Pharmaceutical container with protective layer deposited by atomic layer deposition

Abstract

Disclosed is a pharmaceutical container comprising a lumen defined in part by a wall, the wall having an inner surface facing the lumen, an outer surface, and at least one pH protective layer comprising an oxide of zirconium, titanium, or magnesium, wherein the at least one pH protective layer is a layer produced by atomic layer deposition (ALD) process.

Description

Leydig 771696 1 PHARMACEUTICAL CONTAINER WITH PH PROTECTIVE LAYER DEPOSITED BY ATOMIC LAYER DEPOSITION CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This patent application claims the benefit of U.S. Provisional Patent Application No. 63 / 550,319, filed February 6, 2024, U.S. Provisional Patent Application No.63 / 648,604, filed May 16, 2024, U.S. Patent Application No.18 / 666,677, filed May 16, 2024, and U.S. Provisional Patent Application No.63 / 691,500, filed September 06, 2024, the disclosures of which are incorporated herein by reference in their entirety for all purposes. BACKGROUND OF THE INVENTION

[0002] Pharmaceutical containers such as vials and syringes can have one or more barrier layers of material or materials on their interior walls, such layers being designed to protect the pharmaceutical agent - compound, biological, or other material, that is stored in the vial or syringe from contamination, such as from gases external to the containers or from the material of the containers themselves, which may degrade over time. In this manner, pharmaceutical containers may be delivered safely to an end-use location without excessive requirements for special handling during transport and storage, and the pharmaceutical agent would maintain its effectiveness even when transported and / or stored for extended periods of time. However, known barrier layers tend to degrade over time when in contact with some pharmaceutical agents and, as a result, the shelf life of such containers tend to be reduced.

[0003] Attempts have been made to reduce the degradation rate of the barrier layers with a view to develop pharmaceutical containers that provide long-term storage of stored pharmaceutical compositions. One such attempt includes incorporating a pH protective layer over the barrier layer. However, there remains an unmet need for a pharmaceutical container having a thin pH protective layer having an enhanced long-term storage of pharmaceutical agents. The invention disclosed herein provides such a pharmaceutical container. This and other advantages of the invention, as well as additional inventive features, will be apparent from the description of the invention provided herein.Leydig 771696 2 BRIEF SUMMARY OF THE INVENTION

[0004] In one aspect, the invention provides a pharmaceutical container comprising a lumen defined in part by a wall, the wall having an inner surface facing the lumen, an outer surface, and at least one pH protective layer comprising an oxide of zirconium, titanium, or magnesium, wherein the at least one pH protective layer is a layer produced by atomic layer deposition (ALD) process.

[0005] The pharmaceutical container having a pH protective layer applied by the ALD technique in accordance with an aspect of the invention provides one or more technical advantages. For example, very thin pH protective layers can be applied by the ALD technique. In addition, the pH protective layer applied by this technique is very dense, and as a result, is capable of protecting the underlying gas barrier layer from undesirable pH exposure from the contents of the pharmaceutical container. Furthermore, the pharmaceutical container can be provided a thinner pH protective layer, e.g., the pH protective layer can be 20 nm to 50 nm, which is much less, up to 10 or 12 times less, than conventional thicknesses of about 250 to 400 nm. In addition, the mechnical properties of the pH protective layer applied by the ALD technique are such that the pH protective layer imparts substantial crack resistance and / or flexural strength to the barrier layer. Furthermore, the pH protective layer imparts thermal cycling resistance and / or mechanical deflection to the pharmaceutical container, particularly to the barrier layer. Alternatively, or in addition, since the pH protective layer and / or the barrier layer are very thin, it saves on the production time required in carrying out one or both of these steps during the production of the pharmaceutical container, especially considering that the pH protective layer is to built one atomic or molecular layer at a time by the ALD process. The pH protective layer reduces the rate of dissolution of the gas barrier layer by >90 % when exposed to a pH of 3 to 9 at a temperature of 50 °C for 72 hours.

[0006] In another aspect, the invention provides a pharmaceutical container having a wall having an inner side or surface, the pharmaceutical container comprising a nanolaminate coated on the inner side or surface of the wall of the container, wherein the nanolaminate comprises multiple, thin pH protective layers and multiple, thin gas barrier layers, wherein each of the pH protective layers and of the gas barrier layers are disposed in alternating arrangement, the nanolaminate further comprising a thick pH protective coating layer disposed over theLeydig 771696 3 arrangement of alternating layers in a direction towards the interior of the container, wherein at least one of the thin pH protective layers comprises an oxide of zirconium, titanium, or magnesium and at least one of the thin gas barrier layers comprises an oxide of aluminum, and wherein said at least one pH protective layer and at least one gas barrier layer are deposited by atomic layer deposition (ALD).

[0007] In another aspect, the invention provides a pharmaceutical container further containing a pharmaceutical composition.

[0008] Further and alternative aspects and features of the disclosed invention will be apparent from the following detailed description. As will be appreciated, the methods disclosed herein are capable of being carried out and used in other and different aspects, and capable of being modified in various respects. Accordingly, it is to be understood that both the foregoing general description and the following detailed description are only exemplary and explanatory and do not restrict in any way the scope of the claimed invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0009] FIG.1A is a graph demonstrating the x-ray photoelectron spectroscopy (XPS) depth profile of a silicon wafer coated with 20 nm thick Al2O3 coating. In this analysis, the concentrations of aluminum (Al), carbon (C), oxygen (O), and silicon (Si) were determined at various depths from the top surface of the wafer. The depth scale is estimated based on the Al2O3 rate.

[0010] FIG.1B is a graph demonstrating the XPS depth profile of a silicon wafer coated with 50 nm thick Al2O3coating. In this analysis, the concentrations of aluminum (Al), carbon (C), oxygen (O), and silicon (Si) were determined at various depths. The depth scale is estimated based on the Al2O3rate.

[0011] FIG.1C is a graph demonstrating the XPS depth profile of a silicon wafer coated with 50 nm thick ZrO2 coating over a 50 nm thick Al2O3 coating. In this analysis, the concentrations of aluminum (Al), carbon (C), oxygen (O), silicon (Si), and zirconium (Zr) were determined at various depths. The depth scale is estimated based on the Al2O3 rate.

[0012] FIG.1D is a graph demonstrating the XPS depth profile of a silicon wafer coated with 20 nm thick Al2O3coating and a 20 nm thick ZrO2layer deposited over the Al2O3coating. In thisLeydig 771696 4 analysis the concentration of aluminum (Al), carbon (C), oxygen (O), silicon (Si), and zirconium (Zr) were determined at various depths. The depth scale is estimated based on the Al2O3 rate.

[0013] FIG.2A is a schematic representation of a pharmaceutical container which demonstrates the pH protective layer, the barrier layer, and the optional binder layer deposited over a polymer substrate, wherein the pharmaceutical container is a vial.

[0014] FIG.2B is a schematic representation of a pharmaceutical container which demonstrates the pH protective layer, the barrier layer, and the optional binder layer deposited over a polymer substrate, wherein the pharmaceutical container is a syringe.

[0015] FIG.3A is a schematic representation of the aluminum concentration in the collected pH 9 buffer solutions for a Si wafer coated with a 20 nm Al2O3 gas barrier layer and for a Si wafer with a 20 nm Al2O3 barrier layer and a 20 nm ZrO2 pH protective layer deposited by ALD over the 20 nm Al2O3 barrier layer.

[0016] FIG.3B is a schematic representation of the aluminum concentration in the collected pH 9 buffer solutions for a Si wafer coated with a 50 nm Al2O3gas barrier layer and for a Si wafer with a 50 nm Al2O3barrier layer and a 50 nm ZrO2pH protective layer deposited by ALD over the 50 nm Al2O3barrier layer.

[0017] FIG.3C is a schematic representation of the aluminum concentration in the collected pH 3 buffer solutions for a Si wafer coated with a 20 nm Al2O3 gas barrier layer and for a Si wafer with a 20 nm Al2O3 barrier layer and a 20 nm ZrO2 pH protective layer deposited by ALD over the 20 nm Al2O3 barrier layer.

[0018] FIG.3D is a schematic representation of the aluminum concentration in the collected pH 3 buffer solutions for a Si wafer coated with a 50 nm Al2O3gas barrier layer and for a Si wafer with a 50 nm Al2O3barrier layer and a 50 nm ZrO2pH protective layer deposited by ALD over the 50 nm Al2O3barrier layer.

[0019] FIG.4A is a schematic representation of the STEM surface images of the polypropylene substrate and coating layer at different magnifications (a) is at 200 nm, (b) is at 50 nm, and (c) is at 20 nm. The sample surface is rough and the thickness of the coating layer is about 10 nm to 15 nm.

[0020] FIG.4B is a schematic representation illustrating the energy dispersive spectrometry (EDS) mapping of the Al2O3barrier layer on the polypropylene substrate at a magnification ofLeydig 771696 5 300 nm, (a) is a HAADF-STEM image, (b) is the line mapping of aluminum (Al), (c) is the line mapping of oxygen (O), (d) is the line mapping of carbon (C), and (e) is the line mapping of Al, O, and C combined.

[0021] FIG.4C is a schematic representation illustrating the ZrO2 pH protective layer deposited over the Al2O3 on a polypropylene substrate using STEM at different magnifications, (a) is at 200nm and (b) is at 50 nm. The thickness of the coating layer is about 25 to 35 nm.

[0022] FIG.4D is a schematic representation illustrating the energy dispersive spectrometry (EDS) mapping of the ZrO2pH protective layer deposited by ALD over the Al2O3on the polypropylene substrate at a magnification of 60 nm, (a) is a HAADF-STEM image, (b) is the line mapping of aluminum (Al), (c) is the line mapping of oxygen (O), (d) is the line mapping of zirconium (Zr), (e) is the line mapping of carbon (C), (f) is the line mapping of Al and Zr combined, and (g) is the line mapping of Al, O, C, and Zr combined.

[0023] FIG.5 is a schematic representation of the aluminum concentration in the collected pH 9 buffer solutions for the poly propylene sample coated with just an Al2O3gas barrier layer and for the poly propylene sample coated with a ZrO2pH protective layer by ALD over the Al2O3gas barrier.

[0024] FIG.6 is a schematic representation illustrating the thickness differences in depositing a pH protective layer with atomic layer deposition (ALD) versus plasma-enhanced chemical vapor deposition (PECVD).

[0025] FIG.7 is a schematic representation of a pharmaceutical container which demonstrates the pH protective layer, the barrier layer, and the optional binder layer deposited over a polymer substrate, wherein the pharmaceutical container is a vial or a syringe.

[0026] FIG.8A is a graph demonstrating the x-ray photoelectron spectroscopy (XPS) depth profile of a cyclic olefin copolymer (COP)-based vial coated with a 27 nm thick Al2O3barrier layer. In this analysis, the concentrations of aluminum (Al), carbon (C), and oxygen (O) were determined at various depths at the surface of the bottom of the vial. The depth scale is estimated based on the Al2O3 rate.

[0027] FIG.8B is a graph demonstrating the XPS depth profile of a (COP)-based vial coated with a 27 nm thick Al2O3 barrier layer. In this analysis, the concentrations of aluminum (Al),Leydig 771696 6 carbon (C), and oxygen (O) were determined at various depths at the surface of the vial wall. The depth scale is estimated based on the Al2O3 rate.

[0028] FIG.9A is a graph demonstrating the XPS depth profile of a (COP)-based vial coated with a 41 nm thick Al2O3 barrier layer. In this analysis, the concentrations of aluminum (Al), carbon (C), and oxygen (O) were determined at various depths at the surface of the bottom of the vial. The depth scale is estimated based on the Al2O3rate.

[0029] FIG.9B is a graph demonstrating the XPS depth profile of a (COP)-based vial coated with a 61 nm thick Al2O3barrier layer. In this analysis, the concentrations of aluminum (Al), carbon (C), and oxygen (O) were determined at various depths at the bottom outside surface of the vial. The depth scale is estimated based on the Al2O3 rate.

[0030] FIG.9C is a graph demonstrating the XPS depth profile of a (COP)-based vial coated with an approximately 61 nm thick Al2O3 barrier layer. In this analysis, the concentrations of aluminum (Al), carbon (C), and oxygen (O) were determined at various depths at the inside surface of the vial wall. The depth scale is estimated based on the Al2O3rate. The inside surface of the vial wall appeared to be a bit thinner than the bottom, however, because of an instrument problem, this film was run on a different instrument than the inside bottom. It is possible there is a minor difference between the deposition rates.

[0031] FIG.10 is a graph demonstrating the XPS depth profile of a (COP)-based vial coated with an approximately 30 nm thick Al2O3 barrier layer. In this analysis, the concentrations of aluminum (Al), carbon (C), and oxygen (O) were determined at various depths at the surface of the bottom of the vial. The depth scale is estimated based on the Al2O3 rate.

[0032] FIG.11A is a graph demonstrating the XPS depth profile of a (COP)-based vial coated with a 35 nm thick Al2O3barrier layer and a 35 nm thick ZrO2pH protective layer deposited over the Al2O3barrier. In this analysis, the concentrations of aluminum (Al), carbon (C), oxygen (O), and zirconium (Zr) were determined at various depths at the surface of the bottom of the vial.

[0033] FIG.11B is a graph demonstrating the XPS depth profile of a (COP)-based vial coated with a 35 nm thick Al2O3 barrier layer and a 35 nm thick ZrO2 pH protective layer deposited over the Al2O3 barrier. In this analysis, the concentrations of aluminum (Al), carbonLeydig 771696 7 (C), oxygen (O), and zirconium (Zr) were determined at various depths at the bottom outside surface of the vial.

[0034] FIG.12A is a graph demonstrating the XPS depth profile of a (COP)-based vial coated with a 40 nm thick Al2O3 barrier layer and a 40 nm thick ZrO2 pH protective layer deposited over the Al2O3 barrier. In this analysis, the concentrations of aluminum (Al), carbon (C), oxygen (O), and zirconium (Zr) were determined at various depths at the surface of the bottom of the vial.

[0035] FIG.12B is a schematic representation illustrating the water vapor transmission rate data for a (COP)-based vial coated with a 40 nm thick Al2O3barrier layer and a 40 nm thick ZrO2 pH protective layer deposited over the Al2O3 barrier.

[0036] FIG.12C is a schematic representation illustrating the oxygen transmission rate data for a (COP)-based vial coated with a 40 nm thick Al2O3 barrier layer and a 40 nm thick ZrO2 pH protective layer deposited over the Al2O3 barrier.

[0037] FIG.12D is a schematic representation of the aluminum and zirconium concentrations in the collected pH 9 buffer solutions for a (COP)-based vial coated with a 40 nm thick Al2O3barrier layer and for a (COP)-based vial coated with a 40 nm thick Al2O3barrier layer and a 40 nm thick ZrO2pH protective layer deposited over the Al2O3barrier.

[0038] FIG.12E is a schematic representation of the aluminum and zirconium concentrations in the collected pH 3 buffer solutions for (COP)-based vial coated with a 40 nm thick Al2O3 barrier layer and for a (COP)-based vial coated with a 40 nm thick Al2O3 barrier layer and a 40 nm thick ZrO2 pH protective layer deposited over the Al2O3 barrier.

[0039] FIG.13A is a graph demonstrating the XPS depth profile of a (COP)-based syringe coated with a 40-50 nm thick Al2O3barrier layer and a 40-50 nm thick ZrO2pH protective layer deposited over the Al2O3barrier. In this analysis, the concentrations of aluminum (Al), carbon (C), oxygen (O), and zirconium (Zr) were determined at various depths at the needle end of the syringe.

[0040] FIG.13B is a graph demonstrating the XPS depth profile of a (COP)-based syringe coated with a 40-50 nm thick Al2O3 barrier layer and a 40-50 nm thick ZrO2 pH protective layer deposited over the Al2O3 barrier. In this analysis, the concentrations of aluminum (Al), carbonLeydig 771696 8 (C), oxygen (O), and zirconium (Zr) were determined at various depths at the middle of the syringe.

[0041] FIG.13C is a graph demonstrating the XPS depth profile of a (COP)-based syringe coated with a 40-50 nm thick Al2O3 barrier layer and a 40-50 nm thick ZrO2 pH protective layer deposited over the Al2O3 barrier. In this analysis, the concentrations of aluminum (Al), carbon (C), oxygen (O), and zirconium (Zr) were determined at various depths at the flange end of the syringe.

[0042] FIG.14 is a schematic representation of a pharmaceutical container which demonstrates a nanolaminate consisting of thin alternating layers of a ZrO2pH protective layer and a Al2O3 barrier layer with a thick ZrO2 pH protective coating layer disposed over the arrangement of alternating layers, wherein the pharmaceutical container is a vial or a syringe.

[0043] FIG.15A is a schematic representation of the aluminum and zirconium concentrations in the collected pH 9 buffer solutions for a (COP)-based vial coated with a 50 nm thick Al2O3barrier layer and for a (COP)-based vial coated with a 50 nm nanolaminate comprised of thin alternating layers of a ZrO2pH protective layer and a Al2O3barrier layer with a thick ZrO2pH protective coating layer disposed over the arrangement of alternating layers.

