EA045636B1 - DEVICE AND METHOD FOR OVERFLOWING A CONTAINER WITH MEDICINE - Google Patents

Description

Technical field

Various embodiments of the present invention relate to devices and methods for refilling primary packaging components. More specifically, specific embodiments of the present invention relate to devices and methods for refilling syringes, including pre-filled syringes.

Introduction

Primary packaging components, such as syringes, intravenous fluid containers, ampoules, and other drug containers, are designed to hold the maximum volume of drug in dosage form or other liquid. For example, a syringe may be manufactured and sold at the nominal volume or maximum volume that the syringe has been tested to hold, while still ensuring the proper functioning of the syringe stopper, plunger, and other parts without compromising the contents or integrity of the capped syringe. In particular, the nominal volume of a pre-filled syringe may be specified to ensure that the syringe, once filled, maintains its integrity through various post-fill processes such as packaging and shipping. However, in some situations, the nominal volume of a primary packaging component may be less than the required volume of drug substance dosage form to be included in the primary packaging component, for example due to a mismatch between the nominal packaging volume and the required dosage volume or the lack of suitable packaging bigger size.

The essence of the invention

This invention relates to drugs and methods for their preparation. In particular, the present invention relates to the refilling of primary packaging components using pharmaceutical substances in dosage form.

In an aspect of the present invention, there is provided a method of preparing a medicinal product, comprising introducing a volume of a pharmaceutical substance in the form of a dosage form into a primary packaging component, wherein the volume of the pharmaceutical substance in the form of a dosage form is greater than the nominal volume of the primary packaging component, and placing a stopper in the primary packaging component. wherein placing the plug involves creating a vacuum around the plug.

In an embodiment of the present invention, the primary packaging component is a syringe. In a further embodiment of the present invention, the primary packaging component is a pre-filled syringe. In a further embodiment of the present invention, the primary packaging component is a pre-filled syringe having a nominal volume that is at least 1 ml. In yet another embodiment of the present invention, the primary packaging component is a prefilled syringe having a nominal volume of 1 ml, and placing the stopper within the primary packaging component includes inserting the stopper into the body of the syringe such that the end of the stopper closest to the flange syringe, was at a distance of about 2.5 mm to about 5.0 mm from the syringe flange. In another embodiment of the present invention, applying a vacuum to a portion of the primary packaging component includes subjecting the portion of the primary packaging component to a pressure of between 70 and 75 mbar.

In one embodiment of the present invention, the volume of the drug substance is from 1.05 to 1.30 ml. In a further embodiment of the present invention, the volume of the drug substance in the dosage form is from about 110 to about 140% of the nominal volume of the primary packaging component. In another embodiment of the present invention, the pharmaceutical substance in dosage form is at least 0.05 ml greater than the nominal volume of the primary packaging component. In a further embodiment of the present invention, the pharmaceutical substance in dosage form includes one of the following: a protein, a nucleic acid, or a gene therapy drug. In yet another embodiment of the present invention, the pharmaceutical substance in the form of a dosage form contains an antibody and at least one excipient. In another embodiment of the present invention, the pharmaceutical substance in the form of a dosage form contains a solution of the antibody, in which the antibody is in solution at a concentration of at least 100 mg/ml. In a further embodiment of the present invention, the pharmaceutical substances in the dosage form contain an antibody and have a viscosity of at least 5 cP.

In one embodiment of the present invention, the method includes placing a primary packaging component within a secondary packaging. In another embodiment of the present invention, the method may be repeated for each of a plurality of primary packaging components in a batch. For example, a batch of primary packaging components may contain 80 prefilled syringes.

In a further aspect of the present invention, the drug is prepared by one of the methods described above.

- 1 045636

In another aspect of the present invention, there is provided a method of preparing a medicinal product, including introducing a volume of a pharmaceutical substance in the form of a dosage form into a pre-filled syringe, wherein the pharmaceutical substance in the form of a dosage form contains an antibody, and the volume of the pharmaceutical substance in the form of a dosage form is greater than the nominal volume prefilled syringe, and the closure of the prefilled syringe is accomplished using one of the following methods: vacuum capping process or vacuum capping process.

In another aspect of the invention, there is provided a medicinal product comprising a primary packaging component having a nominal volume, a volume of a pharmaceutical substance in the dosage form of the primary packaging component, wherein the volume of the pharmaceutical substance in the dosage form is greater than the nominal volume, and a stopper. In an embodiment of this aspect of the invention, the primary packaging component is a pre-filled syringe. In a further embodiment of the present invention, the prefilled 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 of the present invention, the nominal volume is 1 ml and the volume of the pharmaceutical substance in the form of a dosage form is at least 1.05 ml. In another embodiment of the present invention, the pharmaceutical substance in the form of a dosage form contains a protein, a nucleic acid, a blood component, a vaccine, an anti-allergenic agent, a gene therapy drug, an antibiotic, an analgesic drug, an anesthetic and/or a hormone. In a further embodiment of the present invention, the pharmaceutical substance in the form of a dosage form contains an antibody.

Brief description of graphic materials

The accompanying drawings, which are included in and constitute a part of this specification, illustrate various exemplary embodiments of the invention and, together with the description, serve to explain the principles of the disclosed embodiments. The drawings show various aspects of the present invention and, where appropriate, reference numerals illustrating the same structures, components, materials and/or elements in different figures are designated the same. It is understood that various combinations of structures, components and/or elements other than those specifically shown are contemplated and are within the scope of this invention.

There are many inventions described and illustrated herein. The inventions described are not limited to any particular aspect or embodiment of the invention, nor to any combinations and/or combinations of such aspects and/or embodiments of the invention. In addition, each of the aspects of the described inventions and/or embodiments thereof may be used alone or in combination with one or more other aspects of the described inventions and/or embodiments thereof. For the sake of brevity, some permutations and combinations are not discussed and/or illustrated separately herein. In particular, the embodiments of the present invention or embodiment described herein by way of example are not to be construed as being preferred or advantageous, for example, over other embodiments of the present invention or embodiments; rather, they are intended to reflect or indicate that the embodiment(s) of the invention is(are) an example of the embodiment(s) of the invention.

In fig. 1A and 1B are graphs showing the viscosities of exemplary antibody solutions as a function of antibody concentration, composition, and temperature.

In fig. 2A and 2B are schematic drawings of the components of an exemplary refillable primary packaging component in accordance with the present invention.

In fig. 3A is a schematic drawing of an exemplary overfilled and occluded primary packaging component in accordance with the present invention.

In fig. 3B is another schematic drawing of an exemplary overfilled and occluded primary packaging component in accordance with the present invention.

In fig. 3C and 3D are partial schematic drawings of an exemplary overfilled and occluded primary packaging component in accordance with the present invention.

In fig. 4 is a flowchart of an exemplary method for refilling a primary packaging component in accordance with the present invention.

In fig. 5A-5D are schematic drawings of the steps in an exemplary capping process for an overfilled primary packaging component.

In fig. 6A-6E provide schematic drawings of the steps in another

- 2 045636 as an example of the process of sealing an overfilled primary packaging component.

As used herein, the terms contains, contains, includes, includes, or any other variation thereof are intended to cover non-exclusive inclusion, such that a process, method, article, or device that contains a list of elements does not include only those elements, but may include includes other elements that are not expressly listed or not inherent in such process, method, product or device. The term exemplified is used in the sense of example, not ideal. In addition, the terms first, second, and the like, as used herein, do not denote any order, quantity, or importance, but rather are used to distinguish an element, structure, step, or process from another. In addition, the singular nouns herein do not denote a limitation of quantity, but rather denote the presence of one or more specified elements.

Detailed description of the invention

Embodiments of the present invention relate to systems and methods for refilling primary packaging components. For example, embodiments of the present invention may relate to systems and methods for refilling drug containers, such as syringes. More specifically, embodiments of the present invention may relate, for example, to systems and methods for refilling prefillable syringes (PFS) for packaging, sale and commercial use. The term overfilling, as used herein, refers to filling a container with more volume of a substance than the container's nominal volume while still maintaining a desired level of safety and/or integrity with respect to the container and its contents.

