BACKGROUND OF THE DISCLOSURE

Some high pH pharmaceutical formulations are stored in glass containers (e.g. vials and syringes) before use. One example of such formulations is fluorescein sodium used in ophthalmology and optometry for the diagnosis of corneal abrasions, corneal ulcers and herpetic corneal infections, and other ophthalmic diseases and conditions.

Intravenous or oral fluorescein is used in fluorescein angiography or angioscopy in diagnosis of vascular disorders including retinal disease macular degeneration, diabetic retinopathy, inflammatory intraocular conditions, and intraocular tumors. It is also being used increasingly during surgery for brain tumors. Diluted fluorescein dye has been used to localize multiple muscular ventricular septal defects during open heart surgery and confirm the presence of any residual defects.

SUMMARY OF THE DISCLOSURE

Provided in one aspect is a kit, comprising: an aqueous formulation comprising an active agent, wherein the formulation has a pH of from about 7 to about 11 (e.g. from about 8 to about 10); and a container holding the aqueous formulation, wherein the aqueous formulation is essentially free of dissolved glass prior to use. In some embodiments, the container is a glass container. In some embodiments, the container is a non-glass container.

In some embodiments, the aqueous formulation has a dissolved silicon concentration upon filling the container (Si_0w), and a dissolved silicon concentration after storage in the container at 60° C. for 10 weeks (Si_10w), wherein Si_10w/Si_0wis from 1 to 1.6.

In some embodiments, Si_10w/Si_0wis from 1 to 1.5. In some embodiments, Si_10w/Si_0wis from 1 to 1.4. In some embodiments, Si_10w/Si_0wis from 1 to 1.3. In some embodiments, Si_10w/Si_0wis from 1 to 1.25. In some embodiments, Si_10w/Si_0wis from 1 to 1.22.

In some embodiments, Si_10wis less than 14 mg/L. In some embodiments, Si_10wis less than 13.5 mg/L. In some embodiments, Si_10wis less than 13 mg/L. In some embodiments, Si_10wis less than 12.5 mg/L. In some embodiments, Si_10wis less than 12 mg/L. In some embodiments, Si_10wis less than 11.5 mg/L.

In some embodiments, the aqueous formulation has a dissolved boron concentration upon filling the container (B_0w), and a dissolved boron concentration after storage in the container at 60° C. for 10 weeks (B_10w), wherein B_10w/B_0wis from 1 to 1.9.

In some embodiments, B_10w/B_0wis from 1 to 1.8. In some embodiments, B_10w/B_0wis from 1 to 1.7. In some embodiments, B_10w/B_0wis from 1 to 1.6. In some embodiments, B_10w/B_0wis from 1 to 1.5. In some embodiments, B_10w/B_0wis from 1 to 1.4. In some embodiments, B_10w/B_0wis from 1 to 1.3.

In some embodiments, B_10wis less than 2.2 mg/L. In some embodiments, B_10wis less than 2.1 mg/L. In some embodiments, B_10wis less than 2.0 mg/L. In some embodiments, B_10wis less than 1.9 mg/L. In some embodiments, B_10wis less than 1.85 mg/L.

In some embodiments, the container has a bottom reaction zone upon filling the container (BTRZ_0w) of no more than 20 nm, and the container has a bottom reaction zone after storage in the glass container at 60° C. for 10 weeks (BTRZ_10w) of no more than 250 nm.

In some embodiments, BTRZ_10wis no more than 200 nm. In some embodiments, BTRZ_10wis no more than 180 nm. In some embodiments, BTRZ_10wis no more than 160 nm. In some embodiments, BTRZ_10wis no more than 150 nm. In some embodiments, BTRZ_10wis no more than 140 nm. In some embodiments, BTRZ_10wis no more than 130 nm. In some embodiments, BTRZ_10wis no more than 100 nm. In some embodiments, BTRZ_10wis no more than 50 nm. In some embodiments, BTRZ_10wis no more than 40 nm. In some embodiments, BTRZ_10wis no more than 30 nm. In some embodiments, BTRZ_10wis no more than 20 nm. In some embodiments, BTRZ_10wis no more than 10 nm.

In some embodiments, BTRZ_0wis no more than 30 nm. In some embodiments, BTRZ_0wis no more than 20 nm. In some embodiments, BTRZ_0wis no more than 10 nm.

In some embodiments, the container has a shoulder reaction zone upon filling the glass container (SHRZ_0w) of no more than 20 nm, and the container has a shoulder reaction zone after storage in the glass container at 60° C. for 10 weeks (SH_10w) of no more than 250 nm.

In some embodiments, the container has a shoulder reaction zone upon filling the glass container (SHRZ_0w) of no more than 20 nm, and the container has a shoulder reaction zone after storage in the container at 60° C. for 10 weeks (SH_10w) of no more than 200 nm.

In some embodiments, the container has a shoulder reaction zone upon filling the container (SHRZ_0w) of no more than 20 nm, and the container has a shoulder reaction zone after storage in the container at 60° C. for 10 weeks (SH_10w) of no more than 190 nm.

In some embodiments, the container has a shoulder reaction zone upon filling the container (SHRZ_0w) of no more than 20 nm, and the container has a shoulder reaction zone after storage in the container at 60° C. for 10 weeks (SH_10w) of no more than 180 nm.

In some embodiments, the container has a shoulder reaction zone upon filling the container (SHRZ_0w) of no more than 20 nm, and the container has a shoulder reaction zone after storage in the container at 60° C. for 10 weeks (SH_10w) of no more than 170 nm.

In some embodiments, the container has a shoulder reaction zone upon filling the container (SHRZ_0w) of no more than 20 nm, and the container has a shoulder reaction zone after storage in the container at 60° C. for 10 weeks (SH_10w) of no more than 160 nm.

In some embodiments, the container has a shoulder reaction zone upon filling the container (SHRZ_0w) of no more than 20 nm, and the container has a shoulder reaction zone after storage in the container at 60° C. for 10 weeks (SH_10w) of no more than 150 nm.

In some embodiments, the container has a shoulder reaction zone upon filling the container (SHRZ_0w) of no more than 20 nm, and the container has a shoulder reaction zone after storage in the container at 60° C. for 10 weeks (SH_10w) of no more than 140 nm.

In some embodiments, the container has a shoulder reaction zone upon filling the container (SHRZ_0w) of no more than 20 nm, and the container has a shoulder reaction zone after storage in the container at 60° C. for 10 weeks (SH_10w) of no more than 100 nm.

In some embodiments, the container has a shoulder reaction zone upon filling the container (SHRZ_0w) of no more than 20 nm, and the container has a shoulder reaction zone after storage in the container at 60° C. for 10 weeks (SH_10w) of no more than 80 nm.

In some embodiments, the container has a shoulder reaction zone upon filling the container (SHRZ_0w) of no more than 20 nm, and the container has a shoulder reaction zone after storage in the container at 60° C. for 10 weeks (SH_10w) of no more than 60 nm.

In some embodiments, the container has a shoulder reaction zone upon filling the container (SHRZ_0w) of no more than 20 nm, and the container has a shoulder reaction zone after storage in the container at 60° C. for 10 weeks (SH_10w) of no more than 50 nm.

In some embodiments, the aqueous formulation has a pH of from about 8.0 to about 10. In some embodiments, the aqueous formulation comprises at least one pH adjusting agent. In some embodiments, the at least one pH adjusting agent comprises sodium hydroxide, hydrochloric acid, or a combination thereof. In some embodiments, the aqueous formulation is a solution.

In some embodiments, the glass container is sealed. In some embodiments, the glass container has a fill volume of from 2 mL to 5 mL. In some embodiments, the glass container has a fill volume of 5 mL. In some embodiments, the glass container has a fill volume of 2 mL.

In some embodiments, the glass container comprises or incorporates at least one glass delamination control feature (GDCF).

In some embodiments, the at least one GDCF is selected from non-thermal terminal sterilization, aseptic filing without terminal sterilization, a non-glass coating (e.g. polymeric coating) on the interior surface of the glass, reduction of glass contact time, coupling with an filter for delaminated glass, use of non-glass material (e.g. plastic or polymer) to form the container, or combinations thereof.

In some embodiments, the at least one GDCF is non-thermal terminal sterilization selected from gamma radiation, Ebeam radiation, vaporized hydrogen peroxide, ethylene oxide, other non-thermal terminal sterilization, or combinations thereof.

In some embodiment, the at least one GDCF is aseptic filling without terminal sterilization. In some embodiments, the aseptic filling occurs in a pre-sterilized container.

In some embodiments, the at least one GDCF is the reduction of glass contact time selected from using a prefilled syringe, using a single-use ampule, using lyophilized active agent to be reconstituted with solvent/diluent in the container prior to use, using pre-sterlized active agent to be reconstituted with solvent/diluent in the container prior to use or combinations thereof.

In some embodiments, the at least one GDCF is a filter for delaminated glass couple to a distal end of the container (e.g. syringe). In some embodiment, the filter for delaminated glass is an external filter attached to the lure lock system of a syringe or otherwise affixed directly to the syringe. In some embodiments, the at least one GDCF is a filter for delaminated glass disposed within the container (e.g. a prefilled syringe). In some embodiment, the at least one GDCF is IV tubing with an in-line filter.

In some embodiments, the aqueous formulation comprises from about 70 mg/mL to about 130 mg/mL of fluorescein sodium as the active agent. In some embodiments, the aqueous formulation comprises from about 90 mg/mL to about 110 mg/mL of fluorescein sodium as the active agent. In some embodiments, the aqueous formulation comprises about 100 mg/mL of fluorescein sodium as the active agent.

In some embodiments, the aqueous formulation comprising from about 200 mg/mL to about 300 mg/mL of fluorescein sodium as the active agent. In some embodiments, the aqueous formulation comprises from about 230 mg/mL to about 270 mg/mL of fluorescein sodium as the active agent. In some embodiments, the aqueous formulation comprises about 250 mg/mL of fluorescein sodium as the active agent.

In some embodiment, the active agent is not fluorescein sodium.

In some embodiments, the formulation is suitable for injection. In some embodiments, the formulation is suitable for intravenous injection.

BRIEF DESCRIPTION OF DRAWINGS

The objects and features of the present can be better understood with reference to the following detailed description and accompanying drawings.

FIG. 1 illustrates a conventional vial, and shows the shoulder-body transition angle (β) and the shoulder-neck transition angle (α) of the vial;

FIG. 2 illustrates another conventional vial, and shows the shoulder-body transition angle (β) and the shoulder-neck transition angle (α) of the vial;

FIG. 3 illustrates one embodiment of a vial according to the present disclosure, and shows the shoulder-body transition angle (β) and the shoulder-neck transition angle (α) of the vial;

FIG. 4 illustrates another embodiment of a vial according to the present disclosure, and shows the shoulder-body transition angle (β) and the shoulder-neck transition angle (α) of the vial;

FIG. 5 illustrates another embodiment of a vial according to the present disclosure, and shows the shoulder-body transition angle (β) and the shoulder-neck transition angle (α) of the vial;

FIG. 6 illustrates visual and optical inspection of a sample vial unrelated to the present disclosure;

FIG. 7 illustrates SEM analysis of a sample vial unrelated to the present disclosure;

FIG. 8 illustrates ICP analysis of a sample vial unrelated to the present disclosure;

FIG. 9 illustrates visual and optical inspection of a sample vial according to one embodiment of the present disclosure;

FIG. 10 illustrates visual and optical inspection of a sample vial according to one embodiment of the present disclosure;

FIG. 11 illustrates SEM analysis of a sample vial according to one embodiment of the present disclosure;

FIG. 12 illustrates SEM analysis of a sample vial according to one embodiment of the present disclosure;

FIG. 13 illustrates SEM analysis of a sample vial according to one embodiment of the present disclosure;

FIG. 14 illustrates SEM analysis of a sample vial according to one embodiment of the present disclosure;

FIG. 15 illustrates SEM analysis of a sample vial according to one embodiment of the present disclosure;

FIG. 16 illustrates SEM analysis of a sample vial according to one embodiment of the present disclosure; and

FIG. 17 illustrates SEM analysis of a sample vial according to one embodiment of the present disclosure.

