WO2022060963A1 - Automated downstream processing of a biologic product - Google Patents

Abstract

The present disclosure provides an automated downstream processing module for processing of a biologic product and methods of using said module. The downstream processing module can process a biologic product from any source, including an automated fully-enclosed upstream production module.

Description

AUTOMATED DOWNSTREAM PROCESSING OF A BIOLOGIC PRODUCT

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] The present application claims benefit of U.S. Provisional Patent Application No. 63/079,860, filed September 17, 2020, the disclosure of which is incorporated by reference herein in its entirety.

FIELD OF THE INVENTION

[0002] The present disclosure provides an automated downstream processing module for processing of a biologic product and methods of using said module. The downstream processing module can process a biologic product from any source, including an automated fully-enclosed upstream production module.

BACKGROUND OF THE INVENTION

[0003] As anticipation builds about accelerated clinical adoption of advanced biologic products such as therapeutic cells, proteins, nucleic acids and other products, more attention is turning to the underlying manufacturing strategies that will allow these products to benefit patients worldwide. While biologic product therapies hold great promise clinically, high manufacturing and processing costs relative to reimbursement present a formidable roadblock to commercialization. Thus, the need for cost effectiveness, process efficiency and product consistency is driving efforts for automation in numerous biologic product therapy fields.

[0004] Automation of various processes is involved in producing biologic products for therapy and various devices and methods have been described, such as in Published U.S. Patent Application No. 2019-0169672 and U.S. Patents 9,701,932 and 9,534,195, which are hereby incorporated by reference. There is a need however for automation of downstream processing of biologic products and integration of biologic product production with automated downstream processing for the isolation or purification of biologic products within a commercial manufacturing platform. The benefits of automation of downstream processing of biologic products include labor time savings associated with using automation as well as improved product consistency, decreased room classification, decreased clean room footprint, decreased training complexities, and improved scale-up and tracking logistics. Furthermore, software can be used to streamline the documentation processes by using automatically generated electronic batch records to provide a history of all processing equipment, reagents, operator identification, in-process sensor data, and so forth.

[0005] An automated, self-contained system in which a biologic product is purified, isolated, and further processed would revolutionize the field of biologic product therapy. There is an urgent need for technology that would allow control of the critical steps of downstream biologic product processing and provide reproducible and stable results, while simultaneously limiting contamination and reducing cost.

SUMMARY OF THE INVENTION

[0006] In some embodiments, provided herein is a module for automated downstream processing of a biologic product, comprising: a housing; one or more units configured to isolate, hold and/or elute the biologic product; one or more sensors and/or mechanisms to detect and/or adjust one or more of the following: pressure, temperature, pH, conductivity, UV absorption, and cell density; and a fluid containment system in fluid communication with said units, sensors and/or mechanisms; wherein the components are contained in the housing.

[0007] Also provided herein is a device providing fully integrated automated upstream production and downstream processing of a biologic product, comprising: an automated upstream production module, wherein the production module comprises: a cell culture chamber; one or more of a temperature sensor, a pH sensor, a glucose sensor, a lactose sensor, an oxygen sensor, a carbon dioxide sensor, and an optical density sensor; and mechanisms to adjust one or more of a temperature, a pH level, a glucose level, a lactose level, an oxygen level, a carbon dioxide level, and an optical density; and an automated downstream processing module, wherein the downstream processing module comprises: a housing; one or more units configured to isolate, hold and/or elute the biologic product; one or more sensors and/or mechanisms to detect and/or adjust one or more of the following parameters: pressure, temperature, pH, conductivity, UV absorption, and cell density; and a fluid containment system in fluid communication with said units, sensors, and/or mechanisms; wherein the components are contained in the housing, and wherein the automated upstream production module is in fluid communication with the automated downstream processing module.

[0008] Also provided herein is a method for downstream processing of a biologic product, comprising: introducing a biologic product into a fully enclosed, downstream processing module; sensing and/or adjusting one or more of the following: pressure, temperature, pH, conductivity, UV absorption, and cell density; isolating and/or eluting the biologic product via one or more columns and/or filtration units; and holding the biologic product; wherein the are carried out in an automated manner.

[0009] Also provided herein is a method for providing fully integrated automated upstream production and downstream processing of a biologic product, comprising: producing a biologic product within an upstream production module, wherein the production module comprises: a cell culture chamber; one or more of a temperature sensor, a pH sensor, a glucose sensor, a lactose sensor, an oxygen sensor, a carbon dioxide sensor, and an optical density sensor; and mechanisms to adjust one or more of a temperature, a pH level, a glucose level, a lactose level, an oxygen level, a carbon dioxide level, and an optical density; and processing the biologic product within a downstream processing module, wherein the downstream processing module comprises: a housing; one or more units configured to isolate, hold and/or elute the biologic product; one or more sensors and/or mechanisms to detect and/or adjust one or more of the following parameters: pressure, temperature, pH, conductivity, UV absorption, and cell density; and a fluid containment system in fluid communication with said units, sensors, and/or mechanisms; wherein the components are contained in the housing, and wherein the upstream production module is in fluid communication with the downstream processing module.

BRIEF DESCRIPTION OF THE DRAWINGS

[0010] FIG. 1 shows a flow diagram for the automated production and downstream processing of a biologic product in accordance with embodiments hereof.

[0011] FIG. 2 shows a closed and automated upstream production module as described in embodiments herein. [0012] FIG. 3 shows a lab space containing exemplary closed and automated upstream production modules as described in embodiments herein.

[0013] FIG. 4 shows a diagram of a biologic product production process that can be performed in a cassette of a closed and automated module as described in embodiments herein.

[0014] FIG. 5 shows a flow diagram of a process within an automated production module as described herein.

[0015] FIG. 6 shows a block diagram of downstream processing in accordance with embodiments hereof.

[0016] FIG. 7A shows a flow diagram of downstream processing in accordance with embodiments hereof.

[0017] FIG. 7B shows exemplary fluid circuits utilized in the downstream processing modules described herein.

[0018] FIGS. 8A-8D show components of a downstream processing module in accordance with embodiments hereof.

[0019] FIGS. 9A-9C show an exemplary software control design for use with a downstream processing module in accordance with embodiments hereof.

[0020] FIGS. 10A and 10B show two views of a downstream processing module in accordance with embodiments hereof.

[0021] FIG. 11 shows an additional example of a downstream processing module in accordance with embodiments hereof.

[0022] FIG. 12 shows a plurality of downstream processing modules arranged in a clinical or clean-room setting in accordance with embodiments hereof.

[0023] FIGS. 13A-13B show an additional example of a downstream processing module in accordance with embodiments hereof. [0024] FIGS. 14A-13D show a still further example of a downstream processing module in accordance with embodiments hereof.

DETAILED DESCRIPTION OF THE INVENTION

[0025] The published patents, patent applications, websites, company names, and scientific literature referred to herein are hereby incorporated by reference in their entirety to the same extent as if each was specifically and individually indicated to be incorporated by reference. Any conflict between any reference cited herein and the specific teachings of this specification shall be resolved in favor of the latter. Likewise, any conflict between an art-understood definition of a word or phrase and a definition of the word or phrase as specifically taught in this specification shall be resolved in favor of the latter.

[0026] The use of the word “a” or “an” when used in conjunction with the term “comprising” in the claims and/or the specification may mean “one,” but it is also consistent with the meaning of “one or more,” “at least one,” and “one or more than one.”

[0027] Throughout this application, the term “about” is used to indicate that a value includes the inherent variation of error for the method/device being employed to determine the value. Typically, the term is meant to encompass approximately or less than 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19% or 20% variability depending on the situation.

[0028] The use of the term “or” in the claims is used to mean “and/or” unless explicitly indicated to refer only to alternatives or the alternatives are mutually exclusive, although the disclosure supports a definition that refers to only alternatives and “and/or.”

