Method of removing metal contaminants from glass syringes

Abstract

The present invention relates to a method of removing metal-containing contaminants from a surface of a glass syringe comprising contacting the surface of the glass syringe with a water treatment medium comprising fluoride ions, at least one acid, or both. The metal-containing contaminant is coupled to a surface of the glass syringe and is present on the surface at a concentration greater than or equal to 50 ppb prior to contact with the water treatment medium, and contacting the water treatment medium with the surface for a period of contact time reduces the concentration of the metal-containing contaminants on the surface of the glass syringe by greater than or equal to 50%. A method of manufacturing a glass syringe may include forming a glass syringe having at least a barrel and a syringe head and then removing metal-containing contaminants from a surface thereof by contact with a water treatment medium.

Description

[0001] Cross - Reference to Related Applications

[0002] This application claims priority to U.S. Provisional Application No. 63 / 427,293, filed on Nov. 22, 2022, under 35 U.S.C. § 119, the content of which is hereby incorporated by reference in its entirety. Technical Field

[0003] This specification generally relates to glass syringes, and more particularly, to methods for removing metal contaminants from the surface of a glass syringe. Background Art

[0004] For a long time, glass has been used as the preferred material for pharmaceutical packaging due to its airtightness, optical transparency, and better chemical durability compared to other materials. Specifically, the glass used for pharmaceutical packaging must have sufficient chemical durability so as not to affect the stability of the pharmaceutical composition contained therein. Glasses with suitable chemical durability include glass compositions that conform to the ASTM standard “Type 1B”, and this type of glass has been verified for chemical durability. Additionally, the glass used for pharmaceutical packaging (such as glass syringes) must be substantially free of contaminants and chemicals that would interact with the contents of the pharmaceutical packaging and thus reduce the effectiveness of the pharmaceutical composition contained therein. Summary of the Invention

[0005] According to a first aspect disclosed herein, a method of manufacturing a glass syringe can include forming a glass syringe having at least a barrel and a syringe tip, wherein forming the syringe tip includes contacting at least one surface of the glass syringe with a forming tool, a forming pin, or both, and the contacting can cause metal - containing contaminants to transfer to at least one surface of the glass syringe. The method can further include contacting at least one surface of the glass syringe with a water treatment medium comprising fluoride ions, at least one acid, or both, wherein the contact with the water treatment medium removes the metal - containing contaminants from at least one surface of the glass syringe.

[0006] According to a second aspect disclosed herein, a method for removing metal-containing contaminants from at least one surface of a glass syringe can include contacting at least one surface of the glass syringe with a water treatment medium comprising fluoride ions, at least one acid, or both, wherein the metal-containing contaminants can be coupled to at least one surface of the glass syringe and are present on at least one surface at a concentration greater than or equal to 8.3 parts per billion by weight (ppbw) prior to contact with the water treatment medium, as determined according to the test method in USP <797>. Contacting the water treatment medium with at least one surface for a contact time can reduce the concentration of the metal-containing contaminants on at least one surface of the glass syringe by greater than or equal to 50%.

[0007] A third aspect of the present disclosure can include either the first or second aspect, wherein at least one surface of the glass syringe can be the inner surface of the syringe tip of the glass syringe.

[0008] A fourth aspect of the present disclosure can include any one of the first to third aspects, wherein the concentration of the metal-containing contaminants on at least one surface of the syringe is 8.3 ppbw to 83 ppbw, as determined according to the test method in the United States Pharmacopeia <797>.

[0009] A fifth aspect of the present disclosure can include any one of the first to fourth aspects, wherein contacting at least one surface of the glass syringe with the water treatment medium can remove greater than or equal to 50% of the metal-containing contaminants from at least one surface of the syringe tip.

[0010] A sixth aspect of the present disclosure can include any one of the first to fifth aspects, wherein after contacting at least one surface of the glass syringe with the water treatment medium, the concentration of the metal-containing contaminants on at least one surface of the glass syringe can be less than 8.3 ppbw, less than or equal to 4 ppbw, less than or equal to 1 ppbw, less than or equal to 0.1 ppbw, less than or equal to 100 pptw, or even less than or equal to 10 pptw, as determined according to the test method in the United States Pharmacopeia <797>.

[0011] A seventh aspect of the present disclosure can include any one of the first to sixth aspects, wherein the metal-containing contaminants can include one or more metals selected from the group consisting of tungsten, platinum, rhodium, tantalum, nickel, and combinations thereof.

[0012] An eighth aspect of the present disclosure can include any one of the first to seventh aspects, wherein the metal-containing contaminants can include tungsten or its derivatives.

[0013] A ninth aspect of the present disclosure can include any one of the first to eighth aspects, wherein the metal-containing contaminants can include tungsten oxide.

[0014] The tenth aspect of the present disclosure may include any one of the first to ninth aspects, wherein the water treatment medium may contain fluoride ions, and as calculated using Visual MINTEQ software with standard settings, the concentration of fluoride ions in the water treatment medium may be about 1000 ppm. TM The concentration of fluoride ions in the water treatment medium may be about 1000 ppm.

[0015] The eleventh aspect of the present disclosure may include any one of the first to tenth aspects, wherein the water treatment medium may contain fluoride ions, and based on the total weight of the water treatment medium, the concentration of fluoride ions in the water treatment medium may be about 0.001 wt.% to 0.15 wt.%.

[0016] The twelfth aspect of the present disclosure may include any one of the first to eleventh aspects, wherein the water treatment medium may contain a source of fluoride ions selected from the group consisting of hydrogen fluoride (HF), sodium fluoride (NaF), ammonium bifluoride (NH4HF2), and combinations thereof.

[0017] The thirteenth aspect of the present disclosure may include any one of the first to twelfth aspects, wherein the water treatment medium may contain at least one acid.

[0018] The fourteenth aspect of the present disclosure may include the thirteenth aspect, wherein the at least one acid may be an organic acid, and the organic acid is a chelating organic acid.

[0019] The fifteenth aspect of the present disclosure may include any one of the first to fourteenth aspects, wherein the at least one acid may be selected from the group consisting of HCl, HBr, HNO3, H2SO4, H2SO3, H3PO4, H3PO2, acetic acid, citric acid, tartaric acid, ascorbic acid, EDTA, methanesulfonic acid, toluenesulfonic acid, and combinations thereof.

[0020] The sixteenth aspect of the present disclosure may include any one of the thirteenth to fifteenth aspects, wherein the at least one acid may be an organic acid selected from the group consisting of acetic acid, citric acid, tartaric acid, ascorbic acid, EDTA, methanesulfonic acid, toluenesulfonic acid, and combinations thereof.

[0021] The seventeenth aspect of the present disclosure may include any one of the thirteenth to sixteenth aspects, wherein the at least one acid may be citric acid.

[0022] The eighteenth aspect of the present disclosure may include any one of the first to seventeenth aspects, which includes contacting at least one surface of a glass syringe with a water treatment medium containing fluoride ions and at least one acid.

[0023] The nineteenth aspect of the present disclosure may include any one of the first to eighteenth aspects, wherein the water treatment medium may contain a source of fluoride ions selected from the group consisting of hydrogen fluoride (HF), sodium fluoride (NaF), ammonium bifluoride (NH4HF2), and combinations thereof, and at least one acid may be selected from the group consisting of HCl, HBr, HNO3, H2SO4, H2SO3, H3PO4, H3PO2, acetic acid, citric acid, tartaric acid, ascorbic acid, EDTA, methanesulfonic acid, toluenesulfonic acid, and combinations thereof.

[0024] The twentieth aspect of the present disclosure may include the nineteenth aspect, wherein the water treatment medium may contain citric acid and ammonium bifluoride.

[0025] The twenty - first aspect of the present disclosure may include the twentieth aspect, wherein the water treatment medium may contain 0.026 moles (M) to 0.26 M of ammonium bifluoride and 0.5 M to 2 M of citric acid.

[0026] The twenty - second aspect of the present disclosure may include any one of the twentieth or twenty - first aspects, wherein the water treatment medium may contain citric acid at a concentration of 1 M and ammonium bifluoride at a concentration of 0.26 M.

[0027] The twenty - third aspect of the present disclosure may include any one of the first to twenty - second aspects, which includes contacting at least one surface of a glass syringe with the water treatment medium at a contact temperature of 0 °C to 105 °C, and the contact time is 10 seconds to 24 hours, such as 2.5 minutes to 30 minutes.

[0028] The twenty - fourth aspect of the present disclosure may include the twenty - third aspect, which includes contacting at least one surface of a glass syringe with the water treatment medium for a contact time of less than or equal to 10 minutes, such as 2.5 minutes to 10 minutes.

[0029] The twenty - fifth aspect of the present disclosure may include any one of the first to twenty - fourth aspects, which includes contacting at least one surface of a glass syringe with the water treatment medium at a contact temperature equal to room temperature.

[0030] The twenty - sixth aspect of the present disclosure may include any one of the first to twenty - fifth aspects, wherein forming a glass syringe may include forming the syringe head of the glass syringe and separating the glass syringe from the glass tube.

[0031] The twenty-seventh aspect of the present disclosure may include the twenty-sixth aspect, wherein forming the syringe head may include: heating the working end of a glass tube; inserting a forming pin into the inner cavity of the glass tube at the working end of the glass tube; and bringing at least two opposing forming tools into contact with the outer surface of the working end of the glass tube. Bringing at least two opposing forming tools into contact with the outer surface of the working end of the glass tube may reduce the outer diameter of the working end of the glass tube to form the syringe head, and the forming pin may remain axially extending through the opening of the syringe head during contact with the at least two opposing forming tools.