INCORPORATION BY REFERENCE

All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

DETAILED DESCRIPTION OF THE DISCLOSURE
Certain Terminology

As used herein, the term “about” is used synonymously with the term “approximately.” Illustratively, the use of the term “about” with regard to a specific amount indicates values slightly outside the cited values, e.g., plus or minus 0.1% to 10%. In some embodiments, “about” indicates values that are plus or minus 10%.

The term “acceptable” with respect to a formulation, composition or ingredient, as used herein, means having no persistent detrimental effect on the general health of the subject being treated.

The term “carrier,” as used herein, refers to relatively nontoxic chemical compounds or agents that facilitate the incorporation of a compound into cells or tissues.

The terms “co-administration” or the like, as used herein, are meant to encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are administered by the same or different route of administration or at the same or different time.

The term “diluent” refers to chemical compounds that are used to dilute the compound of interest prior to delivery. Diluents can also be used to stabilize compounds because they can provide a more stable environment. Salts dissolved in buffered solutions (which also can provide pH control or maintenance) are utilized as diluents in the art, including, but not limited to a phosphate buffered saline solution.

The terms “effective amount” or “therapeutically effective amount,” as used herein, refer to a sufficient amount of an agent or a compound being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result can be reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an “effective amount” for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms. An appropriate “effective” amount in any individual case may be determined using techniques, such as a dose escalation study.

The terms “enhance” or “enhancing,” as used herein, means to increase or prolong either in potency or duration a desired effect. Thus, in regard to enhancing the effect of therapeutic agents, the term “enhancing” refers to the ability to increase or prolong, either in potency or duration, the effect of other therapeutic agents on a system. An “enhancing-effective amount,” as used herein, refers to an amount adequate to enhance the effect of another therapeutic agent in a desired system.

The term “subject” or “patient” encompasses mammals. Examples of mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. In one embodiment, the mammal is a human.

The terms “treat,” “treating” or “treatment,” as used herein, include alleviating, abating or ameliorating at least one symptom of a disease or condition, preventing additional symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition either prophylactically and/or therapeutically.

Provided herein are kits for fluorescein or fluorescein sodium that have reduced amount of delamination or glass attack on the vial, and/or the resulting delaminated glass impurities in the formulation. In some embodiment, the kit has reduced amount of delamination or glass attack on the vial, and/or the resulting delaminated glass impurities in the formulation after storage conditions, e.g. 10 weeks of storage at about 60° C.

Active Agent

Many active agents are formulated into an aqueous solution having a pH of from about 7 to about 11 (e.g. from about 8 to about 10). One example is fluorescein that has been used as a disclosing agent. Fluorescein sodium is the sodium salt of fluorescein and has a molecular formula of C₂₀H₁₀Na₂O₅, molecular weight of 376.28, and the following chemical structure:

[Image Omitted]

The chemical name for fluorescein sodium is spiro[isobenzofuran-1(3H), 9′-[9H]xanthene]-3-one, 3′6′-dihydroxy, disodium salt.

In some embodiments, the fluorescein component of the compositions described herein is fluorescein or the pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutically acceptable salt of fluorescein is a sodium salt.

High pH Formulations

In some embodiments, the aqueous formulation has a pH of from about 7.5 to about 11. In some embodiments, the aqueous formulation has a pH of from about 7.5 to about 10.5. In some embodiments, the aqueous formulation has a pH of from about 7.5 to about 10. In some embodiments, the aqueous formulation has a pH of from about 7.5 to about 9.5. In some embodiments, the aqueous formulation has a pH of from about 7.5 to about 9. In some embodiments, the aqueous formulation has a pH of from about 7.5 to about 8.5. In some embodiments, the aqueous formulation has a pH of from about 7.5 to about 8.

In some embodiments, the aqueous formulation has a pH of from about 8 to about 11. In some embodiments, the aqueous formulation has a pH of from about 8 to about 10.5. In some embodiments, the aqueous formulation has a pH of from about 8 to about 10. In some embodiments, the aqueous formulation has a pH of from about 8 to about 9.5. In some embodiments, the aqueous formulation has a pH of from about 8 to about 9. In some embodiments, the aqueous formulation has a pH of from about 8 to about 8.5.

In some embodiments, the aqueous formulation has a pH of from about 8.5 to about 11. In some embodiments, the aqueous formulation has a pH of from about 8.5 to about 10.5. In some embodiments, the aqueous formulation has a pH of from about 8.5 to about 10. In some embodiments, the aqueous formulation has a pH of from about 8.5 to about 9.5. In some embodiments, the aqueous formulation has a pH of from about 8.5 to about 9.

In some embodiments, the aqueous formulation has a pH of from about 9 to about 11. In some embodiments, the aqueous formulation has a pH of from about 9 to about 10.5. In some embodiments, the aqueous formulation has a pH of from about 9 to about 10. In some embodiments, the aqueous formulation has a pH of from about 9 to about 9.5.

In some embodiments, the aqueous formulation has a pH of from about 9.5 to about 11. In some embodiments, the aqueous formulation has a pH of from about 9.5 to about 10.5. In some embodiments, the aqueous formulation has a pH of from about 9.5 to about 10.

In some embodiments, the aqueous formulation has a pH of from about 10 to about 11. In some embodiments, the aqueous formulation has a pH of from about 10 to about 10.5. In some embodiments, the aqueous formulation has a pH of from about 10.5 to about 11.

In some embodiments, the aqueous formulation comprises at least one pH adjusting agent. In some embodiments, the at least one pH adjusting agent comprises sodium hydroxide, hydrochloric acid, or a combination thereof. In some embodiments, the aqueous formulation is a solution.

In some embodiments, the aqueous formulation comprises from about 70 mg/mL to about 130 mg/mL of fluorescein. In some embodiments, the aqueous formulation comprises from about 90 mg/mL to about 110 mg/mL of fluorescein. In some embodiments, the aqueous formulation comprises about 100 mg/mL of fluorescein.

In some embodiments, the aqueous formulation comprises from about 200 mg/mL to about 300 mg/mL of fluorescein. In some embodiments, the aqueous formulation comprising from about 230 mg/mL to about 270 mg/mL of fluorescein. In some embodiments, the aqueous formulation comprises about 250 mg/mL of fluorescein.

Glass Container

In some embodiments, the glass vial is sealed. In some embodiments, the glass vial has a fill volume of from 2 mL to 5 mL. In some embodiments, the glass vial has a fill volume of 5 mL. In some embodiments, the glass vial has a fill volume of 2 mL.

Conventional Vial

Referring to FIGS. 1-2, two conventional vials (100) for injectable products are illustrated as having a neck portion (110) including a cylindrical neck wall (111) and a body portion (130) including a cylindrical body wall (131). The cylindrical body wall (131) has a diameter large than a diameter of the cylindrical neck wall (111). The vials further include a shoulder portion (120) that interconnects the neck and body portions (110, 130). The shoulder portion (120) includes a frustoconical shoulder wall (121) that extends toward the cylindrical body wall (131) at a transition angle (β) of less than 120°. The frustoconical shoulder wall (121) also extends toward the cylindrical neck wall (111) at a transition angle (α) of less than 120°.

As illustrated in FIG. 1, the shoulder-body transition angle (β) of the conventional vial is close to 90°; and the shoulder-neck transition angle (α) of the conventional vial is also close to 90°. As illustrated in FIG. 2, the shoulder-body transition angle (β) of the conventional vial is close to 110°; and the shoulder-neck transition angle (α) of the conventional vial is also close to 110°.

Improved Vials—General

Referring to FIGS. 3-5, improved vials according to certain aspects of the present disclosure are illustrated as having a neck portion including a cylindrical neck wall and a body portion including a cylindrical body wall. The cylindrical body wall has a diameter larger than a diameter of the cylindrical neck wall. The improved bottle further includes a shoulder portion that interconnects the neck and body portions. The shoulder portion includes a frustoconical shoulder wall that extends toward the cylindrical body wall at a transition angle (β) of at least 120°. The frustoconical shoulder wall also extends toward the cylindrical neck wall at a transition angle (α) of at least 120°.

Improved Vials—Shoulder-Body Transition Angle (β)

In some embodiments, the frustoconical shoulder wall extends toward the cylindrical body wall at a transition angle of between 120°-170°. In some embodiments, the frustoconical shoulder wall extends toward the cylindrical body wall at a transition angle of between 125°-170°. In some embodiments, the frustoconical shoulder wall extends toward the cylindrical body wall at a transition angle of between 130°-170°. In some embodiments, the frustoconical shoulder wall extends toward the cylindrical body wall at a transition angle of between 135°-170°. In some embodiments, the frustoconical shoulder wall extends toward the cylindrical body wall at a transition angle of between 140°-170°. In some embodiments, the frustoconical shoulder wall extends toward the cylindrical body wall at a transition angle of between 150°-170°. In some embodiments, the frustoconical shoulder wall extends toward the cylindrical body wall at a transition angle of between 160°-170° (e.g. FIG. 5).

In some embodiments, the frustoconical shoulder wall extends toward the cylindrical body wall at a transition angle of between 120°-160°. In some embodiments, the frustoconical shoulder wall extends toward the cylindrical body wall at a transition angle of between 125°-160°. In some embodiments, the frustoconical shoulder wall extends toward the cylindrical body wall at a transition angle of between 130°-160°. In some embodiments, the frustoconical shoulder wall extends toward the cylindrical body wall at a transition angle of between 135°-160°. In some embodiments, the frustoconical shoulder wall extends toward the cylindrical body wall at a transition angle of between 140°-160°. In some embodiments, the frustoconical shoulder wall extends toward the cylindrical body wall at a transition angle of between 150°-160° (e.g. FIG. 4).

In some embodiments, the frustoconical shoulder wall extends toward the cylindrical body wall at a transition angle of between 120°-150°. In some embodiments, the frustoconical shoulder wall extends toward the cylindrical body wall at a transition angle of between 125°-150°. In some embodiments, the frustoconical shoulder wall extends toward the cylindrical body wall at a transition angle of between 130°-150°. In some embodiments, the frustoconical shoulder wall extends toward the cylindrical body wall at a transition angle of between 135°-150°. In some embodiments, the frustoconical shoulder wall extends toward the cylindrical ne body ck wall at a transition angle of between 140°-150°.

In some embodiments, the frustoconical shoulder wall extends toward the cylindrical body wall at a transition angle of between 120°-140°. In some embodiments, the frustoconical shoulder wall extends toward the cylindrical body wall at a transition angle of between 125°-140°. In some embodiments, the frustoconical shoulder wall extends toward the cylindrical body wall at a transition angle of between 130°-140°. In some embodiments, the frustoconical shoulder wall extends toward the cylindrical body wall at a transition angle of between 135°-140° (e.g. FIG. 3).

Improved Vials—Shoulder-Neck Transition Angle (α)

In some embodiments, the frustoconical shoulder wall extends toward the cylindrical neck wall at a transition angle of between 120°-170°. In some embodiments, the frustoconical shoulder wall extends toward the cylindrical neck wall at a transition angle of between 125°-170°. In some embodiments, the frustoconical shoulder wall extends toward the cylindrical neck wall at a transition angle of between 130°-170°. In some embodiments, the frustoconical shoulder wall extends toward the cylindrical neck wall at a transition angle of between 135°-170°. In some embodiments, the frustoconical shoulder wall extends toward the cylindrical neck wall at a transition angle of between 140°-170°. In some embodiments, the frustoconical shoulder wall extends toward the cylindrical neck wall at a transition angle of between 150°-170°. In some embodiments, the frustoconical shoulder wall extends toward the cylindrical neck wall at a transition angle of between 160°-170° (e.g. FIG. 5).

In some embodiments, the frustoconical shoulder wall extends toward the cylindrical neck wall at a transition angle of between 120°-160°. In some embodiments, the frustoconical shoulder wall extends toward the cylindrical neck wall at a transition angle of between 125°-160°. In some embodiments, the frustoconical shoulder wall extends toward the cylindrical neck wall at a transition angle of between 130°-160°. In some embodiments, the frustoconical shoulder wall extends toward the cylindrical neck wall at a transition angle of between 135°-160°. In some embodiments, the frustoconical shoulder wall extends toward the cylindrical neck wall at a transition angle of between 140°-160°. In some embodiments, the frustoconical shoulder wall extends toward the cylindrical neck wall at a transition angle of between 150°-160° (e.g. FIG. 4).

