displacement assembly. The drug product container is constructed from at least one of EVA or a polyolefin, and the fluid pathway is constructed from at least one of polyethylene, polyurethane, or PVC.

[0015] According to a fifth aspect, a drug delivery system for delivering a medicament includes a drug container, a fluid pathway for receiving a drug product from a drug product container, and a drug delivery device positioned along and / or adjacent to the fluid pathway. The drug container houses a half-life extended CD19-targeted bispecific T cell engager (BiTE®) antibody. The drug delivery device includes a housing, a fluid displacement assembly at least partially supported by and / or surrounded by the housing, and a drive component at least partially supported by and / or surrounded by the housing. The drive component extrudes the medicament through the fluid displacement assembly. The drug product container and the fluid pathway are constructed from at least one of EVA or a polyolefin.

[0016] According to a fifth aspect, a drug delivery system for delivering a medicament includes a drug container, a fluid pathway for receiving a drug product from a drug product container, and a drug delivery device positioned along and / or adjacent to the fluid pathway. The drug container houses a DLL3-targeted bispecific T cell engager (BiTE®). The drug delivery device includes a housing, a fluid displacement assembly at least partially supported by and / or surrounded by the housing, and a drive component at least partially supported by and / or surrounded by the housing. The drive component extrudes the medicament through the fluid displacement assembly. The drug product container and the fluid pathway are constructed from at least one of EVA or a polyolefin.

[0017] The above need is at least partially met through the provision of systems and methods for drug delivery device reconfiguration described in the following detailed description, studied particularly in conjunction with the drawings.

Brief Description of the Drawings

[0018]

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Mode for Carrying Out the Invention

[0019] One skilled in the art will understand that the elements in the figures are drawn for simplicity and clarity and are not necessarily drawn to scale. For example, the dimensions and / or relative positions of some of the elements in the figures may be exaggerated relative to other elements to aid in understanding the various embodiments of the present invention. Also, commonly understood elements that are useful or necessary in commercially realizable embodiments are often not shown so as not to unduly obscure the figures of these various embodiments. Further, it will be recognized that certain acts and / or steps may be described or shown in a particular order of occurrence, but one skilled in the art will understand that such particularity with respect to order is not actually necessary. It will also be understood that the terms and expressions used herein, unless otherwise described with a different specific meaning in this specification, have the ordinary technical meaning as would be given by one skilled in the art to such terms and expressions, as described above.

[0020] Intravenous solution stabilizers (IVSSs) were developed to prevent the adsorption of BiTE® to surfaces. The adsorption levels were measured and ultimately adjusted to particle enable optimization of the IVSS with respect to it. Surface zeta potential analysis was used to understand the surface interactions between BiTE® and two common types of IV bag materials. This technique could assist in the optimization of IVSS formulations and enable the clinical use of various materials worldwide.

[0021] BiTE® particle is a powerful tool in the armamentarium for cancer. These particular particle are very effective and are often administered at relatively low concentrations. Unfortunately, BiTE® particle has a tendency to adhere to surfaces in low-dose regimens. To prevent the adsorption of BiTE® to surfaces (an example of such adsorption is shown in FIG. 6), intravenous solution stabilizers (IVSSs) may be utilized. Additionally, other IV administration materials and necessities may be used to administer these therapies.

[0022] Exemplary drug delivery systems and devices that can be used to administer drug products such as BiTE® are shown in FIGS. 1-5. More specifically, FIGS. 1 and 2 show a pump head 112 generally having a durable or reusable housing 114a, a disposable housing 114b, a fluid flow path 162, a power source such as a battery 132, a drive assembly such as a motor 140, a controller and display 134, and a pair of pressure sensors (e.g., an inlet pressure transducer 152 and an outlet pressure transducer 154). The two housing components 114a, 114b cooperate to define the overall housing 114. In some examples, the durable or reusable housing 114a may be disposable if appropriate. Similarly, in some examples, the disposable housing 114b may be reusable, although specific sterilization and / or modification processes may be required or desirable to achieve this reusability.

[0023] As further shown in FIG. 2, the medicament from the drug product container may flow into the pump head 112 through the input tube and move out of the pump through the output tube. In other words, the pump can urge the medicament through the pump head 112. The pump head 112 shown in FIG. 2 is a peristaltic pump, although other suitable configurations such as a positive displacement pump may be used. The pump head 112 shown in FIGS. 1 and 2 is a ring pump that utilizes a generally circular loop of tubing 162 to generate a peristaltic force. As a more specific example, the pump head 112 has components that clamp or otherwise occlude a ring-shaped tube portion in a circular motion to urge the fluid passing through the tubing 162.

[0024] Figure 3 shows an exploded view of the pump 110, including sub-components of the housing 114, such as the front case 122 of the controller, the rear case 124 of the controller, the front case 126 of the pump head, and the rear case 128 of the pump head. These four components 122, 124, 126, 128 generally fit together to form at least a majority of the housing 114. These four components 122, 124, 126, 128 may be made of a substantially rigid and lightweight material, such as plastic, composite material, or any other suitable material. The front / rear pair of components (one being 122, 124 and the other being 126, 128) may fit together by means of fasteners, snap-fit connections, adhesives, or any other suitable coupling components / methods. The PCA and the battery assembly 130 are at least partially housed within the housing 114, and the display screen 134 (Figure 2) defines a portion of the housing 114.

[0025] Figure 3 further shows an exploded view of the drive assembly 140 (e.g., a motor assembly), a tube set, and the pressure sensor 150. Referring to Figures 3 and 4, the drive assembly 140 generally includes a motor 142, a retaining ring 143, an eccentric hub 144, a sleeve bearing 145, a pump race 146, an encoder board 147, and one or more substantially flexible / flexible vibration mounts 148. The motor 142 provides a rotational driving force. The retaining ring 143 holds other components (i.e., tubes, as further described below) within the housing and / or aligns the eccentric hub 144. The eccentric hub 144 utilizes a cam mechanism to generate peristalsis. The sleeve bearing 145 provides a barrier between the eccentric hub 144 and a tube (such as the ring tube 158). The pump race 146 is adapted to house the circular tube portion already described. The encoder board 147 is configured to measure the actual speed of the motor to enhance accuracy and precision. The substantially flexible / flexible vibration mounts 148 prevent misalignment of components, reduce drive torque / driving force, and provide compliance for head installation.

[0026] As shown in FIG. 4, an exemplary drug delivery assembly 100 (or “system”) is provided that can use a handheld device 120. For example, the drug delivery assembly 100 includes a drug product container 102 for containing a drug product 102a (or agent), an IV input line 104a, and an IV output line 104d, each of the IV input line 104a and the IV output line 104d being in the form of tube portions 162a, 162d that communicate to and from a pump 114. The tube portion 162d is coupled to the user by any number of suitable means such as, for example, an IV needle or cannula. In some examples, the pump 114 may be worn by the user and / or otherwise coupled to the user.

[0027] In some examples, particle To better understand the specific surface interactions with the materials present within a given IV bag system, surface zeta potential analysis may be used. This evaluation may provide IVSS formulations optimized such that a wide variety of commercially available plastic materials can be utilized in a healthcare facility. In these methods, streaming zeta potential measurements are used to obtain the surface zeta potential of the IV bag 102 and tubing materials 162 (and filters, CSTDs, etc.) for administration lines (Anton Paar Surpass3). Also, the optimal concentration of an IV bag stabilizing solution (IVSS) may be determined to passivate the surface material. Subsequently, the distribution rate of a given BiTE® / protein to adsorb may be compared across different IV bag material surfaces. As shown in FIG. 5, a double-gap flow cell is shown to provide a miniaturized version of the IV bag 104 having an upper layer and a bottom layer and a flow path for a solution to flow between the upper layer and the bottom layer.

