WO2023066988A1

WO2023066988A1 - Glass container with low aluminum content and gas overlay to prevent oxidation of sensitive therapeutic agents

Info

Publication number: WO2023066988A1
Application number: PCT/EP2022/079079
Authority: WO
Inventors: Thomas HIERLMEIER; Mathias STOTZ; Ilaria POSTIGLIONE; Stefan PRASCH; Madeleine SCHREINER; Stephan Weber
Original assignee: Sandoz Ag
Priority date: 2021-10-19
Filing date: 2022-10-19
Publication date: 2023-04-27

Abstract

The present invention relates in general to a glass container comprising a pharmaceutical formulation and a gas overlay in the container headspace above the pharmaceutical formulation, wherein the glass of the glass container has an Al₂O₃ content of less than about 5% Al₂O₃ by weight, and wherein the pharmaceutical formulation comprises an oxidation-sensitive compound. The invention also relates to a medical device comprising such glass container as well as to a method of producing such glass container.

Description

Glass container with low aluminum content and gas overlay to prevent oxidation of sensitive therapeutic agents

The present invention relates to a glass container comprising a pharmaceutical formulation and a gas overlay in the container headspace above the pharmaceutical formulation, wherein the glass of the glass container has an AI2O3 content of less than about 5% (w/w) AI2O3, and wherein the pharmaceutical formulation comprises an oxidation- sensitive compound. The invention also relates to a medical device comprising such glass container as well as to a method of producing such glass container.

Pharmaceutical preparations such as formulations for recombinant proteins, therapeutic antibodies or peptide hormones etc. are frequently oxygen- sensitive and prone to oxidation. Oxidation in turn may lead to a loss of efficacy and potentially even toxicity of the pharmaceutical drug. Moreover, the level of oxidation may differ between different batches of the drug product, making any predictions about the stability of future batches, and in general a sound shelf life determination difficult. Consequently, pharmaceutical manufacturers try to avoid, or at least diminish any form of oxidation in their products and there is a constant need in the art for new means to keep oxidation at low levels, in particular over longer periods of time. Most often, specific formulations containing anti-oxidants or chelating agents are chosen to ensure sufficient stability of the drug product.

An example for an oxidation sensitive biopharmaceutical drug is G-CSF (granulocyte-colony stimulating factor), a polypeptide-based hormone of mammals. It is a cytokine and stimulates inter alia the production of granulocytes. G-CSF also stimulates the survival, proliferation, differentiation, and function of neutrophil precursors and mature neutrophils. G-CSF is used as biopharmaceutical drug to treat pathologically conditions associated with low concentrations in granulocytes and/or neutrophils, such as due to an HIV infection, or as a consequence of chemotherapy. The natural human glycoprotein exists in two forms, a (more active) 174- and (less active) 177-amino-acid-long polypeptide. If the more active form is recombinantly expressed in E. coli, it comprises an extra methionine at its N-terminus. Aggregates of G-CSF can be formed from oxidized forms of the protein that arise by oxidation of methionine residues in the primary sequence of the protein, i.e. either by the methionine residue at the N-terminus or by one of three internal methionine residues.

In this context, EP 1 197 221 Al discloses G-CSF formulations with low content of Met- oxidized G-CSF containing amino acids as stabilizers. Eikewise, EP 1 930 024 A2 discloses a liquid G-CSF formulation in the form of a prefilled syringe formulation containing methionine and additionally arginine or histidine as stabilizer.

Irrespective of these specific formulations, there is still a need in the art for new means to provide for low oxidation levels of pharmaceutical products, in particular of G-CSF formulations. It was therefore an object of the present invention to provide such new means, which allow in particular a more reliable determination of shelf life and low oxidation levels of the drug product in general. Ideally, such new means should avoid the need for anti-oxidants and/or chelating agents in the formulation as such agents may have undesired side effects.

This problem is solved by the subject-matter as set forth below and in the appended claims.