The term nominal volume (also referred to as specified volume or specified capacity) of a container means the maximum capacity of the container as specified by the container manufacturer or safety standards organization. A manufacturer or safety standards organization may specify a nominal volume of a container to indicate that the container can be filled with that volume of liquid (either aseptically or not) and can be closed, sealed, sterilized, packaged, transported and/or used for maintaining the integrity of the sealing of the container, as well as maintaining the safety, sterility and/or aseptic properties of the liquid contained inside. When determining the nominal volume of a container, the manufacturer or safety standards organization may also consider the variability that occurs during normal filling, closing, capping, packaging, transportation, and use procedures. For example, a prefilled syringe may be filled to its nominal fluid volume either manually or using machinery, and then either capped using a release tube or using a vacuum without the filling and capping mechanisms and tools touching. with the contents of the syringe and potentially contaminate it.

Container overfilling may consist of filling a container with more liquid than its rated liquid capacity. For example, overfilling a PFS prefill syringe that has a nominal volume of 1 mL of liquid may involve filling the barrel of the PFS prefill syringe with more than 1 mL of liquid and capping the PFS prefill syringe such that there is little likelihood that the stopper will be dislodged. , dislodged or otherwise damaged during normal packaging, shipping or use, as described in more detail below.

The term pharmaceutical substance in dosage form refers to a substance that contains a therapeutic ingredient (eg, an active pharmaceutical ingredient, such as a biological or conventional pharmaceutical product) and one or more excipients and diluents. As used herein, the term drug product may refer to the volume of a pharmaceutical substance in dosage form dispensed in a primary packaging component for packaging, transport, delivery and/or administration to a patient.

The term primary packaging component refers to a drug packaging component, such as a drug container, that is designed and manufactured to come into direct physical contact with the pharmaceutical substance in the dosage form. (See, for example, Guidance for Industry on Container Closure Systems for Packaging Human Drugs and Biologies, U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research, and Center for Biologies Evaluation and Research (May 1999 d), which is incorporated herein by reference). Examples of primary packaging components include prefilled syringes, Luer lock syringes, cartridges and ampoules made of glass, plastic and/or other materials.

In general, it is desirable that the primary packaging component in which the pharmaceutical substance is packaged in dosage form (e.g., in an aseptic filling process or in a non-aseptic filling process), has been sterilized, sold and/or used, contains an appropriate or required quantity of the finished pharmaceutical substances in the form of medicine

- 3 045636 pharmaceutical form for use (such as, for example, a single dose of a pharmaceutical substance in the form of a dosage form), and at the same time retain the ability to withstand the processes of packaging, transportation and use, remaining secure and closed, maintaining structural integrity and sterility (for example, under aseptic conditions), while remaining safe for handling by healthcare professionals, patients and others, and protecting the pharmaceutical substance in dosage form from the risk of damage or undesirable change. In many cases, standard or commercially available packaging components may have standard or commonly used nominal volumes such as 0.5, 1, 1.5, 2, 2.25, 2.5, 3, 5 ml, etc. However, the required or appropriate volume of the pharmaceutical substance in the dosage form may vary beyond these quantities (for example, volumes of 0.5 to 1 ml, 1 to 2 ml, or 2 to 3 ml) depending on such factors , such as the amount of dose prescribed, the solubility of the active ingredient in the liquid dosage form, and other factors. For example, increasing the concentration of the active ingredient in a liquid dosage form can affect the short- and long-term stability, as well as the solubility of the active ingredient in solution. Increasing the concentration of certain active ingredients (eg, antibodies) may also increase the viscosity of the fluid to an undesirable level, such as a level that cannot be easily administered from a device (eg, by injection from a syringe) or that is unsuitable for the patient's body. For example, in FIG. 1A and 1B are viscosity graphs of two exemplary liquid antibody formulations. In particular, in FIG. 1A illustrates a graph of the viscosity of four different dosage forms of Antibody A versus antibody concentration. In fig. 1B illustrates a graph of the viscosity of Antibody B dosage form versus antibody concentration at two different temperatures (20 and 25°C). As illustrated in FIG. 1A-1B, the viscosity of each dosage form increases exponentially with increasing antibody concentration. Thus, as these exemplary dosage forms demonstrate, even a small increase in the concentration of antibody in the composition can have a proportionately greater effect (eg, exponentially greater effect) on the viscosity of the composition and its suitability for loading into a device for delivery or administration to a patient.

In some cases, in order to deliver the required dose, the volume of drug substance dosage form to be included in the drug product may be slightly larger than the nominal volume of the drug product's primary packaging component (for example, the required volume of drug substance dosage form may be 1. 1 or 1.2 ml, and the nominal volume of the primary packaging component of the medicinal product may only be 1 ml). This can happen for various reasons. For example, research on an active ingredient may reveal that a particular dose of the active ingredient may be effective or beneficial for treating a condition, but the particular dose may not be delivered using only the nominal volume of the primary packaging component because the inclusion of that particular dose of the active ingredient in the volume of liquid, equal to the nominal volume of the primary packaging component may increase the viscosity of the drug product to an undesirable level (as described above). As another example, the concentration of the required dose of active ingredient in a nominal volume of liquid may be too high to be safe or effective in treating a patient (ie, a lower concentration is required for safety, effectiveness, or regulatory standards). Thus, it may be advisable, preferable, or necessary to add to a drug product a larger volume of drug substance dosage form that exceeds the nominal volume of the drug product's primary packaging component, rather than increasing the concentration of the active ingredient in the drug substance dosage form and maintaining the total volume of drug substance. of the dosage form substance in the drug product at a low level (i.e., at or below the nominal volume of the primary packaging component).

In addition, it may be preferable to place a larger amount of the drug substance in the dosage form inside the primary packaging component with a nominal volume that is close to, but slightly less than, the required volume of the drug substance in the dosage form, rather than using either a single drug container, having a larger nominal volume, or using two smaller drug containers that have smaller nominal volumes. For example, it may be preferable to package 1.2 ml of drug substance dosage form in one primary packaging component that has a nominal volume of 1.0 ml, rather than packaging in a primary packaging component that has a nominal volume of 1.5 or 2 .0 ml, or instead of dividing 1.2 ml of the drug substance in the dosage form between two components of the primary packaging, each of which has a nominal volume of 1.0 ml. This could be for a number of reasons.

For example, a primary packaging component with a nominal volume that is exactly the same as or greater than the required volume of the pharmaceutical drug substance

- 4 045636 forms for inclusion in the medicinal product may not be available. For example, a certain type of syringe, such as a ready-to-fill syringe or a fixed-needle syringe, may not be available in sizes having nominal volumes equal to or greater than the required volume of the drug substance in the dosage form. In particular, certain types of primary packaging components have historically been produced in limited, small nominal volumes. For example, some types of syringes have historically been produced with a nominal volume of 1 ml or less. Manufacturing tooling, packaging, sterilization equipment and processes, and delivery devices (eg, auto-injectors) for these syringes may also be designed to accommodate a limited range of syringe sizes.

In some cases, regulatory authorities (such as the U.S. Food and Drug Administration) may permit delivery of a drug in a primary packaging component of a certain size, but not in other primary packaging component sizes.

Using a primary packaging component with a nominal volume greater than the required volume of the drug substance dosage form may result in too much dead or empty air space within the package, which in turn may result in unwanted exposure of the drug substance to the dosage form. , unwanted agitation and formation of bubbles in the packaging and/or other difficulties.

Using a primary packaging component with a nominal volume greater than the required volume of the drug substance in the dosage form may result in higher packaging and transportation costs.

A drug intended to be carried may become less portable if it is contained in a package component that is larger than necessary.

Patients who self-administer a parenteral drug may be more likely to self-inject using a larger syringe than a smaller one.

Drugs that are intended to be administered multiple times throughout the day (eg, on a twice-daily schedule) may result in decreased patient adherence compared to medications that are intended to be administered fewer times, such as once daily.

A primary packaging component designed to function with other devices (for example, a secondary packaging component such as an automedical syringe, pen, needle cap, or safety device) may be less compatible with those devices if it changes in size; and/or primary packaging components with nominal volumes that are slightly less than the required volume of the drug substance in the dosage form may be less expensive or more available at the time filling occurs.

