Claims for Patent: 6,730,286

Summary for Patent: 6,730,286

Title:	Manufacturing process to control particle size
Abstract:	A process for preparing a sterile injectable suspension of radiolabeled macroaggregated serum albumin suitable for use in scanning a mammalian patient consisting of: 1) purifying serum albumin with a saline solution; 2) buffering the purified serum albumin; 3) adding stannous halide in HCl solution to the buffered mixture to obtain a reaction mixture; 4) gradually heating and cooling the reaction mixture to form macroaggregate particles; 5) separating the macroaggregates from the reaction mixture; 6) suspending the macroaggregates in sterile water for injection; 7) adding purified serum albumin; 8) lyophilizing the suspension; and 9) reconstituting the radiolabeled lyophilizate with 99mTc. The invention also includes a process for preparing a stable, sterile lyophilizate of macroaggregate particles of human serum albumin consisting of steps 1-7.
Inventor(s):	Schramm; Ernst (North Brunswick, NJ), Narra; Rama K. (North Brunswick, NJ), Kuczynski; Bruce (Highland Park, NJ), Zodda; Julius P. (Mercerville, NJ)
Assignee:	Bracco Diagnostics, Inc. (Princeton, NJ)
Application Number:	09/795,272
Patent Claims:	1. A process for preparing a sterile, non-pyrogenic injectable suspension of radiolabeled macroaggregate particles of albumin for scanning a mammalian patient comprising the steps of: a) mixing serum albumin with 0.9% w/v saline solution and ultrafiltering the mixture through a membrane having a molecular weight cut-off of 10,000; b) mixing a buffer having a pH of from 4.95 to about 5.25 with the ultrafiltered mixture to obtain a buffered, ultrafiltered mixture; c) passing the buffered, ultrafiltered mixture through a sterilizing filter to obtain a sterile mixture; d) adding a sterile filtered stannous halide in HCl solution to the buffered sterile mixture to obtain a sterile reaction mixture; e) heating the reaction mixture gradually while stirring continuously so that it attains about 75.degree. C. to 95.degree. C. in about 90 to about 110 minutes; f) cooling the reaction mixture gradually while stirring continuously so that the macroaggregates containing the stannous halide are formed; g) separating the macroaggregates from the reaction mixture, resuspending them in sterile water for injection, and filtering them through a sizing screen; h) adjusting the concentration of the macroaggregates with sterile water for injection and adding sterile, filtered, purified albumin; i) transferring the suspension into vials for storage and lyophilization; j) flooding the lyophilized vial with inert gas before sealing the lyophilized vial under an inert gas atmosphere; and k) reconstituting the lyophilized serum albumin with aqueous .sup.99m Tc pertechnate solution. 2. The process of claim 1 wherein said serum albumin is human serum albumin. 3. The process of claim 1 wherein said buffer is sodium acetate and acetic acid. 4. The process of claim 1 wherein said stannous halide is stannous chloride. 5. The process of claim 1 wherein said heating is at about 80.degree. C. in about 100 minutes. 6. The process of claim 1 wherein said cooling is from about 75.degree.-95.degree. C. to about 25.degree. C. in less than 100 minutes. 7. The process of claim 6 wherein said cooling is from about 75.degree.-95.degree. C. to about 25.degree. C. in less than 30 minutes. 8. The process of claim 1 wherein said sizing screen is about 75 microns. 9. The process of claim 1 wherein said macroaggregates have an average particle size of from 10 to 75 microns. 10. The process of claim 9 wherein said macroaggregates have an average particle size of from 40 to 60 microns. 11. The process of claim 10 wherein said macroaggregates have an average particle size of from 45 to 55 microns. 12. A process for preparing a sterile lyophilizate of macroaggregate particles of human serum albumin for reconstitution and radiolabeling with .sup.99m Tc for scanning a mammalian patient comprising the steps of: a) mixing serum albumin with 0.9% w/v saline solution and ultrafiltering the mixture through a membrane having a molecular weight cut-off of 10,000; b) mixing a buffer having a pH of from 4.95 to about 5.25 with the ultrafiltered mixture to obtain a buffered, ultrafiltered mixture; c) passing the buffered, ultrafiltered mixture through a sterilizing filter to obtain a sterile mixture; d) adding a sterile filtered stannous halide in HCl solution to the buffered sterile mixture to obtain a sterile reaction mixture; e) heating the reaction mixture gradually while stirring continuously so that is attains about 75.degree. C. to 95.degree. C. in about 90 to about 110 minutes; f) cooling the reaction mixture gradually while stirring continuously so that the macroaggregates containing the staruious halide are formed; g) separating the macroaggregates from the reaction mixture, resuspending them in sterile water for injection, and filtering them through a sizing screen; h) adjusting the concentration of the macroaggregates with sterile water for injection and adding sterile, filtered, purified albumin; i) transferring the suspension into vials for storage and lyophilization; and j) flooding the lyophilized vial with inert gas before sealing the lyophilized vial under an inert gas atmosphere. 