U.S. patent application number 14/212625 was filed with the patent office on 2014-09-18 for manufacturing beta-lactam combination products.
The applicant listed for this patent is Cubist Pharmaceuticals, Inc.. Invention is credited to Nicole Miller Damour, Joseph Terracciano.
Application Number | 20140274989 14/212625 |
Document ID | / |
Family ID | 50280243 |
Filed Date | 2014-09-18 |
United States Patent
Application |
20140274989 |
Kind Code |
A1 |
Terracciano; Joseph ; et
al. |
September 18, 2014 |
MANUFACTURING BETA-LACTAM COMBINATION PRODUCTS
Abstract
This disclosure relates to the manufacture of pharmaceutical
compositions comprising an antibiotic compound and a beta-lactamase
inhibitor compound when both compounds have a chemical structure
that includes a beta-lactam ring, as well as resulting
pharmaceutical compositions.
Inventors: |
Terracciano; Joseph;
(Concord, MA) ; Damour; Nicole Miller; (Belmont,
MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Cubist Pharmaceuticals, Inc. |
Lexington |
MA |
US |
|
|
Family ID: |
50280243 |
Appl. No.: |
14/212625 |
Filed: |
March 14, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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61793007 |
Mar 15, 2013 |
|
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61792092 |
Mar 15, 2013 |
|
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61882936 |
Sep 26, 2013 |
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61893436 |
Oct 21, 2013 |
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Current U.S.
Class: |
514/192 ;
422/243 |
Current CPC
Class: |
A61P 43/00 20180101;
A61K 47/26 20130101; A61K 47/36 20130101; A61K 47/02 20130101; A61K
9/19 20130101; A61P 31/12 20180101; Y02A 50/473 20180101; A61K
31/546 20130101; A61P 31/00 20180101; A61P 31/04 20180101; A61K
47/12 20130101; A61K 47/183 20130101; A61K 31/431 20130101; Y02A
50/30 20180101; A61K 9/0019 20130101; A61K 31/546 20130101; A61K
2300/00 20130101; A61K 31/431 20130101; A61K 2300/00 20130101 |
Class at
Publication: |
514/192 ;
422/243 |
International
Class: |
A61K 31/546 20060101
A61K031/546; A61K 31/431 20060101 A61K031/431 |
Claims
1. A method of manufacturing an antibacterial pharmaceutical
composition comprising ceftolozane and tazbactam in a facility that
does not manufacture or house beta-lactam products selected from
the group consisting of: penicillins, penems, carbacephems and
monobactams, the pharmaceutical composition comprising a
therapeutically effective amount of ceftolozane sulfate and
tazobactam in a ratio of 1,000 mg ceftolozane active per 500 mg of
tazobactam active, the method comprising the steps of: a.
lyophilizing a first aqueous solution comprising ceftolozane
sulfate to obtain a lyophilized ceftolozane composition in the
absence of tazobactam, penicillins, penems, carbacephems and
monobactams; b. blending the lyophilized ceftolozane composition
with a tazobactam composition in the absence of penicillins,
penems, carbacephems and monobactams, the tazobactam composition
comprising tazobactam prepared and provided in the absence of
ceftolozane to obtain the antibacterial pharmaceutical
composition.
2. The method of claim 1, further comprising the steps of
lyophilizing a second aqueous solution comprising tazobactam in the
absence of ceftolozane to form a second lyophilized tazobactam
composition to obtain the tazobactam composition.
3. The method of claim 2, wherein the second aqueous solution
comprises tazobactam acid and sodium bicarbonate.
4. The method of claim 3, wherein the tazobactam composition
comprises tazobactam sodium.
5. The method of claim 1, wherein the lyophilized ceftolozane
composition is first blended with the tazobactam composition in the
absence of contact with a penem, carbacephem, or monobactam.
6. The method of claim 1, wherein the antibacterial pharmaceutical
composition comprises less than 1% of a compound of formula (III)
detectable at a retention time relative to ceftolozane of 1.22 by
high performance liquid chromatography using a Develosil column
ODS-UG-5; 5 micrometers; 250.times.4.6 mm, a mobile phase of sodium
perchlorate buffer solution (pH 2.5)/CH.sub.3CN 90:10 (v/v) at a
1.0 mL/min flow rate and oven temperature of 45.degree. C.
##STR00008##
7. The method of claim 6, further comprising the step of detecting
less than about 0.03% of the compound of formula (III) by HPLC in
the antibacterial pharmaceutical composition.
8. The method of claim 1, wherein the tazobactam composition is
obtained by lyophilizing a second solution in the absence of
ceftolozane, the second solution comprising tazobactam to form a
second lyophilized tazobactam composition.
9. The method of claim 1, wherein the pharmaceutical composition
comprises 125-500 mg of sodium chloride per 1000 m of ceftolozane
active.
10. The method of claim 1, wherein the first aqueous solution
further comprises citric acid.
11. The method of claim 1, wherein a. the tazobactam composition is
obtained by lyophilizing a second aqueous solution in the absence
of ceftolozane, the second aqueous solution comprising tazobactam
acid and sodium bicarbonate to form a second lyophilized tazobactam
composition; b. the pharmaceutical composition comprises 125 mg-500
mg of sodium chloride per 1,000 mg of ceftolozane active; c. the
ceftolozane and tazobactam are combined in the absence of any
compound belonging to the following classes of beta-lactam
containing compounds: penicillins, penems, carbacephems, and
monobactams.
12. The method of claim 1, performed in the absence of any compound
belonging to the following classes of beta-lactam containing
compounds: penicillins, penems, carbacephems, and monobactams.
13. The method of claim 1, performed in a facility that does not
house or manufacture a compound belonging to the following classes
of beta-lactam containing compounds: penicillins, penems,
carbacephems, and monobactams.
14. The method of claim 1, wherein the first aqueous solution
consists essentially of ceftolozane sulfate, water, citric acid,
sodium chloride and L-arginine.
15. The method of claim 2, wherein the second aqueous solution
consists essentially of tazobactam acid, water, and sodium
bicarbonate.
16. The method of claim 1, wherein the antibacterial pharmaceutical
composition is a unit dosage form comprising: TABLE-US-00014
Nominal Composition mg per Unit Dosage Component form Container
Ceftolozane Ceftolozane 1147 composition Sulfate Citric Acid, 21
Anhydrous Sodium 487 Chloride L-Arginine 600 Tazobactam Sodium 537
Nitrogen Q.S.
17. A facility for manufacturing a pharmaceutical composition
formulated for parenteral administration for the treatment of
complicated intra-abdominal infections or complicated urinary tract
infections, the pharmaceutical composition comprising ceftolozane
sulfate and tazobactam in a ratio of 1,000 mg ceftolozane active
per 500 mg of tazobactam active, the pharmaceutical composition
obtained by a process comprising the steps of a. lyophilizing a
first aqueous solution in the absence of tazobactam, the first
aqueous solution comprising ceftolozane sulfate, 125 mg to 500 mg
of sodium chloride per 1,000 mg of ceftolozane active, to obtain a
first lyophilized ceftolozane composition, b. lyophilizing a second
solution comprising tazobactam in the absence of ceftolozane to
form a second lyophilized tazobactam composition; and c. blending
the first lyophilized ceftolozane composition and the second
lyophilized tazobactam composition to obtain the antibacterial
composition; wherein the process is performed in the absence of any
additional non-cephalosporin beta-lactam compounds.
18. The method of claim 17, wherein the facility is a dedicated
facility to the manufacture of pharmaceutical products comprising a
fixed dose combination of a cephalosporin and a beta-lactamase
inhibitor.
19. The method of claim 17, wherein the facility is a dedicated
facility to the manufacture of pharmaceutical products comprising a
fixed dose combination of a ceftolozane and a beta-lactamase
inhibitor.
20. The method of claim 17, wherein the facility is a dedicated
facility to the manufacture of pharmaceutical products comprising a
fixed dose combination of a ceftolozane and tazobactam.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority to U.S. Provisional
Application No. 61/792,092, filed Mar. 15, 2013; U.S. Provisional
Application No. 61/793,007, filed Mar. 15, 2013; U.S. Provisional
Application No. 61/882,936, filed Sep. 26, 2013; and U.S.
Provisional Application No. 61/893,436, filed Oct. 21, 2013. The
contents of these applications are incorporated hereby by reference
in their entirety.
TECHNICAL FIELD
[0002] This disclosure relates to processes for the manufacture of
pharmaceutical compositions comprising a beta-lactam antibiotic and
a beta-lactam inhibitor compound also containing a beta-lactam
moiety, including compositions comprising ceftolozane and
tazobactam, and resulting pharmaceutical compositions made by these
processes.
BACKGROUND
[0003] The United States Food and Drug Administration (FDA)
recently published guidance relating to the manufacture of
antibiotics with a chemical structure containing a beta-lactam
moiety, including cephalosporins. See U.S. Department of Health and
Human Services Food and Drug Administration, Center for Drug
Evaluation and Research, Non-Penicillin Beta-Lactam Drugs: A CGMP
Framework for Preventing Cross-Contamination (April 2013) ("FDA
Guidance"). Under the FDA Guidance, certain beta-lactam
beta-lactamase inhibitor compounds such as tazobactam are
considered "potential sensitizing agents" for allergic reactions,
and should be the subject of manufacturing controls to reduce the
risk of cross-contamination with all beta-lactam products. The FDA
Guidance can pose significant limitations on facilities that
manufacture products combining: (a) a beta-lactamase inhibitor
having a chemical structure containing a beta-lactam moiety
("BL-BLI," e.g., tazobactam) and (b) a cephalosporin antibiotic
(e.g., ceftolozane) or antibiotics having chemical structures
containing a beta-lactam moiety ("beta-lactam antibiotics"). To
prevent cross-contamination, the manufacture and handling of such a
product cannot occur in a facility handling other beta-lactam
antibiotics in the absence of the BL-BLI, nor can such a facility
handle other beta-lactam antibiotics in any of the four other
recognized structural classes (i.e., penicillins, penems,
carbacephems and monobactams), to which the beta-lactam antibiotic
does not itself belong, even in combination with the BL-BLI.