For any or all of these reasons, it may be preferable to deliver an increased volume of the pharmaceutical substance in dosage form into a primary packaging component (such as a syringe) with a smaller nominal volume, for example, to allow an increase in the dose of the active ingredient while maintaining acceptable viscosity levels without the need for new manufacturing processes and/or devices, instrumentation, packaging, sterilization and/or delivery (or even new regulatory approvals and approvals).

However, some consequences of overfilling primary packaging components may affect the safety, potency, efficacy, sterility, and other aspects of primary packaging components and/or the drug substances they contain. For example, the added volume of drug substance dosage form in a primary packaging component (eg, a syringe) may influence the extent to which the primary packaging component can be securely sealed and handled during packaging, transportation, delivery, and administration.

The systems and methods described herein can advantageously be used to successfully overfill primary packaging components, thereby filling the packaging components with a volume of pharmaceutical substance in dosage form that exceeds their nominal volume, while maintaining the required tightness and integrity of the components primary packaging and their contents. In particular, the systems and methods described herein can advantageously be used to successfully refill a PFS pre-fill syringe. For example, the systems and methods described herein can be used to successfully fill a PFS pre-fill syringe with various liquid substances or liquid pharmaceutical substances in parenteral dosage form, including pharmaceutical substances in dosage form containing active ingredients such as , for example, antibodies, vaccines, antibiotics, pain medications, anesthetics, hormones, proteins, small molecule drugs and any other

- 5 045636 liquid substances or liquid pharmaceutical substances in the form of a dosage form. Although aspects of the present invention are described in terms of filling a PFS pre-fill syringe with liquid, it should be understood that the systems and methods described herein can be used to fill a variety of primary packaging components with different types of liquids. Additionally, while the present invention makes reference to refilling a PFS pre-fill syringe with a pharmaceutical substance in a dosage form that contains a biological substance (e.g., an antibody such as a human monoclonal antibody, a glycosylated protein or other protein, a nucleic acid, a gene drug therapy or post-translational molecule), those skilled in the art will readily understand that aspects of the present invention contemplate refilling a PFS pre-filled syringe with any pharmaceutical substance in dosage form that contains any blood component, vaccine, anti-allergic agent, antibiotic, pain relief medication, anesthetic, hormone and/or small molecule drug.

In fig. 2A illustrates in schematic form an exemplary fixed needle syringe 100 that can be refilled in accordance with the present invention. Portions of the syringe 100 are shown in cross section. The syringe 100 may include a body 102, which may have a flange 104 surrounding an opening at the proximal end of the syringe 100, and a channel 106 leading to a needle 110 at the distal end of the syringe 100. The needle 110 may be covered by a needle 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.

The syringe 100 may be any type of syringe having a nominal volume for parenteral administration of a pharmaceutical substance in a dosage form, such as a standard syringe or a long syringe. For example, syringe 100 may be a PFS pre-fill syringe suitable for sterilization, pre-fill, packaging, delivery and single use. The syringe 100 may be made from any suitable material or combination of materials, such as, for example, glass, plastic and/or metal. The syringe 100 may have any nominal volume, such as, for example, 0.3, 0.5, 1, 1.5, 2, 2.25, 2.5, 3, 5 ml, or any other nominal volume. For example, syringe 100 may be an Ompi EZ-fill® syringe, a Gerresheimer ready-to-fill format syringe, a BD Hypak SCF™ syringe, or other commercially available ready-to-fill or pre-filled syringe. However, the syringe 100 may have a physical liquid capacity greater than its nominal volume. In some embodiments, the syringe 100 may be a reusable syringe. In some embodiments, the syringe 100 may be suitable for loading into an automatic medical syringe.

The body 102 of the syringe 100 may be configured to hold at least the nominal volume of liquid of the syringe 100. The body 102 may be cylindrical or may have any other suitable shape, such as, for example, an elliptical cylinder or a rectangular prism. The housing 102 may be made of any suitable material for containing a pharmaceutical dosage form, such as glass, plastic, metal and/or silicone. The housing 102 may also have a wall thickness suitable to maintain integrity through various processing procedures, such as sterilization, filling, capping, packaging, transportation and/or use. Housing 102 may have an opening 101 at its proximal end through which fluid and a plug assembly (e.g., plug assembly 150 shown in FIG. 2B) may be introduced into the interior portion 107 of housing 102. The interior portion 107 may have a substantially constant size and cross-sectional shape throughout the housing 102 such that, for example, the plug may remain in contact with the interior surface of the walls of the housing 102 as it moves through the interior space 107. In some embodiments, the housing 102 may be transparent, causing any contents placed inside the housing 102, may be visible through the walls of the housing 102.

A flange 104 may surround an opening 101 at the proximal end of the housing 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 provide a grip around the distal side 105 (e.g., a finger grip or a mechanical grip) and/or for a piston flange (e.g., piston flange 154 shown in FIG. 2B) to abut the proximal side 103 when the piston is fully retracted into the housing 102. Depending on the length of the piston rod 152, the flange 104 may serve to restrain the insertion distance of the piston 150 into the housing 107. The flange 104 may have an oval profile, a round profile, or may be a cut flange.

Channel 106 may connect body 102 to needle 110. In some embodiments, channel 106 may be substantially narrower than internal portion 107 to reduce the volume or flow of fluid that may be pushed toward needle 110. Needle 110 may be configured to communicate via fluid with channel 106, as a result of which the liquid can

- 6 045636 may extend from housing 102 through passage 106 and through needle 110. The connection between needle 110 and passage 106 may be any suitable connection that is known in the art. The needle 110 may have an opening (not shown) at or near its distal end through which fluid can be expelled. The needle 110 may be made of any suitable biocompatible tissue injection material, such as stainless steel, titanium, or any other metal. The needle sheath 108 may cover the needle 110 to, for example, protect the tip of the needle 110 and/or prevent fluid from leaking from the needle 110.

The cap 120 may be sized and configured to cover the needle 110 and be attached to the needle body 102 and/or the needle case 108 . The cap 120 may be made of any material suitable for protecting the needle 110, such as, for example, rubber, glass, plastic, thermoplastic elastomer, other polymer, metal, or combinations of such materials. The cap 120 may be attached to the body 102 in any known removable manner, such as a threaded connection or other locking connection. The cap 120 may include, for example, a grip 122 to facilitate removal of the cap 120.

Fig. 2B depicts a schematic diagram of an exemplary plug assembly 150. The plug assembly 150 may include a piston rod 152 and a piston flange 154 . The plug assembly 150 may also include a plug 156 (shown in cross-sectional form), which may be coupled to the piston rod 152 via a connector 158. The plug 156 may also include annular ribs 160, one or more projections 162, and a top portion 164.

The plug assembly 150 may be compatible (e.g., properly sized) with the syringe 100, causing the plunger rod 152 and plug 156 to fit snugly against the body 102 of the syringe 100. The plunger rod 152 and plug 156 may also be compatible with each other, whereby plug 156 can be securely coupled to piston rod 152, for example, using connector 158. In some embodiments, piston rod 152 and plug 156 can be specifically manufactured to be compatible with each other. For example, if the syringe 100 is a 1 ml syringe (e.g., a standard or long syringe), then the plunger rod 152 may be a corresponding 1 ml plunger rod, and the stopper 156 may be a corresponding 1 ml stopper, such as a 1 ml stopper. fluoropolymer coating. In some embodiments, a plug 156 may be fabricated to be inserted into the interior 107 of the housing 102 prior to its connection to the piston rod 152, after which the piston rod 152 may be coupled to the inserted plug 156 via a connector 158. In embodiments where the connector 158 is, for example, a screw connector, plug 156 may have a threaded cavity complementary to the shape of screw connector 158 into which connector 158 can be screwed.

The piston rod 152 may be sized and configured to pull and push the plug 156 through the interior 107 of the housing 102 after being connected to the plug 156 using a connector 158. For this reason, the piston rod 152 may be made of any material suitable to withstand the force that necessary to move the plug 156 through the interior 107 of the housing 102. For example, the piston rod 152 may be made of metal, glass, plastic, other polymer, or a combination thereof. Plug 156 may also be sized and configured to fit snugly against interior portion 107. For example, if interior portion 107 has a substantially uniform circular cross-section (that is, if body 102 is cylindrical), plug 156 may also have a circular cross-section with a diameter designed to fit snugly around the diameter of the inner portion 107. The plug 156 may be made of any suitable material known in the art, such as, for example, rubber, plastic, silicone, or thermoplastic elastomer. In some embodiments, stopper 156 may be coated with a material that reduces the interaction between the material of stopper 156 and the pharmaceutical dosage form contained within housing 102. For example, stopper 156 may be coated with Teflon or fluoropolymer film, or may be silicone-filled. . In addition, plug 156 may have annular ribs 160 and/or one or more projections 162 that may be configured to increase the seal between plug 156 and body 102 without impeding movement of plug 156 in body 102.

