NZ724875B2 - Process for manufacturing glatiramer acetate product - Google Patents

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 40mg/ml glatiramer acetate and 40mg/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.

Description

PROCESS FOR MANUFACTURING GLATIRAMER ACETATE PRODUCT This application claims priority of U.S. Nonprovisional Application No. 14/608,126, filed January 28, 2015, the entire content of which is hereby incorporated by reference herein.

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.

OUND OF THE INVENTION Glatiramer acetate (GA), the active ingredient of Copaxone®, consists of the acetate salts of synthetic polypeptides, ning four naturally occurring amino acids: L-glutamic acid, L—alanine, L- ne, and L-lysine with an average molar fraction of 0.141, 0.427, 0.095, and 0.338, respectively. The peak average lar 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 ence ID: 3443331) [online], TEVA Pharmaceutical Industries Ltd., 2014 eved on December 24, 2014], Retrieved from the Internet: www.accessdata.fda.gov/drugsatfda_docs/label/2014/020622s0891bl.pdf> ).

Chemically, glatiramer acetate is designated amic acid polymer with L-alanine, L-lysine and L-tyrosine, e (salt). Its structural formula is: (Glu,Ala,Lys,Tyr)x.X CH3COOH (C5H9NO4 . C3H7N02 . C6H14N202 . C9H11NO3) x . 2 CAS-l472459 Copaxone® is a clear, ess to slightly yellow, sterile, nonpyrogenic solution for subcutaneous injection. Each 1 mL of Copaxone® solution contains 20mg or 40mg of GA, the active ingredient, and 40mg of mannitol. The pH of the solutions is approximately 5.5 to 7.0. Copaxone® 20mg/mL in a prefilled syringe (PFS) is an approved product, the safety and efficacy of which are supported by over two decades of al research and over a decade of post-marketing experience. ne® 40mg/mL in a PFS was ped as a new formulation of the active ingredient GA.

Copaxone® 40mg/mL is a prescription medicine used for the treatment of people with ing forms of multiple sclerosis (Copaxone, Food and Drug Administration Approved ng (Reference ID: 3443331) [online] , TEVA Pharmaceutical Industries Ltd. , 2014 [retrieved on December 24, 2014], Retrieved from the Internet: www.accessdata.fda.gov/drugsatfda_docs/label/2014/020622s0891bl.pdf> It is an object of the present invention to provide an improved process for manufacturing GA drug products, or to at least provide the public with a useful choice.

In this specification where reference has been made to patent specifications, other external documents, or other sources of information, this is generally for the purpose of providing a context for discussing the features of the invention. Unless specifically stated otherwise, reference to such external nts is not to be construed as an admission that such documents, or such sources of information, in any jurisdiction, are prior art, or form part of the common l knowledge in the art.

SUMMARY OF THI INVENTION The patent provides a process of preparing a pharmaceutical preparation of amer 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 s pharmaceutical solution at a temperature of from above 0°C up to 17.5°C to produce a filtrate; and illing the suitable container with the filtrate ed 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 led syringe containing 40mg of glatiramer e and 40mg mannitol, which syringe is prepared by a process of the invention.

This patent further provides an aqueous pharmaceutical solution comprising 40mg/ml glatiramer acetate and 40mg/ml ol, wherein the aqueous pharmaceutical solution a) has a viscosity in the range of 2.0—3.5 cPa; or b) has an lity in the range of 275—325 mosmol/Kg.

This patent also provides a prefilled syringe containing 1ml of an aqueous pharmaceutical solution prepared by a process of the invention.

This patent also provides an automated injector comprising the led syringe prepared by a process of the invention. s 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 led 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 a particular aspect, the present invention provides a process of preparing a pharmaceutical preparation of glatiramer acetate and mannitol in a suitable container sing 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, wherein the filterability of the aqueous pharmaceutical solution is improved compared to the filterability of the solution at controlled room temperature; and (iii) filling the suitable container with the filtrate obtained after performing step (ii), so as to thereby prepare the pharmaceutical preparation of glatiramer e and mannitol in the suitable container.

