Patent Description:
Injectors are used to deliver medical fluids or drug products, such as liquid drugs, to a patient. In particular, the injector will provide the fluid to the patient through a needle, cannula or catheter that defines a flow path into the patient. Certain injectors have a reservoir that is assembled by the manufacturer already connected to the flow path. These reservoirs are typically provided empty by the manufacturer to the patient or healthcare provider (e.g., doctor, nurse, healthcare assistant, etc.), and then the reservoir is filled at the time of use. Alternatively, the injector may be used in combination with a reservoir that is provided to the patient or healthcare provider prefilled.

In either case, the injector must be prepared prior to use. For example, if the reservoir is provided empty, then the reservoir must be filled. To do this, a syringe is filled with the medical fluid or drug product to be delivered, and then the medical fluid or drug product is injected into the reservoir through an inlet port. Prior to the injection, the inlet port must be sterilized by swabbing the outer surface with an alcohol wipe, for example. Similarly, before the prefilled reservoir is connected to the flow path in the alternative injector, the mating connectors must be sterilized, by swabbing the surface with an alcohol wipe.

In either event, the use of the injector requires additional material and time.

<CIT> relates to a connection for catheters, perfusion units and flasks containing liquids to be perfused parenterally for clinical controls or diagnostic techniques. The connection comprises a chamber containing an antimicrobian product between the components to be connected, that is to say, between the outlet of the container containing the liquid to be perfused and the perfusion unit, or between this latter and the entrance to the catheter, a hollow needle which traverses opposed penetrable wall portions of the chamber and the antimicrobian liquid therein.

<CIT> discloses an aspirating syringe comprising a barrel with a closing wall at its inner end; said barrel including a transparent side wall adjacent said closing wall, a hypodermic needle mounted in the closing wall with the inner end of the needle extended into the barrel and terminating in a stopple piercing point that is visible through the transparent side wall, an ampule contained in the barrel for longitudinal movement and closed at its inner end with a needle pierceable stopple that fits the barrel walls as a piston and an air relief means on the inner surface of the transparent side wall permitting air to escape when the ampule is moved toward the inner end of the barrel.

As set forth in more detail below, the present disclosure provides an improved injector embodying advantageous alternatives to the conventional devices and methods discussed above.

The subassembly of the present invention is defined in independent claim <NUM>. Preferred embodiments thereof and a method of assembling the subassembly are defined in the dependent claims.

The disclosure will be more fully understood from the following description taken in conjunction with the accompanying drawings. Some of the figures may have been simplified by the omission of selected elements for the purpose of more clearly showing other elements. Such omissions of elements in some figures are not necessarily indicative of the presence or absence of particular elements in any of the exemplary embodiments, except as may be explicitly delineated in the corresponding written description. None of the drawings are necessarily to scale. Only <FIG> show embodiments forming part of the claimed invention.

Although the following text sets forth a detailed description of different embodiments of the invention, it should be understood that the legal scope of the invention is defined by the words of the claims set forth at the end of this patent. It should also be understood that, unless a term is expressly defined in this patent using the sentence "As used herein, the term '________' is hereby defined to mean. " or a similar sentence, there is no intent to limit the meaning of that term, either expressly or by implication, beyond its plain or ordinary meaning, and such term should not be interpreted to be limited in scope based on any statement made in any section of this patent (other than the language of the claims). To the extent that any term recited in the claims at the end of this patent is referred to in this patent in a manner consistent with a single meaning, that is done for sake of clarity only so as to not confuse the reader, and it is not intended that such claim term be limited, by implication or otherwise, to that single meaning.

The detailed description is to be construed as exemplary only and does not describe every possible embodiment of the invention.

In general terms, an injector according to the present disclosure includes a container, a fluid delivery system and an actuator. While reference is made to an injector, which in some instances may refer to a delivery device that ensures that a set volume of medical fluid or drug product is delivered, it will be understood that this disclosure also encompasses infusion devices, which in some instances may refer to a delivery device that ensures that a particular rate of delivery is achieved. As used herein, the terms medical fluid and drug product may have the same or different meanings. The term medical fluids may encompass drug products, as well as other patient deliverable substances. It should also be understood that the terms injector and infuser may be used interchangeably when referring to embodiments in the specification. Furthermore, the subassembly of the container and the fluid delivery system may be addressed separately from the remainder of the injector, whether such subassembly is filled or unfilled with a medical fluid or drug product; for example, such subassembly may be transported as a unit during the assembly process in manufacturing the injector.

As illustrated in <FIG> and <FIG>, the container may include a wall with an interior surface and a seal assembly with an interior surface, the interior surfaces of the wall and the seal assembly defining a closed sterile reservoir filled with a medical fluid or drug product. Moreover, the fluid delivery system illustrated in these embodiments may include a sterile container needle, which may also be unsheathed, having a point disposed only partially through the seal assembly in a storage state, and disposed through the interior surface of the seal assembly into the sterile reservoir in a delivery state. As such, the needle is in fluid communication with the container in the delivery state, but not the storage state. According to these embodiments, the injector may include an actuator that is adapted to move the container needle from the storage state to the delivery state, which may involve movement of the needle relative to the container or the container relative to the needle.

As illustrated in <FIG>, and <FIG>, the seal assembly may be a flexible unitary wall having an interior surface that defines the interior surface of the seal assembly, and the point of the container needle may be disposed partially into the unitary wall. Alternatively, as illustrated in <FIG>, the seal assembly may include a flexible wall with an interior surface that defines the interior surface of the seal assembly, and a barrier disposed exterior of the flexible wall to define an enclosed space between the flexible wall and the barrier. According to such embodiments, the point of the container needle is disposed through the barrier into the space in the storage state.

An embodiment of an injector <NUM> according to the present disclosure is illustrated in <FIG>. The injector <NUM> includes a container <NUM>, a fluid delivery system <NUM>, and an actuator <NUM>.

The container <NUM> (which also may be referred to as a cartridge) includes a wall <NUM> with an interior surface <NUM> and an exterior surface <NUM>. While a unitary (i.e., one-piece) wall <NUM> that defines both the interior and exterior surfaces <NUM>, <NUM> is shown in <FIG>, in other embodiments, the wall <NUM> may include a plurality of layers with different layers defining the interior and exterior surfaces <NUM>, <NUM>.

According to certain embodiments of the present disclosure, the wall <NUM> is rigid. In other embodiments, the wall <NUM> is flexible, because of the material that defines the wall or the structure of wall (e.g., a bellows construction). The wall <NUM> may be made of glass, metal or polymer, for example. In particular, polymer versions may be made of polycarbonate, polypropylene, polyethylene (such as high density polyethylene), polytetrafluoroethylene, cyclic olefin polymer, cyclic olefin copolymer, Crystal Zenith® olefinic polymer (available from Daikyo Seiko, Ltd. , Japan), nylon or engineering resins, for example. As to flexible versions of the wall <NUM>, butyl rubber, silicon-based rubber, latex-based rubber, coated rubber, as well as multi-layer polymer films, such as may include polyethylene (such as low density polyethylene) and polypropylene, may be used.

The wall <NUM> may have a generally cylindrical shape, with a shoulder <NUM> separating a first cylindrical section <NUM> having a first cross-sectional diameter from a second cylindrical section <NUM> having a second cross-sectional diameter, the first cross-sectional diameter being smaller than the second cross-sectional diameter. The wall <NUM> may also define two opposed, open ends <NUM>, <NUM>. The wall <NUM>, or more particularly the interior surface <NUM> of the wall <NUM>, may also define a bore <NUM>.

In some embodiments, the container <NUM> may include a flexible unitary wall <NUM> (which may also be referred to as a seal or septum) having an interior surface <NUM> and an exterior surface <NUM>. The wall <NUM> may be disposed in the first open end <NUM> defined by the wall <NUM> and fixedly attached to the wall <NUM> of the container <NUM> such that there is limited relative movement between the wall <NUM> and the wall <NUM>, for example at the points of attachment of the wall <NUM> to the wall <NUM> across the open end or opening <NUM>. The interior surfaces <NUM>, <NUM> of the wall <NUM> and the flexible wall <NUM> may define, at least in part, a closed sterile reservoir <NUM> that is filled with a medical fluid or drug product <NUM>, described in greater detail below. The wall <NUM> may be made of bromobutyl, chlorobutyl or chlorobromobutyl rubber, fluoropolymer rubber, natural rubber, silicon-based rubber, silicon or santoprene, for example.

The container <NUM> may also include a stopper or piston <NUM> with interior and exterior surfaces <NUM>, <NUM>. The piston <NUM> may be received within the end <NUM> defined by the wall <NUM>, and may be moveable along the bore <NUM> between the ends <NUM>, <NUM> of the container <NUM>. According to such an embodiment, the reservoir <NUM> within which the medical fluid or drug product <NUM> is disposed may be defined by the interior surfaces <NUM>, <NUM>, <NUM> of the walls <NUM>, <NUM> and piston <NUM>.