In some embodiments, the frustoconical shoulder wall extends toward the cylindrical neck wall at a transition angle of between 120°-150°. In some embodiments, the frustoconical shoulder wall extends toward the cylindrical neck wall at a transition angle of between 125°-150°. In some embodiments, the frustoconical shoulder wall extends toward the cylindrical neck wall at a transition angle of between 130°-150°. In some embodiments, the frustoconical shoulder wall extends toward the cylindrical neck wall at a transition angle of between 135°-150°. In some embodiments, the frustoconical shoulder wall extends toward the cylindrical neck wall at a transition angle of between 140°-150°.

In some embodiments, the frustoconical shoulder wall extends toward the cylindrical neck wall at a transition angle of between 120°-140°. In some embodiments, the frustoconical shoulder wall extends toward the cylindrical neck wall at a transition angle of between 125°-140°. In some embodiments, the frustoconical shoulder wall extends toward the cylindrical neck wall at a transition angle of between 130°-140° (e.g. FIG. 3). In some embodiments, the frustoconical shoulder wall extends toward the cylindrical neck wall at a transition angle of between 135°-140°.

In some embodiments, the glass vial is a Schott DC vial. In some embodiments, the glass vial is made from Fiolax glass and comprises a strengthened shoulder to reduce delamination.

Glass Delamination/Contamination

Glass vials used for injectable products generally come in two manufacturing formats—molded or tubular. Molded vials are less common and more expensive. The manufacturer molds the vial in one piece by pouring liquid glass into a mold. Tubular vials are manufactured by cutting glass tubes, then forming the tube into the desired shape using heat in an automated process called converting. It is generally believed that molded vials are more resistant to delamination.

There is also a variant of tubular vials called Delamination Control (DC) where the heating/forming/converting process is fine tuned to reduce the likelihood of delamination, such as by removing debris of glass attached to the tube caused by the cutting process. Additionally, the tubes can be made with special glass to reduce delamination.

Example 1 shows key protocols and parameters for glass delamination studies, some of which are used in the present disclosure.

Glass Delamination/Contamination in Fluorescein Product Kits

The present disclosure recognizes that glass vials that contain fluorescein or fluorescein sodium formulations have delamination or glass attack on the vial during storage, which can result in delaminated, dissociated, and/or dissolved glass impurities in the formulations before the formulations are used, for example through intravenous injection.

Referring to Example 2, which includes a delamination/contamination study of 10% fluorescein sodium product kit currently on the market (RLD; 5 mL molded glass vials). Example 4 also includes a study of 10% fluorescein sodium in modified vials that are converted from tubular glass from Schott (Fortis; 5 mL tubular glass vials). Unexpectedly, the RLD product exhibited evidence of delamination at time 0 (i.e. upon filling with the 10% fluorescein sodium bulk solution). Also, the Fortis vial unexpectedly showed early evidence of delamination after 5 weeks storage at 60° C.

Referring now to Example 3, which includes a delamination/contamination study of 10% fluorescein sodium in three glass vials—(1) Piramal molded vial, (2) Schott tubular vial, and (3) Schott tubular DC vial. While the DC vial performed better than the other two vials, all three showed evidence of glass attack and early indicators of delamination after only 2.5 weeks at 60° C.

Fluorescein Product Kits with Improved Glass Delamination/Contamination

Referencing now to Example 6, which includes a delamination/contamination study of 10% fluorescein sodium in improved glass vials. In this non-limiting example, the improved glass vial is made with Fiolax glass and has a strengthened shoulder to make it more delamination resistant. Without wishing to be bound by any particular theory, it is contemplated that while the formulation in the glass vial may not reach the shoulder area of the vial throughout the storage time period, a strengthened shoulder would contribute to reduce the delamination/contamination of the vial during storage, an insight heretofore unknown. As shown in Example 4 and summarized below, evidence of delamination was only observed after 10 weeks at 60° C. indicating the improved vial with strengthened shoulder performed better than the commercial fluorescein product kits and conventional glass vials, including those designed to resist delamination (e.g. Schott's DC vials).

Silicon in Formulation

In some embodiments, the aqueous formulation has a dissolved silicon concentration upon filling the glass vial (Si_0w), and a dissolved silicon concentration after storage in the glass vial at 60° C. for 10 weeks (Si_10w), wherein Si_10w/Si_0wis from 1 to 1.6.

In some embodiments, Si_10w/Si_0wis from 1 to 1.5. In some embodiments, Si_10w/Si_0wis from 1 to 1.4. In some embodiments, Si_10w/Si_0wis from 1 to 1.3. In some embodiments, Si_10w/Si_0wis from 1 to 1.25. In some embodiments, Si_10w/Si_0wis from 1 to 1.22.

In some embodiments, Si_10w/Si_0wis Si_10wis less than 14 mg/L. In some embodiments, Si_10wJ/Si_0wis Si_10wis less than 13.5 mg/L. In some embodiments, Si_10w/Si_0wis Si_10wis less than 13 mg/L. In some embodiments, Si_10w/Si_0wis Si_10wis less than 12.5 mg/L. In some embodiments, Si_10w/Si_0wis Si_10wis less than 12 mg/L. In some embodiments, Si_10w/Si_0wis Show is less than 11.5 mg/L.

Boron in Formulation

In some embodiments, the aqueous formulation has a dissolved boron concentration upon filling the glass vial (B_0w), and a dissolved boron concentration after storage in the glass vial at 60° C. for 10 weeks (B_10w), wherein Si_10w/Si_0wis from 1 to 1.9.

In some embodiments, B_10w/B_0wis from 1 to 1.8. In some embodiments, B_10w/B_0wis from 1 to 1.7. In some embodiments, B_10w/B_0wis from 1 to 1.6. In some embodiments, B_10w/B_0wis from 1 to 1.5. In some embodiments, B_10w/B_0wis from 1 to 1.4. In some embodiments, B_10w/B_0wis from 1 to 1.3.

In some embodiments, B_10wis less than 2.2 mg/L. In some embodiments, B_10wis less than 2.1 mg/L. In some embodiments, B_10wis less than 2.0 mg/L. In some embodiments, B_10wis less than 1.9 mg/L. In some embodiments, B_10wis less than 1.85 mg/L.

In some embodiments, the formulation is essentially free of boron. In some embodiments, the formulation is free of boron.

In some embodiments, the glass vial is a boron-free glass vial. In some embodiments, the glass vial is an aluminosilicate glass vial. In some embodiments, the glass vial is made of Corning Valor® glass. In some embodiments, the glass vial is made of Corning Valor® glass.

Silicon and Boron in Formulation

In some embodiments, the aqueous formulation has a dissolved silicon concentration upon filling the glass vial (Si_0w), and a dissolved silicon concentration after storage in the glass vial at 60° C. for 10 weeks (Si_10w), wherein Si_10w/Si_0wis from 1 to 1.6; and the aqueous formulation has a dissolved boron concentration upon filling the glass vial (B_0w), and a dissolved boron concentration after storage in the glass vial at 60° C. for 10 weeks (B_10w), wherein Si_10w/Si_0wis from 1 to 1.9.

In some embodiments, Si_10w/Si_0wis from 1 to 1.5. In some embodiments, Si_10w/Si_0wis from 1 to 1.4. In some embodiments, Si_10w/Si_0wis from 1 to 1.3. In some embodiments, Si_10w/Si_0wis from 1 to 1.25. In some embodiments, Si_10w/Si_0wis from 1 to 1.22. In some embodiments, Si_10w/Si_0wis Show is less than 14 mg/L. In some embodiments, Si_10w/Si_0wis Si_10wis less than 13.5 mg/L. In some embodiments, Si_10w/Si_0wis Si_10wis less than 13 mg/L. In some embodiments, Si_10w/Si_0wis Si_10wis less than 12.5 mg/L. In some embodiments, Si_10w/Si_0wis Si_10wis less than 12 mg/L. In some embodiments, Si_10w/Si_0wis Si_10wis less than 11.5 mg/L.

In some embodiments, B_10w/B_0wis from 1 to 1.8. In some embodiments, B_10w/B_0wis from 1 to 1.7. In some embodiments, B_10w/B_0wis from 1 to 1.6. In some embodiments, B_10w/B_0wis from 1 to 1.5. In some embodiments, B_10w/B_0wis from 1 to 1.4. In some embodiments, B_10w/B_0wis from 1 to 1.3. In some embodiments, B_10wis less than 2.2 mg/L. In some embodiments, B_10wis less than 2.1 mg/L. In some embodiments, B_10wis less than 2.0 mg/L. In some embodiments, B_10wis less than 1.9 mg/L. In some embodiments, B_10wis less than 1.85 mg/L.

Bottom Reaction Zone

In some embodiments, the glass vial has a bottom reaction zone upon filling the glass vial (BTRZ_0w) of no more than 20 nm, and the glass vial has a bottom reaction zone after storage in the glass vial at 60° C. for 10 weeks (BTRZ_10w) of no more than 250 nm.

In some embodiments, BTRZ_10wis no more than 200 nm. In some embodiments, BTRZ_10wis no more than 180 nm. In some embodiments, BTRZ_10wis no more than 160 nm. In some embodiments, BTRZ_10wis no more than 150 nm. In some embodiments, BTRZ_10wis no more than 140 nm. In some embodiments, BTRZ_10wis no more than 130 nm. In some embodiments, BTRZ_10wis no more than 100 nm. In some embodiments, BTRZ_10wis no more than 50 nm. In some embodiments, BTRZ_10wis no more than 40 nm. In some embodiments, BTRZ_10wis no more than 30 nm. In some embodiments, BTRZ_10wis no more than 20 nm. In some embodiments, BTRZ_10wis no more than 10 nm.

In some embodiments, BTRZ_0wis no more than 30 nm. In some embodiments, BTRZ_0wis no more than 20 nm. In some embodiments, BTRZ_0wis no more than 10 nm.

Shoulder Reaction Zone

In some embodiments, the glass vial has a shoulder reaction zone upon filling the glass vial (SHRZ_0w) of no more than 20 nm, and the glass vial has a shoulder reaction zone after storage in the glass vial at 60° C. for 10 weeks (SH_10w) of no more than 250 nm.

In some embodiments, the glass vial has a shoulder reaction zone upon filling the glass vial (SHRZ_0w) of no more than 20 nm, and the glass vial has a shoulder reaction zone after storage in the glass vial at 60° C. for 10 weeks (SH_10w) of no more than 200 nm.

In some embodiments, the glass vial has a shoulder reaction zone upon filling the glass vial (SHRZ_0w) of no more than 20 nm, and the glass vial has a shoulder reaction zone after storage in the glass vial at 60° C. for 10 weeks (SH_10w) of no more than 190 nm.

In some embodiments, the glass vial has a shoulder reaction zone upon filling the glass vial (SHRZ_0w) of no more than 20 nm, and the glass vial has a shoulder reaction zone after storage in the glass vial at 60° C. for 10 weeks (SH_10w) of no more than 180 nm.

In some embodiments, the glass vial has a shoulder reaction zone upon filling the glass vial (SHRZ_0w) of no more than 20 nm, and the glass vial has a shoulder reaction zone after storage in the glass vial at 60° C. for 10 weeks (SH_10w) of no more than 170 nm.

In some embodiments, the glass vial has a shoulder reaction zone upon filling the glass vial (SHRZ_0w) of no more than 20 nm, and the glass vial has a shoulder reaction zone after storage in the glass vial at 60° C. for 10 weeks (SH_10w) of no more than 160 nm.

In some embodiments, the glass vial has a shoulder reaction zone upon filling the glass vial (SHRZ_0w) of no more than 20 nm, and the glass vial has a shoulder reaction zone after storage in the glass vial at 60° C. for 10 weeks (SH_10w) of no more than 150 nm.