Ceftolozane is a cephalosporin antibacterial agent. The
antibacterial activity of ceftolozane is believed to result from
its interaction with penicillin binding proteins (PBPs) to inhibit
the biosynthesis of the bacterial cell wall which acts to stop
bacterial replication. Ceftolozane is also referred to as CXA-101,
FR264205,
(6R,7R)-3-[(5-amino-4-{[(2-aminoethyl)carbamoyl]amino}-1-methyl-1H-pyrazo-
l-2-ium-2-yl)methyl]-7-({(2Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-[(1-carb-
oxy-1-methylethoxy)imino]acetyl}amino)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-
-2-ene-2-carboxylate, or
(6R,7R)-3-[5-Amino-4-[3-(2-aminoethyl)ureido]-1-methyl-1H-pyrazol-2-ium-2-
-ylmethyl]-7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-[(Z)-1-carboxy-1-methyle-
thoxyimino]acetamido]-3-cephem-4-carboxylic acid). U.S. Pat. No.
7,129,232 discloses ceftolozane and various ceftolozane salts.
Ceftolozane sulfate (formula (I)) is an example of a
pharmaceutically acceptable salt of ceftolozane that can be
combined with sodium chloride and other components to obtain an
antibiotic composition.
##STR00001##
[0004] Tazobactam is a BLI compound approved for use in combination
with piperacillin in an injectable antibacterial product available
under commercial names ZOSYN (U.S.) and TAZOCIN (e.g., in Canada,
and the United Kingdom). Tazobactam sodium, a derivative of the
penicillin nucleus, is a penicillanic acid sulfone having the
chemical name chemical name is sodium
(2S,3S,5R)-3-methyl-7-oxo-3-(1H-1,2,3-triazol-1-ylmethyl)-4-thia-1azabicy-
clo[3.2.0]heptane-2-carboxylate-4,4-dioxide. The chemical formula
is C.sub.10H.sub.11N.sub.4NaO.sub.5S and the molecular weight is
322.3. The chemical structure of formula (IIa) is tazobactam
sodium:
##STR00002##
[0005] Another injectable antibiotic composition called CXA-201
(ceftolozane/tazobactam) comprises ceftolozane and tazobactam in a
2:1 weight ratio formulated for reconstitution prior to parenteral
administration. In one presentation, CXA-201 can be provided as a
composition comprising ceftolozane sulfate and tazobactam sodium,
administered by reconstituting a vial of solid CXA-201 to form a
reconstituted injectable formulation. Each vial of CXA-201 contains
1000 mg of ceftolozane active (free base equivalent weight, e.g.,
provided as a pharmaceutically acceptable salt such as ceftolozane
sulfate) and sterile tazobactam sodium at a quantity equivalent of
500 mg of tazobactam free acid, in a solid form. CXA-201 includes
other components such as sodium chloride and L-arginine. CXA-201
displays potent antibacterial activity against various
gram-negative infections such as, for example, complicated
intra-abdominal infection (cIAI), complicated urinary tract
infection (cUTI), or hospital acquired/ventilator-associated
bacterial pneumonia (HABP/VABP).
[0006] Products containing ceftolozane and tazobactam include both
a non-penicillin beta-lactam cephalosporin (ceftolozane) and a
beta-lactamase inhibitor with a beta-lactam moiety (tazobactam).
There is a need for methods of manufacturing antibiotic
compositions comprising ceftolozane and tazobactam for sale in the
United States in compliance with the FDA Guidance, as well as
antibiotic compositions manufactured in accordance with the FDA
Guidance without affecting the purity, stability, and safety of the
resulting composition.
SUMMARY
[0007] Provided herein are methods of manufacturing or preparing
pharmaceutical compositions containing two or more beta-lactam
compounds in accordance with FDA Guidance, as well as
pharmaceutical compositions manufactured in compliance with FDA
Guidance. Specifically, certain manufacturing methods are provided
herein that conform to standards recommended by FDA Guidance for
the avoidance of cross-contamination of non-penicillin beta-lactam
drugs.
[0008] In one aspect, provided herein is a method of manufacturing
a composition comprising a non-penicillin beta-lactam antibiotic
and a beta-lactam BLI compound in a dedicated production area or in
the absence of any compound belonging to a different class of
beta-lactam containing compounds. The non-penicillin antibiotic can
be a cephalosporin and the beta-lactam BLI compound can be
tazobactam. When the composition includes a cephalosporin and a
beta-lactam BLI, the manufacturing can be carried out in the
absence of any compound belonging to other classes of beta-lactam
containing compounds, including: penicillins, penems, carbacephems,
and monobactams. A composition comprising ceftolozane and
tazobactam can be manufactured by a process that includes the step
of combining ceftolozane with tazobactam in a dedicated production
area or in the absence of any other finished pharmaceuticals or any
other pharmaceutical ingredients with chemical structures
containing a beta-lactam moiety that would be deemed
cross-contaminants under the FDA Guidance. For example, the
finished pharmaceutical or active pharmaceutical ingredient can be
any non-penicillin beta-lactam of a different class than
ceftolozane or tazobactam.
[0009] Certain methods of manufacturing a composition comprising
ceftolozane and tazobactam can include the steps of: (a) receiving
the ceftolozane and tazobactam at a dedicated production area; (b)
sequential, aseptic filling of the ceftolozane and tazobactam into
a container (e.g., a bag or vial); (c) blanketing the container
with an inert gas; (d) sealing the container; and (e) inspecting
the container prior to secondary packaging.
[0010] Compositions formed by sequential, aseptic combination
within a unit dosage form container of a lyophilized ceftolozane
composition obtained in the absence of tazobactam and a separate,
lyophilized tazobactam composition obtained in the absence of
ceftolozane, resulted in ceftolozane-tazobactam compositions with
less than 0.03% of a compound of formula (III) as measured by high
performance liquid chromatography (HPLC), as determined by HPLC
using a Develosil column ODS-UG-5; 5 micrometers; 250.times.4.6 mm,
a mobile phase of sodium perchlorate buffer solution (pH
2.5)/CH.sub.3CN 90:10 (v/v) at a 1.0 mL/min flow rate and oven
temperature of 45.degree. C. The compound of formula (III) was
formed in a lyophilized product obtained by lyophilizing a solution
comprising both ceftolozane and tazobactam.
##STR00003##
[0011] In one embodiment, a pharmaceutical composition can include
ceftolozane and tazobactam with less than 1%, 0.15%, 0.10%, 0.05%
or 0.03% by weight; or from 0.03-0.05%, 0.03-0.1% or 0.03-0.15% by
HPLC or even undetectable amounts of the compound of formula (III)
(e.g., less than about 0.03% of the compound of Formula (III)
measured by HPLC). These pharmaceutical compositions can be
obtained by a process comprising the steps of (a) lyophilizing
ceftolozane in the absence of tazobactam to obtain a lyophilized
ceftolozane composition; and (b) combining the lyophilized
ceftolozane with tazobactam under conditions suitable to obtain
said pharmaceutical composition with the aforementioned purity
levels. The combination of the lyophilized ceftolozane composition
with tazobactam can include blending the lyophilized ceftolozane
composition with lyophilized or crystalline tazobactam
material.
[0012] In one aspect, provided herein is a pharmaceutical
composition comprising a blend of separately lyophilized tazobactam
and ceftolozane sulfate in an amount providing 1,000 mg of
ceftolozane active per 500 mg of tazobactam active, further
comprising less than 0.15%, 0.10%, 0.05% or 0.03% by weight; from
0.03-0.05%, 0.03-0.1% or 0.03-0.15% by HPLC; or even undetectable
amounts (e.g., less than about 0.03% by HPLC) of a compound of
formula (III) detectable at a retention time relative to
ceftolozane of 1.22 by high performance liquid chromatography
(HPLC) using a Develosil column ODS-UG-5; 5 micrometers;
250.times.4.6 mm, a mobile phase of sodium perchlorate buffer
solution (pH 2.5)/CH.sub.3CN 90:10 (v/v) at a 1.0 mL/min flow rate
and oven temperature of 45.degree. C. (hereinafter referred to as
the "method of Example 9").
[0013] CXA-201 compositions comprising less than about 0.15%,
0.10%, 0.05% or 0.03% by weight; or from 0.03-0.05%, 0.03-0.1% or
0.03-0.15% by HPLC of the compound of formula (III) can be obtained
by a process comprising the steps of: (a) forming a first aqueous
solution comprising ceftolozane (e.g., in a pharmaceutically
acceptable salt such as formula (I)), (b) lyophilizing the first
aqueous solution to obtain a lyophilized ceftolozane composition,
and (c) blending the lyophilized ceftolozane composition with a
tazobactam composition (e.g., tazobactam acid lyophilized in the
absence of ceftolozane) in an amount that provides a 2:1 weight
ratio between the amount of ceftolozane active and tazobactam
active.
[0014] The ceftolozane can also be a ceftolozane drug product
intermediate. In one embodiment, the ceftolozane drug product
intermediate further comprises sodium chloride. The ceftolozane
drug product intermediate can be prepared by a method comprising:
(a) compounding a ceftolozane solution for lyophilization; (b)
filtering the solution; (c) lyophilizing the solution into powder;
(d) grinding and sieving the powder; and (e) aseptic packaging the
powder for delivery to the dedicated production area.
[0015] In another aspect, provided herein is a method of receiving
ceftolozane and tazobactam at a dedicated production area, and
combining the ceftolozane with tazobactam in the absence of any
finished pharmaceuticals or active pharmaceutical ingredients other
than ceftolozane and tazobactam to produce a pharmaceutical
composition suitable for administration to a subject.
BRIEF DESCRIPTION OF THE FIGURES
[0016] FIG. 1 is a flowchart showing the steps for preparing a
CXA-201 composition comprising ceftolozane (referred to as CXA-101)
and tazobactam using a blending process, wherein the ceftolozane
and tazobactam are lyophilized separately prior to blending as
described herein.
[0017] FIG. 2 is a flowchart showing the steps for preparing a
CXA-201 composition comprising ceftolozane (referred to as CXA-101)
and tazobactam using a co-lyophilization process, as described
herein.
[0018] FIG. 3 is a flowchart showing the blending process for
preparing a CXA-201 composition comprising ceftolozane (referred to
as CXA-101) and tazobactam in a dedicated production area according
to FDA Guidance for the prevention of cross-contamination.
DETAILED DESCRIPTION
[0019] A pharmaceutical composition comprising ceftolozane and
tazobactam can be prepared in a dedicated production area in the
absence of materials with chemical structures containing a
beta-lactam moiety, other than ceftolozane or tazobactam. The
pharmaceutical composition is preferably prepared in a dedicated
production area for manufacturing antibiotic compounds comprising a
non-penicillin beta-lactam compound (e.g., a cephalosporin) and a
beta-lactamase inhibitor (BLI) compound with a beta-lactam ring
(e.g., tazobactam). Accordingly, the facility that manufactures a
product containing both cephalosporin and a beta-lactam containing
BLI such as tazobactam for sale in the United States is not
simultaneously or subsequently used to manufacture or handle any
other products within another (non-cephalosporin) Beta-Lactam
Class, nor to produce another cephalosporin product without
tazobactam (or beta-lactam compound from the same structural
class).