[0029] As used in this specification and claim(s), the words “comprising” (and any form of comprising, such as “comprise” and “comprises”), “having” (and any form of having, such as “have” and “has”), “including” (and any form of including, such as “includes” and “include”) or “containing” (and any form of containing, such as “contains” and “contain”) are inclusive or open- ended and do not exclude additional, unrecited elements or method steps. It is contemplated that any embodiment discussed in this specification can be implemented with respect to any method, device, system, and/or composition of the invention.

[0030] Technical and scientific terms used herein have the meaning commonly understood by one of skill in the art to which the present application pertains, unless otherwise defined. Reference is made herein to various methodologies and materials known to those of skill in the art.

[0031] In embodiments, provided herein is a module for downstream processing of a biologic product. Suitably, the module is for automated downstream processing of a biologic product.

[0032] As described herein, “a module for downstream processing” refers to a contained system, suitably including a plurality of chambers, and wherein processing of a biologic product takes place in the same or a different chamber of the plurality of chambers of the module for downstream processing. The module can include one or more chambers maintained at a refrigerated temperature (e.g., at about 4-8 °C) and a low pH (e.g., from about pH 4 to about pH 6). In embodiments, the module is configured for automated downstream processing of a biologic product which refers to isolation, holding, and/or elution of a biologic product without the use of input or control from a user, but rather to operate under the input of a microprocessor or computer system.

[0033] Contained” suitably refers to the plurality of chambers being interconnected, including via various tubing or other fluidly connected pathways and connections, to maintain the cleanness, and suitably sterility, of the contained module.

[0034] A “biologic product,” as produced and processed by the upstream producing module and downstream processing module, respectively, refers to a product that is biological in nature, i.e., produced by a living organism, suitably useful for a therapeutic or industrial purpose. Biologic products processed by the various modules and methods described herein can be harvested, purified, isolated and stored until a final desired application or further formulation. Examples of biologic products include but are not limited to amino acids, peptides, polypeptides, antibodies, nanobodies, vesicles, exosomes, nucleic acids, carbohydrates, lipids, enzymes, and any other type of molecule or element produced or found in living organisms known in the art. [0035] In further embodiments, the biologic product is produced from, or is a cell and/or tissue culture, a plant tissue culture, a yeast culture, a multicellular organism, or a mammalian cell. As used herein, the term “mammalian cell” includes cells from any member of the order Mammalia, such as, for example, human cells, mouse cells, rat cells, monkey cells, hamster cells, and the like. In some embodiments, the cell is a mouse cell, a human cell, a Chinese hamster ovary (CHO) cell, a CHOK1 cell, a CHO-DXB11 cell, a CHO-DG44 cell, a CHOK1SV cell including all variants (e.g. POTELLIGENT®, Lonza, Slough, UK), a CHOK1SV GS-KO (glutamine synthetase knockout) cell including all variants (e.g., XCEED™ Lonza, Slough, UK). Exemplary human cells include human embryonic kidney (HEK) cells, such as HEK293, HEK293T, a HeLa cell, or a HT1080 cell.

[0036] Suitably, a multicellular organism is an organism which contains more than one cell. Multicellular organisms include animals, plants, and fungi. Biologic products can be processed from any extract or composition of matter produced or found in animals, plants and fungi, including but not limited to: whole blood, plasma, serum, bile, extracellular fluid, membrane, cell wall, sap, spores, or any type of animal, plant or fungal tissue.

[0037] Fungi, which may be, or may produce the biologic product, include the species Aspergillus nidulans, Aspergillus niger, Claviceps purpurea, Fusarium oxysporum, Myceliophthora thermophile, Neurospora crassa, Penicillium nalgiovense, Taxomyces andrenae, Trichoderma reesei, and other relevant fungi known in the art.

[0038] In some embodiments, the biologic product is, or is produced by a bacterial culture. Bacterial cultures include the species Amycolaptopsis orientalis, Bacillus subtilis, Bacillus licheniformis, Brevibacillus choshinensis, Cephalosporium acremonium, Escherichia coli, Lactococcus lactis, Lactobacillus reuteri, Streptomyces aureofaciens, Streptomyces avermitilis, Saccharopolyspora erythraea, Streptomyces gandocaensis, Streptomyces griseus, Streptomyces iranensis, Streptomyces nodosus, Streptomyces peucetius, Streptomyces rapamycinius, Streptomyces rimosus, Streptomyces tsukubaensis, Streptomyces toxytricini, Streptomyces venezuelae, Streptomyces verticillus, and other relevant bacteria known in the art.

[0039] Mammalian cells include mammalian cell cultures which can be either adherent cultures or suspension cultures. Adherent cultures refer to cells that are grown on a substrate surface, for example a plastic surface, plate, dish or other suitable cell culture growth platform, and may be anchorage dependent. Suspension cultures refer to cells that can be maintained in, for example, culture flasks or large suspension vats, which allows for a large surface area for gas and nutrient exchange. Suspension cell cultures often utilize a stirring or agitation mechanism to provide appropriate mixing. Media and conditions for maintaining cells in suspension are generally known in the art. An exemplary suspension cell culture includes human HEK293 clonal cells.

[0040] Suitably, the downstream processing module described herein comprises a housing. As referred to herein, the word “housing” can mean a barrier that covers a portion or the entire apparatus of the downstream module. Suitably, the housing can be liquid resistant and can protect the mechanisms incorporated into the module.

[0041] Suitably, the module described herein further comprises one or more units configured to isolate, hold and/or elute the biologic product.

[0042] As referred to herein, to “isolate” a biologic product means to separate the biologic product from the matrix (cells, tissue, fluids, etc.) in which the product is produced. Suitably, isolation of a biologic product can comprise subjecting a biological sample containing the biologic product to a series of mechanisms including but not limited to: columns, filters, membranes, centrifuges and other isolation processes known in the art. The word “isolate” is synonymous with the word “purify” in this application.

[0043] As referred to herein, to “hold” a biologic product means to retain the biologic product in one or more of a plurality of chambers at any point during downstream processing. Holding the biologic product may occur at a constant temperature, pressure, or pH.

[0044] As referred to herein, to “elute” a biologic product means to remove or release the biologic product from an isolation mechanism, such as a column, filter, or membrane by washing with a solvent or buffer. Elution can also include a solvent exchange or pH modification of the biologic product. Examples of such buffers and solvents are generally known in the art. [0045] Suitably, the module described herein comprises one or more sensors and/or mechanisms to detect and/or adjust one or more of the following: pressure, temperature, pH, conductivity, UV absorption, and cell density.

[0046] Suitably, said sensors and/or mechanisms to detect and/or adjust the parameters of processing a biologic product are automated and receive input and/or provide output from/to a microprocessor. The “automated” process or “automation” of the process refers to the control of one or more processes described herein by an external control, including a microprocessor, to monitor and change one or more of a temperature, a pH level, a glucose level, a lactose level, an oxygen level, a carbon dioxide level, an optical density, a pressure, a conductivity, a UV absorption, or a cell density based on a defined, or pre-set set of circumstances or desired characteristics. Suitably, “automated” processes require little user input once they are initiated, and in embodiments, require no user input once the process has been started and the appropriate conditions and instructions provided (often by a user) to a microprocessor or computer system.

[0047] Suitably, the module described herein comprises a fluid containment system in fluid communication with said units, sensors, and/or mechanisms.

[0048] As referred to herein, “fluidly connected” means that one or more components of a system are connected via a suitable element that allows for fluids (including gases and liquids) to pass between the components without leaking or losing volume. Exemplary fluid connections include various tubing, channels and connections known in the art, such as silicone or rubber tubing, luer lock connections, etc. It should be understood that components that are fluidly connected can also include additional elements between each of the components, while still maintaining a fluid connection. That is, fluidly connected components can include additional elements, such that a fluid passing between the components can also pass through these additional elements, but is not required to do so.