In fig. 3A schematically illustrates a filled and sealed syringe assembly 200 that includes a plug assembly 150 inserted into the syringe 100, resulting in the plug 156 and a portion of the plunger rod 152 being contained within the housing 102 where the top 164 of the plug 156 is inserted beyond the distal side 105 of the flange. 104 to a distance A. The syringe assembly 200 is filled with the pharmaceutical substance in the form of a dosage form 202.

The pharmaceutical substance in dosage form 202 may be any pharmaceutical substance in a liquid dosage form that is suitable for packaging inside the syringe assembly 200. For example, the pharmaceutical substance in dosage form 202 can be any liquid suitable for parenteral administration through needle 110. The pharmaceutical substance in the form of dosage form 202 may be,

- 7 045636 for example, liquid, gel or suspension. In some embodiments, the drug substance dosage form 202 may contain an active pharmaceutical ingredient (API) in a liquid or gel solution. Such an API active pharmaceutical ingredient may be any suitable API active pharmaceutical ingredient for therapeutic use, 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, pain reliever, anesthetic, hormone or other high or low molecular weight active pharmaceutical ingredient API.

In some embodiments, the volume of drug substance dosage form 202 administered into syringe 100 may exceed the nominal volume of syringe 100. For example, in some embodiments, the volume of drug substance dosage form 202 may be at least about 3% larger. greater than the nominal volume of the syringe 100. In some embodiments, the volume of the drug substance in the dosage form 202 can be from about 3 to about 40% greater than the nominal volume of the syringe 100. In some embodiments, the volume of the drug substance in the dosage form 202 can be from about 3 to about 30%, about 12 to about 25%, or about 14 to about 25% more than the nominal volume of syringe 100. In some embodiments, the volume of the drug substance in dosage form 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 syringe 100. In other embodiments, the volume of pharmaceutical substance in dosage form 202 may be from about 0.1 to 0.3 ml greater than the nominal volume of syringe 100. For example, in a syringe having nominal volume is 1 ml, the volume of the pharmaceutical substance in dosage form 202 may be from about 1.09 to 1.30 ml, for example, from about 1.10 to 1.27 ml, from 1.10 to 1.25 ml, or from 1.10 to 1.15 ml, for example 1.09, 1.10, 1.11, 1.12, 1.13, 1.14, 1.15, 1.16, 1.17, 1.18 , 1.19, 1.20, 1.21, 1.22, 1.23, 1.24, 1.25, 1.26 or 1.27 ml. As another example, in a syringe having a nominal volume of 2 ml, the volume of pharmaceutical substance in dosage form 202 may be from 2.09 to 2.30 ml, for example, from about 2.10 to 2.25 ml, from 2. 10 to 2.20 ml, or from 2.10 to 2.15 ml, for example, 2.09, 2.10, 2.11, 2.12, 2.13, 2.14, 2.15, 2, 16, 2.17, 2.18, 2.19 or 2.20 ml. In some embodiments, the volume of drug substance in dosage form 202 may be greater than the nominal volume of syringe 100, but less than 140, 130, or 120% of the nominal volume of syringe 100.

In some embodiments, the volume of drug substance dosage form 202 administered into the syringe 100 may be slightly greater than the volume of drug substance dosage form 202 that may be expelled from the syringe 100 through the needle 110 due to dead volume. , for example, the remaining volume blocked in the channel 106 (and/or needle 110) after the plug assembly 150 has been completely pushed through the body 102. For example, in a syringe having a nominal volume of 1 ml, the filling volume of the pharmaceutical substance in the form of a dosage form 202 in drug form may be 1.19 mL, but the potential ejection volume or delivered volume of pharmaceutical substance in dosage form 202 through needle 110 may be about 1.14 mL. In other embodiments, the volume of pharmaceutical substance dosage form 202 administered into the syringe 100 may be greater than the combination of the target volume of pharmaceutical substance dosage form 202 and the dead volume of the syringe 100. In addition, in some embodiments In implementing the invention, the target volume of drug substance dosage form 202 injected into the syringe 100 may be slightly larger than the target volume of drug substance dosage form 202 intended to be ejected through the needle 110 in order to account for variability in filling processes and ensure that that the minimum amount of pharmaceutical substance in the form of dosage form 202 has been delivered.

In some embodiments, the air space in the interior 107 of the housing 102 does not exist after the drug substance in the dosage form 202 is added and the stopper 156 is installed within the housing 102. In other embodiments, some such air space may exist. For example, in a syringe having a nominal volume of 1 ml, such air space, measured from any point on the bottom of stopper 156 to any point on the drug substance dosage line 202, may be from about 0.01 to about 1 mm. In some embodiments, the existing air space may be relatively small, such that the air bubble may only be visible when housing 102 is rotated to its side, as illustrated by air bubble 170 in FIG. 3B. In some embodiments, the existing air space may be from about 5 to 250 μl of liquid volume, for example, 150 μl of liquid volume.

Distance A may be the distance from the distal side 105 of the flange 104 to

- 8 045636 the top 164 of the plug 156 or from the hole 101 at the proximal end of the body 102 to the top 164 of the plug 156. In some embodiments of the invention, the distance A may be greater than 0, resulting in the entire plug 156 being located inside the body 102. This can ensure that the pharmaceutical substance in dosage form 202 is completely sealed within the housing 102. In other embodiments, the distance A may be greater than an experimentally determined threshold value. For example, in some syringes having a nominal volume of 1 ml, the distance A may be at least about 1 mm. In some embodiments, the distance A may be at least about 1.5, 2, 2.5, at least about 2.56, at least about 2.57, at least about 3, at least about 3 .5, at least about 4, at least about 4.5, at least about 5.0, or at least about 5.5 mm.

In some embodiments, the distance A may be experimentally determined based in part on the degree to which the plunger rod 152 can be deflected relative to the longitudinal axis of the body 102 in the syringe assembly 200. This may be implemented to prevent excessive tilt of the plunger rod 152 from displacing the plug 156. 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 (e.g., during packaging, shipping, unpacking, or use of syringe assembly 200). In some embodiments, the distance A may be sufficiently large such that any inclination of the piston rod 152 is limited by contact with the wall of the housing 102 to less than a predetermined angle relative to the longitudinal axis of the housing 102.

In fig. 3C and 3D illustrate alternative placements of plug 156 in interior portion 107 of housing 102. As illustrated in FIG. 3C, the distance A is too small because the plunger rod 152 may be tilted to such an extent (eg, at an angle a) that the plug 156 may become detached from the wall of the housing 102 or may be dislodged from the syringe, thereby compromising the integrity of the plug 156 and sterility. stopper 156, syringe 102, and pharmaceutical dosage form 202. As illustrated in FIG. 3D, the distance A is sufficient such that the inclination of the piston rod 152 is limited by the walls of the housing 102 (eg, angle b) and is not sufficient for the plug 156 to become detached from the wall of the housing 102 and become dislodged or otherwise compromised. In some embodiments, for example, in some syringes having a nominal volume of 1 ml, the angle b may be no more than, for example, 20, 15, 12 or 10°.

An overfilled and occluded primary packaging component, such as an overfilled and occluded syringe, can be achieved in a variety of ways. In addition, various methods can be used to pack an overfilled and sealed drug container.

In fig. 4 depicts a flow diagram of steps in a method 300 for refilling a primary packaging component, such as, for example, a medication container. In accordance with step 302, the pharmaceutical substance can be prepared in the form of a dosage form. In accordance with step 304, a drug container having characteristics to hold a nominal volume may be prepared. In accordance with step 306, the drug container may be filled with a volume of pharmaceutical substance in the form of a dosage form, wherein the filling volume exceeds the nominal volume. At step 308, the medication container may be sealed. At step 310, the drug container may be packaged.

