TRANSFER STATION FOR API SEED CRYSTALS

Abstract

The present disclosure is directed to a big-bag transfer station for API seed crystals. The transfer station may permit the filling of smaller containers, such as bags or pouches, from a large container, such as a big bag. The transfer station may permit the transfer without contaminating the atmosphere of the room in which the station is housed. Additionally, the transfer station may limit cross-contamination between filling cycles by employing single-use liners.

Claims

1. An apparatus for the transfer of a biological or pharmaceutical product comprising: a flexible feed sleeve having a first end and a second and opposite end, the flexible feed sleeve defining a tubular passage extending from the first end to the second end, the first end of the flexible feed sleeve being configured to attach to an adjacent structure for receiving the flow of a biological or pharmaceutical product; a piping assembly defining a conduit from a first end to a second end, the second end of the flexible feed sleeve surrounding and being secured to the first end of the piping assembly, the second end of the piping assembly being configured to be in fluid communication with a container for receiving a biological or pharmaceutical product; and a flexible conduit liner that lines the conduit of the piping assembly, the flexible conduit liner being positioned such that a biological or pharmaceutical product flowing through the piping assembly only contacts the flexible conduit liner and prevents contact with a surface of the piping assembly, the flexible conduit liner being removable and replaceable within the piping assembly.

2. An apparatus as defined in claim 1, wherein the piping assembly further includes an access port located along the conduit for periodically removing the flexible feed sleeve or the flexible conduit liner and wherein the access port is surrounded by a flexible containment bag, the flexible containment bag for collecting contaminated components contained within the conduit of the piping assembly.

3. (canceled)

4. (canceled)

5. An apparatus as defined in claim 2, wherein the flexible containment bag includes a continuous supply of flexible material such that multiple individual bags can be formed from the continuous supply.

6. An apparatus as defined in claim 5, wherein the flexible containment bag is configured to extend into the conduit of the piping assembly for collecting contaminated components, and then is configured to be inverted and crimped and sealed for forming individual containment bags.

7. An apparatus as defined in claim 1, further comprising a feed neck collar configured to engage a feed neck of a dispensing container, the first end of the flexible feed sleeve being removably secured to the feed neck collar wherein the feed neck collar comprises an inner ring that cooperates with an outer ring, and wherein the feed neck of a dispensing container is configured to be engaged by the feed neck collar in between the inner ring and the outer ring.

8. An apparatus as defined in claim 1, further comprising a flow control device for controlling flow of a biological or pharmaceutical product from a dispensing container into the piping assembly, the flow control device being configured to be positioned adjacent to an exterior surface of a feed neck of a dispensing container and being configured to constrict the feed neck for controlling flow of a biological or pharmaceutical product.

9. An apparatus as defined in claim 8, wherein the flow control device comprises an iris valve.

10. (canceled)

11. (canceled)

12. (canceled)

13. (canceled)

14. (canceled)

15. (canceled)

16. (canceled)

17. (canceled)

18. A method for transferring a biological or pharmaceutical product from a dispensing container to a receiving container comprising: flowing a biological or pharmaceutical product from a dispensing container through a sealed conduit to a receiving container, the sealed conduit including a rigid section, the rigid section being lined by a flexible conduit liner, the flexible conduit liner including a first end and a second and opposite end, the flexible conduit liner preventing the biological or pharmaceutical product from contacting a surface of the rigid section; containing residual biological or pharmaceutical product within the flexible conduit liner after flow of the biological or pharmaceutical product has ceased; and removing the flexible conduit liner from the conduit without releasing the contained residual biological or pharmaceutical product from within the flexible conduit liner.

19. A method as defined in claim 18, wherein the step of containing residual biological or pharmaceutical product within the flexible conduit liner includes at least one of: sealing the first end of the flexible conduit liner; sealing the second end of the flexible conduit liner; and sealing an access port of the flexible conduit liner.

20. A method as defined in claim 18, wherein the sealed conduit further includes a flexible feed sleeve that extends from the dispensing container to the rigid section of the conduit, and wherein the biological or pharmaceutical product flows through the flexible feed sleeve into the rigid section of the conduit, and wherein the method further includes the steps of: after flow of the biological or pharmaceutical product has ceased, crimping the used flexible feed sleeve at an intermediate section and separating the flexible feed sleeve into two parts wherein each part includes a sealed end where the flexible feed sleeve has been crimped; inserting a second and unused flexible feed sleeve between the two separate parts of the used flexible feed sleeve and extending the second flexible feed sleeve over each part of the used flexible feed sleeve such that the second flexible feed sleeve extends from the dispensing container to the rigid section of the conduit; and removing the separated parts of the used flexible feed sleeve from within the second flexible feed sleeve without permitting release of a residual biological or pharmaceutical product.

21. A method as defined in claim 20, wherein the conduit includes an access port, the access port being covered by a flexible containment bag, and wherein the flexible containment bag is inserted into the conduit for enveloping and removing at least one part of the used flexible feed sleeve.

22. A method as defined in claim 20, wherein the method includes the steps of: inserting the flexible containment bag into the conduit for enveloping a part of the used flexible feed sleeve; and inverting, crimping and sealing the flexible containment bag with the part of the flexible feed sleeve contained inside.

23. A method as defined in claim 21, wherein the flexible containment bag includes a continuous supply of flexible material such that multiple individual bags can be formed from the continuous supply and wherein the flexible containment bag also envelops and removes the flexible conduit liner after flow of the biological or pharmaceutical product has ceased.

24. (canceled)

25. A method as defined in claim 21, wherein the flexible conduit liner envelops a portion of the flexible containment bag after flow of the biological or pharmaceutical product has ceased.

26. (canceled)

27. A method for the transfer of a biological or pharmaceutical product comprising: feeding a biological or pharmaceutical product from a dispensing container through a sealed conduit; constricting the sealed conduit wherein the constriction forms a seal between two portions of the sealed conduit; severing the sealed conduit to form two severed portions of the sealed conduit, wherein at least one of the two severed portions forms an internal seal within the sealed conduit; installing a replacement portion of the sealed conduit over at least one of the constricted severed portions; and removing at least one of the constricted severed portions from within the replacement portion.

28. A method as defined in claim 27, wherein the replacement portion of the sealed conduit is placed over both of the constricted severed portions.

29. A method as defined in claim 27, wherein the sealed conduit comprises a flexible feed sleeve, the flexible feed sleeve being constricted and severed into two portions.

30. A method as defined in claim 29, wherein the sealed conduit further comprises a piping assembly, the flexible feed sleeve being connected to the piping assembly for allowing the flow of the biological or pharmaceutical product therethrough.

31. A method as defined in claim 30, wherein the piping assembly defines an access port, the access port being covered by a flexible containment bag, and wherein the method further includes the step of extending the flexible containment bag into the sealed conduit from the access port for enveloping and removing at least one of the constricted severed portions.

32. A method as defined in claim 29, wherein the piping assembly is lined by a flexible conduit liner that prevents contact between the biological or pharmaceutical product and a surface of the piping assembly, and wherein the liner is removed from the piping assembly after flow of the biological or pharmaceutical product has ceased.

33-42. (canceled)

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0017] A full and enabling disclosure of the present disclosure is set forth more particularly in the remainder of the specification, including reference to the accompanying figures.

[0018] FIG. 1 illustrates one aspect of a transfer station.

[0019] FIG. 2 illustrates another aspect of a transfer station.

[0020] FIG. 3 illustrates a section view of one aspect of a transfer station.

[0021] FIG. 4 illustrates a section view of another aspect of a transfer station.

[0022] FIG. 5 illustrates one aspect of the neck of a big bag.

[0023] FIG. 6 illustrates one aspect of the neck of a big bag.

[0024] FIG. 7 illustrates one aspect of the neck of a big bag.

[0025] FIG. 8 illustrates one aspect of the feed sleeve.

[0026] FIG. 8 illustrates one aspect of the feed sleeve.

[0027] FIG. 9 illustrates a section view of one aspect of a transfer station.

[0028] FIG. 10 illustrates a section view of another aspect of a transfer station.

[0029] FIG. 11 illustrates a section view of another aspect of a transfer station in a first position.

[0030] FIG. 12 illustrates one aspect of a transfer station in a first position.

[0031] FIG. 13 illustrates a section view of another aspect of a transfer station in a second position.

