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.
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, Ltyrosine,
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 December 24, 2014], Retrieved from the Internet:
) •
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 CH3C00H
(C5H9N04 . C3H7N02 . C6H14N202 .C9HiiN03 ) X . XC2H402
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 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 clinical research and over a decade
of post -marketing experience. Copaxone® 40mg/mL in a PFS was
developed as a new formulation of the active ingredient GA.
Copaxone® 40mg/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
December 24, 2014] , Retrieved from the Internet:
) •
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 40mg of
glatiramer acetate 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 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 1ml 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
Figure 1 . Schematic description of filtration process by cooled
receiving vessel and filter housing.
Figure 2 . Schematic description of filtration process by heat
exchanger and cooled filter housing.
Figure 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.
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 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.
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 B .
Figure 1 . Schematic description of filtration process by heat
exchanger and cooled filter housings on both Filter A and Filter B .
Figure 8 . Schematic description of filtration process by cooled
filter housing on only Filter B .
Figure 9 . Schematic description of filtration process by cooled
filter housings on both Filter A and Filter B .
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 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|i7ti or less, wherein the first, the
second or both filters are a sterilizing filter having a pore size
of 0.2|im or less.
In some embodiments the pharmaceutical preparation in the suitable
container is an aqueous pharmaceutical solution comprising 20mg/ml
glatiramer acetate and 40mg/ml mannitol .
In some embodiments the pharmaceutical preparation in the suitable
container is an aqueous pharmaceutical 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
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 1ml of an aqueous
pharmaceutical solution.
This invention provides a prefilled syringe containing 40mg of
glatiramer acetate and 40mg 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 lml of an aqueous
pharmaceutical solution of 40mg/ml of glatiramer acetate and 40mg/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 4 0mg/ml glatiramer acetate and 4 0mg/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.
WO 2016/122722 PCT7US2015/051203
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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
5 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.
10 This invention provides a prefilled syringe containing 1ml 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
15 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
20 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 MR I features consistent with multiple
25 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
3 0 glatiramer acetate and mannitol;
WO 2016/122722 PCT7US2015/051203
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(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
5 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
10 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
15 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.
20 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
25 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
30 filtrate; and
WO 2016/122722 PCT7US2015/051203
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(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.
5 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.
10 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
15 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.
2 0 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;
25 (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
3 0 pharmaceutical preparation of glatiramer acetate and mannitol
in the suitable container.
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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
5 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:
10 (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
15 (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
20 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.
25 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
30 container comprising the steps of:
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(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
5 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.
10 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.
15 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
20 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
25 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
30 in the suitable container.
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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
5 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
10 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. Patent No. 7,855,176, which are
15 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
20 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-
25 tyrosine, acetate (salt). Its structural formula is:
(Glu,Ala,Lys,Tyr)x.X CH3COOH
(C5H9N04.C3H7N02.C6H14N202.C9H11N03) x.x C2H402
CAS-147245-92-9
As used herein "glatiramer acetate drug substance" is the glatiramer
30 acetate active ingredient prior to its formulation into a glatiramer
WO 2016/122722 PCT7US2015/051203
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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
5 manufactured by TEVA Pharmaceutical Industries Ltd. (Israel) , which
is described in Copaxone, Food and Drug Administration Approved
1 Labeling (Reference ID: 3443331) [online], TEVA Pharmaceutical
Industries Ltd., 2014 [retrieved on December 24, 2014] , Retrieved
from the Internet :
, the contents 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
15 of 0.2 |im 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 5 0 mg means
that 1.1, 1.2 . . . 1.9; and 2,3 . . .49 mg unit amounts are
20 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
25 which follow thereafter.
Experimental Details
Methods
Glatiramer Acetate (GA) Injection 40mg/mL in a prefilled syringe (GA
injection 40mg/mL in PFS or Copaxone® 40mg/mL) was developed as a
30 new formulation of the active ingredient glatiramer acetate, which
is also used in the marketed product Copaxone® 20mg/mL solution for
injection in a prefilled syringe. Copaxone® 40mg/mL is to be
administered three times a week by subcutaneous injection to
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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 approved product, the safety and efficacy of which are
5 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 (40mg/mL vs. 20mg/mL) . The amount of mannitol in
10 both Copaxone ® formulations remains unchanged (40mg/mL) .