[0032] The twenty-eighth aspect of the present disclosure may include the twenty-seventh aspect, which further includes removing the at least two opposing forming tools from contact with the outer surface of the working end of the glass tube; and removing the forming pin from inside the glass tube, wherein removing the forming pin may cause friction between the forming pin and at least one surface of the glass tube, which results in the transfer of metal-containing contaminants from the forming pin to at least one surface of the glass tube.

[0033] Additional features and advantages of the glass syringes and methods disclosed herein will be set forth in the detailed description below, and some of the features and advantages will be readily apparent to those skilled in the art from the description, or may be recognized by practicing the embodiments described herein (including the following detailed description, claims, and drawings).

[0034] It should be understood that both the foregoing general description and the following detailed description describe various embodiments and are intended to provide an overview or framework for understanding the nature and characteristics of the claimed subject matter. Drawings are included to provide a further understanding of the various embodiments and are incorporated into and constitute a part of this specification. The drawings illustrate the various embodiments described herein and, together with the detailed description, are used to explain the principles and operations of the claimed subject matter. BRIEF DESCRIPTION OF THE DRAWINGS

[0035] Figure 1 A cross-sectional view of a glass syringe is schematically depicted in accordance with one or more embodiments shown and described herein;

[0036] Figure 2 Schematically shown is a cross-sectional view of a glass tube for manufacturing a Figure 1 glass syringe in accordance with one or more embodiments shown and described herein;

[0037] Figure 3 A front view of a heating station for heating the working end of a glass tube is schematically depicted in accordance with one or more embodiments shown and described herein; Figure 2 of the glass tube

[0038] Figure 4Schematically depicts a forming station for a syringe head of a glass syringe for forming according to one or more embodiments shown and described herein; Figure 1 Front view of the forming station;

[0039] Figure 5 Schematically depicts a front view of the forming station at the end of forming a syringe head of a glass syringe according to one or more embodiments shown and described herein; Figure 4 Front view of the forming station;

[0040] Figure 6 Schematically depicts a cross-sectional view of a syringe head of a glass syringe after forming the syringe head according to one or more embodiments shown and described herein; Figure 1 Cross-sectional view of the syringe head of the glass syringe;

[0041] Figure 7 Schematically depicts a cross-sectional view of a syringe head after treatment with a water treatment medium according to one or more embodiments shown and described herein; Figure 6 Cross-sectional view of the syringe head after treatment with the water treatment medium;

[0042] Figure 8 Graphically depicts the relationship between the metal concentration (y-axis) on the surface of a glass syringe and the contact time with a water treatment medium (x-axis) according to one or more embodiments shown and described herein;

[0043] Figure 9 Graphically depicts the relationship between the molar ratio of sodium to silicon (y-axis) and the contact time with a water treatment medium (x-axis) according to one or more embodiments shown and described herein;

[0044] Figure 10 Graphically depicts the relationship between the tungsten concentration (y-axis) on the surface of a glass syringe and the contact time with a water treatment medium and with phosphoric acid (x-axis) according to one or more embodiments shown and described herein;

[0045] Figure 11A and 11B are scanning electron microscope (SEM) backscattered images of the surface of the glass syringe before contact with the water treatment medium;

[0046] Figure 12A and 12B are SEM backscattered images of the surface of the glass syringe after contact with a citric acid solution at 80°C for 7.5 minutes according to one or more embodiments shown and described herein;

[0047] Figure 13A and 13B are SEM backscattered images of the surface of the glass syringe after contact with phosphoric acid at 80°C for 7.5 minutes according to one or more embodiments shown and described herein; and

[0048] Figure 14A and 14B is a SEM backscattered image of the surface of a glass syringe after contact with a water treatment medium at 20 °C, according to one or more embodiments shown and described herein. DETAILED DESCRIPTION

[0049] Reference will now be made in detail to various embodiments of a glass syringe and a method for removing metal-containing contaminants from the surface of the glass syringe, examples of which are schematically depicted in the accompanying drawings. With reference now to Figure 1 , an embodiment of a glass syringe 100 disclosed herein is schematically depicted. The glass syringe 100 has a barrel 102 and a syringe tip 110 at one end of the barrel 102. In an embodiment, the syringe 100 may have a flange 120 at the other end of the barrel 102. The glass syringe 100 may be prepared from a glass tube by a conversion process during which the working end of the glass tube is heated and then machined with one or more forming tools to form the syringe tip 110, the flange 120, or other features of the glass syringe 100. The method of manufacturing the glass syringe 100 may include forming the glass syringe 100 having at least the barrel 102 and the syringe tip 110. Forming the syringe tip 110 may include contacting at least one surface of the glass syringe 100 with a forming tool, a forming pin, or both. The contact may cause metal-containing contaminants to transfer to at least one surface of the glass syringe 110. The method of manufacturing the glass syringe 100 may further include contacting at least one surface of the glass syringe 100 with a water treatment medium comprising fluoride ions, at least one acid, or both, wherein contacting with the water treatment medium removes at least a portion or all of the metal-containing contaminants from at least one surface of the glass syringe 100.

[0050] As described above, forming the glass syringe 100 from a glass tube may cause metal-containing contaminants to transfer from the forming tool to one or more surfaces of the glass syringe 100. Aspects of the present disclosure may relate to a method for removing metal-containing contaminants from the surface of the glass syringe 100, the method comprising contacting the surface of the glass syringe 100 with a water treatment medium comprising fluoride ions, at least one acid, or both. The metal-containing contaminants may adhere to the surface of the glass syringe 100 and be present on the surface at a concentration greater than or equal to 8.3 parts per billion by weight (ppbw) prior to contact with the water treatment medium, as determined according to the test method in USP <797>. Contacting the water treatment medium with the surface of the glass syringe 100 for a contact time may reduce the concentration of metal-containing contaminants on the surface of the glass syringe 100 by greater than or equal to 50%.

[0051] The methods disclosed herein can provide glass syringes that are substantially free of metal-containing contaminants (such as tungsten or its derivatives) on the surface of the glass syringe, which will allow the glass syringes to be used for sensitive pharmaceutical products (such as protein-based pharmaceutical products that are sensitive to tungsten and / or other metal-containing contaminants). The water treatment medium has a low fluoride content (such as less than commercial toothpaste), is environmentally friendly, and can be scaled up to industrial manufacturing of glass syringes, among other features.

[0052] Unless otherwise expressly stated, no method set forth herein is intended to be construed as requiring that its steps be performed in a particular order, nor is any apparatus herein intended to require a particular orientation. Accordingly, if a method claim does not actually recite the order in which its steps are to be performed, or if an apparatus claim does not actually recite the order or orientation of parts, or if in a claim or description it is not otherwise specifically set forth that the steps will be limited to a particular order, or that the parts of the apparatus will be limited to a particular order or orientation, then it is not intended that any order or orientation be inferred in any respect. This applies to any possible non-explicit basis of interpretation, including: logical issues with respect to step arrangement, operational flow, part order, or part orientation; plain meaning derived from grammatical organization or punctuation; and the number or type of embodiments described in the specification.

[0053] As used herein, directional terms such as up, down, right, left, front, back, top, bottom are made only with reference to the drawings being drawn and are not intended to imply absolute orientation.

[0054] As used herein, unless the context clearly dictates otherwise, the singular forms "a", "an", and "the" include plural referents. Thus, for example, reference to "a" component includes aspects having two or more such components, unless the context clearly states otherwise.

[0055] As used herein, terms such as "container" and "vessel" refer to any article adapted to hold solids or fluids for storage.

[0056] As used herein, the "working end" of a glass tube is the end of the glass tube that is oriented towards the processing station of the glass tube converter and that is heated and shaped to produce one or more features of the glass syringe.

[0057] As used herein, the "non-working end" of a glass tube is the end of the glass tube that is oriented away from the processing station of the glass tube converter.

[0058] When used in reference to a forming tool in a forming station, the term "engagement" means that the forming tool contacts the glass tube. When the forming tool is disengaged, the forming tool does not contact the glass tube.

[0059] As used herein, the term "circumference" of a glass tube refers to the set of points of the glass tube 130 on a 360-degree circumference having a constant radius r, with respect to the central axis D of the glass tube 130, at a particular Z position (i.e., a position on the + / -Z axis of the figure). For example, the circumference of the glass tube 130 may coincide with the outer surface 132 of the glass tube 130 at a particular Z position, or with the inner surface 134 of the glass tube 130 at a particular Z position.

[0060] For a long time, glass has been the material of choice for pharmaceutical packaging due to its gas tightness, optical transparency, and superior chemical durability compared to other materials. Specifically, the glass used for pharmaceutical packaging must have sufficient chemical durability so as not to affect the stability of the pharmaceutical composition contained therein. Glasses having suitable chemical durability include those glass compositions that meet the ASTM standard "Type 1B", and glasses of this type have been verified for chemical durability. Glass can be formed into containers having various shape specifications, which may include, but are not limited to, vials, syringes, cartridges, ampoules, cans, or other types of containers.