[0044] FIG.15B is a schematic representation of the aluminum and zirconium concentrations in the collected pH 3 buffer solutions for a (COP)-based vial coated with a 50 nm thick Al2O3 barrier layer and for a (COP)-based vial coated with a 50 nm nanolaminate comprised of thin alternating layers of a ZrO2 pH protective layer and a Al2O3 barrier layer with a thick ZrO2 pH protective coating layer disposed over the arrangement of alternating layers.

[0045] FIG.15C is a schematic representation of high resolution TEM images which show the structure of nanocrystals (circled areas) in amorphous matrix in both ZrO2and Al2O3layers. Thinner, alternating layers disrupt the formation of nanocrystals. Using alternating layers, a tortuous path is created by the layers for gas permeation due to nano crystal formation.

[0046] FIG.16 is a schematic representation of the STEM surface images of the silicon wafer samples coated with an Al2O3 barrier layer and a ZrO2 pH protective layer by ALD over the Al2O3 barrier at different magnifications (left) is at 200 nm, (middle) is at 150 nm, and (right) is at 50 nm. The ZrO2 pH protective layer is approximately 50 nm thick and the Al2O3 barrier layer is approximately 40 nm thick.Leydig 771696 9

[0047] FIG.17 is a schematic representation of an overlay of a TEM micrograph and XPS depth profile for a sample coated with a with an 50 nm Al2O3 barrier layer and a 50 nm ZrO2 pH protective layer by ALD over the Al2O3 barrier. DETAILED DESCRIPTION OF ASPECTS OF THE INVENTION

[0048] The invention provides a pharmaceutical container comprising a lumen defined in part by a wall, the wall having an inner surface facing the lumen, an outer surface, and at least one pH protective layer comprising an oxide of zirconium, titanium, or magnesium, wherein the at least one pH protective layer is a layer produced by atomic layer deposition (ALD) process.

[0049] The invention also provides a pharmaceutical container having a wall having an inner side, the pharmaceutical container comprising a nanolaminate coated on the inner side of the wall of the container, wherein the nanolaminate comprises multiple, thin pH protective layers and multiple, thin gas barrier layers, wherein each of the pH protective layers and of the gas barrier layers are disposed in alternating arrangement, the nanolaminate further comprising a thick pH protective coating layer disposed over the arrangement of alternating layers in a direction towards the interior of the container, wherein at least one of the thin pH protective layers comprises an oxide of zirconium, titanium, or magnesium and at least one of the thin gas barrier layers comprises an oxide of aluminum, and wherein said at least one pH protective layer and at least one gas barrier layer are deposited by atomic layer deposition (ALD).

[0050] The invention relates in particular to coatings applied over an alumina barrier used in medical packaging. Although the present disclosure relates to any suitable packaging type where purity and stability of a stored material is critical for effectiveness, safety, and the like, in some aspects medical packaging in which an alumina barrier layer with an additional coating layer is applied may include a variety of vessels (e.g., including a lumen) such as vials, syringes (e.g., syringe barrels), blister packages, blood tubes, cartridges, bottles, stents, catheters, and the like.

[0051] In an aspect, the pharmaceutical container is a vial. For example, a vial will generally have an open mouth which may be sealed with a closure, wherein the contents of the vial may be accessed using a needle. Such vials are usually made of glass or plastic. In some aspects, the vial comprises polypropylene, cyclo olefin polymer, cyclo olefin co-polymer, polyethylene, or polyethylene terephthalate. Moreover, the closure of said vial may comprise an elastomer, suchLeydig 771696 10 as vulcanized elastomers and styrenic block copolymer thermoplastic elastomers, but also natural rubber, acrylate-butadiene rubber, cis-polybutadiene, chloro or bromobutyl rubber, chlorinated polyethylene elastomers, polyalkylene oxide polymers, ethylene vinyl acetate, fluorosilicone rubbers, hexafluoropropylene-vinylidene fluoride-tetrafluoroethylene terpolymers, butyl rubbers, polyisobutene, synthetic polyisoprene rubber, silicone rubbers, styrene-butadiene rubbers, tetrafluoroethylene propylene copolymers, thermoplastic-copolyesters, thermo-plastic elastomers, or a combination thereof.

[0052] In another aspect, the pharmaceutical container is a syringe. For example, a syringe will generally have a cylindrical barrel made of glass or plastic, wherein the barrel of the syringe can be operated with a plunger in order to eject the contents of the barrel via the nozzle of the syringe. In some aspects, the syringe is composed of cyclic olefin polymers (COP), cyclic olefin co-polymers (COC), acrylonitrile butadiene styrene (ABS), polycarbonate (PC), polyoxymethylene (POM), polystyrene (PS), polybutylene terephthalate (PBT), polypropylene (PP), polyethylene (PE), polyamide (PA), thermoplastic elastomer (TPE), or combinations thereof. In some aspects, the plunger is composed of an elastomer, such as vulcanized elastomers and styrenic block copolymer thermoplastic elastomers, but also natural rubber, acrylate-butadiene rubber, cis-polybutadiene, chloro or bromobutyl rubber, chlorinated polyethylene elastomers, polyalkylene oxide polymers, ethylene vinyl acetate, fluorosilicone rubbers, hexafluoropropylene-vinylidene fluoride-tetrafluoroethylene terpolymers, butyl rubbers, polyisobutene, synthetic polyisoprene rubber, silicone rubbers, styrene-butadiene rubbers, tetrafluoroethylene propylene copolymers, thermoplastic-copolyesters, thermo-plastic elastomers, or a combination thereof. In some aspects, the syringe is pre-filled with a pharmaceutical composition, allowing for the quick administration of an exact dose to a patient. In some aspects, the pharmaceutical container comprises a syringe and a cartridge, wherein the cartridge is a specialized container that can be inserted into a pen or an auto-injector to act as a pharmaceutical delivery device.

[0053] In some aspects, the pharmaceutical container is a blister package. For example, a blister package may be used for packaging pharmaceuticals and medical devices such as solid dosage forms (tablets, capsules, etc.), transdermal patches, syringes, and the like. The blister package of the present invention comprises a bottom web substrate that is rigid and has one orLeydig 771696 11 more recesses that conform, in order stabilize the contents of the package. The blister package of the present invention also comprises a top web laminate, which is secured to the blister by heat seal and acts as a “lid” to allow access to the contents of the package.

[0054] The alumina barrier layer and coating may be applied to variety of materials used in such medical packaging, such as glass, plastics (e.g., thermoplastics), rubbers, polymers, and ceramics. Accordingly, materials such as pharmaceuticals, vaccines, bodily fluids, compounds, biologics, and the like may be safely stored and transported in a variety of conditions while maintaining safety and effectiveness for far longer than with prior uncoated barrier layers.

[0055] In some aspects, the pharmaceutical container contains an oxygen barrier layer disposed on an inner wall of the container and a pH protective layer disposed on a gas barrier layer. In some aspects, the internal surface of the pharmaceutical container comprises a lumen.

[0056] In some aspects, the pharmaceutical container has a wall comprising a polymer. In some aspects, the wall of the pharmaceutical container can be composed of polypropylene, cyclo olefin polymer (COP), cyclo olefin co-polymer (COC), polyethylene, and / or polyethylene terephthalate. In some aspects, the cyclo olefin co-polymer can include copolymers of a cyclo -olefin, such as ethylene and norbornene or ethylene and tetracyclodecene. In some aspects, the cyclo olefin polymer or cyclo olefin copolymer comprises at least one cyclic olefin selected from cyclobutene, cyclopentene, cyclooctene, norbornene, 5-methylnorbornene, 3-methylnorbornene, ethylnorbornene, phenylnorbomene, dimethylnorbornene, diethylnorbornene, dicyclopentadiene, tetracycloclododecene, methyltetracyclododecene, 6-methylnorbornene, 6-ethylnorbornene, 6-n-butylnorbornene, 5- propylnorbornene, 1-methylnorbornene, 7-methylnorbornene, 5,6-di-methylnorbornene, 5- phenylnorbornene, 5-benzylic norbornene, 8-methyltetracyclo-3-dodecene, 8-ethyltetracyclo-3- dodecene, 8-hexyltetracyclo-3-dodecene, 2,10-dimethyltetracyclo-3-dodecene, and 5,10- dimethyltetracyclo-3-dodecene. In some aspects, the polymer is free of voids, defects, or holes.

[0057] For example, some such polymers are commercially available from Avient as EdgetekTM, Polyplastics as TOPAS®(COC), Zeonex as ZEONOR®(COP), and Mitsui as APEL™(COC). In some aspects, the cyclo olefin copolymer is Edgetek™ COC BLEND-15GF Natural (COC-GF15, Avient), TOPAS®5013F-04 (COC, Polyplastics), TOPAS®6013S-04 (COC, Polyplastics),TOPAS®5013L-10 (COC, Polyplastics), TOPAS®6013F-04 (COC,Leydig 771696 12 Polyplastics), TOPAS®6013M-07 (COC, Polyplastics), TOPAS®6015S-04 (COC, Polyplastics), TOPAS®8007F-04 (COC, Polyplastics), TOPAS®8007F-600 (COC, Polyplastics), TOPAS®8007S-04 (COC, Polyplastics), TOPAS®8007X10 (COC, Polyplastics), TOPAS®9506F-500 (COC, Polyplastics), Topas®5013F-04 (COC, Topas), Topas®5013L-10 (COC, Topas), Topas®5013S-04 (COC, Topas), Topas®6013F-04 (COC, Topas), Topas®6013M-07 (COC, Topas), Topas®6015S-04 (COC, Topas), Topas®6017S-04 (COC, Topas), Topas®7010F-600 (COC, Topas), Topas®8007F-04 (COC, Topas), Topas®8007F-600 (COC, Topas), Topas®8007S-04 (COC, Topas), Topas®8007X10 (COC, Topas), Topas®9506F-500 (COC, Topas), Topas®9903D-10 (COC, Topas), Topas®ELASTOMER E-140 (COC, Topas), APEL™ APL5014DP (COC, Mitsui Chemicals America), APEL™ APL5514ML (COC, Mitsui Chemicals America), APEL™ APL6011T (COC, Mitsui Chemicals America), APEL™ APL6013T (COC, Mitsui Chemicals America), APEL™ APL6015T (COC, Mitsui Chemicals America), APEL™ APL6509T (COC, Mitsui Chemicals America), APEL™ APL8008T (COC, Mitsui Chemicals America), or combinations thereof.

[0058] In some aspects the cyclo olefin polymer is Zeonex®330R (COP, Zeon Corporation), Zeonex®480 (COP, Zeon Corporation), Zeonex®480R (COP, Zeon Corporation), Zeonex®5000 (COP, Zeon Corporation), Zeonex®690R (COP, Zeon Corporation), Zeonex®790R (COP, Zeon Corporation), Zeonex®E48R (COP, Zeon Corporation), Zeonex®F52R (COP, Zeon Corporation), Zeonex®RS420 (COP, Zeon Corporation), Zeonor®1020R (COP, Zeon Corporation), Zeonor®1060R (COP, Zeon Corporation), Zeonor®1420R (COP, Zeon Corporation), ARTON F4520 (COP, JSR Corporation), ARTON F3500 (COP, JSR Corporation), ARTON D4000 (COP, JSR Corporation), ARTON FBK80 (COP, JSR Corporation), ARTON R5000 (COP, JSR Corporation), ARTON RX4500 (COP, JSR Corporation), Zeonex®RS420-LDS (COP, Zeon Corporation), Zeonex®350R (COP, Zeon Corporation), Zeonex®K26R (COP, Zeon Corporation), Zeonor®1430R (COP, Zeon Corporation), or combinations thereof.

[0059] The COC or COP can have a density of 1000 kg / m3to 1030 kg / m3according to ISO 1183 or ASTM D 792, and preferably 1010 kg / m3and 1020 kg / m3; a melt volume rate (MVR) according to ISO 1183 of 2 cm3 / 10min to 20 cm3 / 10min, preferably 4 cm3 / 10min and 13 cm3according to ISO 1183 of 1 g / 10min to 20Leydig 771696 13 according to JIS K6719 of 1 g / 10min to 20 g / 10min, preferably 6 g / 10min and 17 g / 10min; and / or according to ASTM D 1238 of 1 g / 10min to 20 g / 10min, preferably 6 g / 10min and 17 g / 10min.

[0060] The COC or COP can have a water absorption according to either ISO 62 or ASTM D570 of 0.03% or less, preferably 0.01% and 0.01% or less; a tensile modulus (1 mm / min) according to ISO 527-3 of 410 kpsi to 450 kpsi; preferably 420 kpsi and 440 kpsi; a flex modulus according to ASTM D790 of 2000 MPa to 2800 MPa, preferably 2200 MPa and 2600 MPa; a tensile stress at break (5 mm / min) according to ISO 527-3 of 8500 psi to 9300 psi, preferably 8700 psi and 9100 psi; a tensile strain at break (5 mm / min) according to ISO 527 of 2.3% to 2.8%, preferably 2.5% and 2.6%; a tensile strain at break (5 mm / min) according to ISO 527-3 of 5% to 25%, preferably 10% and 20%; a Charpy impact strength at 23 according to ISO 179 / 1eU of 6.5 ft-lbs / in2to 7.35 ft-lbs / in2, preferably 6.7 ft-lbs / in2and 7.1 ft-lbs / in2; a glass transition temperature (10 / min) according to ISO 11357-1,-2,- 1356 of 120 to 180 , preferably 136 and 163 ; a degree of light transmittance according to ISO 13468-2 or ASTM D1003 (3mm) of 90% to 95%, preferably 91% and 92%; and / or a heat distortion temperature according to JIS D648 of 120 to 180 preferably 136 and 161 .

[0061] In some aspects, the the pharmaceutical container has a wall comprising glass. The glass used for a pharmaceutical container is typically, Type 1 borosilicate glass. Borosilicate glass is composed of 25-30% metals by mass. These metals include: boron, aluminumm and iron. A pH protective layer is advantageuous for Type 1 borosilicate glass to prevent Si dissolution at high and low pH and to prevent metal ions from leaching into the drug.

[0062] The pH barrier layer can be applied by any suitable method, particularly, by the atomic layer deposition (ALD) method. ALD is based on typically self-limiting reactions, whereby sequential and alternating pulses of reactants are utilized to deposit one monolayer of deposit per cycle. The deposition conditions and precursors are chosen to provide self-saturating reactions, such that an adsorbed layer of one reactant leaves a surface termination that is non- reactive with the vapor phase reactants of the same reactant. The substrate surface isLeydig 771696 14 subsequently contacted with a different reactant that reacts with the previous termination to enable continued deposition. Thus, each cycle of alternating pulsed reactants generally leaves no more than about one monolayer of the desired material. See, for example, US 11,244,825 B2, Di Mauro et al., Applied Catalysis B: Environmental 196 (2016) 68-76; Ahmed et al., AIP Advances 14, 035133 (2024), and Oviroh et al., Science and Technology of Advanced Materials, 20(1): 465-496 (2019) for procedures involving atomic layer deposition.

[0063] ALD is a coating deposition technology that yields exceptional conformity and allows for tunable coating compositions, wherein the coating thicknesses can be controlled at the atomic level. ALD operates via chemical reactions of two or more precursors which are added into a chamber where a substrate is placed at a given temperature and pressure to enable the deposition of a material on the surface of a substrate layer by layer. While traditional techniques such as chemical vapor deposition (CVD) rely on high temperatures to decompose the precursor at the surface of the substrate, ALD can be performed at lower temperatures. Moreover, when compared to CVD and physical vapor deposition (PVD), ALD can produce high quality coatings with conformality and uniformity and is highly reproducible and easily scalable to industrial process level. In certain aspects, plasma enhanced atomic layer deposition may be used to deposit the barrier layer or pH protective layer at lower temperatures.

[0064] In some aspects, the pharmaceutical container comprises a nanolaminate coated on the inner side of the wall of the container, wherein the nanolaminate comprises multiple, thin pH protective layers and multiple, thin gas barrier layers, wherein each of the pH protective layers and of the gas barrier layers are disposed in alternating arrangement, the nanolaminate further comprising a thick pH protective coating layer disposed over the arrangement of alternating layers in a direction towards the interior of the container, wherein at least one of the thin pH protective layers comprises an oxide of zirconium, titanium or magnesium and at least one of the thin gas barrier layers comprises an oxide of aluminum, and wherein said at least one pH protective layer and at least one gas barrier layer are deposited by atomic layer deposition (ALD), as illustrated, e.g., in Figure 14.

[0065] In some aspects, the thin alternating layers comprise 2-60 pH protective layers and 2- 60 gas barrier layers, e.g., 2 layers, 5 layers, 10 layers, 15 layers, 20 layers, 25 layers, 30 layers, 35 layers, 40 layers, 45 layers, 50 layers, 55 layers, or 60 layers. In some aspects, the thinLeydig 771696 15 alternating layers comprise 10 to 20 layers, e.g., 10 layers, 11 layers, 12 layers, 13 layers, 14 layers, 15 layers, 16 layers, 17 layers, 18 layers, 19 layers, or 20 layers.