In accordance with step 302, the pharmaceutical substance can be prepared in the form of a dosage form. Depending on the pharmaceutical substance dosage form used (eg, pharmaceutical substance dosage form 202 shown in FIGS. 3A and 3B), various formulations may be suitable. For example, the active pharmaceutical ingredient API may be formulated in a liquid (eg, liquid or gel) solution suitable for administration to a patient. In some embodiments, therefore, the active pharmaceutical ingredient API may be formulated to avoid precipitation of the active pharmaceutical ingredient API from solution. As a further example, a previously prepared, frozen and stored pharmaceutical substance in dosage form may be removed from storage and thawed for filling to a suitable temperature, such as, for example, room temperature. As another example, the drug substance may be diluted with various excipients and/or buffers to obtain the drug substance in dosage form. As another example, the pharmaceutical substance in the dosage form may be filtered through a filtration system, for example, to ensure sterility, before filling the drug container. Filtration of the pharmaceutical substance in dosage form through a filtration system may involve one or more of the following: thawing, combining, mixing, equilibrating

- 9 045636 temperature, filtration and/or transfer of the pharmaceutical substance in the form of a dosage form.

In accordance with step 304, a drug container having a nominal volume may be prepared. For example, the syringe assembly 200 shown in FIG. 3A and 3B may be disassembled such that the syringe 100 is separated from the plug 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 filling machine suitable for automatically filling the drug container with a volume of pharmaceutical substance in dosage form. As previously described with respect to the syringe 100 illustrated in FIG. 2A, the drug container may have any nominal volume. In some embodiments, multiple drug containers may be assembled and sterilized in batches, for example, in batches of 80, 100, 160, 200, or more drug containers.

At step 306, the drug container may be filled with a volume of pharmaceutical substance in dosage form that includes a volume greater than the nominal volume of the drug container. This filling step may be performed, for example, by a machine filling process, using an automatic filling machine, using a semi-automatic filling machine, or may be performed manually. In some embodiments, the drug container may be filled under vacuum to prevent air pockets or bubbles from trapping the volume within the drug container. In some embodiments, multiple drug containers may be filled in batches using, for example, an automated fill completion process. For example, batches of 80, 100, 160, 200, or multiple drug containers can be filled as part of an automated filling process. In some embodiments, the drug container may be filled under aseptic conditions. The volume of a pharmaceutical substance in a dosage form may be any amount that exceeds the nominal volume. For example, the volume of the drug substance dosage form may be at least about 10% greater than the nominal volume, or may be any other amount that exceeds the nominal volume, as has been described with respect to the drug substance dosage form 202 in a syringe 200 assembled.

In accordance with step 308, the drug container may be sealed. Sealing involves ensuring proper placement of the closure element in relation to the rest of the drug container. For example, with respect to the syringe assembly 200, closure may include ensuring that the top 164 of the plug 156 at least extends through the distal side 105 of the flange 104 of the housing 102, causing the plug 156 to be completely contained within the interior portion 107 of the housing 102. In some In embodiments of the invention, closure may include ensuring that the top 164 of the plug 156 is inserted at least a required distance from the distal side 105 of the flange 104, as previously described with respect to the syringe 200 assembly.

Sealing in accordance with step 308 may include a vacuum sealing process, as illustrated in FIG. 5A-5D, or vacuum sealing processes as illustrated in FIGS. 6A-6E. In such embodiments, a vacuum may be applied during sealing to prevent or reduce the entrapment of air in the interior portion 107 of the body 102, and to assist in inserting the stopper as deeply as possible into the interior portion 107 of the body 102. Vacuum sealing or vacuum sealing using a vacuum can promote overflow of the syringe 100 because the vacuum can facilitate the replacement of air that is normally trapped in the interior 107 of the housing 102 with an additional volume of pharmaceutical substance in the form of a dosage form 202. The vacuum capping process allows the stopper to be drawn into close proximity to the liquid in the container with drug outside the mechanical parts of the stopper that come into contact with the liquid, and without undesirable deformation (for example, in the form of folds or tears) of the stopper. For these reasons, a vacuum capping process or a vacuum capping process may be preferable to, for example, a mechanical capping process, which may not provide these advantages. In other embodiments, the closure in accordance with step 308 can be performed by any other method known in the art.

In fig. 5A-5D illustrate one exemplary vacuum capping process. In this vacuum sealing process, a vacuum is created on the distal side of the drug container and the stopper is pulled into the container using the vacuum. As illustrated in FIG. 5A-5D, the vacuum body 502 includes a spacer 504, which may surround the vacuum body 502, and a vacuum channel 506. The vacuum body 502 may be sized to hold a plug 156 and may have a diameter comparable to the diameter of the syringe body 102. The pharmaceutical substance in the form of a dosage form 202 can be introduced into the body 202 of the syringe. How

- 10 045636 is illustrated in FIG. 5A, plug 156 may be inserted into vacuum housing 502 by means of an insertion rod 508 that may be seated into cavity 157 of plug 156. As illustrated in FIG. 5B, the vacuum body 502 holding the plug 156 may be positioned above the syringe body 102, causing the gasket 504 to be in contact with the flange 104 of the syringe body 102. The gasket 504 may create a seal between the vacuum housing 502 and the flange 104 of the housing 102. Vacuum may be applied to the sealed area under the plug 156 (i.e., the interior 107 of the housing 102) through the vacuum port 506. The vacuum via the insert rod 508 allows for drawing plug 156 from the vacuum housing 502 into the housing 102, as illustrated in FIG. 5C. The vacuum may help ensure that stopper 156 is positioned as close as possible to the pharmaceutical substance in dosage form 202. Ultimately, as illustrated in FIG. 5D, the vacuum housing 502 can be removed.

In fig. 6A-6E illustrate one exemplary vacuum sealing process. In this vacuum sealing process, a vacuum is applied to the drug container and a stopper insertion tube is used to compress the stopper and insert the stopper inside the drug container using the suction generated by the vacuum. As illustrated in FIG. 6A-6E, plug insertion tube 602 includes a spacer 604 that may surround plug insertion tube 602 and a vacuum passage 606. All or a portion of plug insertion tube 602 may be sized to hold plug 156 in a slightly compressed configuration. and may be placed in a syringe body 102 into which the pharmaceutical substance is administered in the form of a dosage form 202. As illustrated in FIG. 6A, plug 156 may be inserted into plug insertion tube 602 using an insertion rod 608 that may be inserted into cavity 157 of plug 156. As illustrated in FIG. 6B, a plug insertion tube 602 holding the plug 156 may be inserted into the interior portion 107 of the syringe body 102. The gasket 604 may create a seal between the insertion tube 602 and the flange 104 of the housing 102. A vacuum may be applied to the sealed area below the plug 156 through the vacuum passage 606. As illustrated in FIG. 6C, insertion rod 608 may be used to move plug 156 through insertion tube 602. The vacuum may further draw the plug 156 into the body 102, bringing it into close proximity to the pharmaceutical substance in the dosage form 202. As illustrated in FIG. 6D, the insertion tube 602 may be removed. The insert rod 608 may help hold the plug 156 in place, causing the plug 156 to remain and expand to fit into the housing 102. As illustrated in FIG. 6E, the insert rod 608 can be removed. In some embodiments, the insertion rod 608 may be removed before the insertion tube 602 is removed, and a vacuum may continue to be created through the insertion tube 602 to retract the plug 156 into the housing 102 after the insertion rod 608 is removed.

The use of vacuum capping or a vacuum-assisted capping process to draw the stopper into the container can reduce the likelihood that the mechanical closure elements will come into contact with the drug substance in the dosage form within the container, thereby maintaining the sterility of the drug substance in the dosage form.

In some embodiments of the invention illustrated in FIGS. 5A-5D and 6A-6E, a sealing member (e.g., plug 156) may be inserted or retracted into the interior 107 of body 102, using a vacuum or vacuum-assisted sealing process, without a piston rod (e.g., piston rod 152) attached. . The piston rod may be attached to the plug (eg, through cavity 157) after capping is complete.