[0049] Between the various elements of the downstream processing module, an in line 0.2 micron filter is suitably used to protect from bacterial contamination and to remove precipitates. [0050] As illustrated in FIG. 1, following the downstream processing module 108, the biologic product can be passed on for further analytics 110, including measurement of concentration, purity, contamination, etc.

[0051] Suitably, the components of the said processing module are contained in the housing. As referred to herein, “contained” refers to being supported by, and suitably enclosed within, a structure, such as a housing as previously described. In some embodiments, all components of the processing module are contained in the housing. In other embodiments, only some components are contained in the housing. In still further embodiments, components are connected via enclosed tubing but are not fully contained in the housing.

[0052] In some embodiments, the unit configured to isolate, hold, and/or elute the biologic product comprises one or more of the following: a chromatography column, a chromatography filter, a concentration and/or buffer exchange unit, a primary recovery filter, a pH sensor, and a pH adjustment mechanism.

[0053] In further embodiments, the unit configured to isolate, hold and/or elute the biologic product comprises a disposable unit. Suitably, the disposable unit is a cassette.

[0054] Suitably, the downstream processing module described herein comprises durable and disposable parts (Fig. 1). Durable parts are in general fixed and permanent parts of the module and not replaced after each use (though they can be repaired or replaced as needed). Suitably, durable parts are those which are configured to control and operate electronics and which are mechanical components configured to sense and control parameters of processing (e.g., pumps), such as pressure, temperature, pH, conductivity, UV absorption, and cell density. Durable parts or a durable unit (Fig. 8A) are re-arrangeable and customizable in configuration to suit the desired application. Disposable parts (Fig. 1, Fig. 8B-8D) are parts which are configured to isolate, hold and/or elute the biologic product as well as support these processes by means of fluid and/or buffer exchange, pH adjustment, etc. Suitably, disposable parts are removable, disposable, customizable and replaceable to suit the desired application, which ultimately depends on the biologic product being processed by the downstream module. [0055] The disposable parts in Fig. 1 and Fig. 8B-D carry out processes such as isolation, separation, and elution of the biologic product. Suitably, the disposable parts or disposable unit as described herein can comprise a chromatography column, a chromatography filter, a concentration or buffer exchange unit, a primary recovery filter, a centrifuge, or a pH titration unit.

[0056] FIG. 7A shows an exemplary flow diagram and exemplary components of a downstream processing module 108 as described herein. As shown, the downstream processing module suitably includes various buffers and reagents, as well as columns, that can be replaced for each run or for a different biologic product, as well as components that are not replaced, e.g., durable parts such as pumps, valves, control systems, etc. The downstream processing module suitably comprises a plurality of various sensors, such as a flow sensor, a pH sensor, a conductivity sensor, and a UV sensor. FIG. 7B shows exemplary fluid circuit arrangements utilized in the downstream processing modules, as well as exemplary characteristics of the various fluid movement processes.

[0057] Suitably, the disposable units and/or cassettes include: a chromatography column, a chromatography filter, a concentration and/or buffer exchange unit, a primary recovery filter, a pH sensor, and a pH adjustment mechanism.

[0058] Suitably, the downstream processing module as described herein receives and/or provides input to a microprocessing unit or computer control.

[0059] FIGS. 9A-9C shows an exemplary computer control set-up for a downstream processing module 108, showing an interface to control the various valves, pumps, etc., as well as monitoring of the systems. Also shown is a mock output, illustrating various elements that can be monitored, such as pH, conductivity, UV, temperature, pressure, etc. The computer control set-up allows users to run the device and aid in the development of the recipes and control of the system. Exemplary information that can be provided and include a welcome screen to select recipes and let the user know if the correct cassette is loaded; a schematic showing the recipe being run, which valves and pumps are activated and what step of the recipe is being undertaken; a combined graph showing all the sensors loaded on the specific recipe so the user can monitor the output; and manual mode allowing the operator to individually control the sensors, pumps and valves for use in recipe development. [0060] As shown in FIGS. 10A and 10B, downstream processing module 108 can include components such as a radio frequency identification (RFID) reader to correlate a user or a specific sample with a specific module. Also shown are pressure, conductivity and pH sensors, UV sensors, peristaltic pumps and servo valves, which suitably make up the downstream processing module 108. Exemplary pumps that can be utilized in the downstream processing modules include peristaltic pump which can provide continuous volumes (suitable for interfacing with distributed reagent vessels), and syringe pumps which can accommodate potentially higher pressures, along with high precision, non-pulsatile control and scalability to accommodate small and large volumes.

[0061] Suitably, the module further comprises an input to the housing. The input can be used to introduce a biologic product to the downstream processing module and can include openings to the housing, an intake valve, or inlet port, or other mechanisms known in the art.

[0062] FIG. 11 shows an additional downstream processing module 1108, and includes a disposable unit 1110 that is configured to isolate, hold and/or elute the biologic product and durable unit 1120 that can include one or more sensors and/or mechanisms to detect and/or adjust one or more pressure, temperature, pH, conductivity, UV absorption, and cell density. The downstream processing module 1108 suitably includes a door 1130 or other closable mechanism to contain the disposable unit 1110 within the housing 1140 of the downstream processing module 1108.

[0063] FIG. 12 shows an arrangement of multiple downstream processing modules 1108 in a clinical or clean-room setting. Each of the downstream processing modules 1108 is suitably connected to a base unit 1210 that can contain reservoirs for various buffers and fluids that are supplied to the processing modules during the isolation, holding and/or eluting. These reservoirs (not shown within the structure of base unit 1210), can be replaced as needed or can be filled from supply lines to allow for constant maintenance of the desired or required fluids, etc. Base unit 1210 can also include a refrigeration component to keep the buffers, etc., at the desired temperature, as well as various pumps, etc. Connection between downstream processing module 1108 and base unit 1210 suitably occurs via tubing and interconnects, and can be accommodate switching off various downstream processing modules 1108 in a “plug-and-play” manner, allowing for rapid changing of the modules. Also shown in support structure 1220 which can be any suitable table or similar element to provide structural support to the downstream processing module 1108 and base unit 1210. A person of skill in the art can readily envision other types of support structures, as well as configurations that would allow multiple downstream processing modules 1108 to be utilized, and the number of downstream processing modules 1108 that can be supported is not limited to the number as shown in FIG. 12.

[0064] FIGS. 13A-13B show an additional downstream processing module 1308 as provided herein. FIG. 13B illustrates disposable unit 1310 that is configured to isolate, hold and/or elute the biologic product and durable unit 1320 that can include one or more sensors and/or mechanisms to detect and/or adjust one or more pressure, temperature, pH, conductivity, UV absorption, and cell density. As shown, disposable unit 1310 can take the form a cylindrical cassette that includes one or more chromatography columns, chromatography filters, concentration or buffer exchange units, primary recovery filters, a centrifuge, and/or a pH titration unit The downstream processing module 1108 suitably includes a door 1330 or other closable mechanism to contain the disposable unit 1310 within the housing 1340 of the downstream processing module 1308. Downstream processing module 1308 also suitably includes an interface 1350 to control the various valves, pumps, etc., as well as monitoring of the systems, which can be a touchscreen or similar structure to allow interaction with a user of the downstream processing module.

[0065] FIGS. 14A-14D show an additional downstream processing module 1408 as provided herein. FIGS. 14A-14C illustrate disposable unit 1410 that is configured to isolate, hold and/or elute the biologic product. FIG. 14D illustrates durable unit 1420 that can include one or more sensors and/or mechanisms to detect and/or adjust one or more pressure, temperature, pH, conductivity, UV absorption, and cell density. As shown, disposable unit 1410 can take the form a rectangular cassette that includes one or more chromatography columns (e.g., 1402), chromatography filters, concentration or buffer exchange units or buffer storage (e.g., 1404), primary recovery filters, a centrifuge, and/or a pH titration unit. Disposable unit 1410 can also include inlet port 1406 and outlet port 1408, to allow for the filing, exchange or removal of buffers or other reagents. Disposable unit can also include a pump 1410 as well as one or more valves 1412 to control the flow of buffers, etc., during the downstream processing. The downstream processing module 1408 suitably includes a door 1430 or other closable mechanism to contain the disposable unit(s) 1410 within downstream processing module 1408 inserted into slots within the module 1408. Downstream processing module 1408 also suitably includes an interface (not shown) to control the various valves, pumps, etc., as well as monitoring of the systems, which can be a touchscreen, computer interface, keypad, or similar structure to allow interaction with a user of the downstream processing module.