[0066] In some aspects, the pH barrier layer may be a compound of aluminum and oxygen, such as alumina (Al2O3) or Al3O5 (e.g., each compound is called herein an “aluminum oxide” unless expressly specified). The barrier layer may be applied to the packaging or a portion thereof utilizing a process such as atomic layer deposition, and including other precursor steps and binding layers as necessary, to constantly apply an aluminum oxide coating having a desired deposition pattern, thickness, consistency, and other desirable properties for a particular application.

[0067] The barrier layer of the present invention is deposited using atomic layer deposition at a temperature of 200 150 145 aspects, the gas barrier layer is applied by atomic layer deposition at a temperature that is less than the Tg of the material comprising the pharmaceutical container.

[0068] The barrier layer, in an aspect of the present invention has a thickness of 50 nm or less, e.g., 50 nm or less, 45 nm or less, 40 nm or less, 35 nm or less, 30 nm or less, 25 nm or less, 20 nm or less, 15 nm or less, 10 nm or less, or 5 nm or less. In some aspects, each of the thin barrier layers has a thickness of 1 to 5 nm, e.g., 1 nm, 1.5 nm, 2 nm, 2.5 nm, 3 nm, 3.5 nm, 4 nm, 4.5 nm, or 5 nm. In certain aspects, each of the thin barrier layers a thickness of 1 to 3 nm or 3 to 5 nm.

[0069] The pharmaceutical container of the present invention may comprise a binding layer. In some aspects, the binding layer comprises alumina and is deposited between the barrier layer and the lumen. In certain aspects, the binding layer can be deposited using atomic layer deposition at a temperature of 100Leydig 771696 16

[0070] In some aspects, the pH protective layer of the present invention can be deposited over the barrier layer and can be titanium oxide (e.g. TiO2) , zirconium oxide (e.g., ZrO2 or zirconia), magnesium oxide (e.g., MgO or magnesia), or variation and combinations thereof, which are applied over the aluminum oxide barrier layer using atomic layer deposition.

[0071] In some aspects, the titanium dioxide can be applied in its naturally occurring format. In some aspects, the titanium dioxide is deposited by an ALD process by utilizing tetrakis(dimethylamino) titanium (TDMAT), tetrakis(diethylamino) titanium (TDEAT), or tetrakis(ethylmethylamino) titanium (TEMAT) or a combination thereof, as reactant or reactants. In some aspects, the titanium dioxide precursor requires a process temperature of greater than 225 with water or ozone oxidizers.

[0072] In some aspects, the zirconium dioxide is deposited by an ALD process by utilizing tetrakisdimethylamidozirconium (Zr(NMe2)4), tetrakisethylmethylamidozirconium Zr(NMeEt)4, or tetrakisdiethylamidozirconium Zr(NEt2)4, or a combination thereof, as reactant or reactants.

[0073] In some aspects, the magnesium oxide is deposited by an ALD process by utilizing Mg(thd)2(2,2,6,6-tetramethyl-3,5-heptanedionate magnesium), Mg(Cp)2(bis(cyclopentadienyl)magnesium), or Mg(EtCp)2(bis(ethylcyclopentadienyl)magnesium), or a combination thereof, as reactant or reactants.

[0074] The pH protective layer of the present invention is deposited using atomic layer deposition at a temperature of 200 150 145 aspects, the pH protective layer is applied by atomic layer deposition at a temperature that is less than the Tg of the material comprising the pharmaceutical container.

[0075] The pH protective layer of the present invention has a thickness of 50 nm or less, e.g., 45 nm or less, 40 nm or less, 35 nm or less, 30 nm or less, 25 nm or less, 20 nm or less, 15 nm or less, 10 nm or less, or 5 nm or less. In some aspects, each of the thin pH protective layers has a thickness of 1 to 5 nm, e.g., 1 nm, 1.5 nm, 2 nm, 2.5 nm, 3 nm, 3.5 nm, 4 nm, 4.5 nm, or 5 nm.Leydig 771696 17 In certain aspects, each of the thin barrier layers a thickness of 1 to 3 nm or 3 to 5 nm. In some aspects, the thick pH protective layer has a thickness of 40 to 50 nm, e.g., 41 nm, 42 nm, 43 nm, 44 nm, 45 nm, 46 nm, 47 nm, 48 nm, 49 nm, or 50 nm.

[0076] In some aspects, the thicknesses of the barrier layer and pH protective layer are measured using transmission electron microscopy (TEM) or x-ray photoelectron spectroscopy (XPS).

[0077] The pharmaceutical container of the present application is suitable for holding a pharmaceutical composition. In some aspects, the pharmaceutical composition has a pH of from 3 to 12, e.g., 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, or 12. In some aspects the pharmaceutical composition comprises a peptide, protein, monoclonal antibody, or a constituent of blood.

[0078] In other aspects the pharmaceutical composition comprises a biologic drug, for example, a biologic drug selected from abatacept; abciximab; abobotulinumtoxinA; adalimumab; adalimumab-adaz; adalimumab-adbm; adalimumab-afzb; adalimumab-atto; adalimumab-bwwd; ado- trastuzumab emtansine; aflibercept; agalsidase beta; albiglutide; albumin chromated CR- 51 serum; aldesleukin; alefacept; alemtuzumab; alglucosidase alfa; alirocumab; alteplase; anakinra; aprotinin; asfotas alfa; asparaginase; asparaginase Erwinia chrysanthemi; atezolizumab; avelumab; basiliximab; becaplermin; belatacept; belimumab; benralizumab; beractant; bevacizumab; bevacizumab-awwb; bevacizumab- bvzr; bezlotoxumab; blinatumomab; brentuximab vedotin; brodalumab; brolucizumab- dbll; burosumab-twza; calaspargase pegol- mknl; calfactant; canakinumab; caplacizumab-yhdp; capromab pendetide; cemiplimab-rwlc; cenegermin-bkbj; cerliponase alfa; certolizumab pegol; cetuximab; choriogonadotropin alfa; chorionic gonadotropin; chymopapain; collagenase; collagenase Clostridium histolyticum; corticorelin ovine triflutate; crizanlizumab-tmca; daclizumab; daratumumab; daratumumab and hyaluronidase-fihj; darbepoetin alpha; denileukin diftitox; denosumab; desirudin; dinutuximab; dornase alfa; drotrecogin alfa; dulaglutide; dupilumab; durvalumab; ecallantide; eculizumab; efalizumab; elapegademase-lvlr; elosulfase alfa; elotuzumab; emapalumab-lzsg; emicizumab- kxwh; enfortumab vedotin-ejfv; epoetin alfa; epoetin alfa-epbx; erenumab-aooe; etanercept; etanercept-szzs; etanercept-ykro; evolocumab; fam-trastuzumab deruxetecan-nxki; fibrinolysin and desoxyribonuclease combined [bovine], with chloramphenicol; filgrastim; filgrastim-aafi;Leydig 771696 18 filgrastim-sndz; follitropin alfa; follitropin beta; fremanezumab-vfrm; galcanezumab-gnlm; galsulfase; gemtuzumab ozogamicin; glucarpidase; golimumab; guselkumab; hyaluronidase; hyaluronidase human; ibalizumab-uiyk; ibritumomab tiuxetan; idarucizumab; idursulfase; imiglucerase; incobotulinumtoxinA; inebilizumab-cdon; infliximab; infliximab-abda; infliximab- axxq; infliximab-dyyb; infliximab-qbtx; inotuzumab ozogamicin; insulin aspart; insulin aspart protamine and insulin aspart; insulin degludec; insulin degludec and insulin aspart; insulin degludec and liraglutide; insulin detemir; insulin glargine; insulin glargine and lixisenatide; insulin glulisine; insulin human; insulin isophane human; insulin isophane human and insulin human; insulin lispro; insulin lispro protamine and insulin lispro; insulin lispro-aabc; interferon alfa-2a; interferon alfa-2b; interferon alfacon-1 ; interferon alfa-n3 (human leukocyte derived); interferon beta-1 a; interferon beta-1b; interferon gamma-1 b; ipilimumab; isatuximab-irfc; ixekizumab; lanadelumab-flyo; laronidase; lixisenatide; luspatercept-aamt; mecasermin; mecasermin rinfabate; menotropins; mepolizumab; methoxy polyethylene glycol-epoetin beta; metreleptin; mogamulizumab-kpkc; moxetumomab pasudotox-tdfk; muromanab-CD3; natalizumab; necitumumab; nivolumab; nofetumomab; obiltoxaximab; obinutuzumab; ocrelizumab; ocriplasmin; ofatumumab; olaratumab; omalizumab; onabotulinumtoxinA; oprelvekin; palifermin; palivizumab; pancrelipase; panitumumab; parathyroid hormone; pegademase bovine; pegaspargase; pegfilgrastim; pegfilgrastim-apgf; pegfilgrastim-bmez; pegfilgrastim-cbqv; pegfilgrastim-jmdb; peginterferon alfa-2a; peginterferon alfa-2a and ribavirin; peginterferon alfa-2b; peginterferon alfa-2b and ribavirin; peginterferon beta-1 a; pegloticase; pegvaliase-pqpz; pegvisomant; pembrolizumab; pertuzumab; polatuzumab vedotin- piiq; poractant alfa; prabotulinumtoxinA-xvfs; radiolabeled albumin technetium Tc-99m albumin colloid kit; ramucirumab; ranibizumab; rasburicase; ravulizumab-cwvz; raxibacumab; reslizumab; reteplase; rilonacept; rimabotulinumtoxinB; risankizumab-rzaa; rituximab; rituximab and hyaluronidase human; rituximab-abbs; rituximab-pvvr; romiplostim; romosozumab-aqqg; sacituzumab govitecan-hziy; sacrosidase; sargramostim; sarilumab; sebelipase alfa; secukinumab; siltuximab; somatropin; tagraxofusp-erzs; taliglucerase alfa; tbo-filgrastim; technetium 99m tc fanolesomab; tenecteplase; teprotumumab-trbw; tesamorelin acetate; thyrotropin alfa; tildrakizumab-asmn; tocilizumab; tositumomab and iodine 1-131 tositumomab; trastuzumab; trastuzumab and hyaluronidase-oysk; trastuzumab-anns; trastuzumab-dkst;Leydig 771696 19 trastuzumab-dttb; trastuzumab-pkrb; trastuzumab-qyyp; urofollitropin; urokinase; ustekinumab; vedolizumab; velaglucerase alfa; vestronidase alfa-vjbk; Ziv-Aflibercept; Amjevita (adalimumab-atto); Dupixent (dupilumab); Fulphila (pegfilgrastim-jmdb); llaris (canakinumab); Ixifi (infliximab-qbtx); Lyumjev (insulin lispro-aabc); Nyvepria (pegfilgrastim-apgf); Ogivri (trastuzumab-dkst); Semglee (insulin glargine); Uplizna (inebilizumab-cdon); A.P.L. (chorionic gonadotropin); Abrilada (adalimumab-afzb); Aduhelm (aducanumab-avwa); Accretropin (somatropin); Actemra (tocilizumab); Acthrel (corticorelin ovine triflutate); Actimmune (interferon gamma-1 b); Activase (alteplase); Adagen (pegademase bovine); Adakveo (crizanlizumab-tmca); Adbry (tralokinumab-ldrm); Adcetris (brentuximab vedotin); Adlyxin (lixisenatide); Admelog (insulin lispro); Afrezza (insulin human); Aimovig (erenumab-aooe); Ajovy (fremanezumab-vfrm); Aldurazyme (laronidase); Alferon N Injection (interferon alfa-n3 (human leukocyte derived)); Amevive (alefacept); Amphadase (hyaluronidase); Anthim (obiltoxaximab); Apidra (insulin glulisine); Aranesp (darbepoetin alpha); Arcalyst (rilonacept); Arzerra (ofatumumab); Asparlas (calaspargase pegol-mknl); Avastin (bevacizumab); Avonex (interferon beta-1 a); Avsola (infliximab-axxq); Basaglar (insulin glargine); Bavencio (avelumab); Benlysta (belimumab); Beovu (brolucizumab-dbll); Besponsa (inotuzumab ozogamicin); Besremi (ropeginterferon-alfa-2b-njft); Betaseron (interferon beta-1 b); Bexxar (tositumomab and iodine 1-131 tositumomab); Beyfortus (nirsevimab-alip); Bimzelx (bimekizumab); Blincyto (blinatumomab); Botox (onabotulinumtoxinA); Botox Cosmetic (onabotulinumtoxinA); Bravelle (urofollitropin); Brineura (cerliponase alfa); Briumvi (ublituximab-xiiy); Cablivi (caplacizumab-yhdp); Campath (alemtuzumab); Cathflo Activase (alteplase); Cerezyme (imiglucerase); Chorionic Gonadotropin (chorionic gonadotropin); Chromalbin (albumin chromated CR-51 serum); Chymodiactin (chymopapain); Cimzia (certolizumab pegol); Cinqair (reslizumab); Columvi (glofitamab-gxbm); Cosentyx (secukinumab); Cotazym (pancrelipase); Creon (pancrelipase); Crysvita (burosumab-twza); Curosurf (poractant alfa); Cyltezo (adalimumab-adbm); Cyramza (ramucirumab); Darzalex (daratumumab); Darzalex Faspro (daratumumab and hyaluronidase-fihj); Daxxify (daxibotulinumtoixna-lanm); Draximage MAA (kit for the preparation of technetium Tc-99m albumin aggregated); Dysport (abobotulinumtoxinA); Egrifta (tesamorelin acetate); Egrifta SV (tesamorelin acetate); Elahere (mirvetuximab soravtansine-gynx); Elaprase (idursulfase); Elase-Leydig 771696 20 chloromycetin (fibrinolysin and desoxyribonuclease combined [bovine], with chloramphenicol); Elelyso (taliglucerase alfa); Elfabrio (pegunigalsidase alfa-iwxj); Elitek (rasburicase); Elrexfio (elranatamab-bcmm); Elspar (asparaginase); Elzonris (tagraxofusp-erzs); Emgality (galcanezumab-gnlm); Empliciti (elotuzumab); Enbrel (etanercept); Enbrel Mini (etanercept); Enhertu (fam-trastuzumab deruxetecan-nxki); Enjaymo (sutimlimab-jome); Entyvio (vedolizumab); Epkinly (epcoritamab-bysp); Epogen / Procrit (epoetin alfa); Erbitux (cetuximab); Erelzi (etanercept-szzs); Erelzi Sensoready (etanercept-szzs); Erwinaze (asparaginase Erwinia chrysanthemi); Eticovo (etanercept-ykro); Evenity (romosozumab-aqqg); Evkeeza (evinacumab- dgnb), Extavia (interferon beta-1 b); Eylea (aflibercept); Fabrazyme (agalsidase beta); Fasenra (benralizumab); Fiasp (insulin aspart); Follistim (follitropin beta); Follistim AQ (follitropin beta); Follistim AQ Cartridge (follitropin beta); Gamifant (emapalumab-lzsg); Gazyva (obinutuzumab); Genotropin (somatropin); Gonal-f (follitropin alfa); Gonal-f RFF (follitropin alfa); Gonal-f RFF RediJect (follitropin alfa); Granix (tbo-filgrastim); Hadlima (adalimumab- bwwd); Hemlibra (emicizumab-kxwh); Herceptin (trastuzumab); Herceptin Hylecta (trastuzumab and hyaluronidase-oysk); Herzuma (trastuzumab-pkrb); Humalog (insulin lispro); Humalog Mix 50 / 50 (insulin lispro protamine and insulin lispro); Humalog Mix 75 / 25 (insulin lispro protamine and insulin lispro); Humatrope (somatropin); Humegon (menotropins); Humira (adalimumab); Humulin 70 / 30 (insulin isophane human and insulin human); Humulin N (insulin isophane human); Humulin R U-100 (insulin human); Humulin R U-500 (insulin human); Hydase (hyaluronidase); Hylenex recombinant (hyaluronidase human); Hyrimoz (adalimumab- adaz); llumya (tildrakizumab-asmn); Imfinzi (durvalumab); Imjudo (tremelimumab-actl); Increlex (mecasermin); Infasurf (calfactant); Infergen (interferon alfacon-1 ); Inflectra (infliximab- dyyb); Intron A (interferon alfa-2b); Iplex (mecasermin rinfabate); Iprivask (desirudin); Jeanatope (kit for iodinated 1-125 albumin); Jemperli (dostarlimab-gxly); Jetrea (ocriplasmin); Jeuveau (prabotulinumtoxinA-xvfs); Kadcyla (ado-trastuzumab emtansine); Kalbitor (ecallantide); Kanjinti (trastuzumab-anns); Kanuma (sebelipase alfa); Kepivance (palifermin); Kevzara (sarilumab); Keytruda (pembrolizumab); Kimmtrak (tebentafusp-tebn); Kineret (anakinra); Kinlytic (urokinase); Krystexxa (pegloticase); Lamzede (velmanase alfa- tycv); Lantus (insulin glargine); Lartruvo (olaratumab); Lemtrada (alemtuzumab); Leqembi (lecanemab-irmb); Leukine (sargramostim); Levemir (insulin detemir); Libtayo (cemiplimab-Leydig 771696 21 rwlc); Loqtorzi (toripalimab-tpzi); Lucentis (ranibizumab); Lumizyme (alglucosidase alfa); Lumoxiti (moxetumomab pasudotox-tdfk); Lunsumio (mosunetuzumab-axgb); Macrotec (kit for the preparation of technetium Tc-99m albumin aggregated); Megatope (kit for iodinated 1-131 albumin); Menopur (menotropins); Mepsevii (vestronidase alfa-vjbk); Microlite (radiolabeled albumin technetium Tc-99m albumin colloid kit); Mircera (methoxy polyethylene glycol-epoetin beta); Mvasi (bevacizumab-awwb); Myalept (metreleptin); Mylotarg (gemtuzumab ozogamicin); Myobloc (rimabotulinumtoxinB); Myozyme (alglucosidase alfa); Myxredlin (insulin human); N / A (raxibacumab); Naglazyme (galsulfase); Natpara (parathyroid hormone); Neulasta (pegfilgrastim); Neulasta Onpro (pegfilgrastim); Neumega (oprelvekin); Neupogen (filgrastim); NeutroSpec (technetium 99m tc fanolesomab); Nexobrid (anacaulase-bcdb); Nexviazyme (avalglucosidase alfa-ngpt); Ngenla (somatrogon-ghla); Nivestym (filgrastim-aafi); Norditropin (somatropin); Novarel (chorionic gonadotropin); Novolin 70 / 30 (insulin isophane human and insulin human); Novolin N (insulin isophane human); Novolin R (insulin human); Novolog (insulin aspart); Novolog Mix 50 / 50 (insulin aspart protamine and insulin aspart); Novolog Mix 70 / 30 (insulin aspart protamine and insulin aspart); Nplate (romiplostim); Nucala (mepolizumab); Nulojix (belatacept); Nutropin (somatropin); Nutropin AQ (somatropin); Ocrevus (ocrelizumab); Omnitrope (somatropin); Omvoh (mirikizumab-mrkz); Oncaspar (pegaspargase); Ontak (denileukin diftitox); Ontruzant (trastuzumab-dttb); Opdivo (nivolumab); Opdualag (nivolumab and relatlimab-rmbw); Orencia (abatacept); Orthoclone OKT3 (muromanab-CD3); Ovidrel (choriogonadotropin alfa); Oxervate (cenegermin-bkbj); Padcev (enfortumab vedotin-ejfv); Palynziq (pegvaliase-pqpz); Pancreaze (pancrelipase); Pegasys (peginterferon alfa-2a); Pegasys Copegus Combination Pack (peginterferon alfa-2a and ribavirin); Pegintron (peginterferon alfa-2b); Peglntron / Rebetol Combo Pack (peginterferon alfa- 2b and ribavirin); Pergonal (menotropins); Perjeta (pertuzumab); Pertzye (pancrelipase); Plegridy (peginterferon beta-1 a); Polivy (polatuzumab vedotin-piiq); Pombiliti (cipaglucosidase alfa-atga); Portrazza (necitumumab); Poteligeo (mogamulizumab-kpkc); Praluent (alirocumab); Praxbind (idarucizumab); Pregnyl (chorionic gonadotropin); Procrit (epoetin alfa); Proleukin (aldesleukin); Prolia (denosumab); ProstaScint (capromab pendetide); Pulmolite (kit for the preparation of technetium Tc-99m albumin aggregated); Pulmotech MAA (kit for the preparation of technetium Tc-99m albumin aggregated); Pulmozyme (dornase alfa); Raptiva (efalizumab);Leydig 771696 22 Rebif (interferon beta-1 a); Reblozyl (luspatercept-aamt); Regranex (becaplermin); Remicade (infliximab); Renflexis (infliximab-abda); Reopro (abciximab); Repatha (evolocumab); Repronex (menotropins); Retacrit (epoetin alfa-epbx); Retavase (reteplase); Revcovi (elapegademase-lvlr); Rituxan (rituximab); Rituxan Hycela (rituximab and hyaluronidase human); Roferon-A (interferon alfa-2a); Rolvedon (eflapegrastim-xnst); Ruxience (rituximab- pvvr); Rybrevant (amivantamab-vmjw); Rylaze (asparaginase erwinia chrysanthemi (recombinant)-rywn); Ryzneuta; Rystiggo (rozanolixizumab-noli); Ryzodeg 70 / 30 (insulin degludec and insulin aspart); Saizen (somatropin); Santyl (collagenase); Saphnelo (anifrolumab- fnia); Sarclisa (isatuximab-irfc); Serostim (somatropin); Siliq (brodalumab); Simponi (golimumab); Simponi Aria (golimumab); Simulect (basiliximab); Skyrizi (risankizumab-rzaa); Skytrofa (lonapegsomatropin-tcgd); Soliqua 100 / 33 (insulin glargine and lixisenatide); Soliris (eculizumab); Somavert (pegvisomant); Spevigo (spesolimab-sbzo); Stelara (ustekinumab); Strensiq (asfotas alfa); Sucraid (sacrosidase); Survanta (beractant); Susvimo (ranibizumab); Sylvant (siltuximab); Synagis (palivizumab); Takhzyro (lanadelumab-flyo); Taltz (ixekizumab); Talvey (talquetamab-tgvs); Tanzeum (albiglutide); Tecentriq (atezolizumab); Tecvayli (teclistamab-cqyv); Tepezza (teprotumumab- trbw); Tezspire (tezepelumab-ekko); Thyrogen (thyrotropin alfa); Tivdak (tisotumab vedotin-tftv); TNKase (tenecteplase); Toujeo (insulin glargine); Trasylol (aprotinin); Trazimera (trastuzumab-qyyp); Tremfya (guselkumab); Tresiba (insulin degludec); Trodelvy (sacituzumab govitecan-hziy); Trogarzo (ibalizumab-uiyk); Trulicity (dulaglutide); Truxima (rituximab-abbs); Tysabri (natalizumab); Tzield (teplizumab- mzwv); Udenyca (pegfilgrastim-cbqv); Ultomiris (ravulizumab-cwvz); Unituxin (dinutuximab); Vabysmo (faricimab-svoa); Vectibix (panitumumab); Veopoz (pozeilimab-bbfg); Verluma (nofetumomab); Vimizim (elosulfase alfa); Viokace (pancrelipase); Vitrase (hyaluronidase); Voraxaze (glucarpidase); VPRIV (velaglucerase alfa); Vyvgart (efgartigimod alfa-fcab); Vyvgart Hytrulo (efgartigimod alfa and hyaluronidase-qvfc); Xenpozyme (olipudase alfa-rpcp); Xeomin (incobotulinumtoxinA); Xgeva (denosumab); Xiaflex (collagenase Clostridium histolyticum); Xigris (drotrecogin alfa); Xolair (omalizumab); Xultophy 100 / 3.6 (insulin degludec and liraglutide); Yervoy (ipilimumab); Zaltrap (Ziv-Aflibercept); Zarxio (filgrastim-sndz); Zenapax (daclizumab); Zenpep (pancrelipase); Zevalin (ibritumomab tiuxetan); Ziextenzo (pegfilgrastim- bmez); Zinbryta (daclizumab); Zinplava (bezlotoxumab); Zirabev (bevacizumab-bvzr);Leydig 771696 23 Zomacton (somatropin); Zorbtive / Serostim (somatropin); Zymfentra (infliximab); Zynlonta (locastuximab tesirine-lpyl); or Zynyz (retifanlimab-dlwr).