[0028] The surface zeta potential is the potential drop across the mobile portion of the double layer and is related to the surface charge at the solid-liquid interface. When negative charges are adsorbed on the surface of a material (i.e., the IV bag 102 and / or the tube 162), the surface zeta potential is negative, and vice versa. Therefore, particleSurface zeta potential may be used to determine whether it adsorbs to the IV bag 102 and / or the tubing material 162. As shown in FIG. 7, where the effect on zeta potential when increasing the proportion of IVSS was measured, addition of IVSS causes the zeta potential to rise by about 40 mV. The zeta potential levels off with about 1% IVSS. In some other examples, the zeta potential may be measured by applying a known electric field to determine the electrophoretic mobility of the particles.

[0029] Referring to FIG. 8, zeta potential analysis may be used to determine the effect of BiTE® concentration on adsorption to different materials. More specifically, in the exemplary FIG. 8, different concentrations of AMG 596, an anti-EGFRvIII / CD3 BiTE® antibody were observed. A substantial difference in the protection by IVSS against adsorption to the film for polyolefin IV bags is shown as compared to polyvinyl chloride (PVC), a common alternative. Thus, the drug delivery system 100 used with AMG 596 may incorporate a 2% IVSS solution for use with the polyolefin IV bag 102 while preventing adsorption. particle The zeta potential of particle changing the material through which it flows (e.g., EVA, polypropylene, polyurethane, etc.) and simultaneously changing the amount of IVSS added to form a solution containing the drug product may be compared. particle

[0030] Thus, using zeta potential analysis may potentially make it easier to determine whether IVSS is effective for the chemical structures of different types of plastics, and in addition, (e.g., to help in material selection) preferred materials for IV delivery of drug products may be determined. The above techniques and results potentially enable a wide variety of commercially available plastic materials to be clinically utilized worldwide. particleIt can provide the information necessary to optimize the IVSS formulation in a specific way. Furthermore, pre-incubation with 2% IVSS prevents the adsorption of BiTE®. The polyolefin material adsorbs only a measurable amount less BiTE® compared to the PVC material (regardless of the presence or absence of IVSS). This information may be particularly important to address any number of the following potential problems. Plasticizers can be material-specific and may affect stability (DEHP / TOTM); the effectiveness of the barrier may be a consideration for long-term storage (long-term retention and continuous infusion); there may be regional differences in material preferences / preferred use; the material type may affect the restoration of the module; the leaching / extraction profiles may differ.

[0031] Here, additional BiTE® particle and the materials of the appropriate system 100 are described. In a first alternative, a B-cell maturation antigen half-life extended bispecific T-cell engager (BCMA-HLE BiTE®; AMG 701) may be used in system 100. In this example, the drug is determined to be physically stable in 0.9% saline containing 2% IVSS for intravenous administration and is compatible with ethylene vinyl acetate (EVA) and / or polyolefin IV bags 102, and both polyethylene and polyurethane (PU) infusion sets (i.e., tubing 162) with and without a 0.22 μm in-line filter. Furthermore, zeta potential analysis has shown that disposable plastic syringes can also be used. Additionally, tubing 162 constructed from PVC may be used for AMG 701 at concentrations of 25 μg / mL or higher. At concentrations of 0.1 μg / mL or less, the loss of protein due to adsorption is higher than for other material types.

[0032] To prepare AMG 701 for intravenous infusion, IVSS is added at a 1:50 dilution to an IV bag 102 containing 0.9% sodium chloride. The lyophilized drug product 102a is reconstituted with 1.2 mL of Sterile Water for Injection (SWFI) and then an appropriate amount is transferred to the IV bag 102 for dose preparation. The compatibility of AMG 701 containing 2% (1:50 dilution) IVSS in 0.9% saline was examined within an IV bag 102 constructed from ethylene vinyl acetate and polyolefin as well as within silicone-treated disposable syringes and IV infusion sets (including tubing 162) of polyethylene (PE), polyvinyl chloride (PVC), and polyurethane (PU). Further, compatibility with a 0.22 μm in-line filter was observed. As previously stated, AMG 701 maintains stability and efficacy after storage within EVA and polyolefin IV bags 102 as well as within silicone-treated disposable syringes and is compatible with PE and PU infusion sets with and without a 0.22 μm filter. Further, the use of a PVC infusion set resulted in a decrease in protein concentration.

[0033] To support the proposed clinical doses of 2 μg / dose to 6500 μg / dose, stability studies were performed using three concentrations. More specifically, low protein concentration of 0.1 μg / mL, medium concentration of 25 μg / mL, and high protein concentration of 100 μg / mL were performed. Further, ethylene vinyl acetate IV bags, polyolefin IV bags, 20 mL disposable syringes, polyolefin infusion sets, and PVC infusion sets (with and without a 0.22 μm filter), and needles / catheters were examined for each concentration.

Table 1

[0034] Visual inspection and invisible particle analysis were used to determine the physical stability of the drug product 102a in the IV bag 102 and disposable syringe. Size exclusion chromatography was used to examine the amount of high molecular weight (HMW) protein species in the IV bag 102 and disposable syringe. SPR binding assay was used to measure the concentration of the drug product 102a in the IV bag 102 and disposable syringe. Also, the samples were examined by binding assay (efficacy). Visual inspection results for AMG 701 in the IV administration container indicate that the samples are substantially free of visible particles.

[0035] An obscuration device was used to measure invisible particles. The number of invisible particles was below the USP and PhEur limits for particulate matter (i.e., less than 6,000 particles per container for particles 10 μm or greater and less than 600 particles per container for particles 25 μm or greater) for all concentrations in 100 mL IV bags and 20 mL disposable syringes (12 mL volume in the 20 mL syringe) at all temperatures and time points, regardless of the presence or absence of a 0.22 μm in-line filter (see Figure 9).

[0036] Size exclusion chromatography with fluorescence detection was used to examine high molecular weight (HMW) protein species in samples at 25 μg / mL and 100 μg / mL. The relative area under the curve (AUC) due to HMW species of AMG 701 is presented in Figure 10. Samples at 0.1 μg / mL were not analyzed due to the low protein concentration. In summary, AMG 701 was stable against the formation of HMW protein species under the test conditions.

[0037] The protein concentrations in the IV bag 102 and disposable syringe were measured using a surface plasmon resonance (SPR) binding assay. The CD3 binding of samples at 0.1 μg / mL, 25 μg / mL, and 100 μg / mL was measured by SPR, and the protein concentration was estimated by comparing with the standard curve of a solution of AMG 701 with a known protein concentration. First, the solutions at 25 μg / mL and 100 μg / mL were diluted to 0.1 μg / mL and measured by SPR. The protein concentrations in the IV bag and disposable syringe are summarized in FIGS. 11a and 11b. For samples at 25 μg / mL and 100 μg / mL with nominal strength, the protein concentration did not change (±10% or less) within 24 hours in any of the IV administration containers, and was the same with or without a 0.22 μm in-line filter in the IV administration set (24 hours). These results indicate that there is no change in the protein concentration in each IV administration container.

[0038] For the 0.1 μg / mL sample with nominal length, the protein concentration remained stable (e.g., less than ±10% change compared to the 0-hour sample) during storage at 2°C to 8°C for at least 24 hours or at 25°C for at least 4 hours, regardless of the IV administration container. Also, the protein concentration was maintained during 3-hour infusion through a PE infusion set equipped with a 0.22 μm in-line filter. Contact of these samples with a PVC infusion set increased the loss of protein concentration (15 - 34%).