In the description in this ication reference may be made to subject matter which is not within the scope of the appended claims. That subject matter should be y identifiable by a person d in the art and may assist in putting into practice the invention as defined in the ed claims.

Unless the context clearly es otherwise, hout the description and the claims, the words ‘comprise’, ‘comprising’ and the like are to be construed in an inclusive sense as opposed to an exclusive or exhaustive sense; that is to say in the sense of "including but not limited to".

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1. Schematic description of filtration process by cooled receiving vessel and filter g.

Figure 2. Schematic ption of filtration process by heat exchanger and cooled filter g.

Figure 3. Pressure recOrd for Experiment No. 1. * Filtration of GA solution at controlled room temperature was d and the remaining solution was transferred to the cooled receiving vessels.

Figure 4. Pressure record for Experiment No. 2. * Pauses of 3 hours and 5 hours for GA solutions filtered at controlled room temperature and at d temperature, respectively. ** Pause of 10 hours for both GA solutions. *** Filtration of GA solution at controlled room temperature was stopped. Remaining GA solution was ed at reduced temperature.

Figure 5. Pressure record for Experiment No. 3.

Figure 6. Schematic description of filtration process by cooled compounding vessel and cooled filter housings on both Filter A and Filter E.

Figure 7. Schematic description of filtration s by heat exchanger and cooled filter housings on both Filter A and Filter E.

Figure 8. Schematic description of filtration process by cooled filter housing on only Filter E.

Figure 9. Schematic description of filtration process by cooled filter housings on both Filter A and Filter E.

Figure 10. Schematic description. of filtration. process by cooled compounding vessel.

Figure 11. Schematic description of filtration. process by cooled receiving vessel.

DETAILED DESCRIPTION OF THE INVENTION This invention provides a process of ing a ceutical preparation of glatiramer acetate and mannitol in a suitable container comprising the steps of: (i) obtaining an aqueous ceutical 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 ng the ature of the second filter to a temperature from above 0°C up to 17.5°C.

In some embodiments the process r comprises the step of ng the temperature of the aqueous pharmaceutical solution to a temperature from above 06C up to 17.5°C before g 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 ceutical solution to a ature from above 0°C up to 17.5°C after leaving the receiving vessel and before entering into the second filter.

In some ments the process further comprises the step of reducing the temperature of the s pharmaceutical solution to a temperature from above 0°C up to l7.5°C while in the receiving vessel.

In some embodiments the process r comprises the step of reducing the temperature of the first filter to a temperature from above 0°C up to l7.5°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 l7.5°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 r comprises the step of reducing the temperature of the aqueous ceutical solution to a temperature from above 0°C up to l7.5°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 s pharmaceutical solution to a temperature from above 0°C up to l7.5°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 ably at a rate of 3-22 liters/hour.

In some embodiments the aqueous pharmaceutical solution is passed h 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- liters/hour.

In some ments the re during the filtering step (ii) and the pressure during the filling step (iii) is maintained below 5.0 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 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 d to a temperature between 0°C and 14°C.

In some embodiments the temperature of the aqueous ceutical 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°Cl or the temperature of the s pharmaceutical solution is reduced to 2°C — 12°C.

In some embodiments the temperature of the s 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 med using a sterilizing filter having a pore size of 0.2um or less, wherein the first, the second or both filters are a sterilizing filter having a pore size of 0.2um or less.

In some embodiments the ceutical preparation in the suitable container is an aqueous pharmaceutical solution comprising 20mg/ml‘ glatiramer acetate and 40mg/ml mannitol.

In some ments the pharmaceutical preparation in the suitable container is an aqueous ceutical solution comprising 40mg/ml glatiramer acetate and 40mg/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 ized aqueous solution which has been ized 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 ments the suitable container is a syringe.

In some embodiments the syringe contains lml of an aqueous pharmaceutical solution.

This invention provides a prefilled syringe containing 40mg of glatiramer e and 40mg mannitol, which syringe is prepared by a s of the invention.

According to any ment of the prefilled syringe sed herein, the prefilled syringe‘ contains lml of an aqueous pharmaceutical solution of 40mg/ml of glatiramer acetate and 40mg/ml mannitol.

