Process for manufacturing glatiramer acetate product

Abstract

The patent provides a process of preparing a pharmaceutical preparation of glatiramer acetate and mannitol in a suitable container comprising the steps of: (i) obtaining an aqueous pharmaceutical solution of glatiramer acetate and mannitol; (ii) filtering the aqueous pharmaceutical solution at a temperature of from above 0° C. up to 17.5° C. to produce a filtrate; and (iii) filling the suitable container with the filtrate obtained after performing step (ii), so as to thereby prepare the pharmaceutical preparation of glatiramer acetate and mannitol in the suitable container. This patent further provides an aqueous pharmaceutical solution comprising 40 mg/ml glatiramer acetate and 40 mg/ml mannitol, wherein the aqueous pharmaceutical solution a) has a viscosity in the range of 2.0-3.5 cPa; or b) has an osmolality in the range of 275-325 mosmol/Kg. This patent also provides a prefilled syringe, an automated injector and a method of treatment of a human patient.

What is claimed: 
     
         1 . A process of preparing a pharmaceutical preparation of glatiramer acetate and mannitol in a suitable container comprising the steps of:
 (i) obtaining an aqueous pharmaceutical solution of glatiramer acetate and mannitol;   (ii) filtering the aqueous pharmaceutical solution at a temperature of from above 0° C. up to 17.5° C. to produce a filtrate; and   (iii) filling the suitable container with the filtrate obtained after performing step (ii), so as to thereby prepare the pharmaceutical preparation of glatiramer acetate and mannitol in the suitable container.   
     
     
         2 . The process of  claim 1 , wherein the filtering step (ii) comprises filtering the aqueous pharmaceutical solution through a first filter, or a first filter and a second filter. 
     
     
         3 . The process of  claim 2  further comprising the step of reducing the temperature of the second filter to a temperature from above 0° C. up to 17.5° C. 
     
     
         4 . The process of  claim 2  or  claim 3  further comprising the step of reducing the temperature of the aqueous pharmaceutical solution to a temperature from above 0° C. up to 17.5° C. before passing through the second filter. 
     
     
         5 . The process of any one of  claims 2 - 4 , wherein the filtering step (ii) further comprises the step of receiving the aqueous pharmaceutical solution filtered through the first filter in a receiving vessel. 
     
     
         6 . The process of  claim 5  further comprising the step of reducing the temperature of the aqueous pharmaceutical solution to a temperature from above 0° C. up to 17.5° C. after leaving the receiving vessel and before entering into the second filter. 
     
     
         7 . The process of  claim 5  or  claim 6  further comprising the step of reducing the temperature of the aqueous pharmaceutical solution to a temperature from above 0° C. up to 17.5° C. while in the receiving vessel. 
     
     
         8 . The process of any one of  claims 2 - 7  further comprising the step of reducing the temperature of the first filter to a temperature from above 0° C. up to 17.5° C. 
     
     
         9 . The process of any one of  claims 2 - 8  further comprising the step of reducing the temperature of the aqueous pharmaceutical solution to a temperature from above 0° C. up to 17.5° C. before passing through the first filter. 
     
     
         10 . The process of any one of  claims 2 - 9 , wherein the obtaining step (i) comprises compounding the aqueous pharmaceutical solution in a compounding vessel. 
     
     
         11 . The process of  claim 10  further comprising the step of reducing the temperature of the aqueous pharmaceutical solution to a temperature from above 0° C. up to 17.5° C. after leaving the compounding vessel and before entering into the first filter. 
     
     
         12 . The process of  claim 10  or  claim 11  further comprising the step of reducing the temperature of the aqueous pharmaceutical solution to a temperature from above 0° C. up to 17.5° C. while in the compounding vessel. 
     
     
         13 . The process of any one of  claims 2 - 14 , wherein the aqueous pharmaceutical solution is passed through the second filter at a rate of 3-25 liters/hour; preferably at a rate of 3-22 liters/hour; more preferably at a rate of 3-15 liters/hour; or more preferably at a rate of 3-10 liters/hour. 
     
     
         14 . The process of any one of  claims 1 - 12 , wherein the pressure during the filtering step (ii) and the pressure during the filling step (iii) is maintained below 5.0 bar; or preferably below 3.0 bar. 
     
     
         15 . The process of any one of  claims 1 - 13 , wherein the pressure during the filtering step (ii) and the pressure during the filling step (iii) is maintained below 2.0 bar. 
     
     
         16 . The process of any one of  claims 1 - 15 , wherein the temperature of the aqueous pharmaceutical solution is between 0° C. and 14° C., or the temperature of the aqueous pharmaceutical solution is reduced to a temperature between 0° C. and 14° C. 
     
     
         17 . The process of any one of  claims 1 - 15 , wherein the temperature of the aqueous pharmaceutical solution is between 0° C. and 12° C., or the temperature of the aqueous pharmaceutical solution is reduced to a temperature between 00° C. and 12° C. 
     
     
         18 . The process of any one of  claims 1 - 15 , wherein the temperature of the aqueous pharmaceutical solution is 2° C.-12° C., or the temperature of the aqueous pharmaceutical solution is reduced to 2° C.-12° C. 
     
