BACKGROUND OF THE DISCLOSURE

[0001] The exemplary embodiments of present invention relate generally to an aseptic manifold dispensing assembly for processing materials for pharmaceuticals and biologies, e.g., pharmaceutical ingredients.

BRIEF SUMMARY OF THE DISCLOSURE

[0002] In accordance with an exemplary embodiment there is provided an aseptic manifold dispensing assembly for processing pharmaceutical ingredients. The aseptic manifold dispensing assembly includes a connector for connecting to a source, a dispensing manifold in fluid communication with the connector that includes a plurality of outputs, and a filling manifold. The filling manifold includes an inlet for connecting to at least one of the plurality of outputs of the dispensing manifold, a plurality of peristaltic pumps connected in parallel downstream the inlet, and a container downstream the plurality of peristaltic pumps. The aseptic manifold dispensing assembly also includes a scale, and a controller operatively connected to the scale and the filling manifold.

[0003] In an exemplary embodiment, the dispensing manifold includes a plurality of quick connects at its terminus, and the plurality of quick connects can include an occlusion tab for sealing an output of the quick connect. In another embodiment, the dispensing manifold includes a plurality of clamps for blocking the flow of fluid between each of the plurality of outputs.

[0004] In another exemplary embodiment, the filling manifold includes a plurality of branches each having one of the plurality of peristaltic pumps. The filling manifold can further include a pressure sensor in communication with the controller, such as a pressure sensor on each of the plurality of branches for measuring pressure therein. In yet another embodiment, the filling manifold can include a clamp on each of the plurality of branches for occluding flow therethrough. The aseptic manifold dispensing assembly further includes a filter in fluid communication with the connector and between the connector and the dispensing manifold. [0005] In yet another exemplary embodiment, the controller includes a non-transitory computer readable medium including computer instructions that, when executed by a processor causes the filling manifold to cease operation of the peristaltic pumps when an input from the pressure sensor falls outside a predetermined range. In another embodiment, the controller, which can include a timer, includes computer instructions that when executed by a processor causes the filling manifold to cease operation of the peristaltic pumps when an input from the timer exceeds a predetermined time. In a further embodiment, the controller includes computer instructions that when executed by a processor causes the filling manifold to cease operation of the peristaltic pump when a scale reaches a predetermined value or a range of predetermined values, and/or causes the filling manifold to reverse an output of a peristaltic pump when an input from the scale exceeds a predetermined value or a range of predetermined values, and/or causes the filling manifold to reduce an output of the peristaltic pump when an input from the scale exceeds a second predetermined value.

[0006] Other features and advantages of the subject disclosure will be apparent from the following more detail description of the exemplary embodiments.

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

[0007] The foregoing summary, as well as the following detailed description of the exemplary embodiments of the subject disclosure, will be better understood when read in conjunction with the appended drawings. For the purpose of illustrating the present disclosure, there are shown in the drawings exemplary embodiments. It should be understood, however, that the subject application is not limited to the precise arrangements and instrumentalities shown.

[0008] FIG. 1 is a schematic view of an aseptic manifold dispensing assembly according to an exemplary embodiment;

[0009] FIG. 2A is a schematic view of a dispensing manifold, and FIG. 2B and FIG. 2C are schematic views of filling manifolds, all according to exemplary, non-limiting embodiments; [0010] FIG. 3A is a schematic view of an exemplary container applicable to the aseptic manifold dispensing assembly of the present disclosure;

[0011] FIG. 3B is a schematic view of another exemplary container applicable to the aseptic manifold dispensing assembly of the present disclosure;

[0012] FIGS. 4A-4D are perspective views of an exemplary peristaltic pump applicable to the aseptic manifold dispensing assembly of the present disclosure;

[0013] FIG. 5 is a schematic view of an exemplary pump head of a peristaltic pump applicable to the aseptic manifold dispensing assembly of the present disclosure;

[0014] FIG. 6 is a schematic view of a pump head of another exemplary peristaltic pump applicable to the aseptic manifold dispensing assembly of the present disclosure;

[0015] FIG. 7 is a schematic view of another exemplary aseptic manifold dispensing assembly according to an exemplary embodiment of the present disclosure; and

[0016] FIG. 8 is a schematic view of a peristaltic pump control system according to an exemplary embodiment of the present disclosure.