The container <NUM> may be used in conjunction with the fluid delivery system <NUM>, the relevant portions of which are illustrated in <FIG>. In particular, the fluid delivery system <NUM> may include a container needle <NUM> having a point <NUM>. As illustrated, the point <NUM> is disposed only partially into the flexible wall <NUM> in a storage state. The penetration of the point <NUM> of the needle <NUM> into the wall <NUM> may be controlled through a number of methods and/or mechanisms. For example, <FIG> illustrates a jig that may be used in combination with the container <NUM> to control the depth at which the point <NUM> penetrates the wall <NUM>.

The fluid delivery system <NUM> may also include an injection needle <NUM> with a point <NUM>. The point <NUM> of the injection needle <NUM> may be covered with a needle shield <NUM> to prevent contact with and contamination of the point <NUM>. The container needle <NUM> and the injection needle <NUM> may be connected by a cannula or tube <NUM>, which may be a flexible cannula according to certain embodiments of the present disclosure. The needle <NUM>, similarly to the needle <NUM>, may be made of stainless steel, for example. In some embodiments, the container needle <NUM> and the injection needle <NUM> may be formed integrally (i.e., as one piece).

Fluid delivery system <NUM> may be used in conjunction with the actuator <NUM>, illustrated in <FIG>. The actuator <NUM> may be adapted to move the container needle <NUM> between the storage state illustrated in <FIG> and a delivery state illustrated in <FIG>, and thus move the fluid delivery system <NUM> between the storage and delivery states. In the delivery state, the container needle <NUM> is disposed through the interior surface <NUM> of the flexible wall <NUM> into the sterile reservoir <NUM> and is in fluid communication with the reservoir <NUM>.

The movement of the needle <NUM> between the states may occur in a variety of ways. For example, the needle <NUM> may be held fixed relative to the housing of the injector <NUM>, and the container <NUM> may move relative to the needle <NUM> and the housing. Alternatively, the container <NUM> may be held fixed relative to the housing, and the needle <NUM> may be moved relative to the container <NUM> and the housing. In other embodiments, both the container <NUM> and the needle <NUM> move relative to the housing of the injector <NUM>. It will be understood that all of these actions are embraced within the statement that the actuator <NUM> is adapted to move the container needle <NUM> between the storage and delivery states.

The actuator <NUM> may be mechanical, electro-mechanical or electrical. For example, the actuator <NUM> may include a solenoid, motor-driven lever, motor with associated gearing, etc. In some embodiments, a tab or button attached to the container <NUM> or the needle <NUM> permits the user to achieve the relative motion between the container <NUM> and the needle <NUM> manually. The container <NUM> may be received within a tab or button that is depressed into the housing when the injector <NUM> is activated to move the container <NUM> relative to the (fixed) needle <NUM>.

The actuator <NUM> may move the container needle <NUM> between storage and delivery states by moving the needle <NUM> from the storage state to the delivery state, or by moving the needle <NUM> from the delivery state to the storage state. In some embodiments, the actuator may move the container needle <NUM> between the storage and delivery states repeatedly (i.e., multiple times or repetitions). The actuator <NUM> may move the container needle <NUM> immediately upon receipt of an input or signal (e.g., as generated through the depression or manipulation of a button, switch or other input device, which may be mechanical, electro-mechanical or electrical in nature, coupled to the actuator <NUM>), or may delay movement of the container needle <NUM> between storage and delivery states some period of time after an input is received. According to a particular embodiment, the actuator <NUM> may delay movement of the needle <NUM> from the storage state to the delivery state until after such a time delay.

According to embodiments of the present disclosure, both the reservoir <NUM> and the container needle <NUM> (and any attached tubing <NUM> and injection needle <NUM>) are described as sterile, while the remainder of the delivery device/injector <NUM> (e.g., actuator <NUM>) is described as clean. These terms describe the condition of the reservoir <NUM>, the needle <NUM> or remainder of the delivery device as a consequence of their assembly under conditions that will ensure a specified level of freedom from contamination, wherein a sterile object or device is understood to have a relatively higher level of freedom from contamination than a clean object or device. By way of non-limiting example, the concepts of sterility and cleanliness may be discussed with reference to <FIG>, which discussion applies to all of the embodiments described herein.

<FIG> illustrates a manufacturing facility <NUM>, and may be used to discuss a manufacturing process that is conducted within the facility <NUM>. It will be noted that the facility <NUM> is divided into a plurality of spaces <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, which divisions may be maintained through the use of permanent or semi-permanent walls or other barriers. As will be understood, certain spaces or regions may be divided without barriers or walls, but may simply be separated on an organizational level instead. Additionally, a greater or lesser number of spaces or an alternative arrangement of the spaces may be used, such differing numbers or arrangements of spaces being readily determinable by one of ordinary skill in the art.

In some embodiments, the components of the container <NUM> (walls <NUM>, <NUM>, and stopper/piston <NUM>) and the fluid delivery system <NUM> enter the facility <NUM> through space <NUM>, wherein the components are sterilized using e-beam technology, for example. Alternatively, while the container <NUM> and the fluid delivery system <NUM> are defined as separate structures with reference to the embodiments of <FIG>, it would be known to use the manufacturing process described herein with a product where the container <NUM> is attached to the fluid delivery system <NUM> prior to introduction into the space <NUM> (e.g., the container <NUM>/fluid delivery system <NUM> is a syringe), and to sterilize the product. In some embodiments, the components may be sterilized through other currently-known (e.g., treatment with chlorine dioxide or vapor phase hydrogen peroxide) or later-developed sterilization procedures as the components enter the facility <NUM> at entry points <NUM>, <NUM>, <NUM>. The container <NUM> and fluid delivery system <NUM> then pass into space <NUM> for filing with the medical fluid or drug product. The space <NUM> may be operated as an aseptic Class <NUM> clean room. A Class <NUM> clean room is one in which the number of particles of size <NUM> or larger permitted per cubic foot of air is less than <NUM>. Once the fill has been performed and the stopper <NUM> has been disposed in the end <NUM> of the container <NUM>, the container needle <NUM> is inserted partially into wall/septum <NUM>. Because the container needle <NUM> does not penetrate through the wall <NUM>, the reservoir <NUM> and the medical fluid or drug product <NUM> remains sterile (i.e., at the higher level of cleanliness). Moreover, because the fluid delivery system <NUM> is sterile and is assembled to the container <NUM> under sterile conditions, the fluid delivery system <NUM> is believed to remain sterile, in part because of the partial insertion of the container needle <NUM> and in part because of the shield <NUM>.

The prefilled containers <NUM> in combination with the associated fluid delivery systems <NUM> (which combination may be referred to as a prefilled, sterile container combination, or in those embodiments wherein the fluid delivery system <NUM> and containers <NUM> are attached or formed integrally with each other (e.g., a syringe), the container <NUM> and the fluid delivery system <NUM> may also be referred to as prefilled sterile syringes) are moved through transfer space <NUM> (also operated as a Class <NUM> clean room, wherein certain embodiments are also aseptic) before being received within storage space <NUM>. The prefilled, sterile container combinations are moved from the storage space <NUM> into inspection area <NUM> (aseptic in certain embodiments), wherein the prefilled, sterile container combinations are inspected prior to assembly with the actuator <NUM> and other elements of the injector <NUM>. Because the medical fluid or drug product <NUM> is contained within the sealed container <NUM> and the sterility of the fluid delivery system <NUM> is preserved at this point (i.e., the container needle <NUM> is inserted into the wall <NUM> and the injector needle <NUM> is capped with the shield <NUM>), the inspection area may be operated as a Class <NUM>,<NUM> clean room. Once inspected, the prefilled, sterile container combinations may be passed from inspection space <NUM> to assembly space <NUM>.

Similar to the inspection space <NUM>, the assembly space <NUM> may be operated as an aseptic Class <NUM>,<NUM> clean room, or in some embodiments a Class <NUM>,<NUM> clean room. Materials passed into the clean room from spaces <NUM>, <NUM> may be in a sterile condition, or may be sterilized using e-beam technology, for example. Within the assembly space <NUM>, the remainder of the injector <NUM> (e.g., the actuator <NUM>) may be assembled (i.e., the container <NUM> and the fluid delivery system <NUM> may be disposed in the remainder of the injector <NUM>) prior to the injector <NUM> passing into the packaging space <NUM>.