[0079] For example, preferred biologic drug classifications include biologics for tumornecrosis, factor- -stimulation modulators,glucagon-like peptide-1 (GLP-1) agonists or GLP-1 receptor agonists, mRNA based formulations, allergens, tissues, recombinant proteins, personalized medicines (e.g., CAR-T; cell and gene therapy), and biologics listed in the FDA Purple Book (Purple Book: Lists of Licensed Biological Products with Reference Product Exclusivity and Biosimilarity or Interchangeability Evaluations). In some aspects, the personalized medicine is CAR-T medicine or a cell or gene therapy medicine.

[0080] Aspects of the invention described herein may be beneficial alone or in combination, with one or more other aspects. Without limiting the foregoing description, certain non-limiting aspects numbered 1-44 are provided below. As will be apparent to those of skill in the art upon reading this disclosure, each of the individually numbered aspects may be used or combined with any of the preceding or following individually numbered aspects. This is intended to provide support for all such combinations of aspects and is not limited to combinations of aspects explicitly provided below:

[0081] (1) A pharmaceutical container comprising a lumen defined in part by a wall, the wall having an inner surface facing the lumen, an outer surface, and at least one pH protective layer comprising an oxide of zirconium, titanium, or magnesium, wherein the at least one pH protective layer is a layer produced by atomic layer deposition (ALD) process.

[0082] (2) The pharmaceutical container of aspect (1), further comprising at least one gas barrier layer disposed between the inner surface and the at least one pH protective layer.

[0083] (3) The pharmaceutical container of aspect (2), wherein the at least one gas barrier layer comprises Al2O3and / or Al3O5.

[0084] (4) The pharmaceutical container of any one of aspects (1)-(3), wherein the pharmaceutical container wall comprises a polymer.

[0085] (5) The pharmaceutical container of aspect (4), wherein the polymer of the pharmaceutical container is selected from the group consisting of polypropylene, a cyclo olefinLeydig 771696 24 polymer (COP), a cyclo olefin co-polymer (COC), polyethylene, polyethylene terephthalate, and a combination thereof.

[0086] (6) The pharmaceutical container of aspect (5), wherein the polymer is COP, COC, or a combination thereof.

[0087] (7) The pharmaceutical container of aspect (5) or (6), wherein the COP or COC comprises at least one cyclic olefin selected from cyclobutene, cyclopentene, cyclooctene, norbomene, 5-methylnorbornene, 3-methylnorbornene, ethylnorbornene, phenylnorbomene, dimethylnorbornene, diethylnorbornene, dicyclopentadiene, tetracycloclododecene, and methyltetracyclododecene.

[0088] (8) The pharmaceutical container of aspect (5) or (6), wherein the COP or COC comprises at least one cyclic olefin selected from norbornene, 6-methylnorbornene, 6- ethylnorbornene, 6-n-butylnorbornene, 5-propylnorbornene, 1-methylnorbornene, 7- methylnorbornene, 5,6-di-methylnorbornene, 5-phenylnorbornene, 5-benzylic norbornene, 8- methyltetracyclo-3-dodecene, 8-ethyltetracyclo-3-dodecene, 8-hexyltetracyclo-3-dodecene, 2,10- dimethyltetracyclo-3-dodecene, and 5,10-dimethyltetracyclo-3-dodecene.

[0089] (9) The pharmaceutical container of aspect (1), wherein the pharmaceutical container wall comprises glass.

[0090] (10) The pharmaceutical container of any one of aspects (4)-(8), wherein the at least one pH protective layer and / or the at least one gas barrier layer are applied by ALD at a temperature that is less than the Tg of the polymer of the polymer wall.

[0091] (11) The pharmaceutical container of any one of aspects (2)-(9), wherein the at least one gas barrier layer and / or the at least one pH protective layer are deposited by ALD at a temperature of 150 , 140 , 130 , 120 , 110 , or

[0092] (12) The pharmaceutical container of any one of aspects (2)-(11), wherein the at least one gas barrier layer provides a barrier against carbon dioxide, nitrogen, oxygen, and / or water vapor.

[0093] (13) The pharmaceutical container of any one of aspects (2)-(12), wherein the at least one gas barrier layer has a thickness of 50 nm or less.

[0094] (14) The pharmaceutical container of any one of aspects (1)-(13), wherein the at least one pH protective layer has a thickness of 50 nm or less.Leydig 771696 25

[0095] (15) The pharmaceutical container of aspect (13), wherein a thickness of the at least one gas barrier layer is measured by TEM or XPS.

[0096] (16) The pharmaceutical container of aspect (14), wherein a thickness of the at least one pH protective layer is measured by TEM or XPS.

[0097] (17) The pharmaceutical container of any one of aspects (2)-(16), wherein the at least one pH protective layer reduces the rate of dissolution of the at least one gas barrier layer by >90% when exposed to a pH of 3 to 9 at a temperature of 50 °C for 72 hours.

[0098] (18) The pharmaceutical container of any one of aspects (2)-(17), further comprising a nanolaminate coated on the inner surface of the wall of the container, wherein the nanolaminate comprises multiple, thin pH protective layers and multiple, thin gas barrier layers, wherein each of the pH protective layers and each of the gas barrier layers are disposed in alternating arrangement, the nanolaminate further comprising a thick pH protective coating layer disposed over the arrangement of alternating layers in a direction towards the interior of the container.

[0099] (19) The pharmaceutical container of aspect (18), wherein the thin alternating layers comprise 2-60 pH protective layers and / or 2-60 gas barrier layers.

[0100] (20) The pharmaceutical container of aspect (18) or (19), wherein at least one of the thin pH protective layers comprises an oxide of zirconium, titanium, or magnesium and at least one of the thin gas barrier layers comprises an oxide of aluminum, and wherein said at least one pH protective layer and at least one gas barrier layer are deposited by atomic layer deposition (ALD).

[0101] (21) The pharmaceutical container of any one of aspects (18)-(20), wherein the thin gas barrier layers and / or the thin pH protective layers are deposited at a temperature that is less than the Tg of a material comprised in the pharmaceutical container wall.

[0102] (22) The pharmaceutical container of any one of aspects (18)-(21), wherein the thin gas barrier layers and / or the thin pH protective layers are deposited by ALD at a temperature of 150 , 140 , 130 , 120 , 110 , or

[0103] (23) The pharmaceutical container of any one of aspects (18)-(22), wherein the thin gas barrier layers provide a barrier against carbon dioxide, nitrogen, oxygen, and / or water vapor.

[0104] (24) The pharmaceutical container of any one of aspects (18)-(23), wherein each of the thin gas barrier layers has a thickness of 3-5 nm.Leydig 771696 26

[0105] (25) The pharmaceutical container of any one of aspects (18)-(24), wherein each of the thin pH protective layer has a thickness of 3-5 nm.

[0106] (26) The pharmaceutical container of any one of aspects (18)-(25), wherein the thick pH protective layer has a thickness of 40-50 nm.

[0107] (27) The pharmaceutical container of any one of aspects (24)-(26), wherein the thickness of any of the layers is measured by TEM and / or by XPS.

[0108] (28) The pharmaceutical container of any one of aspects (18)-(27), wherein the thin pH protective layers reduce the rate of dissolution of the thin barrier layers by at least 60%, when

[0109] (29) The pharmaceutical container of aspect (28), wherein the thin pH protective layers reduce the rate of dissolution of the thin barrier layers by up to 90% or more, when

[0110] (30) The pharmaceutical container of any one of aspects (1)-(29), wherein the oxide of zirconium is ZrO2.

[0111] (31) The pharmaceutical container of any one of aspects (1)-(29), wherein the oxide of titanium is TiO2.

[0112] (32) The pharmaceutical container of any one of aspects (1)-(29), wherein the oxide of magnesium is MgO.

[0113] (33) The pharmaceutical container of aspect (30), wherein the ZrO2 is deposited by an ALD process by utilizing tetrakisdimethylamidozirconium (Zr(NMe2)4), tetrakisethylmethylamidozirconium Zr(NMeEt)4, or tetrakisdiethylamidozirconium Zr(NEt2)4, or a combination thereof, as a reactant or reactants.

[0114] (34) The pharmaceutical container of aspect (31), wherein the TiO2is deposited by an ALD process by utilizing tetrakis(dimethylamino) titanium (TDMAT), tetrakis(diethylamino) titanium (TDEAT), or tetrakis(ethylmethylamino) titanium (TEMAT) or a combination thereof, as a reactant or reactants.

[0115] (35) The pharmaceutical container of aspect (32), wherein the MgO is deposited by an ALD process by utilizing Mg(thd)2 (2,2,6,6-tetramethyl-3,5-heptanedionate magnesium), Mg(Cp)2 (bis(cyclopentadienyl)magnesium), or Mg(EtCp)2 (bis(ethylcyclopentadienyl)magnesium), or a combination thereof, as a reactant or reactants.Leydig 771696 27

[0116] (36) The pharmaceutical container of any one of aspects (1)-(35), further comprising a binding layer deposited on the lumen.

[0117] (37) The pharmaceutical container of aspect (36), wherein the binding layer comprises alumina.

[0118] (38) The pharmaceutical container of any one of aspects (1)-(37), which contains a pharmaceutical composition.

[0119] (39) The pharmaceutical container of aspect (38), wherein the pharmaceutical composition has a pH of from 3 to 12.

[0120] (40) The pharmaceutical container of aspect (39), wherein the pharmaceutical composition has a pH of from 3 to 9 or a pH of from 6 to 9.