[0066] In further embodiments, the biologic product is produced in an upstream production module in fluid communication with the input to the housing.

[0067] As described herein, “an upstream production module” refers to a closed system, suitably including a plurality of chambers, and wherein production of a biologic product takes place in the same or a different chamber of the plurality of chambers of the biologic production module. Suitably, each of the various biologic product precursors including producer cells or materials along with cell culture medium, are contained in a different chamber of the plurality of the chambers prior to starting production of the biologic product. The upstream production module suitably includes one or more chambers maintained at a temperature for growing and maintaining cells (e.g., at about 37 °C) and at least one of the plurality of chambers is maintained at a refrigerated temperature (e.g., at about 4-8 °C).

[0068] As described herein, in embodiments, the upstream production module includes exemplary members of the COCOON platform , which integrates multiple unit operations in a single turnkey platform. To provide efficient and effective automation translation, the upstream production module described utilizes the concept of applicati on-specific/ sponsor-specific disposable cassettes that combine multiple unit operations— all focused on the core requirements of the biologic product. Exemplary fully enclosed upstream production module systems are described in Published U.S. Patent Application No. 2019-0169572, the disclosure of which is incorporated by reference herein in its entirety. An exemplary fully enclosed biologic production module 102 useful in the methods described herein is shown in FIG. 2 and can include a cassette 202 for carrying out the upstream production. FIG. 3 shows a lab space containing exemplary fully enclosed upstream production module 102 useful for producing biologic products as described in embodiments herein in a high throughput arrangement.

[0069] In some embodiments, the upstream production module is a batch, a semi-fed batch, a fed-batch, a perfusion or a continuous fermentation bioreactor. [0070] As used herein, “bioreactor” can include a fermenter or fermentation unit, or any other reaction vessel and the terms “bioreactor” and “reactor” are used interchangeably with “fermenter.” The term fermenter or fermentation refers to microbial, fungal and mammalian cultures. For example, in some aspects, an example bioreactor unit can perform one or more, or all, of the following: feeding of nutrients and/or carbon sources, injection of suitable gas (e.g., oxygen), inlet and outlet flow of fermentation or cell culture medium, separation of gas and liquid phases, maintenance of temperature, maintenance of oxygen and CO2 levels, maintenance of pH level, agitation (e.g., stirring), and/or cleaning/sterilizing. Example reactor units, such as a fermentation unit, may contain multiple reactors within the unit, for example the unit can have 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, or 100, or more bioreactors in each unit and/or a facility may contain multiple units having a single or multiple reactors within the facility. The methods, systems and devices described herein can be utilized in connection with any suitable bioreactor including but not limited to stirred tank, airlift, fiber, microfiber, hollow fiber, ceramic matrix, fluidized bed, fixed bed, and/or spouted bed bioreactors. Any suitable reactor diameter can be used. In embodiments, the bioreactor can have a volume between about 100 mL and about 50,000 L. Non-limiting examples include a volume of 100 mL, 250 mL, 500 mL, 750 mL, 1 liter, 2 liters, 3 liters, 4 liters, 5 liters, 6 liters, 7 liters, 8 liters, 9 liters, 10 liters, 15 liters, 20 liters, 25 liters, 30 liters, 40 liters, 50 liters, 60 liters, 70 liters, 80 liters, 90 liters, 100 liters, 150 liters, 200 liters, 250 liters, 300 liters, 350 liters, 400 liters, 450 liters, 500 liters, 550 liters, 600 liters, 650 liters, 700 liters, 750 liters, 800 liters, 850 liters, 900 liters, 950 liters, 1000 liters, 1500 liters, 2000 liters, 2500 liters, 3000 liters, 3500 liters, 4000 liters, 4500 liters, 5000 liters, 6000 liters, 7000 liters, 8000 liters, 9000 liters, 10,000 liters, 15,000 liters, 20,000 liters, and/or 50,000 liters. Additionally, suitable reactors can be multi-use, single-use, disposable, or non-disposable and can be formed of any suitable material including metal alloys such as stainless steel (e.g., 316L or any other suitable stainless steel) and Inconel, plastics, and/or glass.

[0071] In some embodiments, the upstream production module and/or the downstream processing module are suitably adjustable by local control. In other embodiments, the upstream production module and/or the downstream processing module are suitably adjustable by remote control. Suitably, “remote control” means that the function(s) of the module(s) is/are controlled from a distance, i.e., more than about 12 inches from the device itself. Remote control can occur via a handheld device or over a wired or wireless network. [0072] In further embodiments, provided herein is a device providing fully integrated automated upstream production and downstream processing of a biologic product. Said device suitably comprises an upstream production module in fluid communication with a downstream processing module. FIG. 1 shows a block diagram of the flow of the automated production and downstream processing processes described herein that take place in such devices.

[0073] Suitably, the automated upstream production module utilized is an upstream production module as described herein, and the downstream processing module utilized is a downstream processing module described herein. Either or both the upstream or downstream module can include both durable and disposable units, which can include cassettes as described herein.

[0074] Suitably, the automated upstream production module comprises a cell culture chamber, one or more of a temperature sensor, a pH sensor, a glucose sensor, a lactose sensor, an oxygen sensor, a carbon dioxide sensor, and an optical density sensor, and mechanisms to adjust one or more of a temperature, a pH level, a glucose level, a lactose level, an oxygen level, a carbon dioxide level, and an optical density. In embodiments, the automated upstream production module is a COCOON system as described in Published U.S. Patent Application No. 2019-0169572 and U.S. Patents 9,701,932 and 9,534,195, the disclosures of which are incorporated by reference herein in their entireties.

[0075] Suitably, the automated downstream processing module comprises a housing, one or more units configured to isolate, hold and/or elute the biologic product, one or more sensors and/or mechanisms to detect and/or adjust one or more of the following parameters: pressure, temperature, pH, conductivity, UV absorption, and cell density, and a fluid containment system in fluid communication with said units, sensors, and/or mechanisms, wherein each of the components of the automated downstream processing module are contained in the housing.

[0076] Suitably, the automated upstream production module is a fully enclosed production module.

[0077] In some embodiments, the unit configured to isolate, hold and/or elute the biologic product comprises one or more of the following: a chromatography column; a chromatography filter; a concentration and/or buffer exchange unit; a primary recovery filter; a pH sensor; and a pH adjustment mechanism.

[0078] Suitably, in some embodiments, the unit configured to isolate, hold and/or elute the biologic product comprises a disposable unit. Suitably, in some embodiments, the disposable unit is a cassette.

[0079] In some embodiments, the disposable units and/or cassettes are: a chromatography column, a chromatography filter; a concentration and/or buffer exchange unit; a primary recovery filter; a pH sensor; and a pH adjustment mechanism.

[0080] Suitably, in some embodiments, one or more parameters of production and/or processing are adjustable by local and/or remote control.

[0081] Provided herein is a method for downstream processing of a biologic product. Suitably, the downstream processing method is automated.

[0082] Suitably, the downstream processing method occurs in the downstream processing module described herein.

[0083] In some embodiments, the method for downstream processing of a biologic product comprises introducing a biologic product into a downstream processing module.

[0084] As referred to herein, the word “introducing” can mean adding the biologic product to one of a plurality of chambers or can indicate the presence of the biologic product within the cassette prior to beginning the method.