[0032] FIG. 14 illustrates one aspect of a transfer station in a second position.

[0033] FIG. 15 illustrates a section view of one aspect of a container for a transfer station.

[0034] FIG. 16 illustrates a section view of one aspect of a transfer station.

[0035] FIG. 17 illustrates a section view of one aspect of a transfer station.

[0036] FIG. 18 illustrates one aspect of a transfer station.

[0037] FIG. 19 illustrates a section view of one aspect of a transfer station.

[0038] FIG. 20 illustrates a section view of one aspect of a transfer station.

[0039] FIG. 21 illustrates a section view of one aspect of a transfer station.

[0040] FIG. 22 illustrates one aspect of a transfer station.

[0041] FIG. 23 illustrates a section view of one aspect of a transfer station.

[0042] FIG. 24 illustrates one aspect of a transfer station.

[0043] FIG. 25 illustrates a section view of one aspect of a transfer station.

[0044] FIG. 26 illustrates one aspect of a transfer station.

[0045] FIG. 27 illustrates a section view of one aspect of a transfer station.

[0046] FIG. 28 illustrates one aspect of a transfer station.

[0047] FIG. 29 illustrates a section view of one aspect of a transfer station.

[0048] FIG. 30 illustrates a section view of one aspect of a transfer station.

[0049] Although various features may be depicted in separate figures, it is to be understood that various features represented in separate figures may be advantageously combined into a single aspect. Repeat use of reference characters in the present specification and drawings is intended to represent the same or analogous features or elements of the present invention.

DETAILED DESCRIPTION

[0050] It is to be understood by one of ordinary skill in the art that the present discussion is a description of exemplary aspects only and is not intended as limiting the broader aspects of the present disclosure.

[0051] In general, the present disclosure is directed to a transfer station for powdery substances, such as active pharmaceutical ingredient (API) seed crystals.

[0052] Of particular advantage, the transfer station as disclosed herein offers particulate containment within mandated occupational exposure limits, such as less than about 0.01 mg/m.sup.3, such as less than about 0.001 mg/m.sup.3, such as less than about 0.0001 mg/m.sup.3, even down to essentially complete containment (about 0 mg/m.sup.3). High levels of containment may advantageously reduce and eliminate the extensive decontamination and cleaning processes required after a product changeover.

[0053] In an additional advantageous aspect, good containment levels may be maintained without relying upon personal protection equipment (PPE) requirements and biocontainment protocols.

[0054] Of additional advantage, a transfer station prepared as herein may reduce the risk of product cross-contamination in some aspects.

[0055] In one aspect, the transfer station of the present disclosure receives a powdery component from at least one feed container or dispensing container, such as from a big bag as is commonly used to store and transport pharmaceutical components, especially in a bulk capacity. Some exemplary bags do not have a particular structure or frame to preserve the shape of the bag, forming a flexible or semi-rigid sack. In some aspects, the bags may have an inner layer and an outer layer, wherein the inner layer is a polymer film (i.e., a liner).

[0056] Some aspects may employ a frame for holding a feed container in a suitable posture for transfer. In some examples, the bags may be elevated, such as hung from a wall, ceiling, or free-standing structure, such as in FIG. 1. In one example, the frame may have a plurality of legs. A platform 110 may support a feed container on top of the frame.

[0057] A neck or spout protruding from the feed container may pass through a neck ring for passage into additional components of the transfer station. In some examples, the neck is integrated into the feed container structure, and in other examples, the neck is added onto an existing feed container for use with a transfer station prepared as disclosed herein.

[0058] In one aspect, the frame also includes an alignment ring 108. The alignment ring may, for example, align subcomponents of the transfer station with the neck ring of the frame platform while providing structural support. For example, FIG. 1 depicts one aspect of a transfer station 100 wherein a feed container 102, transfer system 104, and fill container 106 are aligned by the alignment ring 108.

[0059] The bag frame may form a housing or structure for the entire transfer station as disclosed herein, such as in FIG. 1. Bag frames may, in some aspects, hold one or more bags and one or more transfer stations. For example, a single frame may contain multiple transfer stations, such as 2, 3, 4, 5, or 10, or more, to facilitate a compact floor plan.

[0060] One aspect of a transfer station is depicted in FIG. 2. A container, such as a big bag 102, is hoisted over the frame 110 and into alignment with the transfer system 104. Of particular advantage, the components of the transfer system supported by the frame 110 may form an integrated unit while different bags 102 are installed or removed. For instance, the transfer station frame 110 may be fixed in place and, in some cases, the fill container 106 may be filled without any additional handling or manipulation of the fill container 106 itself. In another aspect, the transfer station frame 110 and an associated container 102 may be mobile and, in some cases, may be relocated adjacent to various fill containers 106 which may be located in the same or different locations. In this manner, the transfer station of the present disclosure affords great flexibility.

[0061] In one aspect, a feed neck 302 extending from the feed container is manipulated by a flow control device as shown in FIG. 3. The feed neck may optionally be a liner within the container, such as a polymer film liner within a big bag. In one example, the feed neck may be fed through an iris valve 304. The iris valve 304 may impinge upon an exterior surface of the feed neck 302 to control flow of a powdery component; the web 306 of the iris valve 304 wraps around the feed neck 302 and constricts the passageway therein. One advantage of manipulating the flow entirely external to the passageway of the flow is that the flow control device does not compromise the integrity of the passageway boundary.

[0062] The flow control device may be manually actuated or may be automated, optionally in conjunction with a mass control system. For example, a mass control system could, in some aspects, sense the change in mass of the feed container, the fill container, or both and control the flow control device to achieve a particular target change in mass.

[0063] The feed neck extending from the feed container may, in some aspects, be captured by a feed neck collar.

[0064] Captivity, as used herein, generally indicates a mechanically secure relationship. In some cases, capture may reflect a sealed relationship at the joint between two components. In some examples, a gasket, such as an o-ring, may be captured within a groove, lip, or slot; a sheet or film may be captured within a clamp, crimping device, or underneath an elastic element; an elastic band, such as an elastic o-ring, may be captured by friction forces on the outside of an object encompassed by the band. Additionally, capture may reflect the use of a temporary or permanent adhesive, such as a chemical adhesive or a thermal bond (e.g., weld). Elements may be captured by distinct other elements, or, in some cases, elements may contain an integral feature, such as an elastic gasket, which permit self-capture against other elements. It is to be understood that although some elements are described as being captured by other elements, each element may, in some aspects, be responsible for the capturing, and the method of capture may be adapted or reconfigured while remaining within the scope of the present disclosure.

[0065] Furthermore, with regard to elements which are described as captured, secured, coupled, or otherwise engaged with another element, it is to be understood that said elements may be arranged in a permanent configuration or, alternatively, in a removable configuration.

[0066] In one example, the feed neck extending from the feed container may be captured by a feed neck collar as shown in FIG. 3. For example, the distal end of the feed neck may be partially inverted as shown in FIG. 3 to pass inside an inner ring 308 and also be captured between the inner ring 308 and an outer ring 312 by a gasket 310. Any suitable gasket member may be used as a gasket as a gasket 310, including, for example, elastic gaskets, rigid gaskets, semi-rigid gaskets, single-use gaskets, and reusable gaskets. The gasket 310 may, in some aspects, be at least partially captive within a recessed channel or groove, such as within the outer ring 312 shown in FIG. 3. In some cases, an outer ring 312 includes a cinching or clasping mechanism to compress the gasket 310 between the feed neck and the inner ring 308.

[0067] A feed sleeve 314, such as a flexible feed sleeve, may contain a gasket member 316 on a first end of the flexible feed sleeve and be captured by the feed neck collar. In FIG. 3, the feed neck collar captures the feed sleeve 314 by the friction of the elastic gasket 316 on the outer ring 312. However, in some examples, one or more grooves, which may be directly adjacent or spaced apart, may be provided for the secure capture of one or more gaskets 316.

[0068] In another example in FIG. 4, the outer ring 312 is not used at all, and the inner ring 308 is extended to have a sloped recess on its exterior surface so that any gasket 316 placed around the circumference of the inner ring 308 will settle into the same location, providing a seal for both the feed neck 302 and the feed sleeve 314. In other aspects, the sloped recess may be employed in a similar manner on the exterior of the outer ring 312. In other aspects, the inner ring 308 may further contain grooves for additional gaskets or clamps to individually secure the feed neck 302 to the inner ring 308. Aspects may also provide clamps around the feed sleeve gasket 316 to increase the strength of the seal.