[0121] (41) The pharmaceutical container of any one of aspects (38)-(40), wherein the pharmaceutical composition comprises a peptide, protein, monoclonal antibody, or a constituent of blood.

[0122] (42) The pharmaceutical container of any one of aspects (38)-(41), wherein the pharmaceutical composition comprises a biologic drug selected from abatacept; abciximab; abobotulinumtoxinA; adalimumab; adalimumab-adaz; adalimumab-adbm; adalimumab-afzb; adalimumab-atto; adalimumab-bwwd; ado-trastuzumab emtansine; aflibercept; agalsidase beta; albiglutide; albumin chromated CR-51 serum; aldesleukin; alefacept; alemtuzumab; alglucosidase alfa; alirocumab; alteplase; anakinra; aprotinin; asfotas alfa; asparaginase; asparaginase Erwinia chrysanthemi; atezolizumab; avelumab; basiliximab; becaplermin; belatacept; belimumab; benralizumab; beractant; bevacizumab; bevacizumab-awwb; bevacizumab-bvzr; bezlotoxumab; blinatumomab; brentuximab vedotin; brodalumab; brolucizumab-dbll; burosumab-twza; calaspargase pegol-mknl; calfactant; canakinumab; caplacizumab-yhdp; capromab pendetide; cemiplimab-rwlc; cenegermin-bkbj; cerliponase alfa; certolizumab pegol; cetuximab; choriogonadotropin alfa; chorionic gonadotropin; chymopapain; collagenase; collagenase Clostridium histolyticum; corticorelin ovine triflutate; crizanlizumab- tmca; daclizumab; daratumumab; daratumumab and hyaluronidase-fihj; darbepoetin alpha; denileukin diftitox; denosumab; desirudin; dinutuximab; dornase alfa; drotrecogin alfa; dulaglutide; dupilumab; durvalumab; ecallantide; eculizumab; efalizumab; elapegademase-lvlr; elosulfase alfa; elotuzumab; emapalumab-lzsg; emicizumab-kxwh; enfortumab vedotin-ejfv;Leydig 771696 28 epoetin alfa; epoetin alfa-epbx; erenumab-aooe; etanercept; etanercept-szzs; etanercept-ykro; evolocumab; fam-trastuzumab deruxetecan-nxki; fibrinolysin and desoxyribonuclease combined [bovine], with chloramphenicol; filgrastim; filgrastim-aafi; filgrastim-sndz; follitropin alfa; follitropin beta; fremanezumab-vfrm; galcanezumab-gnlm; galsulfase; gemtuzumab ozogamicin; glucarpidase; golimumab; guselkumab; hyaluronidase; hyaluronidase human; ibalizumab-uiyk; ibritumomab tiuxetan; idarucizumab; idursulfase; imiglucerase; incobotulinumtoxinA; inebilizumab-cdon; infliximab; infliximab-abda; infliximab-axxq; infliximab-dyyb; infliximab- qbtx; inotuzumab ozogamicin; insulin aspart; insulin aspart protamine and insulin aspart; insulin degludec; insulin degludec and insulin aspart; insulin degludec and liraglutide; insulin detemir; insulin glargine; insulin glargine and lixisenatide; insulin glulisine; insulin human; insulin isophane human; insulin isophane human and insulin human; insulin lispro; insulin lispro protamine and insulin lispro; insulin lispro-aabc; interferon alfa-2a; interferon alfa-2b; interferon alfacon-1 ; interferon alfa-n3 (human leukocyte derived); interferon beta-1 a; interferon beta-1 b; interferon gamma-1 b; ipilimumab; isatuximab-irfc; ixekizumab; lanadelumab-flyo; laronidase; lixisenatide; luspatercept-aamt; mecasermin; mecasermin rinfabate; menotropins; mepolizumab; methoxy polyethylene glycol-epoetin beta; metreleptin; mogamulizumab-kpkc; moxetumomab pasudotox-tdfk; muromanab-CD3; natalizumab; necitumumab; nivolumab; nofetumomab; obiltoxaximab; obinutuzumab; ocrelizumab; ocriplasmin; ofatumumab; olaratumab; omalizumab; onabotulinumtoxinA; oprelvekin; palifermin; palivizumab; pancrelipase; panitumumab; parathyroid hormone; pegademase bovine; pegaspargase; pegfilgrastim; pegfilgrastim-apgf; pegfilgrastim-bmez; pegfilgrastim-cbqv; pegfilgrastim-jmdb; peginterferon alfa-2a; peginterferon alfa-2a and ribavirin; peginterferon alfa-2b; peginterferon alfa-2b and ribavirin; peginterferon beta-1 a; pegloticase; pegvaliase-pqpz; pegvisomant; pembrolizumab; pertuzumab; polatuzumab vedotin-piiq; poractant alfa; prabotulinumtoxinA-xvfs; radiolabeled albumin technetium Tc-99m albumin colloid kit; ramucirumab; ranibizumab; rasburicase; ravulizumab-cwvz; raxibacumab; reslizumab; reteplase; rilonacept; rimabotulinumtoxinB; risankizumab-rzaa; rituximab; rituximab and hyaluronidase human; rituximab-abbs; rituximab- pvvr; romiplostim; romosozumab-aqqg; sacituzumab govitecan-hziy; sacrosidase; sargramostim; sarilumab; sebelipase alfa; secukinumab; siltuximab; somatropin; tagraxofusp-erzs; taliglucerase alfa; tbo-filgrastim; technetium 99m tc fanolesomab; tenecteplase; teprotumumab-trbw;Leydig 771696 29 tesamorelin acetate; thyrotropin alfa; tildrakizumab- asmn; tocilizumab; tositumomab and iodine I-131 tositumomab; trastuzumab; trastuzumab and hyaluronidase-oysk; trastuzumab-anns; trastuzumab-dkst; trastuzumab-dttb; trastuzumab-pkrb; trastuzumab-qyyp; urofollitropin; urokinase; ustekinumab; vedolizumab; velaglucerase alfa; vestronidase alfa-vjbk; Ziv- Aflibercept; Amjevita (adalimumab-atto); Dupixent (dupilumab); Fulphila (pegfilgrastim-jmdb); llaris (canakinumab); Ixifi (infliximab-qbtx); Lyumjev (insulin lispro-aabc); Nyvepria (pegfilgrastim-apgf); Ogivri (trastuzumab-dkst); Semglee (insulin glargine); Uplizna (inebilizumab-cdon); A.P.L. (chorionic gonadotropin); Abrilada (adalimumab-afzb); Aduhelm (aducanumab-avwa); Accretropin (somatropin); Actemra (tocilizumab); Acthrel (corticorelin ovine triflutate); Actimmune (interferon gamma-1 b); Activase (alteplase); Adagen (pegademase bovine); Adakveo (crizanlizumab-tmca); Adbry (tralokinumab-ldrm); Adcetris (brentuximab vedotin); Adlyxin (lixisenatide); Admelog (insulin lispro); Afrezza (insulin human); Aimovig (erenumab-aooe); Ajovy (fremanezumab-vfrm); Aldurazyme (laronidase); Alferon N Injection (interferon alfa-n3 (human leukocyte derived)); Amevive (alefacept); Amphadase (hyaluronidase); Anthim (obiltoxaximab); Apidra (insulin glulisine); Aranesp (darbepoetin alpha); Arcalyst (rilonacept); Arzerra (ofatumumab); Asparlas (calaspargase pegol-mknl); Avastin (bevacizumab); Avonex (interferon beta-1a); Avsola (infliximab-axxq); Basaglar (insulin glargine); Bavencio (avelumab); Benlysta (belimumab); Beovu (brolucizumab-dbll); Besponsa (inotuzumab ozogamicin); Besremi (ropeginterferon-alfa-2b-njft); Betaseron (interferon beta-1 b); Bexxar (tositumomab and iodine I-131 tositumomab); Beyfortus (nirsevimab-alip); Bimzelx (bimekizumab); Blincyto (blinatumomab); Botox (onabotulinumtoxinA); Botox Cosmetic (onabotulinumtoxinA); Bravelle (urofollitropin); Brineura (cerliponase alfa); Briumvi (ublituximab-xiiy); Cablivi (caplacizumab-yhdp); Campath (alemtuzumab); Cathflo Activase (alteplase); Cerezyme (imiglucerase); Chorionic Gonadotropin (chorionic gonadotropin); Chromalbin (albumin chromated CR-51 serum); Chymodiactin (chymopapain); Cimzia (certolizumab pegol); Cinqair (reslizumab); Columvi (glofitamab- gxbm); Cosentyx (secukinumab); Cotazym (pancrelipase); Creon (pancrelipase); Crysvita (burosumab- twza); Curosurf (poractant alfa); Cyltezo (adalimumab-adbm); Cyramza (ramucirumab); Darzalex (daratumumab); Darzalex Faspro (daratumumab and hyaluronidase- fihj); Daxxify (daxibotulinumtoixna-lanm); Draximage MAA (kit for the preparation ofLeydig 771696 30 technetium Tc-99m albumin aggregated); Dysport (abobotulinumtoxinA); Egrifta (tesamorelin acetate); Egrifta SV (tesamorelin acetate); Elahere (mirvetuximab soravtansine-gynx); Elaprase (idursulfase); Elase-chloromycetin (fibrinolysin and desoxyribonuclease combined [bovine], with chloramphenicol); Elelyso (taliglucerase alfa); Elfabrio (pegunigalsidase alfa-iwxj); Elitek (rasburicase); Elrexfio (elranatamab-bcmm); Elspar (asparaginase); Elzonris (tagraxofusp-erzs); Emgality (galcanezumab-gnlm); Empliciti (elotuzumab); Enbrel (etanercept); Enbrel Mini (etanercept); Enhertu (fam-trastuzumab deruxetecan-nxki); Enjaymo (sutimlimab-jome); Entyvio (vedolizumab); Epkinly (epcoritamab-bysp); Epogen / Procrit (epoetin alfa); Erbitux (cetuximab); Erelzi (etanercept-szzs); Erelzi Sensoready (etanercept-szzs); Erwinaze (asparaginase Erwinia chrysanthemi); Eticovo (etanercept-ykro); Evenity (romosozumab-aqqg); Evkeeza (evinacumab- dgnb), Extavia (interferon beta-1b); Eylea (aflibercept); Fabrazyme (agalsidase beta); Fasenra (benralizumab); Fiasp (insulin aspart); Follistim (follitropin beta); Follistim AQ (follitropin beta); Follistim AQ Cartridge (follitropin beta); Gamifant (emapalumab-lzsg); Gazyva (obinutuzumab); Genotropin (somatropin); Gonal-f (follitropin alfa); Gonal-f RFF (follitropin alfa); Gonal-f RFF RediJect (follitropin alfa); Granix (tbo-filgrastim); Hadlima (adalimumab- bwwd); Hemlibra (emicizumab-kxwh); Herceptin (trastuzumab); Herceptin Hylecta (trastuzumab and hyaluronidase-oysk); Herzuma (trastuzumab-pkrb); Humalog (insulin lispro); Humalog Mix 50 / 50 (insulin lispro protamine and insulin lispro); Humalog Mix 75 / 25 (insulin lispro protamine and insulin lispro); Humatrope (somatropin); Humegon (menotropins); Humira (adalimumab); Humulin 70 / 30 (insulin isophane human and insulin human); Humulin N (insulin isophane human); Humulin RU-100 (insulin human); Humulin RU-500 (insulin human); Hydase (hyaluronidase); Hylenex recombinant (hyaluronidase human); Hyrimoz (adalimumab-adaz); llumya (tildrakizumab-asmn); Imfinzi (durvalumab); Imjudo (tremelimumab-actl); Increlex (mecasermin); Infasurf (calfactant); Infergen (interferon alfacon-1 ); Inflectra (infliximab- dyyb); Intron A (interferon alfa-2b); Iplex (mecasermin rinfabate); Iprivask (desirudin); Jeanatope (kit for iodinated 1-125 albumin); Jemperli (dostarlimab-gxly); Jetrea (ocriplasmin); Jeuveau (prabotulinumtoxinA-xvfs); Kadcyla (ado-trastuzumab emtansine); Kalbitor (ecallantide); Kanjinti (trastuzumab-anns); Kanuma (sebelipase alfa); Kepivance (palifermin); Kevzara (sarilumab); Keytruda (pembrolizumab); Kimmtrak (tebentafusp-tebn); Kineret (anakinra); Kinlytic (urokinase); Krystexxa (pegloticase); Lamzede (velmanase alfa-tycv); Lantus (insulinLeydig 771696 31 glargine); Lartruvo (olaratumab); Lemtrada (alemtuzumab); Leqembi (lecanemab-irmb); Leukine (sargramostim); Levemir (insulin detemir); Libtayo (cemiplimab- rwlc); Loqtorzi (toripalimab-tpzi); Lucentis (ranibizumab); Lumizyme (alglucosidase alfa); Lumoxiti (moxetumomab pasudotox-tdfk); Lunsumio (mosunetuzumab-axgb); Macrotec (kit for the preparation of technetium Tc-99m albumin aggregated); Megatope (kit for iodinated I-131 albumin); Menopur (menotropins); Mepsevii (vestronidase alfa-vjbk); Microlite (radiolabeled albumin technetium Tc-99m albumin colloid kit); Mircera (methoxy polyethylene glycol-epoetin beta); Mvasi (bevacizumab-awwb); Myalept (metreleptin); Mylotarg (gemtuzumab ozogamicin); Myobloc (rimabotulinumtoxinB); Myozyme (alglucosidase alfa); Myxredlin (insulin human); N / A (raxibacumab); Naglazyme (galsulfase); Natpara (parathyroid hormone); Neulasta (pegfilgrastim); Neulasta Onpro (pegfilgrastim); Neumega (oprelvekin); Neupogen (filgrastim); NeutroSpec (technetium 99m tc fanolesomab); Nexobrid (anacaulase-bcdb); Nexviazyme (avalglucosidase alfa-ngpt); Ngenla (somatrogon-ghla); Nivestym (filgrastim-aafi); Norditropin (somatropin); Novarel (chorionic gonadotropin); Novolin 70 / 30 (insulin isophane human and insulin human); Novolin N (insulin isophane human); Novolin R (insulin human); Novolog (insulin aspart); Novolog Mix 50 / 50 (insulin aspart protamine and insulin aspart); Novolog Mix 70 / 30 (insulin aspart protamine and insulin aspart); Nplate (romiplostim); Nucala (mepolizumab); Nulojix (belatacept); Nutropin (somatropin); Nutropin AQ (somatropin); Ocrevus (ocrelizumab); Omnitrope (somatropin); Omvoh (mirikizumab-mrkz); Oncaspar (pegaspargase); Ontak (denileukin diftitox); Ontruzant (trastuzumab-dttb); Opdivo (nivolumab); Opdualag (nivolumab and relatlimab-rmbw); Orencia (abatacept); Orthoclone OKT3 (muromanab-CD3); Ovidrel (choriogonadotropin alfa); Oxervate (cenegermin-bkbj); Padcev (enfortumab vedotin-ejfv); Palynziq (pegvaliase-pqpz); Pancreaze (pancrelipase); Pegasys (peginterferon alfa-2a); Pegasys Copegus Combination Pack (peginterferon alfa-2a and ribavirin); Pegintron (peginterferon alfa-2b); Peglntron / Rebetol Combo Pack (peginterferon alfa- 2b and ribavirin); Pergonal (menotropins); Perjeta (pertuzumab); Pertzye (pancrelipase); Plegridy (peginterferon beta-1a); Polivy (polatuzumab vedotin-piiq); Pombiliti (cipaglucosidase alfa-atga); Portrazza (necitumumab); Poteligeo (mogamulizumab-kpkc); Praluent (alirocumab); Praxbind (idarucizumab); Pregnyl (chorionic gonadotropin); Procrit (epoetin alfa); Proleukin (aldesleukin); Prolia (denosumab); ProstaScint (capromab pendetide); Pulmolite (kit for theLeydig 771696 32 preparation of technetium Tc-99m albumin aggregated); Pulmotech MAA (kit for the preparation of technetium Tc-99m albumin aggregated); Pulmozyme (dornase alfa); Raptiva (efalizumab); Rebif (interferon beta-1a); Reblozyl (luspatercept-aamt); Regranex (becaplermin); Remicade (infliximab); Renflexis (infliximab-abda); Reopro (abciximab); Repatha (evolocumab); Repronex (menotropins); Retacrit (epoetin alfa-epbx); Retavase (reteplase); Revcovi (elapegademase-lvlr); Rituxan (rituximab); Rituxan Hycela (rituximab and hyaluronidase human); Roferon-A (interferon alfa-2a); Rolvedon (eflapegrastim-xnst); Ruxience (rituximab- pvvr); Rybrevant (amivantamab-vmjw); Rylaze (asparaginase erwinia chrysanthemi (recombinant)-rywn); Ryzneuta; Rystiggo (rozanolixizumab-noli); Ryzodeg 70 / 30 (insulin degludec and insulin aspart); Saizen (somatropin); Santyl (collagenase); Saphnelo (anifrolumab- fnia); Sarclisa (isatuximab-irfc); Serostim (somatropin); Siliq (brodalumab); Simponi (golimumab); Simponi Aria (golimumab); Simulect (basiliximab); Skyrizi (risankizumab-rzaa); Skytrofa (lonapegsomatropin-tcgd); Soliqua 100 / 33 (insulin glargine and lixisenatide); Soliris (eculizumab); Somavert (pegvisomant); Spevigo (spesolimab-sbzo); Stelara (ustekinumab); Strensiq (asfotas alfa); Sucraid (sacrosidase); Survanta (beractant); Susvimo (ranibizumab); Sylvant (siltuximab); Synagis (palivizumab); Takhzyro (lanadelumab-flyo); Taltz (ixekizumab); Talvey (talquetamab-tgvs); Tanzeum (albiglutide); Tecentriq (atezolizumab); Tecvayli (teclistamab-cqyv); Tepezza (teprotumumab- trbw); Tezspire (tezepelumab-ekko); Thyrogen (thyrotropin alfa); Tivdak (tisotumab vedotin-tftv); TNKase (tenecteplase); Toujeo (insulin glargine); Trasylol (aprotinin); Trazimera (trastuzumab-qyyp); Tremfya (guselkumab); Tresiba (insulin degludec); Trodelvy (sacituzumab govitecan-hziy); Trogarzo (ibalizumab-uiyk); Trulicity (dulaglutide); Truxima (rituximab-abbs); Tysabri (natalizumab); Tzield (teplizumab- mzwv); Udenyca (pegfilgrastim-cbqv); Ultomiris (ravulizumab-cwvz); Unituxin (dinutuximab); Vabysmo (faricimab-svoa); Vectibix (panitumumab); Veopoz (pozeilimab-bbfg); Verluma (nofetumomab); Vimizim (elosulfase alfa); Viokace (pancrelipase); Vitrase (hyaluronidase); Voraxaze (glucarpidase); VPRIV (velaglucerase alfa); Vyvgart (efgartigimod alfa-fcab); Vyvgart Hytrulo (efgartigimod alfa and hyaluronidase-qvfc); Xenpozyme (olipudase alfa-rpcp); Xeomin (incobotulinumtoxinA); Xgeva (denosumab); Xiaflex (collagenase Clostridium histolyticum); Xigris (drotrecogin alfa); Xolair (omalizumab); Xultophy 100 / 3.6 (insulin degludec and liraglutide); Yervoy (ipilimumab); Zaltrap (Ziv-Aflibercept); Zarxio (filgrastim-sndz); ZenapaxLeydig 771696 33 (daclizumab); Zenpep (pancrelipase); Zevalin (ibritumomab tiuxetan); Ziextenzo (pegfilgrastim- bmez); Zinbryta (daclizumab); Zinplava (bezlotoxumab); Zirabev (bevacizumab-bvzr); Zomacton (somatropin); Zorbtive / Serostim (somatropin); Zymfentra (infliximab); Zynlonta (locastuximab tesirine-lpyl); or Zynyz (retifanlimab-dlwr).