DETAILED DESCRIPTION OF THE DISCLOSURE

[0017] Reference will now be made in detail to the various exemplary embodiments of the subject disclosure illustrated in the accompanying drawings. Wherever possible, the same or like reference numbers will be used throughout the drawings to refer to the same or like features. It should be noted that the drawings are in simplified form and are not drawn to precise scale. Certain terminology is used in the following description for convenience only and is not limiting. Directional terms such as top, bottom, left, right, above, below and diagonal, are used with respect to the accompanying drawings. The term “a,” as used in the specification, means “at least one.” The terminology includes the words above specifically mentioned, derivatives thereof, and words of similar import.

[0018] “About” as used herein when referring to a measurable value such as an amount, a temporal duration, and the like, is meant to encompass variations of ±20%, ±10%, ±5%, ±1 %, or ±0.1 % from the specified value, as such variations are appropriate. [0019] “Substantially” as used herein shall mean considerable in extent, largely but not wholly that which is specified, or an appropriate variation therefrom as is acceptable within the field of art. “Exemplary” as used herein shall mean serving as a non-limiting example.

[0020] Throughout the subject application, various aspects thereof can be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the subject disclosure. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1 , 2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless of the breadth of the range.

[0021] “Pharmaceutical ingredient” as used herein shall mean any pharmaceutical or biological component used in the manufacture of a pharmaceutical or biologic product, including starting components, intermediates and final products. For example, the pharmaceutical ingredient can be a cell culture media (e.g., a working cell bank containing yeast cells, metabolized growth media and glycerine), or a cell paste (e.g., a cell paste containing yeast cells, virus-like particles and 3-(N-morpholino) propanesulfonic acid (MOPS). The pharmaceutical ingredient can also be one or more vitamins, such as a vitamin composition that includes thiamine hydrochloride, pyridoxine hydrochloride, nicotinic acid, d-biotin, and/or calcium pantothenate. These examples are illustrative and not offered for purposes of limitation.

[0022] It is understood that all connections described herein are aseptic and a sterile environment is maintained through the entire process, from bulk source to filling. In certain embodiments, the entire process, and all connections, meet the ISO 13408 standard for the aseptic processing of health care products.

[0023] Furthermore, the described features, advantages, and characteristics of the exemplary embodiments of the subject disclosure may be combined in any suitable manner in one or more embodiments. One skilled in the relevant art will recognize, in light of the description herein, that the subject disclosure can be practiced without one or more of the specific features or advantages of a particular exemplary embodiment. In other instances, additional features and advantages may be recognized in certain embodiments that may not be present in all exemplary embodiments of the present disclosure.

[0024] Referring now to the drawings, FIG. 1 illustrates an exemplary aseptic manifold dispensing assembly 100 of the present disclosure connected to a source 1000 (e.g. vat) of a pharmaceutical ingredient. The source can be a vat 1000 (as shown in FIG. 1 ), a drum, a container, or a continuous output of an upstream process. In the present exemplary embodiment, the vat 1000 is a closed container suitable for aseptic batch processing of pharmaceutical ingredients. The vat includes an outlet 1002 to allow the pharmaceutical ingredient to be delivered and processed downstream, which proceeds from left to right as oriented in FIG. 1 .

[0025] The aseptic manifold dispensing assembly 100 includes a connector 102, a dispensing manifold 104, a filling manifold 106, a scale 101 and a controller 800. The connector connects the aseptic manifold dispensing assembly to the source. The filling manifold is downstream the dispensing manifold. The scale provides a means for weighing the output of the filling manifold. The controller is operatively in communication with the scale and the filling manifold to control the amount and speed of filling operations.

[0026] The connector 102 is located upstream from the dispensing manifold for connecting to the outlet 1002 of the vat 1000. The connector 102 can be, for example, a Lynx® valve. In certain non-limiting exemplary embodiments, the connector 102 is an aseptic connector. Alternatively, in other exemplary embodiments the connector 102 is non-sterile or any connector suitable for connecting to the aseptic manifold assembly of the present disclosure.

[0027] The connector 102 is disposable, intended for a single, sterile-use and can be manipulated (e.g., manually twisted) to open the valve and start the flow of process fluid (e.g., the pharmaceutical ingredient). For example, disposable connectors can be constructed from a high temperature-resistant polymer (e.g., polyetherimide) capable of processing steam and other gases, which can be used for sterilization purposes or normal process demands. The connector can be provided with seals (e.g., silicone seals) to reliably prevent leakage and contamination. The connector 102 can be commercially obtained, for example, from Millipore Sigma (e.g., Lynx® ST connectors, that offer easy, quick, validatable, and sterile connectivity to stainless steel tanks, piping and other processing equipment in a range of sizes (e.g., inch, inch and 1 inch operating diameters)). Alternatively, other connectors known in the art and suitable for the intended purpose of the aseptic manifold assembly can be employed, e.g., nondisposable, multiuse connectors, including those formed from metal and other non- polymeric materials.

