Patent Publication Number: US-2018036363-A1

Title: Process for manufacturing glatiramer acetate product

Description:
This application is a continuation of U.S. Ser. No. 15/707,378, filed Sep. 18, 2017, which is a continuation of U.S. Ser. No. 14/860,053, filed Sep. 21, 2015, now U.S. Pat. No. 9,763,993, issued Sep. 19, 2017, which is a continuation of U.S. Ser. No. 14/608,126, filed Jan. 28, 2015, now U.S. Pat. No. 9,155,775, issued Oct. 13, 2015, the contents of each of which are hereby incorporated by reference in their entirety. 
     Throughout this application, various publications are referred to by first author and year of publication. Full citations for these publications are presented in a References section immediately before the claims. The disclosures of these documents and publications referred to herein are hereby incorporated in their entireties by reference into this application in order to more fully describe the state of the art to which this invention pertains. 
    
    
     BACKGROUND OF THE INVENTION 
     Glatiramer acetate (GA), the active ingredient of Copaxone®, consists of the acetate salts of synthetic polypeptides, containing four naturally occurring amino acids: L-glutamic acid, L-alanine, L-tyrosine, and L-lysine with an average molar fraction of 0.141, 0.427, 0.095, and 0.338, respectively. The peak average molecular weight of glatiramer acetate is between 5,000 and 9,000 daltons. Glatiramer acetate is identified by specific antibodies (Copaxone, Food and Drug Administration Approved Labeling (Reference ID: 3443331) [online], TEVA Pharmaceutical Industries Ltd., 2014 [retrieved on Dec. 24, 2014], Retrieved from the Internet: &lt;URL: www.accessdata.fda.gov/drugsatfda_docs/label/2014/020622s0891b1.pdf&gt;). 
     Chemically, glatiramer acetate is designated L-glutamic acid polymer with L-alanine, L-lysine and L-tyrosine, acetate (salt). Its structural formula is: 
       (Glu,Ala,Lys,Tyr)x.X CH3COOH 
       (C 5 H 9 NO 4 .C 3 H 7 NO 2 .C 6 H 14 N 2 O 2 .C 9 H 11 NO 3 ) x .xC 2 H 4 O 2    
       CAS-147245-92-9 
     Copaxone® is a clear, colorless to slightly yellow, sterile, nonpyrogenic solution for subcutaneous injection. Each 1 mL of Copaxone® solution contains 20 mg or 40 mg of GA, the active ingredient, and 40 mg of mannitol. The pH of the solutions is approximately 5.5 to 7.0. Copaxone® 20 mg/mL in a prefilled syringe (PFS) is an approved product, the safety and efficacy of which are supported by over two decades of clinical research and over a decade of post-marketing experience. Copaxone® 40 mg/mL in a PFS was developed as a new formulation of the active ingredient GA. Copaxone® 40 mg/mL is a prescription medicine used for the treatment of people with relapsing forms of multiple sclerosis (Copaxone, Food and Drug Administration Approved Labeling (Reference ID: 3443331) [online], TEVA Pharmaceutical Industries Ltd., 2014 [retrieved on Dec. 24, 2014], Retrieved from the Internet: &lt;URL: www.accessdata.fda.gov/drugsatfda_docs/label/2014/020622s0891b1.pdf&gt;). 
     It is an object of the present invention to provide an improved process for manufacturing GA drug products. 
     SUMMARY OF THE INVENTION 
     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 also provides a prefilled syringe containing 40 mg of glatiramer acetate and 40 mg mannitol, which syringe is prepared by a process of the invention. 
     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 containing 1 ml of an aqueous pharmaceutical solution prepared by a process of the invention. 
     This patent also provides an automated injector comprising the prefilled syringe prepared by a process of the invention. 
     Aspects of the present invention relate to 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 this invention, using the aqueous pharmaceutical solution of this invention, or using the automated injector of this invention so as to treat the human patient. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         FIG. 1 . Schematic description of filtration process by cooled receiving vessel and filter housing. 
         FIG. 2 . Schematic description of filtration process by heat exchanger and cooled filter housing. 
         FIG. 3 . Pressure record for Experiment No. 1. * Filtration of GA solution at controlled room temperature was stopped and the remaining solution was transferred to the cooled receiving vessels. 
         FIG. 4 . Pressure record for Experiment No. 2. * Pauses of 3 hours and 5 hours for GA solutions filtered at controlled room temperature and at reduced temperature, respectively. ** Pause of 10 hours for both GA solutions. *** Filtration of GA solution at controlled room temperature was stopped. Remaining GA solution was filtered at reduced temperature. 
         FIG. 5 . Pressure record for Experiment No. 3. 
         FIG. 6 . Schematic description of filtration process by cooled compounding vessel and cooled filter housings on both Filter A and Filter B. 
         FIG. 7 . Schematic description of filtration process by heat exchanger and cooled filter housings on both Filter A and Filter B. 
         FIG. 8 . Schematic description of filtration process by cooled filter housing on only Filter B. 
         FIG. 9 . Schematic description of filtration process by cooled filter housings on both Filter A and Filter B. 
         FIG. 10 . Schematic description of filtration process by cooled compounding vessel. 
         FIG. 11 . Schematic description of filtration process by cooled receiving vessel. 
     
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     This invention 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.       

