Claims for Patent: 9,643,998

Summary for Patent: 9,643,998

Title:	Real time monitoring and control of protein production processes using impedance spectroscopy
Abstract:	Methods and systems for monitoring and/or controlling protein separation, purification, extraction, and/or fractionation processes are provided. The impedance of a protein mixture undergoing a protein process is measured and compared to a target reference impedance value or range of reference impedance values. If the measured impedance is not within an acceptable deviation of the target reference impedance value, a parameter of the protein mixture or process is adjusted.
Inventor(s):	Wauters; Cary N. (La Crescenta, CA), Zaydenberg; Alexander (Woodland Hills, CA)
Assignee:	BAXALTA GMBH (Opfikon, CH) BAXALTA INCORPORATED (Bannockburn, IL)
Application Number:	13/315,376
Patent Claims:	1. A method for preparing a protein suspension having an impedance within a target reference range of impedance values, said method comprising: admixing a protein solid or paste with a solvent to form a protein suspension; monitoring the impedance of said protein suspension during said admixing step; comparing said impedance to a target reference range of impedance values; continuing said admixing, monitoring and comparing steps until an impedance value is obtained for said protein suspension within the target reference range of impedance values; and removing remaining protein solid or paste from said protein suspension when said impedance value within the target reference range of impedance values is obtained. 2. The method according to claim 1, wherein said protein solid or paste is a fractionated plasma intermediate or a fractionated plasma product from a plasma fractionation process. 3. The method according to claim 2, wherein said plasma fractionation process comprises a Cohn process, an Oncley process, a Kistler process, a Teschner process or a combination thereof. 4. The method according to claim 3, wherein said plasma fractionation process is a Cohn process and said fractionated plasma intermediate is selected from the group consisting of Fraction I, Fraction II+III, Fraction III, Fraction IV-1, Fraction IV-4, and Fraction V from said Cohn process. 5. The method according to claim 3, wherein said plasma fractionation process is an Oncley process and said fractionated plasma intermediate is selected from the group consisting of Fraction II+IIIW, Fraction II, and Fraction III of said Oncley process. 6. The method according to claim 3, wherein said plasma fractionation process is a Kistler process and said fractionated plasma intermediate is selected from the group consisting of Precipitate A, Precipitate B, Precipitate IV, Precipitate C, and Precipitate D of said Kistler process. 7. The method according to claim 3, wherein said plasma fractionation process is a Techsner process and said fractionated plasma intermediate comprises Precipitate G of said Teschner process. 8. The method according to claim 1, wherein said target reference range of impedance values corresponds to a target degree of uniformity of said protein suspension. 9. The method according to claim 1 further comprising: notifying an operator when said impedance of said protein suspension is within the target reference range of impedance values. 10. The method according to claim 1 further comprising: automatically filtering said protein suspension when said impedance of said protein suspension is within the target reference range of impedance values. 11. The method of claim 1, wherein the protein suspension is prepared in an amount of 1.6 L to 10 L. 12. The method of 1, wherein the protein suspension is prepared on at least a liter-scale. 13. A method for controlling a protein separation process for separating a protein from a biologic fluid, said method comprising: obtaining an impedance measurement of said biologic fluid from a step of said protein separation process; determining an amount of modification of a parameter of said biologic fluid that modifies solubility of said protein in said biologic fluid needed to cause the impedance measurement of said biologic fluid to be within an acceptable tolerance of a target impedance value, said parameter selected from the group consisting of solute concentration, solvent concentration, pH, ionic strength, temperature, density, flow rate, and viscosity; bringing about an increase or decrease in solubility of said protein in said biologic fluid by adjusting said parameter that modifies solubility of said protein in said biologic fluid by said amount of modification to bring said impedance value within said acceptable tolerance of said target impedance value; and separating said insoluble protein from said soluble protein remaining in said biologic fluid when impedance of said biologic fluid is within said acceptable tolerance; thereby controlling said protein separation process. 14. The method according to claim 13, wherein said step of said protein separation process comprises precipitating said protein from said biologic fluid. 15. The method according to claim 13, wherein said step of said protein separation process comprises purifying or concentrating said protein. 16. The method according to claim 13, wherein said determining step comprises providing a notification to an operator when said measurement deviates from said target impedance value by more than said acceptable tolerance. 17. The method according to claim 13, wherein said adjusting step comprises triggering an analysis of said biologic fluid. 18. The method according to claim 13, wherein said biologic fluid is selected from the group consisting of blood plasma, fractionated plasma intermediates, protein solutions and suspensions, and cell culture suspensions. 19. The method according to claim 18, wherein said biologic fluid is a blood plasma or a fractionated plasma intermediate. 20. The method according to claim 13, wherein the protein is a fractionated plasma product. 