[0061] Referring again to Figure 1 , one such shape specification is the glass syringe 100. The glass syringe 100 disclosed herein may at least include a barrel 102 and a syringe tip 110 formed at the outlet end 104 of the glass syringe 100. In an embodiment, the glass syringe 100 may further include a flange 120 formed at the open end 106 of the glass syringe 100. The barrel 102 may include an inner surface 103 that defines the inner cavity 108 of the glass syringe 100. When the glass syringe 100 is pre-filled, the inner cavity 108 of the glass syringe 100 may contain one or more pharmaceutical materials. The syringe tip 110 may include an outer surface 112 and an inner surface 114. The outer surface 112 of the syringe tip 110 may include an outer diameter that is smaller than the outer diameter of the outer surface of the barrel 102. In an embodiment, the outer surface 112 of the syringe tip 110 may taper from a larger outer diameter at the junction with the barrel 102 to a smaller outer diameter at the outlet end 104 of the glass syringe 100. The inner surface 114 of the syringe tip 110 may define a channel 116 that extends axially (e.g., in the + / -Z direction of the coordinate axes in Figure 1 ) through the syringe tip 110 from the inner cavity 108 of the glass syringe 100 to the outlet end 104. The channel 116 provides a flow path for pre-filling the glass syringe 100 and / or dispensing the contents of the glass syringe 100 from the inner cavity 108 through the outlet end 104 of the glass syringe 100. In an embodiment, the syringe tip 110 may be configured to receive one or more accessories, such as a needle assembly or other accessories for filling the glass syringe 100 and / or dispensing the contents of the glass syringe 100.

[0062] The glass syringe 100 can be a container for containing any composition, and in embodiments, can be used for containing pharmaceutical compositions. The glass syringe 100 can be made of glass suitable for containing sterile substances, such as but not limited to vaccines, biologics, pharmaceutical compositions, foods, solutions, etc. The pharmaceutical composition can include any chemical substance intended for the medical diagnosis, cure, treatment, or prevention of diseases. Examples of pharmaceutical compositions include but are not limited to pharmaceuticals, drugs, medicaments, remedies, etc. The pharmaceutical composition can be in the form of a liquid, solid, gel, suspension, powder, etc.

[0063] The glass syringe 100 disclosed herein can be formed from a variety of different glass compositions. The specific glass composition of the glass syringe 100 can be selected according to the specific application such that the glass has a desired set of physical properties. In embodiments, the glass of the glass syringe 100 can be a glass composition known to exhibit chemical durability and low thermal expansion, such as but not limited to alkaline borosilicate glass. In embodiments, the glass composition of the glass article 102 can be silicate glass, aluminosilicate glass, alkaline aluminosilicate glass, ion-exchanged aluminosilicate glass, ion-exchanged alkaline aluminosilicate glass, borosilicate glass, ion-exchanged borosilicate glass, soda-lime glass, or a combination thereof. In embodiments, the glass syringe 100 can contain a glass composition that complies with the pharmaceutical glass standards described in the United States Pharmacopeia (USP) <600> or the European Pharmacopoeia 7. According to an embodiment, the glass article 102 can be formed from type I class B glass as defined according to ASTM standard E438-92.

[0064] The glass syringe 100 can have a coefficient of thermal expansion in the range of about 25×10 -7 / °C to 80×10 -7Glass composition formation within the range of / °C. For example, in an embodiment, the glass syringe 100 can be formed from an alkaline aluminosilicate glass composition, which can be easily strengthened by ion exchange. Such glass compositions typically can include a combination of SiO2, Al2O3, at least one alkaline earth metal oxide, and one or more alkaline oxides (such as Na2O and / or K2O). In an embodiment, the glass composition can be free of boron and boron-containing compounds. In an embodiment, the glass composition can further contain a small amount of one or more additional oxides, such as SnO2, ZrO2, ZnO, TiO2, As2O3, etc. The small amount can include an amount of the additional oxide that is less than about 5 weight percent (mol%), less than about 2 mol%, or even less than about 1 mol% based on the total moles of the glass. These additional oxide components can be added as clarifying agents during the glass manufacturing process to further enhance the chemical durability of the glass composition or impart other properties to the glass composition.

[0065] In a specific exemplary embodiment, the glass syringe 100 can be formed from the ion-exchangeable glass composition described in U.S. Patent No. 8,980,777, entitled "Glass Compositions with Improved Chemical and Mechanical Durability," issued on March 17, 2015, which is assigned to Corning, Incorporated. However, it should be understood that the glass syringe 100 described herein can be formed from other glass compositions, including but not limited to ion-exchangeable glass compositions and non-ion-exchangeable glass compositions. For example, in an embodiment, the glass syringe 100 can be formed from borosilicate glass. In an embodiment, the glass syringe 100 can be formed from a Type 1B glass composition, such as Schott Type 1B borosilicate glass. In an embodiment, the glass syringe 100 can be formed from an ion-exchangeable borosilicate glass composition, such as those described in co-pending U.S. Application No. 16 / 533,954, entitled "Ion Exchangeable Borosilicate Glass Compositions and Glass Articles Formed from the Same," filed on August 7, 2019, which is assigned to Corning, Incorporated.

[0066] In the embodiments described herein, the glass syringe 100 can be formed from a glass composition that meets the pharmaceutical glass standards based on its hydrolytic resistance as described by regulatory agencies such as the United States Pharmacopeia (USP), the European Pharmacopeia (EP), and / or the Japanese Pharmacopeia (JP). According to USP <660> and EP 7, borosilicate glass meets Type I standards and is commonly used for parenteral packaging. Examples of borosilicate glass include, but are not limited to 7740, 7800, Wheaton 180, 200, and 400, Schott Duran, Schott Fiolax, N-51A, Gerrescheimer Flint, etc. Soda-lime glass meets Type III standards and is acceptable for the packaging of dry powders that are subsequently dissolved to prepare solutions or buffers. Type III glass is also suitable for packaging liquid formulations that are proven to be insensitive to alkalis. Examples of Type III soda-lime glass include Wheaton 800 and 900. Depleted-alkali soda-lime glass has a higher level of sodium hydroxide and calcium oxide and meets Type II standards. These glasses have a lower leachability than Type I glass but are stronger than Type III glass. Type II glass can be used for products that maintain a pH below 7 during their shelf life. Examples include ammonium sulfate-treated soda-lime glass. These pharmaceutical glasses have different chemical compositions and have a linear coefficient of thermal expansion (CTE) in the range of 20 - 85×10 -7 / °C.

[0067] The glass syringe 100 can be made from a glass tube. Now referring to Figure 2 , the glass tube 130 can be an elongated hollow cylindrical tube made of glass. The glass tube 130 can have a circular cross-sectional shape and can have an outer surface 132, an inner surface 134, and a thickness t. The thickness t of the glass tube 130 can be the radial distance between the outer surface 132 and the inner surface 134 of the glass tube 130. The glass tube 130 can have a length L in the + / −Z direction of the coordinate axes of Figure 2 . The glass tube 130 can have an outer diameter OD as shown in Figure 2 . As described above, throughout the conversion process, the glass tube 130 can rotate about the central axis B of the glass tube 130. The glass tube 130 can have a working end 136 and a non-working end 138. The working end 136 of the glass tube 130 is the end of the glass tube 130 that is oriented towards the processing station of the converter and is also the end of the glass tube 130 that is heated and flame processed to produce the various features of the glass syringe 100. The non-working end of the glass tube 130 is the end opposite to the working end 150 (i.e., the end of the glass tube 130 in the +Z direction of the coordinate axes of Figure 2 ).

[0068] A conversion process can be used to convert a glass tube 130 into a glass syringe 100, or other glass containers for pharmaceutical applications, including but not limited to vials, syringes, ampoules, cartridges, and other glass articles, and the conversion process can be carried out using a "conversion machine". Conversion machines have been in use for over 75 years and are currently manufactured by various commercial and in-house equipment suppliers. Throughout this disclosure, the terms "conversion machine" and "converter" mean the same thing and can be used interchangeably. A converter including multiple processing stations can be used to convert the glass tube 130 into a glass syringe 100. The processing stations can include heating stations, forming stations, separation stations, cooling stations, or other types of processing stations. Conversion machines generally reshape a long glass tube section into multiple glass articles using steps including but not limited to flame working, rotary and stationary tool forming, separation (such as thermal separation or scoring and impact cutting steps), cooling, measuring, polishing, or other processing steps. Thus, the glass articles produced by the conversion process carried out on a conversion machine are subjected to a series of flame burners or other heating elements and forming tools to form the glass tube into a specific shape and size and to separate the formed glass article from the glass tube.

[0069] The converter can be an indexing converter or a continuous converter. In an embodiment, the converter can be an indexing converter, which can be operated to index the glass tube 130 sequentially through each of a plurality of processing stations. In an indexing converter, each processing station can be fixed at a specific position within the loop of the converter. The glass tube 130 can remain in each of the plurality of processing stations for a dwell time and then be indexed to the next processing station in the loop during the indexing time of the converter. In an embodiment, the converter can be a continuous converter, which can be operated to move the glass tube 130 continuously through a plurality of processing stations. In an embodiment, when the glass tube 130 passes through a processing station, heating elements, burners, forming tools, measuring devices, and other elements of the conversion process can move with the glass tube. For both indexing converters and continuous converters, the "active time" of a processing station is the duration that the glass tube 130 remains engaged with at least one heating element, at least one forming tool, at least one cooling nozzle, or other device within the processing station.