     In some embodiments the filtering step (ii) comprises filtering the aqueous pharmaceutical solution through a first filter, or a first filter and a second filter. 
     In some embodiments the process further comprises the step of reducing the temperature of the second filter to a temperature from above 0° C. up to 17.5° C. 
     In some embodiments the process further comprises 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. 
     In some embodiments the filtering step (ii) further comprises the step of receiving the aqueous pharmaceutical solution filtered through the first filter in a receiving vessel. 
     In some embodiments the process further comprises 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. 
     In some embodiments the process further comprises 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. 
     In some embodiments the process further comprises the step of reducing the temperature of the first filter to a temperature from above 0° C. up to 17.5° C. 
     In some embodiments the process further comprises 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. 
     In some embodiments the obtaining step (i) comprises compounding the aqueous pharmaceutical solution in a compounding vessel. 
     In some embodiments the process further comprises 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. 
     In some embodiments the process further comprises 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. 
     In some embodiments the aqueous pharmaceutical solution is passed through the second filter at a rate of 3-25 liters/hour. 
     In some embodiments the aqueous pharmaceutical solution is passed through the second filter preferably at a rate of 3-22 liters/hour. 
     In some embodiments the aqueous pharmaceutical solution is passed through the second filter more preferably at a rate of 3-15 liters/hour. 
     In some embodiments the aqueous pharmaceutical solution is passed through the second filter at a rate more preferably at a rate of 3-10 liters/hour. 
     In some embodiments the pressure during the filtering step (ii) and the pressure during the filling step (iii) is maintained below 5.0 bar. 
     In some embodiments the pressure during the filtering step (ii) and the pressure during the filling step (iii) is maintained preferably below 3.0 bar. 
     In some embodiments the pressure during the filtering step (ii) and the pressure during the filling step (iii) is maintained below 2.0 bar. 
     In some embodiments 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. 
     In some embodiments 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 0° C. and 12° C. 
     In some embodiments 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. 
     In some embodiments 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. 
     In some embodiments 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. 
     In some embodiments the pharmaceutical preparation in the suitable container is an aqueous pharmaceutical solution comprising 20 mg/ml glatiramer acetate and 40 mg/ml mannitol. 
     In some embodiments the pharmaceutical preparation in the suitable container is an aqueous pharmaceutical solution comprising 40 mg/ml glatiramer acetate and 40 mg/ml mannitol. 
     In some embodiments the pharmaceutical preparation in the suitable container is an aqueous pharmaceutical solution having a pH in the range of 5.5-7.0. 
     In some embodiments 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. 
     In some embodiments the pharmaceutical preparation is a lyophilized powder of glatiramer acetate and mannitol. 
     In some embodiments the process further comprises 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. 
     In some embodiments the suitable container is a syringe, vial, ampoule, cartridge or infusion. 
     In some embodiments the suitable container is a syringe. 
     In some embodiments the syringe contains 1 ml of an aqueous pharmaceutical solution. 
     This invention provides a prefilled syringe containing 40 mg of glatiramer acetate and 40 mg mannitol, which syringe is prepared by a process of the invention. 
     According to any embodiment of the prefilled syringe disclosed herein, the prefilled syringe contains 1 ml of an aqueous pharmaceutical solution of 40 mg/ml of glatiramer acetate and 40 mg/ml mannitol. 
     According to any embodiment of the prefilled syringe disclosed herein, 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.       

     According to any embodiment of the prefilled syringe disclosed herein, 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.       

     This invention 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.       

     According to some embodiments of the aqueous pharmaceutical solution, the aqueous pharmaceutical solution has a viscosity in the range of 2.0-3.5 cPa. 
     According to some embodiments of the aqueous pharmaceutical solution, the aqueous pharmaceutical solution has a viscosity in the range of 2.61-2.92 cPa. 
     According to some embodiments of the aqueous pharmaceutical solution, the aqueous pharmaceutical solution has an osmolality in the range of 275-325 mosmol/Kg. 
     According to some embodiments of the aqueous pharmaceutical solution, the aqueous pharmaceutical solution has an osmolality in the range of 300-303 mosmol/Kg. 
     According to some embodiments of the aqueous pharmaceutical solution, the aqueous pharmaceutical solution comprises glatiramer acetate having a viscosity in the range of 2.3-3.2 cPa. 
     According to some embodiments of the aqueous pharmaceutical solution, the aqueous pharmaceutical solution comprises glatiramer acetate having a viscosity in the range of 2.6-3.0 cPa. 
     According to some embodiments of the aqueous pharmaceutical solution, the aqueous pharmaceutical solution comprises glatiramer acetate having an osmolality in the range of 290-310 mosmol/Kg. 
     According to some embodiments of the aqueous pharmaceutical solution, the aqueous pharmaceutical solution comprises glatiramer acetate having an osmolality in the range of 295-305 mosmol/Kg. 
     According to some embodiments of the aqueous pharmaceutical solution, the aqueous pharmaceutical solution has a pH in the range of 5.5-7.0. 
     This invention provides a prefilled syringe containing 1 ml of an aqueous pharmaceutical solution prepared by the invention. 
     This invention provides an automated injector comprising the prefilled syringe prepared by the invention. 
     This invention provides 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 this invention, using the aqueous pharmaceutical solution of this invention, or using the automated injector of this invention so as to treat the human patient. 
     In some embodiments, the human patient is suffering from relapsing-remitting multiple sclerosis. 
     In some embodiments, the human patient has experienced a first clinical episode and has MRI features consistent with multiple sclerosis. 
     This invention 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.       

     In an embodiment, the filtering step (ii) comprises filtering the aqueous pharmaceutical solution through a first filter, and a second filter. 
     In an embodiment, the obtaining step (i) comprises compounding the aqueous pharmaceutical solution in a compounding vessel. 
     In an embodiment, the process further comprises 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. 
     In an embodiment, the process further comprises the step of reducing the temperature of the first filter to a temperature from above 0° C. up to 17.5° C. 
     In an embodiment, the process further comprises the step of reducing the temperature of the second filter to a temperature from above 0° C. up to 17.5° C. 
     This invention 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.       

     In an embodiment, the filtering step (ii) comprises filtering the aqueous pharmaceutical solution through a first filter, and a second filter. 
     In an embodiment, the obtaining step (i) comprises compounding the aqueous pharmaceutical solution in a compounding vessel. 
     In an embodiment, the process further comprises 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. 
     In an embodiment, the process further comprises the step of reducing the temperature of the first filter to a temperature from above 0° C. up to 17.5° C. 
     In an embodiment, the process further comprises the step of reducing the temperature of the second filter to a temperature from above 0° C. up to 17.5° C. 
     This invention 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.       

     In an embodiment, the filtering step (ii) comprises filtering the aqueous pharmaceutical solution through a first filter, and a second filter. 
     In an embodiment, the process further comprises the step of reducing the temperature of the second filter to a temperature from above 0° C. up to 17.5° C. 
     This invention 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.       

     In an embodiment, the filtering step (ii) comprises filtering the aqueous pharmaceutical solution through a first filter, and a second filter. 
     In an embodiment, the process further comprises the step of reducing the temperature of the first filter to a temperature from above 0° C. up to 17.5° C. 
     In an embodiment, the process further comprises the step of reducing the temperature of the second filter to a temperature from above 0° C. up to 17.5° C. 
     This invention 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.       

     In an embodiment, the filtering step (ii) comprises filtering the aqueous pharmaceutical solution through a first filter, and a second filter. 
     In an embodiment, the obtaining step (i) comprises compounding the aqueous pharmaceutical solution in a compounding vessel. 
     In an embodiment, the process further comprises 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. 
     This invention 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.       

