Ultra-high yield intravenous immune globulin preparation

Abstract

An efficacious large-scale alcohol-free plasma fractionation production process which produces a high-yielding, non-denatured, double viral-inactivated intravenous human immune gamma globulin (IgG) product. The process employs sodium citrate in two initial fractionation steps, followed by diafiltration to remove sodium citrate.

1 . A process for blood-based material fractionation for producing a useful, non-denatured intravenous immunoglobulin (IgG) product comprising the steps of: 
 (a) acquiring a predetermined quantity of blood-based material for processing;    (b) preparing said quantity of blood-based material for processing;    (c) preparing for a first fractionation step by adding a first predetermined quantity of a first predetermined concentration of sodium citrate to said quantity to form a first separable product and a first residual product, said first separable product being substantially free of euglobulins;    (d) separating said first separable product from said first residual product;    (e) performing a second fractionation step by adding a second predetermined quantity of a second predetermined concentration of sodium citrate to said separated first separable product to form a second separable product and a second residual product;    (i) separating said second separable product from said second residual product;    (g) preparing said second separable product for diafiltration; and    (h) diafiltering said second separable product to form a lower volume third product substantially free of sodium citrate.    
     
     
         2 . The process for blood-based material fractionation according to  claim 1  wherein step (a) comprises selecting a quantity of plasma as the blood-based material.  
     
     
         3 . The process for blood-based material fractionation according to  claim 1  wherein step (a) comprises selecting a quantity of a blood fractionation product as the blood-based material.  
     
     
         4 . The process for blood-based material fractionation according to  claim 1  wherein step (b) comprises thawing said quantity of blood-based material.  
     
     
         5 . The process for blood-based material fractionation according to  claim 1  wherein step (c) comprises adding a fifty percent sodium citrate solution to said quantity of blood-based material.  
     
     
         6 . The process for blood-based material fractionation according to  claim 5  wherein step (c) comprises forming said first separable product as a first supernatant solution, having a first predetermined sodium citrate concentration, in combination with said first residual product as a first paste residual product, having the same predetermined sodium citrate concentration.  
     
     
         7 . The process for blood-based material fractionation according to  claim 6  wherein step (c) comprises forming said first separable product as a first supernatant solution, having a twelve percent sodium citrate concentration, in combination with said first residual product as a first paste residual product, having the same twelve percent sodium citrate concentration.  
     
     
         8 . The process for blood-based material fractionation according to  claim 6  wherein step (c) comprises forming said first separable product as a first supernatant solution, having a sodium citrate concentration in a first range between ten and fourteen percent, in combination with said first residual product as a first paste residual product, having a sodium citrate concentration in the same first range.  
     
     
         9 . The process for blood-based material fractionation according to  claim 6  wherein step (c) comprises forming said first separable product as a first supernatant solution, having a sodium citrate concentration in a second range between eleven and thirteen percent, in combination with said first residual product as a first paste residual product, having a sodium citrate concentration in the same second range.  
     
     
         10 . The process for blood-based material fractionation according to  claim 1  comprising an additional step of fractionating said first residual product into a group of products comprising blood factors comprising Factors VIII, IX, and vonWillebrand, and fibrinogen.  
     
     
         11 . The process for blood-based material fractionation according to  claim 1  wherein step (d) comprises separating said first separable product from said first residual product by centrifuging.  
     
     
         12 . The process for blood-based material fractionation according to  claim 11  wherein step (d) comprises removing said first separable product as a first supernatant fluid.  
     
     
         13 . The process for blood-based material fractionation according to  claim 12  wherein step (e) comprises adding a fifty percent sodium citrate solution to said first supernatant fluid.  
     
     
         14 . The process for blood-based material fractionation according to  claim 13  wherein step (e) comprises forming a second paste product, having a second predetermined sodium citrate concentration, and a second supernatant product having the same second predetermined sodium citrate concentration.  
     
     
         15 . The process for blood-based material fractionation according to  claim 14  wherein step (e) comprises forming a second paste product, having a twenty-two percent sodium citrate concentration, and a second supernatant product having the same twenty-two percent sodium citrate concentration.  
     
     
         16 . The process for blood-based material fractionation according to  claim 14  wherein step (e) comprises forming a second paste product, having a sodium citrate concentration within a range of twenty to twenty-four percent, and a second supernatant product having the same range of twenty to twenty-four percent sodium citrate concentration.  
     
     
         17 . The process for blood-based material fractionation according to  claim 14  wherein step (e) comprises forming a second paste product, having a sodium citrate concentration within a range of twenty-one to twenty-three percent, and a second supernatant product having the same range of twenty-one to twenty-three percent sodium citrate concentration.  
     
     
         18 . The process for blood-based material fractionation according to  claim 14  comprising an additional step of fractionating said second residual product into a group of products comprising albumin and alpha-1-antitrypsin.  
     
     
         19 . The process for blood-based material fractionation according to  claim 14  wherein step (f) comprises separating said second separable product from said second residual product by centrifuging.  
     
     
         20 . The process for blood-based material fractionation according to  claim 14  wherein step (f) comprises separating said second separable product from said second residual product by filtering.  
     
     
         21 . The process for blood-based material fractionation according to  claim 14  wherein step (f) comprises separating said second separable product as a paste of a third predetermined concentration having a resulting weight.  
     
     
         22 . The process for blood-based material fractionation according to  claim 21  wherein step (g) comprises forming a liquid dilution of said separable paste product of a third predetermined concentration by combining said resulting volume of said separable paste product with a volume of water having four times the resulting weight.  
     