According to any embodiment of the prefilled syringe sed 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. ing to any embodiment of the prefilled syringe disclosed herein, the aqueous pharmaceutical solution a) has a viscosity in the range of 0 cPa; or b) has an osmolality in the range of 275-325 mosmol/Kg.

This invention provides an aqueous pharmaceutical solution comprising 40mg/ml glatiramer acetate and l 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. ing to some embodiments of the aqueous pharmaceutical solution, the aqueous pharmaceutical solution has a viscosity in the range of 5 cPa.

According to some embodiments of the aqueous ceutical 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 ments 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 s pharmaceutical solution comprises glatiramer acetate having a ity in the range of 2.3-3.2 cPa.

According to some ments 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 lity 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 s pharmaceutical solution has a pH in the range of 5.5-7.0.

This invention provides a prefilled syringe containing lml of an aqueous pharmaceutical on 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 ing 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 ted injector of this invention so as to treat the human patient.

In some ments, the human patient is ing from relapsing-remitting multiple sclerosis.

In some embodiments, the human. patient has experienced a first clinical episode and has MRI features consistent with le sclerosis.

This ion provides a process of preparing a pharmaceutical preparation of glatiramer acetate and mannitol in a suitable container sing the steps of: (i) obtaining an aqueous pharmaceutical solution of glatiramer acetate and mannitol; (ii) filtering the s pharmaceutical solution at a temperature of from above 0°C up to l7.5°C to produce a te; and illing the suitable container with the filtrate obtained after performing step (ii), so as to thereby prepare the ceutical preparation of amer 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 ment, the process further comprises the step of reducing the temperature of the aqueous pharmaceutical solution to a ature from above 0°C up to l7.5°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 l7.5°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 l7.5°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 s pharmaceutical solution of glatiramer acetate and mannitol; (ii) filtering the aqueous pharmaceutical solution at a temperature of from above 0°C up to l7.5°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 ment, 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 on 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 l7.5°C. after leaving the compounding vessel and before entering into the first filter.

In an embodiment, the s further comprises the step of reducing the temperature of the first filter to a temperature from above 0°C up to l7.5°C.

.In an embodiment, the process further comprises the step of ng the temperature of the second filter to a temperature from above 0°C up to l7.5°C.

This invention provides a process of preparing a pharmaceutical preparation of glatiramer e and mannitol in a suitable container sing 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 O°Cv up to l7.5°C to produce a filtrate; and (iii)filling the suitable container with the filtrate obtained after performing step (ii), so as to y prepare the pharmaceutical preparation of amer e 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 r comprises the step of reducing the temperature of the second filter to a temperature from above 0°C up to l7.5°C.

This ion provides a process of ing a pharmaceutical preparation of glatiramer acetate and mannitol in a suitable container comprising the steps of: (i) obtaining an aqueous pharmaceutical on of glatiramer acetate and mannitol; (ii) filtering the aqueous pharmaceutical solution at a temperature of from above 0°C up to l7.5°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 ceutical 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 ature from above 0°C up to l7.5°C.

In an embodiment, the process further ses the step of reducing the temperature of the second filter to a temperature from above 0°C up to l7.5°C.

This invention provides a s of preparing a pharmaceutical preparation of .glatiramer acetate and mannitol in a Suitable container comprising the steps of: (i) obtaining an aqueous pharmaceutical on of glatiramer acetate and mannitol; (ii) filtering the aqueous pharmaceutical solution at a temperature of 'from above 0°C up to l7.5°C to produce a filtrate; and (iii)filling the suitable container with the filtrate ed 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 on through a first , 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 ature of the s ceutical solution to a temperature from above 0°C up to l7.5°C while in the compounding vessel.

This invention provides a process of preparing a pharmaceutical preparation of amer acetate and mannitol in a le 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 l7.5°C to produce a filtrate; and (iii)filling the suitable container with the filtrate obtained after ming 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 l7.5°C while in the receiving .