[0070] Examples of converters for converting glass tubes 130 into glass articles include vial forming machines of models RP16 or RP18 with automatic tube feeders, manufactured by AMBEG Dr. J. Dichter. Other examples include vial forming machines of model RP32, manufactured by AMBEG Dr. J. Dichter, and Zeta 098 vial forming machines, manufactured by Euromatic S.R.L. Another example may include a Zeta 103 tube forming machine, manufactured by Euromatic S.R.L., which is a converter for converting glass tubes into glass tubes. The tube converter has similar characteristics to the aforementioned vial converters, but is used to produce glass articles with the shape specifications of tubes rather than vials. Examples of converters for converting glass tubes into glass syringes may include, but are not limited to, syringe converters of models GS24 / 16 and GS36 / 15-2, manufactured by the Stevanato Group. Syringe converters of other brands and models may also be used to convert glass tubes into glass syringes.

[0071] As previously described, the converter for producing the glass syringe 100 may include multiple processing stations. The shape of the glass syringe 100 made from the glass tube 130 may affect the total number of processing stations of the converter. The processing stations may include, for example, but are not limited to, one or more heating stations, forming stations, flame polishing stations, cooling stations, separation stations, measurement stations, feeding stations, discharging stations, other processing stations, or combinations thereof, for producing the glass syringe 100 from the glass tube 130. The type and / or shape of the glass syringe 100 may affect the type and / or order of the processing stations 106 of the converter 100.

[0072] The converter may have a main circuit of processing stations for forming one or more features at the working end of the glass tube and separating the partially finished glass syringe from the glass tube. The converter may further include a secondary circuit having multiple processing stations for forming one or more features, such as a flange 120 or other structure, at the open end 106 of the glass syringe 100. The main circuit may include processing stations configured to form a syringe tip 110 at the outlet end 104 of the glass syringe 100. The main circuit of the converter may include one or more heating stations, one or more forming stations, a separation station, one or more cooling stations, a measurement station, a tube length drop station, a tube loading station, or other types of processing stations. The secondary processing stations of the secondary circuit may include one or more heating stations, forming stations, flame polishing stations, cooling stations, measurement stations, unloading stations, or other stations, or combinations of secondary processing stations.

[0073] Referring now to Figure 3 , the converter may include a plurality of grippers 140 configured to removably grip each glass tube 130 and to continuously convey each glass tube 130 through each processing station of the converter. The grippers 140 may be clamps, chucks, or other gripping devices, or combinations of gripping devices. The grippers 140 may orient each glass tube 130 such that when the grippers 140 index or continuously pass the glass tube 130 through a plurality of processing stations, the working end 136 of the glass tube 130 is positioned within each processing station. The converter may be vertically oriented or horizontally oriented. When vertically oriented, the grippers 140 may grip the glass tube 130 such that the central axis B of the glass tube 130 is parallel to the vertical direction. When horizontally oriented, the grippers 140 may grip the glass tube 130 such that the central axis B of the glass tube 130 is horizontal (e.g., perpendicular to the vertical direction). The grippers 140 are shown in Figure 2 gripping the glass tube 130 such that the central axis B is parallel to Figure 2 the + / -Z direction. It should be understood that the + / -Z direction may be the vertical direction, the horizontal direction, or any other direction.

[0074] Each gripper 140 may be rotated independently relative to the processing station to rotate the glass tube 130 about the central axis B of the glass tube 130. Rotation of the grippers 140 allows the glass tube 130 to rotate about the central axis B of the glass tube 130 relative to a fixed burner, forming tool, cooling nozzle, or other features of the processing station. The heating element or forming tool within the processing station may be held in a fixed position relative to the glass tube 130, and rotation of the glass tube 130 about the central axis B may expose the entire circumference of the glass tube 130 to the heating element or forming tool.

[0075] In a typical converter, the forming station of the main loop may be downstream of the heating station in the direction in which the glass tube 130 is conveyed through the main loop of the processing stations. The forming station may repeatedly form the glass tube 130 to form one or more features of the glass syringe 100, such as the syringe head 110. As described above, one or more heating stations may be provided before each forming station to preheat the target region of the glass tube 130 to a temperature at which the glass tube 130 may be formed and the desired features may be formed. The forming station of the main loop may form the working end 136 of the glass tube 130 to form a feature at the outlet end 104 of the glass syringe 100, and after the partially formed glass syringe has been separated from the glass tube 130, the forming station of the secondary turntable may form the open end of the glass syringe 100.

[0076] As described above, with respect to the conveyance direction of the glass tube 130 through each processing station, the converter may include one or more heating stations upstream of the forming station to preheat a target region of the glass tube 130 before forming in the forming station. Referring again to Figure 3 , an embodiment of a heating station 150 for heating a target region 151 of the glass tube 130 is schematically depicted. Each heating station 150 may include one or more heating elements 152. As Figure 3 shown, in an embodiment, the heating element 152 may include one or more burners 154 for heating the target region 151 of the glass tube 130 before performing a forming operation at the forming station 170 ( Figure 4 ). Although Figure 3 a single burner 154 is depicted, it should be understood that multiple burners 154 may be employed in a single heating station 150. Fuel gas 156, oxygen-containing gas 158, and optional air 160 may be delivered to the burner 154. Examples of fuel gas 156 for the burner 154 may include but are not limited to hydrogen, hydrocarbon fuel gases (such as methane, propane, and butane), other fuel gases, or combinations thereof. The burner 154 burns the fuel gas 156 in the presence of oxygen from the oxygen-containing gas 158 and / or air 160 to produce a flame that at least heats the target region 151 of the glass tube 130. Although the heating station 150 of the converter is described herein as using a burner 154 to heat the glass tube 130, it should be understood that the heating element 152 may comprise other types of heating devices, such as but not limited to lasers (such as CO2 lasers), induction heaters, other heating devices, or combinations thereof. The heating station 150 may further include a heating element locator 162 coupled to the heating element 152. The heating element locator 162 may be operated to position the heating element 152 in one or more directions relative to the position of the working end 136 of the glass tube 130 in the heating station 150.

[0077] Now referring to Figure 4 and 5 , an embodiment of a forming station 170 for forming the syringe head 110 of the glass syringe 100 is schematically depicted. The forming station 170 for forming the syringe head 110 may include a plurality of forming tools 172 and forming pins 180. The forming tool 172 may be a forming wheel rotatable about a tool axis C. The forming tool 172 may be driven or freely rotatable such that the forming wheel rotates by contacting the rotating glass tube 130 in the forming station 170. The forming tool 172 may have a forming surface 174 that may contact the outer surface 132 of the glass tube 130 when the forming tool 172 engages the glass tube 130 in the forming station 170.

[0078] Each forming tool 172 may include a forming tool actuator 176 that may be operable to engage and disengage each forming tool 172 with respect to the glass tube 130, as shown by arrow 178. Moving the forming tool 172 to engage and disengage it with respect to the glass tube 130 may control the contact time of the forming tool 172 with the glass tube 130. The contact time refers to the time during which each forming tool 172 is engaged and disengaged with respect to the glass tube 130 at the forming station 170. Adjusting the contact time of the forming tool 324 may adjust the total contact time of each forming tool 324 in contact with the glass tube 102, the contact sequence of the forming tool 324 with the glass tube 102, or both. Additionally, the forming tool actuator 176 may be operated to move the forming tools 172 gradually towards each other (i.e., in the + / -X direction of the coordinate axes of Figure 4 ), to form the working end 136 of the glass tube 130 into the shape of the syringe head 110 ( Figure 5 ). In an embodiment, each forming tool actuator 176 may include one or more servo motors that may be operated to automatically and / or incrementally adjust the position of the forming tool 172 in one or more directions of the coordinate axes in Figure 4 and 5 . Any other type of positioner that is commercially available or will be commercially available may be used as at least a part of the forming tool actuator 176.

[0079] Referring again to Figure 4 , the forming station 170 further includes a forming pin 180. The forming pin 180 may be a thin rod that is inserted into an opening in the working end 136 of the glass tube 130 during the formation of the syringe head 110. After the syringe head 110 is formed, the forming pin 180 forms an opening or passage that axially extends through the syringe head 110. In an embodiment, the forming pin 180 may be constructed of a material that does not oxidize under glass forming conditions. Materials suitable for the forming pin 180 in the forming station 170 may include, but are not limited to, the following materials: metals or alloys containing tungsten or its derivatives; metals or alloys containing tantalum or its derivatives; metals or alloys containing platinum, platinum group metals or their derivatives; metals or alloys containing nickel or its derivatives; ceramics; silicides; and combinations thereof. In an embodiment, the forming pin 180 may be formed of tungsten or its derivatives. Other semi-precious hard metals may be used. The forming station 170 may further include a pin actuator 182 that is operable to axially (i.e., in the + / -Z direction of the coordinate axes in Figure 4 ) convey the forming pin 180 in and out of the opening in the working end 136 of the glass tube 130, as shown by arrow 184 in Figure 4 .

[0080] Referring again to Figure 4, during the operation of the forming station 170, the glass tube 130 that has been heated at the working end 136 in one or more upstream heating stations 150 is transferred into the forming station 170. In the forming station 170, the pin actuator 182 can axially (i.e., in the +Z direction of the Figure 4 coordinate axis) actuate the forming pin 180 into the opening in the working end 136 of the glass tube 130. When the gripper 140 rotates the glass tube 130 about axis B, the forming tool actuator 176 can be activated to radially (i.e., in the + / −X direction of the Figure 4 coordinate axis) move the forming tool 172 so that the forming surface 174 of the forming tool 172 contacts the outer surface 132 of the glass tube 130. The forming tool actuator 176 can continue to move the forming tools 172 gradually towards each other to form the working end 136 of the glass tube 130 into the shape of the syringe head 110.

