Devices and methods for overfilling drug containers

Abstract

SOLUTION: Disclosed herein are methods for overfilling primary packaging components, and drug products prepared according to such methods. The method may comprise introducing a volume of a formulated drug substance into a primary packaging component having a nominal volume, wherein the volume of the formulated drug substance is greater than the nominal volume of the primary packaging component. In some cases, the primary packaging component may be a prefillable syringe.SELECTED DRAWING: Figure 3D

Description

[Technical Field]

[0001] Various embodiments of the present disclosure relate to devices and methods for filling primary packaging components, and more particularly, certain embodiments of the present disclosure relate to devices and methods for filling syringes, including prefillable syringes. [Background technology]

[0002] Primary packaging components, such as syringes, intravenous fluid containers, vials, and other pharmaceutical containers, are specified to hold a maximum volume of a prescription drug product or other fluid. For example, syringes may be manufactured and sold with a nominal or maximum volume that they are tested to hold while still ensuring that the syringe's stopper, plunger, and other components function properly without compromising the contents or integrity of the stoppered syringe. In particular, the nominal volume of a prefillable syringe may be specified to ensure that the syringe, once filled, will maintain its integrity throughout various post-filling processes, such as packaging and shipping. However, in some situations, the nominal volume of a primary packaging component may be less than the desired volume of a prescription drug to contain in the primary packaging component. This may be due, for example, to a difference between the nominal volume of the packaging and the desired dosage volume, or to a lack of suitable larger packaging. Summary of the Invention [Means for solving the problem]

[0003] FIELD OF THE DISCLOSURE The present disclosure relates to pharmaceutical products and methods for preparing same. In particular, the disclosure relates to filling primary packaging components with prescription drugs. In one aspect of the present disclosure, a method of preparing a drug product is provided, comprising: introducing a volume of a prescription drug into a primary packaging component, wherein the volume of the prescription drug is greater than a nominal volume of the primary packaging component; and disposing a stopper in the primary packaging component, wherein disposing the stopper comprises applying a vacuum to the stopper.

[0004] In one embodiment, the primary packaging component is a syringe. In a further embodiment, the primary packaging component is a prefillable syringe. In a further embodiment, the primary packaging component is a prefillable syringe having a nominal volume of at least 1 mL. In yet another embodiment, the primary packaging component is a prefillable syringe having a nominal volume of 1 mL, and disposing the stopper within the primary packaging component includes inserting the stopper into the body of the syringe such that an end of the stopper closest to the flange of the syringe is spaced from the flange by between about 2.5 mm and about 5.0 mm. In another embodiment, applying a vacuum to a portion of the primary packaging component includes imposing a pressure of between 70 mBar (7 kPa) and 75 mBar (7.5 kPa) on the portion of the primary packaging component.

[0005] In one embodiment, the volume of the formulated drug is between 1.05 mL and 1.30 mL. In a further embodiment, the volume of the formulated drug is between about 110% and about 140% of the nominal volume of the primary packaging component. In another embodiment, the volume of the formulated drug is at least 0.05 mL greater than the nominal volume of the primary packaging component. In a further embodiment, the formulated drug comprises one of a protein, nucleic acid, or gene therapy drug. In yet another embodiment, the formulated drug comprises an antibody and at least one excipient. In another embodiment, the formulated drug comprises an antibody solution, the antibody being present in the solution at a concentration of at least 100 mg / mL. In a further embodiment, the formulated drug comprises an antibody and has a viscosity of at least 5 cPoise (0.005 Pa·s).

[0006] In one embodiment, the method includes placing the primary packaging component into further packaging. In another embodiment, the method may be repeated for each of a plurality of batches of primary packaging components. For example, a batch of primary packaging components may include 80 pre-filled syringes.

[0007] In a further aspect of the present disclosure, the drug product is prepared by one of the methods described above. In another aspect of the present disclosure, there is provided a method of preparing a drug product, comprising: introducing a volume of a prescription drug into a prefillable syringe, wherein the prescription drug includes an antibody, and the volume of the prescription drug is greater than the nominal volume of the prefillable syringe; and attaching a stopper to the prefillable syringe using one of a vacuum stopper attachment process or a vacuum assisted stopper attachment process.

[0008] In another aspect, a pharmaceutical product is provided that includes a primary packaging component having a nominal volume, a volume of a prescription drug within the primary packaging component, the volume of the prescription drug being greater than the nominal volume, and a stopper. In one embodiment of this aspect, the primary packaging component is a prefillable syringe. In a further embodiment, the prefillable syringe has a body and a flange surrounding an opening in the body, and the minimum distance between the flange and the stopper is at least 2.5 mm. In yet another embodiment, the nominal volume is 1 mL and the volume of the prescription drug is at least 1.05 mL. In another embodiment, the prescription drug includes a protein, nucleic acid, blood component, vaccine, anti-allergy agent, gene therapy drug, antibiotic, pain management drug, anesthetic, and / or hormone. In a further embodiment, the prescription drug includes an antibody.

[0009] The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate various exemplary embodiments and, together with the detailed description, serve to explain the principles of the disclosed embodiments. The drawings illustrate various aspects of the disclosure, and, where appropriate, reference numerals that designate like structures, components, materials, and / or elements in different views are similarly designated. It is understood that various combinations of structures, components, and / or elements other than those explicitly shown are contemplated and within the scope of the present disclosure.

[0010] There are many inventions described and illustrated herein. The described inventions are not limited to any single aspect or embodiment of that aspect, nor are they limited to any combinations and / or permutations of such aspects and / or embodiments. Furthermore, each aspect of the described invention and / or its embodiments may be employed alone or in combination with one or more of the other aspects of the described invention and / or its embodiments. For the sake of brevity, certain permutations and combinations are not separately discussed and / or described herein. In particular, an embodiment or implementation described herein as "exemplary" is not to be construed as preferred or advantageous over, for example, other embodiments or implementations, but rather is intended to reflect or indicate that the embodiment(s) are "exemplary" embodiment(s). [Brief explanation of the drawings]

[0011] [Figure 1A] 1 is a graph showing the concentration of an exemplary antibody solution as a function of antibody concentration, composition, and temperature. [Figure 1B] 1 is a graph showing the concentration of an exemplary antibody solution as a function of antibody concentration, composition, and temperature. [Figure 2A] 1 is a schematic diagram of components of an exemplary primary packaging component suitable for overfilling according to the present disclosure. FIG. [Figure 2B] 1 is a schematic diagram of components of an exemplary primary packaging component suitable for overfilling according to the present disclosure. FIG. [Figure 3A] FIG. 1 is a schematic diagram of an exemplary filled and stoppered primary packaging component according to the present disclosure. [Figure 3B] FIG. 2 is another schematic diagram of an exemplary filled and stoppered primary packaging component according to the present disclosure. [Figure 3C] FIG. 1 is a partial schematic view of a primary packaging component with a stopper attached, according to the present disclosure. [Figure 3D]FIG. 1 is a partial schematic view of a primary packaging component with a stopper attached, according to the present disclosure. [Figure 4] FIG. 1 is a flow diagram of an exemplary method for overfilling a primary packaging component according to the present disclosure. [Figure 5A] FIG. 1 is a schematic diagram showing steps of an exemplary process for stoppering a fully filled primary packaging component. [Figure 5B] FIG. 1 is a schematic diagram showing steps of an exemplary process for stoppering a fully filled primary packaging component. [Figure 5C] FIG. 1 is a schematic diagram showing steps of an exemplary process for stoppering a fully filled primary packaging component. [Figure 5D] FIG. 1 is a schematic diagram showing steps of an exemplary process for stoppering a fully filled primary packaging component. [Figure 6A] FIG. 10 is a schematic diagram showing the steps of another exemplary process for stoppering a fully filled primary packaging component. [Figure 6B] FIG. 10 is a schematic diagram showing the steps of another exemplary process for stoppering a fully filled primary packaging component. [Figure 6C] FIG. 10 is a schematic diagram showing the steps of another exemplary process for stoppering a fully filled primary packaging component. [Figure 6D] FIG. 10 is a schematic diagram showing the steps of another exemplary process for stoppering a fully filled primary packaging component. [Figure 6E] FIG. 10 is a schematic diagram showing the steps of another exemplary process for stoppering a fully filled primary packaging component. DETAILED DESCRIPTION OF THE INVENTION