Automated Injection Device The mechanical workings of an automated ion assisting device can be prepared according to the disclosure in European application publication No. EP0693946 and U.S. Patent No. 7,855,176, which are orated herein by reference.

All combinations of the various elements bed herein are within the scope of the invention.

Definitions As used herein, "glatiramer acetate" is a x mixture of the acetate salts of synthetic ptides, containing four naturally occurring amino acids: amic acid, L—alanine, L—tyrosine, and L—lysine. The peak average molecular weight of glatiramer acetate is between 5,000 and 9,000 daltons. ally, amer 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 . C3H7N02 . C6Hl4N202 . C9HllN03) X.X C2H402 CAS—l47245—92—9 As used herein ramer acetate drug substance" is the glatiramer 3O acetate active ingredient prior to its formulation into a glatiramer acetate drug product.

As used herein, a "glatiramer e 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. l), which is described in Copaxone, Food and Drug Administration Approved ' Labeling (Reference ID: 3443331) [online], TEVA Pharmaceutical Industries Ltd., 2014 [retrieved on December 24, 2014], Retrieved from the Internet: www.accessdata.fda.gov/drugsatfda_docs/label/2014/020622s0891bl.pdf> , the ts of which are hereby incorporated by reference.

Copaxone® is available as 20mg/mL administered once per day, and/or 40mg/ml administered three times per week.

As used herein, a "sterilizing filter" is a filter with a pore size of 0.2 um or less which will effectively remove microorganisms.

By any range disclosed herein, it is meant that all hundredth, tenth and integer unit s 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 2O included as embodiments of this ion.

This invention will be better tood by nce 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 e (GA) Injection 40mg/mL in a prefilled syringe (GA injection 40mg/mL in PFS or Copaxone® 40mg/mL) was developed as a new formulation of the active ingredient glatiramer acetate, which is also used in the marketed product ne® 20mg/mL on for injection in a prefilled syringe; Copaxone® 40mg/mL is to be stered 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® 20mg/mL solution for injection in a prefilled syringe. Copaxone® 20mg/mL is an ed 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 ations is the double amount of the active substance used, which results in a solution with double the concentration of glatiramer acetate (40mg/mL vs. 20mg/mL). The amount of mannitol in both Copaxone® formulations s unchanged mL).

The compositions of Copaxone® 20mg/mL and ne® 40mg/mL are detailed in Table 1.

Table 1. Compositions of Copaxone® 20mg/mL and Copaxone® 40mg/mL Water for Injection q.s. to 1.0mL q.s. to 1.0mL 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® 40mg/mL, its manufacturing process and chemical, ical and microbiological utes are appropriate for commercialization. Studies were also conducted to confirm the suitability of the proposed container closure system for packaging Copaxone® 40mg/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 g agent. When the currently marketed ready—tosuse formulation of Copaxone® 20mg/mL solution for ion prefilled syringe was developed, mannitol was used in this formulation as well, as the gulator. Finally, when the new 40mg/mL formulation was developed, based on the Copaxone® 20mg/mL formulation, mannitol ed as the osmoregulator.

Mannitol is widely used in parenteral formulations as an osmo- regulator. It is freely soluble in water and stable in s 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® 40mg/mL is 40mg/mL. ining the mannitol concentration in Copaxone® 40mg/mL resulted in an essentially isotonic solution.

Water for injection (WFI) is the most widely used t and inert e 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® 40mg/mL comprises: 0 Compounding a bulk solution of GA and mannitol in water for injections (WFI). 0 Sterilizing tion of the bulk solution ng the sterile GA solution in bulk. 0 Aseptic filling of e bulk solution into syringe barrels and stoppering. 0 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 A1 and A2, respectively) to a receiving vessel. From the receiving vessel it was transferred to the intermediate vessel in the filling machine and r through dosing pumps and needles into prefilled es. 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 izing filter was named Filter B. See, Figure 1.