21. The method according to claim 20, wherein the fractionated plasma product is selected from the group consisting of albumin, alpha1-proteinase inhibitor, antihemophilic factor, von Willebrand factor complex, anti-inhibitor coagulant complex, antithrombin, C1 esterase inhibitor, coagulation factors, fibrin, fibrinogen, immunoglobulins, protein C concentrate, and thrombin. 22. The method according to claim 13, wherein said adjusting step comprises automatically adjusting said parameter when said measurement deviates from said target impedance value by more than said acceptable tolerance. 23. The method according to claim 22, wherein said adjusting step is performed substantially in real-time. 24. The method according to claim 22, wherein said adjusting step is performed in real-time. 25. The method according to claim 13, wherein said step of said protein separation process comprises a continuous flow process. 26. The method according to claim 25, wherein said biologic fluid is an in-line biologic fluid from said continuous flow process. 27. The method according to claim 13, wherein said step of said protein separation comprises a batch process. 28. The method according to claim 27, wherein said biologic fluid is a batch mixture from said batch process. 29. The method according to claim 13, wherein said step of said protein separation process comprises a filtration process. 30. The method of claim 13, wherein the biologic fluid is used in an amount of 1.6 L to 10 L. 31. The method of claim 13, wherein the protein separation process is performed on at least a liter-scale. 32. A method for separating a protein from a biologic fluid to a targeted degree, the method comprising: adjusting a parameter of said biologic fluid to modify solubility of said protein in said biologic fluid, said parameter selected from the group consisting of solute concentration, solvent concentration, pH, ionic strength, temperature, density, flow rate, and viscosity; monitoring impedance of the biologic fluid during said adjusting step; comparing said impedance to a target impedance value corresponding to a target degree of separation of said protein from said biologic fluid; bringing about an increase or decrease in solubility of said protein in said biologic fluid by further modifying said parameter when said impedance deviates from said target impedance value by more than an acceptable tolerance to bring said impedance value within said acceptable tolerance of said target impedance value; and separating said insoluble protein from said soluble protein remaining in said biologic fluid when impedance of said biologic fluid is within said acceptable tolerance; thereby effecting a protein separation to said targeted degree. 33. The method according to claim 32, wherein said modifying step comprises further modifying said parameter when said impedance deviates from said target impedance value by at least 5%. 34. The method according to claim 32, wherein said modifying step comprises further modifying said parameter when said impedance deviates from said target impedance value by at least 1.0%. 35. The method according to claim 32, wherein said modifying step comprises further modifying said parameter when said impedance deviates from said target impedance value by at least 0.5%. 36. The method according to claim 32, wherein said modifying step comprises providing a notification to an operator when said impedance deviates from said target impedance value by more than said acceptable tolerance. 37. The method according to claim 32, wherein said modifying step further comprises triggering an analysis of said biologic fluid. 38. The method according to claim 32, wherein said biologic fluid is selected from the group consisting of blood plasma, fractionated plasma intermediates, protein solutions and suspensions, and cell culture suspensions. 39. The method according to claim 38, wherein said biologic fluid is a blood plasma or a fractionated plasma intermediate. 40. The method according to claim 32, wherein the protein is a fractionated plasma product. 41. The method according to claim 40, wherein the fractionated plasma product is selected from the group consisting of albumin, alpha1-proteinase inhibitor, antihemophilic factor, von Willebrand factor complex, anti-inhibitor coagulant complex, antithrombin, C1 esterase inhibitor, coagulation factors, fibrin, fibrinogen, immunoglobulin, protein C concentrate, and thrombin. 42. The method according to claim 32, wherein said modifying step comprises automatically modifying said parameter when said impedance deviates from said target impedance value by more than said acceptable tolerance. 43. The method according to claim 42, wherein said modifying step is performed substantially in real-time. 44. The method according to claim 43, wherein said modifying step is performed in real-time. 45. The method according to claim 32, wherein said modifying step comprises: determining an amount of modification of said parameter needed to cause the impedance of said biologic fluid to be at or about said target impedance value when said impedance deviates from said target impedance value by more than said acceptable tolerance; and modifying the parameter by said amount of modification. 46. The method of claim 32, wherein the biologic fluid is used in an amount of 1.6 L to 10 L. 47. The method of claim 32, wherein the protein separation is performed on at least a liter-scale.

Details for Patent 9,643,998

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Baxalta Us Inc.	AUTOPLEX, FEIBA NF, FEIBA VH	anti-inhibitor coagulant complex	For Injection	101447	12/21/1979		2030-12-16
Baxalta Us Inc.	AUTOPLEX, FEIBA NF, FEIBA VH	anti-inhibitor coagulant complex	For Injection	101447	07/31/2000		2030-12-16
Baxalta Us Inc.	AUTOPLEX, FEIBA NF, FEIBA VH	anti-inhibitor coagulant complex	For Injection	101447	08/11/2005		2030-12-16