At step 310, the drug container may be packaged. Packaging may include, for example, enclosing the entire closure of the drug container in a secondary packaging component (ie, packaging not in direct contact with the drug substance in the dosage form), such as a plastic package suitable for transporting the drug container. Step 310 may also, or alternatively, include applying one or more sealable coatings and/or labels to the sealed drug container or packaging thereof. In some embodiments, little or no packaging (outside of the drug container) may be required.

Sealed and packaged drug containers can be stored, transported and/or used as needed. In some embodiments, drug containers may be pre-sterilized and filled and sealed through an aseptic filling process. In additional embodiments of the invention, the packaged drug container may be terminally sterilized. Post-sterilization may be accomplished by any method known in the art that does not adversely affect the sealed drug container, such as by moving the drug container stopper (e.g., stopper 156 in syringe assembly 200) to expose the pharmaceutical substance in medicinal form

- 11 045636 form inside the drug container (for example, the pharmaceutical substance in the form of dosage form 202 in the syringe assembly 200) into a non-sterile environment or causing leakage of the pharmaceutical substance in the form of dosage form. In addition, terminal sterilization may be carried out by any method known in the art that (i) does not expose the sealed drug container and its contents to temperatures and/or pressures that could adversely affect the container or pharmaceutical substance in the form dosage form inside, or (ii) does not result in leaching of residual sterilant from the stopper 156. For example, terminal sterilization can be accomplished using hydrogen peroxide vapor sterilization processes as described in US Patent Application No. 62/477,030, filed March 27, 2017 and 62/472,067, filed March 17, 2017, which are incorporated herein by reference. Final sterilization may also be accomplished, for example, by other methods using hydrogen peroxide vapor, ethylene oxide-EO sterilization, irradiation, vapor or nitrogen dioxide (NO ₂ ), gamma irradiation sterilization, electron beam sterilization, or other processes known in the art. this area.

In some embodiments, any or all of the steps and phases described above may be performed manually, automatically by various machines and preparation, filling and capping methods known in the art, or by a combination of manual and automatic actions. In some embodiments, any or all of the steps and phases described above may be performed in one or multiple batches of drug containers. A batch may contain, for example, a plurality of identical drug containers, which may be prepared, filled, sealed, etc. the whole group. For example, a lot of prefilled syringes may contain 10, 50, 80, 150, 160, 200, 1000, 10000, 20000, 50000, 100000 or more prefilled syringes. In addition, any of the above steps of method 300 may be omitted or combined with another step. In addition, while some of the steps and phases described above may be described in relation to drug containers or, more specifically, syringes, it should be understood that the steps described herein can be applied to a variety of primary packaging components. Moreover, one or more of the above steps may be performed out of the order illustrated in FIG. 4.

Examples

Example 1.

The theoretical possibility of syringe overfilling was determined as follows. The BD Hypak Physiolys SCF™ 1 mL Low Tungsten Syringe (from Beckton Dickinson Medical) was analyzed to determine whether it could fill an injected volume of 1.15 or 1.10 mL of drug when combined with a BD Hypak piston plug. PS Flurotec for 1 ml volume and BD Hypak 21510 PR C piston rod for 1 ml volume (from Beckton Dickinson Medical).

First, the theoretical filling volumes required to achieve drug delivery volumes of 1.15 and 1.10 mL were determined. Theoretical wasted volumes (e.g., dead volumes or volumes remaining in the syringe after the maximum possible volume has been removed, and potential negative deviations from required volumes based on variability in filling processes) were determined based on measurements based on syringe withdrawal, calculated fill heights of the desired volume of the administered drug and the possibility of control during the technological process (IPC, in-process control). These theoretical lost volumes were calculated as follows.

Table 1

Parameter Design conditions Worst case Volume loss due to needle drop 0.003 ml 0.005 ml Volume lost due to syringe dead volume 0.006 ml 0.010 ml IPC (In-process control) capabilities 0.008 ml 0.012-0.014 ml Filling Process Capabilities 0.006 ml 0.008 ml

By adding these theoretical values to the theoretical drug volumes administered of 1.15 and 1.10 mL, it was determined that under the design conditions, the theoretical filling volume required to achieve a drug volume administered of 1.15 mL was 1.173 mL , and the theoretical filling volume required to achieve an administered drug volume of 1.10 ml was 1.123 ml. In the worst case, the theoretical filling volume required to achieve a drug volume of 1.15 mL was determined to be 1.187 mL, and

- 12 045636 the theoretical filling volume required to achieve a drug delivery volume of 1.10 ml was determined to be 1.137 ml.

These volumes were then converted to the highest drug levels in theoretically filled syringes using syringe sizes. The highest drug level point was then combined with the dimensions of the syringes and plug assembly to determine the theoretical plug positions in syringes filled with the desired theoretical fill volumes. Stopper position refers to the distance between the top of the stopper in the filled syringe and the distal side of the syringe flange (eg, distance A indicated in FIGS. 3A-3D of this invention). The height of the bubble in each syringe was also taken into account. The term bubble height refers to the distance between the filling line of the pharmaceutical substance in the form of a dosage form in a filled syringe and the bottom of the stopper. It was first determined that without overflow the plug height would be 7.65mm +/-0.4mm and the bubble height would be 4mm +/-1mm. These values indicate that there will be no unwanted compression of the stopper that could cause wrinkling, cracking, and/or failure to pass visual inspection when the stopper is inserted into the syringe. Plug heights for the required administered drug volumes (ADVs) with overflow of 1.15 and 1.10 mL, assuming a fixed bubble height of 4.0 mm, were then calculated based on the design and worst case scenarios, and The theoretical filling volumes defined above are as follows.

table 2

Parameter Initial Design conditions 1.15 ml ADV (mm) Worst case 1.15 ml ADV (mm) Design conditions 1.10 ml ADV (mm) Worst case 1.10 ml ADV (mm) Inner body length Syringe collection 54.00 53.50 54.00 53.50 Highest point drug level Calculated 37.04 38.69 35.46 37.06 Plug height Calculated 7.85 8.25 7.85 8.25 Housing flange thickness Syringe collection 1.90 1.90 1.90 1.90 Height bubble I'm fixed 4.0 4.0 4.0 4.0 Plug position Calculated 5.11 2.56 6.69 4.19

It was then determined that in a test filled and capped syringe, the stopper must be a certain distance below the syringe flange in order to limit the stopper assembly piston rod from tilting sufficiently to deform the stopper assembly to such an extent that it could potentially compromise the integrity of the seal. formed by a cork. It was found that the plug would not deform to such an extent if the piston rod was not tilted at an angle of more than 12° relative to the longitudinal axis of the syringe body. Based on the syringe, stopper and plunger dimensions provided, this length was determined to be 3.0 mm with a tolerance of +/-0.5 mm. Thus, it was determined that the distance between the top of the stopper in a filled syringe and the distal side of the syringe flange should be at least 2.5 mm, and more specifically, a minimum distance of 3.0 mm +/-0.5 mm (e.g. distance A, as illustrated in Fig. 3A-3D).

It was ultimately determined that since the required theoretical high points of drug level and stopper position were not changed in order to obtain an overfilled syringe without losing the integrity of the stopper within the syringe body, the 4.00 mm bubble height would theoretically be reduced. Using the worst-case scenario of the highest points of drug level and stopper position, the bubble heights for the required 1.15 ml ADV and 1.10 ml ADV were calculated as follows.

- 13 045636

Table 3

Parameter Worst case 1.15 ml ADV (mm) Worst case 1.10 ml ADV (mm) Inner body length 53.50 53.50 Drug filling volume 1.173 ml 1.123 ml Highest point of drug level 38.69 37.06 Plug height 8.25 8.25 Housing flange thickness 1.90 1.90 Plug position 3.00 +/- 0.5 3.00 +/- 0.5 Bubble height 1.66+/- 0.5 3.29 +/- 0.5

Example 2.

Multiple PFS pre-filled syringes were filled by the machine as follows. Five drug 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 The dosage form substances were removed from low temperature storage and thawed for 16 hours. The dosage form substances (except WFI) were mixed, filtered and transferred to a medium at 2-8°C as follows.