[0081] Referring to Figure 5 , the forming pin 180 provides a barrier to prevent the inner surface 134 of the glass tube 130 from contacting or collapsing, thereby maintaining a passage axially through the syringe head 110 after forming. The contact between the forming pin 180 and the inner surface 134 of the glass tube 130 at the working end 136 forms a passage through the syringe head 110. When the syringe head 110 is formed at the end of the contact time, the forming tool actuator 176 can be actuated to move the forming tool 172 away from engagement with the outer surface 132 of the glass tube 130. Once the pressure on the outer surface 132 of the glass tube 130 from the forming tool 172 is released, the pin actuator 182 can be operated to withdraw the forming pin 180 from the working end 136 of the glass tube 130. The withdrawal of the forming pin 180 from the working end 136 leaves a passage that axially (i.e., + / −Z direction) extends through the syringe head 110 formed at the working end 136.

[0082] Pre-filled glass syringes have become an important pharmaceutical packaging solution due to their convenience in administering pharmaceutical products. While these glass syringes offer advantages in use over other types of containers (such as pharmaceutical vials), pre-filled glass syringes can expose the pharmaceutical product to different contaminants than vials. Referring again to Figure 5 , as previously discussed, during the conversion process for forming the glass syringe 100, the syringe head 110 can contact a forming pin 180 that contains a metal (such as but not limited to tungsten (W), tantalum, or other metals or their derivatives) to create an opening for the pharmaceutical composition to enter and leave the syringe barrel 102 ( Figure 1 ). Referring to Figure 5, due to the frictional contact between the forming pin 180 and the inner surface 114 of the syringe head 110, the forming pin 180 can shed materials (such as metal contaminants) onto the inner surface 114 of the syringe head 110. During the removal of the forming pin, the frictional contact between the forming pin 180 and the inner surface 114 of the syringe head 110 can cause wear and consumption of the forming pin 180. Additionally, in embodiments, the glass forming temperature during conversion can be high enough to cause atoms or molecules of the metal to volatilize from the surface of the forming pin 180, and the volatilized metal components can condense on the surface of the glass syringe 100. In some cases, the forming pin 180 can comprise a metal pin coated with a ceramic coating. If the mechanical integrity of the ceramic coating can be maintained, the ceramic coating can effectively inhibit metal deposition during forming. However, if the coating is damaged, the volatility of the underlying metal at the glass forming temperature may create a path for depositing the metal from the ceramic-coated metal forming pin onto the surface of the glass syringe 100.

[0083] Metal-containing contaminants shed from the forming pin 180 can deposit on the inner surface 114 of the syringe head 110. In continuous operation, the forming pin 180 is replaced at a rate per hour. Thus, glass syringes manufactured by this conversion method may be contaminated with metal-containing contaminants (such as but not limited to tungsten, tungsten derivatives, or other metals or their derivatives) at trace levels. The metal contaminants can be present at a concentration of about 8.3 parts per billion by weight (ppbw) to about 83 ppbw per glass syringe 100, as determined according to the test method based on inductively coupled plasma mass spectrometry (ICP-MS) in USP <797>. The interaction of the metal-containing contaminants with sensitive biopharmaceuticals (such as, protein therapies) can cause agglomeration of the active ingredients of the biopharmaceutical, which impairs the drug efficacy.

[0084] In a research environment, metal-containing contaminants, such as tungsten, other metals, or derivatives thereof, can be removed from the interior of a glass syringe by washing in dilute inorganic acid. However, washing with dilute inorganic acid may not provide a practically scalable solution for removing metal-containing contaminants. Inorganic acids typically require mitigation measures for the treatment solution after removing the metal-containing contaminants. For example, in the case where the metal-containing contaminant comprises tungsten or a derivative thereof, a mixture of phosphoric acid and other inorganic acids can be used. However, treatment with phosphoric acid can result in the formation of acid-soluble tungsten species, making the phosphoric acid treatment solution or other inorganic acid treatment solutions difficult to dispose of and thus difficult to use in an industrial environment. In addition, treatment with dilute inorganic acid has a slow reaction rate, which requires heating the dilute inorganic acid solution to an elevated temperature to increase the reaction rate to a rate fast enough for industrial manufacturing processes. Further, when washing with dilute inorganic acid, inconsistent dissolution may occur due to the enhanced chemical durability of tungsten-containing particles and other metal-containing contaminants relative to other components of the glass or contaminants on the glass surface (e.g., Sn particles).

[0085] The present disclosure relates to a method for removing metal-containing contaminants from the inner surface of a glass syringe using a water treatment medium comprising fluoride ions, at least one acid, or both. The water treatment medium and the method of treating the glass syringe with the water treatment medium can effectively reduce the concentration of metal-containing contaminants on the syringe head surface to a concentration below the detection limit of inductively coupled plasma mass spectrometry (ICP-MS) after a contact time of less than 10 minutes at room temperature. The method for removing metal-containing contaminants from the surface of the glass syringe can include contacting the surface of the glass syringe with a water treatment medium comprising fluoride ions, at least one acid, or both, wherein the metal-containing contaminants are attached to the surface of the glass syringe and are present on the surface at a concentration greater than or equal to 8.3 ppbw as determined according to the test method in USP <797> prior to contact with the water treatment medium. Contacting the water treatment medium with the surface for a contact time reduces the concentration of metal-containing contaminants on the surface of the glass syringe by greater than or equal to 50%.

[0086] The method disclosed herein can provide glass syringes that are substantially free of metal-containing contaminants (such as tungsten or its derivatives) on the surface of the glass syringe, which will allow the use of glass syringes for sensitive pharmaceutical products (e.g., protein-based pharmaceutical products). The water treatment medium has a low fluoride content (less than commercial toothpaste), is environmentally friendly, and can be scaled up to industrial manufacturing of glass syringes. Different from the use of mineral acids, the method disclosed herein is scalable, while the use of mineral acids generally requires a large number of mitigation measures. The method disclosed herein uses a scalable and relatively environmentally friendly solution to remove undesired metal-containing contaminants, such as but not limited to tungsten or its derivatives. Additionally, the water treatment medium can contain ingredients that can be ingested, which can reduce the barriers to using the water treatment medium on an industrial manufacturing scale, as well as other features.

[0087] Reference is now made to Figure 6 , as previously discussed, in forming the glass syringe 100 by converting a glass tube into a plurality of glass syringes 100, glass syringes 100 may be produced that have metal-containing contaminants deposited on one or more surfaces of the glass syringe 100. In an embodiment, the metal-containing contaminants may be present on the surface of the glass syringe 100 as metal-containing particles 190 coupled to the surface of the glass syringe 100. The metal-containing contaminants may be deposited on any surface of the glass syringe 100. In an embodiment, the metal-containing contaminants may be present on the outer surface 112, the inner surface 114, or both of the syringe head 110 of the glass syringe 100. In an embodiment, the metal-containing contaminants may be present at least on the inner surface of the syringe head 110. As previously discussed, during the formation of the syringe head 110 in the forming station 170 ( Figure 5 ), the metal-containing contaminants may be deposited on the inner surface 114 of the syringe head 110 by frictional contact between the outer surface of the forming pin 180 ( Figure 5 ) and the inner surface 114 of the syringe head 110.

[0088] The metal-containing contaminants may include one or more metals or their derivatives. The metal of the metal-containing contaminants may be a hard noble metal. In an embodiment, the metal of the metal-containing contaminants may include but not be limited to tungsten, platinum, rhodium, tantalum, nickel, derivatives or alloys of these metals, oxides of these metals, or combinations thereof. In an embodiment, the metal-containing contaminants may include one or more metals selected from the group consisting of: tungsten, platinum, rhodium, tantalum, nickel, derivatives or alloys of these metals, or combinations thereof. In an embodiment, the metal-containing contaminants may contain tungsten or its derivatives. The derivatives of the metal in the metal-containing contaminants may include but not be limited to metal oxides or other metal-containing compounds.

[0089] After the conversion of the glass tube 130 to produce the glass syringe 100, the concentration of metal-containing contaminants in the glass syringe 100 can be greater than or equal to 8.3 parts per billion by weight (ppbw), for example, 8.3 ppbw to 83 ppbw, as determined according to the test methods in the United States Pharmacopeia (USP) <797> or ISO 3749:2022.

[0090] The method for removing metal-containing contaminants from one or more surfaces of a glass syringe disclosed herein can include contacting the one or more surfaces of the glass syringe with a water treatment medium comprising fluoride ions, at least one acid, or both, wherein the contact with the water treatment medium removes metal-containing contaminants from at least one surface of the glass syringe. The water treatment medium can be an aqueous composition capable of dissolving the metal-containing contaminants from the surface of the glass syringe. The water treatment medium comprises fluoride ions, one or more acids, or a combination thereof. In an embodiment, the water treatment medium comprises fluoride ions. When the water treatment medium comprises fluoride ions, the source of fluoride ions can be selected from one or more of HF, NaF, NH4HF2, etc. In an embodiment, the source of fluoride ions can be selected from the group consisting of HF, NaF, NH4HF2, and combinations thereof. In embodiments containing fluoride ions, the water treatment medium can include 0.001 wt.% to 0.15 wt.% fluoride ions, for example, 0.001 wt.% to 0.12 wt.%, or 0.001 wt.% to 0.10 wt.% fluoride ions, based on the total weight of the water treatment medium. In an embodiment, the water treatment medium can contain fluoride ions, and the concentration of fluoride ions in the water treatment medium can be less than or equal to 1500 ppm, less than or equal to 1200 ppm, or even less than or equal to 1000 ppm, as calculated using Visual MINTEQ TM software, which is a tool for estimating the dissociation of molecules and their mixtures in aqueous solutions.