[0039] The results of the binding assay (i.e., efficacy) are summarized in FIG. 12. The 0.1 μg / mL sample was not analyzed due to the low protein concentration. The results for 25 μg / mL and 100 μg / mL indicate that there is no significant difference between the 0-hour sample and the 24-hour sample, and no significant difference between the IV administration containers. All materials are stable and sufficiently effective.

[0040] In a second alternative, a humanized bispecific XmAb T cell-engaging antibody construct (AMG 424) is derived against surface antigen cluster 3 (CD3) and surface antigen cluster 38 (CD38). This molecule comprises three different protein chains, namely a single-chain variable region fragment-constant fragment (scFv-Fc), a heavy chain (HC), and a light chain (LC). The scFv-Fc fragment antigen-binding (Fab) domain binds to the T cell receptor associated with CD3, and the HC and LC Fab domains bind to CD38. Figure 13 shows the proposed structure of AMG 424. The illustrated scFv-Fc, HC, and LC subunits are covalently linked by 10 intra-chain disulfide bonds and 3 inter-chain disulfide bonds. The scFv-Fc and HC each contain an N-linked glycan at the consensus glycosylation site (NST) at asparagines 335 and 295, respectively. The scFv-Fc and HC glycosylation sites are designated as G1 and G2, respectively. AMG 424 contains 1,144 amino acids. The amino acid sequences of the scFv-Fc, HC, and LC are shown in Figure 14. The C-terminal lysines are mostly removed from the scFv-Fc and HC. The scFv-Fc is composed of 485 amino acids with a molecular weight of 52,613 daltons (Da). The HC is composed of 445 amino acids with a molecular weight of 23,470 Da. The complete amino acid sequence of AMG 424 is verified by a combination of intact mass and liquid chromatography mass spectrometry (LC-MS) of trypsin and HNE digested peptide mapping.

[0041] AMG 424 is supplied as a preservative-free, sterile, single-use lyophilized drug product that is reconstituted using sterile water for injection for IV infusion. Each single-use vial contains 6.50 mg of AMG 424. The drug product 102a is formulated at pH 4.2 with 10 mM L-glutamic acid, 9% (w / v) sucrose, and 0.01% polysorbate 80. To prepare AMG 424 for IV infusion, the IVSS is added to infusion bag 102 containing 0.9% sodium chloride at a 1:20 dilution. The lyophilized drug product is reconstituted using 1.25 mL of sterile WFI, and an appropriate amount is transferred into the infusion bag for dose preparation.

[0042] The compatibility of AMG 424 containing 5% (1:20 dilution) IVSS in 0.9% saline was examined in IV bag 102 constructed from polyolefin and vinyl acetate with an IV infusion set having a 0.22 μm filter. Briefly, AMG 424 maintained stability after storage in all containers for up to 24 hours at 2°C to 8°C and 25°C. The protein concentration of the AMG 424 high-dose sample (4 mg / mL) was examined using ultraviolet-visible spectroscopy. The protein concentration of the AMG 424 low-dose (1 μg / mL) sample was below the detection limit of ultraviolet-visible spectroscopy. Therefore, RP-UHPLC was used to examine the concentration of these samples. Separation of AMG 424 from other impurities was achieved using a C8 column. A standard curve of the RP-UHPLC total integration peak area was generated from a set of low-concentration AMG 424 solutions. The standard curve was then used to estimate the concentration of protein present in the unknown samples.

[0043] The inspection is carried out to count invisible particles within a specific size range. The apparatus used to inspect AMG 424 is an electronic in-liquid particle counting system that uses an optical obscuration sensor together with a suitable sample supply device. Four aliquots (each 1 mL or more) from a pool solution with a total volume of 5 mL or more are degassed under vacuum and analyzed. The data from the first aliquot are discarded, and the number of particles per container is calculated from the average of the remaining three measurements. The results are reported as the number of particles per container for particle sizes 10 μm and above and 25 μm and above. Additionally, particles with particle sizes 2 μm and above and 5 μm and above are monitored for each container. This method complies with USP 787 and is considered suitable for AMG 424 as the purpose of this method is specified for therapeutic proteins.

[0044] For the purpose of determining compatibility with different IV infusion delivery materials, stability tests were performed using two concentrations (a low protein concentration of 1 μg / mL and a high protein concentration of 4 mg / mL) for the proposed clinical doses ranging from 50 μg / dose to 200 mg / dose. To cover a representative range of commonly used materials, EVA IV bags, polyolefin IV bags, polyolefin infusion sets (both with and without a 0.22 μm filter), and needles / catheters were examined for each concentration (see Figure 15). Visual inspection and invisible particle analysis were used to determine the physical stability of the drug product in the IV bags and disposable syringes. Figure 16 shows the visual inspection results for AMG 424 in the IV container 102. In summary, visual inspection revealed that the samples were substantially free of visible particles.

[0045] Invisible particles were measured using an optical obscuration device. The number of invisible particles remained below the USP and PhEur limits for particulate matter (i.e., less than 6,000 particles per container for 10 μm and above and less than 600 particles per container for 25 μm and above) for both concentrations in the 250 mL IV bags at all temperatures and time points regardless of the presence or absence of a 0.22 μm in-line filter (see Figure 17).

[0046] As shown in FIG. 18, protein concentration was measured by RP-UHPLC and ultraviolet-visible spectrophotometry assay. After addition and mixing, the concentration of AMG 424 in each bag of the IV administration container 102 was analyzed by RP-UHPLC or ultraviolet-visible spectrophotometry according to the sample concentration. Protein concentration recovery at low dose was based on the comparison of the total peak area of RP-UHPLC of the unknown sample with the standard curve. Ultraviolet-visible spectrophotometry was used to measure protein concentration recovery at high dose. The protein concentration did not change (±10%) within 24 hours in any of the IV administration containers and was the same with (t = 24 h) and without (t = 0) a 0.22 μm in-line filter in the IV administration set. These results indicate that there is no change in the protein concentration in each IV administration container.

[0047] In summary, AMG 424 is physically stable in 0.9% saline containing 5% IVSS for intravenous administration and is compatible with EVA and polyolefin IV bags and tubing materials used during product administration.

[0048] In a third alternative, material compatibility with prostate-specific membrane antigen half-life extended bispecific T cell engager (PMSA-HLE BiTE®; AMG 160) is determined. In summary, AMG 160 is physically stable in 0.9% saline containing 5% IVSS for intravenous administration and is compatible with EVA or polyolefin IV bags and polyethylene and polyurethane infusion sets with and without a 0.22 μm in-line filter and disposable plastic syringes. To prepare AMG 160 for IV infusion, IVSS is added at a 1:20 dilution to an infusion bag 102 containing 0.9% sodium chloride. The lyophilized drug product is reconstituted using 1.2 mL of sterile WFI, and an appropriate amount is transferred into the infusion bag for dose preparation.

[0049] For the purpose of determining the compatibility with different IV infusion delivery materials, stability tests were performed using two concentrations (a low protein concentration of 0.1 μg / mL and a high protein concentration of 62.5 mg / mL) to target the proposed clinical doses. To target a representative range of commonly used materials, EVA IV bags, polyolefin IV bags, disposable syringes (20 mL), PE, PVC, and / or PU infusion sets (both with and without a 0.22 μm filter) and needles / catheters were examined for each concentration (see Figure 19). Appearance analysis and invisible particle analysis were used to determine the physical stability of the drug product in the IV bags and disposable syringes. More specifically, SE-UHPLC was used to examine the amount of high molecular weight (HMW) protein species and the concentration of the drug product in the IV bags and disposable syringes. As an orthogonal method for analyzing the concentration of the drug product in the IV bags and disposable syringes, an SPR binding assay was used. Samples at 62.5 μg / mL were also examined in the binding assay (for efficacy). The appearance results for AMG 160 in the IV administration containers are summarized in Figure 20. In summary, visual inspection revealed that the samples were substantially free of visible particles.