Table 4

Substance in the form of a dosage form Mixing time pH Filtering time Output filtering Total holding time at room temperature after defrosting Placebo 15 minutes 6.10 9 min 96% 30 min 87.7 mg/ml antibody A 12 min 6.10 7 min 94% 50 min 131.6 mg/ml antibody A 11 min 6.07 9 min 91% 71 min 175 mg/ml antibody A And min 6.01 34 min 81% 106 min

The redundant filtration lines consisted of two Millipak 20 units and 1/4 in. x 3/8 in. (6.35 mm x 9.53 mm) platinum catalyzed silicone tubing for product passage. For the 175 mg/mL Antibody A portion, two Millipak 20 units were initially used and were turned off part way through using Millipak 40 units. A peristaltic pump was used as the driving force for filtration. All primary filters have been tested and passed the EP-024 filter integrity test.

The PFS prefilled syringes filled in this procedure included BD Hypak Physiolys SCF™ Low Tungsten 1 mL syringes (from Beckton Dickinson Medical), which had a nominal volume of 1 mL. These syringes were connected to BD Hypak PS Flurotec 1 mL plunger plugs and BD Hypak 21510 PR C 1 mL plunger rods (from Beckton Dickinson Medical). The desired location of the top of the plug was at least 2.57 mm below the distal side of the syringe flange and preferably 5.0 to 2.56 mm below the distal side of the syringe flange. Alternatively, the required location of the plug ridge closest to the top of the plug was at least 4.9 mm below the distal side of the syringe flange. Filling in this procedure was completed using INOVA H3-5V commercial grade syringe filler. Capping was completed using a Becton Dickson Hypak capping machine. The closure height (i.e., the distance between the top of the stopper and the distal side of the syringe flange) was measured using a vernier caliper.

The syringe filler was initially set to a target fill volume of 1.28 mL. The use of water for injection (WFI) resulted in an average delivery volume of 1.27 mL for ten metered syringes. Initially, the capping plant used a capping container vacuum of 70 mbar and a capping delay of 750 ms. With this filling volume and setting the time delay for capping, the cap was sometimes incomplete

- 14 045636 noy, and water for injection (WFI) was drawn into the vacuum chamber.

The syringe filler was then adjusted to a target fill volume of 1.19 mL. This was aimed at maintaining a minimum delivered volume of 1.14 mL while providing a larger operating buffer for vacuum sealing setup and stopper placement requirements. Vacuum capping settings were maintained in the range of 70-75 mBar and the capping dwell time was changed to 250 ms. When tested using Water for Injection (WFI), this eliminated the problem of product being sucked into the vacuum chamber. However, capped syringes met the stopper requirement (the top of the stopper at least 3.0 mm below the distal side of the syringe flange). A lower than desired sealing consistency was achieved, but this was determined to be due to cut syringe flanges. To verify that the cut flanges were the cause of the change in consistency during capping, two containers of 80 syringes each (160 syringes total) with long 1 ml syringes with a round flange were used on the syringe filler. This resulted in a noticeable reduction in cap failure rates compared to the cap failure rates observed with syringes with cut flanges.

A syringe filler was then used to fill the syringes at a set fill volume of 1.19 mL using water for injection (WFI), placebo, and antibody A formulation. 160 syringes were filled with each of five different liquids and at each of three different speeds machines (40, 65 and 90%) (except Antibody A at 87.7 mg/ml at 40% rate, for which only 35 syringes were filled, and Antibody A at 87.7 mg/ml at 65% rate , for which was not completed due to insufficient quantity of product available). All syringes were capped using a Hypak capping machine. The delivered volumes of 20 filled and capped syringes from each batch were then measured. Delivered volumes were measured by displacing the volume from each of 20 syringes, weighing the displaced volume, and converting mass to volume using the following densities.

Table 5

Substance in the form of a dosage form Density Placebo 1.023 g/ml 87.7 mg/ml antibody A 1.047 g/ml 131.6 mg/ml antibody A 1.059 g/ml 175 mg/ml antibody A 1.072 g/ml

Delivered volumes were calculated as follows.

- 15 045636

Table 6

Conditions Average volume (ml) Maximum volume value(ml) Minimum volume value (ml) Water for injection (WFI) - 40% rate 1.18 1.19 1.16 Water for injection (WFI) - 65% speed 1.17 1.18 1.17 Water for injection (WFI) - 90% speed 1.18 1.20 1.15 Placebo - 40% rate 1.18 1.19 1.18 Placebo - 65% rate 1.18 1.19 1.18 Placebo - 90% rate 1.19 1.22 1.18 87.7 mg/ml antibody A - 40% rate 1.17 1.19 1.15 87.7 mg/ml antibody A - 65% rate no data* no data* no data* 87.7 mg/ml antibody A - 90% rate 1.19 1.20 1.17 131.6 mg/ml antibody A - 40% rate 1.16 1.19 1.14 131.6 mg/ml antibody A - 65% rate 1.18 1.20 1.16 131.6 mg/ml antibody A - 90% rate 1.17 1.19 1.15 175 mg/ml antibody A - 40% rate 1.19 1.20 1.17 175 mg/ml antibody A - 65% rate 1.18 211.1 1.17 175 mg/ml antibody A - 90% rate 1.18 1.20 1.15

*There is not enough product to run this test.

The closure height was measured from the top of the stopper to the distal side of the syringe flange and was measured and calculated as follows.

Table 7

Conditions Average value Capping height (mm) Maximum Capping Height (mm) Minimum value Capping height (mm) Water for injection (WFI) - 40% 5.7 6.0 5.4

- 16045636

speed Water for injection (WFI) - 65% speed 5.4 5.5 5.4 Water for injection (WFI) - 90% speed 5.5 5.7 5.3 Placebo - 40% rate 5.4 5.5 5.4 Placebo - 65% rate 5.5 5.7 5.5 Placebo - 90% rate 5.8 6.0 5.5 87.7 mg/ml antibody A - 40% rate 5.5 5.8 5.4 87.7 mg/ml antibody A - 65% rate no data* no data* no data* 87.7 mg/ml antibody A - 90% rate 5.5 6.0 5.4 131.6 mg/ml antibody A - 40% speed 5.5 6.2 5.3 131.6 mg/ml antibody A - 65% rate 5.5 5.6 5.4 131.6 mg/ml antibody A - 90% rate 5.5 5.5 5.4 175 mg/ml antibody A - 40% speed 5.4 5.5 5.2 175 mg/ml antibody A - 65% speed 5.5 5.7 5.4 175 mg/ml antibody A - 90% speed 5.5 6.0 5.4

*There is not enough product to run this test.

Example 3.

Multiple PFS prefilled syringes were manually filled as follows. Three drug formulations (Antibody A 87.7 mg/mL, Antibody A 131.6 mg/mL, Antibody A 175 mg/mL) were prepared and frozen at -80°C. Each substance was removed from low temperature storage and thawed for 16 hours. The substances were mixed, filtered and transferred at 2-8°C as follows.

Table 8

Substance in the form of a dosage form Mixing time pH Filtering time Output filtering Total holding time at room temperature after defrosting 87.7 mg/ml antibody A 12 min 6.04 7 min 94% 100 min 131.6 mg/ml antibody A 12 min 6.11 And min 93% 85 min 175 mg/ml antibody A 11 min 6.02 21 min 91% 60 min

Duplicate filtration lines for 87.7 mg/mL Antibody A and 131.6 mg/mL Antibody A consisted of two Millipak 20 units and 1/4 in. x 3/8 in. (6.35 in.) platinum catalyst silicone tubing. mm x9.53 mm) for the passage of the product. The duplicate filtration lines for 175 mg/mL Antibody A consisted of two Millipak 40 units and a 1/4 in. x 3/8 in. (6.35 mm x 9.53 mm) platinum catalyzed silicone tubing for product passage. . A peristaltic pump was used as the driving force for filtration.

The PFS prefilled syringes filled in this procedure included BD Hypak Physiolys SCF™ Low Tungsten 1 mL syringes (from Beckton Dickinson Medical), connected to BD Hypak PS Flurotec 1 mL plunger plugs and BD 1 mL plunger rods Hypak 21510 PR C (from Beckton Dickinson Medical). The required location of the top of the plug was at least 3.0 mm below the distal side of the syringe flange. Filling in this procedure was performed manually using a Watson-Marlow pump. Capping was performed using a Becton Dickson Hypak vacuum capper.