[0085] In some embodiments, the method for downstream processing includes sensing and/or adjusting one or more of the following: pressure, temperature, pH, conductivity, UV absorption, and cell density.

[0086] FIG. 6 shows an exemplary block diagram of suitable activities that take place within downstream processing module 108. As shown, in embodiments, an expanded cell product (sample) is first subjected to primary recovery to remove cells from a cell culture broth. Cells are then suitably lysed to expose the biologic product, suitably by mechanical (e.g., beads, shaking, etc.) or chemical means (e.g., lysis buffers, detergents, etc.). A capture step is then used to isolate the biologic product. This isolating is suitably a bind/elute column step in which the biologic product remains in the matrix and impurities flow through. Suitable column conditions and media are known in the art. A retronectin or fibronectin coated surface can also be used. This capture step can be repeated as many times as desired until the total amount of biologic product is collected. This isolation can also include the use of sedimentation columns, as well as chromatography columns and various affinity columns, including sepharose columns that can include functionalized surfaces. Following the initial capture, the pH solution is suitably titrated from about pH 5 up to about pH 7.

[0087] A polishing step is then carried out, for example a membrane polishing step in a flow- through mode, to purify the biologic product. In such a polishing, impurities are absorbed on the membrane and the desired biologic product flows through. An exemplary polishing step utilizes a strong ion exchanger such as a SARTOBIND® Q ion exchanger (SARTORIUS®, Gottingen, Germany). This polishing step removes undesired viruses, DNA, producer cell proteins, leached protein A and endotoxins. Exemplary buffers and conditions for carrying out the polishing step are known in the art.

[0088] Following the polishing, a pH titration and hold step are suitably carried out. This suitably involves dropping pH down to below pH 6 or pH 5, holding for a desired time, and then titrating the pH back up to about pH 7. The processing suitably further includes concentrating or diafiltering the biologic product to achieve the desired concentration.

[0089] Following the concentrating, the biologic product can then be formulated for final product. This can include the addition of various excipients (e.g., salts, buffers, osmolarity adjusting agents), as well as different media, etc. The biologic product is then suitably held at a reduced temperature (e.g. about 4-8 °C) until it can be either administered to a patient, or packaged/shipped or stored.

[0090] In some embodiments, the fully enclosed, downstream processing module receives and/or provides input to a further microprocessing unit. [0091] In some embodiments, the biologic product is produced in a fully enclosed automated process, and can be produced any time prior to introduction into the processing module. The biologic product can be produced and immediately introduced to the downstream production module without delay. In some embodiments, the biologic product can be produced seconds, minutes, hours, days, or weeks before being introduced to the downstream processing module. Suitably, in some embodiments, the biologic product is produced from a batch, a semi-fed batch, a fed-batch, a perfusion or a continuous fermentation process.

[0092] In some embodiments, the biologic product produced is a mammalian cell, or produced within a mammalian cell or any other cell as described herein. In some embodiments, the biologic product is a polypeptide, an antibody, nucleic acid, or any other product as described herein.

[0093] In some embodiments, the method comprises membrane polishing and/or formulating the biologic product as described herein.

[0094] In still further embodiments, provided herein is a method for providing fully integrated automated upstream production and downstream processing of a biologic product.

[0095] Suitably, the method for providing fully integrated automated upstream production and downstream processing of a biologic product utilizes an upstream production module and a downstream processing module as described herein.

[0096] In some embodiments, the method comprises producing a biologic product within an upstream production module, wherein the production module comprises: a cell culture chamber, one or more of a temperature sensor, a pH sensor, a glucose sensor, a lactose sensor, an oxygen sensor, a carbon dioxide sensor, and an optical density sensor, and mechanisms to adjust one or more of a temperature, a pH level, a lactose level, an oxygen level, a carbon dioxide level, and an optical density.

[0097] As illustrated in FIG. 1, suitably manipulation 104 and expansion 106 or the production process, take place within a fully enclosed cell engineering system 102. Suitably, the upstream production module is an automated system. [0098] As referred to herein, “manipulation” can include transduction or transfection, genetic modification with a plasmid or vector, activation, or modulation of culture media conditions to stimulate production of a biologic product.

[0099] In embodiments, the manipulating and expanding of cells described herein take place in a cassette 202 of a fully enclosed production module 102 (see FIG. 2 and FIG. 4). Cassette 202 can include a low temperature chamber, for storage of a cell culture media; a high temperature chamber for carrying out processes involved in producing a biologic product (e.g., transfection, activation, etc.), wherein the high temperature chamber is separated from the low temperature chamber by a thermal barrier, the high temperature chamber including a cell culture chamber; and one or more fluidics pathways connected to the cell culture chamber, wherein the fluidics pathways provide recirculation, removal of waste and homogenous gas exchange and distribution of nutrients to the cell culture chamber without disturbing cells within the cell culture chamber. FIG. 4 shows a flow diagram of elements of a biologic product production process that can be performed in a cassette 202 as described in embodiments herein.

[00100] FIG. 5 shows a flow diagram of various components of a cassette 202. FIG. 5 shows a schematic illustrating the connection between cell culture chamber 510, and satellite volume 530. Also illustrated in FIG. 5 are the positioning of various sensors (e.g., pH sensor 550, dissolved oxygen sensor 551), as well as sampling/sample ports 552 and various valves (control valves 553, bypass check valves 554), as well as one or more fluidic pathways 540, suitably comprising a silicone-based tubing component, connecting the components. As described herein, use of a silicone-based tubing component allows oxygenation through the tubing component to facilitate gas transfer and optimal oxygenation for the cell culture. Also shown in FIG. 5 is the use of one or more hydrophobic filters 555 or hydrophilic filters 556, in the flow path of the cassette, along with pump tube 557 and bag/valve module 558. FIG. 5 also illustrates exemplary positions for input 580, where a biologic product producer cell can be introduced into the cassette 202, as well as output 590, where the expanded cell lines can be withdrawn and transferred to a downstream processing module 108.

[00101] As shown in FIG. 1, following the expansion, the produced biologic product is transferred to downstream processing module 108. As used herein “transferred” suitably refers to the direct connection between the fully enclosed cell engineering system 102 and downstream processing module 108, for example by connecting the output 590 of the system 102 to an input of downstream processing module 108 so as to maintain a closed system and process. As described herein, all of the elements of the automated production and processing method (from manipulation, expansion, isolation to purification) are suitably performed in a closed and automated process. The term “closed” process suitably refers to the use of a cartridge and other contained systems that do not allow for interaction with the external environment (unless desired), with a direct connection to a downstream processing module 108, so as to maintain a sterile process. The “automated” process or “automation” of the process refers to the control of one or more process described herein by an external control, including a microprocessor, to monitor and change one or more of a temperature, a pH level, a glucose level, a lactose level, an oxygen level, a carbon dioxide level, an optical density, a pressure, a conductivity, a UV absorption, or a cell density based on a defined, or pre-set set of circumstances or desired characteristics.

[00102] In embodiments, the closed and automated process is a self-adjusting process, that is one that does not require input from an external (human) user and is able, via various computer programs and conditions, to determine the required modifications to a cell culture or other characteristics to optimize the automated process. In embodiments, the closed and automated process includes monitoring with one or more of a temperature sensor, a pH sensor, a glucose sensor, a lactose sensor, an oxygen sensor, a carbon dioxide sensor, and an optical density sensor. As described herein, the use of these various sensors in the fully enclosed cell engineering system occurs at various times and locations within the system and work together in concert to provide the optimization. For example, the closed and automated process can adjust (e.g., raise or lower) one or more of a temperature, a pH level, a glucose level, a lactose level, an oxygen level, a carbon dioxide level, and an optical density of the biologic product-producing cell culture, based on the monitoring.