[0028] The dispensing manifold 104 is in fluid communication with and downstream from the connector 102. The dispensing manifold 104 is configured as best shown in FIGS. 1 and 2A. The dispensing manifold includes a plurality of outputs (e.g., ten), but can alternatively include more or less than ten e.g., 2, 3, 4, 5, 6, 7, 8, 9, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20 or more than 20 outputs. At each output of the dispensing manifold is a quick connector 108.

[0029] The dispensing manifold is formed by a transfer tubing 110 that branches out in parallel terminating at respective quick connectors 108. Tubing 112 connects the transfer tubing of the dispensing manifold to the connector 102. The tubing 112 and other segments of tubing discussed below can be, for example, flexible and non-flexible tubing formed e.g., from a USP medical grade silicone or thermoplastic elastomer (TPE), such as a Dow Corning® Pharma 50 tubing. The tubing 112, and other segments of the tubing such as tubing for the filling manifold (further discussed below) and transfer tubings, can be sized according to process flow demands. As an example, the tubing can have an inner diameter of 3/8 inches and an outer diameter of 5/8 inches to handle flows up to about 6.0 liters/m inute and operating pressures up to about 30 psig, though other sizing can be provided to accommodate other flow rates and operating pressures. [0030] As shown best in FIG. 2A, the tubing 112 and/or transfer tubing 110 is provided with a clamp 114 (e.g., a C-Pinch Clamp) to prevent fluid flow through downstream branches. A collar 116 (e.g., a quick seal collar) is also provided to allow sealing and visual confirmation of the same. Furthermore, secondary and tertiary sealing mechanisms can also be utilized in the dispensing manifold 104, such as, for example, commercially available cut-to-disconnect tube sealing mechanisms (e.g., Quickseal® aseptic disconnects available from Sartorius Stedim Biotech) and tube sealing mechanisms employing heat and/or pressure to seal tubing (e.g., Biosealer® TC sealers also available from Sartorius Stedim Biotech), as desired.

[0031] In operation, a single quick connector 108 is placed into service while the other branches remain sealed to prevent flow. A run of the pharmaceutical ingredient is processed (e.g., preparation of 110-140 containers of pharmaceutical ingredient) using a single particular quick connector. After a single run, the particular quick connector 108 is sealed off to prevent flow and no longer used, and the next quick connector is put into service. Each quick connector can be placed in an open condition for flow by pulling a tab or occlusion tab 118 associated with each respective quick connector 108.

[0032] In FIGS. 1 and 2A, the quick connector 108 can be any connector suitable for connecting the dispensing manifold to an inlet 120 of the filling manifold 106. In the present exemplary embodiment, the quick connector 108 is configured as a “click-pull- twist” connection with the inlet 120, in which the quick connector is in the form of a female connector for receiving the male inlet 120, and is provided with tabs 118 from the quick connector 108. The inlet 120 is also provided with a tab 118’. To place into fluid service, tabs 118 and 118’ are removed, and the quick connector 108 is twisted. Alternatively, other types of aseptic connectors can be used as the quick connector.

[0033] The filling manifold 106 is configured as best shown in FIGS. 1 and 2B and includes the inlet 120 with tab 118’, a plurality of peristaltic pumps 124 (not shown in FIG. 2B) connected in parallel downstream the inlet, and containers 122,128 downstream the plurality of peristaltic pumps 124. [0034] The inlet 120 can be any inlet for connecting to the quick connectors 108 of the dispensing manifold 104, for example, a male connector or any corresponding connector complementary to, and capable of engaging any of the quick connectors 108.

[0035] In the present exemplary embodiment the filling manifold includes thirteen branches 126, 126’ each with a respective peristaltic pump 124 (arranged in parallel) for pumping fluid out of each respective branch of the filling manifold. Twelve of the branches 126 provide the feed of pharmaceutical ingredient to individual polymeric containers 128, disposed downstream from the branches, while the thirteenth branch 126’ feeds a flush/sample container 122 that can be used, for example, in cleaning operations or product sampling. Operation of any one of the peristaltic pumps 124 transfers pharmaceutical ingredient to one of the respective plurality of polymeric containers 128 or container 122. Furthermore, each peristaltic pump 124 can be operated in reverse to draw pharmaceutical ingredient from the containers 128 in the event of an overfill situation.

