In-Process Control for the Manufacture of Glatiramer Acetate

Abstract

The present disclosure provides methods for manufacturing or producing glatiramer acetate having a Mp of 5000-9000 Da. These methods include: polymerizing N-carboxy anhydrides of L-alanine, benzyl-protected L-glutamic acid, trifluoroacetic acid (TFA)-protected L-lysine, and L-tyrosine to generate a sample comprising intermediate-1; treating the sample comprising intermediate-1 to partially depolymerize the protected copolymer and deprotect benzyl-protected L-glutamic acid, measuring the viscosity of the sample comprising intermediate-1 during the treatment, and ending the treatment when the viscosity of the sample is within an endpoint range, thereby generating a sample comprising intermediate-2; treating the sample comprising intermediate-2 to deprotect TFA-protected L-lysine, thereby generating intermediate-3; further processing the intermediate-3 to generate a sample glatiramer acetate; and purifying the glatiramer acetate to generate a composition comprising purified glatiramer acetate having a Mp of 5000-9000 Da.

What is claimed is: 
     
         1 . A method for manufacturing glatiramer acetate drug substance having a Mp of 5000-9000 Da, the method comprising:
 (a) polymerizing N-carboxy anhydrides of L-alanine, benzyl-protected L-glutamic acid, trifluoroacetic acid protected L-lysine and L-tyrosine to generate a composition comprising intermediate-1;   (b) treating the composition comprising intermediate-1 to partially depolymerize intermediate-1 and to deprotect benzyl-protected L-glutamic acid;   (c) measuring the viscosity of the composition during step (b);   (d) ending step (b) when the viscosity of the composition is at a predetermined level that informs that step (f) will yield glatiramer acetate with a Mp of 5000-9000 Da, thereby generating a composition comprising intermediate-2;   (e) treating the composition comprising intermediate-2 to deprotect trifluoroacetic acid protected L-lysine, thereby generating a composition comprising intermediate-3; and   (f) processing the composition comprising intermediate-3 to generate glatiramer acetate drug substance having a Mp of 5000-9000 Da.   
     
     
         2 . The method of  claim 1  wherein viscosity is measured in-process during step (b). 
     
     
         3 . The method of  claim 1  wherein the viscosity is measured intermittently during at least a portion of step (b). 
     
     
         4 . The method of  claim 1  wherein the viscosity is measured continuously during at least a portion of step (b). 
     
     
         5 . The method of  claim 1  wherein the viscosity is measured continuously during a substantial portion of step (b). 
     
     
         6 . The method of  claim 1  wherein the viscosity is measured continuously during step (b). 
     
     
         7 . The method of  claim 1  wherein the predetermined level of viscosity is 77 cP to about 566 cP when viscosity is measured at 15° C. to 35° C. 
     
     
         8 . The method of  claim 1 , wherein the predetermined level of viscosity is 93 cP to about 498 cP at 15° C. to 35° C. 
     
     
         9 . The method of  claim 1 , wherein the predetermined level of viscosity is 103 cP to about 453 cP at 15° C. to 35° C. 
     
     
         10 . The method of  claim 7 , wherein the predetermined level of viscosity is 77 cP to about 566 cP when viscosity is measured at 15° C. to 35° C. and the density of the composition is 0.8-1.6 gm/ml. 
     
     
         11 . The method of  claim 7 , wherein the predetermined level of viscosity is 77 cP to about 566 cP when viscosity is measured at 15° C. to 35° C. and the density of the composition is 1.0-1.4 gm/ml. 
     
     
         12 . The method of  claim 1  wherein the temperate of the composition during step (b) is 15° C.-35° C. 
     
     
         13 . The method of  claim 1  where in the temperature of the composition during step (b) is 19° C.-25° C. 
     
     
         14 . The method of  claim 1  wherein the concentration of Intermediate-1 at the start of step (b) is 7-11% on a weight/weight basis. 
     
     
         15 . The method of  claim 1  wherein the density of the composition during step (b) is 0.8-1.6 gm/ml. 
     
     
         16 . The method of  claim 1 , further comprising measuring the temperature of the composition during at least a portion of step (b). 
     
     
         17 . The method of  claim 16 , wherein both viscosity and temperature are measured during at least a portion of step (b). 
     
     
         18 . The method of  claim 1 , wherein step (b) is ended when the viscosity of the composition is at a predetermined level that informs that step (f) will yield glatiramer acetate with a Mp of 7000-8000 Da. 
     
     
         19 . The method of  claim 1 , wherein step (b) is ended when the viscosity of the composition is at a predetermined level that informs that step (f) will yield glatiramer acetate with a Mp of 7200-7400 Da. 
     
     
         20 . The method of  claim 1  wherein step (b) comprises treating the composition comprising Intermediate-1 with phenol, HBr and acetic acid. 
     
     
         21 . The method  claim 1  wherein step (d) comprises quenching the reaction with water. 
     
     
         22 . The method of  claim 1  wherein Intermediate-1 is present at 7-11% on a weight/weight basis at the start of step (b). 
     
     
         23 . The method of  claim 1  wherein water is present during step (b). 
     
     
         24 . The method of  claim 23  wherein water is present at 0.1-10% on a weight/weight basis relative to the entire reaction. 
     
     
         25 . The method of  claim 1  wherein step (b) is carried out at 19° C.-25° C., water is present at 0.1%-10% on a weight/weight basis relative to the entire reaction, and Intermediate-1 is present at 7%-11% on a weight/weight basis at the start of step (b). 
     
     
         26 . The method of  claim 1 , wherein step (f) comprises filtering the composition comprising intermediate-3. 
     
     
         27 . A method for preparing glatiramer acetate drug product comprising obtaining glatiramer acetate drug substance prepared by the method of  claim 1  and processing the glatiramer acetate drug substance to produce glatiramer acetate drug product. 
     
     
         28 . The method of  claim 25  wherein the step of processing the glatiramer acetate drug substance to produce glatiramer acetate drug product comprises the addition of mannitol. 
     
     
         29 . The method of  claim 24 , further comprising packaging the glatiramer acetate drug product. 
     
     
         30 . The method of  claim 1  comprising ending step (b) when the viscosity of the sample is within a range shown in Table 1 when measured within a corresponding temperate range shown in Table 1. 
     
     
         31 . The method of  claim 1  wherein water is present during step (b) in a range selected from the group consisting of 5-25%, 13-19%, and 14-18% w/w against Intermediate-1 present at the start of step (b).