[0050] Invisible particles were measured using a light obscuration device. The number of invisible particles remained below the USP and PhEur limits for particulate matter for all samples (i.e., less than 6,000 particles per container for particles 10 μm or greater and less than 600 particles per container for particles 25 μm or greater) (see Figures 21a and 21b).

[0051] Referring to FIGS. 22 and 23, SE-UHPLC with fluorescence detection was used to examine the HMW protein species in a 62.5 μg / mL sample. A 0.1 μg / mL sample was not analyzed due to the low protein concentration. In summary, AMG 160 was stable against the formation of HMW protein species under the test conditions shown in an amount remaining less than 1% (FIG. 22). Further, SE-UHPLC with fluorescence detection was used to examine the concentration of the drug product in the IV bag before and after infusion. Again, a 0.1 μg / mL sample was not analyzed due to the low protein concentration. The protein concentration of each sample was calculated from the area under each curve (AUC) using linear regression of a standard curve derived from a solution of AMG 160 at a known concentration. The protein concentrations in the IV bag are summarized in FIG. 23.

[0052] Referring to FIG. 24, surface plasmon resonance binding assays were also used as an orthogonal method to measure the protein concentrations in the IV bag and disposable syringes. The CD3 binding of 0.1 μg / mL and 62.5 μg / mL samples was measured by SPR and the protein concentration was estimated by comparison with a standard curve of a solution of AMG 160 at a known protein concentration. First, a 62.5 μg / mL solution was diluted to 0.1 μg / mL and measured by SPR. The protein concentrations in the IV bag and disposable syringes are summarized in FIG. 24. For a 0.1 μg / mL sample with a nominal strength, the protein concentration did not change over 24 hours (±6% or less) in any of the IV administration containers. The protein concentration also remained stable during infusion and when the solution passed through a 0.22 μm in-line filter. For a 62.5 μg / mL sample with a nominal strength, the protein concentration did not change over 24 hours (±6% or less) in any of the IV administration containers. The protein concentration also remained stable during infusion and when the solution passed through a 0.22 μm in-line filter. Therefore, there is no change in the protein concentration in each IV administration container.

[0053] The results of the binding assay (efficacy) are presented in Figure 25. Again, the 0.1 μg / mL sample was not analyzed due to low protein concentration. The results for 62.5 μg / mL show no significant difference between the 0-hour and 24-hour samples and no significant difference between IV administration containers, indicating that AMG 160 remained stable and sufficiently effective under the test conditions.

[0054] In summary, AMG 160 is physically stable in 0.9% saline containing 5% IVSS for IV administration and is compatible with EVA and polyolefin IV bags, PE, PVC, and PU infusion sets (with and without 0.22 μm inline filters) and disposable plastic (polyolefin) syringes used during product administration.

[0055] In the fourth alternative, the material compatibility with HLE CD19-targeted BiTE® (AMG 562) is determined. To prepare AMG 562 for infusion, the IVSS is added at a 1:20 dilution to the infusion components containing 0.9% sodium chloride. The lyophilized drug product is reconstituted with 1.2 mL of sterile WFI, and an appropriate amount is transferred into the infusion bag for dose preparation. The compatibility of the AMG 562 drug product containing 5% (1:20 dilution) IVSS in 0.9% saline was examined in commonly used IV administration materials (EVA and polyolefin) and silicone-treated disposable syringes with an IV infusion set and a 0.22 μm inline filter. The results showed that AMG 562 maintained stability, was fully recoverable and effective, even after storage in IV administration components for up to 24 hours at 25°C. AMG 562 was bound and eluted using a Protein A column. The protein eluted as a single peak. The total protein loaded was determined by comparing the area under the curve to a known concentration curve.

[0056] For the purpose of determining the compatibility with different IV infusion delivery materials, stability studies were performed using two concentrations (a low protein concentration of 50 ng / mL and a high protein concentration of 10 μg / mL) to target the proposed clinical doses of 100 ng / dose to 1 mg / dose. AMG 562 was prepared using 5% IVSS in IV administration materials (EVA and polyolefin) and disposable syringes over a maximum of 24 hours at 25°C (see Figure 26). To show the effectiveness of 5% IVSS in eliminating protein loss, negative controls without IVSS were added to both IV bag types at the lowest protein concentration. Samples were taken directly from the IV bags at time zero. After 24 hours, a second sample was taken after flowing through the infusion line and filter.

[0057] After the preparation and storage of AMG 562 in the described IV administration materials, the protein concentrations of the 50 ng / mL and 10 μg / mL samples were analyzed by affinity protein A HPLC chromatography and compared to the concentration at time zero to determine if loss occurred due to adsorption to the surface. No significant loss was observed for 50 ng / mL and 10 μg / mL of AMG 562 containing 5% IVSS after storage for 24 hours at 25°C (Figure 27). Protein loss was significant for 50 ng / mL of AMG 562 without IVSS, indicating the need for the addition of 5% IVSS to the IV infusion materials.

[0058] Referring to FIGS. 28-30, aggregation was monitored using SE-UHPLC. The results of SE-UHPLC showed no change in the percentage of HMW species at 10 μg / mL (FIG. 28). The concentration of 50 ng / mL of AMG 562 was below the quantification level of the SE-UHPLC assay. Therefore, the results for 10 μg / mL of AMG 562 were expected to represent lower concentrations. The HIAC (i.e., light obscuration device) was used to quantify the number of invisible particles, and visual analysis was used to confirm the presence of visible particles at both concentrations of 50 ng / mL and 10 μg / mL. The number of invisible particles was 18 particles or less per mL at sizes of 10 μm or greater and 2 particles or less per mL at sizes of 25 μm or greater (FIG. 29). The results of visual inspection indicate that the IV administration materials (EVA and polyolefin) and silicone-treated disposable syringes are substantially free of visible particles.

[0059] The results of the percent relative efficacy showed no change in efficacy at 10 μg / mL (FIG. 30). The 50 ng / mL sample was not analyzed due to the low protein concentration. Therefore, the results for 10 μg / mL of AMG 562 were expected to represent lower concentrations.

[0060] Based on the SE-UHPLC and invisible and visible particle data and the efficacy results, AMG 562 was compatible with silicone-treated disposable syringes and IV bags constructed from EVA or polyolefin and remained physically stable and effective during the test in 0.9% saline containing 5% IVSS.

[0061] In the 5th alternative, the material compatibility with AMG 757 is determined. To prepare AMG 757 for infusion, the IVSS is added at a 1:20 dilution to an infusion component containing 0.9% sodium chloride. The lyophilized drug product is reconstituted using 1.2 mL of sterile WFI, and an appropriate amount is transferred into the infusion bag for dose preparation. The compatibility of the AMG 757 drug product containing 5% (1:20 dilution) IVSS in 0.9% saline was examined in commonly used IV administration materials (EVA and polyolefin) with an IV infusion set having a 0.22 μm inline filter and in silicone-treated disposable syringes. The results showed that AMG 757 maintained stability and was fully effective after storage in all containers for up to 24 hours at 2°C - 8°C and 25°C. The SE-UHPLC assay was used to estimate protein recovery. A standard curve of the SE-UHPLC total integrated peak area was generated from a set of AMG 757 solutions of known concentrations. The standard curve was then used to estimate the concentration of protein present in the unknown samples.