In a first aspect the present invention relates to a glass container comprising a pharmaceutical formulation, and a gas overlay in the container headspace above the pharmaceutical formulation, wherein the glass of the glass container has an AI2O3 content of less than 5% AI2O3, and wherein the pharmaceutical formulation (contained in the container) comprises an oxidation- sensitive compound such as a protein or peptide.

The inventors of the present invention have found that the combined use of a) a gas overlay, in particular with nitrogen, and b) a glass container with a low AI2O3 content provides for a surprisingly efficient means to control oxidation of, e.g., biopharmaceutical products such as proteins and peptides. Using as an example recombinant G-CSF, the inventors showed that while none of a) and b) alone is sufficient to provide for satisfactory control of oxidation over longer periods of time, the combination of both means provides for excellent results.

The container of the present invention is made (at least partially) of glass, preferably neutral glass. Glass is a preferred material for pharmaceutical packing due to its inert character and there are different types of pharmaceutical grade glass and respective standards are covered for example in the European Pharmacopoeia. The glass of the container of the invention is preferably pharmaceutical grade glass, even more preferably pharmaceutical grade glass of type I and type II, most preferably pharmaceutical grade glass of type I. Preferred examples of pharmaceutical glass of type I is borosilicate glass which is particularly hydrolytically resistant and chemically inert. The glass of the glass container of the present invention has a low AI2O3 content, which means lower than about 5% AI2O3. Wherever herein reference is made to a certain percentage of AI2O3, such reference is given in weight percent (w/w%). Preferably, the AI2O3 content is lower than about 4.5%, about 4.0%, about 3.5%, about 3.0%, about 2.9%, about 2.8%, about 2.7%, about 2.6%, about 2.5%, about 2.4%, about 2.3%, about 2.2%, about 2.1%, or even lower than about 2%. Preferably, the AI2O3 content of the inventive glass container is in the range of 1% to 3%, more preferably in the range of 1.5% to 2.5%, most preferably in the range of 2.0 to 2.5%. For example, the glass container may exhibit an AI2O3 content of about 2.0%, about 2.1%, about 2.2%, about 2.3%, about 2.4% or about 2.5%. Commercially available and preferred products meeting the specified requirements are for example W33 from Nipro Pharmapackaging (Belgium, 2.5% AI2O3) and SCHOTT BORO- 8330™ from Schott AG (Germany, 2% AI2O3). It is to be understood that the restriction regarding the AI2O3 content of the glass only applies to those (glass) parts of the glass container, which will indeed come into contact with the pharmaceutical formulation contained in the container, for example during storage. Other parts of the container, which are not, or only transiently in contact with the pharmaceutical formulation, need not (but can of course) meet this limitation. Preferably, the entire glass container has a low AI2O3 content. Preferably, the glass of the glass container is essentially free of iron.

The container may be any type of glass container suitable for pharmaceutical use and primary packaging. The container may for example be a vial, an ampoule, a cartridge, a bottle, a glass syringe, ajar etc. Preferably, the glass container is a vial or glass syringe, even more preferably a glass vial. Most preferably, the glass container is a glass vial made of borosilicate glass. If the container of the invention is a glass vial, such glass vial may comprise a closed bottom and an open bottleneck. Most often, the pharmaceutical formulation will be in direct contact with the surface of the glass container, typically the inner wall of the glass container. However, the inventors also contemplate an embodiment where the glass container is siliconized, i.e., the glass on the inside of the container is (at least partially) coated with an additional layer, such as a silicone layer. In such and similar situations, the pharmaceutical formulation may not be in direct contact with the glass wall of the container. Thereby, the likelihood of oxidative events is even further reduced. However, in most embodiments of the invention such additional precautions are not necessary, i.e., the glass container is not siliconized. In particular, the inner surface of the glass container coming into contact with the pharmaceutical formulation is not siliconized.

The glass container of the present invention is usually a closed container preventing any leakage of the gas contained in the headspace of the glass container. Typically, this means that the inner volume of the glass container is sealed from the outside, effectively preventing undesired leakage of the gas (and the pharmaceutical formulation as a matter of course) from the container and preventing in parallel leakage of oxygen from the environment into the container.