In line with the process for the approved Copaxone® 20mg/mL formulation, all processing steps of the new Copaxone® 40mg/mL formulation were ally ted at controlled room ature. 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 40mg/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 ity. Viscosity, in turn, is usually reciprocal in relation to temperature (Meltzer and Jornitz, Filtration and Purification in the rmaceutical 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 ature 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: 0 Filter Validation Study: Determination of ranges for the manufacturing parameters d to sterilizing Filter A and sterilizing Filter B of the bulk solution, as well as confirmation of filter compatibility with the drug product. 0 Filtration Process: Selection of the sterilizing filtration conditions best suitable for the manufacturing process and the y of the drug product.

Filters USed for ne® 20mg/mL and Copaxone® 40mg/mL cturing The manufacturing process of Copaxone® 40mg/mL was based on the s used to e the marketed Copaxone® 20mg/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 0.2um or less, to effectively remove rganisms.

Sterilization is achieved only by tion 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 0 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. 0 compatibility/adsorption testing - ment of the chemical compatibility of GA L and GA 40mg/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. 0 Residual effect - To ensure that no icant residual GA 20mg/mL or GA 40mg/mL solution that might affect the post use integrity test remains on the filter after filtration. 0 ial 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 m re (up to 5.0 bar). The validation study trated that the selected filtration system is capable of providing a high quality Copaxone® 20mg/mL and ne®‘40mg/mL.

Given the strict and well—defined operational and equipment parameters of the GA 40mg/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 e the filtration process of GA 40mg/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 L sterile bulk solution through Filter B under reduced temperature and lled. 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 Figure 1) and ed through two s: Filter A and Filter The experiments tested two different cooling technologies (cooled receiving vessels vs heat exchanger) with cooled filter. The studies are schematically ed in Figure 1 and Figure 2. Further details about these experiments and their outcomes are provided ter.

Filtration Process — Experiment Nb. 1 The objective of Experiment No. l was to compare the filterability of a batch of bulk solution held and ed 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 tically depicted in Figure l. The experimental design and the obtained results are summarized in Table 2 and Figure Table 2. Experimental Design and Results for Experiment No. 1.

Experiment e Reduced Temperature Controlled Room Filtration Temperature tion Compounding According to standard manufacturing ure1 Holding time in 13 hours 13 hours the receiving vessel Temperature of 6.6-10.7°C2 17.8—24.6°C solution held in the receiving vessel d regimen Intermittent filtration: for filtration Stage I - 5 filtration steps of filtration of though Filter B3 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 125L. 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 on was erred to the cooled receiving vessels. 2 The ature increased (to 14.9°C) once during the filtration following the addition of the remaining solution lO kept at t temperature. 3 The filtrations were carried out in parallel.

Surprisingly, filtration at reduced temperature allowed filtration to be completed‘ without the pressure se ated with filtration at controlled room temperature.

Filtration Process - Experiment Nb. 2 The first objective of Experiment No. 2 was to evaluate whether local cooling of GA 40mg/mL solution using a Heat Exchanger (HE) could improve the filterability h 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. g 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 d to Experiment No. l (in which the solution was cooled by the double—jacketed receiving vessels ing filtration through Filter A and kept cooled prior to filtration through Filter B), the solution in this ment was held at controlled room ature prior to filtration of the locally cooled (by HE) GA solution through Filter B.

The study is schematically depicted in Figure 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 Figure 4.

Table 3. Experimental Design and Results for Experiment No. 2.

Experiment Outline Reduced Temperature Controlled Room Filtration Temperature tion Accordin- to standard cturing ure1 Filtration into a Filtration of all the bulk solution through receiving vessel Filter A into a ing vessel held at controlled room temgerature ature of solution Controlled room temperature held in the receiving vessel Holding time in the 19 hours receiving vessel Planned regimen for The solution is locally The solution is tion 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 solution 6. 4— 12°C No use of HE transferred through the Duration of filtration 24 hours 19 hours through Filter B2 Temperature of solution 5.7— 8.8°C Ambient temperature transferred through Filter B Total volume of bulk solution filtered and filled into s rin-es Storage conditions Long term —8°C) during stability Accelerated2 (25°C/60% RH) — completed 6 months s Stress (40°C/75%RH)— completed 3 months Stability data The stability data showed that the drug product has a similar stability e when it is filtered at controlled room temperature or under reduced temperature ions. Both filtration processes trate 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, ed 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 d temperature.