[0062] For the purpose of determining compatibility with different IV infusion delivery materials, stability tests were performed using two concentrations (a low protein concentration of 20 μg / mL and a high protein concentration of 1 mg / mL) for the proposed clinical doses ranging from 3 μg / dose to 100 mg / dose. EVA and polyolefin IV bags, disposable syringes (60 cc), polyolefin infusion sets with and without a 0.22 μm filter, and needles / catheters were examined for each concentration to cover a representative range of commonly used materials. Figure 31 shows the configuration to be examined in detail.

[0063] Visual inspection and invisible particle analysis were used to determine the physical stability of the drug product in the IV bags and disposable syringes. The SE-UHPLC assay was used to measure the concentration of the drug product in the IV bags. Samples were also examined by a cell-based bioassay (efficacy). Figure 32 shows the visual inspection results for AMG 757 in the IV container 102. In summary, visual inspection revealed that the samples were substantially free of visible particles.

[0064] Invisible particles were measured using a light shielding device. The number of invisible particles was below the USP and PhEur limits for particulate matter (i.e., less than 6,000 particles per container for particles 10 μm and above, and less than 600 particles per container for particles 25 μm and above) for both the concentration in a 100 mL IV bag and in a 60 cc disposable syringe (50 mL volume in the 60 cc syringe) at all temperatures and time points, regardless of the presence or absence of a 0.22 μm in-line filter (see Figure 33).

[0065] Referring to Figure 34, the recovery measurements by SE-UHPLC assay are presented together. After addition and mixing, the concentration of AMG 757 in each IV administration container was analyzed. The recovery was based on the comparison of the total SE-UHPLC peak area of the unknown sample with the standard curve. The protein concentration did not change (±10%) over 24 hours in any of the IV administration containers and was the same with and without a 0.22 μm in-line filter in the IV administration set (t = 24 h and t = 4, respectively). These results indicate that there is no change in the protein concentration in each IV administration container.

[0066] Referring to Figure 35, the results of the cell-based bioassay (efficacy) are presented together, showing no significant difference between the t = 0 sample and the t = 24 h sample, and no significant difference between IV administration containers. The results indicate that all materials are stable and sufficiently effective. In summary, AMG 757 is physically stable in 0.9% saline containing 5% IVSS for intravenous administration and is compatible with the EVA and polyolefin IV bags, tubing materials, and disposable plastic syringes used during product administration.

[0067] In some examples, the IVSS may include polysorbate. In some examples, the IVSS formulation may include about 1.25 M lysine monohydrochloride, 25 mM citric acid monohydrate, 0.1% (w / v) polysorbate 80, and have a pH of about 7.0. In other examples, the IVSS54 includes a similar formulation but may also have at least about 0.9% NaCl and about 0.001 - about 0.1% (w / v) polysorbate 80. It is understood that different BiTE® may require different final ratios of IVSS54 in the delivery container. This ratio can vary between about 0.5% and about 12% of the final volume in the delivery container. Further, citrate may increase the risk of glass delamination when filled in a glass vial. If citrate is required for drug product stabilization (determined for each product), the delivery container may be constructed from CZ or other plastic compositions. Other examples of components for a suitable IVSS54 are possible. A suitable IVSS54 concentration prevents protein - plastic interactions and / or surface adsorption, more specifically, at the lower limit of the concentration range that can potentially vary the effective amount even with a slight loss. The following table shows exemplary component concentrations for various IVSS concentrations.

[0068]

Table 2

[0069] The pharmaceutical product container may be in the form of a similar container including an IV bag, vial, pre-filled syringe, or a reconstitution container body that defines an internal volume. The internal volume may be sterile. In some approaches, the reconstitution container adapter may also be a CSTD that fits, engages, and / or couples to a vial adapter (or, in the example where the pre-filled reconstitution container is in the form of a syringe, the container adapter may be a needle). Additionally or alternatively, the pharmaceutical product can be bulk freeze-dried and filled into a cartridge or container typically used for administration with an IV pump. If needed, the dehydrated forms of IVSS, NaCl, and any other components required for the final administration solution can be bulk freeze-dried for long-term storage and filled into a cassette.

[0070] As already described, in some examples, the pre-filled pharmaceutical product container may be in the form of a pre-filled syringe that contains the pharmaceutical product. In these examples, the pharmaceutical product may be in the form of a liquid BiTE® formulation used in conjunction with a monoclonal antibody (mAb). In these examples, the pharmaceutical product may advantageously simplify and / or improve the supply chain and manufacturing control, and further enable a more compact commercial packaging that occupies less space in the storage system in a medical facility, when more conventional needle-syringe injection / delivery into the container is preferred, and may be added directly to the delivery container without using a vial adapter system (such as the CSTD described above). In these examples, the pre-filled pharmaceutical product vial may or may not need to be reconstituted prior to transfer of the pharmaceutical product to the delivery container.

[0071] The foregoing description has been directed to various devices, assemblies, components, subsystems, and methods related to drug delivery devices. The devices, assemblies, components, subsystems, methods, or drug delivery devices can further include, or be used with, drugs including, but not limited to, the drugs specified below, as well as their generic and biosimilar equivalents. As used herein, the term drug can be used interchangeably with other similar terms and is used to refer to any kind of agent or therapeutic material, including traditional and non-traditional pharmaceuticals, nutraceuticals, supplements, biological agents, biologically active agents and compositions, macromolecules, biosimilars, biological equivalents, therapeutic antibodies, polypeptides, proteins, small molecules, and generic pharmaceuticals. Non-therapeutic injectable materials are also included. The drug can be in liquid form, lyophilized form, or reconstituted from lyophilized form. The following list of exemplary drugs should not be considered exhaustive or limiting.

[0072] The drug is contained within a reservoir. Optionally, the reservoir is a primary container that is either filled or pre-filled with the drug for treatment. The primary container can be a vial, cartridge, or pre-filled syringe.

[0073] In some embodiments, the reservoir of the drug delivery device can be filled with, or the device can be used with, colony-stimulating factors such as granulocyte colony-stimulating factor (G-CSF). Such G-CSF agents include, but are not limited to, Neulasta® (pegfilgrastim, pegylated filgastrim, pegylated G-CSF, pegylated hu-Met-G-CSF) and Neupogen® (filgrastim, G-CSF, hu-MetG-CSF), UDENYCA® (pegfilgrastim-cbqv), Ziextenzo® (LA-EP2006; pegylated filgrastim-bmez), or FULPHILA (pegylated filgrastim-bmez).

[0074] In other embodiments, the drug delivery device may contain or be used with an erythropoiesis stimulating agent (ESA) formulation that can be in liquid or lyophilized form. The ESA is any particle that stimulates erythropoiesis. In some embodiments, the ESA is an erythropoiesis stimulating protein. As used herein, "erythropoiesis stimulating protein" means, for example, any protein that binds to a receptor and directly or indirectly causes activation of the erythropoietin receptor by causing dimerization of the receptor. Erythropoiesis stimulating proteins include erythropoietin and its variants, analogs, or derivatives that bind to and activate the erythropoietin receptor, antibodies that bind to and activate the erythropoietin receptor, or peptides that bind to and activate the erythropoietin receptor. Erythropoiesis stimulating proteins include Epogen® (epoetin alfa), Aranesp® (darbepoetin alfa), Dynepo® (epoetin delta), Mircera® (methoxypolyethylene glycol epoetin beta), Hematide®, MRK-2578, INS-22, Retacrit® (epoetin zeta), Neorecormon® (epoetin beta), Silapo® (epoetin zeta), Binocrit® (epoetin alfa), epoetin alfa Hexal, Abseamed® (epoetin alfa), Ratioepo® (epoetin theta), Eporatio® (epoetin theta), Biopoin® (epoetin theta), epoetin alfa, epoetin beta, epoetin iota, epoetin omega, epoetin delta, epoetin zeta, epoetin theta, and epoetin delta, PEGylated erythropoietin, carbamylated erythropoietin, and their particle or variants or analogs, but are not limited thereto.