     In an embodiment, the filtering step (ii) comprises filtering the aqueous pharmaceutical solution through a first filter, and a second filter. 
     In an embodiment, the filtering step (ii) further comprises the step of receiving the aqueous pharmaceutical solution filtered through the first filter in a receiving vessel. 
     In an embodiment, the process further comprises 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. 
     Automated Injection Device 
     The mechanical workings of an automated injection assisting device can be prepared according to the disclosure in European application publication No. EP0693946 and U.S. Pat. No. 7,855,176, which are incorporated herein by reference. 
     All combinations of the various elements described herein are within the scope of the invention. 
     Definitions 
     As used herein, “glatiramer acetate” is a complex mixture of the acetate salts of synthetic polypeptides, containing four naturally occurring amino acids: L-glutamic acid, L-alanine, L-tyrosine, and L-lysine. The peak average molecular weight of glatiramer acetate is between 5,000 and 9,000 daltons. Chemically, glatiramer acetate is designated L-glutamic acid polymer with L-alanine, L-lysine and L-tyrosine, acetate (salt). Its structural formula is: 
       (Glu,Ala,Lys,Tyr)x.X CH3COOH 
       (C5H9NO4.C3H7NO2.C6H14N2O2.C9H11NO3) x.x C2H4O2 
       CAS-147245-92-9 
     As used herein “glatiramer acetate drug substance” is the glatiramer acetate active ingredient prior to its formulation into a glatiramer acetate drug product. 
     As used herein, a “glatiramer acetate drug product” is a formulation for pharmaceutical use which contains a glatiramer acetate drug substance. Copaxone® is a commercial glatiramer acetate drug product manufactured by TEVA Pharmaceutical Industries Ltd. (Israel), which is described in Copaxone, Food and Drug Administration Approved Labeling (Reference ID: 3443331) [online], TEVA Pharmaceutical Industries Ltd., 2014 [retrieved on Dec. 24, 2014], Retrieved from the Internet: &lt;URL: www.accessdata.fda.gov/drugsatfda_docs/label/2014/020622s0891b1.pdf&gt;, the contents of which are hereby incorporated by reference. Copaxone® is available as 20 mg/mL administered once per day, and/or 40 mg/ml administered three times per week. 
     As used herein, a “sterilizing filter” is a filter with a pore size of 0.2 μm or less which will effectively remove microorganisms. 
     By any range disclosed herein, it is meant that all hundredth, tenth and integer unit amounts within the range are specifically disclosed as part of the invention. Thus, for example, 1 mg to 50 mg means that 1.1, 1.2 . . . 1.9; and 2, 3 . . . 49 mg unit amounts are included as embodiments of this invention. 
     This invention will be better understood by reference to the Experimental Details which follow, but those skilled in the art will readily appreciate that the specific experiments detailed are only illustrative of the invention as described more fully in the claims which follow thereafter. 
     EXPERIMENTAL DETAILS 
     Methods 
     Glatiramer Acetate (GA) Injection 40 mg/mL in a prefilled syringe (GA injection 40 mg/mL in PFS or Copaxone® 40 mg/mL) was developed as a new formulation of the active ingredient glatiramer acetate, which is also used in the marketed product Copaxone® 20 mg/mL solution for injection in a prefilled syringe. Copaxone® 40 mg/mL is to be administered three times a week by subcutaneous injection to patients with Relapsing Remitting Multiple Sclerosis. The new formulation is based on the formulation of the marketed Copaxone® 20 mg/mL solution for injection in a prefilled syringe. Copaxone® 20 mg/mL is an approved product, the safety and efficacy of which are supported by over two decades of clinical research and over a decade of post-marketing experience. The only difference between the formulations is the double amount of the active substance used, which results in a solution with double the concentration of glatiramer acetate (40 mg/mL vs. 20 mg/mL). The amount of mannitol in both Copaxone® formulations remains unchanged (40 mg/mL). 
     The compositions of Copaxone® 20 mg/mL and Copaxone® 40 mg/mL are detailed in Table 1. 
     
       
         
           
               
             
               
                 TABLE 1 
               
             
            
               
                   
               
               
                 Compositions of Copaxone ® 20 mg/mL 
               
               
                 and Copaxone ® 40 mg/mL 
               
            
           
           
               
               
               
               
            
               
                   
                   
                 Copaxone ®  
                 Copaxone ®  
               
               
                   
                   
                 20 mg/mL 
                 40 mg/mL 
               
            
           
           
               
               
               
            
               
                   
                 Components 
                 Content per mL 
               
               
                   
               
            
           
           
               
               
               
               
            
               
                   
                 Glatiramer Acetate 1   
                 20.0 mg 
                 40.0 mg 
               
               
                   
                 Mannitol USP/Ph. Eur. 
                 40.0 mg 
                 40.0 mg 
               
               
                   
                 Water for Injection 
                 q.s. to 1.0 mL 
                 q.s. to 1.0 mL 
               
               
                   
                 USP/Ph. Eur/JP 
               
               
                   
               
               
                   1 Calculated on the dry basis and 100% assay 
               
            
           
         
       
     
     Studies were conducted in order to verify that the formulation of Copaxone® 40 mg/mL, its manufacturing process and chemical, biological and microbiological attributes are appropriate for commercialization. Studies were also conducted to confirm the suitability of the proposed container closure system for packaging Copaxone® 40 mg/mL. 
     Mannitol was chosen as the tonicity agent for the initially formulated Copaxone® (freeze dried product, reconstituted prior to administration) as it is also a bulking agent. When the currently marketed ready-to-use formulation of Copaxone® 20 mg/mL solution for injection prefilled syringe was developed, mannitol was used in this formulation as well, as the osmoregulator. Finally, when the new 40 mg/mL formulation was developed, based on the Copaxone® 20 mg/mL formulation, mannitol remained as the osmoregulator. 
     Mannitol is widely used in parenteral formulations as an osmoregulator. It is freely soluble in water and stable in aqueous solutions. Mannitol solutions may be sterilized by filtration. In solution, mannitol is not affected by atmospheric oxygen in the absence of catalysts. The concentration of mannitol in the Copaxone® 40 mg/mL is 40 mg/mL. Maintaining the mannitol concentration in Copaxone® 40 mg/mL resulted in an essentially isotonic solution. 
     Water for injection (WFI) is the most widely used solvent and inert vehicle in parenteral formulations. Water is chemically stable in all physical states. It is the base for many biological life forms, and its safety in pharmaceutical formulations is unquestioned. 
     Example 1 
     The manufacturing process of Copaxone® 40 mg/mL comprises:
         Compounding a bulk solution of GA and mannitol in water for injections (WFI).   Sterilizing filtration of the bulk solution yielding the sterile GA solution in bulk.   Aseptic filling of sterile bulk solution into syringe barrels and stoppering.   Inspection and final assembly of the filled syringes.       