[0091] In an embodiment, the water treatment medium may contain an acid, such that the water treatment medium is an acidic water treatment medium. Various acidic compounds may be used alone or in combination to formulate an acidic water treatment medium suitable for treating the surface of a glass syringe to remove metal-containing contaminants. The water treatment medium may include inorganic acids, organic acids, or a combination thereof. In an embodiment, the water treatment medium may include an organic acid, which is a chelating organic acid. In an embodiment, the water treatment medium may include an inorganic acid, an organic acid, or an aqueous solution of both. Suitable acids for the water treatment medium may include, but are not limited to, one or more of the following: HCl, HBr, HNO3, H2SO4, H2SO3, H3PO4, H3PO2, HOAc, citric acid, tartaric acid, ascorbic acid, EDTA, methanesulfonic acid, toluenesulfonic acid, mixtures thereof, and combinations containing at least one of the foregoing. In an embodiment, the water treatment medium may contain at least one acid selected from the group consisting of HCl, HBr, HNO3, H2SO4, H2SO3, H3PO4, H3PO2, acetic acid (HOAc), citric acid, tartaric acid, ascorbic acid, EDTA, methanesulfonic acid, toluenesulfonic acid, and combinations thereof. In an embodiment, the water treatment medium may contain at least one organic acid selected from the group consisting of acetic acid (HOAc), citric acid, tartaric acid, ascorbic acid, EDTA, methanesulfonic acid, toluenesulfonic acid, and combinations thereof. In an embodiment, the water treatment medium contains at least one acid, and the acid may include citric acid.

[0092] In an embodiment, the water treatment medium contains fluoride ions and an acid. The components of the water treatment medium may be selected from materials found in consumer goods and may meet two property requirements: etching glassware at a low rate relative to existing formulations and reducing the precipitation of dissolved substances by complexing metal ions in the solution. Citric acid is a naturally occurring organic acid found in citrus fruits. It is a common complexing agent or chelating agent. Ammonium bifluoride provides a source of fluoride ions to etch glass. In an embodiment, the water treatment medium contains an aqueous solution of ammonium bifluoride and citric acid. In an embodiment, the water treatment medium may contain 0.026 moles (M) to 0.26 M ammonium bifluoride, or about 0.26 M ammonium bifluoride. In an embodiment, the water treatment medium may contain 0.5 M to 2 M citric acid, or about 1.0 M citric acid.

[0093] In an embodiment, the pH of the water treatment medium may be less than or equal to 3, such as less than or equal to 2.5, less than or equal to 1, or even less than or equal to 0.5. In some embodiments, the water treatment medium may not be acidic or may be weakly acidic. For example, in an embodiment, the water treatment medium may have a pH of 4 to 12, such as a pH of 6 to 12, 6 to 10, or even 8 to 10.

[0094] In an embodiment, the composition of the water treatment medium is generally considered to be substantially fluoride-free. As used herein, the phrase "substantially fluoride-free" means that the water treatment medium can contain less than or equal to 0.15 wt.% (i.e., 1500 parts per million by weight (ppmw)) of fluoride ions, based on the total weight of the water treatment medium. In an embodiment, based on the total weight of the water treatment medium, the water treatment medium can contain less than or equal to 0.12 wt.% (i.e., 1200 ppmw) of fluoride ions, such as less than or equal to 0.10 wt.% (i.e., 1000 ppmw), less than or equal to 0.095 wt.% (i.e., 950 ppmw), or even less than or equal to about 0.09 wt.% (i.e., 900 ppmw) of fluoride ions. For comparison, the fluoride ion content found in toothpaste is about 1500 ppmw. In some embodiments, the water treatment medium can be fluoride-free. Various compounds can be used alone or in combination to formulate a substantially fluoride-free water treatment medium suitable for removing metal-containing contaminants from the surface of a glass syringe. In an embodiment, the water treatment medium can be an aqueous solution containing water and fluoride ions. In an embodiment, the substantially fluoride-free water treatment medium can be an aqueous solution containing an alkaline component (e.g., NH3) or an alkali metal hydroxide (e.g., NaOH, KOH, LiOH) or an alkaline earth metal hydroxide (e.g., Ca(OH)2 or Ba(OH)2).

[0095] A method for removing metal-containing contaminants from the surface of a glass syringe can include contacting the surface of the glass syringe with the water treatment medium. The step of contacting the surface of the glass syringe with the water treatment medium can be implemented by various techniques, including but not limited to spraying the water treatment medium onto the surface of the glass syringe, partially or completely immersing the glass syringe in a container containing the water treatment medium, or other similar techniques for applying a liquid to a solid surface.

[0096] In the embodiments described herein, it should be understood that the processing conditions can affect the rate of removal of metal-containing contaminants from the glass surface in the water treatment medium (e.g., the etching rate or the dissolution rate of components from the glass), and the processing conditions can be adjusted to control the dissolution rate of one or more components from the glass. For example, the temperature of the water treatment medium and / or the glass syringe can be increased to increase the dissolution rate of the metal-containing contaminants in the water treatment medium, thereby reducing the processing time. Alternatively, the concentration of active components (e.g., acids, fluoride ions, etc.) in the water treatment medium can be increased to increase the dissolution rate of the metal-containing contaminants in the water treatment medium, thereby reducing the processing time.

[0097] The surface of the glass syringe can be in contact with the water treatment medium at a contact temperature and for a contact time sufficient to remove metal-containing contaminants from the surface of the glass syringe to a concentration less than 50% of the starting concentration before contact with the water treatment medium. The contact temperature can be sufficient to cause the removal of metal-containing contaminants at an acceptable etching rate. In an embodiment, the method for removing metal-containing contaminants can include contacting the surface of the glass syringe with the water treatment medium at a contact temperature of 0 °C (zero °C) to 105 °C, such as 0 °C to 100 °C, 0 °C to 80 °C, 0 °C to 50 °C, 10 °C to 105 °C, 10 °C to 100 °C, 10 °C to 80 °C, 10 °C to 50 °C, 20 °C to 105 °C, 20 °C to 100 °C, 20 °C to 80 °C, or 20 °C to 50 °C. In an embodiment, the water treatment medium can contain components capable of removing metal-containing contaminants from the surface of the glass syringe at room temperature (about 20 °C) without raising the temperature to achieve an acceptable etching rate or removal rate. In an embodiment, the method for removing metal-containing contaminants can include contacting the surface of the glass syringe with the water treatment medium at a contact temperature equal to room temperature. In an embodiment, the water treatment medium can contain ammonium bifluoride and citric acid, and the method for removing metal-containing contaminants can include contacting the surface of the glass syringe with the water treatment medium at room temperature.

[0098] The method can include contacting at least one surface of the glass syringe with the water treatment medium for a contact time sufficient to remove at least 50% of the metal-containing contaminants. In an embodiment, the method can include contacting the surface of the glass syringe with the water treatment medium for a contact time of 10 seconds to 24 hours, such as 10 seconds to 30 minutes, 10 seconds to 10 minutes, 1 minute to 24 hours, 1 minute to 30 minutes, 1 minute to 10 minutes, 2 minutes to 24 hours, 2 minutes to 30 minutes, 2 minutes to 10 minutes, 2.5 minutes to 24 hours, 2.5 minutes to 30 minutes, 2.5 minutes to 10 minutes, 10 minutes to 24 hours, 10 minutes to 30 minutes, or 30 minutes to 24 hours.

[0099] After contacting the surface of the glass syringe with the water treatment medium, the surface of the glass syringe can be removed from contact with the water treatment medium. Removing the surface of the glass syringe from contact with the water treatment medium can include removing any residual water treatment medium from the surface of the glass syringe, such as by washing the surface of the glass syringe with water. The surface of the glass syringe can be dried after the water wash.

[0100] Contact the surface of the glass syringe with the water treatment medium at the contact temperature for a contact time to remove at least a portion or all of the metal-containing contaminants from the surface of the glass syringe. Now refer to Figure 7, in an embodiment, the inner surface 114 of the syringe head 110 can be in contact with the water treatment medium, and the inner surface 114 of the syringe head 110 is in contact with the water treatment medium for a contact time at a contact temperature to remove at least a part or all of the metal-containing contaminants from the inner surface 114 of the syringe head 110.

[0101] In an embodiment, contacting at least one surface of the glass syringe 100 (such as but not limited to the inner surface 114 of the syringe head 110) with the water treatment medium can remove greater than or equal to 50% of the metal-containing contaminants from at least one surface of the glass syringe 100. In an embodiment, contacting at least one surface of the glass syringe 100 (such as but not limited to the inner surface 114 of the syringe head 110) with the water treatment medium can remove greater than or equal to 60%, greater than or equal to 70%, greater than or equal to 80%, greater than or equal to 90%, greater than or equal to 95%, greater than or equal to 98%, or even greater than or equal to 99% of the metal-containing contaminants from the surface of the glass syringe 100. In an embodiment, after contacting the surface of the glass syringe 100 with the water treatment medium, the concentration of the metal-containing contaminants on at least one surface of the glass syringe 100 can be less than 10 parts per billion by weight (ppbw), less than or equal to 8.3 ppbw, less than or equal to 8 ppbw, less than or equal to 5 ppbw, less than or equal to 4 ppbw, less than or equal to 2 ppbw, less than or equal to 1 ppbw, less than or equal to 0.1 ppbw, less than or equal to 100 parts per trillion by weight (pptw), or even less than or equal to 10 pptw, as determined according to the test method in the United States Pharmacopeia (USP) <797>.