[00103] The automated process can also be based on the unique characteristics of the starting cell population that produces or is the biologic product, including for example, the total cell number, the source of the cells, the density of the cells, the age of the cells, etc. These starting cell population characteristics can be input into a computer control system prior to beginning the automated methods, upon which the system will make various initial modifications to optimize the methods, e.g., lactose, oxygen and carbon dioxide concentration, flow rates, incubation times, pH, etc. Alternatively, the monitoring of cell processes enables the automated characterization of the progress of the cell culture sequence from the starting population to enable case-by-case adjustment of conditions for optimized final cell culture properties.

[00104] In further embodiments, the production module recirculates nutrients, waste, released cytokines, and/or dissolved gases during the various method processes. This recirculation helps aid in the production of the desired biologic product. Other mechanisms for optimizing the production of the biologic product include modifying and controlling the flow rate of the media provided to the cells that produce the biologic product. As the cells begin to grow, the circulation rate of the media provided is increased, which improves gas exchange and allows oxygen and carbon dioxide to either enter or leave the cell culture, depending on the conditions of the cells and the requirements at the time.

[00105] In embodiments, the steps of the method are performed in a closed and automated process, and suitably include monitoring with one or more of a temperature sensor, a pH sensor, a glucose sensor, a lactose sensor, an oxygen sensor, a carbon dioxide sensor, and an optical density sensor, and automatically adjusting one or more of a temperature, a pH level, a glucose level, a lactose level, an oxygen level, a carbon dioxide level, and an optical density.

[00106] In embodiments, the method further comprises processing the biologic product within a downstream processing module, wherein the downstream processing module comprises: a housing, one or more units configured to isolate, hold and/or elute the biologic product; one or more sensors and/or mechanisms to detect and/or adjust one or more of the following parameters: pressure, temperature, pH, conductivity, UV absorption, and cell density; and a fluid containment system in fluid communication with said units, sensors and/or mechanisms, wherein each of the steps of the downstream processing method that occurs in the downstream processing module are contained in the housing.

[00107] In exemplary embodiments, the method comprises the upstream production module in fluid communication with the downstream processing module. [00108] In further embodiments, the unit configured to isolate, hold and/or elute the biologic product comprises one or more of the following: a chromatography column; a chromatography filter; a concentration and/or buffer exchange unit; a primary recovery filter; a pH sensor; and a pH adjustment mechanism. Suitably, in some embodiments, the unit comprises a disposable unit. In some embodiments, the disposable unit is a cassette.

[00109] In some embodiments, the disposable unit and/or cassette are: a chromatography column; a chromatography filter; a concentration and/or buffer exchange unit; a primary recovery filter; a pH sensor; and a pH adjustment mechanism.

[00110] In further embodiments, the production and/or processing module receives and/or provides input to a further microprocessing unit.

[00111] In still further embodiments, the biologic product is produced from a batch, a semi-fed batch, a fed-batch, a perfusion and/or a continuous fermentation process.

[00112] In some embodiments, the biologic product produced is a mammalian cell, or produced within a mammalian cell or any other cell as described herein. In some embodiments, the biologic product is a polypeptide, an antibody, nucleic acid or any other product as described herein.

[00113] In some embodiments, the method comprises membrane polishing and/or formulating the biologic product as described herein.

Additional Exemplary Embodiments

[00114] Embodiment l is a module for automated downstream processing of a biologic product, comprising: a housing; one or more units configured to isolate, hold and/or elute the biologic product; one or more sensors and/or mechanisms to detect and/or adjust one or more of the following: pressure, temperature, pH, conductivity, UV absorption, and cell density; and a fluid containment system in fluid communication with said units, sensors and/or mechanisms; wherein the components are contained in the housing.

[00115] Embodiment 2 includes the module of embodiment 1, wherein the unit configured to isolate, hold and/or elute the biologic product comprises one or more of the following: a chromatography column; a chromatography filter; a concentration and/or buffer exchange unit; a primary recovery filter; a pH sensor; and a pH adjustment mechanism.

[00116] Embodiment 3 includes the module of any of embodiments 1 and 2, wherein the unit configured to isolate, hold and/or elute the biologic product comprises a disposable unit.

[00117] Embodiment 4 includes the module of embodiment 3, wherein the disposable unit is a cassette.

[00118] Embodiment 5 includes the module of any of embodiments 3 and 4, wherein the disposable units and/or cassettes are: a chromatography column; a chromatography filter; a concentration and/or buffer exchange unit; a primary recovery filter; a pH sensor; and a pH adjustment mechanism.

[00119] Embodiment 6 includes the module of any of embodiments 1-5, wherein the module receives and/or provides input to a microprocessing unit.

[00120] Embodiment 7 includes the module of any of embodiments 1-6, further comprising an input to the housing.

[00121] Embodiment 8 includes the module of embodiment 7, wherein the biologic product is produced in an upstream production module in fluid communication with the input to the housing.

[00122] Embodiment 9 includes the module of embodiment 8, wherein the upstream production module is a batch, a semi-fed batch, a fed-batch, a perfusion or a continuous fermentation bioreactor.

[00123] Embodiment 10 includes the module of embodiment 8, wherein the upstream production module is an automated, fully enclosed production module.

[00124] Embodiment 11 includes the module of any of embodiments 8-10, wherein the module further includes the upstream production module.

[00125] Embodiment 12 includes the module of any of embodiments 1-11, wherein the biologic product is produced from a cell and/or tissue culture. [00126] Embodiment 13 includes the module of any of embodiments 1-11, wherein the biologic product is produced from a plant tissue culture.

[00127] Embodiment 14 includes the module of any of embodiments 1-11, wherein the biologic product is produced in a multicellular organism.

[00128] Embodiment 15 includes the module of any of embodiments 1-11, wherein the biologic product is a mammalian cell.

[00129] Embodiment 16 includes the module of embodiment 15, wherein the mammalian cell is a Chinese hamster ovary (CHO) cell, a chimeric antigen receptor (CAR) T cell, a human embryonic kidney (HEK) cell or a stem cell.

[00130] Embodiment 17 includes the module of any of embodiments 1-14, wherein the biologic product is a polypeptide.

[00131] Embodiment 18 includes the module of any of embodiments 1-14, wherein the biologic product is an antibody.

[00132] Embodiment 19 includes the module of any of embodiments 1-14, wherein the biologic product is a nucleic acid.

[00133] Embodiment 20 includes the module of any of embodiments 1-19, wherein one or more sensors and/or mechanisms to detect and/or adjust one or more of a pressure, temperature, pH, conductivity, UV absorption, and cell density is adjustable by local and/or remote control.

[00134] Embodiment 21 is a device providing fully integrated automated upstream production and downstream processing of a biologic product, comprising: an automated upstream production module, wherein the production module comprises: a cell culture chamber; one or more of a temperature sensor, a pH sensor, a glucose sensor, a lactose sensor, an oxygen sensor, a carbon dioxide sensor, and an optical density sensor; and mechanisms to adjust one or more of a temperature, a pH level, a glucose level, a lactose level, an oxygen level, a carbon dioxide level, and an optical density; and an automated downstream processing module, wherein the downstream processing module comprises: a housing; one or more units configured to isolate, hold and/or elute the biologic product; one or more sensors and/or mechanisms to detect and/or adjust one or more of the following parameters: pressure, temperature, pH, conductivity, UV absorption, and cell density; and a fluid containment system in fluid communication with said units, sensors, and/or mechanisms; wherein each of 2-4 are contained in the housing, and wherein the automated upstream production module (a) is in fluid communication with automated downstream processing module (b).

[00135] Embodiment 22 includes the device of embodiment 21, wherein the automated upstream production module is a fully enclosed production module.

[00136] Embodiment 23 includes the device of any of embodiments 21 and 22, wherein the unit configured to isolate, hold and/or elute the biologic product comprises one or more of the following: a chromatography column; a chromatography filter; a concentration and/or buffer exchange unit; a primary recovery filter; a pH sensor; and a pH adjustment mechanism.