     Initially, filtration of bulk solution from the compounding vessel was performed through a sequential filter train consisting of two sequential sterilizing filters (filters named A 1  and A 2 , respectively) to a receiving vessel. From the receiving vessel it was transferred to the intermediate vessel in the filling machine and further through dosing pumps and needles into prefilled syringes. However, due to a Health Authority request to place the sterilizing filter as close as possible to the filling point, the second sterilizing filter was moved between the receiving and intermediate vessels. In the current filtration train, the first sterilizing filter was named Filter A, and the second relocated sterilizing filter was named Filter B. See,  FIG. 1 . 
     In line with the process for the approved Copaxone® 20 mg/mL formulation, all processing steps of the new Copaxone® 40 mg/mL formulation were originally conducted at controlled room temperature. However, filtration of the higher concentration solution resulted in a pressure build-up on the second filter, Filter B. Despite the observed pressure increase on Filter B, a high-quality drug product could be obtained by filtration of GA 40 mg/mL at controlled room temperature, as confirmed by release and stability data. Nevertheless, an improved filtration process was needed which avoided the build-up on the second filter. 
     Flow rate for fluids can be defined by the differential pressure, and inversely moderated by viscosity. Viscosity, in turn, is usually reciprocal in relation to temperature (Meltzer and Jornitz,  Filtration and Purification in the Biopharmaceutical Industry , Second Edition, CRC Press, 2007, page 166). Increasing the temperature of a solution will normally decrease the viscosity, thereby enhancing the flow rate. 
     In an attempt to solve the pressure build-up problem on the second filter, the temperature condition of the filtration was raised above controlled room temperature. Although the viscosity decreased, the filterability decreased, resulting in a failed attempt. 
     The following studies were performed:
         Filter Validation Study: Determination of ranges for the manufacturing parameters related to sterilizing Filter A and sterilizing Filter B of the bulk solution, as well as confirmation of filter compatibility with the drug product.   Filtration Process: Selection of the sterilizing filtration conditions best suitable for the manufacturing process and the quality of the drug product.
 
Filters Used for Copaxone® 20 mg/mL and Copaxone® 40 mg/mL Manufacturing
       

     The manufacturing process of Copaxone® 40 mg/mL was based on the process used to produce the marketed Copaxone® 20 mg/mL solution for injection in a prefilled syringe. Therefore the same filters used for filtration of marketed product were used. 
     Two sterilizing filters were used, each of which having a pore size of 0.2 μm or less, to effectively remove microorganisms. Sterilization is achieved only by filtration using sterilizing filters and not by using other methods, e.g. sterilization is achieved without using heat, chemicals, or radiation exposure. 
     Filter Validation Study—Confirmation and Setting of Parameters Associated with Filter Compatibility and with Sterilizing Filtration 
     The following tests were performed in order to confirm the filter validity:
         Extractables testing—assessment of extractables released from the filter upon steam sterilization and their removal from the filter by a model solvent, thus assessing the volume to be discarded after the filtration through the Filter B, prior to beginning of the aseptic filling.   Compatibility/adsorption testing—assessment of the chemical compatibility of GA 20 mg/mL and GA 40 mg/mL solution with the filter material and the extent of its adsorption to the filter, thus assessing the volume to be discarded after the filtration through Filter B, prior to beginning of the aseptic filling in order to provide assay within specifications.   Residual effect—To ensure that no significant residual GA 20 mg/mL or GA 40 mg/mL solution that might affect the post use integrity test remains on the filter after filtration.   Bacterial challenge—To ensure that the filtration process does not affect the ability of the filter to provide a sterile solution.       

     The above tests were conducted using maximum pressure (up to 5.0 bar). The validation study demonstrated that the selected filtration system is capable of providing a high quality Copaxone® 20 mg/mL and Copaxone® 40 mg/mL. 
     Given the strict and well-defined operational and equipment parameters of the GA 40 mg/mL solution filtration process, a plan to mitigate the potential increase in pressure by reducing the filtration temperature was developed. 
     Without much expectations, it was decided to examine the filtration process of GA 40 mg/mL sterile bulk solution through Filter B under reduced temperature conditions, using the same filters and filtration train as for the filtration at controlled room temperature. 
     Accordingly, experiments were performed in order to compare the filtration of GA 40 mg/mL sterile bulk solution through Filter B under reduced temperature and controlled room temperature in the production environment and to ensure that there is no difference with regard to the quality and stability profiles of the filtered solutions. In all experiments, the sterile bulk solution was prepared according to the standard compounding and filtration train (see  FIG. 1 ) and filtered through two filters: Filter A and Filter B. 
     The experiments tested two different cooling technologies (cooled receiving vessels vs heat exchanger) with cooled filter. The studies are schematically depicted in  FIG. 1  and  FIG. 2 . Further details about these experiments and their outcomes are provided hereafter. 
     Filtration Process—Experiment No. 1 
     The objective of Experiment No. 1 was to compare the filterability of a batch of bulk solution held and filtered through Filter B at either controlled room temperature or under reduced temperature conditions (cooling by double-jacketed receiving vessel and cooled Filter B housing). 
     The study is schematically depicted in  FIG. 1 . The experimental design and the obtained results are summarized in Table 2 and  FIG. 3 . 
     
       
         
           
               
             
               
                 TABLE 2 
               
             
            
               
                   
               
               
                 Experimental Design and Results for Experiment No. 1. 
               
            
           
           
               
               
               
            
               
                   
                 Reduced Temperature 
                 Controlled Room 
               
               
                 Experiment Outline 
                 Filtration 
                 Temperature Filtration 
               
               
                   
               
            
           
           
               
               
            
               
                 Compounding 
                 According to standard manufacturing procedure 1   
               
            
           
           
               
               
               
            
               
                 Holding time in 
                 13 hours 
                 13 hours 
               
               
                 the receiving 
                   
                   
               
               
                 vessel 
                   
                   
               
               
                 Temperature of 
                 6.6-10.7° C. 2   
                 17.8-24.6° C. 
               
               
                 solution held in 
                   
                   
               
               
                 the receiving 
                   
                   
               
               
                 vessel 
                   
                   
               
            
           
           
               
               
            
               
                 Planned regimen  
                 Intermittent filtration: 
               
               
                 for filtration 
                 Stage I-5 filtration steps of filtration of 
               
               
                 though Filter B 3   
                 about 10 liters of bulk solution-followed by 
               
               
                   
                 pauses of about 50 minutes each, followed by a 
               
               
                   
                 pause of 5 hours. 
               
               
                   
                 Stage II-4 filtration steps of filtration of 
               
               
                   
                 about 10 liters of bulk solution-followed by 
               
               
                   
                 pauses of about 50 minutes each, followed by a 
               
               
                   
                 pause of about 10 hours. 
               
               
                   
                 Stage III-Filtration of remaining solution. 
               
            
           
           
               
               
               
            
               
                 Total volume of 
                 About 125 L. Filtration 
                 About 85 liters. 
               