[0069] In one aspect, the feed neck 302 is as shown in FIG. 5. In particular, a big bag 102 may have multiple layers, and the feed neck 302 may comprise a polymer film liner of the bag 102. As shown in FIG. 6, the feed neck 302 may pass through the interior of an inner ring 308 and invert, as is similarly shown in section view in FIG. 3. A gasket 310 may be placed around the inner ring 308 to capture the feed neck 302 against the inner ring 308, as shown in FIG. 7.

[0070] In one instance, the outer ring 312 is positioned around the inner ring 308 as shown in FIG. 8. The outer ring 312, in the pictured aspect, contains two grooves which capture the feed sleeve gasket 316 in an upper groove and a remnant gasket 318 in a lower groove. In some aspects, the remnant may be removed, vacating the lower groove containing the remnant gasket 318. Accordingly, the feed sleeve gasket may be shifted down to the lower groove previously occupied by the remnant gasket 318. In some aspects, additional sleeves or gaskets may be attached to the outer ring 312 into the upper groove such that the cycle may be repeated.

[0071] In this manner, a sealed conduit may be created between the interior of the feed container and the feed sleeve. In some aspects, such as more compact aspects, the exterior surface of the flow control device (e.g., the iris valve) may act as the feed neck collar, as in FIG. 10.

[0072] The aspect in FIG. 9 demonstrates the flexibility of the presently disclosed transfer station. For instance, the flow control device may be any variety of implement which can control flow from the exterior of the of the flow passageway. In FIG. 9, the flow control device comprises a set of parallel bars 402 situated around the feed sleeve 314. At least one parallel bar 402 may be controlled to compress the feed sleeve 314 between the two parallel bars. In this manner, the feed neck 302 of a feed container 202 may be integrated into the feed neck collar and provide a more compact aspect, wherein the feed sleeve gasket 316 is captured directly on the feed neck 302. Such an example may be useful when the feed container 202 is a rigid container, such as a drum. The feed neck 302 may then be, for example, affixed to the drum, such as by threading, without using a flexible feed neck.

[0073] In general, when the flow control device 304 is opened, as in FIG. 10, a sealed conduit is formed between the feed neck 302 and the feed sleeve 314. In the interest of containing the powdery component, two atmospheres may be distinguished: a room atmosphere 502 and a contaminated atmosphere 504. The captivity of the feed sleeve 314 and the feed neck 302 to the feed neck collar maintains an uncompromised barrier between the room atmosphere 502 and the contaminated atmosphere 504.

[0074] The room atmosphere 502 is generally the ambient atmosphere in which the operators of the transfer station are present. In some cases, the exterior of the container from which the powder is being transferred is exposed to the room atmosphere. In general, the room atmosphere maintains low particle counts of the powder being transferred, such as within mandated occupational exposure limits (measured according to guidelines such as CEN EN 689 and/or TRGS 402), such as less than about 0.01 mg/m.sup.3, such as less than about 0.001 mg/m.sup.3, such as less than about 0.0001 mg/m.sup.3, even down to essentially a complete absence of the powder (about 0 mg/m.sup.3). On the other hand, the contaminated atmosphere 504 exists within the transfer system and comprises the gas (e.g., air) and other components (e.g., films, gaskets, liners, etc.) which have contacted at least one of (i) the bulk powder itself (e.g., in the bag or bags) or (ii) surfaces which the bulk powder has directly contacted (e.g., the various sleeves and/or liners), including surfaces subject to ancillary powder exposure (e.g., liners within adjacent accesses as described herein). In general, the two atmospheres described herein are distinct, even if the atmospheres are in fluid communication via a filtration device. For instance, the contaminated atmosphere may exhaust into the room atmosphere through a filtration device in some aspects, maintaining the distinction between the unfiltered, contaminated atmosphere and the room atmosphere. In some examples, the atmospheres may be distinguished by physical location (e.g., within the transfer system) or by particulate concentration.

[0075] In one aspect, the flexible feed sleeve 314 forms a tubular passage extending from the first end to a second and opposite end which may be connected, coupled, secured, or otherwise engaged with a first end of a piping assembly. For instance, a product may pass through the sealed conduit formed by the feed neck 302 and the feed sleeve 314 into a piping assembly for further processing or for transport. The piping assembly is generally rigid or semi-rigid. For example, as shown in FIG. 11, a product may pass into a piping assembly inlet 602 to be directed to a packaging device. For example, as shown in FIG. 11, the piping assembly inlet 602 and the captured end of the feed neck 302 are spaced a distance apart, forming a gap spanned by the feed sleeve 314. In some aspects, the feed neck collar and the piping assembly inlet 602 may be mounted on a moving assembly. In other aspects, the feed neck collar may be suspended by the flexible feed neck of the bag while the piping assembly inlet 602 is rigidly affixed to a frame.

[0076] As shown in FIG. 12, the feed sleeve 314 forms a sealed, optionally tubular, conduit between the feed neck (shown inside the outer ring 312) and the piping assembly inlet 602. Additionally, the feed sleeve 314 passes through an iris valve 304. While the flow control device may act on the exterior of the feed sleeve in some aspects, the flow control device may also constrict the feed neck.

[0077] For instance, the components may be brought together to form an annular contact point 604, as shown in FIG. 13, by passing the outer ring 312 through the flow control device 304 to be adjacent to the first end of the piping assembly. The contact point 604 may prevent, for example, any powdery component from escaping through the aforementioned gap between the feed neck and the piping assembly and accumulating outside the piping assembly inlet 602 and inside the feed sleeve 314. In one aspect, the components may be clamped or otherwise temporarily affixed in the adjacent position. For example, one clamped arrangement is shown in FIG. 12. For instance, the clamp may comprise a sliding plate 606 (optionally sprung and/or damped) which applies even pressure across the top of the outer ring 312 to form a secure seal at the contact point 604.

[0078] The moving assembly may be activated manually or may be automated in part or in whole. For example, the feed neck collar, the piping assembly, or both may be configured to slide between the configurations shown in FIGS. 11-14. The relative motion between the feed neck collar and the piping assembly may cause deformation of the feed sleeve. For instance, in one aspect, the flexible feed sleeve may collapse along the axis of motion as the feed neck collar and the piping assembly move toward each other, while the flexible feed sleeve may extend as the feed neck collar and the piping assembly move away from each other.

[0079] In some examples, mechanical or electromechanical controls may prevent the flow control device 304 from being opened unless the contact point 604 is formed securely. The contact point 604 may be any variety of surface, such as a sealing flange. In some examples, the contact point 604 may include a gasket. In some aspects, the feed neck collar is configured to mate or otherwise engage with the piping assembly inlet 602 to increase the security of the contact point 604 (e.g., with grooves, tapers, interlocking components, or otherwise).

[0080] After the powdery component passes through the piping assembly inlet 602, some aspects may direct the powder to a packaging device which is in fluid communication with the piping assembly. Fluid communication, in this context, also indicates the fluid-like flow of a powder or powdery component. In some examples, such as shown in FIG. 15, a piping assembly outlet 702 located at a second end of the piping assembly may direct powder though a fill sleeve and into a container. In some examples, the fill sleeve forms a container, such as a fill bag 704. The fill bag 704 may contain a gasket 706 captured around the piping assembly outlet 702.

[0081] A fill bag may include any variety of bag, sack, container, or continuous (endless) liner. For example, a polymer bag or sack may be filled, having a variety of volumes, such as greater than about 1 mL, such as greater than about 10 mL, such as greater than about 100 mL, such as greater than about 1 L, such as greater than about 10 L, such as greater than about 100 L, such as greater than about 1000 L, such as greater than about 10000 L. In some aspects, the bag or sack volume may be less than about 10000 L, such as less than about 1000 L, such as less than about 100 L, such as less than about 10 L, such as less than about 1 L, such as less than about 100 mL, such as less than about 10 mL, such as less than about 1 mL, although it is contemplated that the transfer station of the present disclosure is suitable for the filling of containers of any size. Containers may include rigid drums or any other rigid or semi-rigid vessel with or without a liner, having similar volumes to a bag or a sack as above. Continuous liners may be used in some examples where individual product volumes are defined by pressing, crimping, or otherwise sealing (adhering) two portions of the liner together to form one end of a first defined volume. After a product is deposited within the liner above the sealed portion, a second end of the defined volume is formed by pressing, crimping, or otherwise sealing a second two portions of the liner together. A first sealed volume containing the product is thus created between the first and second sealed portions. The second sealed portion may form one end of a second defined volume for the storage of additional product in a second sealed volume.