[0036] FIG. 2B shows the filling manifold with the peristaltic pumps 124 omitted for purposes of clarity. The inlet 120 of the filling manifold is shaped complementary to the quick connector 108 and is capable of aseptic connection to the dispensing manifold 104. Each branch of the filling manifold feeding the polymeric containers 128, 122 can be provided with a clamp 130 and quick seal collar 132 similar to clamp 114 and collar 116 of the dispensing manifold 104. The clamp and quick seal collar are positioned downstream the inlet 120.

[0037] The filling manifold is formed from a transfer tubing 134 that branches out into a plurality of branches 126, 126’ e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20 or more branches. Each of the manifold branches is arranged in parallel with respect to each other. In the present exemplary embodiment, the manifold branches are formed from tubing, such as tubing 112 etc. discussed above, although other suitable tubing materials for aseptic processing of pharmaceutical ingredients can be used. Tubing 136, of like construction as tubing 112, connects the inlet 120 to the plurality of peristaltic pumps. Tubing 134 further connects each peristaltic pump to respective polymeric containers 128. [0038] In the present exemplary embodiment, the filling manifold is arranged in a vertical fashion such that each branch of the filling manifold is at a different height from the floor. As such, each of the polymeric containers 128 can be positioned to rest on a cart 138 having vertically arranged compartments for storing each respective polymeric container, as best shown in FIG. 1 . In this configuration, the entire cart 138 can be positioned on the scale 101 for weighing said polymeric containers.

[0039] The scale 101 measures the weight of the plurality of containers 128 e.g., during filling operations so that the containers can be monitored for amounts of the pharmaceutical ingredient filled therein. FIG. 1 shows the use of a single scale 101 that measures the weight of the plurality of containers 128 collectively. A weight indicator/display 140 is operatively associated with the scale to display the weight. As further discussed below, the scale is operatively in communication with the controller 800.

[0040] In accordance with an alternative exemplary embodiment, the filling manifold can include a plurality of scales 10T (FIG. 2C) (instead of a single scale collectively weighing all the plurality of containers) that individually measures the weight of each of the plurality of containers 128. Each of the plurality of scales can include respective weight indicators 140’ which are each operatively in communication with the controller 800.

[0041] In this exemplary embodiment of the subject disclosure, the aseptic manifold dispensing assembly 100 does not include any pinch valves for stopping the flow of fluid therethrough. In other words, the flow of fluid and the halting thereof through the aseptic manifold dispensing assembly is completely controlled via the peristaltic pumps.

[0042] Referring back to FIG. 1 , an in-line filter 142 can be included in the dispensing manifold 104 e.g., between the connector and the transfer tubing 110, and/or included in the filling manifold 106.

[0043] The polymeric containers can be, for example, an 8L container 328 as shown in FIG. 3A, which can be particularly useful to contain, for example, a cell paste. The polymeric container’s chamber is composed of a non-leaching material suitable to store pharmaceutical ingredient (e.g., ethylene vinyl acetate). Other size containers of different construction can also be used in accordance with the present disclosure, such as containers of 1 , 2, 4, 6, 10, 12, 14, 16, 18, 20 and 20+ L.

[0044] With continued reference to FIG. 3A, in addition to the branch 330 that feeds the container, auxiliary tubing 332 also provides a sterile inlet and outlet to the container. Auxiliary tubing 332 can, for example, have an inner diameter of 3/8 inches and an outer diameter of about 15/32 inches with a length of about 7.9 inches (200 mm) and can also be composed of ethylene vinyl acetate. In this exemplary embodiment, the auxiliary tubing is provided with a clamp 334 (e.g., a polyethylene terephthalate C- pinch clamp) to prevent and allow flow. The distal end of the auxiliary tubing 332 is provided with a sterile coupling 336 (e.g., a 3/8 inch coupling composed of polycarbonate/siloxane copolymer) and a sealing cap 338 (e.g., a polycarbonate sealing cap).

