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US6214574: Cross-flow filtration and culture method

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Filing Information

Inventor(s) Henry B. Kopf ·
Assignee(s) None listed in document.
Attorney/Agent(s) Steven J. Hultquist · William A. Barrett ·
Primary Examiner David A. Redding ·
Application Number US9397291
Filing date 09/15/1999
Issue date 04/10/2001
Predicted expiration date 11/26/2006
U.S. Classifications 435/41  · 435/325  · 435/170  · 435/236  · 435/238  · 435/239  · 435/252.1  · 435/711  · 435/383  · 435/393  · 435/401  · 435/297.4  · 435/818  · 435/703  ·
International Classifications --
Kind CodeB1
International Classifications 435 41 · 435170 · 435174 · 435183 · 4352351 · 435325 · 435382 · 435383 · 435393 · 435395 · 435401 · 4352974 · 435818 · 435 703 · 435 711 · 435236 · 435238 · 435239 · 4352521 ·
Related U.S. Application DataRELATED APPLICATION
The present application is a divisional of U.S. patent application Ser. No. 09/307,932 filed May 10, 1999, now U.S. Pat. No. 6.127,141, which is in turn a continuation of U.S. patent application Ser. No. 07/207,655, filed Jun. 21, 1988, now U.S. Pat. No. 6,022,742, which is in turn a continuation-in-part of U.S. patent application Ser. No. 06/936,486, filed Nov. 26, 1986, now issued as U.S. Pat. No. 4,885,087.
72 Claims, 8 Drawings


Abstract

A culturing system and method particularly useful for producing cellular products such as viral pathogens of cells. It includes a mass transfer culture segment, stacked filter plates to adjust the medium composition, and a product removal and concentration segment. The mass transfer culture segment utilizes changed directional flow of the medium to maximize cell growth and production of product. The stacked filter plates allow addition of sterile fresh medium and removal of growth inhibitory substances.

Independent Claims | See all claims (72)