[0012] As used herein, the terms "comprises," "comprising," "includes," "including," or any other variation thereof, are intended to cover a non-exclusive inclusion, such that a process, method, article, or apparatus that includes a list of elements does not include only those elements, but may include other elements not expressly listed or inherent in such process, method, article, or apparatus. The term "exemplary" is used in the sense of "example" rather than "ideal." Furthermore, terms such as "first," "second," etc., are used herein not to denote any order, quantity, or importance, but rather to distinguish one element, structure, step, or process from another. Furthermore, the terms "a" and "an" are used herein not to denote a limitation of quantity, but rather to indicate the presence of one or more of the referenced item.

[0013] Embodiments of the present disclosure relate to systems and methods for overfilling primary packaging components. For example, embodiments of the present disclosure may relate to systems and methods for overfilling pharmaceutical containers, such as syringes. More specifically, embodiments of the present disclosure may relate to systems and methods for overfilling prefillable syringes ("PFS"), for example, for packaging, sale, and commercial use. "Overfilling," in the context of the present disclosure, relates to filling a container with a volume of material that is greater than the nominal volume of the container, while still maintaining a desired level of safety and / or integrity for the container and its contents.

[0014] The "nominal volume" (also referred to as "specified volume" or "specified capacity") of a container refers to the maximum capacity of the container, as specified by the container's manufacturer or a safety organization. A manufacturer or safety organization may specify a container's nominal volume to indicate that the container can be filled with that volume of fluid (sterile or non-sterile), closed, stoppered, sterilized, packaged, transported, and / or used while maintaining the integrity of the container's closure and maintaining the safety, sterility, and / or sterility properties of the fluid contained therein. In determining a container's nominal volume, the manufacturer or safety organization may also consider variability that occurs during normal filling, closing, stoppering, packaging, shipping, and administration procedures. As an example, a prefillable syringe may be manually or machine filled with liquid up to the syringe's nominal capacity, and then the stopper may be attached with a vent tube or by vacuum without the filling and stoppering machines and tools coming into contact with and potentially contaminating the contents of the syringe.

[0015] Filling a container may include filling the container with more than the nominal volume of the container with fluid. For example, filling a PFS having a nominal volume of 1 mL of fluid may include filling a barrel of the PFS with more than 1 mL of fluid, as discussed in more detail below, and applying a stopper to the PFS such that the stopper is not dislodged, removed, or otherwise obstructed during packaging, shipping, or administration in a mechanical procedure.

[0016] The term "formulated drug substance" refers to a substance that includes a therapeutically active ingredient (e.g., an active pharmaceutical ingredient, such as a biological or conventional pharmaceutical chemical), and one or more excipients and diluents. The term "drug product," as used herein, may refer to a volume of a formulated drug that is apportioned within a primary packaging component for packaging, shipping, delivery, and / or administration to a patient.

[0017] The term "primary packaging component" refers to a packaging component for a pharmaceutical product, such as a drug container, that is designed and manufactured to be in direct physical contact with a prescription drug. (See, e.g., Guidance for Industry on Container Closure Systems for Packaging Human Drugs and Biologics, U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research, and Center for Biologics Evaluation and Research (May 1999), which is incorporated herein by reference.) Examples of primary packaging components include prefillable syringes, Luer syringes, cartridges, and vials made of glass, plastic, and / or other materials.

[0018] It is generally desirable that primary packaging components in which prescription medications are packaged (e.g., in a sterile or non-sterile fill process), sterilized, sold, and / or used be capable of containing an appropriate or desired amount of prescription medication for use (e.g., a single dose of prescription medication) while also being able to withstand the packaging process, transportation, and use, and remain safe and closed, maintain structural integrity and sterility (e.g., sterile), remain safe for handling by medical professionals, patients, and others, and protect the prescription medication from risk of damage and undesired changes. Often, standardized or mass-produced packaging components may have a standard or commonly used nominal volume, such as 0.5 mL, 1 mL, 1.5 mL, 2 mL, 2.25 mL, 2.5 mL, 3 mL, 5 mL, etc. However, the desired or appropriate volume of a prescribed drug may vary beyond these amounts (e.g., between 0.5 mL and 1 mL, between 1 mL and 2 mL, or between 2 mL and 3 mL) based on factors such as the prescribed dosage, the solubility of the active ingredient in the liquid dosage form, and other factors. For example, increasing the concentration of an active ingredient in a liquid dosage form may affect the short-term and long-term stability and solubility of the active ingredient in solution. Increasing the concentration of some active ingredients (e.g., antibodies) may also increase the viscosity of the liquid to an undesirable level, such as a level that makes it difficult to easily administer from a device (e.g., by injection from a syringe) or that is not suitable for a patient's body. For example, FIGS. 1A and 1B show viscosity plots of two exemplary liquid antibody formulations. Specifically, FIG. 1A shows plots of viscosity of four different formulations as a function of antibody concentration. FIG. 1B shows plots of viscosity of an antibody B formulation as a function of antibody concentration at two different temperatures (20°C and 25°C). As shown in Figures 1A and 1B, the viscosity of each formulation increases rapidly with increasing antibody concentration.Thus, as demonstrated by these exemplary formulations, even a small increase in the concentration of antibody in a composition can have a proportionately large effect (e.g., a dramatic effect) on the viscosity and suitability of the composition for loading into a delivery device or administration to a patient.

[0019] In some cases, the volume of a prescription drug for inclusion within a pharmaceutical product to deliver a desired dosage may be slightly larger than the nominal volume of the pharmaceutical product's primary packaging component (e.g., the desired volume of the prescription drug may be 1.1 mL or 1.2 mL, and the pharmaceutical product's primary packaging component may have a nominal volume of only 1 mL). This may occur for a variety of reasons. For example, research of an active ingredient may reveal that a particular dosage of the active ingredient may produce a desired effect or be beneficial for treating a disease state, but that the particular dosage may not be possible to deliver using only the nominal volume of the primary packaging component because including that particular dosage of the active ingredient in a volume of liquid equal to the nominal volume of the primary packaging component may increase the viscosity of the pharmaceutical product to an undesirable level (as discussed above). As another example, the concentration of an active ingredient at a desired dosage in a nominal volume of fluid may be too high to be safe or effective in treating a patient (i.e., a lower concentration is required due to safety, efficacy, or regulatory standards). Thus, instead of increasing the concentration of the active ingredient in the prescription drug and keeping the total amount of prescription drug in the drug product low (i.e., at or below the nominal volume of the primary packaging components), it may be practical, desirable, or necessary to add a higher volume of prescription drug in the drug product beyond the nominal volume of the drug product's primary packaging components.