In some embodiments, the glass vial has a shoulder reaction zone upon filling the glass vial (SHRZ_0w) of no more than 20 nm, and the glass vial has a shoulder reaction zone after storage in the glass vial at 60° C. for 10 weeks (SH_10w) of no more than 140 nm.

In some embodiments, the glass vial has a shoulder reaction zone upon filling the glass vial (SHRZ_0w) of no more than 20 nm, and the glass vial has a shoulder reaction zone after storage in the glass vial at 60° C. for 10 weeks (SH_10w) of no more than 100 nm.

In some embodiments, the glass vial has a shoulder reaction zone upon filling the glass vial (SHRZ_0w) of no more than 20 nm, and the glass vial 80 nm.

In some embodiments, the glass vial has a shoulder reaction zone upon filling the glass vial (SHRZ_0w) of no more than 20 nm, and the glass vial has a shoulder reaction zone after storage in the glass vial at 60° C. for 10 weeks (SH_10w) of no more than 60 nm.

In some embodiments, the glass vial has a shoulder reaction zone upon filling the glass vial (SHRZ_0w) of no more than 20 nm, and the glass vial has a shoulder reaction zone after storage in the glass vial at 60° C. for 10 weeks (SH_10w) of no more than 50 nm.

Glass Delamination Control Feature (GDCF)

Without wishing to be bound by any particular theory, it is contemplated herein that one of combinations of certain glass delamination control features reduce, alleviate, or altogether prevent glass delamination, in certain embodiments.

In some embodiments, the at least one GDCF is selected from non-thermal terminal sterilization, aseptic filing without terminal sterilization, a non-glass coating (e.g. polymeric coating) on the interior surface of the glass, reduction of glass contact time, coupling with an filter for delaminated glass, use of non-glass material (e.g. plastic or polymer) to form the container, or combinations thereof.

In some embodiments, the at least one GDCF is non-thermal terminal sterilization selected from gamma radiation, Ebeam radiation, vaporized hydrogen peroxide, ethylene oxide, other non-thermal terminal sterilization, or combinations thereof.

In some embodiment, the at least one GDCF is aseptic filling without terminal sterilization. In some embodiments, the aseptic filling occurs in a pre-sterilized container.

In some embodiments, the at least one GDCF is the reduction of glass contact time selected from using a prefilled syringe, using a single-use ampule, using lyophilized active agent to be reconstituted with solvent/diluent in the container prior to use, using pre-sterlized active agent to be reconstituted with solvent/diluent in the container prior to use or combinations thereof.

In some embodiments, the at least one GDCF is a filter for delaminated glass couple to a distal end of the container (e.g. syringe). In some embodiment, the filter for delaminated glass is an external filter attached to the lure lock system of a syringe or otherwise affixed directly to the syringe. In some embodiments, the at least one GDCF is a filter for delaminated glass disposed within the container (e.g. a prefilled syringe). In some embodiment, the at least one GDCF is IV tubing with an in-line filter.

General Methods of Sterilization

Pharmaceutical compositions sometimes need to be sterilized for specific medical or therapeutic applications. The goal is to provide a safe pharmaceutical product, relatively free of infection causing micro-organisms. The U. S. Food and Drug Administration has provided regulatory guidance in the publication “Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing” available at: http://www.fda.gov/cder/guidance/5882fnl.htm, which is incorporated herein by reference in its entirety.

As used herein, sterilization means a process used to destroy or remove microorganisms that are present in a product or packaging. Any suitable method available for sterilization of objects and compositions is used. In some embodiment, a process for the preparation of the in formulation comprises subjecting the formulation to a sterilization method selected from heat sterilization, chemical sterilization, radiation sterilization or filtration sterilization. The method used depends largely upon the nature of the device or composition to be sterilized. Detailed descriptions of many methods of sterilization are given in Chapter 40 of Remington: The Science and Practice of Pharmacy published by Lippincott, Williams & Wilkins, and is incorporated by reference with respect to this subject matter.

Radiation Sterilization

One advantage of radiation sterilization is the ability to sterilize many types of products without heat degradation or other damage. The radiation commonly employed is beta radiation or alternatively, gamma radiation from a ⁶⁰Co source. The penetrating ability of gamma radiation allows its use in the sterilization of many product types, including solutions, compositions and heterogeneous mixtures. The germicidal effects of irradiation arise from the interaction of gamma radiation with biological macromolecules. This interaction generates charged species and free radicals. Subsequent chemical reactions, such as rearrangements and cross-linking processes, result in the loss of normal function for these biological macromolecules. The formulations described herein are also optionally sterilized using beta irradiation. Electron beam (E-beam) irradiation or electron irradiation is a process which involves using electrons, usually of high energy, to treat an object for a variety of purposes. This may take place under elevated temperatures and nitrogen atmosphere. Possible uses for electron irradiation include sterilization. Electron beam processing has the ability to break the chains of DNA in living organisms, such as bacteria, resulting in microbial death and rendering the space they inhabit sterile. E-beam irradiation has been used for the sterilization of medical products and aseptic packaging materials for foods as well as disinfestation, the elimination of live insects from grain, tobacco, and other unprocessed bulk crops. In some embodiments, sterilization with electrons provides quick and reliable sterilization, is compatible with most materials, and does not require any quarantine following the processing. For some materials and products that are sensitive to oxidative effects, radiation tolerance levels for electron beam irradiation may be higher than for gamma exposure. This is due to the higher dose rates and shorter exposure times of e-beam irradiation which have been shown to reduce the degradative effects of oxygen.

Chemical Sterilization

Chemical sterilization methods are an alternative for products that do not withstand the extremes of heat sterilization. In this method, a variety of gases and vapors with germicidal properties, such as ethylene oxide, chlorine dioxide, formaldehyde or ozone are used as the anti-apoptotic agents. The germicidal activity of ethylene oxide, for example, arises from its ability to serve as a reactive alkylating agent. Thus, the sterilization process requires the ethylene oxide vapors to make direct contact with the product to be sterilized.

Filtration Sterilization

Filtration sterilization is a method used to remove but not destroy microorganisms from solutions. Membrane filters are used to filter heat-sensitive solutions. Such filters are thin, strong, homogenous polymers of mixed cellulosic esters (MCE), polyvinylidene fluoride (PVF; also known as PVDF), or polytetrafluoroethylene (PTFE) and have pore sizes ranging from 0.1 to 0.22 _m. Solutions of various characteristics are optionally filtered using different filter membranes. For example, PVF and PTFE membranes are well suited to filtering organic solvents while aqueous solutions are filtered through PVF or MCE membranes. Filter apparatus are available for use on many scales ranging from the single point-of-use disposable filter attached to a syringe up to commercial scale filters for use in manufacturing plants. The membrane filters are sterilized by autoclave or chemical sterilization. Validation of membrane filtration systems is performed following standardized protocols (Microbiological Evaluation of Filters for Sterilizing Liquids, Vol 4, No. 3, Washington, D.C: Health Industry Manufacturers Association, 1981) and involve challenging the membrane filter with a known quantity (ca. 10⁷/cm²) of unusually small microorganisms, such as Brevundimonas diminuta (ATCC 19146).

Pharmaceutical compositions are optionally sterilized by passing through membrane filters. Formulations comprising nanoparticles (U.S. Pat. No. 6,139,870) or multilamellar vesicles (Richard et al., International Journal of Pharmaceutics (2006), 312(1-2):144-50) are amenable to sterilization by filtration through 0.22 ┘m filters without destroying their organized structure.

Heat Sterilization

Many methods are available for sterilization by the application of extreme heat. One method is through the use of a saturated steam autoclave. In some embodiments, saturated steam at a temperature of at least 121° C. is allowed to contact the object to be sterilized. The transfer of heat is either directly to the microorganism, in the case of an object to be sterilized, or indirectly to the microorganism by heating the bulk of an aqueous solution to be sterilized. This method is widely practiced as it allows flexibility, safety and economy in the sterilization process. For example, a typical moist heat sterilization process, heating to 121.5 degrees Celsius and holding for a certain duration is often used to sterilize liquid formulations and this method is often regarded by regulatory agencies as acceptable for ensuring sterility.

Dry heat sterilization is a method which is used to kill microorganisms and perform depyrogenation at elevated temperatures. This process takes place in an apparatus suitable for heating HEPA-filtered microorganism-free air to temperatures of for example 130-180° C. for the sterilization process and to temperatures of for example 230-250° C. for the depyrogenation process. Water to reconstitute concentrated or powdered formulations is also sterilized by autoclave.

Microorganisms

In some embodiments, the compositions or devices are substantially free of microorganisms. Acceptable bioburden or sterility levels are based on applicable standards that define therapeutically acceptable compositions, including but not limited to United States Pharmacopeia Chapters <1111> et seq. For example, acceptable sterility (e.g., bioburden) levels include about 10 colony forming units (cfu) per gram of formulation, about 50 cfu per gram of formulation, about 100 cfu per gram of formulation, about 500 cfu per gram of formulation or about 1000 cfu per gram of formulation. In some embodiments, acceptable bioburden levels or sterility for formulations include less than 10 cfu/mL, less that 50 cfu/mL, less than 500 cfu/mL or less than 1000 cfu/mL microbial agents. In addition, acceptable bioburden levels or sterility include the exclusion of specified objectionable microbiological agents. By way of example, specified objectionable microbiological agents include but are not limited to Escherichia coli (E. coli), Salmonella sp., Pseudomonas aeruginosa (P. aeruginosa) and/or other specific microbial agents.

Sterility of the injectable formulation is confirmed through a sterility assurance program in accordance with United States Pharmacopeia Chapters <61>, <62> and <71>. A key component of the sterility assurance quality control, quality assurance and validation process is the method of sterility testing. Sterility testing, by way of example only, is performed by two methods. The first is direct inoculation wherein a sample of the composition to be tested is added to growth medium and incubated for a period of time up to 21 days. Turbidity of the growth medium indicates contamination. Drawbacks to this method include the small sampling size of bulk materials which reduces sensitivity, and detection of microorganism growth based on a visual observation. An alternative method is membrane filtration sterility testing. In this method, a volume of product is passed through a small membrane filter paper. The filter paper is then placed into media to promote the growth of microorganisms. This method has the advantage of greater sensitivity as the entire bulk product is sampled. The commercially available Millipore Steritest sterility testing system is optionally used for determinations by membrane filtration sterility testing. For the filtration testing of creams or ointments Steritest filter system No. TLHVSL210 are used. For the filtration testing of emulsions or viscous products Steritest filter system No. TLAREM210 or TDAREM210 are used. For the filtration testing of pre-filled syringes Steritest filter system No. TTHASY210 are used. For the filtration testing of material dispensed as an aerosol or foam Steritest filter system No. TTHVA210 are used. For the filtration testing of soluble powders in ampoules or vials Steritest filter system No. TTHADA210 or TTHADV210 are used.

Testing for E. coli and Salmonella includes the use of lactose broths incubated at 30-35° C. for 24-72 hours, incubation in MacConkey and/or EMB agars for 18-24 hours, and/or the use of Rappaport medium. Testing for the detection of P. aeruginosa includes the use of NAC agar. United States Pharmacopeia Chapter <62> further enumerates testing procedures for specified objectionable microorganisms.

In certain embodiments, the formulation described herein has less than about 60 colony forming units (CFU), less than about 50 colony forming units, less than about 40 colony forming units, or less than about 30 colony forming units of microbial agents per gram of formulation. In certain embodiments, the injectable formulations described herein are formulated to be isotonic with the injection site.