DEFINITIONS
[0020] Unless otherwise indicated herein, the phrase "1000 mg
ceftolozane" or "1 g ceftolozane" refers to an amount of
ceftolozane containing the free base equivalent weight of
ceftolozane provided in any suitable salt form. For example, a
composition containing 1000 mg of ceftolozane in the ceftolozane
sulfate solid form will include greater than 1000 mg of material
(e.g., due to at least the additional weight of the sulfate counter
ion). Preferably, a composition containing "1000 mg of ceftolozane"
includes an amount of ceftolozane sulfate comprising 1000 mg of the
ceftolozane molecule in free base equivalent form. For example, as
shown in Table 11, 1147 mg ceftolozane sulfate corresponds to 1000
mg of ceftolozane free base.
[0021] Likewise, the phrases "250-750 mg tazobactam," "250-700 mg
tazobactam," "300-700 mg tazobactam," "300-650 mg tazobactam,"
"350-650 mg tazobactam," "350-600 mg tazobactam," "400-600 mg
tazobactam," "400-550 mg tazobactam," "450-550 mg tazobactam," or
"about 500 mg tazobactam" refer to an amount of tazobactam
containing the free acid equivalent weight of tazobactam provided
in any suitable salt form. For example, a composition containing
500 mg of tazobactam in the tazobactam sodium solid form will
include greater than 500 mg of material (e.g., due to at least the
additional weight of the sodium counter ion). For example, as shown
in Table 11, 537 mg tazobactam sodium corresponds to 500 mg of
tazobactam free acid. Preferably, a composition containing "500 mg
of tazobactam" includes an amount of tazobactam sodium comprising
500 mg of the tazobactam molecule in free acid equivalent form.
[0022] As used herein, "125 to 1000 mg sodium chloride per 1000 mg
of ceftolozane" refers to a ratio of sodium chloride to ceftolozane
free base equivalent. For example, "125 to 1000 mg sodium chloride
per 1000 mg of ceftolozane" includes, for example, 62.5 to 500 mg
sodium chloride per 500 mg of ceftolozane, as well as, for example,
25 to 200 mg sodium chloride per 200 mg ceftolozane, etc.
[0023] As used herein, the term "blending" refers to a process
comprising physically combining ceftolozane and tazobactam, wherein
each of ceftolozane and tazobactam have been individually
lyophilized (i.e., lyophilized in the absence of one another) prior
to blending. Blending refers to mixing the components in a powdered
form, which can occur within a unit dosage form container. Blending
of ceftolozane and tazobactam is described in Examples 3 and 4, and
in FIGS. 1 and 3.
[0024] As used herein, the term "vial" means a container for
storing pharmaceutical preparations. A single vial may be suitable
for holding a single preparation, or may be configured to hold two
or more separate preparations simultaneously without mixing. The
vial may hold enough preparation for a single dose or multiple
doses. The vial may be formed of any suitable material, such as
glass or plastic, and various means may be used to seal the vial
(e.g., stoppering and crimping).
[0025] As used herein, the term "dedicated production area" refers
to a manufacturing facility that complies with U.S. Department of
Health and Human Services Food and Drug Administration, Center for
Drug Evaluation and Research, Non-Penicillin Beta-Lactam Drugs: A
CGMP Framework for Preventing Cross-Contamination (April 2013)
("FDA Guidance"). The FDA Guidance identifies five beta-lactam
antibiotic classes: penicillins, cephalosporins, penems,
carbacephems and monobactams ("Beta-Lactam Classes"). With
reference to the manufacture of a product containing both a
compound from a Beta-Lactam Class and a compound having a chemical
structure with a beta-lactam moiety, a dedicated production area
cannot be simultaneously or subsequently used to manufacture or
handle another product containing a compound from another
Beta-Lactam Class. A "dedicated production area" can include but is
not limited to facilities, air handling equipment, and/or process
equipment. See section IV.D Containment (4.4) of the ICH Q7
guidance.
[0026] As used herein, a beta-lactam BLI refers to any
beta-lactamase inhibitor compound with a chemical structure
including a beta-lactam moiety (e.g., tazobactam).
[0027] Unless otherwise indicated, HPLC measurements reported
herein are obtained using a Develosil column ODS-UG-5; 5
micrometers; 250.times.4.6 mm, a mobile phase of sodium perchlorate
buffer solution (pH 2.5)/CH.sub.3CN 90:10 (v/v) at a 1.0 mL/min
flow rate and oven temperature of 45.degree. C.
[0028] As used herein, "treating," "treat," or "treatment"
describes the management and care of a patient for the purpose of
combating a disease, condition, or disorder and includes the
administration of a pharmaceutical composition of the present
invention to alleviate the symptoms or complications of a disease,
condition or disorder, or to eliminate the disease, condition or
disorder. The term "treat" can also include treatment of a cell in
vitro or an animal model.
[0029] By a "therapeutically effective amount" of a compound of the
invention is meant a sufficient amount of the compound to treat the
disorder (e.g., bacterial infection). The specific therapeutically
effective amount that is required for the treatment of any
particular patient or organism (e.g., a mammal) will depend upon a
variety of factors including the disorder being treated and the
severity of the disorder; the activity of the specific compound or
composition employed; the specific composition employed; the age,
body weight, general health, sex and diet of the patient; the time
of administration, route of administration, and rate of excretion
of the specific compound employed; the duration of the treatment;
drugs used in combination or coincidental with the specific
compound employed; and like factors well known in the medical arts
(see, for example, Goodman and Gilman's, "The Pharmacological Basis
of Therapeutics", Tenth Edition, A. Gilman, J. Hardman and L.
Limbird, eds., McGraw-Hill Press, 155-173, 2001, which is
incorporated herein by reference in its entirety). The
therapeutically effective amount for a given situation can be
readily determined by routine experimentation and is within the
skill and judgment of the ordinary clinician.
[0030] As used herein, the term "ceftolozane active" refers to
active portion of a salt form of ceftolozane, i.e., the free base
form of ceftolozane.
[0031] As used herein, the term "tazobactam active" refers to the
active portion of a salt form of tazobactam, i.e., tazobactam free
acid.
[0032] As used herein, references to an amount of a substance as "%
of the compound of . . . " or "% by HPLC" (unless otherwise
indicated) refer to the % of a compound detected by high
performance liquid chromatography (HPLC) according to the method of
Example 9.
[0033] As used herein, the term "FDA Guidance" refers to the
document U.S. Department of Health and Human Services Food and Drug
Administration, Center for Drug Evaluation and Research,
Non-Penicillin Beta-Lactam Drugs: A CGMP Framework for Preventing
Cross-Contamination (April 2013) ("FDA Guidance").
FDA Guidance
[0034] The FDA Guidance states that manufacturing facilities
dedicated to manufacturing a sensitizing non-penicillin beta-lactam
compound should be "completely and comprehensively separated" from
areas in the facility in which any class of sensitizing beta-lactam
is manufactured. The FDA also considers separation of production
facilities for penicillins to be good manufacturing practice. The
FDA Guidance can be understood to require the use of a dedicated
facility to manufacture antibiotic compounds comprising a
non-penicillin beta-lactam compound (e.g., a cephalosporin) and a
BLI compound with a beta-lactam ring (e.g., tazobactam).
Accordingly, a facility that manufactures a product containing both
cephalosporin and a beta-lactam containing BLI such as tazobactam
for sale in the United States cannot be subsequently used to
manufacture any other products containing beta-lactam ring (e.g.,
other non-penicillin beta-lactam compounds including other
cephalosporin antibiotics cannot be subsequently manufactured in
the facility).
[0035] The FDA Guidance relates to manufacturing and handling
beta-lactam antibiotics and other pharmaceutical ingredients having
a chemical structure containing a beta-lactam ring. Beta-lactam
antibiotics, including penicillin and the non-penicillin classes,
share a basic chemical structure that includes a three-carbon,
one-nitrogen cyclic amine structure known as the beta-lactam ring.
The side chain associated with the beta-lactam ring is a variable
group attached to the core structure by a peptide bond; the side
chain variability contributes to antibacterial activity. As of the
date of this publication, the FDA has approved over 34 beta-lactam
compounds as active ingredients in drugs for human use. (see, e.g.,
FDA's Approved Drug Products with Therapeutic Equivalence
Evaluations, generally known as the Orange Book) Beta-lactam
antibiotics include the following five classes: penicillins (e.g.,
ampicillin, oxacillin); cephalosporins (e.g., cephalexin,
cefaclor); penems (e.g., imipenem, meropenem); carbacephems (e.g.,
loracarbef); and monobactams (e.g., aztreonam). (Yao, J D C, and R
C Moellering, Jr., Antibacterial agents, in Manual of Clinical
Microbiology, 9.sup.th edition, edited by P R Murray et al.,
Washington D.C., ASM Press, 2007.)
[0036] Antibiotic pharmaceutical compositions comprising a
beta-lactam antibiotic compound (i.e., an antibiotic compound
possessing one or more beta-lactam moieties) such as a
cephalosporin (e.g., ceftolozane) can be administered with a
beta-lactamase inhibitor (BLI) compound. The BLI can be selected to
irreversibly inhibit beta-lactamase enzymes responsible for
resistance to the beta-lactam antibiotic, thereby increasing
susceptibility of bacteria to the antibiotic that would otherwise
be resistant in the absence of the BLI. Beta-lactam inhibitor
compounds such as clavulanic acid, tazobactam, and sulbactam have
weak antibacterial activity but are irreversible inhibitors of many
beta-lactamases. Accordingly, BLI compounds can be used in
combination with specific beta-lactam antibiotic agents to provide
antibacterial compositions with an extended antibacterial
spectrum.
[0037] Under the FDA Guidance, a manufacturing facility handling a
product for sale in the United States containing both a
cephalosporin (e.g, ceftolozane) and a penicillin nucleus (e.g.,
tazobactam) cannot be subsequently used in the manufacture of any
other class of beta-lactam products, including all other
penicillins, cephalosporins, penems, carbacephems and monobactams
or in the manufacture of other finished pharmaceuticals or active
pharmaceutical ingredients. The FDA Guidance states that
(non-penicillin) cephalosporin beta-lactam compounds (e.g., such as
ceftolozane) for sale in the United States must be "completely and
comprehensively separated from" manufacturing areas that handle any
other class of beta-lactam compound (e.g., compounds in the
penicillin class).