[0102] During the contact of the surface of the glass syringe 100 with the water treatment medium, the water treatment medium can also etch away the glass components from the surface of the glass syringe 100. Refer to Figure 7 , etching away the glass components from the surface of the glass syringe 100 (such as from the inner surface 114 of the syringe head 110) may result in a minimal change in the glass thickness, such that the thickness t2 of the syringe head 110 after contact with the water treatment medium may be less than the thickness t1 of the syringe head 110 before contact with the water treatment medium. For illustrative purposes, Figure 6 and 7The features in [it] are magnified. The contact temperature, contact time, and composition of the water treatment medium can affect the amount of glass removed from the inner surface 114 of the syringe head 110. The contact temperature, contact time, and composition of the water treatment medium can be selected to remove the desired amount of metal-containing contaminants while avoiding excessive removal of the glass component from the surface of the glass syringe 100. In an embodiment, the thickness change (i.e., t1 - t2) after contact with the water treatment medium can be less than 1 micron. In an embodiment, the dimensions of the glass syringe 100 (such as but not limited to the dimensions of the syringe head 110) can be within the specifications of the glass syringe 100 after contact with the water treatment medium.

[0103] Referring again to Figure 1 , in an embodiment, a method of manufacturing the glass syringe 100 of the present disclosure can include forming a glass syringe 100 having a barrel 102 and a syringe head 110, wherein forming the glass syringe 100 includes contacting at least one surface of the glass syringe with a forming tool, a forming pin, or both, the contact causing the transfer of metal-containing contaminants to the surface of the glass syringe 100. The method can further include contacting the surface of the glass syringe 100 with a water treatment medium comprising fluoride ions, at least one acid, or both, wherein contact with the water treatment medium removes at least a portion of the metal-containing contaminants from the surface of the glass syringe 100. The glass syringe 100 can be formed from a glass tube using a conversion machine as previously described herein. The water treatment medium can have any composition or properties previously discussed herein for the water treatment medium.

[0104] In an embodiment, forming the glass syringe 100 can include forming the syringe head 110 of the glass syringe 100 at the working end of the glass tube and separating the glass syringe 100 from the glass tube. In an embodiment, the method for forming the syringe head 110 can include heating the working end 136 of the glass tube 130 ( Figure 3 ), inserting a metal forming pin 180 into the lumen of the glass tube 130 at the working end 136 of the glass tube 130 ( Figure 4 ), and contacting at least two opposing forming tools 172 with the outer surface of the working end 136 of the glass tube 130 ( Figure 4 ). As Figure 5As shown, the contact of two opposing forming tools 172 with the outer surface 132 of the glass tube 130 reduces the outer diameter of the working end 136 of the glass tube 130 to form the syringe head 110, and the metal forming pin 180 maintains a channel that axially extends through the syringe head 110 during contact with the forming tool 172. The method of manufacturing the glass syringe 100 may further include removing the two opposing forming tools 172 from contact with the outer surface 132 of the working end 136 of the glass tube 130, and removing the metal forming pin 180 from the interior of the glass tube 130. Removing the metal forming pin 180 may cause friction between the metal forming pin 180 and the surface of the glass syringe (such as the inner surface 114 of the syringe head 110), which may cause the transfer of metal-containing contaminants from the metal forming pin 180 to the surface of the glass syringe. After the glass syringe 100 is formed, the surface of the glass syringe 100 (such as but not limited to the inner surface 114 of the syringe head 110) may be contacted with a water treatment medium, and the contact temperature and contact time are sufficient to remove some or all of the metal-containing contaminants from the surface of the glass syringe 100.

[0105] Example

[0106] Various embodiments of the glass syringe and the method of removing metal-containing contaminants from the surface of the glass syringe disclosed herein will be further illustrated by the following examples. The examples are illustrative in nature and should not be construed as limiting the subject matter of the present disclosure.

[0107] Example 1

[0108] In Example 1, metal-containing contaminants were removed from the inner surface of the syringe head of a glass syringe according to the method of contacting with a water treatment medium disclosed herein. The contact time for removing the metal-containing contaminants from the inner surface of the syringe head was studied. For Example 1, a glass syringe was produced from a glass tube using the conversion method described herein. See Figure 4 and 5, the forming station 170 for the syringe head 110 used to produce the glass syringe 100 includes a forming pin 180 made of tungsten-containing metal. The conversion causes metal contaminants containing tungsten oxide to deposit on the inner surface 114 of the syringe head 110. After the conversion, the average concentration of tungsten oxide on the inner surface 114 of the syringe head 110 is determined by normalizing the ICP-MS data. For glass syringes with a contact time increment of 2.5 minutes, the initial concentration of tungsten oxide on the inner surface 114 of the syringe head 110 is about 0.04 μg / g, as determined by the normalization of the ICP-MS data. For the glass syringe 100 processed with a contact time increment of 10 minutes, the measured initial concentration of tungsten oxide is about 1.4 μg / g, which is an order of magnitude greater than that of other syringes tested with a contact time interval of 2.5 minutes. This indicates that there are differences in the concentration of tungsten substances deposited on the surfaces of different glass syringes.

[0109] To remove the metal contaminants from the inner surface of the syringe head, the glass syringes are grouped in bundles of eight and then exposed to a water treatment medium in an amount sufficient to submerge the syringe heads of the glass syringes. The water treatment medium contains water with 1 mole (M) of citric acid and 0.26 M of ammonium bifluoride. The syringe heads of the glass syringes are gradually contacted with the water treatment medium at contact temperatures equal to room temperature in time increments of 2.5 minutes and 10 minutes. Between each contact step, each bundle of glass syringes is rinsed in a 1 M citric acid wash solution. After each repetition of contacting with the water treatment medium and then washing with the citric acid wash solution, chemical analysis is performed on the water treatment medium and the citric acid wash solution to determine the concentration of tungsten substances or other metal substances in the water treatment medium and the citric acid wash solution. This time-series method has a rinsing step between each step of gradually contacting with the water treatment medium, so the time required to remove the metal contaminants from the surface of the glass syringe can be determined. The step-by-step contact method of Example 1 also allows determination of whether the tungsten oxide is loosely bound to the surface (which will be confirmed by the tungsten present in the citric acid wash solution) or firmly bound to the glass surface (the tungsten oxide will only be present in the water treatment medium recovered from the contact step and not in the citric acid wash solution). It was found that the contact with the water treatment medium can also remove tin from the surface of the glass syringe, which is another surface contaminant found on the surface of the glass syringe.

[0110] Now refer to Figure 8 , which graphically depicts the concentrations of tungsten and tin in the water treatment medium recovered from each contact step performed in time increments of 2.5 minutes or 10 minutes. For a contact time increment of 2.5 minutes, the total contact time with the water treatment medium is 7.5 minutes, and for a contact time increment of 10 minutes, the total contact time with the water treatment medium is 30 minutes. Figure 8 The reference numerals of

[0111] Table 1

[0112] Reference Numerals Metallic Substance Contact Interval (min) Total Contact Time (min) 802 Tungsten 2.5 7.5 804 Tungsten 10 30 806 Tin 2.5 7.5 808 Tin 10 30

[0113] As Figure 8 shown, for contact intervals of 2.5 minutes and 10 minutes, the tungsten concentration decays monotonically with each contact step. Despite a two-order-of-magnitude difference in the initial concentration of tungsten in the water treatment medium, after the first contact interval for both the 2.5-minute interval and the 10-minute interval, the tungsten concentration drops below the detection limit, i.e., <0.02 μg / g.

[0114] Furthermore, no tungsten was found in the citric acid wash solution recovered from the rinse step, indicating that the tungsten species adhered well to the surface of the glass syringe. Thus, the glass cleaning procedure removes the tungsten species by an etching mechanism rather than by leaching the tungsten species.

[0115] Interestingly, another known surface contaminant, tin (Sn), is "stickier" and requires significantly more time to be removed from the glass syringe with the water treatment medium. For short time increments (i.e., 2.5 minutes), the tin concentration increases with each step. At longer time increments (i.e., 10 minutes), the tin concentration decays with each contact step, although at a slower rate compared to the removal of tungsten. To ensure that our time series was valid between experiments, we performed a first-order mass balance calculation assuming that Sn was uniformly distributed among the syringe population. We found that Sn was accounted for between the time series, and the variation in tungsten was likely due to syringe-to-syringe variation. This syringe-to-syringe variation may be reasonable because the tungsten pins wear rapidly during the syringe molding process, resulting in variation in the starting concentration of the tungsten species on the surface of the glass syringe.

[0116] Referring now to Figure 9 , for Example 1, the variation of the molar ratio of sodium to silicon in the water treatment medium with time is depicted graphically. Series 902 refers to the experiments conducted at a contact time interval of 2.5 minutes, and Series 904 refers to the experiments conducted at a contact time interval of 10 minutes. Figure 9 Indicates that, as shown by normalizing the Na / Si molar ratio to the value of the bulk glass Na / Si molar ratio after 10 minutes, the glass surface is mildly etched by the water treatment medium. It is known that a flame-processed surface has a lower Na / Si molar ratio relative to bulk glass because Na is a volatile element and is lost from the glass during flame exposure, while Si is relatively refractory. Thus, Figure 9 shows that the glass surface is gently etched into the bulk composition of the glass, with essentially no preferential removal of either Na or Si species from the glass.