Example 3 Filtration Process - Experiment No. 3 One objective of Experiment No. 3 was to confirm whether cooling of GA 40mg/mL bulk solution prior to filtration, using HE and cooled filter housing, allows filtration and g of batches of 130L 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 40mg/mL.

Another objective of Experiment 3 was to demonstrate with a high degree of assurance that locally cooled GA 40mg/mL on filtered through Filter B is not different in its y and ity e from GA 40mg/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 s.

The experimental design and results are summarized in Table 4.

Table 4. Experimental Design and Results for Experiment No. 3 ment Outline Reduced Controlled Reduced Controlled Temperature Room Temperature Room Filtration Temperature Filtration Temperature Filtration tion Batch No.

Compounding Standard Standard Standard Standard compounding compounding compounding compounding Batch size First 130L Remaining 50L from bulk from bulk solution A solution A liiiillllllllllIiiillllllllll Holding time in the 4 hours (same 8 hours 3.5 hours compounding vessel2 bulk on as A) Holding time in the 1.5 hours ing vessel3 on of 7 hours 3 hours 19 . 5 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 ature temperature Temperature range 9.3-11.0°C Controlled 9.0-10.2°C lled after Filter B room room temperature temperature Maximum pressure before Filter B lililiiilllllllllililiiillllllllililiiiillllll Total volume filled into syringes Storage conditions Long term (2- Stress Long term Long term (2- during stability 8°C) 60%RH) (2-a°c) 8°C) s Accelerated Accelerated Accelerated 60%RH) (25°c/60%RH) 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, less of whether it is filtered ‘at controlled room temperature or under reduced temperature ions. Both filtration processes result in product having substantially the same degradation and impurity profile at stress conditions. l 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 lled room temperature was initiated.

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 med that local cooling by heat exchanger is sufficient in order to enable filtration of a 130L batch. In addition, the quality and stability profile of GA 40mg/mL solutions filtered at controlled room temperature and reduced temperature were found to be substantially Example 4 Cooling of GA 40mg/mL bulk solution below 17.5°C in the nding vessel before passing through cooled Filter A and cooled Filter B in sequence (see Figure 6) results in lower pressure during the tion 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 ng 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 40mg/mL bulk solution in the ‘compounding vessel and passing it through cooled Filter A and Filter 'B in sequence (see Figure 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 40mg/mL bulk solution by a heat exchanger and g the solution through cooled Filter A and cooled Filter B in sequence (see Figure 7) results in lower pressure during the filtration step of both Filter A and Filter B as compared to passing the same bulk on held and filtered under controlled room ature.

Reducing the temperature of the GA L bulk solution using a heat exchanger and passing it through cooled Filter A and cooled Filter B in sequence (see Figure 7) significantly reduces impairment of filterability caused by the total duration of the process (holding time) as well as by filtering larger volume, ed to the same bulk solution held and filtered under controlled room ature.

Exam la 6 Passing the sterilized GA 40mg/mL bulk solution from the receiving vessel through cooled Filter B (see Figure 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 40mg/mL bulk on from the ing vessel through cooled Filter B (see Figure 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 L bulk solution from the nding vessel through cooled Filter A and cooled Filter B in sequence (see Figure 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. g GA 40mg/mL bulk solution from the receiving vessel through cooled Filter A and Filter B in sequence (see Figure 9) significantly reduces impairment of filterability caused by the total duration of the process (holding time) as well as by filtering larger , compared to the same bulk solution filtered under controlled room temperature.

Example 8 Cooling of GA 40mg/mL bulk solution below l7.5°C in the compounding vessel before passing through Filter A and Filter B in sequence (see Figure 10) results in lower pressure during the filtration step of both Filter A and Filter B as compared to the holding the same bulk on in the compounding vessel and passing it through Filter A and Filter B at lled room temperature ng of the bulk solution by using double jacketed compounding vessel).

Reducing the temperature of the GA 40mg/mL bulk solution in the compounding vessel and passing it through Filter A and Filter B in series (see Figure 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 40mg/mL bulk solution below 17.5°C in the receiving vessel before passing through Filter B (see Figure 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 nding vessel).

