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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

Document NumberAssigneesInventorsIssue/Pub Date
US3259546 CANADIAN PATENTS DEV Polley Jul 1966
US3259547 SQUIBB & SONS INC Cole Jul 1966
US3821087 DEDRICK R Knazek et al. Jun 1974
US3919044 ARMOUR PHARMA Melnick et al. Nov 1975
US4203801 Burroughs Wellcome Co. Telling et al. May 1980
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Foreign Patent Documents

Document NumberAssigneesInventorsIssue/Pub Date
EP0155237MBR Bio Reactor AGMar 1985
JP6188872Jul 1994

Other Publications

Cheryan et al. in Mebrane Separations in Biotechnology, McGregor (ed), Marcel Dekker Inc., p. 258-261 (1986).
New Brunswick Scientific Product Bulletin, Celltronics, HF-100. The Bench-Top Hollow Fiber Bioreactor System.
Chemical Engineers Handbook, Fifth Edition, McGraw Hill Book Company, Liquid-Solid Systems, 1973.

Patent Family

The current document is not in a family.

Claims 

  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. 2. The method of claim 1 wherein the second set of one or more chambers of the first tangential flow device is connected by a path of fluid communication with the first set of one or more chambers of the second tangential flow device, such that steps 31(d) and 31(e) are performed by flowing the second fluid from the second set of one or more chambers of the first tangential flow device into the first set of one or more chambers of the second tangential flow device via the path of fluid communication.
  3. 3. The method of claim 1 wherein the third fluid comprises the first permeate component in a more pure form.
  4. 4. The method of claim 1 wherein the permeate component of 31(c) enters the first set of one or more chambers of the second tangential flow device and becomes concentrated and/or is rendered into a more pure form.
  5. 5. The method of claim 1 further comprising the following steps; (a) providing one or more tangential flow devices in addition to the first and second tangential flow devices, said additional tangential flow device(s) each 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) introducing an input fluid comprising the first, second and/or third fluid into the first set of one or more chambers of an additional tangential flow device provided in (a), such that additional permeate can traverse the one or more filter means and enter the second set of one or more chambers to provide an output fluid in the second set of one or more chambers; (c) and repeating step (b) for each additional tangential flow device provided in step (a) with the exception that the input fluid in each repetition of step (b) comprises a separated component of the input fluid and/or a more concentrated form of a component of the input fluid.
  6. 6. The method of claim 5 wherein first, second and the additional tangential flow device(s) are joined in serial fluid communication, with the second set of one or more chambers of each tangential flow device being joined in fluid communication to the first set of one or more chambers of a succeeding additional tangential flow device.
  7. 7. The method of claim 6 wherein first, second and the additional tangential flow device(s) are joined in serial fluid communication, with the first set of one or more chambers of each tangential flow device being joined in fluid communication to the first set of one or more chambers of a succeeding additional tangential flow device.
  8. 8. The method of claim 6 wherein first, second and the additional tangential flow device(s) are joined in serial fluid communication, with the first and/or second set of one or more chambers of each tangential flow device being joined in fluid communication to the first and/or second set of one or more chambers of a succeeding additional tangential flow device.
  9. 9. The method of claim 1 wherein: (a) the first fluid comprises a culture medium comprising a microbe; (b) the permeate of 31(c) comprises a metabolic product of the microbe as the first permeate component; and (c) the retentate of 31(e) comprises the metabolic product of the microbe.
  10. 10. The method of claim 1 wherein: (a) the first fluid comprises a culture medium comprising a microbe; (b) the permeate of 31(c) comprises a metabolic product of the microbe as the first permeate component; (c) the permeate of 31(e) comprises the metabolic product of the microbe.
  11. 11. The method of claim 9 or 10 further comprising inactivating the microbe and/or metabolic product.
  12. 12. The method of claim 11 wherein the microbe and/or metabolic product is inactivated by bringing the microbe and/or metabolic product into contact with an inactivating agent.
  13. 13. The method of claim 12 wherein the inactivating agent comprises a detergent treatment or other pathogen treatment.