               
                 bulk solution 
                 was completed. 
                 Filtration was stopped 
               
               
                 filtered 
                   
                 due to increase in 
               
               
                   
                   
                 pressure on Filter B. 
               
               
                   
               
               
                   1 One bulk solution was prepared and divided into two portions. Bulk solution size: 230 liters. Filtration of solution at controlled room temperature was stopped after 85 liters have been pushed through the filter due to increased pressure and the remaining solution was transferred to the cooled receiving vessels. 
               
               
                   2 The temperature increased (to 14.9° C.) once during the filtration following the addition of the remaining solution kept at ambient temperature. 
               
               
                   3 The filtrations were carried out in parallel. 
               
            
           
         
       
     
     Surprisingly, filtration at reduced temperature allowed filtration to be completed without the pressure increase associated with filtration at controlled room temperature. 
     Example 2 
     Filtration Process—Experiment No. 2 
     The first objective of Experiment No. 2 was to evaluate whether local cooling of GA 40 mg/mL solution using a Heat Exchanger (HE) could improve the filterability through cooled Filter B compared to filterability of the same bulk solution at controlled room temperature. 
     The second objective of Experiment No. 2 was to confirm that there is no difference in the quality of the drug product filled into syringes at controlled room temperature and drug product filled into syringes at reduced temperature. 
     Cooling by heat exchanger was evaluated as it seemed to be much easier to steam sterilize than using the double jacketed receiving vessels. The HE was located between the receiving vessel and Filter B. Consequently, as opposed to Experiment No. 1 (in which the solution was cooled by the double-jacketed receiving vessels following filtration through Filter A and kept cooled prior to filtration through Filter B), the solution in this experiment was held at controlled room temperature prior to filtration of the locally cooled (by HE) GA solution through Filter B. 
     The study is schematically depicted in  FIG. 2 . The experimental design and the obtained results are summarized in Table 3. The pressure observed over the course of the filling process of Experiment No. 2 is shown in  FIG. 4 . 
     
       
         
           
               
             
               
                 TABLE 3 
               
             
            
               
                   
               
               
                 Experimental Design and Results for Experiment No. 2. 
               
            
           
           
               
               
               
            
               
                   
                 Reduced Temperature 
                 Controlled Room 
               
               
                 Experiment Outline 
                 Filtration 
                 Temperature Filtration 
               
               
                   
               
            
           
           
               
               
            
               
                 Compounding 
                 According to standard manufacturing  
               
               
                   
                 procedure 1   
               
               
                 Filtration into a 
                 Filtration of all the bulk solution through 
               
               
                 receiving vessel 
                 Filter A into a receiving vessel held at 
               
               
                   
                 controlled room temperature 
               
               
                 Temperature of  
                 Controlled room temperature 
               
               
                 solution held in the  
                   
               
               
                 receiving vessel 
                   
               
               
                 Holding time in the 
                 19 hours 
               
               
                 receiving vessel 
                   
               
            
           
           
               
               
               
            
               
                 Planned regimen for 
                 The solution is locally 
                 The solution is 
               
               
                 filtration through 
                 cooled as it is 
                 filtered through Filter 
               
               
                 Filter B 
                 transferred through a 
                 B at controlled room 
               
               
                   
                 HE and filtered through 
                 temperature. Three 
               
               
                   
                 cooled Filter B. Three 
                 consecutive filtration 
               
               
                   
                 consecutive filtration 
                 and filling stages. 
               
               
                   
                 and filling stages. 
                 About 5 hours break 
               
               
                   
                 About 3 hours break 
                 between Stage I and 
               
               
                   
                 between Stage I and 
                 Stage II and about 10 
               
               
                   
                 Stage II and about 10 
                 hours break between 
               
               
                   
                 hours break between 
                 Stage II and Stage III. 
               
               
                   
                 Stage II and Stage III. 
                   
               
               
                 Temperature of  
                 6.4-12° C. 
                 No use of HE 
               
               
                 solution transferred  
                   
                   
               
               
                 through the HE 
                   
                   
               
            
           
           
               
               
               
               
               
            
               
                 Duration of filtration 
                 24  
                 hours 
                 19  
                 hours 
               
            
           
           
               
               
               
            
               
                 through Filter B 2   
                   
                   
               
               
                 Temperature of  
                 5.7-8.8° C. 
                 Ambient temperature 
               
               
                 solution transferred  
                   
                   
               
               
                 through Filter B 
                   
                   
               
            
           
           
               
               
               
               
               
            
               
                 Total volume of bulk 
                 154  
                 L 
                 63  
                 L 3   
               
            
           
           
               
               
               
            
               
                 solution filtered and 
                   
                   
               
               
                 filled into syringes 
                   
                   
               
            
           
           
               
               
            
               
                 Storage conditions 
                 Long term (2-8° C.) 
               
               
                 during stability 
                 Accelerated (25° C./60% RH)- 
               
               
                 studies 
                 completed 6 months 
               
               
                   
                 Stress (40° C./75% RH)-completed 3 months 
               
               
                 Stability data 
                 The stability data showed that the drug product 
               
               
                   
                 has a similar stability profile when it is 
               
               
                   
                 filtered at controlled room temperature or under 
               
               
                   
                 reduced temperature conditions. Both filtration 
               
               
                   
                 processes demonstrate similar impurity profiles. 
               
               
                   
               
               
                   1 One bulk solution was prepared and divided into two portions. Bulk solution size: 230 liters. 
               
               
                   2 Both filtration processes (reduced and controlled room temperature) were carried out in parallel for comparison. At each stage, filtration was carried out at controlled room temperature, followed by filtration at reduced temperature. 
               
               
                   3 Filtration of solution at controlled room temperature was stopped due to pressure increase and the remaining solution was filtered at reduced temperature. 
               
            
           
         
       
     
     Example 3 
     Filtration Process—Experiment No. 3 
     One objective of Experiment No. 3 was to confirm whether cooling of GA 40 mg/mL bulk solution prior to filtration, using HE and cooled filter housing, allows filtration and filling of batches of 130 L size within various manufacturing regimens. 
     Another objective of Experiment No. 3 was to evaluate the influence of holding time at various stages of the manufacturing process on filterability of GA 40 mg/mL. 
     Another objective of Experiment 3 was to demonstrate with a high degree of assurance that locally cooled GA 40 mg/mL solution filtered through Filter B is not different in its quality and stability profile from GA 40 mg/mL solution filtered through Filter B at controlled room temperature conditions with regard to pre-determined parameters and limits. 
     A series of three batches of bulk solution, manufactured at various regimens, were prepared. Each bulk solution was prepared from an identical combination of the same three drug substance batches. 
     The experimental design and results are summarized in Table 4. 
     