[00137] Embodiment 24 includes the device of any of embodiments 21-23, wherein the unit configured to isolate, hold and/or elute the biologic product comprises a disposable unit.

[00138] Embodiment 25 includes the device of embodiment 24, wherein the disposable unit is a cassette.

[00139] Embodiment 26 includes the device of any of embodiments 24 and 25, wherein the disposable units and/or cassettes are: a chromatography column; a chromatography filter; a concentration and/or buffer exchange unit; a primary recovery filter; a pH sensor; and a pH adjustment mechanism.

[00140] Embodiment 27 includes the device of any of embodiments 21-26, further comprising a local and/or remote control interface configured to adjust one or more of a temperature, a pH level, a glucose level, a lactose level, an oxygen level, a carbon dioxide level, an optical density, a pressure, a conductivity, a UV absorption, or a cell density.

[00141] Embodiment 28 provides a method for downstream processing of a biologic product, comprising: introducing a biologic product into a fully enclosed, downstream processing module; sensing and/or adjusting one or more of the following: pressure, temperature, pH, conductivity, UV absorption, and cell density; isolating and/or eluting the biologic product via one or more columns and/or filtration units; and holding the biologic product; wherein steps (b) through (d) are carried out in an automated manner.

[00142] Embodiment 29 includes the method of embodiment 28, wherein the fully enclosed, downstream processing module receives and/or provides input to a microprocessing unit.

[00143] Embodiment 30 includes the method of any of embodiments 28 and 29, wherein the biologic product is produced in a fully enclosed automated process at any time prior to introduction into the processing module.

[00144] Embodiment 31 includes the method of any of embodiments 28-30, wherein the biologic product is produced from a batch, a semi-fed batch, a fed-batch, a perfusion or a continuous fermentation process.

[00145] Embodiment 32 includes the method of any of embodiments 28-31, wherein the biologic product is a mammalian cell.

[00146] Embodiment 33 includes the method of embodiment 32, wherein the mammalian cell is a Chinese hamster ovary (CHO) cell, a chimeric antigen receptor (CAR) T cell, or a human embryonic kidney (HEK) cell.

[00147] Embodiment 34 includes the method of any one of embodiments 28-31, wherein the biologic product is a polypeptide.

[00148] Embodiment 35 includes the method of any of embodiments 28-31, wherein the biologic product is an antibody.

[00149] Embodiment 36 includes the method of any of embodiments 28-31, wherein the biologic product is a nucleic acid.

[00150] Embodiment 37 includes the method of any of embodiments 28-36, wherein the isolating comprises membrane polishing.

[00151] Embodiment 38 includes the method of any of embodiments 28-36, further comprising formulating the biologic product. [00152] Embodiment 39 provides a method for providing fully integrated automated upstream production and downstream processing of a biologic product, comprising: producing a biologic product within an upstream production module, wherein the production module comprises: a cell culture chamber; one or more of a temperature sensor, a pH sensor, a glucose sensor, a lactose sensor, an oxygen sensor, a carbon dioxide sensor, and an optical density sensor; and mechanisms to adjust one or more of a temperature, a pH level, a glucose level, a lactose level, an oxygen level, a carbon dioxide level, and an optical density; and processing the biologic product within a downstream processing module, wherein the downstream processing module comprises: a housing; one or more units configured to isolate, hold and/or elute the biologic product; one or more sensors and/or mechanisms to detect and/or adjust one or more of the following parameters: pressure, temperature, pH, conductivity, UV absorption, and cell density; and a fluid containment system in fluid communication with said units, sensors, and/or mechanisms; wherein each of 2-4 are contained in the housing, and wherein the upstream production module (a) is in fluid communication with the downstream processing module (b).

[00153] Embodiment 40 includes the method of embodiment 39, wherein the unit configured to isolate, hold and/or elute the biologic product comprises one or more of the following: a chromatography column; a chromatography filter; a concentration and/or buffer exchange unit; a primary recovery filter; a pH sensor; and a pH adjustment mechanism.

[00154] Embodiment 41 includes the method of any of embodiments 39 and 40, wherein the unit configured to isolate, hold and/or elute the biologic product comprises a disposable unit.

[00155] Embodiment 42 includes the method of embodiment 41, wherein the disposable unit is a cassette.

[00156] Embodiment 43 includes the method of any of embodiments 41 and 42, wherein the disposable units and/or cassettes are: a chromatography column; a chromatography filter; a concentration and/or buffer exchange unit; a primary recovery filter; a pH sensor; and a pH adjustment mechanism.

[00157] Embodiment 44 includes the method of any of embodiments 39-43, wherein the production and/or processing module receives and/or provides input to a microprocessing unit. [00158] Embodiment 45 includes the method of any of embodiments 39-44, wherein the biologic product is produced from a batch, a semi-fed batch, a fed-batch, perfusion and/or a continuous fermentation process.

[00159] Embodiment 46 includes the method of any of embodiments 39-44, wherein the biologic product is produced from a cell culture and/or tissue culture.

[00160] Embodiment 47 includes the method of any of embodiments 39-44, wherein the biologic product is produced in a multicellular organism.

[00161] Embodiment 48 includes the method of any of embodiments 39-44, wherein the biologic product is a mammalian cell.

[00162] Embodiment 49 includes the method of embodiment 48, wherein the mammalian cell is a Chinese hamster ovary (CHO) cell, chimeric antigen receptor (CAR) T cell, a human cell, or a human embryonic kidney (HEK) cell.

[00163] Embodiment 50 includes the method of any of embodiments 39-44, wherein the biologic product is a polypeptide.

[00164] Embodiment 51 includes the method of any of embodiments 39-44, wherein the biologic product is an antibody.

[00165] Embodiment 52 includes the method of any of embodiments 39-44, wherein the biologic product is a nucleic acid.

[00166] Embodiment 53 includes the method of any of embodiments 39-52, wherein the isolating comprises membrane polishing.

[00167] Embodiment 54 includes the method of any of embodiments 39-53, further comprising formulating the biologic product. [00168] It is to be understood that while certain embodiments have been illustrated and described herein, the claims are not to be limited to the specific forms or arrangement of parts described and shown. In the specification, there have been disclosed illustrative embodiments and, although specific terms are employed, they are used in a generic and descriptive sense only and not for purposes of limitation. Modifications and variations of the embodiments are possible in light of the above teachings. It is therefore to be understood that the embodiments may be practiced otherwise than as specifically described.

[00169] All publications, patents and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated by reference.

Claims

CLAIMS What is claimed is:

1. A module for automated downstream processing of a biologic product, comprising:

(a) a housing;

(b) one or more units configured to isolate, hold and/or elute the biologic product;

(c) one or more sensors and/or mechanisms to detect and/or adjust one or more of the following: pressure, temperature, pH, conductivity, UV absorption, and cell density; and

(d) a fluid containment system in fluid communication with said units, sensors and/or mechanisms; wherein (b) through (d) are contained in the housing.

2. The module of claim 1, wherein the unit configured to isolate, hold and/or elute the biologic product comprises one or more of the following:

(a) a chromatography column;

(b) a chromatography filter;

(c) a concentration and/or buffer exchange unit;

(d) a primary recovery filter;

(e) a pH sensor; and

(f) a pH adjustment mechanism.

3. The module of any one of claims 1 and 2, wherein the unit configured to isolate, hold and/or elute the biologic product comprises a disposable unit.