The pharmaceutical formulation contained in the glass container of the present invention can be any pharmaceutical formulation of interest, since the technical solution of the present invention will effectively reduce the number of oxidative events, irrespective of the formulation and therapeutic agent contained in the glass container. Typically, but not necessarily, the pharmaceutical formulation will be a liquid. Lyophilized formulations (e.g., to be reconstituted upon use of the pharmaceutical formulation) are also contemplated. Moreover, the formulation will usually be sterile.

The pharmaceutical formulation comprises at least one oxidation- sensitive agent, which will typically (but not necessarily) be the therapeutic agent itself. In preferred embodiments of the invention, the therapeutic agent will be a biopharmaceutical compound, for example a protein or peptide. Other examples are RNA and DNA-based drug products, fatty acids, etc. Proteins and peptides are composed of amino acids and a number of amino acids are susceptible to oxidation, in particular methionine and cysteine, but also histidine, tyrosine, tryptophan and phenylalanine. The pharmaceutical formulation of the present invention may thus comprise a therapeutic protein or peptide comprising one or more of these amino acid residues. In those embodiments where the oxidation- sensitive agent is a protein or peptide, the protein or peptide is preferably a recombinant protein or recombinant peptide. In particular, the protein or peptide may be a (e.g., recombinant) antibody or a (e.g., recombinant) peptide hormone. Most preferably, the therapeutic agent is granulocyte-colony stimulating factor (hG-CSF), in particular human granulocyte-colony stimulating factor (hG-CSF). An example for recombinant human granulocyte-colony stimulating factor (hG-CSF) is provided in SEQ ID NO:1). An example for an antibody which may be contained in the pharmaceutical formulation is adalimumab. The inventors have shown exemplarily for G-CSF that therapeutic agents benefit from using the inventive combination of gas overlay and low AI2O3 content glass.

In embodiments, where the therapeutic agent is G-CSF, such pharmaceutical formulation is characterized by having in the glass container of the present invention (which is preferably a glass vial) at most an increase to 6.6% in oxidation of G-CSF (determined by reversed phase HPLC as detailed in Table 2) after storage for 24 months at 5°C.

Due to the effective protection against oxidative events, there is less need for the pharmaceutical formulation to comprise excipients which protect against oxidation. This may be reflected by a reduced number and/or reduced amount of such excipients as compared to other formulations of the therapeutic agent in the art. For example, the pharmaceutical formulation of the present invention may be free of citrate, which is frequently used as anti-oxidant and chelator, respectively. Likewise, the pharmaceutical formulation in the inventive container may be free of EDTA, another chelator frequently used in the art. In a preferred embodiment, the pharmaceutical formulation is free of citrate and EDTA. The formulation may in some embodiments also be free of any free amino acids used as stabilizers for the therapeutic agent. Most preferably, the pharmaceutical formulation does not comprise any anti-oxidant and/or chelator at all. Therefore, the invention has a positive effect on treatment (e.g., reduced injection pain caused by citrate) and formulation development (e.g., less complex formulation needed).

Aside of the use of low AI2O3 content glass, the present invention additionally requires a gas overlay in the headspace above the pharmaceutical formulation. Such gas overlay is generally understood and applied in the art and serves the purpose to reduce the content of oxygen in the air coming into contact with the pharmaceutical formulation. The gas is filled into the container to displace oxygen residing there. The gas can in principle be any gas which does not promote oxidation. Evidently, oxygen is not a gas contemplated for use in the present invention. Typically, the gas will be nitrogen or argon. Both gases are inert and do not promote oxidation. Most preferably, the gas is nitrogen. However, the use of a gas overlay does not imply that there is no oxygen at all in the headspace above the pharmaceutical formulation. It merely implies that the concentration of oxygen is reduced significantly below the levels normally contained in air, i.e. about 21.95% oxygen. Ideally, the oxygen content is reduced as low as possible. This requirement is typically limited by the degassing device used, but levels of below 5% (v/v) oxygen are generally possible. Preferably, the oxygen levels in the headspace above the pharmaceutical formulation in the inventive glass container headspace are equal to or less than 5% (v/v), more preferably equal to or less than 4.5% (v/v), more preferably equal to or less than 4% (v/v), more preferably equal to or less than 3.5% (v/v), more preferably equal to or less than 3% (v/v), more preferably equal to or less than 2.5% (v/v), more preferably equal to or less than 2% (v/v), more preferably equal to or less than 1.5% (v/v), more preferably equal to or less than 1% oxygen (v/v). Exemplary devices, which allow a corresponding reduction in headspace oxygen, are commercially available (for example, nitrogen needle gassing systems in pharmaceutical filling lines as well as lyophilisators which enable gas exchange of the interior chamber).