Endotoxins

In some embodiments, the compositions or devices are substantially free of endotoxins. An additional aspect of the sterilization process is the removal of by-products from the killing of microorganisms (hereinafter, “Product”). The process of depyrogenation removes pyrogens from the sample. Pyrogens are endotoxins or exotoxins which induce an immune response. An example of an endotoxin is the lipopolysaccharide (LPS) molecule found in the cell wall of gram-negative bacteria. While sterilization procedures such as autoclaving or treatment with ethylene oxide kill the bacteria, the LPS residue induces a proinflammatory immune response, such as septic shock. Because the molecular size of endotoxins can vary widely, the presence of endotoxins is expressed in “endotoxin units” (EU). One EU is equivalent to 100 picograms of E. coli LPS. Humans can develop a response to as little as 5 EU/kg of body weight. The bioburden (e.g., microbial limit) and/or sterility (e.g., absence of microbes) or endotoxin level is expressed in any units as recognized in the art. In certain embodiments, the injectable formulations described herein contain lower endotoxin levels (e.g. <4 EU/kg of body weight of a subject) when compared to conventionally acceptable endotoxin levels (e.g., 5 EU/kg of body weight of a subject). In some embodiments, the injectable formulation has less than about 5 EU/kg of body weight of a subject. In other embodiments, the injectable formulation has less than about 4 EU/kg of body weight of a subject. In additional embodiments, the injectable formulation has less than about 3 EU/kg of body weight of a subject. In additional embodiments, the injectable formulation has less than about 2 EU/kg of body weight of a subject.

In some embodiments, the injectable formulation or device has less than about 5 EU/kg of formulation. In other embodiments, the injectable formulation has less than about 4 EU/kg of formulation. In additional embodiments, the injectable formulation has less than about 3 EU/kg of formulation. In some embodiments, the injectable formulation has less than about 5 EU/kg Product. In other embodiments, the injectable formulation has less than about 1 EU/kg Product. In additional embodiments, the injectable formulation has less than about 0.2 EU/kg Product. In some embodiments, the injectable formulation has less than about 5 EU/g of unit or Product. In other embodiments, the injectable formulation has less than about 4 EU/g of unit or Product. In additional embodiments, the injectable formulation has less than about 3 EU/g of unit or Product. In some embodiments, the injectable formulation has less than about 5 EU/mg of unit or Product. In other embodiments, the injectable formulation has less than about 4 EU/mg of unit or Product. In additional embodiments, the injectable formulation has less than about 3 EU/mg of unit or Product. In certain embodiments, injectable formulation described herein contain from about 1 to about 5 EU/mL of formulation. In certain embodiments, injectable formulation described herein contain from about 2 to about 5 EU/mL of formulation, from about 3 to about 5 EU/mL of formulation, or from about 4 to about 5 EU/mL of formulation.

In certain embodiments, injectable formulation or devices described herein contain lower endotoxin levels (e.g. <0.5 EU/mL of formulation) when compared to conventionally acceptable endotoxin levels (e.g., 0.5 EU/mL of formulation). In some embodiments, the injectable formulation or device has less than about 0.5 EU/mL of formulation. In other embodiments, the injectable formulation has less than about 0.4 EU/mL of formulation. In additional embodiments, the injectable formulation has less than about 0.2 EU/mL of formulation.

Pyrogen detection, by way of example only, is performed by several methods. Suitable tests for sterility include tests described in United States Pharmacopoeia (USP)<71> Sterility Tests (23rd edition, 1995). The rabbit pyrogen test and the Limulus amebocyte lysate test are both specified in the United States Pharmacopeia Chapters <85> and <151> (USP23/NF 18, Biological Tests, The United States Pharmacopeial Convention, Rockville, MD, 1995). Alternative pyrogen assays have been developed based upon the monocyte activation-cytokine assay. Uniform cell lines suitable for quality control applications have been developed and have demonstrated the ability to detect pyrogenicity in samples that have passed the rabbit pyrogen test and the Limulus amebocyte lysate test (Taktak et al, J. Pharm. Pharmacol. (1990, 43:578-82). In an additional embodiment, the injectable formulation is subject to depyrogenation. In a further embodiment, the process for the manufacture of the injectable formulation comprises testing the formulation for pyrogenicity. In certain embodiments, the formulations described herein are substantially free of pyrogens.

Medical Uses

In some embodiments, the formulation is suitable for injection. In some embodiments, the formulation is suitable for intravenous injection. In some embodiments, the kit is used in diagnosis of an ophthalmic disease or condition. In some embodiments, the kit is used in fluorescein angiography.

All of the various embodiments or options described herein can be combined in any and all variations. The following Examples serve only to illustrate the invention and are not to be construed in any way to limit the invention.

NON-LIMITING EMBODIMENTS

The present disclosure is illustrated herein by the embodiments described below, which should not be construed as limiting. Those skilled in the art will understand that this disclosure may be embodied in many different forms and should not be construed as limited to the embodiments set forth herein.

While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.

- 1. A kit, comprising: an aqueous formulation comprising an active agent, wherein the formulation has a pH of from about 7 to about 11; and a container holding the aqueous formulation, wherein the aqueous formulation is essentially free of dissolved glass prior to use.
- 2. The kit of Embodiment 1, wherein the aqueous formulation has a dissolved silicon concentration upon filling the container (Si_0w), and a dissolved silicon concentration after storage in the container at 60° C. for 10 weeks (Si_10w), wherein Si_10w/Si_0wis from 1 to 1.6.
- 3. The kit of Embodiment 2, wherein Si_10w/Si_0wis from 1 to 1.5.
- 4. The kit of Embodiment 2, wherein Si_10w/Si_0wis from 1 to 1.4.
- 5. The kit of Embodiment 2, wherein Si_10w/Si_0wis from 1 to 1.3.
- 6. The kit of Embodiment 2, wherein Si_10w/Si_0wis from 1 to 1.25.
- 7. The kit of Embodiment 2, wherein Si_10w/Si_0wis from 1 to 1.22.
- 8. The kit of Embodiment 2-7, wherein Si_10wis less than 14 mg/L.
- 9. The kit of Embodiment 2-7, wherein Si_10wis less than 13.5 mg/L.
- 10. The kit of Embodiment 2-7, wherein Si_10wis less than 13 mg/L.
- 11. The kit of Embodiment 2-7, wherein Si_10wis less than 12.5 mg/L.
- 12. The kit of Embodiment 2-7, wherein Si_10wis less than 12 mg/L.
- 13. The kit of Embodiment 2-7, wherein Si_10wis less than 11.5 mg/L.
- 14. The kit of Embodiment 1-13, wherein the aqueous formulation has a dissolved boron concentration upon filling the container (B_0w), and a dissolved boron concentration after storage in the container at 60° C. for 10 weeks (B_10w), wherein B_10w/B_0wis from 1 to 1.9.
- 15. The kit of Embodiment 14, wherein B_10w/B_0wis from 1 to 1.8.
- 16. The kit of Embodiment 14, wherein B_10w/B_0wis from 1 to 1.7.
- 17. The kit of Embodiment 14, wherein B_10w/B_0wis from 1 to 1.6.
- 18. The kit of Embodiment 14, wherein B_10w/B_0wis from 1 to 1.5.
- 19. The kit of Embodiment 14, wherein B_10w/B_0wis from 1 to 1.4.
- 20. The kit of Embodiment 14, wherein B_10w/B_0wis from 1 to 1.3.
- 21. The kit of Embodiment 14-20, wherein B_10wis less than 2.2 mg/L.
- 22. The kit of Embodiment 14-20, wherein B_10wis less than 2.1 mg/L.
- 23. The kit of Embodiment 14-20, wherein B_10wis less than 2.0 mg/L.
- 24. The kit of Embodiment 14-20, wherein B_10wis less than 1.9 mg/L.
- 25. The kit of Embodiment 14-20, wherein B_10wis less than 1.85 mg/L.
- 26. The kit of Embodiment 1-25, wherein the glass container has a bottom reaction zone upon filling the container (BTRZ_0w) of no more than 20 nm, and the glass container has a bottom reaction zone after storage in the container at 60° C. for 10 weeks (BTRZ_10w) of no more than 250 nm.
- 27. The kit of Embodiment 26, wherein BTRZ_10wis no more than 200 nm.
- 28. The kit of Embodiment 26, wherein BTRZ_10wis no more than 180 nm.
- 29. The kit of Embodiment 26, wherein BTRZ_10wis no more than 160 nm.
- 30. The kit of Embodiment 26, wherein BTRZ_10wis no more than 150 nm.
- 31. The kit of Embodiment 26, wherein BTRZ_10wis no more than 140 nm.
- 32. The kit of Embodiment 26, wherein BTRZ_10wis no more than 130 nm.
- 33. The kit of Embodiment 26, wherein BTRZ_10wis no more than 100 nm.
- 34. The kit of Embodiment 26, wherein BTRZ_10wis no more than 50 nm.
- 35. The kit of Embodiment 26, wherein BTRZ_10wis no more than 40 nm.
- 36. The kit of Embodiment 26, wherein BTRZ_10wis no more than 30 nm.
- 37. The kit of Embodiment 26, wherein BTRZ_10wis no more than 20 nm.
- 38. The kit of Embodiment 26, wherein BTRZ_10wis no more than 10 nm.
- 39. The kit of Embodiment 26-38, wherein BTRZ_0wis no more than 30 nm.
- 40. The kit of Embodiment 26-38, wherein BTRZ_0wis no more than 20 nm.
- 41. The kit of Embodiment 26-38, wherein BTRZ_0wis no more than 10 nm.
- 42. The kit of Embodiment 1-41, wherein the container has a shoulder reaction zone upon filling the container (SHRZ_0w) of no more than 20 nm, and the container has a shoulder reaction zone after storage in the container at 60° C. for 10 weeks (SH_10w) of no more than 250 nm.
- 43. The kit of Embodiment 1-41, wherein the container has a shoulder reaction zone upon filling the container (SHRZ_0w) of no more than 20 nm, and the container has a shoulder reaction zone after storage in the container at 60° C. for 10 weeks (SH_10w) of no more than 200 nm.
- 44. The kit of Embodiment 1-41, wherein the container has a shoulder reaction zone upon filling the container (SHRZ_0w) of no more than 20 nm, and the container has a shoulder reaction zone after storage in the container at 60° C. for 10 weeks (SH_10w) of no more than 190 nm.
- 45. The kit of Embodiment 1-41, wherein the container has a shoulder reaction zone upon filling the container (SHRZ_0w) of no more than 20 nm, and the container has a shoulder reaction zone after storage in the container at 60° C. for 10 weeks (SH_10w) of no more than 180 nm.
- 46. The kit of Embodiment 1-41, wherein the container has a shoulder reaction zone upon filling the container (SHRZ_0w) of no more than 20 nm, and the container has a shoulder reaction zone after storage in the container at 60° C. for 10 weeks (SH_10w) of no more than 170 nm.
- 47. The kit of Embodiment 1-41, wherein the container has a shoulder reaction zone upon filling the container (SHRZ_0w) of no more than 20 nm, and the container has a shoulder reaction zone after storage in the container at 60° C. for 10 weeks (SH_10w) of no more than 160 nm.
- 48. The kit of Embodiment 1-41, wherein the container has a shoulder reaction zone upon filling the container (SHRZ_0w) of no more than 20 nm, and the container has a shoulder reaction zone after storage in the container at 60° C. for 10 weeks (SH_10w) of no more than 150 nm.
- 49. The kit of Embodiment 1-41, wherein the container has a shoulder reaction zone upon filling the container (SHRZ_0w) of no more than 20 nm, and the container has a shoulder reaction zone after storage in the container at 60° C. for 10 weeks (SH_10w) of no more than 140 nm.
- 50. The kit of Embodiment 1-41, wherein the container has a shoulder reaction zone upon filling the container (SHRZ_0w) of no more than 20 nm, and the container has a shoulder reaction zone after storage in the container at 60° C. for 10 weeks (SH_10w) of no more than 100 nm.
- 51. The kit of Embodiment 1-41, wherein the container has a shoulder reaction zone upon filling the container (SHRZ_0w) of no more than 20 nm, and the container has a shoulder reaction zone after storage in the container at 60° C. for 10 weeks (SH_10w) of no more than 80 nm.
- 52. The kit of Embodiment 1-41, wherein the container has a shoulder reaction zone upon filling the container (SHRZ_0w) of no more than 20 nm, and the container has a shoulder reaction zone after storage in the container at 60° C. for 10 weeks (SH_10w) of no more than 60 nm.
- 53. The kit of Embodiment 1-41, wherein the container has a shoulder reaction zone upon filling the container (SHRZ_0w) of no more than 20 nm, and the container has a shoulder reaction zone after storage in the container at 60° C. for 10 weeks (SH_10w) of no more than 50 nm.
- 54. The kit of Embodiment 1-53, wherein the aqueous formulation comprises from about 70 mg/mL to about 130 mg/mL of fluorescein sodium.
- 55. The kit of Embodiment 1-53, wherein the aqueous formulation comprises from about 90 mg/mL to about 110 mg/mL of fluorescein sodium.
- 56. The kit of Embodiment 1-53, wherein the aqueous formulation comprises about 100 mg/mL of fluorescein sodium.
- 57. The kit of Embodiment 1-53, wherein the aqueous formulation comprises from about 200 mg/mL to about 300 mg/mL of fluorescein sodium.
- 58. The kit of Embodiment 1-53, wherein the aqueous formulation comprises from about 230 mg/mL to about 270 mg/mL of fluorescein sodium.
- 59. The kit of Embodiment 1-53, wherein the aqueous formulation comprises about 250 mg/mL of fluorescein sodium.
- 60. The kit of Embodiment 1-59, wherein the aqueous formulation comprises at least one pH adjusting agent.
- 61. The kit of Embodiment 60, wherein the at least one pH adjusting agent comprises sodium hydroxide, hydrochloric acid, or a combination thereof.
- 62. The kit of Embodiment 1-61, wherein the aqueous formulation is a solution.
- 63. The kit of Embodiment 1-62, wherein the container is sealed.
- 64. The kit of Embodiment 1-63, wherein the container has a fill volume of from 2 mL to 5 mL.
- 65. The kit of Embodiment 1-63, wherein the container has a fill volume of 5 mL.
- 66. The kit of Embodiment 1-65, wherein the aqueous formulation has a pH of from about 8.0 to about 10.0.
- 67. The kit of Embodiment 1-66, wherein the container comprises at least one glass delamintion control feature (GDCF).
- 68. The kit of Embodiment 67, wherein the at least one GDCF is selected from non-thermal terminal sterilization, aseptic filing without terminal sterilization, a non-glass coating on the interior surface of the glass, reduction of glass contact time, coupling with an filter for delaminated glass, use of non-glass material to form the container, or combinations thereof.
- 69. The kit of Embodiment 67, wherein the at least one GDCF is non-thermal terminal sterilization selected from gamma radiation, Ebeam radiation, vaporized hydrogen peroxide, ethylene oxide, other non-thermal terminal sterilization, or combinations thereof.
- 70. The kit of Embodiment 67, wherein the at least one GDCF is aseptic filling without terminal sterilization.
- 71. The kit of Embodiment 70, wherein the aseptic filling occurs in a pre-sterilized container.
- 72. The kit of Embodiment 67, wherein the at least one GDCF is the reduction of glass contact time selected from using a prefilled syringe, using a single-use ampule, using lyophilized active agent to be reconstituted with solvent/diluent in the container prior to use, using pre-sterlized active agent to be reconstituted with solvent/diluent in the container prior to use or combinations thereof.
- 73. The kit of Embodiment 67, wherein the at least one GDCF is a filter for delaminated glass couple to a distal end of the container.
- 74. The kit of Embodiment 73, wherein the filter for delaminated glass is an external filter attached to the lure lock system of a syringe or otherwise affixed directly to the syringe.
- 75. The kit of Embodiment 73, wherein the at least one GDCF is a filter for delaminated glass disposed within the container, and optionally the container is a prefilled syringe.
- 76. The kit of Embodiment 67, wherein the at least one GDCF is IV tubing with an in-line filter.
- 77. The kit of Embodiment 1-76, wherein the container is a glass container
- 78. The kit of Embodiment 1-66, wherein the formulation is suitable for injection.
- 79. The kit of Embodiment 1-66, wherein the formulation is suitable for intravenous injection
- 80. The kit of Embodiment 1-79, wherein the active agent is fluorescein or fluorescein sodium.
- 81. The kit of Embodiment 1-79, wherein the active agent is not fluorescein or fluorescein sodium.
- 82. The kit of Embodiment 1-81, wherein the container is a boron-free glass container.
- 83. The kit of Embodiment 82, wherein the container is an aluminosilicate glass container.
- 84. The kit of Embodiment 1-83, wherein the aqueous formulation essentially boron-free.
- 85. The kit of Embodiment 82, wherein the aqueous formulation boron-free.