[0045] Alternatively, the polymeric containers can be, for example, a 5L container 328’ as shown in FIG. 3B, which can be particularly useful to contain, for example, working seeds. Like container 328, container 328’ is composed of a suitable material for sterile storage of a pharmaceutical ingredient, such as ethylene vinyl acetate. Alternatively, other materials can be used, for example containers composed of a S71 film, which is a multi-layer film that includes an ethylene vinyl alcohol (EVOH) gas barrier layer and an ethylene-vinyl acetate (EVA) product contacting layer. Other polymeric containers suitable for storage of biopharmaceutical solutions, intermediates and bulk products can also be used in accordance with the present disclosure.

[0046] In the present exemplary embodiment, the container 328' is provided with identification information, such as for example a hanging tag that includes particular information about the date of manufacture and run identification numbers for a particular container. Alternatively, the container 328’ can have affixed thereon a label or other indicia e.g., a hot stamp seal 330’, onto which such particular information about the particular container can be displayed on the seal via, for example, a dry printing process. [0047] Referring to FIG. 3B, the container 328’ includes a first auxiliary tubing 332’ and a second auxiliary tubing 334’. The first auxiliary tubing 332’ can, for example, have an inner diameter of 3/16 inches and an outer diameter of about 1/4 inches with a length of about 4 inches (100 mm) and can also be composed of ethylene vinyl acetate. In this exemplary embodiment, the distal end of the first auxiliary tubing includes an aseptic plug 346’ (e.g., a 5/32 inch press in plug composed of polypropylene), from which ingredient can be aseptically sampled in a sterile fashion when engaged with a complimentary member (e.g., an aseptic male coupling, not shown), or from which other additives can be placed into the container. Alternatively, the first auxiliary tubing 332’ and/or the second auxiliary tubing 334’ can be provided with Luer® sterile connectors. Still further, in other exemplary embodiments, one the first auxiliary tubing or the second auxiliary tubing can be omitted.

[0048] The second auxiliary tubing 334’ of container 328’, includes a first tube segment 334’ (e.g., a inch ID, 5/16 inch OD, 100 mm long ethylene vinyl acetate tube) and a relatively narrow second tube segment 342’ (e.g., a 1/8 inch ID, inch OD, 150 mm long ethylene vinyl acetate tube) that are joined by a reducer junction 340’ (e.g., a inch x 1/8 inch polypropylene reducer). The distal end of the second tube segment 342’ includes an aseptic plug 344’, similar to aseptic plug 346’, but sized accordingly to fit the relatively narrow second tube segment (e.g., a 1/8 inch press in plug composed of polypropylene). The reducer junction facilitates the reduction in tubing diameter from the first tube segment 338’ to the second tube segment 342'.

[0049] The peristaltic pump applicable to the aseptic manifold dispensing assembly can be, for example, a peristaltic pump 400 as depicted in FIGS. 4A-5, although other roller-type, positive displacement pumps can also find use according to the present disclosure. The peristaltic pump includes a pump head 402, a pump drive 404 and a manual controller 406. As shown in FIG. 4A, multiple pump heads can be mounted on a single drive, or alternatively a single drive can be devoted to each single pump head.

[0050] The pump head 402 includes a top portion 408 that includes a lever 410 movable from left to right as shown in FIG. 4B to open the top portion a distance from a bottom portion 412 to allow tubing (e.g., branched tubing 126 from filling manifold 106) to be threaded on a recess 414 provided along an outer perimeter of the bottom portion of the pump head 402. Once the tubing is threaded, the lever 410 is rotated to the left to close the head, and the tubing can automatically be retained by the top portion 408 of the pump head. An occlusion setting can be manually made using a knob 416 located along the perimeter of the top portion 408. As no pump components come in contact with process flow, the peristaltic pump 400 allows for the aseptic processing of pharmaceutical ingredient.

[0051] FIG. 5 depicts internal components of the bottom portion 412 of the pump head. In this exemplary embodiment, three rollers 418 are provided, although other numbers of rollers can alternatively be employed. A peristaltic pump with three rollers or more is preferable as the use of three or more rollers advantageously provides a retention of fluid means within the tubing when the peristaltic pump is stopped. This advantageously provides a means to stop the flow of fluid within the tubing, results in less leakage upon pump stoppage, and more accuracy in dosage delivery by the pump. That is, the three or more rollers compress the tubing creating a suction to retain fluid within the tubing. The rollers can be composed of e.g., cold-rolled steel or stainless steel.