In a second aspect, the present invention relates to a medical device comprising a glass container according to the present invention. For example, the glass container may be an ampoule or vial and the device an injection device which is configured for injection of the pharmaceutical formulation from the container into a given patient in need of the pharmaceutical formulation. The injection device may for example be an auto-injector.

In a third aspect, the present invention relates to a method of producing a sealed glass container comprising a pharmaceutical formulation, the glass container having an AI2O3 content of less than about 5% (w/w) AI2O3, the pharmaceutical formulation comprising an oxidation- sensitive compound such as a protein or peptide, and the method comprising the following steps: a) filling a gas into the headspace of the glass container to displace oxygen from the headspace, and b) sealing the glass container to prevent leakage of the gas from the container.

It is understood that the glass container of the method of the present invention may be the same glass container as set out above in detail for the first aspect of the invention and that respective embodiments of the first aspect of the invention may also be used in the context of the method of the invention. Likewise, the pharmaceutical formulation and gas may be the same as set out above for the first aspect of the invention. Preferably, the method of the present invention uses a glass vial made of borosilicate glass, the gas is nitrogen, and/or the oxidation- sensitive compound is adalimumab or G-CSF, preferably G-CSF. The term "comprising", as used herein, shall not be construed as being limited to the meaning "consisting of" (i.e. excluding the presence of additional other matter). Rather, "comprising" implies that optionally additional matter, features or steps may be present. The term "comprising" encompasses as particularly envisioned embodiments falling within its scope "consisting of (i.e. excluding the presence of additional other matter) and "comprising but not consisting of" (i.e. requiring the presence of additional other matter, features or steps), with the former being more preferred.

The use of the word “a” or “an”, when used herein, may mean “one,” but it is also consistent with the meaning of “one or more,” “at least one,” and “one or more than one.”

The term “oxidation- sensitive compound” is generally understood in the art and is intended to refer to a compound which may undergo oxidation in presence of oxidizing conditions. The term excludes compounds which are chemically stable in presence of oxygen and/or other oxidizing conditions, in particular under standard conditions and over prolonged periods of time (e.g. months). Proteins and peptides comprising one or more methionine, cysteine, histidine, tyrosine, tryptophan and/or phenylalanine residue are examples for oxidation- sensitive compounds.

Figures

In the following a brief description of the appended figures will be given. The figure is intended to illustrate the present invention in more detail. However, it is not intended to limit the scope of the invention to only these specifically illustrated embodiments.

Fig. 1: illustrates the relative levels of the Met-122-oxidation variant in different 0.3 mg/mL G- CSF formulations filled in glass vials of composition 2 wt% vs 5 wt% AI2O3 and with different headspace oxygen content (ambient air (21% O2) vs N2 overlay (<5% residual O2)). The levels were determined by reversed phase high performance liquid chromatography (RP-HPLC) and fluorescence detection performed as detailed in Table 2. Examples

In the following, specific examples illustrating various embodiments and aspects of the invention are presented. However, the present invention shall not to be limited in scope by the specific embodiments described herein. Indeed, various modifications of the invention in addition to those described herein will become readily apparent to those skilled in the art from the foregoing description, accompanying figures and the examples below. All such modifications fall within the scope of the appended claims.