NON-LIMITING EXAMPLES

The present disclosure is illustrated herein by the experiments described by the following examples, which should not be construed as limiting. Those skilled in the art will understand that this disclosure may be embodied in many different forms and should not be construed as limited to the examples set forth herein.

Example 1—Glass Delamination/Contamination Study Design/Protocol

The present disclosure provides compatibility testing for drug products in glass vials including a delamination screening package aligned with USP <790>, USP <1660>, and EP 3.2.1. recommendations. The design of such studies provides reliable data for risk assessment for drug container compatibility. The factor for the suitability of such investigations is the categorization of different observations with respect to their criticality and that features need to be found which are early indicators for the later occurrence of delamination.

The containers to be tested and filled with drug product (fluorescein sodium) or placebo solution, can be drawn from real-time stability studies or stored under accelerated ageing conditions. The extent of glass corrosion and chemical attack is assessed by analyses of the inner glass surface morphology, the concentrations of extracted elements in solution, and by identification of particles and flakes. Exemplary analytical techniques are described and illustrated herein.

Visual and Optical Inspection

This analytical technique is used to detect particles via visual inspection by eye and camera (filled vials) and to visualize coloration and scattering (for empty and for emptied vials). This allows for the identification of containers with high particle load and with changed surface and surface near regions to determine the worst samples of a set by stereo-microscopy. FIG. 6 illustrates visual and optical inspection of a sample unrelated to the present disclosure.

SEM Cross-Section Analysis

This analytical technique is used to determine the extent of chemical attack of inner glass surface and of surface near regions. This allows for classification between different levels of glass corrosion. Typical features are roughening, formation of reaction zones and/or delaminated areas at the interior surface in contact with the drug product. FIG. 7 illustrates SEM analysis of a sample unrelated to the present disclosure.

ICP Analysis

This analytical technique is used to quantify the amounts of leached glass elements. Allows for the confirmation of the chemical mechanism of drug container interaction. FIG. 8 illustrates ICP analysis of a sample unrelated to the present disclosure.

SEM/EDS and Raman Microscopy

This analytical technique is used to analyze the composition of particles after filtration. This allows identification of morphology (SEM), elemental components (SEM/EDS), and molecular structure (Raman) of isolated particles to distinguish between glass flakes and other particles.

Study Protocol

An exemplary delamination study protocol is provided below.

Step 1: Visual inspection by eye and magnifying video camera with respect to the presence of particles or flakes (10 filled vials per time point according to Tables 1+2).

Step 2: Optical inspection of emptied containers per time point, using stereo-microscopy with extended depth of focus to qualitatively determine if there are any indications for reaction zones or scattering present on the interior surface (10 vials per time point according to Tables 1+2). Selection of two “worst” samples on the basis of stereo-microscopic inspection for subsequent SEM cross-section analyses.

Step 3: SEM (scanning electron microscopy) cross-section analyses on the interior surface of two “worst” vials for selected test conditions and selected time points as described in Tables 1+2; analyses of three areas: wall near bottom, middle of the vial body, and wall near shoulder. These investigations reveal the presence of a potential reaction zone.

Step 4: ICP (inductively coupled plasma) analyses of 10 mL drug solution pooled from the vials of each batch for selected test conditions and selected time points according to Tables 1+2 to quantitatively determine the amount of “glass” elements leached into solution for selected “glass” elements (e.g. Si, B, Ca, Al) to ascertain if the amounts and ratios found are normal or if there is a pronounced chemical attack.

Step 5: Filtration of the solution of one selected vial through a silver membrane (pore size approx. 0.2 μm) using a vacuum filtration unit. Subsequent SEM/EDS and Raman analyses of found particulate matter to determine the elemental composition and morphology of the particles by SEM/EDS and the molecular structure by match of Raman signals to library.

Optional Step 6 (if the mechanism of glass corrosion is unclear or reaction zones are observed): SIMS (secondary ion mass spectrometry) depth profiling of the interior surface to get information about the composition of the surface near region.

In some cases, the protocol described above is applied at different time points under accelerated storage conditions. These conditions are defined on the basis of the drug product application and customer requirements.

Example 2—Delamination/Contamination Study of RLD Vials and Fortis Vials

A glass delamination testing in accordance with USP <1660> for “Fluorescein Injection 10%” in two vial presentations: 5 mL clear molded conventional vial (RLD) and an improved vials (Fortis 4R clear vial) converted from SCHOTT Fiolax CHR tubing. The shelf-life of the drug product is 24 months at 25° C. and its pH range is 8.0-9.8. The formulation contains fluorescein sodium, water, hydrochloric acid and/or sodium hydroxide for pH adjustment. The filled vial undergoes terminal sterilization. The delamination screening study was performed at 60° C. to determine if there is any evidence for glass delamination, predelamination, or glass attack by the formulation. In addition, characterization of the conventional vial (RLD) with respect to composition, the glass type, and identifying in a best effort approach the glass manufacturer based on published glass compositions. The samples were analyzed with respect to indications for glass delamination in alignment with the recommendations of the USP <1660>.

1. Samples

TABLE 1

List of samples

Sample

set No.
Sample identification
Description

01
AK-FLUOR ® 10% Fluorescein Injection
RLD vials

USP, 100 mg/mL, NDC 17478-253-10

LOT: 021576A, EXP: 02/2018

Manufactured by: Akorn, Inc.

02
Container: 5 mL Unprinted Clear Glass
Empty

Fortis Zenith (Soffieria Bertolini)
control vials

Mfg Date: 07 Aug. 2019

03
Fluorescein Injection, USP 10
Fortis, t0:

% w/v, 100 mg/mL, 5 mL
initial vials

B.No: FLUO15PG1/013

Mfg Date: 07 Aug. 2019

04
Fluorescein Injection, USP 10
Fortis, t1:

% w/v, 100 mg/mL, 5 mL
5 weeks,

B.No: FLUO15PG1/013
60° C.

Mfg Date: 07 Aug. 2019

05
Fluorescein Injection, USP 10
Fortis, t2:

% w/v, 100 mg/mL, 5 mL
10 weeks,

B.No: FLUO15PG1/013
60° C.

Mfg Date: 07 Aug. 2019

06
Fluorescein Injection, USP
Matrix

Bulk solution, Filtered in non-glass
solution

bottle, B.No: FLUO15PG1/013

Mfg Date: 07 AUG. 2019

1.1 Sample Preparation

- Removing labels and re-labeling of the samples with a water- and chemical-proof permanent marker.
- Emptying of filled samples after visual inspection.
- Rinsing 3 times with hot tap water and 3 times with demineralized water.
- Rinsing 5 times isopropanol and 3 times with acetone.
- Drying of containers in a laminar air flow cabinet.

Additional for Part 2:

- Two vials of sample set01 were ground and fused to a tablet for semi-quantitative XRF-screening analysis (w/o boron) according to standard operating procedure “SCHOTT_CA_0015”. For wet chemical analysis of boron, a chemical glass digestion was performed previously to the analysis according to standard operating procedure “AAW_CA_0521”.