[0020] Additionally, instead of using a single drug container with a larger nominal volume, or using two smaller drug containers with smaller nominal volumes, it may be desirable to fit more of the prescription drug into a primary packaging component with a nominal volume that is close to, but slightly lower than, the desired volume of the prescription drug. For example, instead of primary packaging components with nominal volumes of 1.5 mL or 2.0 mL, or splitting 1.2 mL of the prescription drug into two primary packaging components each with a nominal volume of 1.0 mL, it may be desirable to package 1.2 mL of the prescription drug into a single primary packaging component with a nominal volume of 1.0 mL. This may be for a number of reasons, for example: Primary packaging components with nominal volumes that are clearly equal to or greater than the desired amount of prescription drug to be included in a pharmaceutical product may not be readily available. For example, certain types of syringes, such as ready-to-fill syringes or staked needle syringes, may not be available in sizes with nominal volumes that are equal to or greater than the desired volume of prescription drug. Specifically, some types of primary packaging components have historically been produced in limited, small nominal volumes. For example, some types of syringes have historically been offered in nominal volumes of 1 mL or less. The manufacturing tools, packaging, and sterilization equipment and processes for these syringes, as well as delivery devices (e.g., autoinjectors), may similarly be designed for a limited range of syringe sizes.

[0021] In some cases, regulatory agencies (such as the US Food and Drug Administration) may specify that a drug product must be delivered in primary packaging components of certain sizes and not in primary packaging components of other sizes.

[0022] Using a primary packaging component with a nominal volume that is larger than the desired volume of the prescription drug may result in too much "dead" space or empty air space within the packaging, which may lead to undesirable exposure of the prescription drug to air, undesirable agitation and bubble formation within the packaging, and / or other problems.

[0023] Using primary packaging components with nominal volumes greater than the desired volume of the prescription drug can lead to higher packaging and shipping costs. Drug products designed to be portable may be rendered less portable if they are contained in packaging components that are larger than necessary.

[0024] Patients who self-administer parenteral drug products may be more reluctant to inject themselves with a large syringe than with a small syringe. Drug products designed to be administered multiple times (e.g., twice-daily schedules) may result in lower patient compliance than drug products designed to be administered less frequently, such as once-daily.

[0025] Primary packaging components designed to work with other devices (e.g., secondary packaging components such as autoinjectors, pens, needle covers, or safety devices) may be less compatible with those devices if the size changes; and / or Primary packaging components with a nominal volume slightly lower than the desired volume of the prescribed drug may be less expensive or more readily available at the time filling is taking place.

[0026] For any or all of these reasons, it may be desirable to deliver an increased volume of prescribed drug in a primary packaging component (such as a syringe) of a smaller nominal volume, for example to allow for an increased formulation amount of active ingredient, while maintaining acceptable viscosity levels, without requiring the use of new manufacturing, tooling, packaging, sterilization, and / or delivery processes and / or devices (or even new regulatory clearances).

[0027] However, some of the consequences of overfilling a primary packaging component may affect the safety, efficacy, efficiency, sterility, and other aspects of the primary packaging component and / or the medication within it. For example, the volume of prescription medication added to a primary packaging component (e.g., a syringe) may affect the extent to which the primary packaging component can be securely stoppered and handled during packaging, shipping, delivery, and administration.

[0028] The systems and methods disclosed herein may be advantageously used to successfully fill a primary packaging component, thereby allowing the packaging component to be filled with a volume of prescription drug that is greater than its nominal volume while maintaining the desired closure and integrity of the primary packaging component and its contents. Specifically, the systems and methods disclosed herein may be advantageously used to successfully fill a PFS. For example, the systems and methods disclosed herein may be used to successfully fill a PFS with a variety of liquid or fluid prescription drugs for parenteral administration, including prescription drugs having active ingredients such as antibodies, vaccines, antibiotics, pain management drugs, anesthetics, hormones, proteins, small molecules, and any other liquid or fluid prescription drug. While embodiments of the present disclosure are described with respect to filling a PFS with a liquid, it should be understood that the systems and methods disclosed herein may be applied to filling a variety of primary packaging components with various types of fluids. Additionally, while the present disclosure refers to filling the PFS with prescription drugs, including biologics (e.g., antibodies such as human monoclonal antibodies, glycosylated or other proteins, nucleic acids, gene therapy drugs, or post-translational molecules), one of skill in the art will readily understand that embodiments of the present disclosure contemplate filling the PFS with any prescription drug, such as those including any blood constituent, vaccine, anti-allergy substance, antibiotic, pain management drug, anesthetic, hormone, and / or small molecule.

[0029] FIG. 2A illustrates, in schematic form, an exemplary stake-type syringe 100 that may be filled in accordance with the present disclosure. Components of the syringe 100 are shown in cross-section. The syringe 100 may include a body 102. The body 102 may have a flange 104 surrounding an opening at the proximal end of the syringe 100 and a passageway 106 at the distal end of the syringe 100 that leads to a needle 110. The needle 110 may be covered by a sheath 108. The syringe 100 may also include a cap 120 that may cover the needle 110. The cap 120 may include a grip 122 and a reinforced tip 124.

[0030] Syringe 100 may be any type of syringe having a nominal volume for parenteral administration of prescription drugs, such as a standard syringe or a long syringe. For example, syringe 100 may be a PFS suitable for sterilization, pre-filling, packaging, shipping, and single-use administration. Syringe 100 may be formed of any suitable material or combination of materials, such as, for example, glass, plastic, and / or metal. Syringe 100 may have any nominal volume, such as, for example, 0.3 mL, 0.5 mL, 1 mL, 1.5 mL, 2 mL, 2.25 mL, 2.5 mL, 3 mL, 5 mL, or any other nominal volume. For example, syringe 100 may be an Ompi EZ-fill® syringe, a Gerresheimer ready-to-fill syringe, a BD Hypak SCF™ syringe, or other bulk-processed ready-to-fill or prefillable syringe. However, syringe 100 may have the capacity to physically hold a volume of fluid that is greater than its nominal volume. In some embodiments, syringe 100 may be a multi-use syringe. In some embodiments, syringe 100 may be suitable for loading into an autoinjector.

[0031] The body 102 of the syringe 100 may be configured to hold at least the syringe's 100's nominal volume of fluid. The body 102 may be cylindrical or have any other suitable shape, such as an oval cylinder or a rectangular prism. The body 102 may be formed of any suitable material for holding prescription medications, such as glass, plastic, metal, and / or silicone. The body 102 may have a wall thickness appropriate for maintaining its integrity throughout various handling procedures, such as sterilization, filling, stoppering, packaging, shipping, and / or use. The body 102 may have an opening 101 at its proximal end through which a fluid and a stopper assembly (e.g., stopper assembly 150 shown in FIG. 2B ) may be introduced into the interior 107 of the body 102. Interior 107 may have a substantially constant cross-sectional size and shape throughout body 102, such that, for example, a stopper may remain in contact with the inner surface of the wall of body 102 while being moved through interior 107. In some embodiments, body 102 may be transparent, such that any contents placed within body 102 may be visible through the wall of body 102.

[0032] A flange 104 may surround the opening 101 at the proximal end of the body 102. The flange 104 may have a proximal side 103 and a distal side 105. In some embodiments, the flange 104 may be configured to allow gripping (e.g., a finger grip or a mechanical grip) around the distal side 105 and / or to allow a plunger flange (e.g., plunger flange 154 shown in FIG. 2B ) to rest against the proximal side 103 when the plunger is fully inserted into the body 102. Depending on the length of the plunger rod 152, the flange 104 may serve to limit the insertion distance of the plunger 150 into the body 107. The flange 104 may have an oval profile, a circular profile, or may be a truncated flange.