Reducing the temperature of the GA 40mg/mL bulk solution in the receiving vessel (see Figure 10) significantly s impairment of filterability caused by the total duration of the process (holding 2O time) as well as by filtering larger , compared to the same bulk solution held under lled room ature.

Discussion of Examples 1-9 Reducing the temperature of GA 40mg/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 ature. 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 on during filtration through.

Filter B vely affects the filterability of the solution.

However, the total duration of the process (holding time) impaired the filterability significantly less when tion 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 n the solution filtered under reduced temperature conditions and the on filtered at controlled room temperature.

In sum, the performed experiments show that reduced temperature filtration through Filter B significantly improved the filterability of GA 40mg/mL on 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 h Filter A, or reducing the temperature of Filter A also improves the filterability of GA 40mg/mL on compared to the filterability of the solution at controlled room temperature.

Consequently, the proposed manufacturing s for cial batches of GA 20mg/mL and GA 40mg/mL includes cooling of the solution prior to filtration of the bulk on through Filter B.

Example 10 Container Closure System The container closure systems selected for the Copaxone® 40mg/mL are the same as those used for the marketed product Copaxone® L PFS. The container closure system consists of a colorless glass barrel, a plastic plunger rod and a grey rubber r, Long Term and Accelerated Stability Studies Satisfactory stability‘ data after up to 36 months storage under long—term storage conditions (5°C i 3°C) and after 6 months storage under rated conditions (25° i 2°C/60i 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® 40mg/mL be similarly packed in PVC transparent rs inside a carton box, which provides light protection. The light protection of the proposed packaging when used for the Copaxone® 40mg/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 ry package); Glass barrel syringe and plunger rod in a arent blister (partial ary package); Glass barrel syringe and plunger rod in a arent 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 um 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 ed s from the photostability study are within the ications. However, the impurity' peak detected is lower when the drug product is packed in its complete packaging configuration. The ycarton 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 e statement to protect the product from light exposure should be added to the product label.

Microbiological Attributes The medicinal t 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 hout stability studies of the drug product, using pharmacopoeia. methods. The limits d. are cal to those applied for the marketed ne®.

The same container closure systems are used for the Copaxone® 20mg/mL and Copaxone® 40mg/mL. The integrity testing studies performed to demonstrate the efficacy of the container e systems on use for the marketed product are also considered relevant for ne® 40mg/mL.

Example 11 Viscosity The average viscosity of batches of Copaxone® 20mg/mL ed under controlled room temperature and the average viscosity of batches of Copaxone® 40mg/mL filtered under reduced temperature were obtained and compared. The average viscosity of different batches of Copaxone® 20mg/mL filtered under controlled room temperature are reported in Table 5. The average viscosity of different batches of ne® 40mg/mL filtered under reduced temperature are reported in Table 6.

Table 5. Viscosity of Batches of Copaxone® 20mg/mL Filtered Under Controlled Room Temperature Average Standard Viscosity [cPa] Deviation , 1.921 0.03 1.581 1.581 1.572 1.672 Water for 0.932 Injection Average 1.664 1 Each value is an average of 3 individual results. Values obtained using lc V2.5 Model LV, e CP40, speed 80 rpm, Shear Rate 600 1/sec, Temperature 25'CiO.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'C10.1 Table 6. Viscosity of Batches of Copaxone® 40mg/mL Filtered Uhder Reduced ature Batch No. Average Standard Viscosity [cPa]1 Deviation 2 91 0.010 2 73 0.021 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°Ci0.1 Osmolality The osmolality of batches of Copaxone® 20mg/mL filtered under controlled room ature and the osmolality of batches of Copaxone® 40mg/mL ed under reduced temperature were measured.

Samples from each batch were tested in cates. The results are reported in Table 7.