2. Study Protocol:
Part 1: Glass Delamination Study (Sample Sets 01-06)

- Visual inspection by eye of 10 filled vials of sample sets 01 and 03-05 with respect to the presence/absence of particles in general according to USP <790>/EP 2.9.20. [4]; and visual inspection by eye and magnifying video camera of 10 filled vials of sample sets 01 and 03-05 with respect to the presence/absence of “flake-like” particles (In-house method) [5].
- Optical inspection: SM [6] of 10 vials of sample set 01 (molded) with extended depth of focus to determine qualitatively if there are any indications for conspicuous areas present on the sample interior surface. If present, these areas were classified with respect to coloration and light scattering. According to the experiences so far, especially the coloration indicates a delamination risk [7].
- Optical inspection by SM [6] of 10 vials of sample sets 03-05 (tubular) and 5 vials of sample set 02 (tubular, controls) with extended depth of focus to determine qualitatively
- if there are any indications for reaction zones present on the vial interior surface. The optical inspection by means of stereo-microscopy is focused on the wall near bottom and wall near shoulder areas. Within the wall near bottom area, a distinction is made between two neighboring sections A and B, while in the wall near shoulder area, the section C was investigated. The areas were classified with respect to coloration and light scattering. According to the experiences so far, especially the coloration indicates a delamination risk [7].
- SEM [8] cross-section analyses at the vial interior surface in the conspicuous areas of the 2 vials of sample set 01 (molded) as identified by stereo-microscopy. If no such areas were present, the analyses were carried out in the wall near bottom, the wall near shoulder, and the reference area (in the mid-body). This investigation reveals the presence or absence of a potential reaction zone [9].
- SEM [8] cross-section analyses at the vial interior surface in the vulnerable areas of the 2 “worst” vials of sample sets 02-04 (tubular) as identified by stereo-microscopy. The analyses were carried out in the wall near bottom, wall near shoulder, and a reference area (in the mid-body). This investigation reveals the presence or absence of a potential reaction zone [9].
- ICP-MS/-OES [10] analyses of the drug solution pooled from 10 vials of sample sets 01, 03, and 04 to determine quantitatively the concentration of “glass” elements in solution for 4 elements (Al, B, Ca, and Si) to ascertain if the amount found is normal or if there is a pronounced chemical attack. This investigation helps to determine the corrosion mechanism [11].

Part 2: Characterization of One Vial Type (Sample Set 01)

- Glass appearance characterization (clear/amber glass, molded/tubular glass).
- Determination of chemical composition by XRF [12,13] and wet chemical analysis (B₂O₃) [14]. Identification of glass type I A/I B or soda-lime glass and glass manufacturer; if not SCHOTT glass based on published data in a best effort approach
- SM: Stereo-Microscopy (visual appearance)
- SEM: Scanning Electron Microscopy (surface morphology)
- ICP-MS/-OES: Inductively Coupled Plasma (-MS Mass Spectrometry,-OES Optical Emission
- Spectroscopy) (trace analyses within solution)
- XRF: X-Ray Fluorescence (determination of composition)

TABLE 2

Test methods for each sample set (with number of vials)

Sample set No./Storage condition

04
05

02
03
Fortis,
Fortis,

01
Fortis,
Fortis,
t1:
t2:

RLD
empty
t0:
5 weeks,
10 weeks,

Method
Guideline
vials
controls
initial
60° C.
60° C.

Visual
USP <790>/
10
—
10
10
10

Inspection
EP 2.9.20.,

USP <1660>,

In-house

method

Stereo-
USP <1660>
10
5
10
10
10

microscopy

SEM cross-

2
2
2
2
No²

section

analyses

ICP-analyses

Yes
—
Yes
Yes
No²

Filtration and

No¹
—
No¹
No¹
No²

SEM/EDS

particle

analyses

Glass
—
Yes
—
—
—
—

characterization

¹During visual inspection, no “flake-like” particles were observed by eye. Thus, no filtration and subsequent SEM/EDS particle characterization were conducted.

²Customer stopped the study before these methods were conducted.

3. Results
3.1 Sample Set 01 (RLD Vials)
Part 1: Glass Delamination Study

Visual inspection (Table 5):

The results of the inspection of filled vials by eye and with a magnifying camera are summarized in Table 5. Particles in general were inspected according to USP <790>/EP 2.9.20. at 10,000 lux; “flake-like” particles were characterized by an In-house method. The inspection was done for 10 filled vials of sample set 01.

- No “flake-like“particles” were observed by eye and the camera system (In-house method).
- In accordance with USP <790>/EP 2.9.20, no particles were seen.
  
  Optical inspection of the “critical” areas using stereo-microscopy (Table 6): The inspection was done for 10 vials of sample set 01. The representative photographs of the two “worst” vials are characterized below.
- In the wall near shoulder area, up to medium scattering was observed.
- Up to weak scattering was found in the wall near bottom area.
- No coloration was present.
  
  Investigation of the morphology of the interior surface using SEM (FIGS. 11-12 and Table 9): Three areas out of the selected vials were characterized by SEM cross-section analysis (wall near bottom, wall near shoulder, and reference area). More or less 5 characteristic features were found: Delaminated areas, reaction zones, micro-roughness, deposits (particulate), and shallow pits. The appearance of the characteristic features is summarized in Table 9.
- Delaminated areas and reaction zones with thicknesses up to about 150 nm were observed in the wall near shoulder area.
- Micro-roughness and deposits (particulate) were found in the wall near shoulder, wall near bottom, and reference area.
- Shallow pits were present in the wall near shoulder and wall near bottom area.
  
  Concentration of dissolved “glass” elements (Table 10):
  
  The entire data set of the ICP measurements is listed in Table 10.
- The concentration of Si was about 11 mg/L, the concentration of B about 1.5 mg/L and the concentration of Ca about 0.68 mg/L.
- The concentration of Al was below the limit of quantification of 0.05 mg/L.

Part 2: Characterization of One Vial Type

Visual Appearance and Glass Composition by XRF and Wet Chemistry (B₂O₃)

From the visual appearance of the vials, sample set 01 can be ascribed to clear molded glass. The concentrations of the glass components measured by XRF and wet chemical analysis for B₂O₃are summarized in Table 11.

TABLE 3

Chemical composition of sample set 01

(RLD vials) in % [w/w]

Sample 01

Oxide
Method
Concentration

Al₂O₃
XRF
5.43 ± 0.11

BaO
XRF
2.23 ± 0.07

B₂O₃
wet chemistry
11.77 ± 0.20

CaO
XRF
1.41 ± 0.03

Fe₂O₃
XRF
0.046 ± 0.009

K₂O
XRF
1.12 ± 0.06

MgO
XRF
<0.05

MnO
XRF
0.041 ± 0.008

Na₂O
XRF
8.0 ± 0.3

SiO₂
XRF
69.5 ± 0.5

SrO
XRF
0.041 ± 0.008

TiO₂
XRF
<0.02

ZnO
XRF
0.022 ± 0.007

ZrO₂
XRF
0.064 ± 0.013

Note:

The vial was ground and fused to a tablet for semi-quantitative XRF analysis. Easily volatile elements (F, Cl, S, As) can evaporate during melting. Li, C, N, and O cannot be determined by XRF analysis. It was assumed that all elements were present as oxides.

3.2 Sample Set 02 and 03 (Empty Controls and t0)
Part 1: Glass Delamination Study
Visual Inspection (Table 5):

The results of the inspection of filled vials by eye and with a magnifying camera are summarized in Table 5. Particles in general were inspected according to USP <790>/EP 2.9.20. at 10,000 lux; “flake-like” particles were characterized by an In-house method. The inspection was done for 10 filled vials of sample set 03.

- Up to a few “flake-like” particles were found applying the camera system (In-house method).
- No “flake-like” particles were observed by eye (In-house method).
- In accordance with USP <790>/EP 2.9.20., no particles were seen.
  
  Optical inspection of the “critcal” areas using stereo-microscopy (Table 7+8): The inspection was done for 10 vials per sample set. The representative photographs of the two “worst” vials are characterized below.
- One vial out of 5 from sample set 02 featured weak coloration in the wall near bottom area A.
- Up to strong scattering was found in the wall near bottom area A for sample set 03, while up to a medium scattering was observed in this area for sample set 02.
- Up to medium scattering was present in the wall near bottom area B for sample set 03.
- In the wall near shoulder area, up to weak scattering was observed for sample sets 02 and 03.
  
  Investigation of the morphology of the interior surface using SEM (FIGS. 13-15 and Table 9): Three areas out of the selected vials were characterized by SEM cross-section analysis (wall near bottom, wall near shoulder, and reference area). More or less 5 characteristic features were found: Micro-roughness, deposits (particulate), deposits (planar), shallow bumps, and shallow pits. The appearance of the characteristic features is summarized in Table 9.
- Sample set 03 featured micro-roughness in the wall near bottom and reference area, while this feature was observed for sample set 02 in the wall near shoulder area.
- Deposits (particulate) and deposits (planar) were found in the wall near shoulder area for sample set 02, while deposits (particulate) were present in the wall near bottom and reference area for sample set 03.
- Shallow pits were observed in the wall near shoulder and reference area for sample set 02, while this feature was observed in the wall near bottom area for sample set 03.
- Shallow bumps were observed in the reference area for sample set 02.

Concentration of Dissolved “Glass” Elements (Table 10):

The entire data set of the ICP measurements is listed in Table 10.

Matrix Solution (Sample Set 06)

- The Ca-concentration was about 2.1 mg/L in the matrix solution.
- The concentrations of Al, B, and Si were below the respective limit of quantification.

Initial Time Point t0 (Sample Set 03)

- Compared to the matrix solution, the concentrations of Si, B, and Al increased significantly above the respective limit of quantification for sample set 03.
- The concentration of Ca found for sample set 03 was in agreement with the value obtained for the matrix solution.

3.3 Sample Set 04 (t1: 5 Weeks, 60° C.)
Part 1: Glass Delamination Study
Visual Inspection (Table 5):

The results of the inspection of filled vials by eye and with a magnifying camera are summarized in Table 5. Particles in general were inspected according to USP <790>/EP 2.9.20. at 10,000 lux; “flake-like” particles were characterized by an In-house method. The inspection was done for 10 filled vials of sample set 04.

- For one vial out of 10, a few “flake-like” particles were found applying the camera system (In-house method).
- No “flake-like” particles were observed by eye (In-house method).
- In accordance with USP <790>/EP 2.9.20., no particles were seen.
  
  Optical inspection of the “critical” areas using stereo-microscopy (Table 7+8): The inspection was done for 10 vials per sample set. The representative photographs of the two “worst” vials are characterized below.
- Up to weak coloration and up to strong scattering were observed in the wall near bottom areas A and B.
- In the wall near shoulder area C, no coloration and no scattering were found.
  
  Investigation of the morphology of the interior surface using SEM (Firs. 16-17 and Table 91: Three areas out of the selected vials were characterized by SEM cross-section analysis (wall near bottom, wall near shoulder, and reference area). More or less 5 characteristic features were found: Delaminated areas, reaction zones, micro-roughness, deposits (particulate), and shallow pits. The appearance of the characteristic features is summarized in Table 9.
- Delaminated areas, reaction zones with thicknesses up to approx. 470 nm, and micro-roughness were present in the wall near bottom area.
- Deposits (particulate) were found in the wall near bottom, wall near shoulder, and reference area.
- Shallow pits were observed in the wall near bottom and wall near shoulder area.

Concentration of Dissolved “Glass” Elements (Table 10):

The entire data set of the ICP measurements is listed in Table 10.

- Compared to the initial time point (sample set 03), the concentrations of Si (about 13 mg/L) and B (about 2.0 mg/L) increased slightly.
- The concentrations of Al (about 0.070 mg/L) and Ca (about 2.2 mg/L) remained constant with respect to the previous time point and considering the measuring uncertainties.

3.4 Sample Set 05 (t2: 10 Weeks, 60° C.)
Part 1: Glass Delamination Study
Visual Inspection (Table 5):

The results of the inspection of filled vials by eye and with a magnifying camera are summarized in Table 5. Particles in general were inspected according to USP <790>/EP 2.9.20. at 10,000 lux; “flake-like” particles were characterized by an In-house method. The inspection was done for 10 filled vials of sample set 05.

- For 3 vials out of 10, a few “flake-like” particles were found applying the camera system (In-house method).
- No “flake-like” particles were observed by eye (In-house method).
- No particles were seen in accordance with USP <790>/EP 2.9.20.
  
  Optical inspection of the “critical” areas using stereo-microscopy (Table 7+8): The inspection was done for 10 vials per sample set. The representative photographs of the two “worst” vials are characterized below.
- Up to strong coloration was observed in the wall near bottom area B, while all vials featured weak coloration in the wall near bottom area A.
- Up to strong scattering was found in the wall near bottom area A, medium scattering in the wall near bottom area B, and up to weak scattering in the wall near shoulder area C.