Other processing, in addition to assembly, may occur at this point. According to certain embodiments, it may desirable to arrange the fluid delivery system <NUM> in one configuration prior to assembly with the remainder of the injector <NUM>, for ease of transport for example, but to have the fluid delivery system <NUM> assume a different arrangement once assembled in the injector <NUM>. For example, it may be desirable for the fluid path between the container needle <NUM> and the injector needle <NUM> to have straight configuration prior to assembly with the remainder of the injector, but to assume a curved, bent (e.g., <NUM> degrees, <NUM> degrees, etc) or other non-straight configuration when assembled with the remainder of the injector <NUM>. By maintaining the fluid delivery system <NUM> in a straight configuration, the spacing between the prefilled, sterile container combinations in a tray or other holder used to transport the prefilled, sterile container combinations may be maximized in that the additional room required to accommodate a curved, bent or other non-straight configuration may be avoided. This may also have an effect on the costs of filling the containers <NUM>, in that each tray can accommodate a larger number of container <NUM>/fluid delivery system <NUM> combinations, and thus the number of trays passing through the space <NUM> may be limited. The change in configuration may be performed in the assembly space <NUM>, for example, so as to minimize the need to accommodate the curved, bent or otherwise non-straight fluid delivery systems <NUM> elsewhere in the facility <NUM>.

The embodiment of the injector <NUM> illustrated in <FIG> is exemplary. <FIG> illustrate variants of the injector illustrated in <FIG>.

According to the embodiment of <FIG>, the injector <NUM> includes a container <NUM>, a fluid delivery device <NUM>, and an actuator <NUM>. Similar to the embodiment of <FIG>, the container <NUM> includes a wall <NUM> with interior and exterior surfaces <NUM>, <NUM>. The wall <NUM> may have two opposed ends <NUM>, <NUM> with the interior surface <NUM> of the wall <NUM> defining a bore <NUM> between the opposing ends <NUM>, <NUM>.

Unlike the container <NUM>, the container <NUM> has a fixed plug <NUM> that closes the end <NUM>. In addition, while the container <NUM> has a flexible unitary wall <NUM> with interior and exterior surfaces <NUM>, <NUM>, the wall <NUM> is disposed within the end <NUM> of the container <NUM>, and thus performs the role of the stopper/piston <NUM> in the container <NUM>. Consequently, the wall <NUM> is moveable along the bore <NUM> between the opposing ends <NUM>, <NUM>. The interior surfaces <NUM>, <NUM> of the walls <NUM>, <NUM> define a sterile reservoir <NUM> in which a medical fluid or drug product <NUM> is disposed.

The fluid delivery device <NUM> may include a sterile container needle <NUM> having a point <NUM>. The point <NUM> of the needle <NUM>, like the point <NUM> of the needle <NUM>, is disposed only partially into the flexible wall <NUM> in a storage state, with the actuator <NUM> causing the point <NUM> to move between the storage state and a delivery state wherein the point <NUM> is disposed through the interior surface <NUM> of the flexible wall <NUM> into the sterile reservoir <NUM>. The container needle <NUM> may be in fluid communication with a injection needle <NUM> having a point <NUM> covered with a shield <NUM> through a cannula <NUM> received within a piston rod <NUM>, for example, which rod <NUM> may be used to move the stopper/piston <NUM> between the ends <NUM>, <NUM> of the container <NUM>.

According to the embodiment illustrated in <FIG>, a container has a wall <NUM> with interior and exterior surfaces <NUM>, <NUM>. Unlike the containers discussed previously, the wall <NUM> defines a closed end <NUM> and an open end <NUM>. The container also includes a flexible wall <NUM>, like the wall <NUM> of the embodiment of <FIG>, which wall <NUM> is moveable within the container between the open end <NUM> and the closed end <NUM>. According to this embodiment, a separate structure is not required to close off one of the ends <NUM>, <NUM> because the wall <NUM> defines the closed end <NUM> itself. The closed end <NUM> may be resized so that it is radially larger than illustrated in <FIG>.

Having discussed a plurality of embodiments wherein a seal assembly includes only a flexible unitary wall, a further plurality of embodiments will be discussed with reference to <FIG> wherein the seal assembly includes a plurality of walls and/or seals. This structure may be referred to as a compartmentalized seal (or septum with reference to <FIG>, or stopper with reference to <FIG>). While these walls and/or seals may be illustrated and referred to as a wall and a barrier, it will be recognized that these structures may be defined as part of a single structure (e.g., a single septum with a space formed in the center).

Referring to <FIG>, an injector <NUM> includes a container <NUM>, a fluid delivery system <NUM>, and an actuator <NUM>.

The container <NUM> includes a wall <NUM> with an interior surface <NUM> and an exterior surface <NUM>. Similar to the container of <FIG>, the wall <NUM> may have a generally cylindrical shape, with a shoulder <NUM> separating a first cylindrical section <NUM> having a first cross-sectional diameter from a second cylindrical section <NUM> having a second cross-sectional diameter, the first cross-sectional diameter being smaller than the second cross-sectional diameter. The wall <NUM> may also define two opposed, open ends <NUM>, <NUM>. The wall <NUM>, or more particularly, the interior surface <NUM> of the wall <NUM>, may also define a bore <NUM>.

Unlike the container <NUM> of <FIG>, the container <NUM> of <FIG> has a seal assembly that includes more than a single, unitary wall. The seal assembly of the container <NUM> includes a flexible wall <NUM> and a barrier <NUM>. The flexible wall <NUM> has an interior surface <NUM> and an exterior surface <NUM>, while the barrier <NUM> has an interior surface <NUM> and an exterior surface <NUM>. The interior surfaces <NUM>, <NUM> of the wall <NUM> and the flexible wall <NUM> define a closed sterile reservoir <NUM> to be filled with a medical fluid or drug product <NUM>. In some embodiments, the barrier <NUM> is disposed exterior of the flexible wall <NUM> to define an enclosed space <NUM> between the flexible wall <NUM> and the barrier <NUM>. The space <NUM> may be defined by the interior surface <NUM> of the wall <NUM>, the exterior surface <NUM> of the flexible wall <NUM>, and the interior surface <NUM> of the barrier <NUM>.

The embodiment of <FIG> also includes the fluid delivery system <NUM> comprising a sterile container needle <NUM> having a point <NUM> disposed through the barrier <NUM> into the space <NUM> in a storage state, and disposed through the interior surface <NUM> of the flexible wall <NUM> into the sterile reservoir <NUM> in a delivery state. The container needle <NUM> only partially penetrates the seal assembly. The fluid delivery system <NUM> may also include an injection needle <NUM> with a point <NUM> covered at least initially with a needle shield <NUM> to prevent contact with and contamination of the point <NUM>. The container needle <NUM> and the injection needle <NUM> may be connected by a cannula or tube <NUM>, which may be a flexible cannula according to certain embodiments of the present disclosure.

As shown in <FIG>, the seal assembly of an injector <NUM> is disposed in a container <NUM> in place of the stopper/piston <NUM> illustrated relative to the container <NUM>. That is, the container <NUM> includes a wall <NUM> that defines a bore <NUM>, and a flexible wall <NUM> and a barrier <NUM> each define a stopper that is moveable along the bore <NUM>. While the wall <NUM> of the container <NUM> does not define opposing open and closed ends in the embodiment illustrated, such an alternative is possible.

<FIG> illustrate variants to the embodiment illustrated in <FIG>, which variants include additional features to permit the space or region between the flexible wall and the barrier to be evacuated or exhausted. These additional features may be referred to as vents, valves or bypasses, but all of these structures permit gases to escape from the space or region between the flexible wall and the barrier when an actuator moves the associated container needle from a storage state to a delivery state. This is not to suggest that the inner wall and exterior barrier cannot remain separated, for example through the use of a spacer or spacers, according to other embodiments of the present disclosure. The embodiments shown in <FIG> illustrate options for evacuating the space where the inner wall and exterior barrier come together. It would be understood that the vents, valves, and bypasses would preserve a sterile condition within the space until the space is evacuated or exhausted.

A container <NUM> is illustrated in <FIG> including a wall <NUM> and a seal assembly, the assembly including a flexible wall <NUM> and a barrier <NUM>. The flexible wall <NUM> has an interior surface <NUM> and an exterior surface <NUM>, while the barrier <NUM> has an interior surface <NUM> and an exterior surface <NUM>. An interior surface <NUM> of the wall <NUM> and the interior surface <NUM> of the flexible wall <NUM> define a closed sterile reservoir <NUM> to be filled with a medical fluid or drug product <NUM>. The barrier <NUM> is disposed exterior of the flexible wall <NUM> to define an enclosed space <NUM> between the flexible wall <NUM> and the barrier <NUM>. The space <NUM> may be defined by the interior surface <NUM> of the wall <NUM>, the exterior surface <NUM> of the flexible wall <NUM>, and the interior surface <NUM> of the barrier <NUM>.