[0075] Among certain exemplary proteins are the specific proteins described below, including fusions, fragments, analogs, variants, or derivatives thereof. OPGL-specific antibodies (also referred to as RANKL-specific antibodies, peptibodies, etc.), peptibodies, related proteins, etc., including fully humanized and human OPGL-specific antibodies, particularly fully human monoclonal antibodies; myostatin-binding proteins, peptibodies, related proteins, etc., including myostatin-specific peptibodies; IL-4 receptor-specific antibodies, peptibodies, related proteins, etc., particularly those that inhibit activities mediated by binding to the receptors for IL-4 and / or IL-13; interleukin 1-receptor 1 (“IL1-R1”)-specific antibodies, peptibodies, related proteins, etc.; Ang2-specific antibodies, peptibodies, related proteins, etc.; NGF-specific antibodies, peptibodies, related proteins, etc.; CD22-specific antibodies, peptibodies, related proteins, etc., particularly humanized and fully human antibodies, including but not limited to humanized and fully human monoclonal antibodies, such as human CD22-specific IgG antibodies, including but not limited to the dimer of human-mouse monoclonal hLL2 gamma chain disulfide bound to the human-mouse monoclonal hLL2 kappa chain, for example, the human CD22-specific fully humanized antibody of epratuzumab (CAS Registry Number 501423-23-0); IGF-1 receptor-specific antibodies, peptibodies, and related proteins, etc., including but not limited to anti-IGF-1R antibodies; B-7-related protein 1-specific antibodies, peptibodies, related proteins, etc. (also referred to as “B7RP-1” and also as B7H2, ICOS-L, B7h, and CD275), including but not limited to those that inhibit the interaction of B7RP-1 with ICOS, its natural receptor on activated T cells, including but not limited to fully human IgG2 monoclonal antibodies that bind to the epitope of the first immunoglobulin-like domain of B7RP-1, including but not limited to B7RP-specific fully human monoclonal IgG2 antibodies; IL-15-specific antibodies, peptibodies, related proteins, etc., including but not limited to HuMax IL-15 antibody and related proteins, such as 145c7, particularly humanized monoclonal antibodies, etc.IFN-gamma specific antibodies, peptibodies, related proteins, etc. including but not limited to human IFN-gamma specific antibodies and fully human anti-IFN-gamma antibodies; TALL-1 specific antibodies, peptibodies, related proteins, etc., and other TALL specific binding proteins; parathyroid hormone ("PTH") specific antibodies, peptibodies, related proteins, etc.; thrombopoietin receptor ("TPO-R") specific antibodies, peptibodies, related proteins, etc.; hepatocyte growth factor ("HGF") specific antibodies, peptibodies, related proteins, etc. including those targeting the HGF:cMet axis (HGF / SF:c-Met) such as fully human monoclonal antibodies that neutralize hepatocyte growth factor / scatter factor (HGF / SF); TRAIL-R2 specific antibodies, peptibodies, related proteins, etc.; activin A specific antibodies, peptibodies, proteins, etc.; TGF-beta specific antibodies, peptibodies, related proteins, etc.; amyloid beta protein specific antibodies, peptibodies, related proteins, etc.; c-Kit specific antibodies, peptibodies, related proteins, etc. including but not limited to proteins that bind to c-Kit and / or other stem cell factor receptors; OX40L specific antibodies, peptibodies, related proteins, etc. including but not limited to proteins that bind to OX40L and / or other ligands of the OX40 receptor; Activase® (alteplase, tPA), Aranesp® (darbepoetin alfa), erythropoietin [30-asparagine, 32-threonine, 87-valine, 88-asparagine, 90-threonine], darbepoetin alfa, novel hematopoietic stimulating protein (NESP); Epogen® (epoetin alfa, or erythropoietin); GLP-1, Avonex® (interferon beta-1a); Bexxar® (tositumomab, anti-CD22 monoclonal antibody); Betaseron® (interferon-beta); Campath® (alemtuzumab, anti-CD52 monoclonal antibody); Dynepo® (epoetin delta); Velcade® (bortezomib); MLN0002 (anti-α4β7 mAb); MLN1202 (anti-CCR2 chemokine receptor mAb);Enbrel (registered trademark) (etanercept, TNF receptor / Fc fusion protein, TNF blocker); Eprex (registered trademark) (epoetin alfa); Erbitux (registered trademark) (cetuximab, anti-EGFR / HER1 / c-ErbB-1); Genotropin (registered trademark) (somatropin, human growth hormone); Herceptin (registered trademark) (trastuzumab, anti-HER2 / neu (erbB2) receptor mAb); Kanjinti (trademark) (trastuzumab-anns) anti-HER2 monoclonal antibody, biosimilar of Herceptin (registered trademark), or another product containing trastuzumab for the treatment of breast cancer or gastric cancer; Humatrope (registered trademark) (somatropin, human growth hormone); Humira (registered trademark) (adalimumab); Vectibix (registered trademark) (panitumumab); Xgeva (registered trademark) (denosumab); Prolia (registered trademark) (denosumab), immunoglobulin G2 human monoclonal antibody against RANK ligand, Enbrel (registered trademark) (etanercept, TNF-receptor / Fc fusion protein, TNF blocker), Nplate (registered trademark) (romiplostim), rilotumumab, ganitumab, conatumumab, brodalumab, insulin in solution; Infergen (registered trademark) (interferon alfa-con-1); Natrecor (registered trademark) (nesiritide; recombinant human B-type natriuretic peptide (hBNP); Kineret (registered trademark) (anakinra); Leukine (registered trademark) (sargramostim, rhuGM-CSF); LymphoCide (registered trademark) (epratuzumab, anti-CD22 mAb); Benlysta (trademark) (lynphosphostat B, belimumab, anti-BlyS mAb); Metalyse (registered trademark) (tenecteplase, t-PA analog); Mircera (registered trademark) (methoxypolyethylene glycol-epoetin beta); Mylotarg (registered trademark) (gemtuzumab ozogamicin); Raptiva (registered trademark) (efalizumab); Cimzia (registered trademark) (certolizumab pegol, CDP 870); Soliris (trademark) (eculizumab); pexelizumab (anti-complement C5); Numax (registered trademark) (MEDI-524); Lucentis (registered trademark) (ranibizumab);Panorex (registered trademark) (17-1A, edrecolomab); Trabio (registered trademark) (lerdelimumab); TheraCim hR3 (nimotuzumab); Omnitarg (pertuzumab, 2C4); Osidem (registered trademark) (IDM-1); OvaRex (registered trademark) (B43.13); Nuvion (registered trademark) (visilizumab); Cantuzumab mertansine (huC242-DM1); NeoRecormon (registered trademark) (epoetin beta); Neumega (registered trademark) (oprelvekin, human interleukin-11); Orthoclone OKT3 (registered trademark) (muromonab-CD3, anti-CD3 monoclonal antibody); Procrit (registered trademark) (epoetin alpha); Remicade (registered trademark) (infliximab, anti-TNFα monoclonal antibody); Reopro (registered trademark) (abciximab, anti-GP lIb / Ilia receptor monoclonal antibody); Actemra (registered trademark) (anti-IL6 receptor mAb); Avastin (registered trademark) (bevacizumab), HuMax-CD4 (zanilimumab); Mvasi (trademark) (bevacizumab-awwb); Rituxan (registered trademark) (rituximab, anti-CD20 mAb); Tarceva (registered trademark) (erlotinib); Roferon-A (registered trademark) (interferon alpha-2a); Simulect (registered trademark) (basiliximab); Prexige (registered trademark) (lumiracoxib); Synagis (registered trademark) (palivizumab); 145c7-CHO (anti-IL15 antibody, see U.S. Patent No. 7,153,507); Tysabri (registered trademark) (natalizumab, anti-α4 integrin mAb); Valortim (registered trademark) (MDX-1303, anti-Bacillus anthracis protective antigen mAb); ABthrax (trademark); Xolair (registered trademark) (omalizumab); ETI211 (anti-MRSA mAb); IL-1 trap (Fc portion of human IgG1 and extracellular domains of both IL-1 receptor components (type I receptor and receptor accessory protein)); VEGF trap (Ig domain of VEGFR1 fused to IgG1 Fc); Zenapax (registered trademark) (daclizumab); Zenapax (registered trademark) (daclizumab, anti-IL-2Rα mAb);Zevalin (registered trademark) (ibritumomab tiuxetan); Zetia (registered trademark) (ezetimibe); Orencia (registered trademark) (abatacept, TACI-Ig); anti-CD80 monoclonal antibody (galiximab); anti-CD23 mAb (lumiliximab); BR2-Fc (huBR3 / huFc fusion protein, soluble BAFF antagonist); CNTO 148 (golimumab, anti-TNFα mAb); HGS-ETR1 (mapatumumab; human anti-TRAIL receptor-1 mAb); HuMax-CD20 (ocrelizumab, anti-CD20 human mAb); HuMax-EGFR (cetuximab); M200 (volociximab, anti-α5β1 integrin mAb); MDX-010 (ipilimumab, anti-CTLA-4 mAb, and VEGFR-1 (IMC-18F1); anti-BR3 mAb; anti-C. difficile toxin A and toxin B C mAb MDX-066 (CDA-1) and MDX-1388); anti-CD22 dsFv-PE38 conjugate (CAT-3888 and CAT-8015); anti-CD25 mAb (HuMax-TAC); anti-CD3 mAb (NI-0401); adecatumumab; anti-CD30 mAb (MDX-060); MDX-1333 (anti-IFNAR); anti-CD38 mAb (HuMax CD38), anti-CD40L mAb; anti-Cripto mAb; anti-CTGF idiopathic pulmonary fibrosis phase 1 fibrinogen (FG-3019); anti-CTLA4 mAb; anti-eotaxin-1 mAb (CAT-213); anti-FGF8 mAb; anti-ganglioside GD2 mAb; anti-ganglioside GM2 mAb; anti-GDF-8 human mAb (MYO-029); anti-GM-CSF receptor mAb (CAM-3001); anti-HepC mAb (HuMax HepC); anti-IFNα mAb (MEDI-545, MDX-198); anti-IGF1R mAb; anti-IGF-1R mAb (HuMax-Inflam); anti-IL12 mAb (ABT-874); anti-IL12 / IL23 mAb (CNTO 1275); anti-IL13 mAb (CAT-354); anti-IL2Ra mAb (HuMax-TAC); anti-IL5 receptor mAb; anti-integrin receptor mAb (MDX-018, CNTO 95); anti-IP10 ulcerative colitis mAb (MDX-1100); BMS-66513;Anti-mannose receptor / hCGβ mAb (MDX-1307); anti-mesothelin dsFv-PE38 conjugate (CAT-5001); anti-PD1 mAb (MDX-1106 (ONO-4538)); anti-PDGFRα antibody (IMC-3G3); anti-TGFβ mAb (GC-1008); anti-TRAIL receptor-2 human mAb (HGS-ETR2); anti-TWEAK mAb; anti-V; EGFR / Flt-1 mAb, and anti-ZP3 mAb (HuMax-ZP3).