[0033] The passageway 106 may connect the body 102 with the needle 110. In some embodiments, the passageway 106 may be substantially narrower than the interior 107, thereby reducing the flow rate of fluid that may be forced toward the needle 110. The needle 110 may be fluidly connected to the passageway 106, allowing fluid to pass from the body 102, through the passageway 106, and through the needle 110. The connection between the needle 110 and the passageway 106 may be any suitable connection known in the art. The needle 110 may have an opening (not shown) at or proximal to its distal end through which fluid may be released. The needle 110 may be made of any suitable biocompatible material for injection into tissue, such as stainless steel, titanium, or any other metal. The sheath 108 may cover the needle 110, for example, to protect the tip of the needle 110 and / or to prevent fluid from leaking out of the needle 110.

[0034] The cap 120 is sized and configured to cover the needle 110 and may be secured to the body 102 and / or sheath 108. The cap 120 may be formed of any material suitable for protecting the needle 110, such as, for example, rubber, glass, plastic, thermoplastic elastomer, other polymers, metal, or a combination of such materials. The cap 120 may be securable to the body 102 in any known removable manner, such as a threaded connection or other mating connection. The cap 120 may include a grip 122, for example, to allow for easy removal of the cap 120.

[0035] 2B illustrates in schematic form an exemplary stopper assembly 150. Stopper assembly 150 may include a plunger rod 152 and a plunger flange 154. Stopper assembly 150 may also include a stopper 156 (shown in cross section) that may be connected to plunger rod 152 via a connector 158. Stopper 156 may also include a circumferential rib 160, one or more protrusions 162, and a crest 164.

[0036] Stopper assembly 150 may be compatible (e.g., appropriately sized) with syringe 100 so that plunger rod 152 and stopper 156 fit snugly within body 102 of syringe 100. Plunger rod 152 and stopper 156 may likewise be compatible with one another so that stopper 156 can be securely coupled to plunger rod 152, for example, via connector 158. In some embodiments, plunger rod 152 and stopper 156 may be specially manufactured to be compatible with one another. For example, if syringe 100 is a 1 mL syringe (e.g., a standard or long syringe), plunger rod 152 may be a corresponding 1 mL plunger rod, and stopper 156 may be a corresponding 1 mL stopper, such as a fluoropolymer-coated stopper. In some embodiments, stopper 156 may be fabricated to be insertable into interior 107 of body 102 before being connected to plunger rod 152, after which plunger rod 152 may be connected by connector 158 into the inserted stopper 156. In embodiments in which connector 158 is a threaded connector, for example, stopper 156 may have a cavity threaded in a manner complementary to the shape of the helical threads of connector 158, into which connector 158 may be threaded.

[0037] The plunger rod 152 may be sized and configured to pull and push the stopper 156 through the interior 107 of the body 102 when connected to the stopper 156 via the connector 158. The plunger rod 152 may therefore be formed of any material suitable for withstanding the force required to move the stopper 156 through the interior 107 of the body 102. For example, the plunger rod 152 may be formed of metal, glass, plastic, other polymers, or combinations thereof. The stopper 156 may similarly be sized and configured to fit snugly within the interior 107. For example, if the interior 107 has a substantially constant circular cross-section (i.e., if the body 102 is cylindrical), the stopper 156 may similarly have a circular cross-section with a diameter designed to fit snugly within the diameter of the interior 107. The stopper 156 may be formed of any suitable material known in the art, such as, for example, rubber, plastic, silicone, or a thermoplastic elastomer. In some embodiments, the stopper 156 may be coated with a material that reduces interactions between the material of the stopper 156 and the prescription medication contained within the body 102. For example, the stopper 156 may be coated with a Teflon or fluoropolymer film, or a bonded silicone oil. Additionally, the stopper 156 may have a circumferential rib 160 and / or one or more protrusions 162, which may be configured to improve the seal between the stopper 156 and the body 102 without interfering with the movement of the stopper 156 within the body 102.

[0038] 3A shows in schematic form a filled, stoppered syringe assembly 200 including a stopper assembly 150 inserted into the syringe 100 such that the stopper 156 and a portion of the plunger rod 152 are inside the body 102 until the top 164 of the stopper 156 is inserted a distance A beyond the distal side 105 of the flange 104. The syringe assembly 200 is filled with a prescribed medication 202.

[0039] The prescription drug 202 may be any fluid prescription drug suitable for packaging within the syringe assembly 200. For example, the prescription drug 202 may be any fluid suitable for parenteral administration through the needle 110. The prescription drug 202 may be, for example, a liquid, a gel, or a suspension. In some embodiments, the prescription drug 202 may include an active pharmaceutical ingredient (API) in a liquid or gel solution. Such an API may be any suitable API for therapeutic administration, such as a protein (e.g., an antibody, such as a human monoclonal antibody, a glycosylated protein, or other protein), a nucleic acid, a gene therapy drug, an antibiotic, a pain management drug, an anesthetic, a hormone, or other high or low molecular weight API.

[0040] In some embodiments, the volume of the prescribed medication 202 introduced into the syringe 100 may be greater than the nominal volume of the syringe 100. For example, in some embodiments, the volume of the prescribed medication 202 may be at least about 3% greater than the nominal volume of the syringe 100. In some embodiments, the volume of the prescribed medication 202 may be about 3% to about 40% greater than the nominal volume of the syringe 100. In some embodiments, the volume of the prescribed medication 202 may be about 3% to about 30%, about 12% to about 25%, or about 14% to about 25% greater than the nominal volume of the syringe 100. In some embodiments, the volume of the prescribed medication 202 may be about 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, or 30% greater than the nominal volume of the syringe 100. In further embodiments, the volume of the prescribed medication 202 may be about 0.1 mL to about 0.3 mL greater than the nominal volume of the syringe 100. For example, for a syringe with a nominal capacity of 1 mL, the volume of the prescribed medication 202 may be between about 1.09 mL and 1.30 mL, such as between about 1.10 mL and 1.27 mL, 1.10 mL and 1.25 mL, or 1.10 mL and 1.15 mL, such as between about 1.09 mL, 1.10 mL, 1.11 mL, 1.12 mL, 1.13 mL, 1.14 mL, 1.15 mL, 1.16 mL, 1.17 mL, 1.18 mL, 1.19 mL, 1.20 mL, 1.21 mL, 1.22 mL, 1.23 mL, 1.24 mL, 1.25 mL, 1.26 mL, or 1.27 mL. As another example, for a syringe having a nominal capacity of 2 mL, the volume of the prescribed medication 202 may be between about 2.09 mL and 2.30 mL, such as between about 2.10 mL and 2.25 mL, 2.10 mL and 2.20 mL, or 2.10 mL and 2.15 mL, such as between about 2.09 mL, 2.10 mL, 2.11 mL, 2.12 mL, 2.13 mL, 2.14 mL, 2.15 mL, 2.16 mL, 2.17 mL, 2.18 mL, 2.19 mL, or 2.20 mL.In some embodiments, the volume of the prescribed medication 202 is greater than the nominal volume of the syringe 100, but may be less than 140%, 130%, or 120% of the nominal volume of the syringe 100.