[0123] (43) The pharmaceutical container of any one of aspects (38)-(42), wherein the pharmaceutical composition comprises a biologic for tumor necrosis, a factor- a interleukin inhibitor, a selective co-stimulation modulator, a glucagon-like peptide-1 (GLP-1) agonist or GLP-1 receptor agonist, an mRNA based formulation, an allergen, a tissue, a recombinant protein, a personalized medicine, (e.g., CAR-T; cell and gene therapy), or a biologic listed in the FDA Purple Book.

[0124] (44) The pharmaceutical container of aspect (43), wherein the personalized medicine is CAR-T medicine or a cell or gene therapy medicine. EXAMPLES

[0125] These following examples further illustrate the invention but, of course, should not be construed as in any way limiting its scope. EXAMPLE 1

[0126] This example illustrates a method for preparing a pH protective coating layer by the atomic layer deposition (ALD) technique. Thus, pH protective layers were applied on a silicon wafer containing an Al2O3barrier layer that served as a model for the surface of the pharmaceutical container.

[0127] Thus, pH protective layers were applied onto the following silicon wafers (each 1 cm x 1cm): (i) a Si wafer with a 20 nm Al2O3 barrier layer, (ii) a Si wafer with a 50 nm Al2O3 barrier layer, (iii) a 50 nm ZrO2 pH protective layer deposited over the 50 nm Al2O3 barrier layer, and (iv) a Si wafer with a 20 nm Al2O3 barrier layer and a 20 nm ZrO2 pH protective layer deposited over the 20 nm Al2O3barrier layer.

[0128] The samples were evaluated to determine the coating stack in several locations on the Si wafer using XPS. XPS experiments were performed using a Physical Electronics VersaProbe -Leydig 771696 34 concentric hemispherical analyzer. Charge neutralization was performed using both low energy electrons (<5 eV) and argon ions. The binding energy axis was calibrated using sputter cleaned Cu (Cu 2p3 / 2 3 / 2 7 / 2 charge referenced to CHx band in the carbon 1s spectra at 284.8 eV. Measurements were made at a takeoff angle of 45° with respect to the sample surface plane. This resulted in a typical sampling depth of 3-6 nm (95% of the signal originated from this depth or shallower). Quantification was done using instrumental relative sensitivity factors (RSFs) that account for the x-ray cross section and inelastic mean free path of the electrons. On homogeneous samples major elements (>5 atom%) tend to have standard deviations of <3% while minor elements can be significantly higher. The analysis size was ~200μm in diameter. Ion sputtering was done using 2 kV Ar+ rastered over a 2 mm X 2 mm area. The Al2O3 sputtering rate was 1.4 nm / minute based on the assumed thickness of 50 nm.

[0129] Figures 1A-1D demonstrate the XPS depth profiles for the different samples.

[0130] This study indicated that silicon becomes less visible as the thickness of the Al2O3increased. EXAMPLE 2

[0131] This example demonstrates illustrative methods for developing a functional pH protective layer using atomic layer deposition (ALD) on a silicon wafer by determining the dissolution of the Al2O3 barrier layer at a pH of 3 and 9.

[0132] In this study, samples were placed in either a HCl pH 3 or a pH 9 phosphate buffer after the 72 hours, and the concentration of aluminum was determined using inductively coupled plasma mass spectrometry (ICP-MS) or optical emission spectroscopy (OES). The samples that were analyzed consisted of: (i) a Si wafer with a 20 nm Al2O3 barrier layer, (ii) a Si wafer with a 50 nm Al2O3 barrier layer, (iii) a Si wafer with a 20 nm Al2O3 barrier layer and a 20 nm ZrO2 pH protective layer deposited over the 20 nm Al2O3 barrier layer, and (iv) a Si wafer with a 50 nm Al2O3 barrier layer and a 50 nm ZrO2 pH protective layer deposited over the 50 nm Al2O3 barrier layer.Leydig 771696 35

[0133] FIG. 3A is a schematic representation of the aluminum concentration in the collected pH 9 buffer solutions for a Si wafer coated with a 20 nm Al2O3 gas barrier layer and for a Si wafer with a 20 nm Al2O3 barrier layer and a 20 nm ZrO2 pH protective layer deposited over the 20 nm Al2O3 barrier layer. FIG.3B is a schematic representation of the aluminum concentration in the collected pH 9 buffer solutions for a Si wafer coated with a 50 nm Al2O3 gas barrier layer and for a Si wafer with a 50 nm Al2O3barrier layer and a 50 nm ZrO2pH protective layer deposited over the 50 nm Al2O3barrier layer. FIG. 3C is a schematic representation of the aluminum concentration in the collected pH 3 buffer solutions for a Si wafer coated with a 20 nm Al2O3gas barrier layer and for a Si wafer with a 20 nm Al2O3barrier layer and a 20 nm ZrO2pH protective layer deposited over the 20 nm Al2O3 barrier layer. FIG.3D is a schematic representation of the aluminum concentration in the collected pH 3 buffer solutions for a Si wafer coated with a 50 nm Al2O3 gas barrier layer and for a Si wafer with a 50 nm Al2O3 barrier layer and a 50 nm ZrO2 pH protective layer deposited over the 50 nm Al2O3 barrier layer.

[0134] This example provides illustrative methods for determining the dissolution at pH 3 or pH 9 of a coating system deposited on a silicon wafer. The data indicates that when the silicon wafer was only coated with either a 20 nm or 50 nm Al2O3barrier layer, the concentration of aluminum in the pH 9 buffer solution was 8.9 μg and 55 μg, respectively. In contrast, when there is either a 20 nm or 50 nm ZrO2 pH protective layer deposited over a 20 nm or 50 nm Al2O3 gas barrier layer, then the concentration of aluminum in the pH 9 buffer solution is 0.7 μg and <0.5 μg, respectively. Furthermore, the data indicates that when the silicon wafer is only coated with either a 20 nm or 50 nm Al2O3 barrier layer, the concentration of aluminum in the pH 3 buffer solution is 11 μg and 36 μg, respectively. In contrast, when there is either a 20 nm or 50 nm ZrO2pH protective layer deposited over a 20 nm or 50 nm Al2O3gas barrier layer, then the concentration of aluminum in the pH 3 buffer solution was <0.5 μg and 2.2 μg, respectively. EXAMPLE 3

[0135] This example demonstrates illustrative methods for characterizing the gas barrier layer and pH protective layer that are deposited on a poly propylene substrate via atomic layer deposition using scanning transmission electron microscopy (STEM) and energy dispersive spectrometry (EDS).Leydig 771696 36

[0136] In this study, samples were analyzed using STEM and EDS to characterize the gas barrier layer and pH protective layer. The poly propylene film samples used for this study had a length of 1.08 cm to 1.57 cm, a width of 0.88 cm to 1.25 cm, and an area of 0.95 cm2to 1.86 cm2.

[0137] Figures 4A-4D are schematic representations of the gas barrier layer and / or pH protective layer on a poly propylene substrate.

[0138] This example demonstrates illustrative methods for characterizing the gas barrier layer and pH protective layer that are deposited on a poly propylene substrate via atomic layer deposition using scanning transmission electron microscopy (STEM). The data indicates that the Al2O3 gas barrier layer is about 10 nm to 15 nm thick, and the coating layer comprising the Al2O3 gas barrier layer and the ZrO2 pH protective layer is 25 nm to 35 nm thick. EXAMPLE 4

[0139] This example demonstrates illustrative methods for developing a functional pH protective layer deposited via atomic layer deposition (ALD) on a polypropylene substrate by determining the dissolution of the Al2O3 barrier layer at pH 9.

[0140] In this study, samples were placed in a pH 9 phosphate buffer solution and incubated was determined using inductively coupled plasma mass spectrometry (ICP-MS) or optical emission spectroscopy (OES). The polypropylene film samples used for this study had a length of 1.08 cm to 1.57 cm, a width of 0.88 cm to 1.25 cm, and an area of 0.95 cm2to 1.86 cm2.

[0141] FIG. 5 is a schematic representation of the aluminum concentration in the collected pH 9 buffer solutions for the sample coated with just an Al2O3gas barrier layer and for the sample coated with a ZrO2pH protective layer over the Al2O3gas barrier.

[0142] This example provides illustrative methods for determining the dissolution at pH 9 of a coating system deposited on a poly propylene substrate. The data indicates that when there is no pH protective layer present, the concentration of aluminum in the pH 9 buffer solution is 35 μg. In contrast, when there is a ZrO2 pH protective layer deposited over the Al2O3 gas barrier layer, then the concentration of aluminum in the pH 9 buffer solution is 23 μg.Leydig 771696 37 EXAMPLE 5

[0143] This example demonstrates the differences in depositing a pH protective layer with atomic layer deposition (ALD) versus plasma-enhanced chemical vapor deposition (PECVD).

[0144] In this study, a pH protective layer was deposited over a gas barrier layer, and the thicknesses of the pH protective layers were determined for both application methods. For the ALD system, the pH protective layer was found to be 20 nm to 50 nm thick, while for the PECVD system, the pH protective layer was found to be 250 nm to 400 nm thick.

[0145] FIG.6 is a schematic representation illustrating the differences in depositing a pH protective layer with atomic layer deposition (ALD) versus plasma-enhanced chemical vapor deposition (PECVD).

[0146] This example demonstrates the differences in depositing a pH protective layer with either ALD or PECVD. The data indicates that a ZrO2 pH protective layer deposited using ALD is approximately 10 times thinner than when applied with PECVD, with no change in functionality. The advantage of a thinner coating is that it provides a more robust polymer pharmaceutical container that can withstand thermal cycling and mechanical deflection of the container without risk of the pH protective coating cracking or becoming damaged. EXAMPLE 6

[0147] This example illustrates a method for preparing a barrier layer by the atomic layer deposition (ALD) technique. Thus, a (COP)-based vial was coated with an Al2O3 barrier layer using ALD.

[0148] Thus, the Al2O3

[0149] Figures 8A and 8B demonstrate the XPS depth profiles for bottom of the vial and wall of the vial, respectively.

[0150] This study indicated that the die wall and bottom contained Al2O3coatings with no detectable carbon in the oxide and well resolved Al2O3-polymer interface. The films were determined to be approximately 27 nm in thickness.Leydig 771696 38 EXAMPLE 7

[0151] This example illustrates a method for preparing a barrier layer by the atomic layer deposition (ALD) technique. Thus, a (COP)-based vial was coated with an Al2O3 barrier layer using ALD.

[0152] Thus, the Al2O3

[0153] Figures 9A-9C demonstrate the XPS depth profiles for the inside surface of the bottom of the vial, the outside surface of the bottom of the vial, and inside wall of the vial, respectively.

[0154] This study indicated that the inside bottom surface film was approximately 41 nm thick while the outside bottom surface film was approximately 61 nm thick. The sidewall appeared to be a bit thinner than the bottom, however because of an instrument problem this film was run on a different instrument than the inside bottom. It is possible there is a minor difference in deposition rate. EXAMPLE 8

[0155] This example illustrates a method for preparing a barrier layer by the atomic layer deposition (ALD) technique. Thus, a (COP)-based vial was coated with an Al2O3 barrier layer using ALD.

[0156] Thus, the Al2O3

[0157] Figures 10 demonstrates the XPS depth profile for the inside surface of the bottom of the vial.

[0158] This study was a repeat of Example 7 and used to confirm the depth of the Al2O3barrier layer at the inside surface of the bottom of the vial. EXAMPLE 9

[0159] This example illustrates a method for preparing a pH protective coating layer by the atomic layer deposition (ALD) technique. Thus, a Al2O3 barrier layer was deposited on a (COP)-based vial using ALD and then a ZrO2pH protective layer was deposited over the Al2O3barrier layer using ALD.

[0160] The Al2O3barrier layer and ZrO2Leydig 771696 39

[0161] Figures 11A and 11B demonstrate the XPS depth profiles for the inside surface of the bottom of the vial and the outside surface of the bottom of the vial, respectively.

[0162] This study indicated that the ZrO2 pH protective layer was extremely thin or patchy on the inside of the vial. The outside of the vial (sidewall area) was analyzed and found to have intact ZrO2and Al2O3 films of ~35 nm each. EXAMPLE 10

[0163] This example illustrates a method for preparing a pH protective coating layer by the atomic layer deposition (ALD) technique. Thus, a Al2O3 barrier layer was deposited on a (COP)-based vial using ALD and then a ZrO2 pH protective layer was deposited over the Al2O3 barrier layer using ALD.

[0164] The Al2O3barrier layer and ZrO2

[0165] Figure 12A demonstrates the XPS depth profile for the inside surface of the bottom of the vial.

[0166] This study indicated that the inside surface of the bottom of the vial had an approximately 40 nm ZrO2 layer on top of a 40 nm layer of Al2O3. EXAMPLE 11

[0167] This example illustrates a method for determining the water vapor transmission rate and oxygen transmission rate for the coated (COP)-based vial of Example 10.

[0168] Figures 12B and 12C demonstrate the water vapor transmission rate and oxygen transmission rate for the coated (COP)-based vial of Example 10.

[0169] This study indicated that the coated (COP)-based vial had a water vapor transmission rate of 0.0000250 g / pkg-day, while the uncoated (COP)-based vial had a water vapor transmission rate of 0.0000780 g / pkg-day. Moreover, the coated (COP)-based vial had an oxygen transmission rate of 0.0002100 cc / pkg-day, while the uncoated (COP)-based vial had an oxygen transmission rate of 0.0120000 cc / pkg-day.Leydig 771696 40 EXAMPLE 12

[0170] This example demonstrates illustrative methods for determining the dissolution of the Al2O3 barrier layer at a pH of 3 and 9.

[0171] In this study, samples were placed in either a HCl pH 3 or a pH 9 phosphate buffer after the 72 hours, and the concentration of aluminum and zirconium was determined using inductively coupled plasma mass spectrometry (ICP-MS) or optical emission spectroscopy (OES). The samples that were analyzed consisted of a vial with a 40 nm Al2O3barrier layer and a vial with a 40 nm Al2O3barrier layer and a 40 nm ZrO2pH protective layer deposited over the 40 nm Al2O3barrier layer.