[0052] A shaft 420, which can be of varying length (e.g., inches or 1 .19 inches) is provided for connection to the pump drive 404. Depending on the particular pump drive, from 6 to 650 RPM can provide flow capacities of from about 0.01 to 13 LPM (0.002 to 3.5 GPM) in this particular embodiment. The pump can flow in forward or reverse for high precision filling of the container, as well as recovery from an overfill event

[0053] FIG. 6 depicts another exemplary peristaltic pump 600 that can be used according to an alternate, exemplary embodiment. The peristaltic pump 600 includes a pair of rollers 602 attached to a rotor 604. The peristaltic pump further includes a casing 606 that includes a track 609 sized to accommodate flexible tubing (e.g., branched tubing 126 in FIG. 1 ). The peristaltic pump 600 includes a manual controller 608, which includes a user interface 610 to display output and settings of the pump (e.g., rotational speed) of the peristaltic pump. In operation, the rotor rotates and the rollers compress the flexible tubing to occlude flow while rotating, and subsequently releases the tubing as the tube segment passes a cam, to pump the fluid (i.e. , peristalsis). A second roller also engages the tubing in a like manner, working in cooperation with the first roller, but which also serves as a valve means (similar to a pinch valve) to retain and hold fluid pumped through the tubing.

[0054] The peristaltic pump can be, e.g., a Masterflex™ pump available from Cole- Parmer, such as HL-77601 series pump heads and HL-07591 series pump drives, a Watson-Marlow pump, such as a 600 series mid-flow process pump (e.g., a 630Du, Du, 630 Bp, 630 PbN, 630En and EnN peristaltic process pumps). (See, e.g., https://www.watson-marlow.com/us-en/range/watson-marlow/600- series-rnid-flow- process-pumps/).

[0055] Other peristaltic pumps can alternatively be employed. For example, peristaltic pumps from New Era Pump Systems (e.g., Programmable Peristaltic Pump, 9000 series); and Blue-White Industries (e.g., Flex-Pro® A2, A3, and A4 Proseries Peristaltic Pumps) can be used in accordance with the present disclosure.

[0056] FIG. 7 illustrates another aseptic manifold dispensing assembly 700 in accordance with another exemplary embodiment of the present disclosure. The dispensing assembly 700 includes a single-use connector 702, such as a single use connector for sterile connection to a source 1000’ of the pharmaceutical ingredient, which can be a vat, tank or similar apparatus for storing a pharmaceutical ingredient. A pressure gauge 744 is provided in proximity to or downstream from the source to measure the pressure of the pharmaceutical ingredient outputted from the source 1000’. Valved flush lines (not shown) can be provided between the source of the pharmaceutical ingredient and the connector 702 to relieve high pressure situations at the source.

[0057] Flexible tubing 712 is provided downstream from the single-use connector 702. A pump 746 (e.g., a peristaltic pump) can optionally be provided downstream of the connector. A pair of filters, 748a, 748b (e.g., micron filters) can be provided in series downstream of the connector 702 and upstream from a dispensing manifold 704. A flush valve or flush mechanism can be positioned, for example, between the first filter 748a and the second filter 748b. [0058] Pressure sensors 750 and 752 are positioned upstream and downstream from the pair of filters 748a, 748b. This configuration allows an operator to monitor the filters e.g., to confirm that they are not clogged and able to sufficiently meet process flow demands by ascertaining the pressure drop caused by the filter. A pressure drop above a certain tolerance could indicate that the filters 748a, 748b need to replaced or flushed, which can be achieved by e.g., separate tubing or piping (not shown) to allow a flushing solution to be applied to the filters.

[0059] The tubing 712 terminates at the dispensing manifold 704, which is similar to dispensing manifold 104 described in connection with FIG. 1. In this exemplary aseptic manifold dispensing assembly embodiment 700, a plurality (for example, fifteen) of quick connect first (e.g., female) members 708 is provided at the outputs of the dispensing manifold. A quick connect second (e.g., male) member 720 that is complementary to, and engageable with any one of the first members 708 is provided on the filling manifold 706.

[0060] Production can be processed through the dispensing manifold 704 similar to as described above in connection with FIG. 1 , or alternatively the dispensing manifold can be sterilized and used multiple times. In this regard, the dispensing manifold is provided in this exemplary embodiment with separate tubing or piping 754 which can be used, for example, to receive a cleaning solution or air flush introduced to clean or empty out the manifold, with the cleaning solution and/or remnants in the manifold being collected in flush container 756. It is noted that an air flush container is not required in embodiments in which the dispensing manifold is only operated once per run, and then taken out of service.