  14. 14. The method of claim 11 wherein the step of inactivating the microbe and/or metabolic product comprises means selected from the group consisting of heat and steam.
  15. 15. The method of claim 11 wherein the inactivated microbe is selected from the group consisting of mammalian cells, bacterial cells, yeast cells and cells of Mycoplasma species.
  16. 16. The method of claim 11 wherein the inactivated metabolic product is selected from the group consisting of viruses and viral products, antibodies, cell fragments, peptides, proteins, and carbohydrates.
  17. 17. The method of claims 9 or 10 wherein the metabolic product is a therapeutic compound.
  18. 18. The method of claim 12 wherein the detergent treatment or other pathogen treatment comprises a chemical capable of inactivating the virus to render it uninfective.
  19. 19. The method of claim 14 wherein the bacterial cells are cells of a Mycoplasma species.
  20. 20. The method of claim 12 wherein the inactivating agent comprises a pathogen-destroying substance.
  21. 21. The method of claim 1 wherein the first and/or second tangential flow device comprises multiple filter means in serial connection.
  22. 22. The method of claim 1 wherein the first and/or second tangential flow device comprises multiple filter means in parallel connection.
  23. 23. The method of claim 1 wherein the filter means of the first and/or second tangential flow device is selected and arranged within the housing such that the first or second set of one or more chambers comprises an intra-filter volume and the other of the first or second set of one or more chambers comprises an extra-filter volume.
  24. 24. The method of claim 1 wherein the filter means of the first and/or second tangential flow device comprises one or more flat sheet filters.
  25. 25. The method of claim 1 wherein the filter means of the first and/or second tangential flow device comprises one or more hollow fiber filters.
  26. 26. The method of claim 1 further comprising periodically redirecting the flow of fluid in first and/or second set of one or more chambers of the first and/or second tangential flow device.
  27. 27. The method of claim 1 further comprising filtering the first fluid prior to introducing the first fluid in to the first set of one or more chambers of the first tangential flow device.
  28. 28. The method of claim 1 further comprising the step of sterilizing and/or sanitizing the first and/or second tangential flow device.
  29. 29. The method of claim 28 wherein the sterilizing and/or sanitizing of the first and/or second tangential flow device is accomplished without removing the first and/or second tangential flow device.
  30. 30. The method of claim 28 further comprising: (a) removing the first and/or second tangential flow device prior to sterilization and/or sanitization; and (b) aseptically replacing the sterilized first and/or second flow.
  31. 31. The method of claim 28 further comprising: (a) providing a pre sanitized and/or sterilized first and/or second tangential flow device; and (b) aseptically assembling the pre-sanitized or sterilized first and/or second flow.
  32. 32. The method of claim 28 wherein the step of sanitizing and/or sterilizing employs a sanitizing and/or sterilizing means selected from the group consisting of chemical agents, heat and steam.
  33. 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.
  34. 34. The method of claim 33 further comprising dialyzing the retentate solution comprising adding a dialyzing solution to the reservoir after incubating the solution to increase permeation of the inactivating agent and/or substance of interest across the filter means.
  35. 35. The method of claim 33 wherein the inactivation agent comprises a detergent treatment or other pathogen treatment.
  36. 36. The method of claim 33 where the pathogen is selected from the group consisting of viruses, viral fragments, viral particles bacteria, bacterial fragments, and yeasts.
  37. 37. The method of claim 33 where the solution comprises culture fluid.
  38. 38. The method of claim 37 wherein the culture fluid is formulated for culturing an organism selected from the group consisting of viruses, bacteria, mammalian cells, and yeast.
  39. 39. The method of claim 33 wherein the inactivation agent comprises a virus-destroying chemical.
  40. 40. The method of claim 33 where the solution comprises blood.
  41. 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.
  42. 42. The method of claim 41 wherein adding a suitable dialyzing solution to the reservoir is accomplished after an incubation period.
  43. 43. The method of claim 41 where the pathogen is selected from the group consisting of viruses, viral fragments, viral particles, bacteria, bacterial fragments, and yeasts.