As illustrated in <FIG>, a fluid delivery system <NUM> including a container needle <NUM> is used in conjunction with the seal assembly. The container needle <NUM> is shown in the storage state. The container needle <NUM> is disposed through the barrier <NUM> so that a point <NUM> of the needle <NUM> is disposed in the space <NUM>. The point <NUM> will penetrate the flexible wall <NUM> and depend into the reservoir <NUM> in a delivery state (not shown). The needle <NUM> is not drawn to scale particularly as to its length.

The container <NUM> illustrated in <FIG> includes at least one vent <NUM>. The vents <NUM> are in fluid communication with the space <NUM> between the barrier <NUM> and the flexible wall <NUM>. The vents <NUM> are selectively actuated to permit gas trapped between the barrier <NUM> and the flexible wall <NUM> to escape through the vents <NUM> when the seal assembly is moved between the illustrated storage state and the delivery state, wherein the barrier <NUM> is advanced in the direction of the flexible wall <NUM> to permit the point <NUM> of the container needle <NUM> to penetrate through the wall <NUM>. In some embodiments, the vents <NUM> may be in a sealed condition relative to the environment until actuated, for example, by a change in the pressure within the space <NUM>.

The vents <NUM> are disposed within the barrier <NUM>, and extend between the interior surface <NUM> and the exterior surface <NUM> of the barrier <NUM>. A flap <NUM> covers the end of the vent <NUM> proximate to the exterior surface <NUM>, and thereby seals the end of the vent <NUM> until the vent is actuated, preserving the sterility of the space <NUM> between the barrier <NUM> and the flexible wall <NUM>. Alternatively, the vents <NUM> may be arranged, for example, in the wall <NUM> of the container <NUM>.

<FIG> illustrate a further variant on the system of <FIG>, wherein a container <NUM> includes a wall <NUM> and a seal assembly, the assembly including a flexible wall <NUM> and a barrier <NUM>. The flexible wall <NUM> has an interior surface <NUM> and an exterior surface <NUM>, while the barrier <NUM> has an interior surface <NUM> and an exterior surface <NUM>. An interior surface <NUM> of the wall <NUM> and the interior surface <NUM> of the flexible wall <NUM> define a closed sterile reservoir <NUM> to be filled with a medical fluid or drug product <NUM>. The barrier <NUM> is disposed exterior of the flexible wall <NUM> to define an enclosed space <NUM> between the flexible wall <NUM> and the barrier <NUM>. The space <NUM> may be defined by the interior surface <NUM> of the wall <NUM>, the exterior surface <NUM> of the flexible wall <NUM>, and the interior surface <NUM> of the barrier <NUM>.

As illustrated in <FIG>, a fluid delivery system <NUM> including a container needle <NUM> is used in conjunction with the seal assembly. The container needle <NUM> is illustrated in the storage state, wherein the container needle <NUM> is disposed through the barrier <NUM> so that a point <NUM> of the needle <NUM> is disposed in the space <NUM>. The point <NUM> will penetrate the flexible wall <NUM> and depend into the reservoir <NUM> in a delivery state, not shown.

In contrast with the previously discussed embodiments, the container <NUM> illustrated in <FIG> includes at least one bypass or vent <NUM>. The bypasses <NUM> are in fluid communication with the reservoir <NUM>. The bypasses <NUM> are selectively actuated to permit gas trapped between the barrier <NUM> and the flexible wall <NUM> to escape through the bypasses <NUM> into the reservoir <NUM> when the seal assembly is moved between the illustrated storage state and the delivery state, wherein the barrier <NUM> is advanced in the direction of the flexible wall <NUM> to permit the point <NUM> of the container needle <NUM> to penetrate through the wall <NUM>.

The bypasses <NUM> are not in fluid communication with the space <NUM> until the flexible wall <NUM> has moved from the storage state illustrated in <FIG> to an intermediate state illustrated in <FIG>. As illustrated in <FIG>, the bypasses <NUM> may be defined in the interior surface <NUM> of the wall <NUM>, and may take the form of a groove <NUM> formed in the wall <NUM>. The groove <NUM> may have a distal end <NUM> and a proximal end <NUM>. As will be recognized, until the exterior surface <NUM> of the flexible wall <NUM> moves past the distal end <NUM> of the grooves <NUM>, the reservoir <NUM> is in a sealed condition relative to the space <NUM>. However, once the exterior surface <NUM> of the flexible wall <NUM> moves past distal end <NUM> of the grooves <NUM>, the gases trapped between the barrier <NUM> and the flexible wall <NUM> may exhaust into the reservoir <NUM>. This may facilitate the movement of the barrier <NUM> and needle <NUM> toward the flexible wall <NUM>.

Other embodiments of the present disclosure include embodiments where the container needle is not disposed through the seal assembly, or where the container needle is disposed fully through the seal assembly. Two such alternatives are illustrated in <FIG>.

<FIG> illustrate embodiments wherein the container needle is disposed through the flexible wall (defining the stopper or septum) and a valve is used to seal the reservoir off from the injection needle. The valve may also be used to control the flow of medical fluid or drug product from the reservoir in the container. In this fashion, the valve may be used to meter an amount of medical fluid or drug product from the reservoir, or to delay the flow of the medical fluid or drug product until a time delay has elapsed relative to receipt of an input from an input device (e.g., button or switch), for example.

<FIG> illustrates an injector <NUM> with a container <NUM>, a fluid delivery system <NUM>, and an actuator <NUM>. The container <NUM> includes a flexible wall <NUM>, which may be in the form of a septum. The flexible wall <NUM> has an interior surface <NUM> and an exterior surface <NUM>. Additionally, the fluid delivery system <NUM> includes a container needle <NUM>, an injection needle <NUM>, and a flexible cannula or tubing <NUM> connecting the container needle <NUM> and the injection needle <NUM>. The injection needle <NUM> may be received within a cover <NUM> that preserves the sterility of the needle <NUM>.

The container needle <NUM> (and in particular a point <NUM> of the container needle <NUM>) is disposed through the flexible wall <NUM> and through the interior surface <NUM>. The needle <NUM> is thus in fluid communication with a sterile reservoir <NUM> and a medical fluid or drug product <NUM> disposed within the reservoir <NUM>. Fluid communication between the container needle <NUM> and the injection needle <NUM> is interrupted by valve <NUM> disposed in or along the flexible tubing <NUM>. Unlike the other embodiments discussed above relative to <FIG>, the actuator <NUM> of the injector <NUM> is not used to move the container needle <NUM> relative to the flexible wall <NUM>, but instead to manipulate the valve between a closed state wherein fluid communication is interrupted between the needles <NUM>, <NUM> and an open state wherein the container needle <NUM> is in fluid communication with the injection needle <NUM>.

The valve <NUM> may take a variety of shapes and forms, two of which are illustrated in <FIG>. In particular, <FIG> illustrates an embodiment of the injector <NUM> wherein a rotatable valve <NUM> is disposed in the flexible tubing <NUM>, or has an internal valve member that is in fluid communication with the fluid flow path defined between the container needle <NUM> and the injection needle <NUM>. <FIG> illustrates an embodiment of the injector wherein a pinch valve <NUM> is disposed along the flexible tubing <NUM>, and thus cooperates with an exterior surface of the tubing <NUM> to interrupt the fluid communication between the container needle <NUM> and the injection needle <NUM>.

Embodiments such as those illustrated in <FIG> could also be used with a container that has a permanently attached needle, such that the container is in the form of a syringe, for example. In addition, the method described relative to <FIG> could be used with any of the embodiments mentioned heretofore, as well as with an embodiment like those illustrated in <FIG> wherein no valve is used, but the syringe (i.e., a container with permanently attached needle) has an injection needle that is covered by a shield to maintain its sterility.

The embodiments illustrated in <FIG> may be further modified to incorporate a seal assembly including a plurality of walls and/or seals, such as is illustrated in <FIG>, for example. <FIG> illustrates such an embodiment.

In particular, <FIG> illustrates an injector <NUM> with a container <NUM>, a fluid delivery system <NUM>, an actuator <NUM>, and a seal assembly <NUM>. The fluid delivery system <NUM> may include a container needle <NUM>, an injection needle <NUM>, and a flexible cannula or tubing <NUM> connecting the container needle <NUM> and the injection needle <NUM>. The injection needle <NUM> may be received within a cover <NUM> that preserves the sterility of the needle <NUM>. The needle <NUM> may also be in selective fluid communication with a sterile reservoir <NUM> and a medical fluid or drug product <NUM> disposed within the reservoir <NUM> via a valve <NUM> disposed in or along the flexible tubing <NUM>. In this regard, the injector <NUM> is similar to those injector embodiments illustrated in <FIG>.

However, the seal assembly <NUM> of the injector <NUM> also has a flexible wall <NUM> and a barrier <NUM>. The flexible wall <NUM> and the barrier <NUM> each have interior and exterior surfaces, with the interior surface of the flexible wall <NUM> defining, in part, the closed sterile reservoir <NUM>. The barrier <NUM> is disposed exterior of the flexible wall <NUM> to define an enclosed space <NUM> between the flexible wall <NUM> and the barrier <NUM> in which a point <NUM> of the container needle <NUM> may be disposed.