[0082] In some aspects, at least one fill bag gasket 706 is applied external to the bag itself. In other aspects, at least one fill bag gasket 706 is integral to the bag, such as welded to or captured within a fringe or hem of the bag opening. Selection of external gaskets, integral gaskets, or both may permit reusability (e.g., with external gaskets) or single-use (e.g., with integral gaskets).

[0083] Just as the feed sleeve 314 may provide a sealed conduit between the feed neck 302 and the piping assembly inlet 602, a fill sleeve may provide a sealed conduit between the piping assembly outlet 702 and a container, chute, or conduit. For example, a rigid container, in some aspects, may have a fill container collar analogous to the feed neck collar, and a fill sleeve may be captive to both the piping assembly outlet and the fill container collar, analogous to how the feed sleeve 314 may be captive to both the feed neck collar and the piping assembly inlet 602.

[0084] In some aspects, after a container is filled, the feed sleeve 314 is contaminated and is desired to be replaced without exposing the room atmosphere 502 to the contaminated atmosphere 504. To this end, the feed sleeve may be crimped, such as with a crimp ring 802 as shown in FIG. 16. The crimp ring 802 divides the feed sleeve into two portions: an upper remnant 314-1 and a lower remnant 314-2. The crimp ring 802 may be cut or otherwise subdivided into an upper crimp 802-1 attached to the upper remnant 314-1 and a lower crimp 802-2 attached to the lower remnant 314-2, as shown in FIG. 17 and FIG. 18. The upper and lower crimps contain the contaminated atmosphere 504 within the respective remnants. After the crimp ring 802 has been severed, or subdivided, a new feed sleeve 804 may be situated over the upper and lower remnants, surrounding both the remnants and the gaskets of the remnants, as shown in FIG. 17. The gaskets of the new feed sleeve 804 may also be captive to the feed neck collar and the piping assembly inlet, sealing off the remnants from the room atmosphere 502.

[0085] In a similar fashion, some aspects employing a contaminated fill sleeve may be crimped, subdivided, and subsequently enveloped by a new fill sleeve. In some examples, after subdividing the crimp ring on the fill sleeve, the filled container to which the lower remnant of the fill sleeve is attached may be removed and a new container may be put in its place. Subsequently, the new fill sleeve may be captured by the piping assembly outlet and the fill container collar, such as a collar on a new container, sealing off the new container from the room atmosphere 502. Additionally, the filled container remains sealed from the room atmosphere 502 by the lower remnant and may be suitable for further handling or packaging steps.

[0086] Additionally or alternatively, aspects with a fill bag 704 may be handled as shown in FIG. 19. The fill bag may be crimped, such as with a crimp ring 802, forming an upper remnant 704-1 and a lower filled remnant 704-2. When the crimp ring 802 is subdivided into an upper crimp 802-1 and a lower crimp 802-2, the lower filled remnant 704-2 remains sealed by the lower crimp 802-2 and may be removed for further handling or packaging steps. Subsequently, a new bag 902 may be situated around the pipe assembly outlet 702, enveloping the upper remnant 704-1 and the gasket of the upper remnant, as shown in FIG. 20. In some aspects, wherein the fill bag 704 is fashioned from a continuous liner, a new bag is formed by extending the liner portion which is the upper remnant or by extending a new liner portion over the upper remnant and forming a new bag from the new liner portion around the upper remnant.

[0087] A flexible containment bag may, in some aspects, be situated circumferentially around one orifice or access port of the piping system. In some aspects, the flexible containment bag may be formed by a portion of a continuous liner. For example, some aspects of the piping assembly may have an access port 1002, as shown in FIG. 21. The access port 1002 may be enveloped by a flexible containment bag 1004. The flexible containment bag 1004, which may be a continuous liner, may be inverted and inserted into the access to form a lined access 1006. The lined access 1006 may permit any or all of the remnants (e.g., 314-1, 314-2, and 704-1) to be removed from their points of capture (e.g., the feed neck collar, the piping assembly inlet, and the piping assembly outlet, respectively) without breaching the barrier between the room atmosphere 502 and the contaminated atmosphere 504.

[0088] In one aspect, a user may reach into the access port as shown in FIG. 22 and remove the remnants by a hand shielded by the lined access 1006. After the removal of the remnants, the new feed sleeve gasket 316 may be situated in the position previously inhabited by the remnant gasket 318 as discussed above. However, it is to be understood that a plurality of grooves or gasket locations may be provided such that the new sleeve gasket 316 need not necessarily be moved. Alternatively, or additionally, at least the outer ring 312 may be configured to provide for the movement of the new feed sleeve gasket 316 automatically; for instance, the outer ring 312 may have a sloped recess in which, after the remnant gasket 318 is removed, the new feed sleeve gasket 316 naturally slides, rolls, or otherwise settles into the position previously inhabited by the remnant gasket.

[0089] After removal of the various articles, such as remnants, from their respective points of capture, the removed articles may be collected in a bag 1102 formed by crimping the flexible containment bag 1004 with a crimp ring 1104, as shown in FIG. 23 and FIG. 24. The crimp ring 1104 may be subdivided and the collected articles may be appropriately disposed. In some aspects, the transfer station may be in readiness to complete another filling cycle after disposal of the remnants.

[0090] In some aspects, the piping assembly may contain a flexible conduit liner 1202, as shown in FIG. 25 and FIG. 26. In some aspects, the flexible conduit liner 1202 may be the only component of the piping assembly which contacts the contaminated atmosphere 504. For example, the flexible conduit liner 1202 may be wrapped around the piping assembly and sealed with gaskets 1210. In some aspects, the filling cycle as described above is not influenced by the presence of the flexible conduit liner 1202.

[0091] However, when the liner needs to be replaced (e.g., for a product changeover), after the lower remnant 314-2 and the upper remnant 704-1 have been formed, the remnants may be captured within the contaminated flexible conduit liner 1202 and removed from the piping assembly without compromising the room atmosphere 502. For example, as shown in FIG. 27 and FIG. 28, inlet ends 1204-1 and 1204-2 at a first end of the flexible conduit liner may be connected and sealed to envelop the lower remnant 314-2, access ends 1206-1 and 1206-2 at an access port of the flexible conduit liner may be connected to envelop the flexible containment bag 1004, and outlet ends 1208-1 and 1208-2 at a second end of the flexible conduit liner may be connected to envelop the upper remnant 704-1. When all ends are connected, the flexible conduit liner 1202 forms within itself a bag containing all contaminated components as well as residual product on the inner surfaces of the flexible conduit liner 1202. At this point, the sealed flexible conduit liner 1202 may be removed from the piping assembly without releasing the contaminated components or the residual product. After removal, the flexible conduit liner may be replaced, along with all other components, such as a new flexible containment bag 1004, a new feed sleeve 314, and a new fill sleeve 704, which may each be captured by the newly lined piping assembly, ready to complete a new filling cycle without risk of cross-contamination.

[0092] A filter 1212 may be embedded or attached to the flexible conduit liner 1202 to enable the safe discharge of displaced air and off-gasses from the product. For example, in some aspects, a particulate filter may be employed having a collection efficiency of the most penetrating particle size of at least about 99.995%, such as at least about 99.9995%, such as at least about 99.99995%. In some aspects, a filter meeting HEPA standards may be used. For instance, a HEPA H14, U15, U16, or U17 filter may be used. In another example, a filter rated according to ISO 45 H, 50 H, 55 U, 60 U, 65 U, 70 U, or 75 U may be used. Alternatively or additionally, a filter 1212 could contain a gas separation device to trap or otherwise prevent harmful off-gasses from venting to the atmosphere in the facility. For example, a filter 1212 could be attached via a removable duct to a fume hood. The filter 1212 may be molded directly into the flexible conduit liner 1202. Alternatively or additionally, the filter or a filter housing may be sealed to the flexible conduit liner 1202, such as by thermal or chemical welding. The filter may optionally be positioned to align with an orifice of the piping assembly, such as a filter port as shown in FIG. 27. Alternatively, or additionally, the filter could be remotely located; the filter could be attached to a pipe or a section of liner which extends some distance away from the piping assembly.