[0041] In some embodiments, the volume of prescribed medication 202 introduced into syringe 100 may be slightly greater than the volume of prescribed medication 202 that may be expelled from syringe 100 through needle 110 due to "dead volume," e.g., the volume remaining within passageway 106 (and / or needle 110) after stopper assembly 150 is fully pushed through body 102. For example, in a syringe having a nominal capacity of 1 mL, the fill volume of prescribed medication 202 may be 1.19 mL, while the potential expelled or administered volume of prescribed medication 202 through needle 110 may be approximately 1.14 mL. In further embodiments, the volume of prescribed medication 202 introduced into syringe 100 may be greater than the combination of the target volume of prescribed medication 202 and the dead volume of syringe 100. Additionally, in some embodiments, the target volume of the prescribed drug 202 introduced into the syringe 100 may be slightly larger than the target volume of the prescribed drug 202 expelled through the needle 110 to account for variability in the filling process and to ensure that a minimum amount of the prescribed drug 202 is delivered.

[0042] In some embodiments, after the prescribed medication 202 is added and the stopper 156 is seated within the body 102, no air space exists within the interior 107 of the body 102. In further embodiments, some such air space may exist. For example, in a syringe having a nominal capacity of 1 mL, the air space measured from any point at the bottom of the stopper 156 to any point on the dispensing line of the prescribed medication 202 may be between about 0.01 mm and about 1 mm. In some embodiments, the air space present may be relatively small, such that only an air bubble may be visible when the body 102 is turned on its side, as shown by air bubble 170 in FIG. 3B . In some embodiments, the existing air space may occupy between about 5 μL and 250 μL of fluid volume, such as 150 μL of fluid volume.

[0043] Distance A may be the distance from the distal side 105 of flange 104 to the apex 164 of stopper 156, or from the opening 101 at the proximal end of body 102 to the apex 164 of stopper 156. In some embodiments, distance A may be greater than zero, such that the entire stopper 156 is contained within body 102. This may ensure that the prescription medication 202 is completely sealed within body 102. In further embodiments, distance A may be greater than an empirically determined threshold. For example, for some syringes having a nominal capacity of 1 mL, distance A may be at least about 1 mm. In some embodiments, distance A may be at least about 1.5 mm, 2 mm, 2.5 mm, at least about 2.56 mm, at least about 2.57 mm, at least about 3 mm, at least about 3.5 mm, at least about 4 mm, at least about 4.5 mm, at least about 5.0 mm, or at least about 5.5 mm.

[0044] In some embodiments, distance A may be experimentally determined based, in part, on the amount that plunger rod 152 may be allowed to tilt relative to the longitudinal axis of body 102 within syringe assembly 200. This may be to prevent excessive tilt of plunger rod 152 from displacing stopper 156 (e.g., during packaging, shipping, unpacking, or use of syringe assembly 200), thereby breaking the sterile seal between stopper 156 and body 102 or otherwise compromising the integrity of stopper 156, body 102, and / or syringe assembly 200. In some embodiments, distance A may be sufficiently large so that any tilt of plunger rod 152 is limited to less than a given angle relative to the longitudinal axis of body 102 by contact with the walls of body 102.

[0045] 3C and 3D show alternative placements of stopper 156 within interior 107 of body 102. In FIG. 3C, distance A is very small because plunger rod 152 could tilt an amount (e.g., angle a) such that stopper 156 could be pulled away from the wall of body 102 or pushed away from the syringe, thus compromising the integrity of stopper 156 and the sterility of stopper 156, syringe 102, and prescription medication 202. In FIG. 3D, distance A is adequate so that tilting of plunger rod 152 is limited by the wall of body 102 (e.g., angle b) and is not sufficient to cause stopper 156 to be pulled away, pushed away, or otherwise obstructed from the wall of body 102. In some embodiments, for a syringe having a nominal capacity of 1 mL, for example, angle b may be, for example, 20 degrees, 15 degrees, 12 degrees, or 10 degrees or less.

[0046] Filling and stoppering primary packaging components, such as filled and stoppered syringes, may be accomplished by a variety of methods. Additionally, a variety of methods may be used to package filled and stoppered drug containers.

[0047] 4 shows a flow diagram of the steps of a method 300 for filling a primary packaging component, such as a drug container. According to step 302, a prescription drug may be prepared. According to step 304, a drug container with specifications for holding a nominal volume may be prepared. According to step 306, the drug container may be filled with a volume of the prescription drug, where the fill volume is greater than the nominal volume. According to step 308, a stopper may be applied to the drug container. According to step 310, the drug container may be packaged.

[0048] According to step 302, a prescription drug may be prepared. Depending on the prescription drug used (e.g., prescription drug 202 shown in FIGS. 3A and 3B), various preparations may be appropriate. For example, the API may be prepared in a solution in a fluid (e.g., a liquid or gel) appropriate for administration to a patient. In some embodiments, the API may thus be prepared to avoid precipitation of the API out of solution. As a further example, a preformed, frozen, stored prescription drug may be removed from storage and thawed to a temperature appropriate for filling, such as room temperature. As another example, the drug may be diluted with various additives and / or buffers to form the prescription drug. As a still further example, the prescription drug may be filtered through a filtration system prior to filling into a drug container, e.g., to ensure sterility. Filtering the prescription drug through a filtration system may include one or more of thawing, storing, mixing, temperature equilibrating, filtering, and / or transporting the prescription drug.

[0049] According to step 304, a drug container having a nominal capacity may be prepared. For example, the syringe assembly 200 shown in FIGS. 3A and 3B may be disassembled such that the syringe 100 is separated from the stopper assembly 150. In some embodiments, the drug container may be assembled, removed from packaging, cleaned, or sterilized. In some embodiments, the drug container may be loaded into a suitable filling machine for automatically filling the drug container with a volume of a prescribed medication. As described above with respect to the syringe 100 shown in FIG. 2A, the drug container may have any nominal capacity. In some embodiments, a plurality of drug containers may be assembled and sterilized in a batch, for example, of 80, 100, 160, 200, or more drug containers.

[0050] According to step 306, a drug container may be filled with a volume of prescription medication, where this volume is greater than the nominal volume of the drug container. This filling step may be accomplished by a machine-based filling process, for example, using an automatic or semi-automatic filling machine, or may be accomplished manually. In some embodiments, the drug container may be filled under vacuum to prevent air pockets or bubbles from occupying the volume within the drug container. In some embodiments, multiple drug containers may be filled in bulk, for example, using an automated fill completion process. For example, a batch of 80, 100, 160, 200, or more drug containers may be filled as part of an automated filling process. In some embodiments, the drug container may be filled in a sterile condition. The volume of prescription medication provided may be any amount greater than the nominal volume. For example, the volume of prescription drug prepared may be at least about 10% greater than the nominal volume, or may be any other amount greater than the nominal volume, such as those described with respect to prescription drug 202 in syringe assembly 200.

[0051] According to step 308, a stopper may be applied to the drug container. Applying the stopper includes ensuring proper placement of the stopper element relative to the remainder of the drug container. For example, with respect to syringe assembly 200, applying the stopper may include ensuring that the top 164 of stopper 156 at least clears the distal side 105 of flange 104 of body 102, such that stopper 156 is completely within interior 107 of body 102. In some embodiments, applying the stopper may include ensuring that the top 164 of stopper 156 is inserted at least a desired distance beyond the distal side 105 of flange 104, as described above with respect to syringe assembly 200.