The embodiment of <FIG> has two potential barriers: one in the form of the valve <NUM> and a second in the form of the placement of the point <NUM> within the space <NUM>. In some embodiments, the valve <NUM> may be controlled to provide a delay in the injection of the medical fluid or drug product <NUM> after the container needle <NUM> has been caused to penetrate trough the flexible wall <NUM> into the reservoir <NUM>.

The devices according to the present disclosure may have one or more advantages relative to conventional technology, any one or more of which may be present in a particular embodiment in accordance with the features of the present disclosure included in that embodiment. As one example, these embodiments maintain the sterility of the medical fluid or drug product until the time of use. As another example, the potential for mixing of the medical fluid or drug product is limited or eliminated prior to the time of use. As a still further example, unintended delivery of the medical fluid or drug product is limited or prevented prior to the time of use.

For illustrative purposes only, <FIG> provides a further method <NUM> for assembling delivery devices according to any of the embodiments disclosed above. The method <NUM> follows the general processing flow outlined above relative to <FIG>. However, rather than referring to the cleanroom classifications according to U. Federal Standard 209E, reference is made to cleanroom classifications according to the GMP EU standard. Moreover, the method <NUM> provides additional optional paths (represented as a left or right branch) that may be followed in the assembly of the delivery device. Consequently, the method <NUM> of <FIG> may be viewed as supplementary to the discussion above relative to <FIG>.

The method <NUM> for assembling delivery devices begins at block <NUM>. The containers used in the device are initially stored in sealed tubs. These containers may be sterilized. At block <NUM>, the tubs are debagged, for example using an automated debagger in a Grade C cleanroom. At block <NUM>, the Tyvek seal is peeled off (e.g., by a robot) and removed, for example, in a space operated as a Grade A cleanroom, perhaps within an isolator in a space otherwise operated a Grade C cleanroom.

The containers are filled, and the stoppers and the fluid systems are attached, and then the containers are re-nested in open tubs, at block <NUM>, in a space operated as a Grade A cleanroom, perhaps within an isolator in a space otherwise operated a Grade C cleanroom. From this point, two different alternative paths, or branches, are possible.

The filled containers may be left in the open tubs at block <NUM>. The tubs may be conveyed and carted to a storage space (e.g., cold room) at block <NUM>.

If the route of block <NUM>, <NUM> is followed, then the method <NUM> may continue with the tubs being transferred for processing to an inspection room at block <NUM>. The filled containers are then denested from the open tubs at block <NUM>, and supplied to an automated inspection machine at block <NUM>. Automated inspection of the filled containers occurs at block <NUM>, followed by optional, additional semi-automated or manual inspection at block <NUM>.

Alternatively, the tubs may be resealed, rebagged, and labeled, at block <NUM>. For example, the tubs may be resealed with Tyvek (e.g., using a Bausch + Strobel tub sealer), rebagged, and then labeled in a Grade C cleanroom at block <NUM>. The tubs may then be stored, or even shipped, if necessary, at blocks <NUM>, <NUM>.

Once storage or transport is completed, the tubs are debagged, for example using an automated debagger at block <NUM>. At block <NUM>, the Tyvek seal is peeled off and removed. The filled containers may then be denested for inspection, at block <NUM>. The actions at blocks <NUM>, <NUM>, <NUM> are performed in a Grade C cleanroom. An automated inspection may then be carried out using a visual inspection machine designed for operation in a Grade C cleanroom at block <NUM>.

Following either procedure, the filled, inspected containers may then be transferred to rondo trays at block <NUM>.

According to a first procedure, the rondo trays may be sent directly to storage at block <NUM>. If the route of block <NUM> is followed, then the rondo trays are transferred for processing to the device assembly room at block <NUM>. The containers are denested at block <NUM>, and assembled with the other elements of the delivery device at block <NUM> to define an assembled delivery device (e.g., an injector or an infuser).

Alternatively, the containers may be moved into tubs, which are sealed, bagged, and labeled, at block <NUM>. For example, the tubs may be resealed with Tyvek, bagged, and then labeled in a Grade C cleanroom. The tubs may then be stored, or even shipped for further processing, if necessary, at blocks <NUM>, <NUM>. Once storage or transport completed, the tubs are debagged, for example using an automated debagger at block <NUM>. At block <NUM>, the Tyvek seal is peeled off and removed, and the containers are denested. The filled containers may then be assembled with the other elements of the delivery device at block <NUM>. The actions at blocks <NUM>, <NUM>, <NUM> may all occur in a Grade C cleanroom.

In either event, the assembled devices are packaged at block <NUM>, and the packaged, assembled devices are stored at block <NUM>. Finally, the packaged, assembled devices are transported to the distributor, and/or for other distribution actions at block <NUM>.

While numerous embodiments of an injector have been described above, still further embodiments are possible. <FIG> and <FIG> illustrate a number of embodiments utilizing a mechanical connection or coupling between the container and the container needle. With reference to <FIG>, an injector <NUM> according to such additional embodiments includes a container <NUM>, a seal assembly <NUM> and a fluid delivery system <NUM>, which fluid delivery system <NUM> includes a sterile container needle <NUM>. The fluid delivery system <NUM> may include sterile flexible tubing connected at a first end to the container needle <NUM> and a second end to a sterile injection needle received within a sterile cover that closes off the sterile injection needle, as discussed above. Unlike the embodiments described above, the sterile container needle <NUM> is attached to a connector <NUM>, the connector <NUM> being mechanically connected or coupled to the container <NUM> to secure the sterile container needle <NUM> to the container <NUM>.

As illustrated in <FIG>, the container <NUM> has a container wall <NUM> with an interior surface <NUM>. In some embodiments, the container <NUM> may include a rigid wall formed using, for example, any of the materials discussed above relative to the other containers discussed herein. The container <NUM>, and more particularly the container wall <NUM>, defines a bore <NUM>, and the container <NUM> may include a stopper (or plunger) <NUM> that is moveable along the bore <NUM> between opposite ends <NUM>, <NUM>.

While the plunger <NUM> closes one end <NUM> of the container <NUM>, the other end <NUM> of the container <NUM> is closed by the seal assembly <NUM>. As illustrated, the seal assembly <NUM> includes a flexible seal assembly wall <NUM> and a barrier <NUM>.

The flexible seal assembly wall <NUM> has an interior surface <NUM>, the interior surfaces <NUM>, <NUM> of the container wall <NUM> and the seal assembly wall <NUM> defining a closed sterile reservoir <NUM> that may be filled with a medical fluid or drug product. The container <NUM> has an opening <NUM> at the first end <NUM> of the bore <NUM>, which opening <NUM> is in fluid communication with the reservoir <NUM>, and the flexible seal assembly wall <NUM> defines a septum disposed across the opening <NUM>. The flexible seal assembly wall <NUM> is fixedly attached to the container wall <NUM> as described in detail below relative to an exemplary embodiment.

The barrier <NUM> is disposed exterior of the seal assembly wall <NUM> (relative to the reservoir <NUM>) to define an enclosed space <NUM> between the flexible wall <NUM> and the barrier <NUM>. In particular, the barrier <NUM> may have a cup-like shape defined by a plate <NUM> with exterior and interior surfaces <NUM>, <NUM> and a rim <NUM> depending axially from the interior surface <NUM> of the plate <NUM>. A surface <NUM> of the rim <NUM> is disposed on an exterior surface <NUM> of the seal assembly wall <NUM>, the enclosed space <NUM> being disposed between interior surface <NUM> of the plate <NUM>, the exterior surface <NUM> of the seal assembly wall <NUM> and the rim <NUM>. In some embodiments, the barrier <NUM> and the flexible seal assembly wall <NUM> may be formed as a single structure with a space defined therebetween.

The fluid delivery system <NUM> includes the sterile container needle <NUM>. This needle <NUM> has a point <NUM> that is disposed only through the barrier <NUM> in a storage state (see <FIG>), and that is disposed through the flexible wall <NUM> into the sterile reservoir <NUM> in a delivery state (see <FIG>). As mentioned above, the sterile container needle <NUM> is attached to a connector <NUM> that is mechanically attached to the container <NUM> to secure the sterile container needle <NUM> to the container <NUM> with the needle <NUM> in the storage state. An actuator <NUM> (see <FIG>) is included that is itself adapted to move the container needle <NUM> from the storage state to the delivery state, for example after receipt of a signal from a mechanical, electro-mechanical, or electrical input device coupled to the actuator <NUM>. According to certain embodiments, the actuator <NUM> is adapted to delay movement of the container needle <NUM> from the storage state to the delivery state to some predetermined time after an input is received.