[0076] In some embodiments, the drug delivery device contains a sclerostin antibody such as romosozumab, blosozumab, BPS 804 (Novartis), Evenity™ (romosozumab-aqqg), or another product containing romosozumab for the treatment of postmenopausal osteoporosis and / or fracture healing, but is not limited thereto. In other embodiments, the drug delivery device may contain or be used with a monoclonal antibody (IgG) that binds to human proprotein convertase subtilisin / kexin type 9 (PCSK9). Such PCSK9-specific antibodies include, but are not limited to, Repatha® (evolocumab) and Praluent® (alirocumab). In other embodiments, the drug delivery device may contain or be used with rilotumumab, vismodegib, trebananib, ganitumab, conatumumab, motesanib diphosphate, brodalumab, vidupiprant, or panitumumab. In some embodiments, the reservoir of the drug delivery device may be filled with IMLYGIC® (talimogene laherparepvec) or another oncolytic HSV for the treatment of melanoma or other cancers, including but not limited to OncoVEXGALV / CD; OrienX010; G207, 1716; NV1020; NV12023; NV1034; and NV1042, or the device may be used with these. In some embodiments, the drug delivery device may contain or be used with an endogenous tissue inhibitor of metalloproteinase (TIMP) such as, but not limited to, TIMP-3. In some embodiments, the drug delivery device may contain or be used with Aimovig® (erenumab-aooe), an anti-human CGRP-R (calcitonin gene-related peptide type 1 receptor), or another product containing erenumab for the treatment of migraine. Antagonistic antibodies of the human calcitonin gene-related peptide (CGRP) receptor, such as erenumab, as well as bispecific antibody molecules that target the CGRP receptor and other headache targets, but are not limited thereto, may also be delivered using the drug delivery devices of the present disclosure.In addition, bispecific T cell engager (BiTE®) antibodies, such as but not limited to BLINCYTO® (blinatumomab), can be used in or with the drug delivery devices of the present disclosure. In some embodiments, the drug delivery device may contain or be used with an APJ macromolecule agonist, such as but not limited to apelin or an analog thereof. In some embodiments, a therapeutically effective amount of anti-thymic stromal lymphopoietin (TSLP) or a TSLP receptor antibody is used in or with the drug delivery devices of the present disclosure. In some embodiments, the drug delivery device may contain or be used with Avsola™ (infliximab-axxq), an anti-TNFα monoclonal antibody, a biosimilar of Remicade® (infliximab) (Janssen Biotech, Inc.) or another product containing infliximab for the treatment of autoimmune diseases. In some embodiments, the drug delivery device may contain or be used with Kyprolis® (carfilzomib), (2S)-N-((S)-1-((S)-4-methyl-1-((R)-2-methyloxiran-2-yl)-1-oxopentan-2-ylcarbamoyl)-2-phenylethyl)-2-((S)-2-(2-morpholinoacetamido)-4-phenylbutanamide)-4-methylpentanamide, or another product containing carfilzomib for the treatment of multiple myeloma. In some embodiments, the drug delivery device may contain or be used with Otezla® (apremilast), N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide, or another product containing apremilast for the treatment of various inflammatory diseases.In some embodiments, the drug delivery device may contain or be used with Parsabiv (trademark) (etelcalcetide HCl, KAI-4169) or another product containing etelcalcetide HCl for the treatment of secondary hyperparathyroidism (sHPT) in patients with chronic kidney disease (KD) during hemodialysis. In some embodiments, the drug delivery device may contain or be used with ABP 798 (rituximab), a biosimilar candidate for Rituxan (registered trademark) / MabThera (trademark), or another product containing an anti-CD20 monoclonal antibody. In some embodiments, the drug delivery device may contain or be used with a VEGF antagonist such as a non-antibody VEGF antagonist and / or a VEGF-Trap (Ig domain 2 derived from VEGFR1 and Ig domain 3 derived from VEGFR2 fused to the Fc domain of IgG1) such as aflibercept. In some embodiments, the drug delivery device may contain or be used with ABP 959 (eculizumab), a biosimilar candidate for Soliris (registered trademark), or another product containing a monoclonal antibody that specifically binds to complement protein C5. In some embodiments, the drug delivery device may contain or be used with rozibafusp alfa (previously known as AMG 570), a novel bispecific antibody-peptide conjugate that simultaneously blocks ICOS-L and BAFF activity. In some embodiments, the drug delivery device may contain or be used with omecamtiv mecarbil, a small molecule selective myosin activator of the heart's contractile mechanism, or a myotrope, or another product containing a small molecule selective myosin activator. In some embodiments, the drug delivery device may contain sotrasib (previously known as AMG 510), KRAS. G12C a small molecule inhibitor, or KRAS G12CAnother product containing a small molecule inhibitor may be contained or used together therewith. In some embodiments, the drug delivery device may contain or be used together with another product containing tezepelumab, a human monoclonal antibody that inhibits the action of thymic stromal lymphopoietin (TSLP), or a human monoclonal antibody that inhibits the action of TSLP. In some embodiments, the drug delivery device may contain or be used together with another product containing AMG 714, a human monoclonal antibody that binds to interleukin-15 (IL-15), or a human monoclonal antibody that binds to interleukin-15 (IL-15). In some embodiments, the drug delivery device may contain or be used together with another product containing AMG 890, a small interfering RNA (siRNA) that reduces lipoprotein(a), also known as Lp(a), or a small interfering RNA (siRNA) that reduces lipoprotein(a). In some embodiments, the drug delivery device may contain and / or be used together with another product containing ABP 654 (human IgG1 kappa antibody), a biosimilar candidate for Stelara®, or a human IgG1 kappa antibody that binds to the p40 subunit of human cytokines interleukin (IL)-12 and IL-23. In some embodiments, the drug delivery device may contain or be used together with another product containing Amjevita™ or Amgevita™ (previously ABP 501) (mab anti-TNF human IgG1), a biosimilar candidate for Humira®, or a human mab anti-TNF human IgG1. In some embodiments, the drug delivery device may contain or be used together with another product containing AMG 160, or a half-life extended (HLE) anti-prostate specific membrane antigen (PSMA) × anti-CD3 BiTE® (bispecific T cell engager) construct. In some embodiments, the drug delivery device may contain or be used together with another product containing AMG 119, or a delta-like ligand 3 (DLL3) CAR T (chimeric antigen receptor T cell) cell therapy.In some embodiments, the drug delivery device may contain or be used with AMG 119, or another product containing a delta-like ligand 3 (DLL3) chimeric antigen receptor T cell (CAR T cell) therapy. In some embodiments, the drug delivery device may contain or be used with AMG 133, or another product containing a gastric inhibitory polypeptide receptor (GIPR) antagonist and a glucagon-like peptide-1 receptor (GLP-1R) agonist. In some embodiments, the drug delivery device may contain or be used with AMG 171, or another product containing a growth differentiation factor 15 (GDF15) analog. In some embodiments, the drug delivery device may contain or be used with AMG 176, or another product containing a small molecule inhibitor of myeloid cell leukemia 1 (MCL-1). In some embodiments, the drug delivery device may contain or be used with AMG 199, or another product containing a half-life extended (HLE) bispecific T cell engager construct (BiTE®). In some embodiments, the drug delivery device may contain or be used with AMG 256, or another product containing an anti-PD-1×IL21 mutein and / or an IL-21 receptor agonist designed to selectively activate the interleukin-21 (IL-21) pathway in programmed cell death-1 (PD-1)-positive cells. In some embodiments, the drug delivery device may contain or be used with AMG 330, or another product containing an anti-CD33×anti-CD3 BiTE® (bispecific T cell engager) construct. In some embodiments, the drug delivery device may contain or be used with AMG 404, or another product containing a human anti-programmed cell death-1 (PD-1) monoclonal antibody that is being investigated as a treatment for patients with solid tumors.In some embodiments, the drug delivery device may contain or be used with another product containing AMG 427, or a half-life extended (HLE) anti-fms-like tyrosine kinase 3 (FLT3) × anti-CD3 BiTE® (bispecific T cell engager) construct. In some embodiments, the drug delivery device may contain or be used with another product containing AMG 430 or an anti-Jagged-1 monoclonal antibody. In some embodiments, the drug delivery device may contain or be used with another product containing AMG 506, or a multispecific FAP × 4-1BB-targeted DARPin® biologic being investigated as a treatment for solid tumors. In some embodiments, the drug delivery device may contain or be used with another product containing AMG 509, or a bivalent T cell engager designed using the XmAb® 2+1 technology. In some embodiments, the drug delivery device may... It may contain or be used with another product containing AMG 562, or a half-life extended (HLE) CD19×anti-CD3 BiTE® (bispecific T cell engager) construct. In some embodiments, the drug delivery device may contain or be used with another product containing efalizumab alpha (formerly AMG 592) or an IL-2 mutein Fc fusion protein. In some embodiments, the drug delivery device may contain or be used with another product containing AMG 596, or a CD3×epidermal growth factor receptor vIII (EGFRvIII) BiTE® (bispecific T cell engager) molecule. In some embodiments, the drug delivery device may contain or be used with another product containing AMG 673, or a half-life extended (HLE) anti-human CD33×anti-anti-human CD3 BiTE® (bispecific T cell engager) construct. In some embodiments, the drug delivery device may contain or be used with another product containing AMG 701, or a half-life extended (HLE) anti-B cell maturation antigen (BCMA)×anti-CD3 BiTE® (bispecific T cell engager) construct. In some embodiments, the drug delivery device may contain or be used with another product containing AMG 757, or a half-life extended (HLE) anti-delta-like ligand 3 (DLL3)×anti-CD3 BiTE® (bispecific T cell engager) construct. In some embodiments, the drug delivery device may contain or be used with another product containing AMG 910, or a half-life extended (HLE) epithelial tight junction constituent protein claudin 18.2×anti-CD3 BiTE® (bispecific T cell engager) construct.