[0038] According to the FDA Guidance, non-penicillin beta-lactam
drugs can be sensitizing agents and cross-contamination with these
types of drugs can initiate the same types of drug-induced
hypersensitivity reactions that can be triggered by penicillins,
such as life-threatening allergic reactions. Allergic reactions
associated with these beta-lactam-type drugs range from rashes to
life-threatening anaphylaxis. These allergic reactions are mediated
by Immunoglobulin E (IgE) and are a primary concern because they
can be associated with significant morbidity and mortality.
Patients with a history of hypersensitivity to penicillin may also
experience IgE-mediated reactions to other beta-lactams, such as
cephalosporins (e.g., ceftolozane) (see, e.g., Saxon, A, G N Beall,
A S Rohr, and D C Adelman, 1987, Immediate hypersensitivity
reactions to beta-lactam antibiotics, Ann Intern Med,
107(2):204-215).
[0039] Further, the FDA Guidance can be understood to take the
position that non-penicillin beta-lactams (including, e.g.,
tazobactam) have the potential to sensitize individuals, and
subsequent exposure to penicillin may result in severe allergic
reactions. The FDA Guidance also states that beta-lactam
intermediates and derivatives (precursors to the Active
Pharmaceutical Ingredients), including the product prior to
purification, can have sensitizing properties or result in
antigenic responses that produce allergic reactions. Thus the FDA
Guidance states that chemical manufacturing processes associated
with non-penicillin beta-lactam drugs should also be designed to
reduce the risk of cross-contamination. The FDA Guidance also can
be understood to take the position that there is a lack of suitable
animal or receptor testing models that are predictive of human
sensitivity (see, e.g., Olson, H. et al., 2000, Concordance of the
toxicity of pharmaceuticals in humans and in animals, Regul.
Toxicol. Pharmacol., 32:56-67), and the threshold dose at which
allergenic response could occur is extremely low and difficult to
detect with current analytical methods (see, e.g., Pimiento, A. P.
et al., 1998, Aztreonam and ceftazidime: evidence of in vivo
cross-allergenicity, Allergy, 53:624625 and Shepard, G. M., 1991,
Allergy to .beta.-lactam antibiotics, Immunol. Allergy Clin. North
Am., 11(3):611-633).
[0040] The FDA Guidance also states that while beta-lactam
antibiotics are similar to one another in many ways, they may
differ in pharmacokinetics, antibacterial activity, and potential
to cause serious allergic reactions. Because allergy testing
methods have not been well-validated, it is clinically difficult to
determine the occurrence and rate of cross-reactivity between
beta-lactam antibiotics in humans. (Bernstein, I L, et al., 2008,
Allergy diagnostic testing: an updated practice parameter, Ann.
Allergy Asthma Immunol., 100:S1-S148). Therefore, undiagnosed or
underreported cases of cross-reactivity likely exist. Some
beta-lactam antibiotics have negligible potential for
cross-reactivity with beta-lactams of other classes, whereas other
beta-lactam compounds may exhibit sensitizing activity as
derivatives before the incorporation of side chains that confer
antibacterial activity. According to the FDA Guidance, although
there have been no case reports confirming anaphylactic reactions
to a beta-lactamase inhibitor that is also a beta-lactam, these
compounds are potentially sensitizing agents, and manufacturers
should implement controls to reduce the risk of cross-contamination
with beta-lactamase inhibitors as with all other beta-lactam
products.
[0041] There is a need for methods for preventing
cross-contamination in compliance with the FDA Guidance for the
manufacture of pharmaceutical compositions comprising two or more
beta-lactam molecules with different structures (e.g., ceftolozane
and tazobactam), given the position taken in the FDA Guidance that
it is difficult to define the minimal dose below which allergic
responses are unlikely to occur in humans. (see, e.g., Dayan, A.
D., 1993, Allergy to antimicrobial residues in food: assessment of
the risk to man, Vet. Microbiol., 35:213-226 and Blanca M., et al.,
1996, Anaphylaxis to penicillins after non-therapeutic exposure: an
immunological investigation, Clin. Exp. Allergy, 26:335-340). Given
the health risks associated with cross-reactivity
(cross-sensitivity) of any beta-lactams, and the uncertainty in
quantifying the risk, implementing methods for preventing
cross-contamination of any pharmaceutical product with
beta-lactam-type drugs is of current concern to the FDA. Just as
the FDA considers the separation of production facilities for
penicillins to be current good manufacturing practice, FDA expects
manufacturers to treat sensitizing non-penicillin beta-lactam-based
products similarly. Specifically, the FDA recommends that
manufacturers establish appropriate separation and control systems
designed to prevent two types of contamination: (1) the
contamination of a non-penicillin beta-lactam by any other
non-penicillin beta-lactam, and (2) the contamination of any other
type of product by a non-penicillin beta-lactam. Accordingly, the
FDA recommends that the area in which any class of sensitizing
beta-lactam is manufactured be separated from areas in which any
other products are manufactured, and have an independent air
handling system ("dedicated production area"). Dedicated production
areas can include separate facilities, air handling equipment,
and/or process equipment (see, e.g., IV.D Containment (4.4) of the
ICH Q7 guidance, available at http://www.fda.gov/Drugs/Guidance
ComplianceRegulatoryInformation/Guidances/default.htm). This
control applies to each of the five classes of sensitizing
beta-lactams; the area in which any class of sensitizing
beta-lactam is manufactured should be separated from areas in which
any other products are manufactured, including any other class of
sensitizing beta-lactam.
[0042] The FDA Guidance also recommends that firms that manufacture
beta-lactam intermediates or receive them for further processing,
as well as firms whose manufacturing processes result in
beta-lactam derivatives, should evaluate their manufacturing
operations for the possibility of cross-contamination and implement
appropriate controls to reduce or mitigate the potential for
cross-contamination. As with penicillin and non-penicillin
beta-lactam drugs, such controls could include, but are not limited
to, isolation and separation of intermediate and derivative
materials, facilities, equipment, and personnel.
Pharmaceutical Compositions
[0043] Referring to FIG. 1, a pharmaceutical composition can be
manufactured by combining a ceftolozane composition and a
tazobactam composition. The ceftolozane composition comprises
ceftolozane prepared and obtained in the absence of tazobactam, and
the tazobactam composition comprises tazobactam prepared and
obtained in the absence of ceftolozane. The combination of the
ceftolozane composition and the tazobactam composition can be
performed within a facility that is compliant with the FDA Guidance
(e.g., a facility that is dedicated to the exclusive manufacture of
products that include combinations of compounds within the same
beta-lactam containing structural classes, such as tazobactam and
another cephalosporin).
[0044] More particularly, the ceftolozane composition in FIG. 1 can
be prepared in the absence of tazobactam by forming a first aqueous
solution comprising ceftolozane sulfate and other components
including excipients, stabilizers, pH adjusting additives (e.g.,
buffers) and the like. Ceftolozane is a cephalosporin antibacterial
agent of formula (Ib).
##STR00004##
Ceftolozane and/or pharmaceutically acceptable salts thereof are
also referred to as CXA-101, FR264205, or by chemical names such as
(6R,7R)-3-[(5-amino-4-{[(2-aminoethyl)carbamoyl]amino}-1-methyl-1H-pyrazo-
l-2-ium-2-yl)methyl]-7-({(2Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-[(1-carb-
oxy-1-methylethoxy)imino]acetyl}amino)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-
-2-ene-2-carboxylate, and
7.beta.-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethox-
yimino)acetamido]-3-{3-amino-4-[3-(2-aminoethyl)ureido]-2-methyl-1-pyrazol-
io}methyl-3-cephem-4-carboxylate. Ceftolozane can be obtained as a
pharmaceutically acceptable salt. U.S. Pat. No. 7,129,232 discloses
ceftolozane and various ceftolozane salts. For example, a
ceftolozane hydrogen sulfate salt is disclosed among ceftolozane
salts that can be formed "with a base or an acid addition salt such
as a salt with an inorganic base, for example, an alkali metal salt
[e.g., sodium salt, potassium salt, etc.], an alkaline earth metal
salt [e.g., calcium salt, magnesium salt, etc.], an ammonium salt;
a salt with an organic base, for example, an organic amine salt
[e.g., trimethylamine salt, triethylamine salt, pyridine salt,
picoline salt, ethanolamine salt, triethanolamine salt,
dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, etc.];
an inorganic acid addition salt [e.g., hydrochloride, hydrobromide,
sulfate, hydrogen sulfate, phosphate, etc.]; an organic carboxylic
or sulfonic acid addition salt [e.g., formate, acetate,
trifluoroacetate, maleate, tartrate, citrate, fumarate,
methanesulfonate, benzenesulfonate, toluenesulfonate, etc.]; and a
salt with a basic or acidic amino acid [e.g., arginine, aspartic
acid, glutamic acid, etc.]." Ceftolozane sulfate is a
pharmaceutically acceptable ceftolozane salt of formula (I) that
can be formulated for intravenous administration or infusion.
##STR00005##
[0045] A ceftolozane composition can also include other components
such as (without limitation) sodium chloride, citric acid and
L-arginine. The use of sodium chloride results in greater
ceftolozane stability (e.g., 125-500 mg sodium chloride per 1,000
mg of ceftolozane active in the ceftolozane composition. L-arginine
can be included in the ceftolozane composition to adjust pH of the
aqueous solution such that the composition is suitable for
injection (e.g., to pH 5-7, including 6-7) prior to lyophilization
and to increase the solubility of ceftolozane.
[0046] Preferably, the first aqueous solution comprises the
composition of Table 11 in the Examples. The ceftolozane can be
included in the ceftolozane composition as an amount of ceftolozane
sulfate of formula (I) containing a therapeutically effective
amount of ceftolozane such as at least about 1,000 mg ceftolozane
active (e.g., about 1,147 mg ceftolozane sulfate). In certain
embodiments, the ceftolozane composition comprises 125-500 mg
sodium chloride per 1000 mg of ceftolozane active, more preferably
about 450-500 mg (including, e.g., 480-500 mg) of sodium chloride
per 1,000 mg of ceftolozane active. In one embodiment, the
composition comprises about 487 mg sodium chloride per 1000 mg of
ceftolozane active (e.g., about 1,147 mg of ceftolozane sulfate),
and an amount of tazobactam sodium providing the equivalent of
about 500 mg of tazobactam active.