[0052] Applying the stopper in step 308 may include a vacuum stopper application process, as shown in FIGS. 5A-5D , or a vacuum-assisted stopper application process, as shown in FIGS. 6A-6E . In such embodiments, a vacuum may be applied during stopper application to prevent or reduce air retention within the interior 107 of the body 102 and to facilitate inserting the stopper as far as possible into the interior 107 of the body 102. Vacuum stopper application or vacuum-assisted stopper application may facilitate overfilling the syringe 100 because the vacuum may facilitate replacement of air normally remaining within the interior 107 of the body 102 with an additional volume of the prescribed medication 202. A vacuum stopper application process may, for example, allow the stopper to be drawn adjacent to the fluid in the drug container without the mechanical stopper application components coming into contact with the fluid and without undesirable deformation of the stopper (e.g., wrinkles or tears). For these reasons, a vacuum or vacuum-assisted stopper attachment process may be preferable to, for example, a mechanical stopper attachment process, which may not offer these benefits. In other embodiments, stopper attachment according to step 308 may be accomplished by any other method known in the art.

[0053] 5A through 5D illustrate an exemplary vacuum stopper installation process. In this vacuum stopper installation process, a vacuum is applied to the distal side of the drug container, and the stopper is drawn into the container by the vacuum. As shown in FIGS. 5A through 5D, a vacuum housing 502 includes a gasket 504, which may surround the vacuum housing 502, and a vacuum conduit 506. The vacuum housing 502 may be sized to hold the stopper 156 and may have a diameter that matches the diameter of the syringe body 102. A prescription drug 202 may be loaded into the syringe body 202. As shown in FIG. 5A, the stopper 156 may be loaded into the vacuum housing 502 with the aid of an insertion rod 508, which may fit into a cavity 157 in the stopper 156. As shown in FIG. 5B, the vacuum housing 502 holding the stopper 156 may be positioned over the syringe body 102 such that the gasket 504 contacts the flange 104 of the syringe body 102. A gasket 504 may form a seal between the vacuum housing 502 and the flange 104 of the body 102. A vacuum may be applied to the sealed area below the stopper 156 (i.e., the interior 107 of the body 102) via the vacuum conduit 506. The vacuum allows the stopper 156 to be pulled out of the vacuum housing 502 and into the body 102 with the aid of an insertion rod 508, as shown in FIG. 5C. The vacuum may help ensure that the stopper 156 is positioned as close as possible to the prescription medication 202. Finally, the vacuum housing 502 may be removed, as shown in FIG. 5D.

[0054] 6A through 6E illustrate an exemplary vacuum-assisted stopper installation process. In this vacuum-assisted stopper installation process, a vacuum is applied to the drug container, and a stopper insertion tube is used to press on the stopper, assisted by the suction created by the vacuum, and insert the stopper into the drug container. As shown in FIGS. 6A through 6E, the stopper insertion tube 602 includes a gasket 604, which may surround the stopper insertion tube 602, and a vacuum conduit 606. All or a portion of the stopper insertion tube 602 may be sized to hold the stopper 156 in a slightly compressed configuration and may fit within the syringe body 102, into which the prescription drug 202 has been loaded. As shown in FIG. 6A, the stopper 156 may be loaded into the stopper insertion tube 602 with the assistance of an insertion rod 608, which may fit within the cavity 157 of the stopper 156. As shown in FIG. 6B , the stopper insertion tube 602, holding the stopper 156, may be introduced into the interior 107 of the syringe body 102. A gasket 604 may form a seal between the insertion tube 602 and the flange 104 of the body 102. A vacuum may be applied to the sealed area below the stopper 156 via a vacuum conduit 606. As shown in FIG. 6C , an insertion rod 608 may be used to move the stopper 156 through the insertion tube 602. The vacuum may help draw the stopper 156 further into the body 102 so that the stopper 102 is proximal to the prescription drug 202. As shown in FIG. 6D , the insertion tube 602 may be removed. The insertion rod 608 may help hold the stopper 156 in place so that the stopper 156 is left behind and expands to fit within the body 102. As shown in FIG. 6E , the insertion rod 608 may be removed. In some embodiments, the insertion rod 608 may be removed before removing the insertion tube 602, and vacuum may continue to be applied through the insertion tube 602 to draw the stopper 156 into the body 102 after removal of the insertion rod 608.

[0055] By using a vacuum or vacuum-assisted stopper attachment process to draw the stopper into the container, the likelihood of the mechanical stopper attachment element coming into contact with the prescription medication within the container can be reduced, thus maintaining the sterility of the prescription medication.

[0056] 5A-5D and 6A-6E, a stopper attachment element (e.g., stopper 156) may be inserted or retracted into interior 107 of body 102 without an attached plunger rod (e.g., plunger rod 152) using a vacuum or vacuum-assisted stopper attachment process. The plunger rod may be connected to the stopper (e.g., via cavity 157) after stopper attachment is complete.

[0057] According to step 310, the drug container may be packaged. Packaging may include enclosing the entire stoppered drug container within a secondary packaging component (i.e., packaging that is not in direct contact with the prescription drug), such as, for example, plastic packaging suitable for shipping the drug container. Step 310 may also or alternatively include applying one or more seals and / or labels to the stoppered drug container or its packaging. In some embodiments, little or no packaging (beyond the drug container) may be required.

[0058] The stoppered and packaged drug container may be stored, shipped, and / or used as desired. In some embodiments, the drug container may be pre-sterilized, filled, and stoppered via a sterile filling process. In further embodiments, the packaged drug container may be "terminally" sterilized. Terminally sterilization may be performed by any method known in the art that does not negatively impact the stoppered drug container, for example, by exposing the prescription drug in the drug container (e.g., prescription drug 202 in syringe assembly 200) to an unsterile environment or by moving the drug container's stopper (e.g., stopper 156 in syringe assembly 200) to cause leakage of the prescription drug. Furthermore, terminal sterilization may be accomplished by any method known in the art that does not (i) expose the stoppered medication container and its contents to temperatures and / or pressures that may adversely affect the container or the prescription drug therein, or (ii) result in sterilization residues leaching from the stopper 156. For example, terminal sterilization may be achieved by a vaporized hydrogen peroxide sterilization process, such as the processes disclosed in U.S. Patent Application No. 62 / 477,030, filed March 27, 2017, and U.S. Patent Application No. 62 / 472,067, filed March 17, 2017, which are incorporated herein by reference. Terminal sterilization may also be achieved by, for example, vaporized hydrogen peroxide, ethylene oxide (EO) sterilization, other processes using radiation, steam, or nitrogen dioxide (NO), gamma radiation sterilization, electron beam sterilization, or other processes known in the art.

[0059] In some embodiments, any or all of the above steps and phases may be performed manually, automatically by various priming, filling, and stoppering machines and methods known in the art, or by a combination of manual and automated operations. In some embodiments, any or all of the above steps and phases may be performed on one or more batches of drug containers. A batch may include, for example, multiple identical drug containers that may be primed, filled, stoppered, etc., as a group. For example, a batch of prefillable syringes may include 10, 50, 80, 150, 160, 200, 1,000, 10,000, 20,000, 50,000, 100,000, or more prefillable syringes. Additionally, any of the above steps of method 300 may be omitted or combined with another step. Additionally, while some of the steps and phases described above may be described with reference to a drug container, or more specifically, a syringe, it should be understood that each step disclosed herein may be applied to a variety of primary packaging components. Additionally, one or more of the steps described above may be performed in an order other than that shown in FIG. [Example]

[0060] Example 1 The theoretical feasibility of filling a syringe was determined as follows: A 1 mL BD Hypak Physiolys SCF™ low-tungsten syringe (Beckton Dickinson Medical) was analyzed to determine whether it could be filled with a 1.15 mL or 1.10 mL dose volume when paired with a 1 mL BD Hypak PS Flurotec plunger stopper and a 1 mL BD Hypak 21510 PR C plunger rod (Beckton Dickinson Medical).