[0077] Although drug delivery devices, assemblies, components, subsystems, and methods have been described from the perspective of exemplary embodiments, they are not limited thereto. This detailed description should be construed as illustrative only and does not describe all possible embodiments of the present disclosure. Many alternative embodiments can be implemented using either current technology or technology developed after the filing date of this patent, and such embodiments are still within the scope of the claims that define the invention disclosed herein.

[0078] Those skilled in the art will understand that various modifications, changes, and combinations can be made to the above embodiments without departing from the spirit and scope of the invention disclosed herein, and such modifications, changes, and combinations are construed to be within the scope of the concept of the present invention.

Claims

1. A method for determining material compatibility of components of a drug delivery system, comprising evaluating surface interactions between desired particles and at least one material present within a given IV bag system using surface zeta potential analysis, wherein the at least one material comprises a first potential material, the method comprising: providing within the given IV bag system a gap flow cell having an upper layer, a bottom layer, and a flow path for the desired particles to flow between the upper layer and the bottom layer, wherein the upper layer and the bottom layer are constructed from the first potential material; measuring a first zeta potential of the given IV bag system when the desired particles flow through the first potential material of the upper layer and the first potential material of the bottom layer; and further comprising.

2. wherein the at least one material further comprises a second potential material, replacing the first potential material with the second potential material; measuring a second zeta potential of the given IV bag system when the desired particles flow through the second potential material of the upper layer and the second potential material of the bottom layer; comparing the first zeta potential with the second zeta potential; and further comprising the method according to claim 1.

3. The method according to claim 2, wherein the desired particles comprise a drug product for intravenous delivery.

4. forming a solution with the drug product and an intravenous solution stabilizer for the drug product; measuring the zeta potential of the drug product in the solution; and further comprising the method according to claim 3.

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