[0047] As shown in FIG. 1, the ceftolozane composition can be with
a tazobactam composition. The tazobactam composition can be
prepared in the absence of ceftolozane by forming a second solution
comprising tazobactam acid. The compound
(2S,3S,5R)-3-methyl-7-oxo-3-(1H-1,2,3-triazol-1-ylmethyl)-4-thia-1-azabic-
yclo[3.2.0]heptane-2-carboxylic acid 4,4-dioxide (also known as
tazobactam) is a .beta.-lactamase inhibitor of the following
structure:
##STR00006##
Unless otherwise indicated, tazobactam can be a free acid, a sodium
salt, an arginine salt, or a hydrate or solvate thereof. In an
embodiment, the tazobactam is tazobactam sodium. The tazobactam
sodium powder can be generated by neutralizing tazobactam acid with
an alkalizing agent, such as sodium bicarbonate or sodium
hydroxide, followed by lyophilization. Alternatively, the
tazobactam sodium can be generated by neutralizing tazobactam acid
with an alkalizing agent, such as sodium bicarbonate or sodium
hydroxide. In other embodiments, the tazobactam composition can
include a crystalline form of tazobactam, such as tazobactam
arginine crystal, for combination with the ceftolozane
composition.
[0048] The pharmaceutical antibiotic composition comprising
ceftolozane and tazobactam in a 2:1 weight ratio of ceftolozane
active to tazobactam acid ("CXA-201") displays potent antibacterial
activity, including antibiotic activity against infections caused
by many Gram-negative pathogens such as Pseudomonas aeruginosa (P.
aeruginosa), Escherichia coli (E. coli), Klebsiella pneumonia (K.
pneumonia). In particular, CXA-201 is a pharmaceutical composition
useful for intravenous administration for the treatment of
complicated intra-abdominal infections and/or complicated urinary
tract infections, and is being evaluated for treatment of
pneumonia. In CXA-201, ceftolozane is combined with the
.beta.-lactamase inhibitor ("BLI") tazobactam. Tazobactam is a BLI
against Class A and some Class C .beta.-lactamases, with
well-established in vitro and in vivo efficacy in combination with
active .beta.-lactam antibiotics.
[0049] The pharmaceutical compositions comprising CXA-201 are
useful, for example, for the treatment of bacterial infections in a
mammal, comprising administering to said mammal a therapeutically
effective amount of a pharmaceutical composition prepared according
to the methods described herein. A method for the treatment of
bacterial infections in a mammal can comprise administering to said
mammal a therapeutically effective amount of a pharmaceutical
composition comprising ceftolozane sulfate and sodium chloride.
Non-limiting examples of bacterial infections that can be treated
by the methods of the invention include infections caused by:
aerobic and facultative gram-positive microorganisms (e.g.,
Staphylococcus aureus, Enterococcus faecalis, Staphylococcus
epidermidis, Streptococcus agalactiae, Streptococcus pneumonia,
Streptococcus pyogenes, Viridans group streptococci), aerobic and
facultative gram-negative microorganisms (e.g., Acinetobacter
baumanii, Escherichia coli, Haemophilus influenza, Klebsiella
pneumonia, Pseudomonas aeruginosa, Citrobacter koseri, Moraxella
catarrhalis, Morganella morganii, Neisseria gonorrhoeae, Proteus
mirabilis, Proteus vulgaris, Serratia marcescens, Providencia
stuartii, Providencia rettgeri, Salmonella enterica), gram-positive
anaerobes (Clostridium perfringens), and gram-negative anaerobes
(e.g., Bacteroides fragilis group (e.g., B. fragilis, B. ovatus, B.
thetaiotaomicron, and B. vulgates), Bacteroides distasonis,
Prevotella melaminogenica). In certain embodiments of the methods
described herein, bacterial infection is associated with one or
more of the following conditions: complicated intra-abdominal
infections, complicated urinary tract infections (cUTIs) and
pneumonia (e.g., community-acquired, or nosocomial pneumonia).
Community-acquired pneumonia (moderate severity only) can include
infections caused by piperacillin-resistant, beta-lactamase
producing strains of Haemophilus influenza. Nosocomial pneumonia
(moderate to severe) caused by piperacillin-resistant,
beta-lactamase producing strains of Staphylococcus aureus and by
Acinetobacter baumanii, Haemophilus influenzae, Klebsiella
pneumoniae, and Pseudomonas aeruginosa.
Manufacturing
[0050] The manufacturing process for the pharmaceutical
compositions can be selected to comply with the FDA Guidance while
reducing decomposition of the constituent drug substances and to
produce a composition that is stable under a variety of storage
conditions. The facility can include separation and control
systems, or dedicated production areas, that prevent the
contamination of a non-penicillin beta-lactam with another
non-penicillin beta-lactam and the contamination of any other
product by a non-penicillin beta-lactam.
[0051] Pharmaceutical compositions comprising one or more drug
substances can be prepared by lyophilization of various solutions
containing the drug substance(s). Lyophilization is a process of
freeze-drying in which water is sublimed from a frozen solution of
one or more solutes. Specific methods of lyophilization are
described in Remington's Pharmaceutical Sciences, Chapter 84, page
1565, Eighteenth Edition, A. R. Gennaro, (Mack Publishing Co.,
Easton, Pa., 1990).
[0052] The pharmaceutical compositions comprising ceftolozane and
tazobactam can be prepared by a blending process, wherein the
ceftozolane and tazobactam are individually lyophilized in the
absence of one another, followed by blending the individually
lyophilized ceftozolane and tazobactam.
[0053] Surprisingly, pharmaceutical compositions comprising
ceftolozane and tazobactam prepared by blending (e.g., as described
in Example 3) have a different composition compared to compositions
prepared by co-lyophilization (e.g., as described in Example 1). In
particular, ceftolozane and tazobactam individually lyophilized
prior to blending, led to a pharmaceutical composition comprising a
much lower amount of the compound of formula (III):
##STR00007##
[0054] This compound of formula (III) has a relative retention time
(RRT) of 1.22 (relative to ceftolozane using the HPLC analysis).
This compound is also referred to herein as "the compound RRT
1.22." Without being bound by theory, the compound RRT 1.22 can be
formed by a reaction between ceftolozane and formylacetic acid, a
by-product of tazobactam as illustrated in Marunaka et al. (Chem.
Pharm. Bull. 1988, Vol. 36 (11), pp. 4478-4487.
[0055] The presence of compound RRT 1.22 was detected by HPLC in
compositions of ceftolozane and tazobactam, wherein the
compositions were formed through co-lyophilization, i.e., the
ceftolozane and tazobactam were combined and co-lyophilized
together, as opposed to being individually lyophilized and blended
together (see, e.g., Examples 1 and 2).
[0056] Compositions with controlled amounts of the compound RRT1.22
(formula (III)) (e.g., up to 1% by weight of formula III) can be
obtained by blending a first composition comprising a
therapeutically effective amount of ceftolozane in the absence of
tazobactam with a second composition comprising a therapeutically
effective amount of tazobactam in the absence of ceftolozane to
form a blended pharmaceutical composition.
[0057] Pharmaceutical compositions comprising ceftolozane and
tazobactam with reduced or even undetectable levels of the compound
of formula (III) (e.g., including levels of compound of formula
(III) that are not detectable by HPLC according to Example 9 and/or
comprise less than 1%, 0.15%, 0.10%, 0.05% or 0.03% by weight; or
from 0.03-0.05%, 0.03-0.1% or 0.03-0.15% by HPLC according to
Example 9) can be obtained by blending a ceftolozane composition
comprising a therapeutically effective amount of ceftolozane in the
absence of tazobactam with a tazobactam composition comprising a
therapeutically effective amount of tazobactam in the absence of
ceftolozane to form a blended pharmaceutical composition.
[0058] More specifically, the pharmaceutical compositions can be
obtained by a method comprising:
[0059] a) combining ceftolozane and an amount of sodium chloride
effective to stabilize the ceftolozane (e.g., 125-500 mg sodium
chloride per 1,000 mg ceftolozane active) to form a ceftolozane
aqueous solution;
[0060] b) lyophilizing the ceftolozane aqueous solution in the
absence of tazobactam to obtain the ceftolozane composition in FIG.
1; and
[0061] c) combining the ceftolozane composition with tazobactam
obtained in the absence of ceftolozane (e.g., by lyophilizing a
tazobactam solution comprising tazobactam acid and sodium
bicarbonate to obtain the Tazobactam Composition in FIG. 1).
[0062] In another embodiment of the pharmaceutical composition
provided herein, the composition is prepared by a method
comprising: [0063] a) combining ceftolozane and sodium chloride to
form a composition comprising ceftolozane and sodium chloride;
[0064] b) lyophilizing the ceftolozane and sodium chloride
composition in the absence of tazobactam; [0065] c) lyophilizing
the tazobactam in the absence of ceftolozane; and [0066] d)
combining the separately lyophilized ceftolozane and sodium
chloride mixture with the separately lyophilized tazobactam. In one
embodiment, the steps of combining the ceftolozane and sodium
chloride and lyophilizing the ceftolozane and sodium chloride
composition are performed in a dedicated production area. In
another embodiment, the step of lyophilizing the tazobactam is
performed in a dedicated production area.
[0067] In one aspect of the invention, an antibiotic pharmaceutical
composition is formulated for parenteral administration for the
treatment of infections. The composition has a therapeutically
effective amount of ceftolozane sulfate and tazobactam in a ratio
of 1,000 mg ceftolozane active per 500 mg of tazobactam active. The
pharmaceutical composition is obtained by a process comprising the
steps of lyophilizing a first aqueous solution in the absence of
tazobactam, wherein the first aqueous solution comprises
ceftolozane sulfate, 125 mg to 500 lyophilizing a first aqueous
solution in the absence of tazobactam, the first aqueous solution
comprising ceftolozane sulfate, to obtain a first lyophilized
ceftolozane composition, and blending the lyophilized ceftolozane
composition with a tazobactam composition comprising tazobactam
prepared and provided in the absence of ceftolozane. The process is
performed in the absence of other non-cephalosporin beta-lactam
compounds.
[0068] According to a first embodiment of the invention, the
pharmaceutical composition comprises an amount of ceftolozane
sulfate providing 2,000 mg of ceftolozane active and an amount of
tazobactam providing 1,000 mg of tazobactam acid. In another
embodiment, composition further comprises 125 mg-500 mg of sodium
chloride per 1,000 mg of ceftolozane active. In still another
embodiment, the composition of claim 1, manufactured in the absence
of any compound belonging to the following classes of beta-lactam
containing compounds: penicillins, penems, carbacephems, and
monobactams.