4. Interpretation
4.1 Sample Set 01 (RLD Vials)

Delamination was confirmed by delaminated areas that were observed by SEM cross-section analyses for sample set 01. In addition, this sample set featured reaction zones, which are classified as early indicators for delamination. Furthermore, glass attack was observed as micro-roughness and a Si-concentration in solution of about 11 mg/L. This indicates that an alteration to the inner glass surface by the formulation has taken place. Deposits (particulate) were found on the inner surface of the glass containers for sample set 01. This is most probably due to an interaction between the formulation and the interior glass surface, too.

Sample set 01 was made of clear molded glass. Based on the current analyses and considering the measuring uncertainties, it can be confirmed, that the glass composition of sample set 01 was very similar to Type I, class B alumino-borosilicate clear glass within the so-called 5.1 COE class with a coefficient of thermal expansion in the range of 4.8-5.6 [10⁻⁶K⁻¹] (see specification in ASTM E 438). Best fit to published glass compositions was found for “Kimble KG-35” and “Bormioli Rocco Type I” clear glass (see Table 11). Due to the numerous suppliers of clear molded glass vials and non-published compositions, other glass manufacturers are feasible, too.

4.2 Sample Sets 02 and 03 (Empty Controls and t0)

No delamination (delaminated areas and/or sharp edges) and no early indicators for delamination (i.e. reaction zones) were confirmed for sample sets 02 and 03. Glass attack was observed as micro-roughness for both sample sets. In addition, sample set 03 featured strong scattering and a Si-concentration of approx. 9.4 mg/L. These three features indicate that an alteration to the inner glass surface by the formulation has taken place. Deposits were found on the inner surface of the glass containers for both sample sets. Due to their appearance, these might be related to a pretreatment process or the converting process in the case of sample set 02, while these might be caused by an interaction between the drug formulation and the interior glass surface in the case of sample set 03. Shallow pits and shallow bumps are typical converting features of tubular containers and are not considered as critical with respect to delamination.

4.3 Sample Set 04 (Ti: 5 Weeks, 60° C.)

SEM cross-section analyses confirmed delamination by the observation of delaminated areas in the wall near bottom area. In addition, early indicators were found as coloration in combination with reaction zones. Glass attack was observed as micro-roughness, strong scattering, and a Si-concentration in solution of about 13 mg/L. These features indicate that an alteration to the inner glass surface by the formulation has taken place. Deposits (particulate) were found on the inner surface of the glass containers. This is most probably due to an interaction between the formulation and the interior glass surface. Shallow pits are typical features of tubular vials, which were initiated during the converting process and are not considered as critical regarding delamination.

4.4 Sample Set 05 (t2:10 Weeks, 60° C.)

Based on visual inspection and optical inspection by SM, glass attack was confirmed as strong scattering.

TABLE 4

Short summary with respect to delamination

Sample set No.

01
02
03
04
05

Fortis,
Fortis,
Fortis, t1:
Fortis, t2:

RLD
empty
t0:
5 weeks,
10 weeks,

Shortage
vials
controls
initial
60° C.
60° C.

Delamination
Yes
No
No
Yes
—

confirmedª

Early indicators for
Yes
No
No
Yes
—

delamination^b

Glass attack^c
Yes
Yes
Yes
Yes
—

Others^d
Yes
Yes
Yes
Yes
Yes

^aDelamination confirmed: Sharp edges or delaminated areas (SEM) Glass flakes (visual inspection + particle analyses) Flakes composed of glass elements in combination with formulation components (visual inspection + particle analyses)

^bEarly indicators: Reaction zone at the interior surface (SEM) Coloration observed by optical inspection (SM) in combination with reaction zone at the interior surface (SEM) Si/B concentration ratio below or equal to 5 and Si concentration above 7.1 mg/L (for vial format above 2 mL up to 5 mL)

^cGlass attack Micro-roughness of the interior surface (SEM)Strong scattering observed by optical inspection (SM) Si concentration above 7.1 mg/L (for vial format above 2 mL up to 5 mL)

^dOthers Shallow pits, shallow bumps, small holes, deposits (SEM) Weak-to-medium scattering observed by optical inspection (SM) Local reaction zone/local delaminated area (lateral dimension below 20 μm) (SEM) Coloration observed by optical inspection (SM) without reaction zones (SEM)

5. Enclosure

TABLE 5

Summary of the visual inspection of filled vials with respect to

“flake-like” particles and particles in general

In-house method¹
USP <790>/

Flakes
Flakes
EP 2.9.20.²

Sample set No.
camera
eye
Particles

01: RLD vials
0 (10/10)
0 (10/10)
No (10/10)

03: Fortis, t0: initial
I (5/10)
0 (10/10)
No (10/10)

0 (5/10)

04: Fortis, t1: 5 weeks,
I (1/10)
0 (10/10)
No (10/10)

60° C.
0 (9/10)

05: Fortis, t2: 10 weeks,
I (3/10)
0 (10/10)
No (10/10)

60° C.
0 (7/10)

¹Quantity of flakes: 0 = none, I = a few, II = a lot (The camera system is able to detect much smaller flakes compared to the inspection by eye).

²The inspection was performed at 10,000 lux due to the colored solution.

TABLE 6

Summary of the results of optical inspection by

stereo-microscopy³(molded vials)

Sample set No.
Scattering¹
Coloration²
Scattering area

01: RLD vials
I (7/10)
0 (10/10)
Wall near bottom

0 (3/10)

01: RLD vials
II (9/10)
0 (10/10)
Wall near shoulder

I (1/10)

¹Intensity of the light scattering

²Intensity of the coloration

³Qualitative classification

0: not observed

I: weak

II: medium

III: strong

TABLE 7

Summary of the results of optical inspection by

stereo-microscopy⁴(tubular vials)

Scattering¹,
Coloration²,
Scattering³,

Sample set No.
area A
area A/B
area B

02: Fortis,
II (2/5)
I A/0 B (1/5)
0 (5/5)

empty controls
I (3/5)
0 A/0 B (4/5)

03: Fortis,
III (2/10)
0 (10/10)
II (1/10)

t0: initial
II (8/10)

I (9/10)

04: Fortis, t1: 5
III (5/10)
I A/0 B (3/10)
III (2/10)

weeks, 60° C.
II (5/10)
0 A/I B (2/10)
II (7/10)

0 A/0 B (5/10)
I (1/10)

05: Fortis, t2: 10
III (5/10)
I A/III B (1/10)
II (10/10)

weeks, 60° C.
II (5/10)
I A/IB (9/10)

¹Intensity of the light scattering in the circumferential zone A (“white ring”; FIG. 9)

²Intensity of the coloration in the circumferential zones A and B (FIG. 9)

³Intensity of the light scattering in the circumferential zone B (between “white ring” and bottom; FIG. 9)

⁴Qualitative classification

0: not observed

I: weak

II: medium

III: strong

TABLE 8

Summary of the results of optical inspection by

stereo-microscopy³(tubular vials)

Scattering¹,
Coloration²,

Sample set No.
area C
area C

02: Fortis, empty
I (1/5)
0 (5/5)

controls
0 (4/5)

03: Fortis, t0: initial
I (2/10)
0 (10/10)

0 (8/10)

04: Fortis, t1: 5
0 (10/10)
0 (10/10)

weeks, 60° C.

05: Fortis, t2: 10
I (6/10)
0 (10/10)

weeks, 60° C.
0 (4/10)

¹Intensity of the light scattering in the circumferential zone C (“shoulder”; FIG. 10)

²Intensity of the coloration in the circumferential zone C (“shoulder”; FIG. 10)

³Qualitative classification

0: not observed

I: weak

II: medium

III: strong

TABLE 9

Summary of the characteristic features found by SEM analyses¹

Sample

set No.
Body Wall (near bottom)
Body wall (middle)
Body wall (near shoulder)

01
Micro-roughness, 2x
Micro-roughness, 2x
Delaminated areas, 1x

(FIGS.
Deposits (particulate), 2x
Deposits (particulate), 2x
Reaction zones, up to

11-12)
Shallow pits, 2x

about 150 nm*, 2x

Micro-roughness, 2x

Deposits (particulate), 2x

Shallow pits, 2x

02
None
Shallow bumps, 1x
Micro-roughness, 2x

(FIG. 13)

Shallow pits, 1x
Deposits (particulate), 2x

Deposit (planar), 1x

Shallow pits, 1x

03
Micro-roughness, 2x
Micro-roughness, 2x
None

(FIGS.
Deposits (particulate), 2x
Deposits (particulate), 2x

14-15)
Shallow pits, 2x

04
Delaminated areas, 2x
Deposits (particulate), 2x
Deposits (particulate), 2x

(FIGS.
Reaction zones, up to

Shallow pits, 1x

16-17)
about 470 nm*, 2x

Micro-roughness, 2x

Deposits (particulate), 2x

Shallow pits, 2x

¹A classification is made between 8 characteristic features: Shallow pits, shallow bumps, micro-roughness, small holes, deposits (particulate), deposits (planar), reaction zones, and delaminated areas.

*Approximate maximum thickness in nm (the thickness is not homogeneous).

Note:

The digit before “ x” denotes the number of containers with these features.

TABLE 10

Concentrations of the dissolved “glass” elements (ICP-analyses)

Element
Al
B
Ca
Si

Method
ICP-MS
ICP-OES
ICP-OES
ICP-OES

Unit
mg/L
mg/L
mg/L
mg/L

01: RLD vials
<0.05
1.5 ± 30%
0.68 ± 30%
11 ± 15%

03: Fortis,
0.068 ± 30%
1.4 ± 30%
2.3 ± 30%
9.4 ± 1%

t0: initial

04: Fortis, t1:
0.070 ± 30%
2.0 ± 30%
2.2 ± 30%
13 ± 15%

5 weeks, 60° C.

06: Matrix
<0.05
<0.5
2.1 ± 30%
<0.5

solution

Limit of
0.05
0.5
0.5
0.5

Quantification

The relative measurement uncertainties (given in %) were calculated using k = 2.

TABLE 11

Data comparison for chemical composition of sample

set 01 (RLD vial) in % [w/w]

Bormioli
ASTM E

Kimble ¹
Rocco ²
438 ³Type I,

Oxide
Sample 01
KG-35
Type I clear
Class B

Al₂O₃
5.43 ± 0.11
6
5.5
7

BaO
2.23 ± 0.07
2
2.5
0-2

B₂O₃
11.77 ± 0.20
13
11.5
10

CaO
1.41 ± 0.03
1
1
1

MgO
<0.05
0
—
<0.3

K₂O
1.12 ± 0.06
1
1.5
1

Na₂O
8.0 ± 0.3
8
7.5
6

SiO₂
69.5 ± 0.5
69
70.5
73

ZnO
0.022 ± 0.007
0
—
0.1

Fe₂O₃
0.046 ± 0.009
0
—
sum <1.0

MnO
0.041 ± 0.008
0
—

SrO
0.041 ± 0.008
—
—

TiO₂
<0.02
0
—

ZrO₂
0.064 ± 0.013
—
—

¹Ibrahim, H., Blundell, R., Gray, M. Device for Packaging an Oxaliplatin Solution, United States Patent Application 2008/0108697.

²Bormioli Rocco, Alberto Biavati et al., “Complexing Agents and pH Influence on Chemical Durability of Type 1 Moulded Glass Containers”, 2014 PDA Europe Parental Packaging, Mar. 11-12, 2014, Brussles, slide 4.

³ASTM E 438-92-Standard Specifications for Glasses in Laboratory Apparatus.

Example 3—Glass Delamination/Contamination Study of Piramal Molded Vials, Schott Tubular Vials, and Schott Tubular DC Vials

Three additional types of vials of the improved anti-delamination featured according to the present disclosure—Piramal Molded Vials, Schott Tubular Vials, and Schott Tubular DC Vials—were tested using the same protocol in Example 4. Similar results were achieved and summarized in “Example 3” of U.S. Provisional Application 63/317,529.

Example 4—Glass Delamination/Contamination Study of Improved Vials

One additional type of vials of the improved anti-delamination featured according to the present disclosure—Fortis 4R—were tested using the same protocol in Example 4. Similar results were achieved and summarized in “Example 4” of U.S. Provisional Application 63/317,529.