     
         23 . The process for blood-based material fractionation according to  claim 22  wherein step (h) comprises passing the liquid dilution over a filtering membrane for the purpose of separating a portion of the third product from the added sodium citrate to provide the substantially free of sodium citrate third product.  
     
     
         24 . The process for blood-based material fractionation according to  claim 22  wherein step (h) comprises passing the liquid dilution over a 30 KD diafiltering membrane for the purpose of separating a portion of third product from the added sodium citrate to provide the substantially free of sodium citrate third product.  
     
     
         25 . The process for blood-based material fractionation according to  claim 23  wherein step (h) comprises testing conductivity of the third product for a first predetermined conductivity prior to diafiltration and testing the substantially free of sodium citrate third product for a second predetermined conductivity.  
     
     
         26 . The process for blood-based material fractionation according to  claim 25  wherein step (h) comprises testing the conductivity to assure third product conductivity is in the range of 500 microSiemens/cm (uS/cm) plus or minus 400 microSiemens/cm (uS/cm).  
     
     
         27 . The process for blood-based material fractionation according to  claim 25  wherein step (h) comprises testing the conductivity to assure the substantially free of sodium citrate third product conductivity is in the range of 500 microSiemens/centimeter (uS/cm) plus or minus 400 microSiemens/centimeter (uS/cm).  
     
     
         28 . The process for blood-based material fractionation according to  claim 27  comprising the following additional step: 
 (i) adding a predetermined volume of a predetermined concentration of detergent selected from a group of detergents comprising a solvent detergent and an augmented solvent detergent for the purpose of inactivating viruses contained in the substantially free of sodium citrate third product to produce an IgG viral inactivated solution.    
     
     
         29 . The process for blood-based material fractionation according to  claim 1  comprising a following additional step of cooling the IgG inactivated solution to a range of two to eight degrees Centigrade.  
     
     
         30 . The process for blood-based material fractionation according to  claim 29  comprising the following additional steps: 
 (j) performing column chromatography on the IgG viral inactivated solution to produce a resin bound IgG and an effluent;    (k) separating the resin bound IgG from the effluent; and    (l) washing the column resin bound IgG with a predetermined concentration of sodium chloride to produce an IgG rich solution free of viral inactivation chemicals.    
     
     
         31 . The process for blood-based material fractionation according to  claim 30  wherein step (j) comprises using a weak cationic exchange resin for the purpose of purifying the IgG rich solution free of viral inactivation chemicals to produce a purified IgG solution.  
     
     
         32 . The process for blood-based material fractionation according to  claim 30  wherein step (j) comprises using a Toyopearl CM-650C resin.  
     
     
         33 . The process for blood-based material fractionation according to  claim 30  wherein step (j) comprises testing conductivity of the IgG rich solution free of viral inactivation chemicals to assure said solution has a conductivity in the range of 100-900 microSiemens/centimeter (uS/cm).  
     
     
         34 . The process for blood-based material fractionation according to  claim 30  comprising a following additional step: 
 (m) concentrating the purified IgG solution to a predetermined concentration of IgG solution by ultrafiltering said solution.    
     
     
         35 . The process for blood-based material fractionation according to  claim 34  wherein step (m) comprises concentrating the purified IgG solution to a twelve percent concentration of IgG solution by ultrafiltering said solution.  
     
     
         36 . The process for blood-based material fractionation according to  claim 34  comprising a following additional step: 
 (n) stabilizing the predetermined concentration of IgG solution by adding a stabilizing chemical selected from a group of chemicals including maltose and sorbitol to produce a stabilized IgG concentrated solution.    
     
     
         37 . The process for blood-based material fractionation according to  claim 36  comprising a following additional step: 
 (o) if desired, nanofiltering the stabilized IgG concentrated solution to produce a nanofiltered stabilized IgG concentrated solution.    
     
     
         38 . The process for blood-based material fractionation according to  claim 37  comprising a following additional step: 
 (p) using sterile water for injection, diluting the stabilized IgG concentrated solution to a predetermined concentration of bulk purified IgG.    
     
     
         39 . The process for blood-based material fractionation according to  claim 36  comprising a following additional step: 
 (q) using sterile water for injection, diluting the stabilized IgG concentrated solution to a concentration of ten percent bulk purified IgG.    
     
     
         40 . The process for blood-based material fractionation according to  claim 38  comprising a following additional step: 
 (r) filtering for the purpose of sterilizing the bulk purified IgG concentrated solution.    
     
     
         41 . The process for blood-based material fractionation according to  claim 40  comprising a following additional step: 
 (s) dispensing the sterilized bulk purified concentrated IgG solution into sterile vials for distribution.    
     
     
         42 . The process for blood-based material fractionation according to  claim 41  comprising a following additional step: 
 (t) testing samples of contents of the sterile vials for safety and efficacy and, when vials pass predetermined testing criteria, releasing the vials to distribution channels.    
     
     
         43 . The process for blood-based material fractionation according to  claim 1  wherein a further step following step (f) processes said second residual product to separate out albumin and alpha-1-antitrypsin.  
     
     
         44 . A method for separating euglobulins from blood elements being fractionated from blood-based material for the purpose of performing a subsequent diafiltration procedure on the separated blood elements comprising the steps of: 
 (a) acquiring a predetermined volume of blood-based material for processing;    (b) preparing said volume of blood-based for processing;    (c) preparing for a first fractionation step by adding a first predetermined volume of a first predetermined concentration of sodium citrate to said sample to form a first separable supernatant product and a first residual product, said first separable supernatant product being substantially free of euglobulins.