       
         
           
               
             
               
                 TABLE 4 
               
             
            
               
                   
               
               
                 Experimental Design and Results for Experiment No. 3 
               
            
           
           
               
               
               
               
               
            
               
                   
                   
                 Controlled 
                   
                 Controlled 
               
               
                   
                 Reduced 
                 Room 
                 Reduced 
                 Room 
               
               
                   
                 Temperature 
                 Temperature 
                 Temperature 
                 Temperature 
               
               
                 Experiment Outline 
                 Filtration 
                 Filtration 
                 Filtration 
                 Filtration 
               
               
                   
               
               
                 Batch No. 
                 A 
                 A-2 1   
                 B 
                 C 
               
               
                 Compounding 
                 Standard 
                 Standard 
                 Standard 
                 Standard 
               
               
                   
                 compounding 
                 compounding 
                 compounding 
                 compounding 
               
               
                 Batch size 
                 First 130 L 
                 Remaining 50 L 
                 180 L 
                 180 L 
               
               
                   
                 from bulk 
                 from bulk 
                   
                   
               
               
                   
                 solution A 
                 solution A 
                   
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                 Holding time in the 
                 4  
                 hours 
                 4  
                 hours 
                 8  
                 hours 
                 3.5  
                 hours 
               
            
           
           
               
               
               
               
               
            
               
                 compounding vessel 2   
                   
                 (same bulk  
                   
                   
               
               
                   
                   
                 solution as A) 
                   
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                 Holding time in the 
                 1.5  
                 hours 
                 10.5  
                 hours 4   
                 16  
                 hours 
                 13  
                 hours 
               
            
           
           
               
               
               
               
               
            
               
                 receiving vessel 3   
                   
                   
                   
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                 Duration of 
                 7  
                 hours 
                 3  
                 hours 
                 19.5  
                 hours 
                 13  
                 hours 
               
            
           
           
               
               
               
               
               
            
               
                 filtration through 
                   
                   
                   
                   
               
               
                 Filter B 
                   
                   
                   
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                 Total duration of 
                 12.5  
                 hours 
                 17.5  
                 hours 
                 43.5  
                 hours 
                 29.5  
                 hours 
               
            
           
           
               
               
               
               
               
            
               
                 entire process 
                   
                   
                   
                   
               
               
                 (total holding 
                   
                   
                   
                   
               
               
                 time) 
                   
                   
                   
                   
               
               
                 Temperature range 
                 10.4-12.2° C. 
                 Controlled 
                 10.2-11.7° C. 
                 Controlled 
               
               
                 before Filter B 
                   
                 room 
                   
                 room 
               
               
                   
                   
                 temperature 
                   
                 temperature 
               
               
                 Temperature range 
                  9.3-11.0° C. 
                 Controlled 
                  9.0-10.2° C. 
                 Controlled 
               
               
                 after Filter B 
                   
                 room 
                   
                 room 
               
               
                   
                   
                 temperature 
                   
                 temperature 
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                 Maximum pressure 
                 0.6  
                 bar 
                 0.3  
                 bar 
                 0.6  
                 bar 
                 2.5  
                 bar 5   
               
            
           
           
               
               
               
               
               
            
               
                 before Filter B 
                   
                   
                   
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                 Total volume filled 
                 130  
                 L 
                 50  
                 L 
                 180  
                 L 
                 134  
                 L 
               
            
           
           
               
               
               
               
               
            
               
                 into syringes 
                   
                   
                   
                   
               
               
                 Storage conditions 
                 Long term  
                 Stress 
                 Long term 
                 Long term  
               
               
                 during stability 
                 (2-8° C.) 
                 (40° C./60% RH) 
                 (2-8° C.) 
                 (2-8° C.) 
               
               
                 studies 
                 Accelerated 
                 Accelerated 
                 Accelerated 
                   
               
               
                   
                 (25° C./60% RH) 
                   
                 (25° C./60% RH) 
                 (25° C./60% RH) 
               
               
                   
                 Stress 
                   
                 Stress 
                 Stress 
               
               
                   
                 (40° C./60% RH) 
                   
                 (40° C./60% RH) 
                 (40° C./60% RH) 
               
            
           
           
               
               
            
               
                 Stability data and 
                 Stability data showed that the drug product has a similar 
               
               
                 conclusions 
                 stability profile at all three storage conditions, regardless 
               
               
                   
                 of whether it is filtered at controlled room temperature or 
               
               
                   
                 under reduced temperature conditions. Both filtration 
               
               
                   
                 processes result in product having substantially the same 
               
               
                   
                 degradation and impurity profile at stress conditions. 
               
               
                   
               
               
                   1 Batches A and A-2 are from the same bulk solution. Filter B was replaced with a new filter prior to filtration of A-2. 
               
               
                   2 Compounding and subsequent holding time in the compounding vessel (incl. filtration through filter A). 
               
               
                   3 Time from end of filtration through Filter A to beginning of filtration through Filter B and filling. 
               
               
                   4 Since A-2 was filtered and filled into syringes subsequent to the filtration and filling of A, the stated holding time represents the sum of the holding time of A in addition to the time A-2 was held until the filtration at controlled room temperature was initiated. 
               
               
                   5 Throughout the filling, gradual Increase of filtration pressure was required in order to maintain flow rate that would correspond to the rate required for continuous filling. 
               
            
           
         
       