     
         19 . The process of any one of  claims 1 - 15 , wherein the temperature of the aqueous pharmaceutical solution is 4° C.-12° C., or the temperature of the aqueous pharmaceutical solution is reduced to 4° C.-12° C. 
     
     
         20 . The process of any one of  claims 1 - 19 , wherein the filtering is performed using a sterilizing filter having a pore size of 0.2 μm or less, wherein the first, the second or both filters are a sterilizing filter having a pore size of 0.2 μm or less. 
     
     
         21 . The process of any one of  claims 1 - 20 , wherein the pharmaceutical preparation in the suitable container is an aqueous pharmaceutical solution comprising 20 mg/ml glatiramer acetate and 40 mg/ml mannitol. 
     
     
         22 . The process of any one of  claims 1 - 20 , wherein the pharmaceutical preparation in the suitable container is an aqueous pharmaceutical solution comprising 40 mg/ml glatiramer acetate and 40 mg/ml mannitol. 
     
     
         23 . The process of any one of  claims 1 - 22 , wherein the pharmaceutical preparation in the suitable container is an aqueous pharmaceutical solution having a pH in the range of 5.5-7.0. 
     
     
         24 . The process of any one of  claims 1 - 23 , wherein the pharmaceutical preparation in the suitable container is an aqueous pharmaceutical solution which is a sterilized aqueous solution which has been sterilized by filtration and without subjecting the aqueous pharmaceutical solution to heat, chemicals, or radiation exposure. 
     
     
         25 . The process of any one of  claims 1 - 20 , wherein the pharmaceutical preparation is a lyophilized powder of glatiramer acetate and mannitol. 
     
     
         26 . The process of any one of  claims 1 - 20  or  25  further comprising a step of lyophilizing the filtrate after it has been filled into the suitable container so as to form a lyophilized powder of glatiramer acetate and mannitol in the suitable container. 
     
     
         27 . The process of any one of  claims 1 - 26 , wherein the suitable container is a syringe, vial, ampoule, cartridge or infusion. 
     
     
         28 . The process of  claim 27 , wherein the suitable container is a syringe. 
     
     
         29 . The process of  claim 28 , wherein the syringe contains 1 ml of an aqueous pharmaceutical solution. 
     
     
         30 . A prefilled syringe containing 40 mg of glatiramer acetate and 40 mg mannitol, which syringe is prepared by the process of any one of  claims 1 - 29 . 
     
     
         31 . The prefilled syringe of  claim 30 , wherein the prefilled syringe contains 1 ml of an aqueous pharmaceutical solution of 40 mg/ml of glatiramer acetate and 40 mg/ml mannitol. 
     
     
         32 . The prefilled syringe of  claim 31 , wherein the aqueous pharmaceutical solution
 a) has a viscosity in the range of 2.0-3.5 cPa; or   b) has an osmolality in the range of 270-330 mosmol/Kg.   
     
     
         33 . The prefilled syringe of  claim 32 , wherein the aqueous pharmaceutical solution
 a) has a viscosity in the range of 2.2-3.0 cPa; or   b) has an osmolality in the range of 275-325 mosmol/Kg.   
     
     
         34 . An aqueous pharmaceutical solution comprising 40 mg/ml glatiramer acetate and 40 mg/ml mannitol, wherein the aqueous pharmaceutical solution
 a) has a viscosity in the range of 2.0-3.5 cPa; or   b) has an osmolality in the range of 275-325 mosmol/Kg.   
     
     
         35 . The aqueous pharmaceutical solution of  claim 34 , wherein the aqueous pharmaceutical solution has a viscosity in the range of 2.0-3.5 cPa. 
     
     
         36 . The aqueous pharmaceutical solution of  claim 34  or  35 , wherein the aqueous pharmaceutical solution has a viscosity in the range of 2.61-2.92 cPa. 
     
     
         37 . The aqueous pharmaceutical solution of  claim 34 , wherein the aqueous pharmaceutical solution has an osmolality in the range of 275-325 mosmol/Kg. 
     
     
         38 . The aqueous pharmaceutical solution of any one of  claims 34 - 37 , wherein the aqueous pharmaceutical solution has an osmolality in the range of 300-303 mosmol/Kg. 
     
     
         39 . The aqueous pharmaceutical solution of any one of  claims 34 - 38 , wherein the aqueous pharmaceutical solution has a pH in the range of 5.5-7.0. 
     
     
         40 . A prefilled syringe containing 1 ml of the aqueous pharmaceutical solution of any one of  claims 34 - 39 . 
     
     
         41 . An automated injector comprising the prefilled syringe of any one of  claims 30 - 33  or  40 . 
     
     
         42 . A method of treatment of a human patient suffering from a relapsing form of multiple sclerosis comprising administration to the human patient of three subcutaneous injections of a 40 mg/ml dose of glatiramer acetate per week using the prefilled syringe of any one of  claims 30 - 33  or  40 , using the aqueous pharmaceutical solution of any one of  claims 34 - 39 , or using the automated injector of  claim 41  so as to treat the human patient. 
     
     
         43 . The method of  claim 42 , wherein the human patient is suffering from relapsing-remitting multiple sclerosis. 
     
     
         44 . The method of  claim 42 , wherein the human patient has experienced a first clinical episode and has MRI features consistent with multiple sclerosis.