[0093] In some examples, the flexible conduit liner 1202 may include flaps 1302 which prevent any powder from accumulating in the access 1002 of the piping assembly or in the filter neck of the piping assembly, as shown in FIG. 29. The flaps 1302 advantageously prevent such accumulation while permitting the lined access 1006 via the liner 1004 as shown in FIG. 21.

[0094] In some aspects, the flexible containment bag 1004 need not be disposed entirely within the flexible conduit liner 1202 when replacing the flexible conduit liner. For example, as shown in FIG. 30, the flexible containment bag 1004 could be situated behind the gasket 1210 of the flexible conduit liner 1202 while being captured against the flexible conduit liner 1202 by an externally applied gasket 1402. In such an aspect, the entirety of the flexible containment bag 1004 is not exposed to the contaminated atmosphere 504: only the portion of the flexible containment bag 1004 within the gasket 1402 is contaminated. Therefore, if the continuous liner is cut, such as at cut point 1404, access ends of the flexible conduit liner, namely 1206-1 and 1206-2, may be connected to envelop only the contaminated portion of the flexible containment bag 1004. After replacement of the flexible conduit liner 1202, the flexible containment bag 1004 may be extended over the flexible conduit liner 1202, sealed at the end (e.g., crimped shut), and captured against the new flexible conduit liner with new gaskets 1402 to again form the configuration shown in FIG. 30, ready for a filling cycle without risk of cross-contamination.

[0095] Alternatively, for some aspects, such as those requiring only a single cycle, the flexible conduit liner 1202 may optionally subsume the function of the flexible containment bag 1004. For example, in one aspect, the piping system has no access 1002 and no flexible containment bag 1004, or, alternatively, a modified flexible conduit liner blocks the access 1002 of a piping system having an access 1002. After a single cycle, inlet ends 1204-1 and 1204-2 may be connected to envelop the lower remnant 314-2 and outlet ends 1208-1 and 1208-2 may be connected to envelop the upper remnant 704-1. When all ends are connected, the flexible conduit liner 1202 forms within itself a sealed bag containing all contaminated components. At this point, the sealed liner 1202 may be removed from the piping assembly and replaced.

[0096] In general, the transfer station disclosed herein employs single-use liners. “Single-use” is not to be restricted to items removed and/or disposed of after every use cycle. For example, if cycle 1 and cycle 2 bring a first single-use flexible conduit liner 1202 in contact with only a product A, the flexible conduit liner 1202 need not necessarily be replaced between cycles 1 and 2. If, however, cycle 3 introduces a product B, then the flexible conduit liner 1202 would possibly need to be replaced between cycles 2 and 3.

[0097] In general, the material of any of the bags, liners, or sleeves of the present disclosure can be any acceptable flexible film. For example, in one aspect, the material may be a monolayer film. Alternately, the material may include a multi-layer film. For example, in one aspect, the film materials used herein can be compound films composed of 2 or more layers bonded with adhesives or via thermal bonding into a film. The multi-layer film includes an interior surface facing the cavity within the sleeve or liner. The multi-layer film further comprises an opposite exterior surface facing the exterior of the sleeve or liner. The layer(s) of the film may be selected to convey any suitable properties. For example, in an aspect wherein the film material includes at least 2 layers, the exterior layer may be selected to confer one property, e.g. mechanical strength, middle layer(s), if present, may be selected to confer additional properties, e.g. gas barrier properties, and the interior layer may be selected, for example, to be suitable for contacting the powdery substance or product. The inner layer may be configured to contact the product within the sleeve or liner while minimizing production effects due to the contact. For example, the inner layer may be treated with an anti-static composition to reduce the amount of product clinging to the sleeves or liners. Additionally or alternatively, the material may be selected with internal or innate anti-cling, anti-static, and/or lubricity properties.

[0098] For example, the inner layer may be generally formed of low density polyethylene. In one particular example, the interior surface of the multi-layer film may comprise a low density polyethylene that has been modified to form a hydrophilic surface. Other layers may be added to further modify the properties of the film. For example, in one aspect, acrylamide may be grafted onto LDPE film. As another example, oxidized polyethylene can be used. Additional examples include polyethylene blends with poly(2-hydroxyethyl methacrylate), poly(2,3-dihydroxypropyl methacrylate), and the like. Other polymers, including other polyethylenes, may be suitable for use herein. In certain aspects, any of the film layers described herein may be subjected to irradiation, photo or plasma induction, or oxidation.

[0099] In general, the materials of any of the components described herein may be selected to be suitable for the desired application. For example, materials may be selected for strength, weight, chemical stability, flexibility, or otherwise. For example, the piping assembly may be metal or plastic, and rigid or semi-rigid. Although the aspects described herein have introduced a number of discrete components, any variety of components may be combined as an integrated assembly without departing from the scope of the disclosure. For example, any of the gaskets described herein need not be distinct and separate components and may be embedded or integrated into any of the adjoining components.

[0100] The process and system of the present disclosure can be used for the handling and transfer of any suitable pharmaceutical or biopharmaceutical products—such as polypeptide products, nucleic acid products (for example DNA or RNA), or cells and/or viruses such as those used in cellular and/or viral therapies.