[0069] Another embodiment discloses combining ceftolozane with
tazobactam within a dedicated production area that does not
simultaneously house a cephalosporin other than ceftolozane, or any
compound selected from the group consisting of: penicillins,
penems, carbacephems, and monobactams. According to one embodiment,
the tazobactam composition is obtained by lyophilizing a second
solution in the absence of ceftolozane, and the second solution
comprises tazobactam to form a second lyophilized tazobactam
composition. The second solution may comprise tazobactam acid and
sodium bicarbonate. The pharmaceutical composition further
comprises 125 mg-500 mg of sodium chloride per 1,000 mg of
ceftolozane active. The ceftolozane and tazobactam are combined in
the absence of any compound belonging to the following classes of
beta-lactam containing compounds: penicillins, penems,
carbacephems, and monobactams.
[0070] In a further embodiment, a the unit dosage form is
formulated for parenteral administration for the treatment of
complicated intra-abdominal infections or complicated urinary tract
infections; and the pharmaceutical composition comprises an amount
of ceftolozane sulfate providing 1,000 mg of ceftolozane active and
an amount of tazobactam providing 500 mg of tazobactam acid.
[0071] According to still another embodiment, the pharmaceutical
composition in the unit dosage form is formulated for parenteral
administration for the treatment of pneumonia; and the
pharmaceutical composition comprises an amount of ceftolozane
sulfate providing 2,000 mg of ceftolozane active and an amount of
tazobactam providing 1,000 mg of tazobactam acid.
[0072] In one aspect of the invention, a method of manufacturing a
composition comprising ceftolozane and tazobactam comprises the
steps of receiving the ceftolozane and tazobactam at the dedicated
production area; filling a vial with a blend of the ceftolozane and
tazobactam; and sealing the vial.
[0073] In one aspect, antibiotic pharmaceutical compositions
comprising ceftolozane and tazobactam with less than about 0.15%,
0.10%, 0.05% or 0.03% by weight; or from 0.03-0.05%, 0.03-0.1% or
0.03-0.15% by HPLC of the compound of formula (III) are obtained by
a process comprising the steps of: (a) lyophilizing ceftolozane in
the absence of tazobactam to obtain a lyophilized ceftolozane
composition, and (b) blending the lyophilized ceftolozane
composition with a composition comprising tazobactam under
conditions suitable for attaining the aforementioned purity levels,
e.g., by blending with crystalline tazobactam or lyophilized
tazobactam.
[0074] In another aspect, antibiotic pharmaceutical compositions
comprising ceftolozane and tazobactam and less than about 0.15%,
0.10%, 0.05% or 0.03% by weight; or from 0.03-0.05%, 0.03-0.1% or
0.03-0.15% by HPLC of the compound of formula (III) are obtained by
a process comprising the steps of: (a) lyophilizing tazobactam in
the absence of ceftolozane to obtain a lyophilized tazobactam
composition, and (b) blending the lyophilized tazobactam
composition with a composition comprising ceftolozane (e.g.,
lyophilized ceftolozane sulfate).
[0075] In a third aspect, antibiotic pharmaceutical compositions
comprising ceftolozane and tazobactam and less than about 0.15%,
0.10%, 0.05% or 0.03% by weight; or from 0.03-0.05%, 0.03-0.1% or
0.03-0.15% by HPLC of the compound of formula (III) are obtained by
a process comprising the steps of: (a) lyophilizing tazobactam in
the absence of ceftolozane to obtain a lyophilized tazobactam
composition, (b) lyophilizing ceftolozane in the absence of
tazobactam to obtain a lyophilized ceftolozane composition, and (c)
blending the lyophilized tazobactam composition with the
lyophilized ceftolozane composition.
[0076] Other pharmaceutical antibiotic compositions can include
ceftolozane sulfate and the compound of formula (III). For example,
pharmaceutical compositions comprising up to 1% by weight (e.g.,
0.13%, 0.15%, 0.30%, 0.38%, 0.74% or 0.97%) of the compound of
formula (III) are herein. The pharmaceutical antibiotic
compositions can be provided in a unit dosage form (e.g., in a
vial). The unit dosage form can be dissolved with a
pharmaceutically acceptable carrier, and then intravenously
administered. The unit dosage form comprises 1000 mg of ceftolozane
active and 500 mg tazobactam, typically 1000 mg ceftolozane active
as ceftolozane sulfate and 500 mg of tazobactam active as
tazobactam sodium, argininate or free acid. The unit dosage forms
are commonly stored in vials.
[0077] According to one embodiment, the pharmaceutical composition
in a unit dosage form is formulated for parenteral administration
for the treatment of pneumonia. Citric acid can be included in an
aqueous ceftolozane solution that is lyophilized to obtain the
ceftolozane composition in an amount effective to prevent
discoloration of the product, due to its ability to chelate metal
ions. In one embodiment, the citric acid is anhydrous citric acid.
In another embodiment, the amount of the citric acid is 5-40 mg
anhydrous citric acid per 1000 mg of ceftolozane active (including,
e.g, 5-35 mg anhydrous citric acid per 1000 mg of ceftolozane,
about 21 mg anhydrous citric acid per 1000 mg of ceftolozane and
other ranges between 5-40 mg citric acid per 1,000 mg of
ceftolozane active).
[0078] An aqueous ceftolozane solution that is lyophilized to
obtain the ceftolozane composition can further comprise L-arginine,
in an amount effective to provide a pH of about 5-7, preferably
6-7, alone or in combination with citric acid and/or ceftolozane
sulfate. In one embodiment, the amount of the L-arginine is 450-750
mg L-arginine per 1000 mg of ceftolozane active, (including
intermediate ranges and values, e.g, 450-700 mg L-arginine per 1000
mg of ceftolozane active, 550-600 mg L-arginine per 1000 mg of
ceftolozane active, or about 587 mg L-arginine per 1000 mg of
ceftolozane active). In one specific embodiment, the amount of the
L-arginine is about 600 mg L-arginine per 1000 mg of ceftolozane
active.
[0079] In an embodiment, provided herein is a facility for
manufacturing a pharmaceutical composition formulated for
parenteral administration for the treatment of complicated
intra-abdominal infections or complicated urinary tract infections,
the pharmaceutical composition comprising ceftolozane sulfate and
tazobactam in a ratio of 1,000 mg ceftolozane active per 500 mg of
tazobactam active, the pharmaceutical composition obtained by a
process comprising the steps of (a) lyophilizing a first aqueous
solution in the absence of tazobactam, the first aqueous solution
comprising ceftolozane sulfate, 125 mg to 500 mg of sodium chloride
per 1,000 mg of ceftolozane active, to obtain a first lyophilized
ceftolozane composition, (b) lyophilizing a second solution
comprising tazobactam in the absence of ceftolozane to form a
second lyophilized tazobactam composition; and (c) blending the
first lyophilized ceftolozane composition and the second
lyophilized tazobactam composition to obtain the antibacterial
composition; wherein the process is performed in the absence of any
additional non-cephalosporin beta-lactam compounds.
EXAMPLES
Example 1
Manufacturing Process of a CXA-201 Composition Comprising
Tazobactam and CXA-101/Ceftolozane by Co-Lyophilization
[0080] The manufacturing process of a CXA-201 composition
comprising tazobactam and ceftolozane by co-lyophilization is shown
in FIG. 2. Non-sterile bulk tazobactam and bulk ceftolozane were
mixed, followed by dissolution and sterile filtration. The filtrate
was then tray-lyophilized to obtain the CXA-201 composition. The
CXA-201 composition can be vial-filled as a final drug product. The
components of a CXA-201 composition prepared by co-lyophilization
are shown in Table 1.
TABLE-US-00001 TABLE 1 Components of a CXA-201 Composition Prepared
by Co-lyophilization Component Function Amount (mg/vial)
ceftolozane Active pharmaceutical 1000 ingredient (potency)
L-arginine Alkalization reagent 587 Citric acid Buffer 21
(anhydrous) Sodium chloride Stabilizer 476 Tazobactam Active
pharmaceutical 500 (free acid) ingredient Sodium Alkalization
reagent Quantity sufficient.sup.1 bicarbonate for pH 4.8 to 7.0
water Dissolution solvent Not more than 4% by weight Nitrogen Inert
gas Sufficient quantity .sup.1Sodium content is approximately 78
mg/g of tazobactam in drug product after lyophilization.
.sup.2Water is removed during the lyophilization process and is
controlled at no more than 4% by weight.
Example 2
Assessment of Co-Lyophilized Combo Drug Product (i.e., a CXA-201
Composition)
A. Preparation of the Co-Lyophilized Combo Drug Product (i.e. the
CXA-201 Composition)
[0081] The components of the co-lyophilized CXA-201 composition are
shown in Table 2. This composition was prepared, as described above
in Example 1.
TABLE-US-00002 TABLE 2 Components of the CXA-201 Composition
Prepared by Co-Lyophilization CXA-201 16.3 g active ceftolozane
Composition 8.1 g active Tazobactam free ac. 15.5 g L-Arginine 350
mg Citric acid 7.9 g NaCl 6.1 pH compounded solution
B. Stressed Stability Test
[0082] Stability studies of this CXA-201 composition prepared by
co-lyophilization were carried out at 25.degree. C. and 40.degree.
C. The composition was analyzed using HPLC. The following Tables 3
and 4 are summaries of the HPLC measurements at time zero, after
one month (T1), and after three months (T2).