The connector <NUM> may be mechanically connected or coupled to the container <NUM> using a variety of different mechanisms. For example, the connector may simply be press fit onto the container. <FIG> illustrates such an embodiment of the connector, which connector is formed of a cup-shaped collar <NUM> through which the sterile container needle <NUM> depends. The collar <NUM> has a plate <NUM> with exterior and interior surfaces <NUM>, <NUM>, and a rim <NUM> depending axially from the interior surface <NUM> of the plate <NUM>. The end of the container would be received within a space <NUM> defined by the interior surface <NUM> of the plate <NUM> and the rim <NUM>, and an inner surface <NUM> of the rim <NUM> would frictionally engage the container to limit or prevent separation.

According to the invention, the connector <NUM> is a first connector of a pair of connectors, and a second connector <NUM> of the pair of connectors is attached to the container <NUM>. See, e.g., <FIG>. The first and second connectors <NUM>, <NUM> are mechanically coupled to secure the sterile container needle <NUM> to the container <NUM> in the storage state as illustrated in <FIG>. For example, a family of connectors useful according embodiments of the disclosure may include first and second connectors each of which include one of a pair of facing surfaces. The facing surfaces abut to limit movement of the first and second connectors axially along a longitudinal axis of the sterile container needle, and thus limit or prevent separation of the sterile container needle from the container and the seal assembly.

<FIG> and <FIG> illustrate an embodiment of such a connector pair. According to this embodiment, the first and second connectors <NUM>, <NUM> engage to rotatably couple the pair of connectors <NUM>, <NUM> to secure the sterile container needle <NUM> to the container <NUM> in the storage state. That is, the illustrated first and second connectors <NUM>, <NUM> limit or prevent separation of the sterile container needle <NUM> from the container <NUM> in the axial direction, but do not work to limit or prevent the needle <NUM> and associated connector <NUM> from rotating relative to the container/seal assembly <NUM>/<NUM>.

As seen in <FIG>, the connector includes a cup-shaped collar <NUM> through which the sterile container needle <NUM> depends. The collar <NUM> has a plate <NUM> with exterior and interior surfaces <NUM>, <NUM>, and a rim <NUM> depending axially from the interior surface <NUM> of the plate <NUM>. The rim <NUM> defines an opening <NUM> through which an end of the container <NUM> is disposed when the sterile container needle <NUM> is secured to the container <NUM>. Disposed about the opening <NUM> is an inwardly directed flange <NUM> that defines one surface <NUM> of a pair of facing surfaces, an outwardly directed flange <NUM> attached to the container <NUM> defining the other surface <NUM>. See also <FIG>. The abutment of the facing surfaces <NUM>, <NUM> limits or prevents separation once the needle <NUM> and connector <NUM> have been advanced in the direction of the container <NUM> such that the flange <NUM> is moved axially past the flange <NUM> in the direction of the container <NUM>.

According to the embodiment illustrated in <FIG>, and <FIG>, the container <NUM> comprises a rim <NUM> disposed about the opening <NUM>. The seal assembly <NUM> is disposed over the opening <NUM> of the container <NUM>, with a portion of the seal assembly wall <NUM> disposed through the opening <NUM>. The second connector <NUM> includes an outwardly-directed flange <NUM> that defines a rim, at least the portion of the second connector <NUM> defined by the rim <NUM> disposed over the seal assembly <NUM>. The container <NUM> further includes a crimp ring <NUM>, the ring <NUM> being formed about the rim <NUM> of the container <NUM> and the rim <NUM> of the second connector <NUM> with the seal assembly <NUM> disposed between the rims <NUM>, <NUM> to secure the seal assembly <NUM> between the rim <NUM> of the container <NUM> and the rim <NUM> of the second connector <NUM>.

According to this embodiment, the second connector <NUM> also has an passage <NUM> therethrough. The sterile container needle <NUM> is disposed through the passage <NUM> in the second connector <NUM> and through the barrier <NUM> in the storage state, and through the passage <NUM>, the barrier <NUM> and the seal assembly wall <NUM> in the delivery state. Of course, such an embodiment has been included by way of illustration, and not by way of limitation.

To assemble the device illustrated in <FIG>, the container needle <NUM> and the connector <NUM> is advanced in the direction of the container <NUM>. As the needle <NUM> passes through the barrier <NUM>, the inwardly-directed flange <NUM> of the connector <NUM> moves past the outwardly directed flange <NUM> of the connector <NUM> attached to the container <NUM>. Once the flange <NUM> has moved past the flange <NUM>, the movement of the container needle <NUM> and the associated connector <NUM> is prevented by abutting surfaces <NUM>, <NUM>. The material selected for the flange <NUM> and/or the flange <NUM> may be selected to resist a significant force applied to the container needle <NUM> and the connector <NUM> to separate the needle <NUM> from the container <NUM>. The material is also selected, however, to permit the flanges <NUM>, <NUM> to move past each other so that the mechanical coupling can be formed, and/or the collar <NUM> of the connector <NUM> may have features (e.g., axial slots) that permit the collar <NUM> or sections of the collar <NUM> to flex to permit the motion of the flange <NUM> past the flange <NUM>.

<FIG> illustrates a connector that may be used with a different embodiment of the connector pair. According to this embodiment, the first and second connectors of the connector pair would threadingly engage to couple the connector pair to secure the sterile container needle to the container in the storage state. Accordingly, relative rotational motion between the first and second connector would cause the connectors to either be securely coupled to each other or to decouple from each other, and thus relative rotational motion is to be limited (unlike the embodiment of <FIG> and <FIG>, wherein relative rotation motion is permitted). As illustrated in <FIG>, the first connector of such a connector paid may have a collar <NUM> with a plate <NUM> having exterior and interior surfaces <NUM>, <NUM>, and a rim <NUM> depending axially from the interior surface <NUM> of the plate <NUM>. The rim <NUM> defines an opening <NUM> through which an end of the container is disposed when the sterile container needle is secured to the container. On an inner surface of the rim <NUM>, a thread <NUM> is formed, which thread <NUM> would be matched with a mating thread formed on the second connector.

As illustrated in <FIG>, the first connector of a connector pair may include a collar that is disposed continuously about the sterile container needle. Alternatively, as illustrated in <FIG>, the first connector may include a collar that is disposed discontinuously about the sterile container needle. According to the embodiment illustrated in <FIG>, the connector includes a collar <NUM> that is significantly discontinuous, to the point where the collar <NUM> defines only a pair of arms <NUM> disposed opposite from each other relative to the container needle <NUM> that is disposed between the two arms <NUM>. The arms <NUM> are connected to a plate <NUM> having exterior and interior surfaces <NUM>, <NUM>. Because of the relatively limited width of the arms <NUM>, the arms <NUM> may have an end <NUM> that is attached to the plate <NUM> and that defines a living hinge, permitting the arms <NUM> to pivot relative to the plate <NUM> and the end <NUM>. The arms <NUM> may also have an inwardly-directed flange or finger <NUM> that will mate with a corresponding structure of the container, such as the flange <NUM> of the container <NUM> illustrated in <FIG>, to limit or prevent axial motion between the container <NUM> and the needle <NUM> such that the container needle <NUM> would separate from the container <NUM>.

Accordingly, a method <NUM> of assembling an injector, such as the injector <NUM> illustrated in <FIG> and <FIG>, is illustrated in <FIG>. The method <NUM> may include sterilizing a reservoir <NUM> at block <NUM> and filling a sterile reservoir <NUM> of a container <NUM> with a medical fluid or drug product under sterile conditions at block <NUM>, the reservoir <NUM> defined by an interior surface <NUM> of a wall <NUM> of the container <NUM>. A sterile fluid delivery system <NUM> (e.g., the container needle <NUM>) may be mechanically connected or coupled to the container <NUM> under sterile conditions, the fluid delivery system <NUM> not in fluid communication with the reservoir <NUM> in a storage state and in fluid communication with the reservoir <NUM> in a delivery state, and assembling the remainder of the injector <NUM> under clean room conditions. In particular, the steps of sterilizing and filling the sterile reservoir <NUM> may follow the step of mechanically connecting or coupling the sterile fluid delivery system <NUM> to the container <NUM>, as illustrated at block <NUM>. According to other embodiments, the step of mechanically connecting or coupling the sterile fluid delivery system <NUM> to the container <NUM> may follow the step of filling the sterile reservoir <NUM>, as illustrated at block <NUM>. The step of mechanically connecting or coupling the sterile fluid delivery system <NUM> may occur within a fill/finish suite, for example. Assembly of the remainder of the injector <NUM> may also include attaching the fluid delivery system <NUM> to an actuator <NUM> under clean room conditions at block <NUM>, the actuator <NUM> adapted to change the state of the fluid delivery system <NUM> from the storage state to a delivery state.