     
     Based on the results of Experiment No. 3, it was confirmed that local cooling by heat exchanger is sufficient in order to enable filtration of a 130 L batch. In addition, the quality and stability profile of GA 40 mg/mL solutions filtered at controlled room temperature and reduced temperature were found to be substantially identical. 
     Example 4 
     Cooling of GA 40 mg/mL bulk solution below 17.5° C. in the compounding vessel before passing through cooled Filter A and cooled Filter B in sequence (see  FIG. 6 ) results in lower pressure during the filtration step of both Filter A and Filter B as compared to the holding the same bulk solution in the compounding vessel and passing it through Filter A and Filter B at controlled room temperature (Cooling of the bulk solution by using double jacketed compounding vessel and cooling the filters by using double jacketed filter housings). 
     Reducing the temperature of the GA 40 mg/mL bulk solution in the compounding vessel and passing it through cooled Filter A and Filter B in sequence (see  FIG. 6 ) significantly reduces impairment of filterability caused by the total duration of the process (holding time) as well as by filtering larger volume, compared to the same bulk solution held and filtered under controlled room temperature. 
     Example 5 
     Local cooling of GA 40 mg/mL bulk solution by a heat exchanger and passing the solution through cooled Filter A and cooled Filter B in sequence (see  FIG. 7 ) results in lower pressure during the filtration step of both Filter A and Filter B as compared to passing the same bulk solution held and filtered under controlled room temperature. 
     Reducing the temperature of the GA 40 mg/mL bulk solution using a heat exchanger and passing it through cooled Filter A and cooled Filter B in sequence (see  FIG. 7 ) significantly reduces impairment of filterability caused by the total duration of the process (holding time) as well as by filtering larger volume, compared to the same bulk solution held and filtered under controlled room temperature. 
     Example 6 
     Passing the sterilized GA 40 mg/mL bulk solution from the receiving vessel through cooled Filter B (see  FIG. 8 ) significantly results in lower pressure during the filtration step compared to passing the same bulk solution filtered through Filter B under controlled room temperature. 
     Passing the sterilized GA 40 mg/mL bulk solution from the receiving vessel through cooled Filter B (see  FIG. 8 ) significantly reduces impairment of filterability caused by the total duration of the process (holding time) as well as by filtering larger volume, compared to the same bulk solution held and filtered under controlled room temperature. 
     Example 7 
     Passing GA 40 mg/mL bulk solution from the compounding vessel through cooled Filter A and cooled Filter B in sequence (see  FIG. 9 ) results in lower pressure during the filtration step of both Filter A and Filter B as compared to passing the same bulk solution filtered under controlled room temperature. 
     Passing GA 40 mg/mL bulk solution from the receiving vessel through cooled Filter A and Filter B in sequence (see  FIG. 9 ) significantly reduces impairment of filterability caused by the total duration of the process (holding time) as well as by filtering larger volume, compared to the same bulk solution filtered under controlled room temperature. 
     Example 8 
     Cooling of GA 40 mg/mL bulk solution below 17.5° C. in the compounding vessel before passing through Filter A and Filter B in sequence (see  FIG. 10 ) results in lower pressure during the filtration step of both Filter A and Filter B as compared to the holding the same bulk solution in the compounding vessel and passing it through Filter A and Filter B at controlled room temperature (Cooling of the bulk solution by using double jacketed compounding vessel). 
     Reducing the temperature of the GA 40 mg/mL bulk solution in the compounding vessel and passing it through Filter A and Filter B in series (see  FIG. 10 ) significantly reduces impairment of filterability caused by the total duration of the process (holding time) as well as by filtering larger volume, compared to the same bulk solution held and under controlled room temperature. 
     Example 9 
     Cooling of GA 40 mg/mL bulk solution below 17.5° C. in the receiving vessel before passing through Filter B (see  FIG. 11 ) results in lower pressure during the filtration step of Filter B as compared to the holding the same bulk solution in the compounding vessel at controlled room temperature (Cooling of the bulk solution by using double jacketed compounding vessel). 
     Reducing the temperature of the GA 40 mg/mL bulk solution in the receiving vessel (see  FIG. 10 ) significantly reduces impairment of filterability caused by the total duration of the process (holding time) as well as by filtering larger volume, compared to the same bulk solution held under controlled room temperature. 
     Discussion of Examples 1-9 
     Reducing the temperature of GA 40 mg/mL sterile bulk solution significantly improved its filterability, as demonstrated by the much lower increase in pressure on Filter B during filtration and filling and by the larger volume that can be filtered at reduced temperature. Pressure increases were observed when the sterile bulk solution was held and filtered at controlled room temperature, while there was no significant increase in the pressure when the solution was filtered under reduced temperature conditions. 
     The holding time of the bulk solution during filtration through Filter B negatively affects the filterability of the solution. However, the total duration of the process (holding time) impaired the filterability significantly less when filtration was performed under reduced temperature conditions. Consequently, longer holding time can be used with reduced temperature filtration. 
     Both cooling of the solution by passing it through a heat exchanger (local cooling) and/or cooling of the whole bulk (e.g. by double-jacketed receiving vessel) before filtration through cooled Filters A or B or A and B were found to be suitable solutions for reduced temperature filtration. 
     Accumulated stability data indicate that there is no substantial difference with regard to quality and stability profile between the solution filtered under reduced temperature conditions and the solution filtered at controlled room temperature. 
     In sum, the performed experiments show that reduced temperature filtration through Filter B significantly improved the filterability of GA 40 mg/mL solution compared to the filterability of the solution when filtered at controlled room temperature. Moreover, reducing the temperature of the bulk solution during the compounding stage or before passing through Filter A, or reducing the temperature of Filter A also improves the filterability of GA 40 mg/mL solution compared to the filterability of the solution at controlled room temperature. 
     Consequently, the proposed manufacturing process for commercial batches of GA 20 mg/mL and GA 40 mg/mL includes cooling of the solution prior to filtration of the bulk solution through Filter B. 
     Example 10 
     Container Closure System 
     The container closure systems selected for the Copaxone® 40 mg/mL are the same as those used for the marketed product Copaxone® 20 mg/mL PFS. The container closure system consists of a colorless glass barrel, a plastic plunger rod and a grey rubber stopper. 
     Long Term and Accelerated Stability Studies 
     Satisfactory stability data after up to 36 months storage under long-term storage conditions (5° C.±3° C.) and after 6 months storage under accelerated conditions (25°±2° C./60±5% RH) are available. The data demonstrate that the proposed container closure systems are suitable for protection and maintenance of the drug product quality throughout its proposed shelf-life. 
     Protection from Light 
     Marketed Copaxone® should be stored protected from light. Based on this recommendation, it is proposed that Copaxone® 40 mg/mL be similarly packed in PVC transparent blisters inside a carton box, which provides light protection. The light protection of the proposed packaging when used for the Copaxone® 40 mg/mL is recommended in accordance with the results obtained from a photostability study comparing the following packaging configurations:
     1. Glass barrel syringe and plunger rod (Primary package);
       Glass barrel syringe and plunger rod in a transparent blister (partial secondary package);   Glass barrel syringe and plunger rod in a transparent blister inside carton box (complete intended packaging configuration).   
       

     As a reference, the following configurations were added:
     2. Glass barrel syringe and plunger rod wrapped in aluminum foil;
       Glass barrel and plunger rod in a transparent blister wrapped in aluminum foil.   
       