[0061] First, the theoretical fill volumes required to achieve 1.15 mL and 1.10 mL dose volumes were determined. The theoretical lost volumes (e.g., dead volume, or the volume remaining in the syringe after expelling as much volume as possible, and the potential negative deviation from the desired volume due to variability in the filling process) were determined based on measurements from the syringe drawings, the calculated fill height of the desired dose volume, and in-process control (IPC) capabilities. These theoretical lost volumes were calculated as follows:

[0062] [Table 1]

[0063] By adding these theoretical values ​​to the theoretical doses of 1.15 mL and 1.10 mL, the theoretical fill volume required to achieve a 1.15 mL dose was determined to be 1.173 mL in the nominal case, and the theoretical fill volume required to achieve a 1.10 mL dose was determined to be 1.123 mL. In the most unfavorable case, the theoretical fill volume required to achieve a 1.15 mL dose was determined to be 1.187 mL, and the theoretical fill volume required to achieve a 1.10 mL dose was determined to be 1.137 mL.

[0064] These volumes were then converted to a "medication height" within a theoretical filled syringe using the syringe dimensions. The drug height was then combined with the dimensions of the syringe and stopper assembly to determine the theoretical stopper position within a syringe filled with the desired theoretical fill volume. The "stopper position" relates to the distance between the top of the stopper within the filled syringe and the distal side of the syringe flange (e.g., distance A in Figures 3A-3D of the present disclosure). The bubble height of each syringe was also considered. The "bubble height" relates to the distance between the fill line of the prescribed drug within the filled syringe and the bottom of the stopper. It was initially determined that the stopper height was 7.65 + / - 0.4 mm and the bubble height was 4 mm + / - 1 mm when not fully filled. These values ​​indicated the absence of undesirable stopper compression during insertion into the syringe, which could result in wrinkles, cracks, and / or failure of the stopper to pass visual inspection. The stopper heights for desired fully filled dose volumes (ADV) of 1.15 mL and 1.10 mL, assuming a fixed bubble height of 4.0 mm, were then calculated for the nominal and worst case scenarios, as well as the theoretical fill volume determined above, as follows:

[0065] [Table 2]

[0066] Next, the filled, stoppered syringe was tested, and it was determined that the stopper needed to be a certain distance below the syringe flange to limit the plunger rod of the stopper assembly from tilting enough to deform the stopper to an extent that could potentially compromise the integrity of the seal formed by the stopper. It was determined that the stopper would not deform to such an extent that the plunger rod was prevented from tilting to an angle greater than 12 degrees relative to the longitudinal axis of the syringe body. Based on the provided dimensions of the syringe, stopper, and plunger, this length was determined to be 3.0 mm, with a tolerance of + / - 0.5 mm. Thus, it was determined that a distance of at least 2.5 mm, and more specifically, a minimum distance of 3.0 mm + / - 0.5 mm, should be maintained between the top of the stopper in the filled syringe and the distal side of the syringe flange (e.g., distance A as shown in Figures 3A-3D).

[0067] Finally, it was determined that the 4.00 mm foam height could theoretically be reduced because the desired theoretical drug height and stopper position could not be altered to achieve a fully filled syringe without losing the integrity of the stopper within the syringe body. Using the worst case scenario drug height and stopper position, the desired foam heights for 1.15 mL ADV and 1.10 mL ADV were calculated as follows:

[0068] [Table 3]

[0069] Example 2 Multiple PFS were filled by machine as follows: Five formulations (87.7 mg / mL Antibody A, 131.6 mg / mL Antibody A, 175 mg / mL Antibody A, placebo solution, and water for injection (WFI)) were prepared and frozen at -80°C. Each formulation was removed from frozen storage and thawed for 16 hours. The formulations (except WFI) were mixed, filtered, and transferred to a 2°C to 8°C environment as follows:

[0070] [Table 4]

[0071] The redundant filtration lines consisted of two Millipak 20 units and 1 / 4" x 3 / 8" Pt-hardened silicone tubing for product passage. In the case of 175 mg / mL antibody A, two Millipak 20 units were used first, then a portion of the flow path was switched to a Millipak 40 unit. A peristaltic pump was used as the driving force for filtration. All of the primary filters were tested and passed the filter integrity standard of EP-024.

[0072] The PFS filled in this procedure included 1 mL BD Hypak Physiolys SCF™ low-tungsten syringes (Beckton Dickinson Medical) with a nominal volume of 1 mL. These syringes were paired with 1 mL BD Hypak PS Flurotec plunger stoppers and 1 mL BD Hypak 21510 PR C plunger rods (Beckton Dickinson Medical). The desired placement of the top of the stopper was at least 2.57 mm below the distal flange of the syringe, preferably between 5.0 mm and 2.56 mm below the distal flange of the syringe. Alternatively, the desired placement of the stopper rib closest to the top of the stopper was 4.9 mm below the distal flange of the syringe. Filling in this procedure was completed using an INOVA H3-5V commercial-scale syringe filter. Stopper installation was completed using a Becton Dickson Hypak stopper installation unit. Stopper installation height (e.g., the distance between the top of the stopper and the distal side of the syringe flange) was measured using Vernier calipers.

[0073] The syringe filler was initially set up for a target fill volume of 1.28 mL. Using WFI, this resulted in an average deliverable volume of 1.27 mL for the 10 dosage syringes. A vacuum setting of 70 mBar (7 kPa) and a stoppering time of 750 ms on the stoppering unit was initially used to stop the stoppering tank. At this fill volume and stoppering time setting, stoppering was sometimes incomplete, and WFI was drawn into the vacuum chamber.

[0074] Therefore, the syringe filling machine was set up for a target fill volume of 1.19 mL. This was targeted to maintain a minimum deliverable volume of 1.14 mL while providing greater operational buffering for the vacuum stopper setting and stopper placement requirements. The vacuum stopper setting was maintained between 70 mBar (7 kPa) and 75 mBar (7.5 kPa) while varying the stopper dwell time to 250 ms. This eliminated the issue of product being drawn into the vacuum chamber when tested using WFI. However, the stopper placement requirement (top of stopper at least 3.0 mm distal to the syringe flange) was met with the stoppered syringes. Lower than desired stopper placement consistency was achieved, which was determined to be due to the truncated syringe flange. To assess whether the truncated flange was the reason for stopper set consistency, two tabs of 80 syringes each (160 syringes total) of round flange, 1 mL long syringes were used in a syringe filling machine. This resulted in a significant reduction in stopper set rejection compared to that seen in runs with truncated flange syringes.