The compositions of Copaxone® 20mg/mL and Copaxone® 40mg/mL are
detailed in Table 1 .
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Table 1 . Compositions of Copaxone ® 20mg/mL and Copaxone ® 40xtvg/mL
Components
Glatiramer Acetate1
Mannitol USP/Ph.Eur.
Water for Injection
USP/Ph.Eur/JP
Copaxone® 20mg/mL Copaxone® 4 0mg/mL
Content per mL
2 0.Omg
40.0mg
q.s. to 1.OmL
40.Omg
4 0.Omg
q.s. to l.OmL
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,
5 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 ® 40mg/mL.
Mannitol was chosen as the tonicity agent for the initially
10 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 ® 20mg/mL solution for
injection prefilled syringe was developed, mannitol was used in this
formulation as well, as the osmoregulator . Finally, when the new
15 40mg/mL formulation was developed, based on the Copaxone ® 20mg/mL
formulation, mannitol remained as the osmoregulator.
Mannitol is widely used in parenteral formulations as an osmo-'
regulator. It is freely soluble in water and stable in aqueous
solutions. Mannitol solutions may be sterilized by filtration. In
20 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. Maintaining the mannitol concentration in
Copaxone ® 40mg/mL resulted in an essentially isotonic solution.
Water for injection (WFI) is the most widely used solvent and inert
25 vehicle in parenteral formulations. Water is chemically stable in
WO 2016/122722 PCT7US2015/051203
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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:
5 · 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
10 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 Ai and A2,
15 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
20 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, Figure 1 .
In line with the process for the approved Copaxone ® 2 0mg/mL
25 formulation, all processing steps of the new Copaxone ® 4 0mg/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
30 high-quality drug product could be obtained by filtration of GA
40mg/mL at controlled room temperature, as confirmed by release and
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21
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
5 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 .
10 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:
15 · 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
20 conditions best suitable for the manufacturing process and the
quality of the drug product.
Filters Used for Copaxone® 20mg/mL and Copaxone® 40mg/mL
Manufacturing
The manufacturing process of Copaxone® 40mg/mL was based on the
25 process used to produce the marketed Copaxone® 2 0mg/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|im or less, to effectively remove microorganisms.
30 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.
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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:
5 · 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.
10 · Compatibility/adsorption testing - assessment of the chemical
compatibility of GA 20mg/mL 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
15 provide assay within specifications.
• Residual effect - To ensure that no significant residual GA
20mg/mL or GA 40mg/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
20 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® 20mg/mL and
Copaxone ® 4Omg/mL .
25 Given the strict and well-defined operational and equipment
parameters of the GA 4Omg/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
30 process of GA 40mg/mL sterile bulk solution through Filter B under
reduced temperature conditions, using the same. filters and
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filtration train as for the filtration at controlled room
temperature .
Accordingly, experiments were performed in order to compare the
filtration of GA 40mg/mL sterile bulk solution through Filter B
5 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
10 (see Figure 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 Figure 1 and Figure 2 . Further details
15 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
20 conditions (cooling by double- jacketed receiving vessel and cooled
Filter B housing) .
The study is schematically depicted in Figure 1 . The experimental
design and the obtained results are summarized in Table 2 and Figure
3 .
25
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Table 2 . Experimental Design and Results for Experiment No. 1 .
Experiment Outline Reduced Temperature
Filtration
Controlled Room
Temperature Filtration
Compounding According to standard manufacturing procedure 1
Holding time in
the receiving
vessel
13 hours 13 hours
Temperature of
solution held in
the receiving
vessel
6.6-10.7°C2 17.8-24.6°C
Planned regimen
for filtration
though Filter B3
Intermittent filtration:
Stage 1 - 5 filtration steps of filtration of
about 10 liters of bulk solution - followed bypauses
of about 5 0 minutes each, followed by a
pause of 5 hours.