[0061] Flexible tubing 736 is provided downstream from the second (e.g., male) member 720 of the quick connect where it meets the filling manifold 706, which in turn is provided with twelve branches 726 of flexible tubing. Each branch 726 is respectively provided with a peristaltic pump 724, which can be similar to peristaltic pumps 124, 400, 600 or other roller-type positive displacement pumps known in the art. [0062] In this exemplary embodiment, pressure sensors 758 are provided along each branch 726 and located downstream of the respective peristaltic pump, and upstream from the containers 728.

[0063] The peristaltic pumps 724 can be operated alone or in tandem to draw pharmaceutical ingredient from and feed a plurality (e.g., 12) of, for example, 5L polymeric containers 728 to collect the pharmaceutical ingredient and store it for subsequent use. As discussed below in connection with FIG. 8, the peristaltic pumps can be controlled by a controller or computer.

[0064] The containers 728 are housed in a housing 760, which can be disposed on a cart 738, and disposed on a weight scale 701 fared to indicate the weight of the pharmaceutical ingredients stored in the polymeric containers 728. A weight indicator 740 can indicate the weight of one or more of the containers, and also communicate the weight to a controller 800. The controller controls operation of the peristaltic pumps 724, when the peristaltic pumps are off and flow through respective branches 726 is halted.

[0065] Any one component, or all the components of the aseptic manifold dispensing assembly is mobile, e.g., the component(s) can be disposed on a movable cart, such as cart 138, as shown in FIG. 1 or cart 738 as shown in FIG. 7 supporting both the dispensing and filling manifolds. Indeed, in certain embodiments, all or substantially all of the dispensing manifold and/or the filling manifold are mobile and can be transported as needed about the production area of a processing facility.

[0066] Referring to FIG. 8, flow to the polymeric containers 128, i.e. , the plurality of containers is controlled by the peristaltic pumps which are, in turn, controlled by the controller or computer 800. The controller 800 includes computer instructions executable by a processor to execute e.g., an automation code. The automation code can be based on a logic sequence stored in, for example, a memory or computer readable medium (e.g., a non-transitory computer readable medium), of the controller, which is based on, for example, one or more of inputs e.g., filling times, filling weights, pressure readings and/or number of pump revolutions (e.g., RPM) of the peristaltic pumps. The automation code can also, in certain embodiments, provide an option to “override” the logic sequence, to, for example, require the manual operation of the aseptic manifold dispensing assembly 100 and peristaltic pumps 124. Further, this “override” sequence can be automatically triggered, to shut down automatic operation of the peristaltic pumps, upon a registered overpressure or overfilling event, such as when the scale weighs a weight that exceeds a predetermined weight limit.

[0067] In this exemplary embodiment, the controller controls the speed of flow through each branch 126 of the filling manifold via controlling the speed (e.g., RPM) of the peristaltic pump 124, which is in turn governed by an automation code based on a logic sequence, which includes an override automation code to allow the peristaltic pumps to be operated manually. The automation code also includes instructions to reverse the flow of material, and recover dosing accuracy by removing material in the event of an overfill.

[0068] The controller is operatively in communication with the peristaltic pumps, pressure sensors, scale and weight indicator. As such, feedback control of the peristaltic pump 124 based on a pressure sensor 758 is provided via the controller. An acceptable predetermined operating range for pressure can be established based on the material being dispensed and stored in the controller e.g., on a controller memory. Thus, if pressure goes out of range an alarm tied to the automation code for high and low pressures outside the acceptable range can be activated. For example, if the pressures are over the acceptable range (to prevent the system from being overfilled or rupturing) or below the acceptable range (to minimize any spill when/if a connection is not mated correctly, or there is a cut in the line, or other atypical circumstances), then the controller can interlock the aseptic manifold assembly i.e. , put the system in a hold status.

[0069] The controller 800 utilizes instructions defined in an automation code to turn the pump on, to an appropriate speed (with the option for ramp up rates and ramp down rates to increase filling accuracy). The utilization of pressure sensors enhances and ensures a safe state of operations. Hi and Low setpoints on the pressure feedback will trigger a logic sequence to stop the pumps when the pressure is too high and there is a blockage in the system, and when the pressure is low and the connection/closed boundary has likely been compromised. The weight and pressure feedback to the controller indicates, when, how fast, what direction the peristaltic pumps should operate, and if the pumps should be on.