13. The process of claim 12 wherein said serum albumin is human serum albumin. 14. The process of claim 12 wherein said buffer is sodium acetate and acetic acid. 15. The process of claim 12 wherein said stannous halide is stannous chloride. 16. The process of claim 12 wherein said heating is at about 80.degree. C. in about 100 minutes. 17. The process of claim 12 wherein said cooling is from about 75.degree. C.-95.degree. C. to about 25.degree. C. in less than 100 minutes. 18. The process of claim 12 wherein said sizing screen is about 75 micron. 19. A process for preparing a stable, sterile lyophilizate of macroaggregate particles of human serum albumin for reconstitution and radiolabeling with technetium-99m and scanning the lungs of a patient comprising the steps of: a) mixing one part 25% w/v human serum albumin with five parts 0.9% w/v saline solution; b) ultrafiltering the mixture through a membrane having a molecular weight cut-off of 10,000 using a sufficient volume of 0.9% w/v NaCI solution to purify the human serum albumin; adjusting the volume by ultrafiltration or by addition of the NaCI solution to c) adjusting the volume by ultrafiltration or by addition of the NaCI solution to mixture so that the final concentration of the mixture is about 50 mg of purified human serum albumin/ml of the mixture; d) adding with stirring to two parts purified human serum albumin one part sodium acetate/acetic and acid buffer having a pH of from 4.95 to 5.25 and about three parts water for injection to obtain a reagent mixture; e) filtering the reagent mixture through a sterile 0.2 micron filter into a reaction kettle; f) filtering through a sterile 0.2 micron filter about two parts 0.43% w/v stannous halide solution in HCl into the reaction kettle to obtain a uniform reaction mixture; g) heating with stirring the reaction mixture gradually so that it attains about 80.degree. C. in about 100 minutes; h) cooling with stirring the reaction mixture gradually to about 25.degree. C.; i) centrifuging the cooled reaction mixture to obtain the macroaggregates and to discard the supernatant; j) resuspending the macroaggregates in sterile water for injection k) passing the resuspended macroaggregates through a 75 micron sterile sizing screen into a sterile calibrated container; l) determining the protein concentration of the suspension; m) calculating the batch volume with which will have a concentration for the macroaggregated albumin of 1.5 mg/ml; n) adding through a 0.2 micron filter sufficient water for injection and purified albumin (5% w/v albumin) to the batch so that it contains a total of 10 mg/ml purified undenatured albumin; and o) transferring 1.0 ml aliquots into sterile glass vials; and lyophilizing the aliquots to dryness and sealing under inert atmosphere. 20. The process of claim 19 wherein said macroaggregates have an average particle size diameter of from 10 to 75 microns. 21. The process of claim 20 wherein said macroaggregates have an average particle size of from 40 to 60 microns. 22. The process of claim 21 wherein said macroaggregates have an average particle size of from 45 to 55 microns. 23. A process for preparing a sterile, non-pyrogenic, injectable suspension of macroaggregate particles of albumin for radiolabeling and scanning a mammalian patient comprising the steps of: a) mixing serum albumin with 0.9% w/v saline solution and ultrafiltering the mixture through a membrane having a molecular weight cut-off of 10,000; b) mixing a buffer having a pH of from 4.95 to about 5.25 with the ultrafiltered mixture to obtain a buffered, ultrafiltered mixture; c) passing the buffered, ultrafiltered mixture through a sterilizing filter to obtain a sterile mixture; d) adding a sterile filtered stannous halide in HCl solution to the buffered sterile mixture to obtain a sterile reaction mixture; e) heating the reaction mixture gradually while stirring continuously so that is attains about 75.degree. C. to 95.degree. C. in about 90 to about 110 minutes; f) cooling the reaction mixture gradually while stirring continuously so that the denatured macroaggregates containing the stannous halide are formed; g) separating the macroaggregates from the reaction mixture, resuspending them in sterile water for injection, and filtering them through a sizing screen; and h) adjusting the concentration of the macroaggregates with sterile water for injection and adding sterile, filtered, purified albumin.

Details for Patent 6,730,286

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Grifols Therapeutics Llc	ALBUKED, PLASBUMIN-20, PLASBUMIN-25, PLASBUMIN-5	albumin (human)	For Injection	101138	10/21/1942		2039-09-23
Baxalta Us Inc.	BUMINATE, FLEXBUMIN	albumin (human)	Injection	101452	03/03/1954		2039-09-23
Csl Behring Ag	ALBURX	albumin (human)	Injection	102366	07/23/1976		2039-09-23
Grifols Biologicals Llc	ALBUTEIN	albumin (human)	Injection	102478	08/15/1978		2039-09-23
Instituto Grifols, S.a.	HUMAN ALBUMIN GRIFOLS	albumin (human)	Injection	103352	02/17/1995		2039-09-23