Stage II - 4 filtration steps of
about 10 liters of bulk solution
pauses of about 5 0 minutes each,
pause of about 10 hours.
Stage III - Filtration of remaining solution.
filtration of
- followed by
followed by a
Total volume of
bulk solution
filtered
About 125L. Filtration
was completed.
About 8 5 liters.
Filtration was stopped
due to increase in
pressure on Filter B .
10
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.
The temperature increased (to 14.9°C) once during the
filtration following the addition of the remaining solution
kept at ambient temperature .
The filtrations were carried out in parallel.
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Surprisingly, filtration at reduced temperature allowed filtration
to be completed without the pressure increase associated with
filtration at controlled room temperature.
Example 2
5 Filtration Process - Experiment No. 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 through cooled Filter B compared to
f ilterability of the same bulk solution at controlled room
10 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 .
15 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
20 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 Figure 2 . The experimental
25 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 .
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Table 3. Experimental Design and Results for Experiment No. 2.
Experiment Outline
Compounding
Filtration into a
receiving vessel
Temperature of solution
held in the receiving
vessel
Holding time in the
receiving vessel
Planned regimen for
filtration through
Filter B
Temperature of solution
transferred through the
HE
Duration of filtration
through Filter B2
Temperature of solution
transferred through
Filter B
Total volume of bulk
solution filtered and
filled into syringes
Storage conditions
during stability
studies
Stability data
Reduced Temperature
Filtration
Controlled Room
Temperature Filtration
According to standard manufacturing procedure1
Filtration of all the bulk solution through
Filter A into a receiving vessel held at
controlled room temperature
Controlled room temperature
19 hours
The solution is locally
cooled as it is
transferred through a
HE and filtered through
cooled Filter B. Three
consecutive filtration
and filling stages.
About 3 hours break
between Stage I and
Stage II and about 10
hours break between
Stage II and Stage III.
6.4-12°C
24 hours
5.7-8.8°C
154L
The solution is
filtered through Filter
B at controlled room
temperature. Three
consecutive filtration
and filling stages.
About 5 hours break
between Stage I and
Stage II and about 10
hours break between
Stage II and Stage III.
No use of HE
19 hours
Ambient temperature
63L3
Long term (2-8°C)
Accelerated (25°C/60% RH) - completed 6 months
Stress (4 0°C/75%RH)- completed 3 months
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
5 2
10
One bulk solution was prepared and divided into two portions. Bulk
solution size: 230 liters.
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.
Filtration of solution at controlled room temperature was stopped due
to pressure increase and the remaining solution was filtered at
reduced temperature.
3
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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
5 filter housing, allows filtration and filling 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.
10 Another objective of Experiment 3 was to demonstrate with a high
degree of assurance that locally cooled GA 4 0mg/mL solution filtered
through Filter B is not different in its quality and stability
profile from GA 40mg/mL solution filtered through Filter B at
controlled room temperature conditions with regard to pre-determined
15 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 .
20
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Table 4. Experimental Design and Results for Experiment No. 3
10
15
Experiment Outline
Batch No.
Compounding
Batch size
Holding time in the
compounding vessel2
Holding time in the
receiving vessel3
Duration of
filtration through
Filter B
Total duration of
entire process
(total holding time)
Temperature range
before Filter B
Temperature range
after Filter B
Maximum pressure
before Filter B
Total volume filled
into syringes
Storage conditions
during stability
studies
Stability data and
conclusions
Reduced
Temperature
Filtration
A
Standard
compounding
First 130L
from bulk
solution A
4 hours
1.5 hours
7 hours
12.5 hours
10.4-12.2°C
9.3-11.0°C
0.6 bar
130L
Long term (2-
8°C)
Accelerated
(25°C/60%RH)
Stress
(40°C/60%RH)
Controlled
Room
Temperature
Filtration
A-21
Standard
compounding
Remaining 50L
from bulk
solution A
4 hours (same
bulk solution
as A)
10.5 hours4
3 hours
17.5 hours
Controlled
room
temperature
Controlled
room
temperature
0.3 bar
50L
Stress
(40°C/60%RH)
Reduced
Temperature
Filtration
B
Standard
compounding
180L
8 hours
16 hours
19.5 hours
43.5 hours
10.2-11.7°C
9.0-10.2°C
0.6 bar
180L
Long term
(2-8°C)
Accelerated
(25°C/60%RH)
Stress
(40°C/60%RH)
Controlled
Room
Temperature
Filtration
C
Standard
compounding
180L
3.5 hours
13 hours
13 hours
2 9.5 hours
Controlled
room
temperature
Controlled
room
temperature
2.5 bar5
134L
Long term (2-
8°C)
Accelerated
(25°C/60%RH)
Stress
(40°C/60%RH)
Stability data showed that the drug product has a similar
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.