The connection of the needle to the container (and specifically to the flexible seal assembly wall/barrier) prior to the sterilization and filing of the container is not limited to the embodiments of <FIG>. It will be recognized that the method <NUM> described in regard to the <FIG> may be performed in accordance with the method described in <FIG>. In particular, rather than assembling the container needle with the reservoir at block <NUM> of the method <NUM> of <FIG>, the container needle (and associated tubing/delivery needle) may be assembled with the reservoir even prior to block <NUM>, such that the container needle/container assembly may be filled and renested in the tub at block <NUM>. The method <NUM> may then continue as described above.

It will also be recognized that while the embodiments of <FIG> have been described relative to a system wherein a combination of a seal wall and a barrier is provided, a similar system with mechanical connection or coupling of the container needle and container may be provided utilizing any of the embodiments described in <FIG>. To illustrate this point, an additional embodiment according to the present disclosure is provided in <FIG> with an injector <NUM> including a container <NUM>, a seal assembly <NUM> and a fluid delivery system <NUM>, which fluid delivery system <NUM> includes a sterile container needle <NUM>. The fluid delivery system <NUM> may include sterile flexible tubing connected at a first end to the container needle <NUM> and a second end to a sterile injection needle received within a sterile cover that closes off the sterile injection needle, as discussed above. The sterile container needle <NUM> is attached to a connector <NUM>, the connector <NUM> being mechanically connected or coupled to the container <NUM> to secure the sterile container needle <NUM> to the container <NUM>.

The container <NUM> may have a container wall <NUM> with an interior surface <NUM>, and a stopper (or plunger) <NUM> that is moveable between opposite ends <NUM>, <NUM>. While the plunger <NUM> closes one end <NUM> of the container <NUM>, the other end <NUM> of the container <NUM> is closed by the seal assembly <NUM>. As illustrated, the seal assembly <NUM> includes a flexible seal assembly wall <NUM>.

The flexible seal assembly wall <NUM> has an interior surface <NUM>, the interior surfaces <NUM>, <NUM> of the container wall <NUM> and the seal assembly wall <NUM> defining a closed sterile reservoir <NUM>. The container <NUM> has an opening <NUM> at the first end <NUM> in fluid communication with the reservoir <NUM>, and the flexible seal assembly wall <NUM> defines a septum disposed across the opening <NUM>. The needle <NUM> has a point <NUM> that is disposed only partially through the wall <NUM> in a storage state, as illustrated in <FIG>, and that is disposed through the flexible wall <NUM> into the sterile reservoir <NUM> in a delivery state.

As mentioned above, the sterile container needle <NUM> is attached to a connector <NUM> that is mechanically attached to the container <NUM> to secure the sterile container needle <NUM> to the container <NUM> with the needle <NUM> in the storage state. In particular, a second connector <NUM> is connected to the container <NUM>. The connector <NUM> has an inwardly directed flange <NUM> that defines one surface <NUM> of a pair of facing surfaces, an outwardly directed flange <NUM> attached to the container <NUM> defining the other surface <NUM>. The abutment of the facing surfaces <NUM>, <NUM> limits or prevents separation once the needle <NUM> and connector <NUM> have been advanced in the direction of the container <NUM> such that the flange <NUM> is moved axially past the flange <NUM> in the direction of the container <NUM>
Advantages and embodiments not specifically listed herein may also be recognizedFor example, while the operation of the actuator has been described with regard to the foregoing embodiments as moving, the container needle from a storage state to a delivery state, it will be understood that the actuator may also move the container needle from the delivery state to the storage state. If a dose of medical fluid or drug product is to be delivered that is less than the volume of the reservoir (such as may be the case wherein the injector is designed to be programmed to deliver an adjustable dose according to the needs of the patient (e.g., pediatric vs. adult patient)), then the actuator may move the container needle from the storage state to the delivery state prior to delivery of the dose, and from the delivery state to the storage state after delivery of the dose. The movement from the delivery state to the storage state will in effect reseal the container and close the fluid path to the patient. This sequence of movement between the storage state and the delivery state may be repeated. As noted above, maintaining a closed fluid path until delivery is initiated is advantageous in that the opportunity for unintended delivery of the medical fluid or drug product to the patient and/or mixing of the medical fluid or drug product with the patient's bodily fluids is reduced.

The injectors according to the present disclosure may be used with a variety of medical fluids or drug products, including colony stimulating factors, such as granulocyte colouny-stimulating factor (G-CSF). Such G-CSF agents include, but are not limited to, Neupogen® (filgrastim) and Neulasta® (pegfilgrastim). In various other embodiments, the drug delivery device may be used with various pharmaceutical products, such as an erythropoiesis stimulating agent (ESA), which may be in a liquid or a lyophilized form. An ESA is any molecule that stimulates erythropoiesis, such as Epogen® (epoetin alfa), Aranesp® (darbepoetin alfa), Dynepo® (epoetin delta), Mircera® (methyoxy polyethylene glycol-epoetin beta), Hematide®, MRK-<NUM>, INS-<NUM>, Retacrit® (epoetin zeta), Neorecormon® (epoetin beta), Silapo® (epoetin zeta), Binocrit® (epoetin alfa), epoetin alfa Hexal, Abseamed® (epoetin alfa), Ratioepo® (epoetin theta), Eporatio® (epoetin theta), Biopoin® (epoetin theta), epoetin alfa, epoetin beta, epoetin zeta, epoetin theta, and epoetin delta, as well as the molecules or variants or analogs thereof as disclosed in the following patents or patent applications: <CIT>; <CIT>; <CIT>; <CIT>: <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; and <CIT>; and <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; and <CIT>.

An ESA can be an erythropoiesis stimulating protein. As used herein, "erythropoiesis stimulating protein" means any protein that directly or indirectly causes activation of the erythropoietin receptor, for example, by binding to and causing dimerization of the receptor. Erythropoiesis stimulating proteins include erythropoietin and variants, analogs, or derivatives thereof that bind to and activate erythropoietin receptor; antibodies that bind to erythropoietin receptor and activate the receptor; or peptides that bind to and activate erythropoietin receptor. Erythropoiesis stimulating proteins include, but are not limited to, epoetin alfa, epoetin beta, epoetin delta, epoetin omega, epoetin iota, epoetin zeta, and analogs thereof, pegylated erythropoietin, carbamylated erythropoietin, mimetic peptides (including EMP1/hematide), and mimetic antibodies. Exemplary erythropoiesis stimulating proteins include erythropoietin, darbepoetin, erythropoietin agonist variants, and peptides or antibodies that bind and activate erythropoietin receptor (and include compounds reported in <CIT> and <CIT>) as well as erythropoietin molecules or variants or analogs thereof as disclosed in the following patents or patent applications: <CIT>; <CIT>; <CIT>; <CIT>: <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; and <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; and <CIT>; and <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; and <CIT>.

Examples of other pharmaceutical products for use with the device may include, but are not limited to, antibodies such as Vectibix® (panitumumab), Xgeva™ (denosumab) and Prolia™ (denosamab); other biological agents such as Enbrel® (etanercept, TNF-receptor /Fc fusion protein, TNF blocker), Neulasta® (pegfilgrastim, pegylated filgastrim, pegylated G-CSF, pegylated hu-Met-G-CSF), Neupogen® (filgrastim , G-CSF, hu-MetG-CSF), and Nplate® (romiplostim); small molecule drugs such as Sensipar® (cinacalcet). The device may also be used with a therapeutic antibody, a polypeptide, a protein or other chemical, such as an iron, for example, ferumoxytol, iron dextrans, ferric glyconate, and iron sucrose. The pharmaceutical product may be in liquid form, or reconstituted from lyophilized form.

Among particular illustrative proteins are the specific proteins set forth below, including fusions, fragments, analogs, variants or derivatives thereof:.

OPGL specific antibodies, peptibodies, and related proteins, and the like (also referred to as RANKL specific antibodies, peptibodies and the like), including fully humanized and human OPGL specific antibodies, particularly fully humanized monoclonal antibodies, including but not limited to the antibodies described in PCT Publ. No. <CIT>, as to OPGL specific antibodies and antibody related proteins, particularly those having the sequences set forth therein, particularly, but not limited to, those denoted therein: 9H7; 18B2; 2D8; 2E11; 16E1; and 22B3, including the OPGL specific antibodies having either the light chain of SEQ ID NO: <NUM> as set forth therein in <FIG> and/or the heavy chain of SEQ ID NO:<NUM>, as set forth therein in <FIG>;.