TABLE-US-00003 TABLE 3 Stability Data of Co-Lyophilized CXA-201
Composition at 25.degree. C./RH = 60% Test items Related Substances
Spec. D.P. T0 T1 25.degree. C. T2 25.degree. C. Peak1 .ltoreq.1.50%
0.31% 0.54% 0.71% Peak2 .ltoreq.0.40% 0.07% 0.07% 0.09% Peak3
.ltoreq.0.30% <0.03% <0.03% <0.03% Peak4 .ltoreq.0.80%
0.08% 0.08% 0.09% Peak5 .ltoreq.1.00% 0.27% 0.26% 0.29% Peak6
.ltoreq.0.15% <0.03% <0.03% <0.03% Peak7 .ltoreq.2.00%
0.64% 0.65% 0.66% Peak8 .ltoreq.0.15% <0.03% <0.03% <0.03%
Peak9 .ltoreq.0.60% 0.05% 0.11% 0.10% Peak10, 11 .ltoreq.0.15% each
0.04% 0.04% 0.04% Peak12 .ltoreq.2.00% <0.03% <0.03%
<0.03% Others (RRT 0.43) .ltoreq.0.15% <0.03% <0.03% 0.04%
Others (RRT 1.22) .ltoreq.0.15% 0.13% 0.30% 0.38% Others (RRT 2.18)
.ltoreq.0.15% 0.03% <0.03% 0.05% Others (RRT 2.77) .ltoreq.0.15%
<0.03% 0.03% 0.03% Sing. Unk. .ltoreq.0.15% 0.05% 0.07% 0.05%
Total .ltoreq.5.00% 1.67% 2.19% 2.77% pH report value 5.5 4.83
TABLE-US-00004 TABLE 4 Stability Data of Co-Lyophilized CXA-201
Composition at 40.degree. C./RH = 75% Test items Related Substances
Spec. D.P. T0 T1 40.degree. C. T2 40.degree. C. Peak1 .ltoreq.1.50%
0.31% 1.77% 2.22% Peak2 .ltoreq.0.40% 0.07% 0.10% 0.16% Peak3
.ltoreq.0.30% <0.03% <0.03% 0.06% Peak4 .ltoreq.0.80% 0.08%
0.09% 0.09% Peak5 .ltoreq.1.00% 0.27% 0.27% 0.30% Peak6
.ltoreq.0.15% <0.03% <0.03% <0.03% Peak7 .ltoreq.2.00%
0.64% 0.69% 0.78% Peak8 .ltoreq.0.15% <0.03% <0.03% 0.10%
Peak9 .ltoreq.0.60% 0.05% 0.09% 0.09% Peak10, 11 .ltoreq.0.15% each
0.04% 0.04% 0.05% Peak12 .ltoreq.2.00% <0.03% <0.03%
<0.03% Others (RRT 0.43) .ltoreq.0.15% <0.03% 0.09% 0.15%
Others (RRT 1.22) .ltoreq.0.15% 0.13% 0.74% 0.97% Others (RRT 2.18)
.ltoreq.0.15% 0.03% <0.03% 0.08% Others (RRT 2.77) .ltoreq.0.15%
<0.03% <0.03% 0.04% Sing. Unk. .ltoreq.0.15% 0.05% 0.11%
0.25% Total .ltoreq.5.00% 1.67% 4.49% 6.32% pH report value 5.5
4.09
C. Conclusion:
[0083] A new compound having RRT=1.22 was observed in the
co-lyophilized CXA-201 compositions. While not wishing to be bound
by theory, the compound RRT 1.22 was identified as a compound
formed by a reaction between ceftolozane and formylacetic acid,
which was a by-product of tazobactam as illustrated in Marunaka et
al. (Chem. Pharm. Bull. 1988, Vol. 36 (11), pp. 4478-4487). The
stability data at 25.degree. C. and at 40.degree. C. have confirmed
the continued formation of the compound RRT 1.22 over the course of
time.
Example 3
Manufacturing Process of a CXA-201 Composition (Comprising
Tazobactam and Ceftolozane) by Blending
A. Sterile Dry Blending of Bulk Lyophilized Ceftolozane and Bulk
Lyophilized Tazobactam
[0084] A low energy drum blender that agitates the material by
tumbling and also moving the bed up and down is used. A
representative process of blending is described as follows, also
shown in FIG. 1. The blender was charged with 23.4 kg of CXA-101
bulk product, and 5.4 kg of tazobactam bulk product. Both the
CXA-101 and tazobactam were individually lyophilized beforehand.
The material was blended for 180 minutes. In-process tests of
content assay for both CXA-101 and tazobactam were performed to
assess the homogeneity using the samples of blend materials taken
from three places. The relative standard deviation (RSD) for each
of CXA-101 and tazobactam content assay was no greater than 2% and
the RSD for the ratio of CXA-101/tazobactam was no greater than 2%
(See Table 5).
TABLE-US-00005 TABLE 5 In-Process Testing of Blending Samples of a
CXA-201 Composition at Three Places Acceptance Limits Results
(expected 60 120 180 Test value) Sampling minute minute minute
Content: 30.4%-37.2% 1 34.24 34.07 34.42 Ceftolozane.sup.1 2 34.62
34.21 34.66 3 34.71 34.60 34.85 Mean .sup.3 34.52 34.30 34.64 RSD %
0.72 0.80 0.63 Content: 15.2%-18.6% 1 17.96 18.20 17.12
Tazobactam.sup.2 2 16.90 18.26 16.51 3 17.27 16.93 17.02 Mean
.sup.3 17.38 17.80 16.89 RSD % 3.10 4.22 1.96 Ratio of 2.00.sup.4 1
1.91 1.87 2.01 Content (w/w) 2 2.05 1.87 2.10 ceftolozane/ 3 2.01
2.04 2.05 tazobactam Mean .sup.3 1.99 1.93 2.05 RSD % 3.69 5.12 2.2
RSD = relative standard deviation .sup.1Theoretical value: 33.96%
Acceptance limits are 90%-110% of the theoretical value.
.sup.2Theoretical value: 16.99% Acceptance limits are 90%-110% of
the theoretical value. .sup.3 Three samples are taken at each time
point at three places to measure the percentage by weight of
ceftolozane and tazobactam. The "Mean" is the average of the
percentages or the weight ratios of Ceftolozane/tazobactam.
.sup.4Acceptance limits were established based on batch
history.
B. Packaging into Sterbags.RTM. The blended powder is then
discharged into Sterbags.RTM..
C. Finished CXA-201 Drug Product
[0085] A fill and finish process is utilized for the final drug
product, which is a pharmaceutical composition comprising CXA-101
and tazobactam at a ratio of 1000 mg/500 mg. Glass vials are washed
with WFI and depyrogenated in a Class 100 depyrogenation tunnel at
a temperature of 320.degree. C. Pre-washed and pre-siliconized
stoppers are autoclaved for 40 minutes at 121.degree. C. The bulk
drug product is packaged in a Sterbag.RTM. system comprised of
three bags. The outer bag is cleaned with disinfectant in a Class
10,000 clean room. The bag system is placed in a pass-through UV
box where it is subjected to UV radiation (>20 .mu.W/cm.sup.2)
for 20 minutes to sterilize the surface of the outer bag. The outer
bag is removed and left in the UV box. The middle bag is placed in
a Class A laminar airflow (LAF) hood. The sterile middle bag is
removed under LAF. The sterile, bottle-shaped inner bag is then
placed in a sterile stainless steel carrier and attached to the
filling machine.
[0086] Sterile bulk CXA-101/tazobactam drug product is filled under
a nitrogen blanket into 30-mL, Type I clear glass vials. The
sterile drug product is gravity-fed into the filling machine under
LAF. Vial fill weights are periodically checked throughout the
filling operation to ensure proper operation of the filling line.
Filling and stoppering operations are performed under Class 100 LAF
conditions. Capping and vial washing are done in the Class 10,000
clean room.
Example 4
Assessment of Blend Combination Drug Product
A. Preparation of the Blend Combination Drug Product (CXA-201
Composition)
[0087] The blend drug product was prepared, as described above in
Example 3, on lab scale using a small blender. The components of
the blend composition are shown in Table 6.
TABLE-US-00006 TABLE 6 Components of the Blend Composition Quantity
as active Component Composition components CXA-201 CXA-101 for
Ceftolozane 10.8 g Composition Injection Bulk L-Arginine 6.7 g (25
g) Citric acid 233 mg Sodium chloride 5.2 g Tazobactam 5.4 g sodium
sterile (as Tazo Bulk (6 g) free acid)
B. Stressed Stability Test
[0088] Stability studies of this CXA-201 composition prepared by
the blending process were carried out at 25.degree. C. and
40.degree. C. The composition was analyzed by HPLC. The following
Tables 7 and 8 are summaries of the HPLC measurements at time zero,
after one month (T1), and after three months (T2).
TABLE-US-00007 TABLE 7 Stability Data of Blend CXA-201 Composition
at 25.degree. C./RH = 60% Test items Related Substances
Specifications T0 T1 25.degree. C. T2 25.degree. C. Peak1
.ltoreq.1.50% 0.61% 0.93% 1.08% Peak2 .ltoreq.0.40% <0.03%
<0.03% <0.03% Peak3 .ltoreq.0.30% <0.03% <0.03%
<0.03% Peak4 .ltoreq.0.80% 0.03% 0.03% 0.04% Peak5 .ltoreq.1.00%
0.09% 0.12% 0.13% Peak6 .ltoreq.0.15% <0.03% <0.03% <0.03%
Peak7 .ltoreq.2.00% 1.28% 1.34% 1.35% Peak8 .ltoreq.0.15% <0.03%
<0.03% <0.03% Peak9 .ltoreq.0.60% 0.03% <0.03% 0.03%
Peak10, 11 .ltoreq.0.30% <0.03% 0.04% 0.05% Sing. Unk.
.ltoreq.0.15% 0.13% 0.13% 0.14% Total .ltoreq.5.00% 2.49% 3.03%
3.28% Assay CXA-101 Teor. % = 32.6% 32.5% n.a. n.a. Assay Teor. % =
17.4% 18.2% n.a. n.a. Tazobactam Tazobactam .ltoreq.4.0% 0.07%
0.12% 0.14% Related Compound A K.F. .ltoreq.4.0% 2.6% n.a. n.a. pH
5.0-7.0 6.0 5.6 5.1
TABLE-US-00008 TABLE 8 Stability Data of Blend CXA-201 Composition
at 40.degree. C./RH = 75% Test items Related Substances
Specifications T0 T1 40.degree. C. T2 40.degree. C. Peak1
.ltoreq.1.50% 0.61% 1.66% 2.28% Peak2 .ltoreq.0.40% <0.03%
<0.03% <0.03% Peak3 .ltoreq.0.30% <0.03% <0.03% 0.04%
Peak4 .ltoreq.0.80% 0.03% 0.04% 0.05% Peak5 .ltoreq.1.00% 0.09%
0.13% 0.14% Peak6 .ltoreq.0.15% <0.03% <0.03% <0.03% Peak7
.ltoreq.2.00% 1.28% 1.41% 1.46% Peak8 .ltoreq.0.15% <0.03%
<0.03% <0.03% Peak9 .ltoreq.0.60% 0.03% <0.03% 0.03%
Peak10, 11 .ltoreq.0.30% <0.03% 0.08% 0.09% Sing. Unk.