[0075] To this end, a syringe filling machine set to a target fill volume of 1.19 mL was used to fill syringes using the WFI, placebo, and antibody A formulations. One hundred and sixty syringes were filled with each of five different fluids and at each of three different machine speeds (40%, 65%, and 90%) (except for the 87.7 mg / mL antibody A fill at 40% speed, in which only 35 syringes were filled, and the 87.7 mg / mL antibody A fill at 65% speed, in which no syringes were filled due to insufficient product available). All syringes were stoppered using a Hypak stoppering machine. The deliverable volume from the 20 filled and stoppered syringes from each bundle was then measured. The deliverable volume was determined by expelling a volume from each of the 20 syringes, weighing the expelled volume, and converting the weight to volume using the following concentrations:

[0076] [Table 5]

[0077] The transportable capacity was calculated as follows:

[0078] [Table 6]

[0079] The stopper mounting height was measured from the top of the stopper to the distal side of the syringe flange and was measured and calculated as follows:

[0080] [Table 7]

[0081] Example 3 Multiple PFS were manually filled as follows: Three formulations (87.7 mg / mL Antibody A, 131.6 mg / mL Antibody A, and 175 mg / mL Antibody A) were prepared and frozen at -80°C. Each formulation was removed from frozen storage and thawed for 16 hours. Each formulation was mixed, filtered, and transferred to 2°C to 8°C as follows:

[0082] [Table 8]

[0083] The redundant filtration lines for the 87.7 mg / mL and 131.6 mg / mL antibody A consisted of two Millipak 20 tubes and 1 / 4 inch x 3 / 8 inch Pt-hardened silicone tubing for product passage. The redundant filtration lines for the 175 mg / mL antibody A consisted of two Millipak 40 tubes and 1 / 4 inch x 3 / 8 inch Pt-hardened silicone tubing for product passage. A peristaltic pump was used as the driving force for the filtration.

[0084] The PFS filled in this procedure included a 1 mL BD Hypak Physiolys SCF™ low-tungsten syringe (Beckton Dickinson Medical) paired with a 1 mL BD Hypak PS Flurotec plunger stopper and a 1 mL BD Hypak 21510 PR C plunger rod (Beckton Dickinson Medical). The desired placement of the top of the stopper was at least 3.0 mm below the distal flange of the syringe. Filling in this procedure was completed manually using a Watson-Marlow pump. Stopper installation was completed using a Becton Dickinson Hypak vacuum stopper installation unit.

[0085] The target fill volume was set at 1.19 mL for this procedure. 160 syringes (two tubs containing 80 syringes each) were filled with each of the three different formulations. The deliverable volume from 10 successfully filled and stoppered syringes from each bundle was then measured. The deliverable volume was determined by expelling a volume from each syringe, measuring the weight of the expelled volume, and converting the weight to volume using the concentrations shown in Table 5. The deliverable volume was calculated as follows:

[0086] [Table 9]

[0087] As can be seen by comparing these volumes with those in Table 6, the deliverable volumes of the manually filled syringes were comparable to the deliverable volumes of the machine filled syringes.

[0088] The stopper seat height was measured from the top of the stopper to the distal side of the syringe flange using a Vernier caliper for 15 manually filled samples. The measurements were as follows:

[0089] [Table 10]

[0090] As can be seen by comparing these stopper seat heights with the stopper seat heights in Table 7, the stopper seat heights of the manually filled syringes were comparable to the stopper seat heights of the machine filled syringes.

[0091] The above description and examples are illustrative and not intended to be limiting. Those skilled in the art may make numerous modifications and / or variations without departing from the overall scope of the invention. For example, as noted, the above-described embodiments (and / or aspects thereof) may be used in combination with each other. In addition, parts of the above-described embodiments may be removed without departing from the scope of the invention. Furthermore, modifications may be made to the teachings of the various embodiments to adapt to a particular situation or material without departing from the scope of the various embodiments. Many other embodiments will be apparent to those skilled in the art upon reviewing the above description.

[0092] The term "about," as used herein in reference to a value, may refer to a variation of 10% above or below the stated value. Additionally, while numerous objects and advantages of the disclosed embodiments (and variations thereof) have been described herein, not necessarily all such objects or advantages may be achieved in accordance with any particular embodiment. Thus, for example, those skilled in the art will understand that the systems and techniques described herein may be implemented or performed in a manner that achieves or maximizes one advantage or group of advantages taught herein without necessarily achieving other objects or advantages that may be taught or implied herein.

Claims

1. introducing a volume of a prescription drug into a primary packaging component, the volume of the prescription drug being greater than a nominal volume of the primary packaging component; and placing a stopper within the primary packaging component, wherein placing the stopper includes applying a vacuum to the stopper.

2. The method of claim 1 , wherein the primary packaging component is a syringe.

3. The method of claim 1 , wherein the primary packaging component is a prefillable syringe.

4. 10. The method of claim 1, wherein the primary packaging component is a prefillable syringe having a nominal volume of at least 1 mL.

5. 10. The method of claim 1, wherein the volume of the prescription drug is at least 0.05 mL greater than the nominal volume of the primary packaging component.

6. 10. The method of claim 1, wherein the prescribed drug comprises one of a protein, nucleic acid, or gene therapy drug.

7. 10. The method of claim 1, wherein the prescribed drug comprises an antibody and at least one excipient.

8. 10. The method of claim 1, wherein the prescribed medication comprises an antibody solution, and the antibody is present in the solution at a concentration of at least 100 mg / mL.

9. 10. The method of claim 1, wherein the formulated drug comprises an antibody and has a viscosity of at least 5 cPoise (0.005 Pa s).

10. The method of claim 1 further comprising placing the primary packaging component in further packaging.

11. 10. A method for preparing a plurality of pharmaceutical products, the method comprising repeating the steps of claim 1 for each of a plurality of batches of primary packaging components.

12. 12. The method of claim 11, wherein the bundle of primary packaging components comprises 80 pre-filled syringes.

13. 10. A pharmaceutical product prepared by the method of claim 1.

14. 10. The method of claim 1, wherein the primary packaging component is a prefillable syringe, the nominal volume is 1 mL, and wherein placing the stopper within the primary packaging component further comprises inserting the stopper into the body of the syringe such that the end of the stopper closest to the flange of the syringe is spaced from the flange of the syringe by between about 2.5 mm and about 5.0 mm.

15. 10. The method of claim 1, wherein the volume of the prescribed medication is between 1.05 mL and 1.30 mL.

16. 10. The method of claim 1, wherein the volume of the prescription drug is between about 110% and about 140% of the nominal volume of the primary packaging component.

17. 10. The method of claim 1, wherein applying the vacuum to the portion of the primary packaging component comprises imposing a pressure of between 70 mBar (7 kPa) and 75 mBar (7.5 kPa) on the portion of the primary packaging component.

18. introducing a volume of a prescription drug into a prefillable syringe, the prescription drug including an antibody, the volume of the prescription drug being greater than the nominal volume of the prefillable syringe; and attaching a stopper to said prefillable syringe using one of a vacuum stoppering process or a vacuum assisted stoppering process.

19. a primary packaging component having a nominal volume; a volume of prescription medication in the primary packaging component, the volume of prescription medication being greater than the nominal volume; and A medicinal product comprising: a stopper;

20. 20. The pharmaceutical product of claim 19, wherein the primary packaging component is a prefillable syringe.

21. 20. The drug product of claim 19, wherein the nominal volume is 1 mL and the prescribed drug volume is at least 1.05 mL.

22. 20. The pharmaceutical product of claim 19, wherein the primary packaging component is a prefillable syringe having a body and a flange surrounding an opening in the body, the minimum distance between the flange and the stopper being at least 2.5 mm.

23. 20. The pharmaceutical product of claim 19, wherein the prescription drug comprises a protein, a nucleic acid, a blood component, a vaccine, an anti-allergy agent, a gene therapy agent, an antibiotic, a pain management agent, an anesthetic, and / or a hormone.

24. 20. The pharmaceutical product of claim 19, wherein the prescription drug comprises an antibody.

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