  1. 1. A method for separating one or more components from an input fluid, said method comprising: (a) providing a first tangential flow device comprising: (i) a first housing enclosing an interior volume; (ii) one or more filter means separating the interior volume of the first housing into a first set of one or more chambers and a second set of one or more chambers; (iii) at least one entrance port and at least one exit port in fluid communication with the first set of one or more chambers; (iv) at least one entrance and/or exit port in fluid communication with the second set of one or more chambers; (b) providing a second tangential flow device comprising: (i) a second housing enclosing an interior volume; (ii) one or more filter means separating the interior volume of the second housing into a first set of one or more chambers and a second set of one or more chambers; (iii) at least one entrance port and at least one exit port in fluid communication with the first set of one or more chambers; (iv) at least one entrance and/or exit port in fluid communication with the second set of one or more chambers; (c) in the first tangential flow device, introducing a first fluid via a port into the first set of one or more chambers, such that a permeate comprising a first permeate component from the first fluid can traverse the one or more filter means and enter the second set of one or more chambers to provide a second fluid comprising the first permeate component; (d) removing the second fluid from the second set of one or more chambers of the first tangential flow device via an exit port; and (e) in the second tangential flow device, introducing the second fluid collected in step (d) via an entrance port into the first set of one or more chambers, such that a permeate comprising the first permeate component and/or comprising a second permeate component can traverse the one or more filter means and enter the second set of one or more chambers to provide a third fluid comprising the first and/or second permeate component.
  2. 33. A method of inactivating a pathogen in an aqueous biological solution which contains a substance of interest, the method comprising: (a) providing a tangential flow device comprising: (i) a first housing enclosing an interior volume; (ii) one or more filter means separating the interior volume of the first housing into a first set of one or more chambers and a second set of one or more chambers; (iii) at least one entrance port and at least one exit port in fluid communication with the first set of one or more chambers; (iv) at least one entrance and/or exit port in fluid communication with the second set of one or more chambers; (b) providing a reservoir in loop fluid communication with the tangential flow device, the reservoir comprising a solution comprising a pathogen; (c) adding an inactivation agent to the reservoir; (d) incubating the agueous biological solution in the reservoir with the inactivating agent; and (e) separating the inactivating agent from the substance of interest by flowing the solution from the reservoir through the first set of one or more chambers of the tangential flow device and back to the reservoir with sufficient power to generate a permeate stream; wherein the inactivating agent or the substance of interest is retained by the tangential flow device and the other inactivating agent or substance of interest passes through the filter means from the first set of one or more chambers to the second set of one or more chambers with the permeate stream.
  3. 41. A method of removing a pathogen from a solution comprising blood, the pathogen and a substance of interest, the method comprising: (a) providing a tangential flow device comprising: (i) a housing enclosing an interior volume; (ii) one or more filter means separating the interior volume of the housing into a first set of one or more chambers and a second set of one or more chambers; (iii) at least one entrance port and at least one exit port in fluid communication with the first set of one or more chambers; (iv) at least one entrance and/or exit port in fluid communication with the second set of one or more chambers; (b) providing a reservoir in loop fluid communication with the tangential flow device; (c) flowing the solution from the reservoir through the first set of one or more chambers of the tangential flow device and back to the reservoir with sufficient power to generate a permeate stream, passing into the second set of one or more chambers, wherein the pathogen or the substance of interest is retained by the filter means and the other pathogen or substance of interest passes through the filter means from the first set of one or more chambers to the second set of one or more chambers with the permeate stream of (c); (d) adding a dialyzing solution to the reservoir for increasing permeation of the pathogen and/or substance of interest.
  4. 49. A method of producing and isolating a metabolic product of a culturable organism, the method comprising: (a) providing a reservoir comprising a culture fluid; (b) providing a first tangential flow membrane device in loop fluid communication with the reservoir, suitable for retaining cells comprising: (i) a first housing enclosing an interior volume; (ii) one or more filter means separating the interior volume of the first housing into a first set of one or more chambers and a second set of one or more chambers; (iii) at least one entrance port and at least one exit port in fluid communication with the first set of one or more chambers; (iv) at least one entrance and/or exit port in fluid communication with the second set of one or more chambers; (c) flowing the culture fluid from the reservoir through first set of one or more chambers of the tangential flow membrane device and back to the reservoir with sufficient power to generate a permeate stream; (d) monitoring the culture fluid for one or more parameters selected from the group consisting of oxygen, pH, temperature and CO2; (e) providing a means for adding to the culture fluid one or more supplements selected from the group consisting of oxygen, culture media, acids, bases, buffers and cellular nutrients; (f) inoculating the culture fluid with a culturable organism; (g) providing a second tangential flow membrane device, suitable for concentrating or isolating the metabolic product, the second tangential flow membrane device comprising: (i) a second housing enclosing an interior volume; (ii) one or more filter means separating the interior volume of the second housing into a first set of one or more chambers and a second set of one or more chambers; (iii) at least one entrance port and at least one exit port in fluid communication with the first set of one or more chambers; (iv) at least one entrance and/or exit port in fluid communication with the second set of one or more chambers; (h) removing the permeate fluid from (c) via an exit port; and (i) in the second tangential flow device, flowing the permeate of the first tangential flow device through the first set of one or more chambers of the second tangential flow membrane device with sufficient power to generate a permeate stream, thereby concentrating or isolating the metabolite.