[0117] Example 2: After 1 washing for 7.5 minutes

[0118] In Example 2, a glass syringe was contacted with a water treatment medium for a single contact time interval of 7.5 minutes. As described in Example 1, the glass syringe was fabricated using a tungsten-containing forming pin according to the method disclosed herein. The water treatment medium comprised water containing 1 mole (M) of citric acid and 0.26 M of ammonium bifluoride. The syringe tip of the glass syringe was contacted with the water treatment medium for a contact time of 7.5 minutes at a contact temperature equal to room temperature.

[0119] Reference Figure 11A and 11B show a SEM backscattered image of the surface of the glass syringe prior to contact with the water treatment medium. Compared with Figure 11A , Figure 11B was taken at a higher resolution. Figure 11B The bright spots in

[0120] Now refer to Figure 14A and 14B , which show SEM backscattered images of the surface of the glass syringe taken at two different resolutions after contact with the water treatment solution at room temperature for 7.5 minutes. As Figure 14A and 14B show, the surface of the glass syringe appears to be completely free of bright regions indicative of tungsten oxide deposits.

[0121] Comparative Example 3: Treatment with Citric Acid Solution

[0122] For Comparative Example 3, a glass syringe having tungsten oxide deposits on its glass surface was treated with a citric acid solution at a contact temperature of 80 °C for a contact time of 7.5 minutes. The glass syringe was prepared as described in Example 1. The citric acid solution used for Comparative Example 3 comprised an aqueous solution of 1 M citric acid. Reference Figure 12A and 12B depict SEM backscattered images of the surface of the glass syringe of Comparative Example 3 at two different resolutions. As Figure 12A and 12B show, treating the glass with a citric acid solution without fluoride ions is not sufficient to remove tungsten oxide deposits from the glass even at a high temperature of 80 °C instead of room temperature.

[0123] Comparative Example 4: Treatment with Phosphoric Acid Solution

[0124] For Comparative Example 4, a glass syringe having tungsten oxide deposits on its glass surface was treated with a phosphoric acid solution at a contact temperature of 80 °C for a contact time of 7.5 minutes. The glass syringe was prepared as described in Example 1. The phosphoric acid solution used for Comparative Example 4 comprised an aqueous solution of 1 M phosphoric acid. ReferenceFigure 13A and 13B depict SEM backscattered images of the surface of the glass syringe of Comparative Example 4 at two different resolutions. As Figure 13B shown, Figure 13B the bright spots in indicate that treating the glass with the phosphoric acid solution for a contact time of 7.5 minutes, even at a high temperature of 80°C rather than at room temperature, failed to remove all of the tungsten oxide deposits.

[0125] Now referring to Figure 10 graphically depicts the change in the tungsten concentration in the water treatment medium (reference numeral 1002) of Example 2 and the tungsten concentration in the phosphoric acid solution (reference numeral 1004) of Comparative Example 4 over time. As Figure 10 shown, compared with the phosphoric acid solution of Comparative Example 4, the water treatment medium of Example 2 enables the removal of tungsten oxide deposits from the glass syringe surface more quickly. At 10 seconds, the concentration in the water treatment medium (reference numeral 1002) of Example 2 has reached 0.04, indicating that tungsten oxide can be removed almost immediately by the water treatment medium. In contrast, the tungsten concentration in the phosphoric acid solution (reference numeral 1004) of Comparative Example 4 at 10 seconds is much lower, indicating a slower removal rate. The concentration of tungsten in the phosphoric acid solution did not reach 0.04 μg / g until 2.5 minutes after the start of the contact period. In addition, the concentration of tungsten species in the water treatment medium (reference numeral 1002) of Example 2 is zero at about 5 minutes, indicating that tungsten oxide is almost completely removed within less than or equal to 5 minutes. After 5 minutes, the phosphoric acid solution (reference numeral 1004) of Comparative Example 4 still has a tungsten species concentration of more than 0.02 μg / g, indicating that the phosphoric acid solution is still removing tungsten species from the glass surface. The tungsten concentration in the phosphoric acid solution of Comparative Example 4 did not reach zero until 7.5 minutes later. Therefore, compared with the phosphoric acid solution of Comparative Example 4, the water treatment medium of Example 2 is at least 2.5 minutes faster in removing tungsten oxide species.

[0126] Those skilled in the art will appreciate that various modifications and variations can be made to the embodiments described herein without departing from the spirit and scope of the claimed subject matter. Accordingly, this specification is intended to cover modifications and variations of the various embodiments described herein, provided that such modifications and variations fall within the scope of the appended claims and their equivalents.

Claims

1. A method of manufacturing a glass syringe, the method comprising: forming the glass syringe having at least a barrel and a syringe tip, wherein forming the syringe tip comprises contacting at least one surface of the glass syringe with a forming tool, a forming pin, or both, the contacting causing transfer of metal contaminants to at least one surface of the glass syringe; and contacting the at least one surface of the glass syringe with a water treatment medium comprising fluoride ions, at least one acid, or both, wherein the contacting with the water treatment medium removes the metal contaminants from the at least one surface of the glass syringe.

2. The method according to claim 1, wherein the concentration of the metal contaminants on the at least one surface of the syringe is from 8.3 parts per billion by weight to 83 parts per billion by weight as determined by the test method in <797> of the U.S. Pharmacopeia.

3. The method according to claim 1, wherein contacting the at least one surface of the glass syringe with the water treatment medium removes greater than or equal to 50% of the metal contaminants from at least one surface of the syringe tip.

4. The method according to claim 1, wherein after contacting the at least one surface of the glass syringe with the water treatment medium, the at least one surface of the glass syringe has a metal contaminant concentration of less than 8.3 ppbw as determined by the test method in the U.S. Pharmacopeia <797>.

5. The method according to claim 1, wherein the metal contaminants comprise one or more metals selected from the group consisting of tungsten, platinum, rhodium, tantalum, nickel, and combinations thereof.

6. The method according to claim 1, wherein the metal contaminants comprise tungsten or a derivative thereof.

7. The method according to claim 1, wherein the water treatment medium contains the fluoride ion, and as calculated using Visual MINTEQ TM software with standard settings, the concentration of the fluoride ion in the water treatment medium is about 1000 ppm.

8. The method according to claim 1, wherein the water treatment medium comprises a source of the fluoride ions selected from the group consisting of hydrogen fluoride (HF), sodium fluoride (NaF), ammonium bifluoride (NH4HF2), and combinations thereof.

9. The method according to claim 1, wherein the water treatment medium comprises the at least one acid selected from the group consisting of HCl, HBr, HNO3, H2SO4, H2SO3, H3PO4, H3PO2, acetic acid, citric acid, tartaric acid, ascorbic acid, EDTA, methanesulfonic acid, toluenesulfonic acid, and combinations thereof.

10. The method according to claim 1, which comprises contacting the at least one surface of the glass syringe with the water treatment medium comprising fluoride ions and at least one acid.

11. The method according to claim 1, wherein: the water treatment medium comprises a source of the fluoride ions selected from the group consisting of hydrogen fluoride (HF), sodium fluoride (NaF), ammonium bifluoride (NH4HF2), and combinations thereof; and The at least one acid is selected from the group consisting of: HCl, HBr, HNO3, H2SO4, H2SO3, H3PO4, H3PO2, acetic acid, citric acid, tartaric acid, ascorbic acid, EDTA, methanesulfonic acid, toluenesulfonic acid, and combinations thereof.

12. The method according to claim 1, wherein the water treatment medium comprises 0.026 moles (M) to 0.26 M ammonium bifluoride and 0.5 M to 2 M citric acid.

13. The method according to claim 1, comprising contacting at least one surface of the glass syringe with the water treatment medium at a contact temperature of 0 °C to 105 °C for a contact time of 10 seconds to 24 hours.

14. A method for removing metal-containing contaminants from the surface of a glass syringe, the method comprising contacting the surface of the glass syringe with a water treatment medium comprising fluoride ions, at least one acid, or both, wherein: the metal-containing contaminants are coupled to the surface of the glass syringe and are present on the surface at a concentration of greater than or equal to 8.3 ppbw before contact with the water treatment medium, as determined by the test method in USP <797>; and contacting the water treatment medium with the surface for a contact time will reduce the concentration of the metal-containing contaminants on the surface of the glass syringe by greater than or equal to 50%.

15. The method according to claim 14, wherein the concentration of the metal-containing contaminants on the surface of the glass syringe is 8.3 ppb to 83 ppb, as determined by the test method in USP <797>.

16. The method according to claim 14, wherein the surface of the glass syringe is the inner surface of the syringe tip of the glass syringe.

17. The method according to claim 14, wherein after contacting the surface of the glass syringe with the water treatment medium, the surface of the glass syringe has a metal-containing contaminant concentration of less than 8.3 ppbw, as determined by the test method in USP <797>.

18. The method according to claim 14, wherein the metal-containing contaminants comprise one or more metals selected from the group consisting of tungsten, platinum, rhodium, tantalum, nickel, and combinations thereof.

19. The method according to claim 14, wherein the metal-containing contaminants comprise tungsten or a derivative thereof.

20. The method according to claim 14, wherein: the water treatment medium comprises a source of the fluoride ions selected from the group consisting of hydrogen fluoride (HF), sodium fluoride (NaF), ammonium bifluoride (NH4HF2), and combinations thereof; and the at least one acid is selected from the group consisting of: HCl, HBr, HNO3, H2SO4, H2SO3, H3PO4, H3PO2, acetic acid, citric acid, tartaric acid, ascorbic acid, EDTA, methanesulfonic acid, toluenesulfonic acid, and combinations thereof.

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