  44. 44. The method according to claim 36, or 43 wherein the pathogen comprises a Mycoplasma species.
  45. 45. The method of claim 41 where the pathogen is a virus.
  46. 46. The method of claim 44 wherein the solution is a culture fluid formulated for culturing an organism selected from the group consisting of viruses, bacteria, mammalian cells, and yeast.
  47. 47. The method of claim 38 or 46 wherein the culture fluid is formulated for culturing a Mycoplasma species.
  48. 48. The method of claim 41 where the solution comprises an aqueous biological solution.
  49. 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.
  50. 50. The method according to claim 49 wherein the metabolic product is retained by the filter means of the second tangential flow membrane device thereby concentrating the metabolic product.
  51. 51. The method according to claim 49 wherein the metabolic product traverses the filter means of the second tangential flow membrane device, thereby entering the second set of one or more chambers of the second tangential flow device in a more pure form.
  52. 52. The method according to claim 49 further comprising providing a second reservoir in loop fluid communication with the first set of one or more chambers of the second tangential flow membrane device.
  53. 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.
  54. 54. The method according to claim 53 further comprising providing a means for reversing the direction of the flowing culture fluid.
  55. 55. The method according to claim 53 further comprising providing a means for reversing the direction of the flowing fluid in loop communication between the second set of one or more chambers of the tangential flow membrane device and the second reservoir.
  56. 56. The method according to claim 53 further comprising: (a) providing a second tangential flow membrane 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) attaching the second tangential flow membrane device in loop fluid communication with the reservoir and the first tangential flow device via the entrance and exit ports of the first set of one or more chambers of the second tangential flow membrane device provided in 79(b)(iii); (c) attaching a suitable gas supply to the entrance port of the second set of one or more chambers of the second tangential flow device provided in 79(b)(iv).
  57. 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.
  58. 58. The method according to claim 57 wherein the second tangential flow membrane device concentrates the metabolic product.
  59. 59. The method according to claim 57 wherein the metabolic product traverses the filter means of the second tangential flow membrane device, thereby entering the second set of one or more chambers of the second tangential flow device in a more pure form.
  60. 60. The method according to claim 57 further comprising: (a) providing a second reservoir in loop fluid communication with the first set of one or more chambers of the second tangential flow membrane device; (b) transferring the culture fluid in the first reservoir to the second reservoir; (c) flowing the culture 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 reservoir with sufficient strength to generate a permeate.
  61. 61. The method according to claim 49, 53, 56, or 57 further comprising sanitizing and/or sterilizing the elements in contact with the culture fluid.
  62. 62. The method according to claim 61 comprising sanitizing and/or sterilizing the elements in place.
  63. 63. The method according to claim 61 comprising sanitizing and/or sterilizing the elements individually and aseptically assembling them in place.
  64. 64. The method according to claim 61 wherein the sanitizing and/or sterilizing the elements is accomplished by purchasing presanitized and/or presterilized elements and aseptically assembling them in place.
  65. 65. The method according to claim 49, 53, 56, or 57 further comprising sanitizing and/or sterilizing the culture fluid.
  66. 66. The method according to claim 65 wherein the sanitizing and/or sterilizing of the culture fluid is accomplished by means selected from the group consisting of sterilizing filtration, heat and steam.
  67. 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.
  68. 68. The method according to claim 56 or 57 wherein the metabolic product is selected from the group consisting of viruses, viral fragments, viral particles, bacteria, bacterial fragments, and yeasts.
  69. 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.
  70. 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.
  71. 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.
  72. 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.

Full Specification