Example 1: Levels of Met- 122 oxidation in liquid in vial (LIVI) formulations of G-CSF

Relative levels of Met-122-oxidation variant in 0.3 mg/mL G-CSF formulations filled in glass vials of different composition (2 wt% vs 5wt% Al) and with different headspace oxygen content (ambient air (21%) vs N2 overlay (<5% residual 02)) were determined by reversed phase high performance liquid chromatography (RP-HPLC) and fluorescence detection. See table 1 for details on the data set. See table 2 for details on RP-HPLC settings.

Table 1 Data basis for Fig 1

A1₂O₃ Headspace Total # batches Batch age Sample content gas results at test matrix

[wt%] [months]

2.00% air 168 67 1-36 50 mg/mL sorbitol, 40 pg/mL PS80, 10 mM acetic acid, pH 4.0

2.00% N2 162 1 0-30 50 mg/mL sorbitol, 40 pg/mL PS80, 10 mM Glutamic acid, pH 4.4

5.00% Air 894 6 0-30 50 mg/mL sorbitol, 40 pg/mL PS80, 10 mM Glutamic acid, pH 4.4 AI2O3 Headspace Total # batches Batch age Sample content gas results at test matrix

[wt%] [months]

5.00% N2 684 6 0-30 50 mg/mL sorbitol, 40 pg/mL PS80, 10 mM Glutamic acid, pH 4.4

Table 2 RP-HPLC method parameters

Parameter Setting

Column C18, 300A, 3.5 pm, 150 x 4.6 mm i.d.

Applied amount 3 pg (10 pL injection)

Detection Fluorescence (excitation at 280nm, emission detection at 345nm)

Claims

CLAIMS A glass container comprising a pharmaceutical formulation and a gas overlay in the container headspace above the pharmaceutical formulation, wherein the glass of the glass container has an AI2O3 content of less than about 5% AI2O3 (wt%), and wherein the pharmaceutical formulation comprises an oxidation- sensitive compound such as a protein or peptide. The glass container of claim 1, wherein the glass container is a vial, an ampoule, a cartridge, a bottle, a glass syringe or ajar, preferably wherein the glass container is a vial or syringe, most preferably a vial. The glass container of any one of the preceding claims, wherein the glass of the glass container is made of pharmaceutical grade glass, preferably pharmaceutical grade glass of type 1. The glass container of any one of the preceding claims, wherein the glass of the glass container is borosilicate glass. The glass container of any one of the preceding claims, wherein the glass of the glass container has an AI2O3 content of less than 3% AI2O3 (wt%), preferably an AI2O3 content in the range of about 2.0 to about 2.5 % AI2O3 (wt%). The glass container of any one of the preceding claims, wherein the gas is nitrogen or argon, preferably nitrogen. The glass container of any one of the preceding claims, wherein the oxygen levels in the headspace are equal to or less than about 5% (v/v), preferably equal to or less than about 2% (v/v), more preferably about 1% (v/v) or less. The glass container of any one of the preceding claims, wherein the pharmaceutical formulation is in direct contact with the inner surface of the glass container. The glass container of any one of the preceding claims, wherein the oxidation- sensitive compound is a protein or peptide, in particular an antibody or a peptide hormone. The glass container of any one of the preceding claims, wherein the oxidation- sensitive compound is granulocyte-colony stimulating factor (G-CSF), in particular human granulocyte-colony stimulating factor (hG-CSF). The glass container of any one of the preceding claims, wherein the pharmaceutical formulation does not contain citrate and/or EDTA. The glass container of any one of the preceding claims, wherein the pharmaceutical formulation does not contain an anti-oxidant. The glass container of any one of the preceding claims, wherein the pharmaceutical formulation does not contain a chelating agent. A medical device comprising a glass container of any one of the preceding claims. Method of producing a sealed glass container comprising a pharmaceutical formulation, the glass container having an AI2O3 content of less than about 5% AI2O3 (wt%), the pharmaceutical formulation comprising an oxidation- sensitive compound such as a protein or peptide, and the method comprising the following steps: a) filling a gas into the headspace of the glass container to displace oxygen from the headspace, and b) sealing the glass container to prevent leakage of the gas from the container.