Table 7. Osmolality of Batches of ne® 20mg/mL Filtered under Controlled Room ature and Batches of Copaxone® 40mg/mL Filtered Under Reduced Temperature Batch No. GA Dose Mannitol Average ve Dose Osmolality rd ‘ Deviation (RSD) Copaxone® 40 mg/ml 40 mg/ml 303 40mg/mL mosmol/Kg No. l Copaxone® 40 mg/ml 40 mg/ml 3001 H \] 40mg/mL No. 2 --mosmOl/Kg Copaxone® 40 mg/ml 40 mg/ml 302 2.1 40mg/mL No. 3 ||||||||||||||||||||||||||||IHHHHHHIHHIIIIII Copaxone® 20 mg/ml 40 mg/ml 268 2.6 20mg/mL mosmol/Kg No. l Copaxone® 20 mg/ml 40 mg/ml 264 ‘ 1.2 20mg/mL mosmol/Kg - No. 2 Placebo ----0 mg/ml 40 mg/ml 227 1 Calculated from 4 measurements.

The results show that the osmolality of batches of Copaxone® 40mg/mL were well within the ranges of an isotonic solution. The results also show that the s of Copaxone® 40mg/mL conformed to the general parenteral drug product osmolality limits of 300 :30 mosmol/Kg. Further, the results indicate that batches of Copaxone® 20mg/mL were slightly hypotonic.

Claims (3)

What is claimed:

1. A process of preparing a pharmaceutical preparation of glatiramer acetate and mannitol in a suitable container comprising the steps of: 5 (i) obtaining an aqueous pharmaceutical solution of amer acetate and mannitol; (ii) filtering the aqueous ceutical solution at a temperature of from above 0°C up to 17.5°C to produce a filtrate, wherein the filterability of 10 the aqueous pharmaceutical solution is improved compared to the filterability of the solution at controlled room temperature; and (iii) filling the suitable container with the filtrate obtained after performing step (ii), so as to 15 y prepare the pharmaceutical preparation of glatiramer acetate and mannitol in the suitable container.

2. The s of claim 1, wherein the filtering step (ii) comprises filtering the aqueous pharmaceutical solution 20 h 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 ature from above 0°C up to 17.5°C. 25

4. The process of claim 2 or claim 3 further comprising the step of reducing the temperature of the aqueous ceutical 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 ing 30 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 sing 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 5 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. 10

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 .

9. The process of any one of claims 2-8 further comprising the step of reducing the temperature of the aqueous 15 pharmaceutical solution to a ature from above 0°C up to 17.5°C before passing through the first .

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. 20

11. The process of claim 10 further comprising the step of reducing the temperature of the aqueous pharmaceutical on to a temperature from above 0°C up to 17.5°C after leaving the compounding vessel and before entering into the first filter. 25

12. The process of claim 10 or claim 11 r sing 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 s of any one of claims 2-14, wherein the s 30 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 ably below 3.0 bar. 5

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 s of any one of claims 1-15, wherein the temperature of the aqueous pharmaceutical solution is between 10 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 15 0°C and 12°C, or the temperature of the aqueous pharmaceutical on is reduced to a ature between 0°C and 12°C.

18. The process of any one of claims 1-15, wherein the temperature of the aqueous pharmaceutical on is 2°C - 20 12°C, or the temperature of the s 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 25 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 izing filter having a pore size of 0.2µm or less, wherein the first, the second or both filters are a izing filter having a pore size of 0.2µm or less. 30

21. The process of any one of claims 1-20, wherein the pharmaceutical preparation in the suitable container is an aqueous pharmaceutical solution comprising 20mg/ml glatiramer acetate and 40mg/ml mannitol.

22. The process of any one of claims 1-20, n the pharmaceutical preparation in the suitable container is an aqueous pharmaceutical solution comprising 40mg/ml glatiramer e and l mannitol. 5

23. The process of any one of claims 1-22, wherein the pharmaceutical ation 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 10 pharmaceutical ation 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. 15

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 20 been filled into the suitable ner so as to form a lized 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. 25

28. The process of claim 27, n the suitable container is a syringe.

29. The process of claim 28, wherein the syringe contains 1ml of an aqueous pharmaceutical solution~33»: .1855 anion was 23 m manage“? m wu?ava??a mummy?

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