  5. 53. A method of culturing cells comprising: (a) providing a reservoir comprising a culture fluid; (b) providing a tangential flow membrane device in loop fluid communication with the reservoir, suitable for retaining cells comprising: (i) a first housing enclosing an interior volume; (ii) one or more filter means separating the interior volume of the first housing into a first set of one or more chambers and a second set of one or more chambers; (iii) at least one entrance port and at least one exit port in fluid communication with the first set of one or more chambers; (iv) at least one entrance and/or exit port in fluid communication with the second set of one or more chambers; (c) flowing the culture fluid from the reservoir through the tangential flow membrane device and back to the reservoir with sufficient power to generate a permeate stream; (d) monitoring the culture fluid for one or more parameters selected from the group consisting of oxygen, pH, temperature and CO2; (e) providing a means for addition of one or more supplements selected from the group consisting of oxygen, culture media, acids, bases, buffers and cellular nutrients; (f) inoculating the culture fluid contained in the second set of one or more chambers provided in (b)(iv) with a culturable organism; (g) providing a second reservoir in loop fluid communication with the second set of one or more chambers of the tangential flow membrane device; (h) providing a means for flowing the fluid from the second reservoir through the second set of one or more chambers of the tangential flow membrane device and back to the reservoir.
  6. 57. A method of producing and isolating a metabolic product of a culturable organism comprising: (a) providing a first reservoir comprising a culture fluid; (b) providing a first tangential flow membrane device in loop fluid communication with the reservoir, suitable for retaining cells comprising: (i) a first housing enclosing an interior volume; (ii) one or more filter means separating the interior volume of the first housing into a first set of one or more chambers and a second set of one or more chambers; (iii) at least one entrance port and at least one exit port in fluid communication with the first set of one or more chambers; (iv) at least one entrance and/or exit port in fluid communication with the second set of one or more chambers; (c) flowing the culture fluid from the reservoir through the first set of one or more chambers of the first tangential flow membrane device and back to the reservoir; (d) monitoring the culture fluid for one or more parameters selected from the group consisting of oxygen, pH, temperature and CO2; (e) providing a means for adding to the culture fluid one or more supplements selected from the group consisting of oxygen, culture media, acids, bases, buffers and cellular nutrients; (f) inoculating the culture fluid with a culturable organism; (g) providing a second tangential flow membrane device in fluid communication with the first set of one or more chambers of the first tangential flow device, suitable for isolating the metabolic product comprising: (i) a first housing enclosing an interior volume; (ii) one or more filter means separating the interior volume of the first housing into a first set of one or more chambers and a second set of one or more chambers; (iii) at least one entrance port and at least one exit port in fluid communication with the first set of one or more chambers; (iv) at least one entrance and/or exit port in fluid communication with the second set of one or more chambers; (h) in the second tangential flow device, flowing the culture fluid through the first set of one or more chambers of the second tangential flow membrane device with sufficient power to generate a permeate stream.
  7. 67. The method according to 49, 53, 56, or 57 wherein the culturable organism is selected from the group consisting of viruses, viral fragments, viral particles, bacteria, bacterial fragments and yeast.
  8. 69. A method of inactivating a pathogen in a solution which contains a substance of interest, the method comprising: (a) providing a tangential flow device comprising: (i) a first housing enclosing an interior volume; (ii) one or more filter means separating the interior volume of the first housing into a first set of one or more chambers and a second set of one or more chambers; (iii) at least one entrance port and at least one exit port in fluid communication with the first set of one or more chambers; (iv) at least one entrance and/or exit port in fluid communication with the second set of one or more chambers; (b) providing a reservoir in loop fluid communication with the tangential flow device, the reservoir comprising a solution comprising a viral pathogen; (c) adding a virus-destroying chemical to the reservoir; (d) incubating the solution in the reservoir with the virus-destroying chemical; and (e) separating the virus-destroying chemical from the substance of interest by flowing the solution from the reservoir through the first set of one or more chambers of the tangential flow device and back to the reservoir with sufficient power to generate a permeate stream; wherein the virus-destroying chemical or the substance of interest is retained by the tangential flow device and the other virus-destroying chemical or substance of interest passes through the filter means from the first set of one or more chambers to the second set of one or more chambers with the permeate stream.