[0101] In aspects, the protein is, e.g., BOTOX, Myobloc, Neurobloc, Dysport (or other serotypes of botulinum neurotoxins), alglucosidase alpha, daptomycin, YH-16, choriogonadotropin alpha, filgrastim, cetrorelix, interleukin-2, aldesleukin, teceleulin, denileukin diftitox, interferon alpha-n3 (injection), interferon alpha-nl, DL-8234, interferon, Suntory (gamma-la), interferon gamma, thymosin alpha 1, tasonermin, DigiFab, ViperaTAb, EchiTAb, CroFab, nesiritide, abatacept, alefacept, Rebif, eptoterminalfa, teriparatide (osteoporosis), calcitonin injectable (bone disease), calcitonin (nasal, osteoporosis), etanercept, hemoglobin glutamer 250 (bovine), drotrecogin alpha, collagenase, carperitide, recombinant human epidermal growth factor (topical gel, wound healing), DWP401, darbepoetin alpha, epoetin omega, epoetin beta, epoetin alpha, desirudin, lepirudin, bivalirudin, nonacog alpha, Mononine, eptacog alpha (activated), recombinant Factor VIII+VWF, Recombinate, recombinant Factor VIII, Factor VIII (recombinant), Alphnmate, octocog alpha, Factor VIII, palifermin,Indikinase, tenecteplase, alteplase, pamiteplase, reteplase, nateplase, monteplase, follitropin alpha, rFSH, hpFSH, micafungin, pegfilgrastim, lenograstim, nartograstim, sermorelin, glucagon, exenatide, pramlintide, iniglucerase, galsulfase, Leucotropin, molgramostirn, triptorelin acetate, histrelin (subcutaneous implant, Hydron), deslorelin, histrelin, nafarelin, leuprolide sustained release depot (ATRIGEL), leuprolide implant (DUROS), goserelin, Eutropin, KP-102 program, somatropin, mecaserm in (growth failure), enlfavirtide, Org-33408, insulin glargine, insulin glulisine, insulin (inhaled), insulin lispro, insulin deternir, insulin (buccal, RapidMist), mecaserm in rinfabate, anakinra, celmoleukin, 99 mTc-apcitide injection, myelopid, Betaseron, glatiramer acetate, Gepon, sargramostim, oprelvekin, human leukocyte-derived alpha interferons, Bilive, insulin (recombinant), recombinant human insulin, insulin aspart, mecasenin, Roferon-A, interferon-alpha 2, Alfaferone, interferon alfacon-1, interferon alpha, Avonex′ recombinant human luteinizing hormone, dornase alpha, trafermin, ziconotide, taltirelin, diboterminalfa, atosiban, becaplermin, eptifibatide, Zemaira, CTC-111, Shanvac-B, HPV vaccine (quadrivalent), octreotide, lanreotide, ancestirn, agalsidase beta, agalsidase alpha, laronidase, prezatide copper acetate (topical gel), rasburicase, ranibizumab, Actimmune, PEG-Intron, Tricomin, recombinant house dust mite allergy desensitization injection, recombinant human parathyroid hormone (PTH) 1-84 (sc, osteoporosis), epoetin delta, transgenic antithrombin III, Granditropin, Vitrase, recombinant insulin, interferon-alpha (oral lozenge), GEM-21S, vapreotide, idursulfase, omnapatrilat, recombinant serum albumin, certolizumab pegol, glucarpidase, human recombinant Cl esterase inhibitor (angioedema), lanoteplase, recombinant human growth hormone, enfuvirtide (needle-free injection, Biojector 2000), VGV-1, interferon (alpha), lucinactant, aviptadil (inhaled, pulmonary disease), icatibant, ecallantide, omiganan, Aurograb, pexigananacetate, ADI-PEG-20, LDI-200, degarelix, cintredelinbesudotox, Favld, MDX-1379, ISAtx-247, liraglutide, teriparatide (osteoporosis), tifacogin, AA4500, T4N5 liposome lotion, catumaxomab, DWP413, ART-123, Chrysalin, desmoteplase, amediplase, corifollitropinalpha, TH-9507, teduglutide, Diamyd, DWP-412, growth hormone (sustained release injection), recombinant G-CSF, insulin (inhaled, AIR), insulin (inhaled, Technosphere), insulin (inhaled, AERx), RGN-303, DiaPep277, interferon beta (hepatitis C viral infection (HCV)), interferon alpha-n3 (oral), belatacept, transdermal insulin patches, AMG-531, MBP-8298, Xerecept, opebacan, AIDSVAX, GV-1001, LymphoScan, ranpirnase, Lipoxysan, lusupultide, MP52 (beta-tricalciumphosphate carrier, bone regeneration), melanoma vaccine, sipuleucel-T, CTP-37, Insegia, vitespen, human thrombin (frozen, surgical bleeding), thrombin, TransMlD, alfimeprase, Puricase, terlipressin (intravenous, hepatorenal syndrome), EUR-1008M, recombinant FGF-I (injectable, vascular disease), BDM-E, rotigaptide, ETC-216, P-113, MBI-594AN, duramycin (inhaled, cystic fibrosis), SCV-07, OPI-45, Endostatin, Angiostatin, ABT-510, Bowman Birk Inhibitor Concentrate, XMP-629, 99 mTc-Hynic-Annexin V, kahalalide F, CTCE-9908, teverelix (extended release), ozarelix, rornidepsin, BAY-504798, interleukin4, PRX-321, Pepscan, iboctadekin, rhlactoferrin, TRU-015, IL-21, ATN-161, cilengitide, Albuferon, Biphasix, IRX-2, omega interferon, PCK-3145, CAP-232, pasireotide, huN901-DMI, ovarian cancer immunotherapeutic vaccine, SB-249553, Oncovax-CL, OncoVax-P, BLP-25, CerVax-16, multi-epitope peptide melanoma vaccine (MART-1, gp100, tyrosinase), nemifitide, rAAT (inhaled), rAAT (dermatological), CGRP (inhaled, asthma), pegsunercept, thymosinbeta4, plitidepsin, GTP-200, ramoplanin, GRASPA, OBI-1, AC-100, salmon calcitonin (oral, eligen), calcitonin (oral, osteoporosis), examorelin, capromorelin, Cardeva, velafermin, 1311-TM-601, KK-220, T-10, ularitide, depelestat, hematide, Chrysalin (topical), rNAPc2, recombinant Factor V111 (PEGylated liposomal), bFGF, PEGylated recombinant staphylokinase variant, V-10153, SonoLysis Prolyse, NeuroVax, CZEN-002, islet cell neogenesis therapy, rGLP-1, BIM-51077, LY-548806, exenatide (controlled release, Medisorb), AVE-0010, GA-GCB, avorelin, ACM-9604, linaclotid eacetate, CETi-1, Hemospan, VAL (injectable), fast-acting insulin (injectable, Viadel), intranasal insulin, insulin (inhaled), insulin (oral, eligen), recombinant methionyl human leptin, pitrakinra subcutancous injection, eczema), pitrakinra (inhaled dry powder, asthma), Multikine, RG-1068, MM-093, NBI-6024, AT-001, PI-0824, Org-39141, Cpn10 (autoimmune diseases/inflammation), talactoferrin (topical), rEV-131 (ophthalmic), rEV-131 (respiratory disease), oral recombinant human insulin (diabetes), RPI-78M, oprelvekin (oral), CYT-99007 CTLA4-Ig, DTY-001, valategrast, interferon alpha-n3 (topical), IRX-3, RDP-58, Tauferon, bile salt stimulated lipase, Merispase, alaline phosphatase, EP-2104R, Melanotan-II, bremelanotide, ATL-104, recombinant human microplasmin, AX-200, SEMAX, ACV-1, Xen-2174, CJC-1008, dynorphin A, SI-6603, LAB GHRH, AER-002, BGC-728, malaria vaccine (virosomes, PeviPRO), ALTU-135, parvovirus B19 vaccine, influenza vaccine (recombinant neuraminidase), malaria/HBV vaccine, anthrax vaccine, Vacc-5q, Vacc-4x, HIV vaccine (oral), HPV vaccine, Tat Toxoid, YSPSL, CHS-13340, PTH(1-34) liposomal cream (Novasome), Ostabolin-C, PTH analog (topical, psoriasis), MBRI-93.02, MTB72F vaccine (tuberculosis), MVA-Ag85A vaccine (tuberculosis), FARA04, BA-210, recombinant plague FIV vaccine, AG-702, OxSODrol, rBetV1, Der-p1/Der-p2/Der-p7 allergen-targeting vaccine (dust mite allergy), PR1 peptide antigen (leukemia), mutant ras vaccine, HPV-16 E7 lipopeptide vaccine, labyrinthin vaccine (adenocarcinoma), CML vaccine, WT1-peptide vaccine (cancer), IDD-5, CDX-110, Pentrys, Norelin, CytoFab, P-9808, VT-111, icrocaptide, telbermin (dermatological, diabetic foot ulcer), rupintrivir, reticulose, rGRF, HA, alpha-galactosidase A, ACE-011, ALTU-140, CGX-1160, angiotensin therapeutic vaccine, D-4F, ETC-642, APP-018, rhMBL, SCV-07 (oral, tuberculosis), DRF-7295, ABT-828, ErbB2-specific immunotoxin (anticancer), DT3SSIL-3, TST-10088, PRO-1762, Combotox, cholecystokinin-B/gastrin-receptor binding peptides, 111In-hEGF, AE-37, trasnizumab-DM1, Antagonist G, IL-12 (recombinant), PM-02734, IMP-321, rhIGF-BP3, BLX-883, CUV-1647 (topical), L-19 based radioimmunotherapeutics (cancer), Re-188-P-2045, AMG-386, DC/1540/KLH vaccine (cancer), VX-001, AVE-9633, AC-9301, NY-ESO-1 vaccine (peptides), NA17.A2 peptides, melanoma vaccine (pulsed antigen therapeutic), prostate cancer vaccine, CBP-501, recombinant human lactoferrin (dry eye), FX-06, AP-214, WAP-8294A (injectable), ACP-HIP, SUN-11031, peptide YY [3-36] (obesity, intranasal), FGLL, atacicept, BR3-Fc, BN-003, BA-058, human parathyroid hormone 1-34 (nasal, osteoporosis), F-18-CCR1, AT-1100 (celiac disease/diabetes), JPD-003, PTH(7-34) liposomal cream (Novasome), duramycin (ophthalmic, dry eye), CAB-2, CTCE-0214, GlycoPEGylated erythropoietin, EPO-Fc, CNTO-528, AMG-114, JR-013, Factor XIII, aminocandin, PN-951, 716155, SUN-E7001, TH-0318, BAY-73-7977, teverelix (immediate release), EP-51216, hGH (controlled release, Biosphere), OGP-I, sifuvirtide, TV4710, ALG-889, Org-41259, rhCC10, F-991, thymopentin (pulmonary diseases), r(m)CRP, hepatoselective insulin, subalin, L19-IL-2 fusion protein, elafin, NMK-150, ALTU-139, EN-122004, rhTPO, thrombopoietin receptor agonist (thrombocytopenic disorders), AL-108, AL-208, nerve growth factor antagonists (pain), SLV-317, CGX-1007, INNO-105, oral teriparatide (eligen), GEM-OS1, AC-162352, PRX-302, LFn-p24 fusion vaccine (Therapore), EP-1043, S pneumoniae pediatric vaccine, malaria vaccine, Neisseria meningitidis Group B vaccine, neonatal group B streptococcal vaccine, anthrax vaccine, HCV vaccine (gpE1+gpE2+MF-59), otitis media therapy, HCV vaccine (core antigen+ISCOMATRIX), hPTH(1-34) (transdermal, ViaDerm), 768974, SYN-101, PGN-0052, aviscumnine, BIM-23190, tuberculosis vaccine, multi-epitope tyrosinase peptide, cancer vaccine, enkastim, APC-8024, GI-5005, ACC-001, TTS-CD3, vascular-targeted TNF (solid tumors), desmopressin (buccal controlled-release), onercept, and TP-9201.