[0172] FIG.12D is a schematic representation of the aluminum and zirconium concentrations in the collected pH 9 buffer solutions for a (COP)-based vial coated with a 40 nm thick Al2O3 barrier layer and for a (COP)-based vial coated with a 40 nm thick Al2O3 barrier layer and a 40 nm thick ZrO2 pH protective layer deposited over the Al2O3 barrier.

[0173] FIG.12E is a schematic representation of the aluminum and zirconium concentrations in the collected pH 3 buffer solutions for (COP)-based vial coated with a 40 nm thick Al2O3barrier layer and for a (COP)-based vial coated with a 40 nm thick Al2O3barrier layer and a 40 nm thick ZrO2pH protective layer deposited over the Al2O3barrier.

[0174] This example provides illustrative methods for determining the dissolution at pH 3 or pH 9 of a coating system deposited on a (COP)-based vial. The data indicates that when the (COP)-based vial was only coated with a 40 nm Al2O3 barrier layer, the concentration of aluminum in the pH 9 buffer solution was 100 μg. In contrast, when a 40 nm ZrO2 pH protective layer deposited over the 40 nm Al2O3 barrier layer, then the concentration of aluminum in the pH 9 buffer solution is 14 μg. Furthermore, the data indicates that when the (COP)-based vial is only coated with 40 nm Al2O3barrier layer, the concentration of aluminum in the pH 3 buffer solution is 175 μg. In contrast, when there is a 40 nm ZrO2pH protective layer deposited over the 40 nm Al2O3barrier layer, then the concentration of aluminum in the pH 3 buffer solution was 2.7 μg.Leydig 771696 41 EXAMPLE 13

[0175] This example illustrates a method for preparing a pH protective coating layer by the atomic layer deposition (ALD) technique. Thus, a Al2O3 barrier layer was deposited on a (COP)-based syringe using ALD and then a ZrO2 pH protective layer was deposited over the Al2O3 barrier layer using ALD.

[0176] Thus, the Al2O3 barrier layer and ZrO2

[0177] Figure 13A-13C demonstrate the XPS depth profiles for needle end, middle, and flange end of the syringe.

[0178] This study indicated that all areas contained well defined layers 40-50 nm in thickness of ZrO2on top of Al2O3. EXAMPLE 14

[0179] This example demonstrates illustrative methods for determining the dissolution of the Al2O3barrier layer at a pH of 3 and 9 when deposited as a nanolaminate comprising alternating layers of a Al2O3barrier layer and ZrO2pH protective layer on a (COP)-based vial.

[0180] In this study, samples were placed in either a HCl pH 3 or a pH 9 phosphate buffer after the 72 hours, and the concentration of aluminum and zirconium was determined using inductively coupled plasma mass spectrometry (ICP-MS) or optical emission spectroscopy (OES). The samples that were analyzed consisted of a vial with a 50 nm Al2O3 barrier layer and a vial with 50 nm nanolaminate comprising alternating layers of a Al2O3 barrier layer and ZrO2 pH protective layer.

[0181] FIG.15A is a schematic representation of the aluminum and zirconium concentrations in the collected pH 9 buffer solutions for a (COP)-based vial coated with a 50 nm thick Al2O3barrier layer and for a (COP)-based vial coated with a 50 nm nanolaminate comprised of thin alternating layers of a ZrO2 pH protective layer and a Al2O3 barrier layer with a thick ZrO2 pH protective coating layer disposed over the arrangement of alternating layers.

[0182] FIG.15B is a schematic representation of the aluminum and zirconium concentrations in the collected pH 3 buffer solutions for a (COP)-based vial coated with a 50 nm thick Al2O3barrier layer and for a (COP)-based vial coated with a 50 nm nanolaminateLeydig 771696 42 comprised of thin alternating layers of a ZrO2pH protective layer and a Al2O3barrier layer with a thick ZrO2 pH protective coating layer disposed over the arrangement of alternating layers.

[0183] This example provides illustrative methods for determining the dissolution at pH 3 or pH 9 of a coating system deposited on a (COP)-based vial. The data indicates that when the (COP)-based vial was only coated with a 50 nm Al2O3 barrier layer, the concentration of aluminum in the pH 9 buffer solution was 100 μg. In contrast, when a 50 nm nanolaminate comprising alternating layers of a Al2O3barrier layer and ZrO2pH protective layer, then the concentration of aluminum in the pH 9 buffer solution is 0.8 μg. Furthermore, the data indicates that when the (COP)-based vial is only coated with 50 nm Al2O3barrier layer, the concentration of aluminum in the pH 3 buffer solution is 175 μg. In contrast, when there is a 50 nm nanolaminate comprising alternating layers of a Al2O3 barrier layer and ZrO2 pH protective layer, then the concentration of aluminum in the pH 3 buffer solution was 9.2 μg.

[0184] All references, including publications, patent applications, and patents, cited herein are hereby incorporated by reference to the same extent as if each reference were individually and specifically indicated to be incorporated by reference and were set forth in its entirety herein.

[0185] The use of the terms “a” and “an” and “the” and “at least one” and similar referents in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. The use of the term “at least one” followed by a list of one or more items (for example, “at least one of A and B”) is to be construed to mean one item selected from the listed items (A or B) or any combination of two or more of the listed items (A and B), unless otherwise indicated herein or clearly contradicted by context. The terms “comprising,” “having,” “including,” and “containing” are to be construed as open-ended terms (i.e., meaning “including, but not limited to,”) unless otherwise noted. Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as”) provided herein, is intended merely to better illuminate the inventionLeydig 771696 43 and does not pose a limitation on the scope of the invention unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention.

[0186] Preferred aspects of this invention are described herein, including the best mode known to the inventors for carrying out the invention. Variations of those preferred aspects may become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventors expect skilled artisans to employ such variations as appropriate, and the inventors intend for the invention to be practiced otherwise than as specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.

Claims

Leydig 771696 44 CLAIMS:

1. A pharmaceutical container comprising a lumen defined in part by a wall, the wall having an inner surface facing the lumen, an outer surface, and at least one pH protective layer comprising an oxide of zirconium, titanium, or magnesium, wherein the at least one pH protective layer is a layer produced by atomic layer deposition (ALD) process.

2. The pharmaceutical container of claim 1, further comprising at least one gas barrier layer disposed between the inner surface and the at least one pH protective layer.

3. The pharmaceutical container of claim 2, wherein the at least one gas barrier layer comprises Al2O3and / or Al3O5.

4. The pharmaceutical container of any one of claims 1-3, wherein the pharmaceutical container wall comprises a polymer.

5. The pharmaceutical container of claim 4, wherein the polymer of the pharmaceutical container is selected from the group consisting of polypropylene, a cyclo olefin polymer (COP), a cyclo olefin co-polymer (COC), polyethylene, polyethylene terephthalate, and a combination thereof.

6. The pharmaceutical container of claim 5, wherein the polymer is COP, COC, or a combination thereof.

7. The pharmaceutical container of claim 5 or 6, wherein the COP or COC comprises at least one cyclic olefin selected from cyclobutene, cyclopentene, cyclooctene, norbomene, 5-methylnorbornene, 3-methylnorbornene, ethylnorbornene, phenylnorbomene, dimethylnorbornene, diethylnorbornene, dicyclopentadiene, tetracycloclododecene, and methyltetracyclododecene.

8. The pharmaceutical container of claim 5 or 6, wherein the COP or COC comprises at least one cyclic olefin selected from norbornene, 6-methylnorbornene, 6- ethylnorbornene, 6-n-butylnorbornene, 5-propylnorbornene, 1-methylnorbornene, 7- methylnorbornene, 5,6-di-methylnorbornene, 5-phenylnorbornene, 5-benzylic norbornene, 8-Leydig 771696 45 methyltetracyclo-3-dodecene, 8-ethyltetracyclo-3-dodecene, 8-hexyltetracyclo-3-dodecene, 2,10- dimethyltetracyclo-3-dodecene, and 5,10-dimethyltetracyclo-3-dodecene.

9. The pharmaceutical container of any one of claim 1, wherein the pharmaceutical container wall comprises glass.

10. The pharmaceutical container of any one of claims 4-8, wherein the at least one pH protective layer and / or the at least one gas barrier layer are applied by ALD at a temperature that is less than the Tg of the polymer of the polymer wall.

11. The pharmaceutical container of any one of claims 2-8 or 10, wherein the at least one gas barrier layer and / or the at least one pH protective layer are deposited by ALD at a temperature of 150 , 140 , 130 , 120 , 110 , or 12. The pharmaceutical container of claim 11, wherein the at least one gas barrier layer provides a barrier against carbon dioxide, nitrogen, oxygen, and / or water vapor.

13. The pharmaceutical container of any one of claims 2-8 and 10-12, wherein the at least one gas barrier layer has a thickness of 50 nm or less.

14. The pharmaceutical container of any one of claims 1-13, wherein the at least one pH protective layer has a thickness of 50 nm or less.

15. The pharmaceutical container of claim 13, wherein a thickness of the at least one gas barrier layer is measured by TEM or XPS.

16. The pharmaceutical container of claim 14, wherein a thickness of the at least one pH protective layer is measured by TEM or XPS.

17. The pharmaceutical container of any one of claims 2-16, wherein the at least one pH protective layer reduces the rate of dissolution of the at least one gas barrier layer by >90% when exposed to a pH of 3 to 9 at a temperature of 50 °C for 72 hours.

18. The pharmaceutical container of any one of claims 2-17, further comprising a nanolaminate coated on the inner surface of the wall of the container, wherein the nanolaminateLeydig 771696 46 comprises multiple, thin pH protective layers and multiple, thin gas barrier layers, wherein each of the pH protective layers and each of the gas barrier layers are disposed in alternating arrangement, the nanolaminate further comprising a thick pH protective coating layer disposed over the arrangement of alternating layers in a direction towards the interior of the container.

19. The pharmaceutical container of claim 18, wherein the thin alternating layers comprise 2-60 pH protective layers and / or 2-60 gas barrier layers.

20. The pharmaceutical container of claim 18 or 19, wherein at least one of the thin pH protective layers comprises an oxide of zirconium, titanium, or magnesium and at least one of the thin gas barrier layers comprises an oxide of aluminum, and wherein said at least one pH protective layer and at least one gas barrier layer are deposited by atomic layer deposition (ALD).

21. The pharmaceutical container of any one of claims 18-20, wherein the thin gas barrier layers and / or the thin pH protective layers are deposited at a temperature that is less than the Tg of a material comprised in the pharmaceutical container wall.

22. The pharmaceutical container of any one of claims 18-21, wherein the thin gas barrier layers and / or the thin pH protective layers are deposited by ALD at a temperature of 150 , 140 , 130 , 120 , 110 , or 23. The pharmaceutical container of any one of claims 18-22, wherein the thin gas barrier layers provide a barrier against carbon dioxide, nitrogen, oxygen, and / or water vapor.

24. The pharmaceutical container of any one of claims 18-23, wherein each of the thin gas barrier layers has a thickness of 3-5 nm.

25. The pharmaceutical container of any one of claims 18-24, wherein each of the thin pH protective layer has a thickness of 3-5 nm.

26. The pharmaceutical container of any one of claims 18-25, wherein the thick pH protective layer has a thickness of 40-50 nm.Leydig 771696 47 27. The pharmaceutical container of any one of claims 24-26, wherein the thickness of any of the layers is measured by TEM and / or by XPS.

28. The pharmaceutical container of any one of claims 18-27, wherein the thin pH protective layers reduce the rate of dissolution of the thin barrier layers by at least 60%, when 29. The pharmaceutical container of claim 28, wherein the thin pH protective layers reduce the rate of dissolution of the thin barrier layers by up to 90% or more, when exposed to a 30. The pharmaceutical container of any one of claims 1-29, wherein the oxide of zirconium is ZrO2.

31. The pharmaceutical container of any one of claims 1-29, wherein the oxide of titanium is TiO2.

32. The pharmaceutical container of any one of claims 1-29, wherein the oxide of magnesium is MgO.

33. The pharmaceutical container of claim 30, wherein the ZrO2is deposited by an ALD process by utilizing tetrakisdimethylamidozirconium (Zr(NMe2)4), tetrakisethylmethylamidozirconium Zr(NMeEt)4, or tetrakisdiethylamidozirconium Zr(NEt2)4, or a combination thereof, as a reactant or reactants.

34. The pharmaceutical container of claim 31, wherein the TiO2is deposited by an ALD process by utilizing tetrakis(dimethylamino) titanium (TDMAT), tetrakis(diethylamino) titanium (TDEAT), or tetrakis(ethylmethylamino) titanium (TEMAT) or a combination thereof, as a reactant or reactants.

35. The pharmaceutical container of claim 32, wherein the MgO is deposited by an ALD process by utilizing Mg(thd)2 (2,2,6,6-tetramethyl-3,5-heptanedionate magnesium), Mg(Cp)2 (bis(cyclopentadienyl)magnesium), or Mg(EtCp)2 (bis(ethylcyclopentadienyl)magnesium), or a combination thereof, as a reactant or reactants.Leydig 771696 48 36. The pharmaceutical container of any one of claims 1-35, further comprising a binding layer deposited on the lumen.

37. The pharmaceutical container of claim 36, wherein the binding layer comprises alumina.

38. The pharmaceutical container of any one of claims 1-37, which contains a pharmaceutical composition.

39. The pharmaceutical container of claim 38, wherein the pharmaceutical composition has a pH of from 3 to 12.

40. The pharmaceutical container of claim 39, wherein the pharmaceutical composition has a pH of from 3 to 9 or a pH of from 6 to 9.

41. The pharmaceutical container of any one of claims 38-40, wherein the pharmaceutical composition comprises a peptide, protein, monoclonal antibody, or a constituent of blood.

