# US 11,111,471 B2 · Continuous perfusion bioreactor system > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 11,111,471 B2 - Document ID: US11111471B2 - Status: Granted - Kind: B2 - Application number: 14/743,960 - Filed: 2015-06-18 - Published: 2015-12-24 - Granted: 2021-09-07 - Earliest claimed: 2008-05-20 - Assignees: Global Life Sciences Solutions USA LLC - Applicants: Global Life Sciences Solutions USA LLC - Inventors: Parrish M. Galliher; Geoffrey L. Hodge; Michael Fisher; Patrick Guertin; Dan Mardirosian - Web page: https://patentgrep.com/patent/US11111471B2 ## CPC - C12M 29/10: {Perfusion} - B01D 29/13: Supported filter elements - C12M 23/14: {Bags} - C12M 23/26: {flexible (flexible containers for laboratory use B01L3/505)} - C12M 23/48: {Holding appliances; Racks; Supports (holding devices for laboratory apparatus B01L9/00)} - C12M 27/02: {Stirrer or mobile mixing elements} - C12M 27/20: {Baffles; Ribs; Ribbons; Auger vanes} - C12M 29/00: {Means for introduction, extraction or recirculation of materials, e.g. pumps (pumps per se F04B)} - C12M 29/18: {External loop; Means for reintroduction of fermented biomass or liquid percolate (loop type reactors for chemical or physical processes B01J19/2435)} - C12M 47/10: {Separation or concentration of fermentation products (bioreactors combined with means for distillation or extraction of liquid fuel C12M43/02)} - C12M: APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; {APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS} - B01D: SEPARATION (separating solids from solids by wet methods B03B, B03D; by pneumatic jigs or tables B03B; by other dry methods B07; magnetic or electrostatic separation of solid materials from solid materials or fluids, separation by high-voltage electric fields B03C; centrifuges, vortex apparatus B04; presses per se for squeezing-out liquid from liquid-containing material B30B9/02; treatment of water C02F, e.g. softening by ion-exchange C02F1/42; {arrangements of air intake cleaners in gas turbine plants F02C7/05} ; arrangements or mounting of filters in air-conditioning, air-humidification or ventilation F24F13/28) ## Abstract Systems and methods for containing and manipulating liquids, including vessels and unit operations or components of cell culture, cell containment, bioreactor, and/or pharmaceutical manufacturing systems, are provided. The apparatus may include a disposable, collapsible bag adapted for containing a liquid, the collapsible bag in fluid communication with a liquid-solids (e.g., cell) separation device. For example, an outlet of the collapsible bag may be connected to an inlet of the separation device, and an outlet of the separation device may be connected to an inlet of the collapsible bag for recycle. Accordingly, after separating the cells from the liquid in the separation device, the cells can be flowed back into the collapsible bag where they can be re-harvested. Meanwhile, product contained in the liquid can be collected in a separate container. The efficiency of product formation in such a system may be enhanced by using mixing systems described herein. ## Claims ### Claim 1 A system, comprising: a first apparatus, comprising: a disposable first collapsible bag adapted for containing a liquid, the first collapsible bag including at least first and second inlets, at least a first outlet, and a base plate that is attached to the collapsible bag and configured to support an impeller; a first reusable support structure adapted for surrounding and supporting the first collapsible bag and configured to permit passage of the at least first and second inlets and the at least a first outlet through support structure walls; and a second apparatus comprising: a second disposable collapsible bag and a second reusable support structure having support structure walls adapted for supporting the second collapsible bag, the second collapsible bag further configured with at least one inlet and at least a first and second outlets and further configured to separate solids from the liquid in the interior of the second disposable collapsible bag; and, wherein the first outlet of the first collapsible bag is in fluid communication with an inlet of the second collapsible bag via the passage of fluid through the walls of the first support structure, wherein the first outlet of the second collapsible bag in the second support structure of the second apparatus is in fluid communication with the first inlet of the first collapsible bag in the first support structure of the first apparatus further configured to recycle solids separated from the liquid in the second collapsible bag back to the first collapsible bag; wherein the second outlet of the second apparatus is configured to remove a first volume of liquid from the second apparatus; and, wherein the second inlet of the first apparatus is configured to receive a second volume of liquid that maintains a substantially constant liquid volume in the first and second apparatuses with continuous fluid flow through the first and second apparatuses. ### Claim 2 (depends on 1) A system as in claim 1, wherein the