     All packages were simultaneously exposed to standardized sunlight ( 5  KLUX) for 10 days and to near UV light for additional 5 days. 
     All the obtained results from the photostability study are within the specifications. However, the impurity peak detected is lower when the drug product is packed in its complete packaging configuration. The carton box was shown to improve the photostability and gives light protection as good as that of aluminum foil, which is regarded as a complete light protector. The intended packaging configuration is therefore considered suitable for its use. 
     A storage statement to protect the product from light exposure should be added to the product label. 
     Microbiological Attributes 
     The medicinal product is a sterile, single dose, parenteral dosage form. Sterilization is achieved by sterile filtration. 
     A microbial limits test is performed for the drug substance. The sterility and bacterial endotoxins are monitored upon release and throughout stability studies of the drug product, using pharmacopoeia methods. The limits applied are identical to those applied for the marketed Copaxone®. 
     The same container closure systems are used for the Copaxone® 20 mg/mL and Copaxone® 40 mg/mL. The integrity testing studies performed to demonstrate the efficacy of the container closure systems on use for the marketed product are also considered relevant for Copaxone® 40 mg/mL. 
     Example 11 
     Viscosity 
     The average viscosity of batches of Copaxone® 20 mg/mL filtered under controlled room temperature and the average viscosity of batches of Copaxone® 40 mg/mL filtered under reduced temperature were obtained and compared. The average viscosity of different batches of Copaxone® 20 mg/mL filtered under controlled room temperature are reported in Table 5. The average viscosity of different batches of Copaxone® 40 mg/mL filtered under reduced temperature are reported in Table 6. 
     
       
         
           
               
             
               
                 TABLE 5 
               
             
            
               
                   
               
               
                 Viscosity of Batches of Copaxone ® 20 mg/mL 
               
               
                 Filtered Under Controlled Room Temperature 
               
            
           
           
               
               
               
               
            
               
                   
                   
                 Average 
                 Standard 
               
               
                   
                 Batch No. 
                 Viscosity [cPa] 
                 Deviation 
               
               
                   
               
               
                   
                 1 
                 1.92 1   
                 0.03 
               
               
                   
                 2 
                 1.58 1   
                 0.00 
               
               
                   
                 3 
                 1.58 1   
                 0.00 
               
               
                   
                 4 
                 1.57 2   
                 0.00 
               
               
                   
                 5 
                 1.67 2   
                 0.01 
               
               
                   
                 Water for 
                 0.93 2   
                 0.00 
               
               
                   
                 Injection 
                   
                   
               
               
                   
                 Average 
                 1.664 
               
               
                   
               
               
                   1 Each value is an average of 3 individual results. Values obtained using Rheocalc V2.5 Model LV, Spindle CP40, speed 80 rpm, Shear Rate 600 1/sec, Temperature 25° C. ± 0.1 
               
               
                   2 Each value is an average of 6 individual results. Values obtained using Rheocalc V2.5 Model LV, Spindle CP40, speed 80 rpm, Shear Rate 600 1/sec, Temperature 25° C. ± 0.1 
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 6 
               
             
            
               
                   
               
               
                 Viscosity of Batches of Copaxone ® 40 mg/mL 
               
               
                 Filtered Under Reduced Temperature 
               
            
           
           
               
               
               
               
            
               
                   
                   
                 Average 
                 Standard 
               
               
                   
                 Batch No. 
                 Viscosity [cPa] 1   
                 Deviation 
               
               
                   
               
               
                   
                 1 
                 2.82 
                 0.000 
               
               
                   
                 2 
                 2.92 
                 0.008 
               
               
                   
                 3 
                 2.91 
                 0.010 
               
               
                   
                 4 
                 2.61 
                 0.012 
               
               
                   
                 5 
                 2.61 
                 0.004 
               
               
                   
                 6 
                 2.73 
                 0.021 
               
               
                   
                 7 
                 2.61 
                 0.016 
               
               
                   
                 Average 
                 2.743 
                 0.007 
               
               
                   
               
               
                   1 Each value is an average of 6 individual results. Values obtained using Rheocalc V2.5 Model LV, Spindle CP40, speed 80 rpm, Shear Rate 600 1/sec, Temperature 25° C. ± 0.1 
               
            
           
         
       
     
     Osmolality 
     The osmolality of batches of Copaxone® 20 mg/mL filtered under controlled room temperature and the osmolality of batches of Copaxone® 40 mg/mL filtered under reduced temperature were measured. 
     Samples from each batch were tested in triplicates. The results are reported in Table 7. 
     
       
         
           
               
             
               
                 TABLE 7 
               
             
            
               
                   
               
               
                 Osmolality of Batches of Copaxone ® 20 mg/mL  
               
               
                 Filtered Under Controlled Room Temperature  
               
               
                 and Batches of Copaxone ® 40 mg/mL 
               
               
                 Filtered Under Reduced Temperature 
               
            
           
           
               
               
               
               
               
            
               
                   
                   
                   
                   
                 Relative 
               
               
                   
                   
                   
                   
                 Standard 
               
               
                   
                   
                 Mannitol 
                 Average 
                 Deviation 
               
               
                 Batch No. 
                 GA Dose 
                 Dose 
                 Osmolality 
                 (RSD) 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 Copaxone ® 
                 40 mg/ml 
                 40 mg/ml 
                 303  
                 mosmol/Kg 
                 1.2 
               
            
           
           
               
               
               
               
               
            
               
                 40 mg/mL 
                   
                   
                   
                   
               
               
                 No. 1 
                   
                   
                   
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 Copaxone ® 
                 40 mg/ml 
                 40 mg/ml 
                 300 1    
                 mosmol/Kg 
                 1.7 
               
            
           
           
               
               
               
               
               
            
               
                 40 mg/mL 
                   
                   
                   
                   
               
               
                 No. 2 
                   
                   
                   
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 Copaxone ® 
                 40 mg/ml 
                 40 mg/ml 
                 302  
                 mosmol/Kg 
                 2.1 
               
            
           
           
               
               
               
               
               
            
               
                 40 mg/mL 
                   
                   
                   
                   
               
               
                 No. 3 
                   
                   
                   
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 Copaxone ® 
                 20 mg/ml 
                 40 mg/ml 
                 268  
                 mosmol/Kg 
                 2.6 
               
            
           
           
               
               
               
               
               
            
               
                 20 mg/mL 
                   
                   
                   
                   
               
               
                 No. 1 
                   
                   
                   
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 Copaxone ® 
                 20 mg/ml 
                 40 mg/ml 
                 264  
                 mosmol/Kg 
                 1.2 
               
            
           
           
               
               
               
               
               
            
               
                 20 mg/mL 
                   
                   
                   
                   
               
               
                 No. 2 
                   
                   
                   
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 Placebo 
                  0 mg/ml 
                 40 mg/ml 
                 227  
                 mosmol/Kg 
                 0 
               
               
                   
               
               
                   1 Calculated from 4 measurements. 
               
            
           
         
       
     
     The results show that the osmolality of batches of Copaxone® 40 mg/mL were well within the ranges of an isotonic solution. The results also show that the batches of Copaxone® 40 mg/mL conformed to the general parenteral drug product osmolality limits of 300±30 mosmol/Kg. Further, the results indicate that batches of Copaxone® 20 mg/mL were slightly hypotonic.