[0102] In some aspects, the polypeptide is adalimumab (HUMIRA), infliximab (REMICADE™), rituximab (RITUXAN™/MAB THERA™) etanercept (ENBREL™) bevacizumab (AVASTIN™), trastuzumab (HERCEPTIN™), pegrilgrastim (NEULASTA™), or any other suitable polypeptide including biosimilars and biobetters.

[0103] Other suitable polypeptides are those listed below and in Table 1 of US2016/0097074:

TABLE-US-00001 TABLE I Protein Product Reference Listed Drug interferon gamma-1b Actimmune ® alteplase; tissue plasminogen activator Activase ®/Cathflo ® Recombinant antihemophilic factor Advate human albumin Albutein ® Laronidase Aldurazyme ® Interferon alfa-N3, human leukocyte Alferon N ® derived human antihemophilic factor Alphanate ® virus-filtered human coagulation factor IX AlphaNine ® SD Alefacept; recombinant, dimeric fusion Amevive ® protein LFA3-Ig Bivalirudin Angiomax ® darbepoetin alfa Aranesp ™ Bevacizumab Avastin ™ interferon beta-1a; recombinant Avonex ® coagulation factor IX BeneFix ™ Interferon beta-1b Betaseron ® Tositumomab BEXXAR ® antihemophilic factor Bioclate ™ human growth hormone BioTropin ™ botulinum toxin type A BOTOX ® Alemtuzumab Campath ® acritumomab; technetium-99 labeled CEA-Scan ® alglucerase; modified form of beta- Ceredase ® glucocerebrosidase imiglucerase; recombinant form of beta- Cerezyme ® glucocerebrosidase crotalidae polyvalent immune Fab, ovine CroFab ™ digoxin immune fab [ovine] DigiFab ™ Rasburicase Elitek ® Etanercept ENBREL ® epoietin alfa Epogen ® Cetuximab Erbitux ™ algasidase beta Fabrazyme ® Urofollitropin Fertinex ™ follitropin beta Follistim ™ Teriparatide FORTEO ® human somatropin GenoTropin ® Glucagon GlucaGen ® follitropin alfa Gonal-F ® antihemophilic factor Helixate ® Antihemophilic Factor; Factor XIII HEMOFIL adefovir dipivoxil Hepsera ™ Trastuzumab Herceptin ® Insulin Humalog ® antihemophilic factor/von Willebrand Humate-P ® factor complex-human Somatotropin Humatrope ® Adalimumab HUMIRA ™ human insulin Humulin ® recombinant human hyaluronidase Hylenex ™ interferon alfacon-1 Infergen ® eptifibatide Integrilin ™ alpha-interferon Intron A ® Palifermin Kepivance Anakinra Kineret ™ antihemophilic factor Kogenate ® FS insulin glargine Lantus ® granulocyte macrophage colony- Leukine ®/ stimulating factor Leukine ® Liquid lutropin alfa for injection Luveris OspA lipoprotein LYMErix ™ Ranibizumab LUCENTIS ® gemtuzumab ozogamicin Mylotarg ™ Galsulfase Naglazyme ™ Nesiritide Natrecor ® Pegfilgrastim Neulasta ™ Oprelvekin Neumega ® Filgrastim Neupogen ® Fanolesomab NeutroSpec ™ (formerly LeuTech ®) somatropin [rDNA] Norditropin ®/Norditropin Nordiflex ® Mitoxantrone Novantrone ® insulin; zinc suspension; Novolin L ® insulin; isophane suspension Novolin N ® insulin, regular; Novolin R ® Insulin Novolin ® coagulation factor VIIa NovoSeven ® Somatropin Nutropin ® immunoglobulin intravenous Octagam ® PEG-L-asparaginase Oncaspar ® abatacept, fully human soluable fusion Orencia ™ protein muromomab-CD3 Orthoclone OKT3 ® high-molecular weight hyaluronan Orthovisc ® human chorionic gonadotropin Ovidrel ® live attenuated Bacillus Calmette-Guerin Pacis ® peginterferon alfa-2a Pegasys ® pegylated version of interferon alfa-2b PEG-Intron ™ Abarelix (injectable suspension); Plenaxis ™ gonadotropin-releasing hormone antagonist epoietin alfa Procrit ® Aldesleukin Proleukin, IL-2 ® Somatrem Protropin ® dornase alfa Pulmozyme ® Efalizumab; selective, reversible T-cell RAPTIVA ™ blocker combination of ribavirin and alpha interferon Rebetron ™ Interferon beta 1a Rebif ® antihemophilic factor Recombinate ® rAHF/ antihemophilic factor ReFacto ® Lepirudin Refludan ® Infliximab REMICADE ® Abciximab ReoPro ™ Reteplase Retavase ™ Rituxima Rituxan ™ interferon alfa-2.sup.a Roferon-A ® Somatropin Saizen ® synthetic porcine secretin SecreFlo ™ Basiliximab Simulect ® Eculizumab SOLIRIS (R) Pegvisomant SOMAVERT ® Palivizumab; recombinantly produced, Synagis ™ humanized mAb thyrotropin alfa Thyrogen ® Tenecteplase TNKase ™ Natalizumab TYSABRI ® human immune globulin intravenous 5% and Venoglobulin-S ® 10% solutions interferon alfa-n1, lymphoblastoid Wellferon ® drotrecogin alfa Xigris ™ Omalizumab; recombinant DNA-derived Xolair ® humanized monoclonal antibody targeting immunoglobulin-E Daclizumab Zenapax ® ibritumomab tiuxetan Zevalin ™ Somatotropin Zorbtive ™ (Serostim ®)

[0104] In aspects, the polypeptide is a hormone, blood clotting/coagulation factor, cytokine/growth factor, antibody molelcule, fusion protein, protein vaccine, or peptide as shown in Table 2.

TABLE-US-00002 TABLE 2 Exemplary Products Therapeutic Product type Product Trade Name Hormone Erythropoietin, Epoein-α Epogen, Procrit Darbepoetin-α Aranesp Growth hormone (GH), Genotropin, Humatrope, Norditropin, somatotropin NovIVitropin, Nutropin, Omnitrope, Human follicle-stimulating Protropin, Siazen, Serostim, Valtropin hormone (FSH) Gonal-F, Follistim Human chorionic Ovidrel gonadotropin Luveris Lutropin-α GlcaGen Glucagon Geref Growth hormone releasing ChiRhoStim (human peptide), SecreFlo hormone (GHRH) (porcine peptide) Secretin Thyrogen Thyroid stimulating hormone (TSH), thyrotropin Blood Factor VIIa NovoSeven Clotting/Coagulation Factor VIII Bioclate, Helixate, Kogenate, Factors Factor IX Recombinate, ReFacto Antithrombin III (AT-III) Benefix Protein C concentrate Thrombate III Ceprotin Cytokine/Growth Type I alpha-interferon Infergen factor Interferon-αn3 (IFNαn3) Alferon N Interferon-β1a (rIFN- β) Avonex, Rebif Interferon-β1b (rIFN- β) Betaseron Interferon-γ1b (IFN γ) Actimmune Aldesleukin (interleukin Proleukin 2(IL2), epidermal Kepivance theymocyte activating Regranex factor; ETAF Anril, Kineret Palifermin (keratinocyte growth factor; KGF) Becaplemin (platelet- derived growth factor; PDGF) Anakinra (recombinant IL1 antagonist) Antibody molecules Bevacizumab (VEGFA Avastin mAb) Erbitux Cetuximab (EGFR mAb) Vectibix Panitumumab (EGFR Campath mAb) Rituxan Alemtuzumab (CD52 Herceptin mAb) Orencia Rituximab (CD20 Humira chimeric Ab) Enbrel Trastuzumab (HER2/Neu Remicade mAb) Amevive Abatacept (CTLA Ab/Fc Raptiva fusion) Tysabri Adalimumab (TNFα mAb) Soliris Etanercept (TNF Orthoclone, OKT3 receptor/Fc fusion) Infliximab (TNFα chimeric mAb) Alefacept (CD2 fusion protein) Efalizumab (CD11a mAb) Natalizumab (integrin α4 subunit mAb) Eculizumab (C5mAb) Muromonab-CD3 Other: Insulin Humulin, Novolin Fusion Hepatitis B surface antigen Engerix, Recombivax HB proteins/Protein (HBsAg) Gardasil vaccines/Peptides HPV vaccine LYMErix OspA Rhophylac Anti-Rhesus(Rh) Fuzeon immunoglobulin G QMONOS Enfuvirtide Spider silk, e.g., fibrion

[0105] In aspects, the protein is multispecific protein, e.g., a bispecific antibody as shown in Table 3.