second apparatus is configured to receive a first liquid comprising a first concentration of a component from the first apparatus and to deliver a second liquid comprising a second concentration of the component to the first apparatus, wherein the first and second concentrations are different. ### Claim 3 (depends on 1) A system as in claim 1, wherein the components include a solid object that comprises a cell. ### Claim 4 (depends on 1) A system as in claim 1, wherein the second apparatus comprises a second reusable support structure adapted for surrounding and supporting the second collapsible bag. ### Claim 5 (depends on 1) A system as in claim 1, further comprising an impeller associated with the base plate wherein the impeller is magnetically-driven. ### Claim 6 (depends on 1) A system as in claim 1, wherein the first apparatus forms at least part of a bioreactor system. ### Claim 7 (depends on 1) A system as in claim 1, wherein the first apparatus forms at least part of a pharmaceutical manufacturing system. ### Claim 8 (depends on 1) A system as in claim 1, wherein the first collapsible bag has a volume of at least 40 L. ### Claim 9 (depends on 1) A system as in claim 1, wherein the second apparatus forms at least part of a separation device and the separation device is a liquid-solids separation device. ### Claim 10 (depends on 1) A system as in claim 1, wherein the second apparatus forms at least part of a separation device and the separation device comprises a centrifuge. ### Claim 11 (depends on 1) A system as in claim 1, wherein the second apparatus forms at least part of a separation device and the separation is adapted for separating cells from a liquid. ### Claim 12 (depends on 1) A system as in claim 1, wherein the second apparatus forms at least part of a separation device and the separation device comprises a hollow fiber filter. ### Claim 13 (depends on 1) A system as in claim 1, wherein the second apparatus forms at least part of a media or buffer storage tank. ### Claim 14 (depends on 1) A system as in claim 1, wherein the second apparatus forms at least part of a mixing system. ### Claim 15 (depends on 1) A system as in claim 1, wherein the second apparatus forms at least part of a batch harvesting tank. ### Claim 16 A system, comprising: a first apparatus in the form a portable module, comprising: a disposable first collapsible bag adapted for containing a liquid; a first reusable support structure adapted for surrounding and supporting the collapsible bag and configured to permit passage of the at least first and second inlets and the at least a first outlet through the support structure walls; and a second apparatus in the form a portable module having walls adapted for supporting a second collapsible bag the second apparatus in fluid communication with the first apparatus, wherein the second apparatus comprises a liquid-solids separation device as part of a disposable second collapsible bag configured to recycle solids separated from the liquid back to the first collapsible bag, wherein upon fluid communication between the first and second apparatuses, each apparatus can be moved relative to the other without breaking the connection; wherein the second apparatus is configured to remove a first volume of liquid from the second apparatus; and, wherein the first apparatus is configured to receive a second volume of liquid that maintains a substantially constant liquid volume in the first and second apparatuses with continuous liquid flow through the first and second apparatuses. ### Claim 17 (depends on 16) A system as in claim 16, wherein the first collapsible bag comprises a base plate that is attached to the collapsible bag and configured to support an impeller. ### Claim 18 (depends on 17) A system as in claim 17, further comprising an impeller associated with the base plate wherein the impeller is magnetically-driven. ### Claim 19 A system, comprising: a first apparatus comprising: a disposable first collapsible bag adapted for containing a liquid, the first collapsible bag including at least first and second inlets, and at least a first outlet; a first reusable support structure adapted for surrounding and supporting the first collapsible bag and configured to permit passage of the at least first and second inlets and the at least a first outlet through the support structure walls; and a second apparatus in fluid communication with the first apparatus and operative to separate solids from the liquid, the second apparatus comprising: a disposable second collapsible bag adapted for containing the liquid, the second collapsible bag including at least one inlet and at least a first and second outlets; and a second reusable support structure adapted for supporting the second collapsible bag, wherein wherein the first outlet of the first collapsible bag is in fluid communication with an inlet of the second collapsible bag; wherein the first outlet of the second collapsible bag is in fluid communication with the first inlet of the first collapsible bag further configured recycle to solids separated from the liquid in the second