For this procedure, the target fill volume was set at 1.19 mL. 160 syringes (in two containers of 80 syringes each) were filled with each of three different substances in the form of a dosage form. The delivered volumes of 10 filled and capped syringes from each batch were then measured. Delivered volumes were measured by displacing the volume from each syringe, weighing the displacement volume, and converting mass to volume using the densities listed in Table 1. 5. Delivered volumes were calculated as follows.

Table 9

Conditions Average volume(ml) Maximum volume value(ml) Minimum volume value (ml) 87.7 mg/ml antibody A (bottle 1 of 2) 1.19 1.23 1.15 87.7 mg/ml antibody A (bottle 2 of 2) 1.18 1.22 1.17 131.6 mg/ml antibody A (capacity 1 of 2) 1.18 1.21 1.16 131.6 mg/ml antibody A (capacity 2 of 2) 1.18 1.18 1.15 175 mg/ml Antibody A (bottle 1 of 2) 1.17 1.20 1.15 175 mg/ml Antibody A (Capacity 2 of 2) 1.16 1.17 1.15

As can be seen from a comparison of these volumes with the data in table. 6, the delivered volumes of hand-filled syringes were comparable to the delivered volumes of machine-filled syringes.

Capping height was measured on 15 hand-filled samples using a vernier caliper and was taken from the top of the cap to the distal side of the syringe flange. The measurement results were as follows.

Table 10

Conditions Average Capping Height (mm) Maximum Capping Height (mm) Minimum Capping Height (mm) 87.7 mg/ml antibody A (bottle 1 of 2) 5.7 6.0 5.4 87.7 mg/ml antibody A (bottle 2 of 2) 5.6 6.2 5.4 131.6 mg/ml antibody A (bottle 1 of 2) 6.2 6.6 6.0

-

Claims (16)

131.6 mg/ml antibody A (bottle 2 of 2) 6.0 6.2 5.8 175 mg/ml Antibody A (bottle 1 of 2) 6.2 6.8 6.0 175 mg/ml Antibody A (Capacity 2 of 2) 6.3 6.7 6.2 As can be seen from a comparison of these capping height values with the values indicated in table. 7, the capping heights of manually filled syringes were comparable to the capping heights of machine-filled syringes. The above description and examples are illustrative and not intended to be limiting. Numerous modifications and/or changes can be made by one skilled in the art without departing from the general scope of the invention. For example, and as described, the above-described embodiments of the invention (and/or aspects thereof) may be used in combination with each other. In addition, portions of the above-described embodiments may be deleted without departing from the scope of the invention. In addition, modifications may be made to adapt a particular situation or material to the teachings of various embodiments of the invention without departing from their scope. Many other embodiments of the invention will also be apparent to those skilled in the art upon reading the foregoing description. As used herein, the term about in relation to a value may refer to a deviation of 10% above or below a specified value. In addition, although a number of objects and advantages of the embodiments of the invention disclosed herein (and variations thereof) are described, not all such objects or advantages can necessarily be achieved in accordance with any particular embodiment of the invention. Thus, for example, those skilled in the art will understand that the systems and manufacturing techniques described herein may be implemented or implemented to achieve or optimize a single benefit or group of benefits as described herein without the need for achieve other purposes or benefits that may be set forth or suggested herein. CLAIM 1. A method for manufacturing a medicinal product, including: determining a theoretical filling volume, where the theoretical filling volume is the sum of the theoretical volume lost and the theoretical volume of drug administered; determining the height of the medicinal product based on the theoretical filling volume and the dimensions of the primary packaging component; introducing a volume of the finished medicinal substance into a syringe, wherein the volume of the finished medicinal substance corresponds to the theoretical filling volume and exceeds the specified volume of the syringe, and the specified volume of the finished medicinal substance is from 110 to 140% of the specified volume of the syringe, where the specified volume is the maximum volume established the manufacturer or safety standards organization for the syringe; and placing a stopper inside the syringe to seal the injected volume of the finished medicinal substance; In this case, the positioning of the plug includes: determining the position of the plug within the primary packaging component, wherein determining the position of the plug includes determining a distance below the flange of the primary package of the component that limits the tilt of the piston rod connected to the plug to deform the plug to an extent that provides a seal formed by the plug and applying a vacuum to a plug, wherein the syringe includes a housing in which the plug is sized and configured to fit tightly against the interior of the housing; in this case, the plug is located at a blockage distance from 1 to 5.5 mm behind the proximal end of the syringe; and at the same time, at the specified plugging distance, the inclination of the piston rod connected to the plug, relative to the longitudinal axis of the body, is limited by the walls of the body to the maximum angle of inclination of the piston rod and the maximum angle of inclination of the piston rod is insufficient to pull the plug so that the plug can come off the body wall and break the tightness; in this case, the plug located at the plugging distance behind the proximal end of the syringe is configured to maintain the volume of the finished medicinal substance from 110 to 140% when the piston rod is at the maximum angle of inclination. 2. Method according to claim 1, characterized in that the syringe is a pre-filled syringe, - 19 045636 having a specified volume of at least 1 ml. 3. The method according to claim 1, characterized in that the volume of the finished medicinal substance is at least 0.05 ml greater than the specified volume of the syringe. 4. The method according to claim 1, further comprising placing the syringe in additional packaging. 5. A method of preparing a plurality of syringes, comprising repeating the steps of claim 1 for each of the plurality of syringes in the batch. 6. The method according to claim 5, characterized in that the batch of syringes contains 80 pre-filled syringes. 7. The method according to claim 1, wherein the syringe is a pre-filled syringe, the said volume of which is 1 ml, and placing the stopper inside the syringe further includes inserting the stopper inside the body of the syringe so that the end of the stopper located closest to the flange syringe, was located from the syringe flange at a distance of 2.5 to 5.0 mm. 8. The method according to claim 1, characterized in that the volume of the pharmaceutical substance in the form of a dosage form is from 1.05 to 1.30 ml. 9. The method according to claim 1, characterized in that applying a vacuum to the syringe plug involves exposing the syringe plug to a pressure of 70 to 75 mbar. 10. The method according to claim 1, characterized in that the maximum angle of inclination of the piston rod is 20°. 11. The method according to claim 10, characterized in that the specified volume of the syringe is 1 ml. 12. The method according to claim 11, characterized in that there is no air space in the inside of the syringe body after placing the stopper inside the syringe in the stopper position. 13. A medicinal product having a specified volume, wherein the specified volume is the maximum volume established by the manufacturer or safety standards organization for the medicinal product; in this case, the volume of the finished medicinal substance exceeds the specified volume; and the volume of the finished drug substance is from 110 to 140% of the specified volume of the syringe, wherein the volume of the finished drug substance in the primary packaging component corresponds to a predetermined theoretical filling volume, wherein the theoretical filling volume is the sum of the theoretical volume lost and the theoretical volume of drug administered ; and the plug is connected to the piston rod and extends proximally from the plug, wherein the syringe includes a housing, the size of the plug and its configuration providing a tight fit to the wall of the inner part of the housing; wherein the stopper is located within the syringe at a closure distance of 1.0 to 5.5 mm beyond the proximal end of the syringe, thereby sealing the volume of drug substance, wherein the location of the stopper includes the application of a vacuum to the stopper, wherein the position of the stopper is based on a certain distance below the flange a syringe that restricts the piston rod connected to the stopper from tilting so as to deform the stopper to such an extent that the seal formed by the stopper is engaged; and at the same time, at the specified blockage distance, the inclination of the piston rod, relative to the longitudinal axis of the body, is limited by the walls of the body to the maximum angle of inclination of the piston rod and the maximum angle of inclination of the piston rod is insufficient for the plug to come off the body wall and break the tightness; in this case, the plug located at the plugging distance behind the proximal end of the syringe is configured to maintain the volume of the finished medicinal substance from 110 to 140% when the piston rod is at the maximum angle of inclination. 14. The medicinal product according to claim 13, characterized in that said volume is 1 ml and the volume of the finished medicinal substance is at least 1.05 ml. 15. The medicinal product according to claim 13, wherein the syringe is a pre-filled syringe having a body and a flange surrounding an opening in the body, and wherein the minimum distance between the flange and the stopper is at least 2.5 mm. 16. The medicinal product according to claim 13, characterized in that the maximum angle of inclination of the piston rod is 20° and that the specified volume of the syringe is 1 ml. -