TABLE-US-00003 TABLE 3 Bispecific Formats Name (other names, Proposed Diseases (or sponsoring BsAb mechanisms of Development healthy organizations) format Targets action stages volunteers) Catumaxomab BsIgG: CD3, Retargeting of T Approved in Malignant (Removab ®, Triomab EpCAM cells to tumor, Fc EU ascites in Fresenius mediated EpCAM positive Biotech, Trion effector tumors Pharma, functions Neopharm) Ertumaxomab BsIgG: CD3, HER2 Retargeting of T Phase I/II Advanced solid (Neovii Biotech, Triomab cells to tumor tumors Fresenius Biotech) Blinatumomab BiTE CD3, CD19 Retargeting of T Approved in Precursor B-cell (Blincyto ®, AMG cells to tumor USA ALL 103, MT 103, Phase II and ALL MEDI 538, III DLBCL Amgen) Phase II NHL Phase I REGN1979 BsAb CD3, CD20 (Regeneron) Solitomab (AMG BiTE CD3, Retargeting of T Phase I Solid tumors 110, MT110, EpCAM cells to tumor Amgen) MEDI 565 (AMG BiTE CD3, CEA Retargeting of T Phase I Gastrointestinal 211, MedImmune, cells to tumor adenocancinoma Amgen) RO6958688 BsAb CD3, CEA (Roche) BAY2010112 BiTE CD3, PSMA Retargeting of T Phase I Prostate cancer (AMG 212, cells to tumor Bayer; Amgen) MGD006 DART CD3, CD123 Retargeting of T Phase I AML (Macrogenics) cells to tumor MGD007 DART CD3, gpA33 Retargeting of T Phase I Colorectal (Macrogenics) cells to tumor cancer MGD011 DART CD19, CD3 (Macrogenics) SCORPION BsAb CD3, CD19 Retargeting of T (Emergent cells to tumor Biosolutions, Trubion) AFM11 (Affimed TandAb CD3, CD19 Retargeting of T Phase I NHL and ALL Therapeutics) cells to tumor AFM12 (Affimed TandAb CD19, CD16 Retargeting of Therapeutics) NK cells to tumor cells AFM13 (Affimed TandAb CD30, Retargeting of Phase II Hodgkin's Therapeutics) CD16A NK cells to Lymphoma tumor cells GD2 (Barbara T cells CD3, GD2 Retargeting of T Phase I/II Neuroblastoma Ann Karmanos preloaded cells to tumor and Cancer Institute) with BsAb osteosarcoma pGD2 (Barbara T cells CD3, Her2 Retargeting of T Phase II Metastatic breast Ann Karmanos preloaded cells to tumor cancer Cancer Institute) with BsAb EGFRBi-armed T cells CD3, EGFR Autologous Phase I Lung and other autologous preloaded activated T cells solid tumors activated T cells with BsAb to EGFR- (Roger Williams positive tumor Medical Center) Anti-EGFR- T cells CD3, EGFR Autologous Phase I Colon and armed activated preloaded activated T cells pancreatic T-cells (Barbara with BsAb to EGFR- cancers Ann Karmanos positive tumor Cancer Institute) rM28 (University Tandem CD28, Retargeting of T Phase II Metastatic Hospital scFv MAPG cells to tumor melanoma Tübingen) IMCgp100 ImmTAC CD3, peptide Retargeting of T Phase I/II Metastatic (Immunocore) MHC cells to tumor melanoma DT2219ARL 2 scFv CD19, CD22 Targeting of Phase I B cell leukemia (NCI, University linked to protein toxin to or lymphoma of Minnesota) diphtheria tumor toxin XmAb5871 BsAb CD19, (Xencor) CD32b NI-1701 BsAb CD47, CD19 (NovImmune) MM-111 BsAb ErbB2, (Merrimack) ErbB3 MM-141 BsAb IGF-1R, (Merrimack) ErbB3 NA (Merus) BsAb HER2, HER3 NA (Merus) BsAb CD3, CLEC12A NA (Merus) BsAb EGFR, HER3 NA (Merus) BsAb PD1, undisclosed NA (Merus) BsAb CD3, undisclosed Duligotuzumab DAF EGFR, Blockade of 2 Phase I and II Head and neck (MEHD7945A, HER3 receptors, ADCC Phase II cancer Genentech, Colorectal Roche) cancer LY3164530 (Eli Not EGFR, MET Blockade of 2 Phase I Advanced or Lily) disclosed receptors metastatic cancer MM-111 HSA body HER2, Blockade of 2 Phase II Gastric and (Merrimack HER3 receptors Phase I esophageal Pharmaceuticals) cancers Breast cancer MM-141, IgG-scFv IGF-1R, Blockade of 2 Phase I Advanced solid (Merrimack HER3 receptors tumors Pharmaceuticals) RG7221 CrossMab Ang2, VEGF Blockade of 2 Phase I Solid tumors (RO5520985, A proangiogenics Roche) RG7716 (Roche) CrossMab Ang2, VEGF Blockade of 2 Phase I Wet AMD A proangiogenics OMP-305B83 BsAb DLL4/VEGF (OncoMed) TF2 Dock and CEA, HSG Pretargeting Phase II Colorectal, (Immunomedics) lock tumor for PET or breast and lung radioimaging cancers ABT-981 DVD-Ig IL-1α, IL-1β Blockade of 2 Phase II Osteoarthritis (AbbVie) proinflammatory cytokines ABT-122 DVD-Ig TNF, IL- Blockade of 2 Phase II Rheumatoid (AbbVie) 17A proinflammatory arthritis cytokines COVA322 IgG- TNF, IL17A Blockade of 2 Phase I/II Plaque psoriasis fynomer proinflammatory cytokines SAR156597 Tetravalent IL-13, IL-4 Blockade of 2 Phase I Idiopathic (Sanofi) bispecific proinflammatory pulmonary tandem cytokines fibrosis IgG GSK2434735 Dual- IL-13, IL-4 Blockade of 2 Phase I (Healthy (GSK) targeting proinflammatory volunteers) domain cytokines Ozoralizumab Nanobody TNF, HSA Blockade of Phase II Rheumatoid (ATN103, proinflammatory arthritis Ablynx) cytokine, binds to HSA to increase half-life ALX-0761 Nanobody IL-17A/F, Blockade of 2 Phase I (Healthy (Merck Serono, HSA proinflammatory volunteers) Ablynx) cytokines, binds to HSA to increase half-life ALX-0061 Nanobody IL-6R, HSA Blockade of Phase I/II Rheumatoid (AbbVie, Ablynx; proinflammatory arthritis cytokine, binds to HSA to increase half-life ALX-0141 Nanobody RANKL, Blockade of Phase I Postmenopausal (Ablynx, HSA bone resorption, bone loss Eddingpharm) binds to HSA to increase half-life RG6013/ACE910 ART-Ig Factor IXa, Plasma Phase II Hemophilia (Chugai, Roche) factor X coagulation

[0106] Various aspects of the present disclosure can also be characterized by the following numbered statements:

[0107] These and other modifications and variations to the present invention may be practiced by those of ordinary skill in the art, without departing from the spirit and scope of the present invention, which is more particularly set forth in the appended claims. In addition, it should be understood that aspects of the various aspects may be interchanged either in whole or in part. Furthermore, those of ordinary skill in the art will appreciate that the foregoing description is by way of example only, and is not intended to limit the invention so further described in such appended claims.