collapsible bag back to the first collapsible bag; wherein the second outlet of the second collapsible bag is configured to remove a first volume of liquid from the second collapsible bag; and, wherein the second inlet of the first collapsible bag is configured to receive a second volume of liquid that maintains a substantially constant liquid volume in the first and second collapsible bags with continuous fluid flow through the first and second collapsible bags. ### Claim 20 (depends on 19) A system as in claim 19, wherein the first collapsible bag comprises a base plate that is attached to the collapsible bag and configured to support an impeller. ### Claim 21 (depends on 20) A system as in claim 20, further comprising an impeller associated with the base plate wherein the impeller is magnetically-driven. ### Claim 22 (depends on 19) The system of claim 19, wherein the first and the second collapsible bags are seamless. ### Claim 23 A system, comprising: a first apparatus comprising: a disposable first collapsible bag adapted for containing a liquid; a first reusable support structure adapted for surrounding and supporting the collapsible bag and configured to permit passage of at least first and second inlets and at least a first outlet through the support structure walls; and a second apparatus in fluid communication with the first apparatus, the second apparatus comprising a centrifuge containing a disposable second collapsible bag adapted for separating a plurality of particulates or solid objects from a liquid-solids mixture and further configured to recycle the particulates or solids separated from the liquid back to the first collapsible bag while maintaining a substantially constant liquid volume in the first and second apparatuses with continuous fluid flow through the first and second collapsible bags. ### Claim 24 A method, comprising: transferring a first liquid comprising a plurality of particulates or solid objects from a first collapsible bag to an apparatus including a liquid-solids separation device, wherein the first collapsible bag is supported by a first reusable support structure adapted for surrounding and supporting the first collapsible bag and configured to permit passage of the first liquid through a support structure wall; separating at least a portion of the plurality of particulates or solid objects from the first liquid in the apparatus; and transferring a second liquid from the apparatus to the first collapsible bag via passage of fluid through a wall of the first support structure, wherein the first and second liquids have different concentrations of the particulates or solid objects. ### Claim 25 (depends on 24) A method as in claim 24, wherein the apparatus is external to the collapsible bag. ### Claim 26 A method comprising: continuously introducing a first liquid into a collapsible bag comprising an impeller, the first liquid having a first concentration of a particulate or solid objects, wherein the collapsible bag is supported by a reusable support structure adapted for surrounding and supporting the collapsible bag and further configured to permit the passage of fluid through a wall of the support structure; continuously removing a second liquid from the collapsible bag, the second liquid having a second concentration of the particulate or solid objects, wherein the first and second concentrations of the particulate or solid objects is different; and maintaining a substantially constant volume within the collapsible bag during the introducing and removing steps. ### Claim 27 (depends on 26) A method as in claim 26, further comprising continuously mixing a liquid in the collapsible bag. ### Claim 28 A method, comprising: introducing a first liquid into a collapsible bag comprising an impeller, the first liquid having a first concentration of a particulate or solid objects, wherein the collapsible bag is supported by a reusable support structure adapted for surrounding and supporting the collapsible bag and further configured to permit the passage of a liquid through a support structure wall; mixing the first liquid in the collapsible bag using the impeller; and removing a second liquid from the collapsible bag, the second liquid having a second concentration of the particulate or solid objects, wherein the first and second concentrations of the particulate or solid object is different, wherein the second liquid is substantially homogenous with respect to liquid remaining in the collapsible bag immediately after removal, such that the concentration of the particulate or solid objects in the second liquid removed from the collapsible bag is substantially equivalent to the concentration of the particulate or solid objects in the liquid remaining in the collapsible bag immediately after removal; causing a liquid to flow from the collapsible bag to an apparatus; and causing a liquid to flow from the apparatus to the collapsible bag. ### Claim 29 (depends on 28) A method as in claim 28, further comprising maintaining a substantially constant volume within the collapsible bag during the introducing and removing steps.