[0070] More particularly, as shown in FIG 8, in a pre-run sequence 802, the controller 800 receives as inputs a maximum operating speed (RPMmax), a maximum filling time (tmax), minimum and maximum acceptable pressures (Pmax, Pmin) and the desired filling weight (Wmax). A start sequence 804 is begun, for example, when it is established that if, and only if, the pressure reading, P, from the pressure sensor 758, is between Pmax and Pmin and the weight, W of the container 128 from the weight indicator 140 is less than 0.8 (Wmax), then the peristaltic pump speed is set to RPMmax and the container 128 is filled with pharmaceutical ingredient, and a timer is initiated (t=0). This start sequence 804 is continued so long as Pmin < P < Pmax, W < 0.8(Wmax), and the filling time, t, < tmax. If at any time the measured P falls outside of (Pmin, Pmax), or if t > tmax, then automatic operation of the peristaltic pump 124 is ceased.

[0071] Once the weight W of the container reaches 0.8 (Wmax), a ramp down sequence 806 is initiated, which reduces the operating speed of the peristaltic pump 822 to 0.1 (RPMmax). The ramp down sequence 806 continues until W > Wmax, preferably ending at W = Wmax (i.e. , within an acceptable weight tolerance of the final desired container weight), in which a pause sequence 808 is initiated and the pump speed is set to 0 RPM. The pause sequence 808 pauses the pump for a time sufficient for the manifold system to reach equilibrium, and the weight, W of the container is again ascertained in a confirmation sequence 810. If the weight, W of the container is within an acceptable tolerance, the process with respect to a particular bag is ceased in an end sequence 812, and the next container is filled under an analogous process control scheme. If it is found that the weight, W exceeds Wmax, then an overfill sequence 814 is initiated which reverses the pump to run at -0.05(RPM Max) until W equals Wmax. If an overcorrection occurs as a result of the overfill sequence 814, then the pump is again placed back in the ramp down sequence 806 and the process is repeated until it is confirmed in confirmation sequence 810 that W=Wmax (i.e. , W is within a predefined tolerance for filling the container).

[0072] In certain embodiments, the logic sequence can include a self-correcting feature in which, for example, the weight, W, measured in the pause sequence 808 is registered. Upon reaching a specified level or number of registered abnormal result(s), such as three-consecutive registered weight, W, values that exceed a predefined tolerance, then the logic sequence takes corrective action to prevent overfill situations in the future. For example, upon registering three consecutive overweight W values, the logic sequence can then provide for RPM=0.75 RPMmax in the start sequence 804, to have the ramp down sequence 806 begin at 0.7Wmax instead of 0.8Wmax, and decrease the RPM of the peristaltic pump in the ramp down sequence 806 to 0.05 RPMmax. Other logic sequences incorporating registered results, such as described above, can be employed.

[0073] The controller or computer can be a microprocessor-based control system known in the art, such as a distributed control system (DCS) and capable of real-time electronic communication with field level sensors (e.g., pressure sensors and/or weight indicators). Such systems can be obtained and implemented in coordination with various commercial vendors, such as for example, from ABB Ltd., Emerson Electric Co., and Honeywell International Inc.

[0074] Peristaltic pumps allow for greater operational flexibility than pinch valves. As shown above, peristaltic pumps can be employed to control the filling of the containers more precisely, as each pump can be controlled to precisely deliver controlled amounts of pharmaceutical ingredient to the container. As the presently disclosed subject matter provides, in certain embodiments, a plurality of peristaltic pumps, quicker fillings times can also be achieved. This is particularly helpful given that there is generally a specified and limited time period in which pharmaceutical ingredient must or should be transferred from the source (e.g., a vat) to the containers.

[0075] Furthermore, the instant aseptic manifold dispensing assembly offers numerous operational advantages and efficiencies, as compared to, for example, single-fill systems. According to the present disclosure, a field-level operator only needs to manage connection of the dispensing manifold 104 to the filling manifold, which is isolated from the containers themselves. This minimizes handling of the containers by the operators to ensure bag integrity. Furthermore, an ergonomic advantage is obtained, as a single connection of a filling manifold to a single connector 108, will allow for the filling of multiple bags (e.g., 10 or 12 per run) with minimum operator involvement required.

[0076] It will be appreciated by those skilled in the art that changes could be made to the exemplary embodiments described above without departing from the broad inventive concept thereof. It is to be understood, therefore, that this disclosure is not limited to the particular exemplary embodiments disclosed, but it is intended to cover modifications within the spirit and scope of the subject disclosure as disclosed above and claimed.