  9. 70. A method of inactivating a pathogen in a solution comprising blood and a substance of interest, the method comprising: (a) providing a tangential flow device comprising: (i) a first housing enclosing an interior volume; (ii) one or more filter means separating the interior volume of the first housing into a first set of one or more chambers and a second set of one or more chambers; (iii) at least one entrance port and at least one exit port in fluid communication with the first set of one or more chambers; (iv) at least one entrance and/or exit port in fluid communication with the second set of one or more chambers; (b) providing a reservoir in loop fluid communication with the tangential flow device, the reservoir comprising a solution comprising a pathogen; (c) adding an inactivating agent to the reservoir to inactivate the pathogen; (d) incubating the blood-comprising solution in the reservoir with the inactivating agent; and (e) separating the inactivating agent from the substance of interest by flowing the solution from the reservoir through the first set of one or more chambers of the tangential flow device and back to the reservoir with sufficient power to generate a permeate stream; wherein the inactivating agent or the substance of interest is retained by the tangential flow device and the other (inactivating agent or substance of interest) passes through the filter means from the first set of one or more chambers to the second set of one or more chambers with the permeate stream.
  10. 71. A method for the production and subsequent viral reduction of a metabolic product of interest produced by a culturable organism, the method comprising: (a) providing a first reservoir comprising a culture fluid; (b) providing a first tangential flow membrane device in loop fluid communication with the first reservoir, suitable for retaining cells comprising: (i) a first housing enclosing an interior volume; (ii) one or more filter means separating the interior volume of the first housing into a first set of one or more chambers and a second set of one or more chambers; (iii) at least one entrance port and at least one exit port in fluid communication the first set of one or more chambers; (iv) at least one entrance and/or exit port in fluid communication with the second set of one or more chambers; (c) flowing fluid from the first reservoir through the first set of one or more chambers of the first tangential flow membrane device and back to the reservoir; (d) monitoring the culture fluid for one or more parameters selected from the group consisting of oxygen, pH, temperature and CO2; (e) adding to the culture fluid one or more supplements selected from the group consisting of oxygen, culture media, acids, bases, buffers and cellular nutrients; (f) inoculating the culture fluid contained in the second set of one or more chambers of the first tangential flow membrane device with a culturable organism capable of producing a metabolic product of interest; (g) providing a second reservoir suitable for receiving fluid from the second set of one or more chambers of the first tangential flow membrane device; (h) providing a second tangential flow membrane device suitable for the retention of virus and passage of the metabolic product of interest in loop fluid communication with the second reservoir comprising: (i) a second housing enclosing an interior volume; (ii) one or more filter means separating the interior volume of the second housing into a first set of one or more chambers and a second set of one or more chambers; (iii) at least one entrance port and at least one exit port in fluid communication the first set of one or more chambers; <(iv) at least one entrance and/or exit port in fluid communication with the second set of one or more chambers; (i) transferring fluid from the second set of one or more chambers of the first tangential flow membrane device to the second reservoir; (j) flowing fluid from the second reservoir through the first set of one or more chambers of the second tangential flow membrane device and back to the second reservoir with sufficient power to generate a permeate stream; (k) optionally adding a dialyzing solution and/or one or more inactivating agents to the second reservoir.
  11. 72. A method for the production and subsequent viral reduction of a metabolic product of interest produced by a culturable organism, the method comprising: (a) providing a first reservoir comprising a culture fluid; (b) providing a first tangential flow membrane device in loop fluid communication with the first reservoir, suitable for retaining cells comprising: (i) a housing enclosing an interior volume; (ii) one or more filter means separating the interior volume of the housing into a first set of one or more chambers and a second set of one or more chambers; (iii) at least one entrance port and at least one exit port in fluid communication the first set of one or more chambers; (iv) at least one entrance and/or exit port in fluid communication with the second set of one or more chambers; (c) flowing the fluid from the first reservoir through the first set of one or more chambers of the first tangential flow membrane device and back to the reservoir with sufficient power to generate a permeate stream; (d) monitoring the culture fluid for one or more parameters selected from the group consisting of oxygen, pH, temperature and CO2; (e) adding to the culture fluid one or more supplements selected from the group consisting of oxygen, culture media, acids, bases, buffers and cellular nutrients; (f) inoculating the culture fluid contained in the first reservoir with a culturable organism capable of producing a metabolic product of interest; (g) providing a second reservoir suitable for receiving fluid from the second set of one or more chambers of the first tangential flow membrane device; (h) providing a second tangential flow membrane device suitable for the retention of virus and passage of the metabolic product of interest in loop fluid communication with the second reservoir, the second tangential flow membrane device comprising: (i) a second housing enclosing an interior volume; (ii) one or more filter means separating the interior volume of the second housing into a first set of one or more chambers and a second set of one or more chambers; (iii) at least one entrance port and at least one exit port in fluid communication the first set of one or more chambers; (iv) at least one entrance and/or exit port in fluid communication with the second set of one or more chambers; (i) transferring fluid from the second set of one or more chambers of the first tangential flow membrane device to the second reservoir; (j) flowing fluid from the second reservoir through the first set of one or more chambers of the second tangential flow membrane device and back to the second reservoir with sufficient power to generate a permeate stream comprising the substance of interest, while retaining the virus; and (k) optionally adding a dialyzing solution and/or one or more inactivating agents to the second reservoir.

References Cited

U.S. Patent Documents

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Other Publications

Cheryan et al. in Mebrane Separations in Biotechnology, McGregor (ed), Marcel Dekker Inc., p. 258-261 (1986).
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Patent Family

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