Myostatin binding proteins, peptibodies, and related proteins, and the like, including myostatin specific peptibodies, particularly those described in <CIT> and <CIT>, particularly in parts pertinent to myostatin specific peptibodies, including but not limited to peptibodies of the mTN8-<NUM> family, including those of SEQ ID NOS: <NUM>-<NUM>, including TN8-<NUM>-<NUM> through TN8-<NUM>-<NUM>, TN8-<NUM> con1 and TN8-<NUM> con2; peptibodies of the mL2 family of SEQ ID NOS: <NUM>-<NUM>; the mL15 family of SEQ ID NOS: <NUM>-<NUM>; the mL17 family of SEQ ID NOS: <NUM>-<NUM>; the mL20 family of SEQ ID NOS: <NUM>-<NUM>; the mL21 family of SEQ ID NOS: <NUM>-<NUM>; the mL24 family of SEQ ID NOS: <NUM>-<NUM>; and those of SEQ ID NOS: <NUM>-<NUM>;.

IL-<NUM> receptor specific antibodies, peptibodies, and related proteins, and the like, particularly those that inhibit activities mediated by binding of IL-<NUM> and/or IL-<NUM> to the receptor, including those described in PCT Publ. No. <CIT> or PCT Appl. No. <CIT> and in <CIT>, particularly in parts pertinent to IL-<NUM> receptor specific antibodies, particularly such antibodies as are described therein, particularly, and without limitation, those designated therein: L1H1; L1H2; L1H3; L1H4; L1H5; L1H6; L1H7; L1H8; L1H9; L1H10; L1H11; L2H1; L2H2; L2H3; L2H4; L2H5; L2H6; L2H7; L2H8; L2H9; L2H10; L2H11; L2H12; L2H13; L2H14; L3H1; L4H1; L5H1; L6H1;.

Interleukin <NUM>-receptor <NUM> ("IL1-R1") specific antibodies, peptibodies, and related proteins, and the like, including but not limited to those described in <CIT>, in parts pertinent to IL1-R1 specific binding proteins, monoclonal antibodies in particular, especially, without limitation, those designated therein: 15CA, 26F5, 27F2, 24E12, and 10H7;.

Ang2 specific antibodies, peptibodies, and related proteins, and the like, including but not limited to those described in <CIT> and <CIT>, particularly in parts pertinent to Ang2 specific antibodies and peptibodies and the like, especially those of sequences described therein and including but not limited to: L1(N); L1(N) WT; L1(N) <NUM> WT; 2xL1(N); 2xL1(N) WT; Con4 (N), Con4 (N) <NUM> WT, 2xCon4 (N) <NUM>; L1C; L1C <NUM>; 2xL1C; Con4C; Con4C <NUM>; 2xCon4C <NUM>; Con4-L1 (N); Con4-L1C; TN-<NUM>-<NUM> (N); C17 (N); TN8-<NUM>(N); TN8-<NUM> (N); Con <NUM> (N), also including anti-Ang <NUM> antibodies and formulations such as those described in PCT Publ. No. <CIT>, particularly Ab526; Ab528; Ab531; Ab533; Ab535; Ab536; Ab537; Ab540; Ab543; Ab544; Ab545; Ab546; A551; Ab553; Ab555; Ab558; Ab559; Ab565; AbF1AbFD; AbFE; AbFJ; AbFK; AbG1D4; AbGC1E8; AbH1C12; AblA1; AblF; AblK, AblP; and AblP, in their various permutations as described therein,.

NGF specific antibodies, peptibodies, and related proteins, and the like including, in particular, but not limited to those described in <CIT> and <CIT>, particularly as to NGF-specific antibodies and related proteins in this regard, including in particular, but not limited to, the NGF-specific antibodies therein designated 4D4, 4G6, 6H9, 7H2, 14D10 and 14D11,.

CD22 specific antibodies, peptibodies, and related proteins, and the like, such as those described in <CIT>, as to CD22 specific antibodies and related proteins, particularly human CD22 specific antibodies, such as but not limited to humanized and fully human antibodies, including but not limited to humanized and fully human monoclonal antibodies, particularly including but not limited to human CD22 specific IgG antibodies, such as, for instance, a dimer of a human-mouse monoclonal hLL2 gamma-chain disulfide linked to a human-mouse monoclonal hLL2 kappa-chain, including, but limited to, for example, the human CD22 specific fully humanized antibody in Epratuzumab, <NPL>;.

IGF-<NUM> receptor specific antibodies, peptibodies, and related proteins, and the like, such as those described in PCT Publ. No. <CIT>, as to IGF-<NUM> receptor specific antibodies and related proteins, including but not limited to the IGF-<NUM> specific antibodies therein designated L1H1, L2H2, L3H3, L4H4, L5H5, L6H6, L7H7, L8H8, L9H9, L10H10, L11H11, L12H12, L13H13, L14H14, L15H15, L16H16, L17H17, L18H18, L19H19, L20H20, L21H21, L22H22, L23H23, L24H24, L25H25, L26H26, L27H27, L28H28, L29H29, L30H30, L31H31, L32H32, L33H33, L34H34, L35H35, L36H36, L37H37, L38H38, L39H39, L40H40, L41H41, L42H42, L43H43, L44H44, L45H45, L46H46, L47H47, L48H48, L49H49, L50H50, L51H51, L52H52, and IGF-1R-binding fragments and derivatives thereof,.

Also among non-limiting examples of anti-IGF-1R antibodies for use in the methods and compositions of the present invention are each and all of those described in:.

Also included can be a sclerostin antibody, such as but not limited to romosozumab, blosozumab, or BPS <NUM> (Novartis). Further included can be therapeutics such as rilotumumab, bixalomer, trebananib, ganitumab, conatumumab, motesanib diphosphate, brodalumab, vidupiprant, panitumumab, denosumab, NPLATE, PROLIA, VECTIBIX or XGEVA. Additionally, included in the device can be a monoclonal antibody (IgG) that binds human Proprotein Convertase Subtilisin/Kexin Type <NUM> (PCSK9), e.g. <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, and <CIT>.

Also included can be talimogene laherparepvec or another oncolytic HSV for the treatment of melanoma or other cancers. Examples of oncolytic HSV include, but are not limited to talimogene laherparepvec (<CIT> and <CIT>); OncoVEXGALV/CD (<CIT>); OrienX010 (<NPL>); G207, <NUM>; NV1020,;NV12023; NV1034 and NV1042 (<NPL>).

Also included are TIMPs. TIMPs are endogenous tissue inhibitors of metalloproteinases (TIMPs) and are important in many natural process. TIMP-<NUM> is expressed by various cells or and is present in the extracellular matrix; it inhibits all the major cartilage-degrading metalloproteases, and may play a role in role in many degradative diseases of connective tissue, including rheumatoid arthritis and osteoarthritis, as well as in cancer and cardiovascular conditions. The amino acid sequence of TIMP-<NUM>, and the nucleic acid sequence of a DNA that encodes TIMP-<NUM>, are disclosed in <CIT>. Description of TIMP mutations can be found in <CIT>, <CIT>, <CIT>, and <CIT>.

Also included are antagonistic antibodies for human calcitonin gene-related peptide (CGRP) receptor and bispecific antibody molecule that target the CGRP receptor and other headache targets. Further information concerning these molecule can be found in WO2A075238A1.

Claim 1:
A subassembly comprising:
a container (<NUM>) including a container wall (<NUM>) with an interior surface (<NUM>), wherein the container wall (<NUM>) defines a bore (<NUM>);
a seal assembly (<NUM>) including a flexible seal assembly wall (<NUM>) with an interior surface (<NUM>), the interior surfaces (<NUM>, <NUM>) of the container wall (<NUM>) and the seal assembly (<NUM>) defining a closed sterile reservoir (<NUM>) filled with medical fluid or drug product, and a barrier (<NUM>) disposed exterior of the flexible seal assembly wall (<NUM>) to define an enclosed space (<NUM>) between the flexible seal assembly wall (<NUM>) and the barrier (<NUM>)
a fluid delivery system (<NUM>) comprising a container needle (<NUM>) having a point (<NUM>) disposed only through the barrier (<NUM>) in a storage state such that the container needle (<NUM>) is not in fluid communication with the reservoir (<NUM>), and disposed through the flexible seal assembly wall (<NUM>) into the reservoir (<NUM>) in a delivery state such that the container needle (<NUM>) is in fluid communication with the reservoir (<NUM>);
the container needle (<NUM>) attached to a first connector (<NUM>) of a pair of connectors (<NUM>, <NUM>), a second connector (<NUM>) mechanically coupled to the container (<NUM>), and the first and second of the pair of connectors (<NUM>, <NUM>) mechanically coupled to secure the container needle (<NUM>) to the container (<NUM>) with the container needle (<NUM>) in the storage state, characterized in that
the barrier (<NUM>) and the flexible seal assembly wall (<NUM>) define the enclosed space (<NUM>) in both the storage state and the delivery state, and
the subassembly further comprises an actuator (<NUM>) adapted to move the container needle (<NUM>) from the storage state to the delivery state.