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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 130L batch. In addition, the quality and stabilityprofile
of GA 40mg/mL solutions filtered at controlled room
5 temperature and reduced temperature were found to be substantially
identical .
Example 4
Cooling of GA 40mg/mL bulk solution below 17.5°C in the compounding
vessel before passing through cooled Filter A and cooled Filter B in
10 sequence (see Figure 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
15 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
20 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
25 passing 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 solution held and filtered under controlled room
temperature .
3 0 Reducing the temperature of the GA 40mg/mL 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
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(holding time) as well as by filtering larger volume, compared to
the same bulk solution held and filtered under controlled room
temperature .
Example 6
5 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 .
10 Passing the sterilized GA 40mg/mL bulk solution from the receiving
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
15 controlled room temperature.
Example 7
Passing GA 40mg/mL bulk solution from the compounding 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
20 A and Filter B as compared to passing the same bulk solution
filtered under controlled room temperature.
Passing 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
25 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 40mg/mL bulk solution below 17.5°C in the compounding
30 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
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 4 0mg/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 compounding vessel) .
Reducing the temperature of the GA 4 0mg/mL bulk solution in the
receiving vessel (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 under controlled room temperature.
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
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 doublejacketed
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 40mg/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 40mg/mL solution
compared to the filterability of the solution at controlled room
temperature .
Consequently, the proposed manufacturing process for commercial
batches of GA 2 0mg/mL and GA 4 0mg/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® 4 0mg/mL are
the same as those used for the marketed product Copaxone® 2Omg/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 3 6 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® 40mg/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® 4 0mg/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 ®
2 0mg/mL and Copaxone® 4 0mg/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® 4 0mg/mL.
Example 11
Viscosity
The average viscosity of batches of Copaxone® 20mg/mL filtered under
controlled room temperature and the average viscosity of batches of
Copaxone® 4Omg/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
Copaxone® 40mg/mL filtered under reduced temperature are reported in
Table 6 .
Table 5 . Viscosity of Batches of Copaxone® 2Omg/mL Filtered Under
Controlled Room Temperature
1 Each value is an average of 3 individual results. Values obtained
using Rheocalc V2 . 5 Model LV, Spindle CP40, speed 8 0 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 8 0 rpm, Shear Rate
600 1/sec, Temperature 25"C+0.1
Table 6. Viscosity of Batches of Copaxone® 4 0mg/mL Filtered Under
Reduced Temperature
1 Each value is an average of 6 individual results. Values obtained
using Rheocalc V2.5 Model LV, Spindle CP40, speed 8 0 rpm, Shear Rate
600 1/sec, Temperature 25°C+0.1
Osmolality
The osmolality of batches of Copaxone ® 2Omg/mL filtered under
controlled room temperature and the osmolality of batches of
Copaxone ® 4 Omg/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® 20mg/mL Filtered Under
Controlled Room Temperature and Batches of Copaxone® 40mg/mL
Filtered Under Reduced Temperature
1 Calculated from 4 measurements.
The results show that the osmolality of batches of Copaxone® 4 0mg/mL
were well within the ranges of an isotonic solution. The results
also show that the batches 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®
2 0mg/mL were slightly hypotonic.

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