42. The pharmaceutical container of any one of claims 38-41, wherein the pharmaceutical composition comprises a biologic drug selected from abatacept; abciximab; abobotulinumtoxinA; adalimumab; adalimumab-adaz; adalimumab-adbm; adalimumab-afzb; adalimumab-atto; adalimumab-bwwd; ado-trastuzumab emtansine; aflibercept; agalsidase beta; albiglutide; albumin chromated CR-51 serum; aldesleukin; alefacept; alemtuzumab; alglucosidase alfa; alirocumab; alteplase; anakinra; aprotinin; asfotas alfa; asparaginase; asparaginase Erwinia chrysanthemi; atezolizumab; avelumab; basiliximab; becaplermin; belatacept; belimumab; benralizumab; beractant; bevacizumab; bevacizumab-awwb; bevacizumab- bvzr; bezlotoxumab; blinatumomab; brentuximab vedotin; brodalumab; brolucizumab- dbll; burosumab-twza; calaspargase pegol-mknl; calfactant; canakinumab; caplacizumab-yhdp; capromab pendetide; cemiplimab-rwlc; cenegermin-bkbj; cerliponase alfa; certolizumab pegol; cetuximab; choriogonadotropin alfa; chorionic gonadotropin; chymopapain; collagenase; collagenase Clostridium histolyticum; corticorelin ovine triflutate; crizanlizumab- tmca; daclizumab; daratumumab; daratumumab and hyaluronidase-fihj; darbepoetin alpha;Leydig 771696 49 denileukin diftitox; denosumab; desirudin; dinutuximab; dornase alfa; drotrecogin alfa; dulaglutide; dupilumab; durvalumab; ecallantide; eculizumab; efalizumab; elapegademase-lvlr; elosulfase alfa; elotuzumab; emapalumab-lzsg; emicizumab-kxwh; enfortumab vedotin-ejfv; epoetin alfa; epoetin alfa-epbx; erenumab-aooe; etanercept; etanercept-szzs; etanercept-ykro; evolocumab; fam-trastuzumab deruxetecan-nxki; fibrinolysin and desoxyribonuclease combined [bovine], with chloramphenicol; filgrastim; filgrastim-aafi; filgrastim-sndz; follitropin alfa; follitropin beta; fremanezumab-vfrm; galcanezumab-gnlm; galsulfase; gemtuzumab ozogamicin; glucarpidase; golimumab; guselkumab; hyaluronidase; hyaluronidase human; ibalizumab-uiyk; ibritumomab tiuxetan; idarucizumab; idursulfase; imiglucerase; incobotulinumtoxinA; inebilizumab-cdon; infliximab; infliximab-abda; infliximab-axxq; infliximab-dyyb; infliximab- qbtx; inotuzumab ozogamicin; insulin aspart; insulin aspart protamine and insulin aspart; insulin degludec; insulin degludec and insulin aspart; insulin degludec and liraglutide; insulin detemir; insulin glargine; insulin glargine and lixisenatide; insulin glulisine; insulin human; insulin isophane human; insulin isophane human and insulin human; insulin lispro; insulin lispro protamine and insulin lispro; insulin lispro-aabc; interferon alfa-2a; interferon alfa-2b; interferon alfacon-1 ; interferon alfa-n3 (human leukocyte derived); interferon beta-1 a; interferon beta-1 b; interferon gamma-1 b; ipilimumab; isatuximab-irfc; ixekizumab; lanadelumab-flyo; laronidase; lixisenatide; luspatercept-aamt; mecasermin; mecasermin rinfabate; menotropins; mepolizumab; methoxy polyethylene glycol-epoetin beta; metreleptin; mogamulizumab-kpkc; moxetumomab pasudotox-tdfk; muromanab-CD3; natalizumab; necitumumab; nivolumab; nofetumomab; obiltoxaximab; obinutuzumab; ocrelizumab; ocriplasmin; ofatumumab; olaratumab; omalizumab; onabotulinumtoxinA; oprelvekin; palifermin; palivizumab; pancrelipase; panitumumab; parathyroid hormone; pegademase bovine; pegaspargase; pegfilgrastim; pegfilgrastim-apgf; pegfilgrastim-bmez; pegfilgrastim-cbqv; pegfilgrastim-jmdb; peginterferon alfa-2a; peginterferon alfa-2a and ribavirin; peginterferon alfa-2b; peginterferon alfa-2b and ribavirin; peginterferon beta-1 a; pegloticase; pegvaliase-pqpz; pegvisomant; pembrolizumab; pertuzumab; polatuzumab vedotin-piiq; poractant alfa; prabotulinumtoxinA-xvfs; radiolabeled albumin technetium Tc-99m albumin colloid kit; ramucirumab; ranibizumab; rasburicase; ravulizumab-cwvz; raxibacumab; reslizumab; reteplase; rilonacept; rimabotulinumtoxinB; risankizumab-rzaa; rituximab; rituximab and hyaluronidase human; rituximab-abbs; rituximab-Leydig 771696 50 pvvr; romiplostim; romosozumab-aqqg; sacituzumab govitecan-hziy; sacrosidase; sargramostim; sarilumab; sebelipase alfa; secukinumab; siltuximab; somatropin; tagraxofusp-erzs; taliglucerase alfa; tbo-filgrastim; technetium 99m tc fanolesomab; tenecteplase; teprotumumab-trbw; tesamorelin acetate; thyrotropin alfa; tildrakizumab- asmn; tocilizumab; tositumomab and iodine I-131 tositumomab; trastuzumab; trastuzumab and hyaluronidase-oysk; trastuzumab-anns; trastuzumab-dkst; trastuzumab-dttb; trastuzumab-pkrb; trastuzumab-qyyp; urofollitropin; urokinase; ustekinumab; vedolizumab; velaglucerase alfa; vestronidase alfa-vjbk; Ziv- Aflibercept; Amjevita (adalimumab-atto); Dupixent (dupilumab); Fulphila (pegfilgrastim-jmdb); llaris (canakinumab); Ixifi (infliximab-qbtx); Lyumjev (insulin lispro-aabc); Nyvepria (pegfilgrastim-apgf); Ogivri (trastuzumab-dkst); Semglee (insulin glargine); Uplizna (inebilizumab-cdon); A.P.L. (chorionic gonadotropin); Abrilada (adalimumab-afzb); Aduhelm (aducanumab-avwa); Accretropin (somatropin); Actemra (tocilizumab); Acthrel (corticorelin ovine triflutate); Actimmune (interferon gamma-1 b); Activase (alteplase); Adagen (pegademase bovine); Adakveo (crizanlizumab-tmca); Adbry (tralokinumab-ldrm); Adcetris (brentuximab vedotin); Adlyxin (lixisenatide); Admelog (insulin lispro); Afrezza (insulin human); Aimovig (erenumab-aooe); Ajovy (fremanezumab-vfrm); Aldurazyme (laronidase); Alferon N Injection (interferon alfa-n3 (human leukocyte derived)); Amevive (alefacept); Amphadase (hyaluronidase); Anthim (obiltoxaximab); Apidra (insulin glulisine); Aranesp (darbepoetin alpha); Arcalyst (rilonacept); Arzerra (ofatumumab); Asparlas (calaspargase pegol-mknl); Avastin (bevacizumab); Avonex (interferon beta-1a); Avsola (infliximab-axxq); Basaglar (insulin glargine); Bavencio (avelumab); Benlysta (belimumab); Beovu (brolucizumab-dbll); Besponsa (inotuzumab ozogamicin); Besremi (ropeginterferon-alfa-2b-njft); Betaseron (interferon beta-1 b); Bexxar (tositumomab and iodine I-131 tositumomab); Beyfortus (nirsevimab-alip); Bimzelx (bimekizumab); Blincyto (blinatumomab); Botox (onabotulinumtoxinA); Botox Cosmetic (onabotulinumtoxinA); Bravelle (urofollitropin); Brineura (cerliponase alfa); Briumvi (ublituximab-xiiy); Cablivi (caplacizumab-yhdp); Campath (alemtuzumab); Cathflo Activase (alteplase); Cerezyme (imiglucerase); Chorionic Gonadotropin (chorionic gonadotropin); Chromalbin (albumin chromated CR-51 serum); Chymodiactin (chymopapain); Cimzia (certolizumab pegol); Cinqair (reslizumab); Columvi (glofitamab- gxbm); Cosentyx (secukinumab); Cotazym (pancrelipase); Creon (pancrelipase); CrysvitaLeydig 771696 51 (burosumab- twza); Curosurf (poractant alfa); Cyltezo (adalimumab-adbm); Cyramza (ramucirumab); Darzalex (daratumumab); Darzalex Faspro (daratumumab and hyaluronidase- fihj); Daxxify (daxibotulinumtoixna-lanm); Draximage MAA (kit for the preparation of technetium Tc-99m albumin aggregated); Dysport (abobotulinumtoxinA); Egrifta (tesamorelin acetate); Egrifta SV (tesamorelin acetate); Elahere (mirvetuximab soravtansine-gynx); Elaprase (idursulfase); Elase-chloromycetin (fibrinolysin and desoxyribonuclease combined [bovine], with chloramphenicol); Elelyso (taliglucerase alfa); Elfabrio (pegunigalsidase alfa-iwxj); Elitek (rasburicase); Elrexfio (elranatamab-bcmm); Elspar (asparaginase); Elzonris (tagraxofusp-erzs); Emgality (galcanezumab-gnlm); Empliciti (elotuzumab); Enbrel (etanercept); Enbrel Mini (etanercept); Enhertu (fam-trastuzumab deruxetecan-nxki); Enjaymo (sutimlimab-jome); Entyvio (vedolizumab); Epkinly (epcoritamab-bysp); Epogen / Procrit (epoetin alfa); Erbitux (cetuximab); Erelzi (etanercept-szzs); Erelzi Sensoready (etanercept-szzs); Erwinaze (asparaginase Erwinia chrysanthemi); Eticovo (etanercept-ykro); Evenity (romosozumab-aqqg); Evkeeza (evinacumab- dgnb), Extavia (interferon beta-1b); Eylea (aflibercept); Fabrazyme (agalsidase beta); Fasenra (benralizumab); Fiasp (insulin aspart); Follistim (follitropin beta); Follistim AQ (follitropin beta); Follistim AQ Cartridge (follitropin beta); Gamifant (emapalumab-lzsg); Gazyva (obinutuzumab); Genotropin (somatropin); Gonal-f (follitropin alfa); Gonal-f RFF (follitropin alfa); Gonal-f RFF RediJect (follitropin alfa); Granix (tbo-filgrastim); Hadlima (adalimumab- bwwd); Hemlibra (emicizumab-kxwh); Herceptin (trastuzumab); Herceptin Hylecta (trastuzumab and hyaluronidase-oysk); Herzuma (trastuzumab-pkrb); Humalog (insulin lispro); Humalog Mix 50 / 50 (insulin lispro protamine and insulin lispro); Humalog Mix 75 / 25 (insulin lispro protamine and insulin lispro); Humatrope (somatropin); Humegon (menotropins); Humira (adalimumab); Humulin 70 / 30 (insulin isophane human and insulin human); Humulin N (insulin isophane human); Humulin RU-100 (insulin human); Humulin RU-500 (insulin human); Hydase (hyaluronidase); Hylenex recombinant (hyaluronidase human); Hyrimoz (adalimumab-adaz); llumya (tildrakizumab-asmn); Imfinzi (durvalumab); Imjudo (tremelimumab-actl); Increlex (mecasermin); Infasurf (calfactant); Infergen (interferon alfacon-1 ); Inflectra (infliximab- dyyb); Intron A (interferon alfa-2b); Iplex (mecasermin rinfabate); Iprivask (desirudin); Jeanatope (kit for iodinated 1-125 albumin); Jemperli (dostarlimab-gxly); Jetrea (ocriplasmin); Jeuveau (prabotulinumtoxinA-xvfs); Kadcyla (ado-trastuzumab emtansine); Kalbitor (ecallantide);Leydig 771696 52 Kanjinti (trastuzumab-anns); Kanuma (sebelipase alfa); Kepivance (palifermin); Kevzara (sarilumab); Keytruda (pembrolizumab); Kimmtrak (tebentafusp-tebn); Kineret (anakinra); Kinlytic (urokinase); Krystexxa (pegloticase); Lamzede (velmanase alfa-tycv); Lantus (insulin glargine); Lartruvo (olaratumab); Lemtrada (alemtuzumab); Leqembi (lecanemab-irmb); Leukine (sargramostim); Levemir (insulin detemir); Libtayo (cemiplimab- rwlc); Loqtorzi (toripalimab-tpzi); Lucentis (ranibizumab); Lumizyme (alglucosidase alfa); Lumoxiti (moxetumomab pasudotox-tdfk); Lunsumio (mosunetuzumab-axgb); Macrotec (kit for the preparation of technetium Tc-99m albumin aggregated); Megatope (kit for iodinated I-131 albumin); Menopur (menotropins); Mepsevii (vestronidase alfa-vjbk); Microlite (radiolabeled albumin technetium Tc-99m albumin colloid kit); Mircera (methoxy polyethylene glycol-epoetin beta); Mvasi (bevacizumab-awwb); Myalept (metreleptin); Mylotarg (gemtuzumab ozogamicin); Myobloc (rimabotulinumtoxinB); Myozyme (alglucosidase alfa); Myxredlin (insulin human); N / A (raxibacumab); Naglazyme (galsulfase); Natpara (parathyroid hormone); Neulasta (pegfilgrastim); Neulasta Onpro (pegfilgrastim); Neumega (oprelvekin); Neupogen (filgrastim); NeutroSpec (technetium 99m tc fanolesomab); Nexobrid (anacaulase-bcdb); Nexviazyme (avalglucosidase alfa-ngpt); Ngenla (somatrogon-ghla); Nivestym (filgrastim-aafi); Norditropin (somatropin); Novarel (chorionic gonadotropin); Novolin 70 / 30 (insulin isophane human and insulin human); Novolin N (insulin isophane human); Novolin R (insulin human); Novolog (insulin aspart); Novolog Mix 50 / 50 (insulin aspart protamine and insulin aspart); Novolog Mix 70 / 30 (insulin aspart protamine and insulin aspart); Nplate (romiplostim); Nucala (mepolizumab); Nulojix (belatacept); Nutropin (somatropin); Nutropin AQ (somatropin); Ocrevus (ocrelizumab); Omnitrope (somatropin); Omvoh (mirikizumab-mrkz); Oncaspar (pegaspargase); Ontak (denileukin diftitox); Ontruzant (trastuzumab-dttb); Opdivo (nivolumab); Opdualag (nivolumab and relatlimab-rmbw); Orencia (abatacept); Orthoclone OKT3 (muromanab-CD3); Ovidrel (choriogonadotropin alfa); Oxervate (cenegermin-bkbj); Padcev (enfortumab vedotin-ejfv); Palynziq (pegvaliase-pqpz); Pancreaze (pancrelipase); Pegasys (peginterferon alfa-2a); Pegasys Copegus Combination Pack (peginterferon alfa-2a and ribavirin); Pegintron (peginterferon alfa-2b); Peglntron / Rebetol Combo Pack (peginterferon alfa- 2b and ribavirin); Pergonal (menotropins); Perjeta (pertuzumab); Pertzye (pancrelipase); Plegridy (peginterferon beta-1a); Polivy (polatuzumab vedotin-piiq); Pombiliti (cipaglucosidaseLeydig 771696 53 alfa-atga); Portrazza (necitumumab); Poteligeo (mogamulizumab-kpkc); Praluent (alirocumab); Praxbind (idarucizumab); Pregnyl (chorionic gonadotropin); Procrit (epoetin alfa); Proleukin (aldesleukin); Prolia (denosumab); ProstaScint (capromab pendetide); Pulmolite (kit for the preparation of technetium Tc-99m albumin aggregated); Pulmotech MAA (kit for the preparation of technetium Tc-99m albumin aggregated); Pulmozyme (dornase alfa); Raptiva (efalizumab); Rebif (interferon beta-1a); Reblozyl (luspatercept-aamt); Regranex (becaplermin); Remicade (infliximab); Renflexis (infliximab-abda); Reopro (abciximab); Repatha (evolocumab); Repronex (menotropins); Retacrit (epoetin alfa-epbx); Retavase (reteplase); Revcovi (elapegademase-lvlr); Rituxan (rituximab); Rituxan Hycela (rituximab and hyaluronidase human); Roferon-A (interferon alfa-2a); Rolvedon (eflapegrastim-xnst); Ruxience (rituximab- pvvr); Rybrevant (amivantamab-vmjw); Rylaze (asparaginase erwinia chrysanthemi (recombinant)-rywn); Ryzneuta; Rystiggo (rozanolixizumab-noli); Ryzodeg 70 / 30 (insulin degludec and insulin aspart); Saizen (somatropin); Santyl (collagenase); Saphnelo (anifrolumab- fnia); Sarclisa (isatuximab-irfc); Serostim (somatropin); Siliq (brodalumab); Simponi (golimumab); Simponi Aria (golimumab); Simulect (basiliximab); Skyrizi (risankizumab-rzaa); Skytrofa (lonapegsomatropin-tcgd); Soliqua 100 / 33 (insulin glargine and lixisenatide); Soliris (eculizumab); Somavert (pegvisomant); Spevigo (spesolimab-sbzo); Stelara (ustekinumab); Strensiq (asfotas alfa); Sucraid (sacrosidase); Survanta (beractant); Susvimo (ranibizumab); Sylvant (siltuximab); Synagis (palivizumab); Takhzyro (lanadelumab-flyo); Taltz (ixekizumab); Talvey (talquetamab-tgvs); Tanzeum (albiglutide); Tecentriq (atezolizumab); Tecvayli (teclistamab-cqyv); Tepezza (teprotumumab- trbw); Tezspire (tezepelumab-ekko); Thyrogen (thyrotropin alfa); Tivdak (tisotumab vedotin-tftv); TNKase (tenecteplase); Toujeo (insulin glargine); Trasylol (aprotinin); Trazimera (trastuzumab-qyyp); Tremfya (guselkumab); Tresiba (insulin degludec); Trodelvy (sacituzumab govitecan-hziy); Trogarzo (ibalizumab-uiyk); Trulicity (dulaglutide); Truxima (rituximab-abbs); Tysabri (natalizumab); Tzield (teplizumab- mzwv); Udenyca (pegfilgrastim-cbqv); Ultomiris (ravulizumab-cwvz); Unituxin (dinutuximab); Vabysmo (faricimab-svoa); Vectibix (panitumumab); Veopoz (pozeilimab-bbfg); Verluma (nofetumomab); Vimizim (elosulfase alfa); Viokace (pancrelipase); Vitrase (hyaluronidase); Voraxaze (glucarpidase); VPRIV (velaglucerase alfa); Vyvgart (efgartigimod alfa-fcab); Vyvgart Hytrulo (efgartigimod alfa and hyaluronidase-qvfc); Xenpozyme (olipudase alfa-rpcp); XeominLeydig 771696 54 (incobotulinumtoxinA); Xgeva (denosumab); Xiaflex (collagenase Clostridium histolyticum); Xigris (drotrecogin alfa); Xolair (omalizumab); Xultophy 100 / 3.6 (insulin degludec and liraglutide); Yervoy (ipilimumab); Zaltrap (Ziv-Aflibercept); Zarxio (filgrastim-sndz); Zenapax (daclizumab); Zenpep (pancrelipase); Zevalin (ibritumomab tiuxetan); Ziextenzo (pegfilgrastim- bmez); Zinbryta (daclizumab); Zinplava (bezlotoxumab); Zirabev (bevacizumab-bvzr); Zomacton (somatropin); Zorbtive / Serostim (somatropin); Zymfentra (infliximab); Zynlonta (locastuximab tesirine-lpyl); or Zynyz (retifanlimab-dlwr).

43. The pharmaceutical container of any one of claims 38-42, wherein the pharmaceutical composition comprises a biologic for tumor necrosis, a factor- a interleukin inhibitor, a selective co-stimulation modulator, a glucagon-like peptide-1 (GLP-1) agonist or GLP-1 receptor agonist, an mRNA based formulation, an allergen, a tissue, a recombinant protein, a personalized medicine, a CAR-T cell thereapy medicine, a gene therapy medicine, or a biologic listed in the FDA Purple Book.

44. The pharmaceutical container of claim 43, wherein the personalized medicine is CAR-T medicine or a cell or gene therapy medicine.

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