4. The module of claim 3, wherein the disposable unit is a cassette.

5. The module of any one of claims 3 and 4, wherein the disposable units and/or cassettes are:

(a) a chromatography column;

(b) a chromatography filter;

(c) a concentration and/or buffer exchange unit; (d) a primary recovery filter;

(e) a pH sensor; and

(f) a pH adjustment mechanism. The module of any one of claims 1-5, wherein the module receives and/or provides input to a microprocessing unit. The module of any one of claims 1-6, further comprising an input to the housing. The module of claim 7, wherein the biologic product is produced in an upstream production module in fluid communication with the input to the housing. The module of claim 8, wherein the upstream production module is a batch, a semi-fed batch, a fed-batch, a perfusion or a continuous fermentation bioreactor. The module of claim 8, wherein the upstream production module is an automated, fully enclosed production module. The module of any one of claims 8-10, wherein the module further includes the upstream production module. The module of any one of claims 1-11, wherein the biologic product is produced from a cell and/or tissue culture. The module of any one of claims 1-11, wherein the biologic product is produced from a plant tissue culture. The module of any one of claims 1-11, wherein the biologic product is produced in a multicellular organism. The module of any one of claims 1-11, wherein the biologic product is a mammalian cell. The module of claim 15, wherein the mammalian cell is a Chinese hamster ovary (CHO) cell, a chimeric antigen receptor (CAR) T cell, a human embryonic kidney (HEK) cell or a stem cell. The module of any one of claims 1-14, wherein the biologic product is a polypeptide. The module of any one of claims 1-14, wherein the biologic product is an antibody. The module of any one of claims 1-14, wherein the biologic product is a nucleic acid. The module of any one of claims 1-19, wherein one or more sensors and/or mechanisms to detect and/or adjust one or more of pressure, temperature, pH, conductivity, UV absorption, and cell density is adjustable by local and/or remote control. A device providing fully integrated automated upstream production and downstream processing of a biologic product, comprising: a) an automated upstream production module, wherein the production module comprises: i. a cell culture chamber; ii. one or more of a temperature sensor, a pH sensor, a glucose sensor, a lactose sensor, an oxygen sensor, a carbon dioxide sensor, and an optical density sensor; and iii. mechanisms to adjust one or more of a temperature, a pH level, a glucose level, a lactose level, an oxygen level, a carbon dioxide level, and an optical density; and b) an automated downstream processing module, wherein the downstream processing module comprises:

1. a housing;

2. one or more units configured to isolate, hold and/or elute the biologic product;

3. one or more sensors and/or mechanisms to detect and/or adjust one or more of the following parameters: pressure, temperature, pH, conductivity, UV absorption, and cell density; and

4. a fluid containment system in fluid communication with said units, sensors, and/or mechanisms; wherein each of 2-4 are contained in the housing, and wherein the automated upstream production module (a) is in fluid communication with automated downstream processing module (b). The device of claim 21, wherein the automated upstream production module is a fully enclosed production module. The device of any one of claims 21 and 22, wherein the unit configured to isolate, hold and/or elute the biologic product comprises one or more of the following:

(a) a chromatography column;

(b) a chromatography filter;

(c) a concentration and/or buffer exchange unit;

(d) a primary recovery filter;

(e) a pH sensor; and

(f) a pH adjustment mechanism. The device of any one of claims 21-23, wherein the unit configured to isolate, hold and/or elute the biologic product comprises a disposable unit. The device of claim 24, wherein the disposable unit is a cassette. The device of any one of claims 24 and 25, wherein the disposable units and/or cassettes are:

(a) a chromatography column;

(b) a chromatography filter;

(c) a concentration and/or buffer exchange unit; (d) a primary recovery filter;

(e) a pH sensor; and

(f) a pH adjustment mechanism. The device of any one of claims 21-26, further comprising a local and/or a remote control interface configured to adjust one or more of a temperature, a pH level, a glucose level, a lactose level, an oxygen level, a carbon dioxide level, an optical density, a pressure, a conductivity, a UV absorption, or a cell density. A method for downstream processing of a biologic product, comprising:

(a) introducing a biologic product into a fully enclosed, downstream processing module;

(b) sensing and/or adjusting one or more of the following: pressure, temperature, pH, conductivity, UV absorption, and cell density;

(c) isolating and/or eluting the biologic product via one or more columns and/or filtration units; and

(d) holding the biologic product; wherein steps (b) through (d) are carried out in an automated manner. The method of claim 28, wherein the fully enclosed, downstream processing module receives and/or provides input to a microprocessing unit. The method of any one of claims 28 and 29, wherein the biologic product is produced in a fully enclosed automated process at any time prior to introduction into the processing module. The method of any one of claims 28-30, wherein the biologic product is produced from a batch, a semi-fed batch, a fed-batch, a perfusion or a continuous fermentation process. The method of any one of claims 28-31, wherein the biologic product is a mammalian cell. The method of claim 32, wherein the mammalian cell is a Chinese hamster ovary (CHO) cell, a chimeric antigen receptor (CAR) T cell, or a human embryonic kidney (HEK) cell. The method of any one of claims 28-31, wherein the biologic product is a polypeptide. The method of any one of claims 28-31, wherein the biologic product is an antibody. The method of any one of claims 28-31, wherein the biologic product is a nucleic acid. The method of any one of claims 28-36, wherein the isolating comprises membrane polishing. The method of any one of claims 28-36, further comprising formulating the biologic product. A method for providing fully integrated automated upstream production and downstream processing of a biologic product, comprising: a) producing a biologic product within an upstream production module, wherein the production module comprises: i. a cell culture chamber; ii. one or more of a temperature sensor, a pH sensor, a glucose sensor, a lactose sensor, an oxygen sensor, a carbon dioxide sensor, and an optical density sensor; and iii. mechanisms to adjust one or more of a temperature, a pH level, a glucose level, a lactose level, an oxygen level, a carbon dioxide level, and an optical density; and b) processing the biologic product within a downstream processing module, wherein the downstream processing module comprises:

1. a housing;

2. one or more units configured to isolate, hold and/or elute the biologic product;

3. one or more sensors and/or mechanisms to detect and/or adjust one or more of the following parameters: pressure, temperature, pH, conductivity, UV absorption, and cell density; and

4. a fluid containment system in fluid communication with said units, sensors, and/or mechanisms; wherein each of 2-4 are contained in the housing, and wherein the upstream production module (a) is in fluid communication with the downstream processing module (b). The method of claim 39, wherein the unit configured to isolate, hold and/or elute the biologic product comprises one or more of the following:

(a) a chromatography column;

(b) a chromatography filter;

(c) a concentration and/or buffer exchange unit;

(d) a primary recovery filter;

(e) a pH sensor; and

(f) a pH adjustment mechanism. The method of any one of claims 39 and 40, wherein the unit configured to isolate, hold and/or elute the biologic product comprises a disposable unit. The method of claim 41, wherein the disposable unit is a cassette. The method of any one of claims 41 and 42, wherein the disposable units and/or cassettes are:

(a) a chromatography column;

(b) a chromatography filter;

(c) a concentration and/or buffer exchange unit;

(d) a primary recovery filter;

(e) a pH sensor; and

(f) a pH adjustment mechanism. The method of any one of claims 39-43, wherein the production and/or processing module receives and/or provides input to a microprocessing unit. The method of any one of claims 39-44, wherein the biologic product is produced from a batch, a semi-fed batch, a fed-batch, a perfusion and/or a continuous fermentation process. The method of any one of claims 39-44, wherein the biologic product is produced from a cell culture and/or tissue culture. The method of any one of claims 39-44, wherein the biologic product is produced in a multicellular organism. The method of any one of claims 39-44, wherein the biologic product is a mammalian cell. The method of claim 48, wherein the mammalian cell is a Chinese hamster ovary (CHO) cell, chimeric antigen receptor (CAR) T cell, a human cell, or a human embryonic kidney (HEK) cell. The method of any one of claims 39-44, wherein the biologic product is a polypeptide. The method of any one of claims 39-44, wherein the biologic product is an antibody. The method of any one of claims 39-44, wherein the biologic product is a nucleic acid. The method of any one of claims 39-52, wherein the isolating comprises membrane polishing. The method of any one of claims 39-53, further comprising formulating the biologic product.