.ltoreq.0.15% 0.13% 0.14% 0.13% Total .ltoreq.5.00% 2.49% 4.21%
5.27% Assay CXA-101 Teor. % = 32.6% 32.5% n.a. n.a. Assay Teor. % =
17.4% 18.2% n.a. n.a Tazobactam Tazobactam .ltoreq.4.0% 0.07% 0.35%
0.54% Related Compound A K.F. .ltoreq.4.0% 2.6% n.a. n.a. pH
5.0-7.0 6.0 5.0 4.4
C. Conclusion
[0089] The data at both 25.degree. C. and at 40.degree. C. have
shown that the blending process completely inhibits formation of
the compound RRT=1.22.
Example 5
Development and Implementation of a System to Prevent
Cross-Contamination in Accordance with FDA Guidance
[0090] A recently published (April 2013) Food and Drug
Administration Guidance for Industry Non-Penicillin Beta-Lactam
Drugs: A CGMP Framework for Preventing Cross-Contamination provides
direction on prevention of cross-contamination for facilities that
manufacture non-penicillin beta-lactam drugs. Provided herein are
steps for the development and implementation of a system to prevent
cross-contamination due to the introduction of both sterile
ceftolozane drug product intermediate and tazobactam sodium into a
facility that is in conformance with FDA Guidance.
[0091] Segregation steps to conform with FDA Guidance can include,
but are not limited to: [0092] Relocation all other drug products
to other sites [0093] Separating the ceftolozane/tazobactam product
filling line and the veterinary cephapirin product filling line
[0094] Creating separate HVAC systems [0095] Establishing separate
warehouse areas [0096] Formalizing separate material, waste and
personnel flows [0097] Constructing temporary facilities for
gowning and entrance to the line used for the
ceftolozane/tazobactam drug product. [0098] Constructing new walls,
modifying and reinforcing existing walls [0099] Equipping the
existing emergency egress with alarms and gaskets to completely
separate both lines throughout all the floors of the building
[0100] Creating the permanent separation of locker, rest and break
rooms for both lines of the facility: [0101] Dedicated maintenance
and operations personnel for each part of the facility including
different uniform colors for each part of the facility [0102]
Dedicated equipment and tools for each part of the facility [0103]
An Emergency Recovery plan
Example 6
Components of a CXA-201 Composition
[0104] An example of a batch formulae for ceftolozane composition
(compounding of ceftolozane substance with excipients such as
citric acid, sodium chloride, and L-arginine followed by sterile
lyophilization) is found below in Table 9.
TABLE-US-00009 TABLE 9 Batch Formula for Ceftolozane composition
Target Composition Amount per Batch (kg) Component mg/g 1 2
Ceftolozane Sulfate.sup.1) 172.1 114.0 202.6 Citric Acid, 3.2 2.1
3.7 Anhydrous, USP Sodium Chloride, USP 73.1 48.3 86.0 L-Arginine,
USP ~90 59.7 106.0 QS to achieve target pH .sup.2) Water for
Injection, QS to 1000 QS QS USP Total Batch Size 660 1175
.sup.1)Ceftolozane sulfate is charged based on its measured potency
to obtain 150 mg free base/g solution. .sup.2) L-arginine is added
as needed to obtain pH 6.5 .+-. 0.5 in the bulk solution; 90 mg per
gram solution is considered a representative amount.
[0105] An example of a batch formula for the ceftolozane/tazobactam
drug product is presented in Table 10 below.
TABLE-US-00010 TABLE 10 Batch Formula Ceftolozane/Tazobactam Drug
Product Amount per Amount per Component vial, mg Batch, kg
Ceftolozane 2255 112.8 composition.sup.1) Tazobactam.sup.2) 537
26.9 Nitrogen, NF.sup.3) -- -- Total 2792 139.7 Total Batch Size,
kg 139.7 Total Vial Quantity 50,000 .sup.1)The target fill for
ceftolozane is 1000 mg free base, added to the vial as the
composition. The amount 2255 mg is based on 100% theoretical
potency of the composition. Actual weight will vary based on
composition measured potency. .sup.2)The target fill for tazobactam
is 500 mg free acid, added to the vial as its sodium salt form. The
amount 537 mg is based on 100% theoretical potency. .sup.3)Nitrogen
is used as a processing aid to blanket vials after powder filling
and prior to insertion of stopper.
[0106] An example of the unit composition of ceftolozane/tazobactam
drug product for injection is presented in Table 11 below.
TABLE-US-00011 TABLE 11 Unit Compositions of Ceftolozane/Tazobactam
for Injection, 1000 mg/500 mg Nominal Composition Component
Function mg per Vial Ceftolozane Ceftolozane Active 1147
composition.sup.1) Sulfate Citric Acid, Chelating 21 Anhydrous
Agent Sodium Stabilizing 487 Chloride Agent L-Arginine Alkalizing
600.sup.2) Agent Q.S. for pH adjustment Tazobactam Sodium.sup.3)
Active 537 Nitrogen Processing Q.S. Aid.sup.4) Total Weight 2792
.sup.1)Actual amount of ceftolozane composition will vary based on
the measured potency. Ceftolozane sulfate, 1147 mg, corresponds to
1000 mg ceftolozane free base. .sup.2)L-arginine is added as needed
to achieve pH 6.5 .+-. 0.5; 600 mg per vial is considered a
representative total amount. .sup.3)Actual weight of tazobactam
sodium will vary based on the measured potency. Tazobactam sodium
537 mg, corresponds to 500 mg tazobactam free acid .sup.4)Nitrogen
blanket is applied after powders are dispensed to the vial and
prior to insertion of stopper.
Example 7
Physicochemical and Biological Properties Ceftolozane/Tazobactam
for Injection, 1000 mg/500 mg
[0107] As a product intended for intravenous use, several
properties are important for physiological compatibility. These
include particulate matter, sterility, endotoxin limit, pH, and
osmolality. Particulate matter and sterility are controlled at the
point of manufacture. The drug product is processed aseptically
throughout the entire manufacturing process, inclusive of
ceftolozane, tazobactam sodium, and ceftolozane/tazobactam in-vial
drug product.
[0108] The ceftolozane/tazobactam drug product is controlled to a
pH suitable for making an injectable product, e.g., 5-7, including
6-7, to provide physiological comfort, while still assuring
adequate stability for the drug substances. The ceftolozane drug
product intermediate is controlled during compounding to pH
6.5.+-.0.5 and is controlled at release to pH 5 to 7. The
tazobactam sodium is controlled at release to pH 5 to 7.
[0109] Ceftolozane/tazobactam following reconstitution with normal
saline and dilution for infusion also in normal saline (10 mg/mL
ceftolozane; 5 mg/mL tazobactam) is slightly hypertonic, with
osmolality approximately 500 mOsm/kg. However, slightly hypertonic
intravenous infusion solutions are not uncommon as drug products
are commonly prepared and diluted with already-isotonic solutions,
such as normal saline. The generally accepted maximum upper limit
for peripheral intravenous administration is approximately 900
mOsm/kg, though admixtures 600 to 900 mOsm/kg are typically
administered through a central line. Therefore, to be within the
limits of this range, the infusion product is less than 600
mOsm/kg.
Example 8
Excipients in Ceftolozane Drug Product Intermediate
[0110] The excipients in ceftolozane composition were chosen to
ensure stability and processability of the ceftolozane drug
substance into the drug product. The specific excipients, their
quantities and functions are provided in Table 12. All excipients
are compendial and typical for sterile pharmaceutical dosage forms,
requiring no additional treatment prior to use in the formulation.
The excipients are used in levels within the range established in
other FDA approved products as described in the Inactive
Ingredients Database (IID).
TABLE-US-00012 TABLE 12 Excipients Used in Ceftolozane composition
Inactive Concentration Ingredients Amount, in Infusion Rationale
for Database Component Function mg/Vial Solution, % Inclusion (IID)
Range Citric Chelating 21 0.02 Used to prevent 0.0025 to 50% acid
agent discoloration and degradation Sodium Stabilizing 487 0.49
Used as a 0.187 to 45% Chloride agent stabilizing agent for
ceftolozane sulfate L-arginine Alkalizing .sup. 600.sup.1) 0.60
Used to adjust 0.29 to 88% agent Q.S. for pH ceftolozane adjustment
solution pH .sup.1)L-arginine is added as needed to achieve pH 6.5
.+-. 0.5; 600 mg per vial is considered a representative total
amount.
Example 9
Analytical HPLC Method
[0111] Unless otherwise indicated, HPLC measurements reported
herein are obtained using a Develosil column ODS-UG-5; 5
micrometers; 250.times.4.6 mm, a mobile phase of sodium perchlorate
buffer solution (pH 2.5)/CH.sub.3CN 90:10 (v/v) at a 1.0 mL/min
flow rate and oven temperature of 45.degree. C.
A. Operative Conditions
TABLE-US-00013 [0112] Column Develosil ODS-UG-5; 5 .mu.m, 250
.times. 4.6 mm (Nomura Chemical, Japan) Mobile phase Sodium
Perchlorate Buffer Solution (PH 2.5)/CH.sub.3CN 90:10 (vlv) Flow
rate 1.0 mL/min Wavelength 254 nm Injection volume 10 .mu.L Oven
Temperature 45.degree. C. Run Time 85 minutes Gradient Profile:
Time (min) A % B % 0 75 25 30 70 30 60 0 100 85 0 100 85.1 75 25
110 75 25
B. Mobile Phase Preparation.
[0113] Sodium Perchlorate Buffer Solution was made by dissolving
14.05 g of sodium perchlorate Monohydrate in 1000.0 mL of water
followed by adjusting pH to 2.5 with diluted perchloric acid (1 in
20),
[0114] Mobile Phase was then made by mixing Sodium Perchlorate.
Buffer Solution (pH 2.5) and acetonitrile in the ratio 90:10
(v/v).
[0115] Sodium Acetate Buffer Solution pH 5.5 (Diluent) was made by
dissolving 1.36 g of sodium acetate trihydrate in 1000.0 mL of
water followed by adjusting to pH 5.5 with diluted acetic acid (1
in 10).
C. Sample Preparation.
[0116] Sample solution: dissolve 20.0 mg, exactly weighed, of
Sample, in 20.0 mL of water (Prepare just before injection into
HPLC system).
[0117] System Suitability Solution (1%): take 1.0 mL of the Sample
Solution (use first sample if more are present) and transfer into a
100.0 mL volumetric flask, dilute with water to volume and mix.
D. HPLC Analysis Procedure
[0118] 1. Inject Blank (water) 2. Inject System Suitability
Solution and check for tailing factor and theoretical plate number
for CXA-101 peak: [0119] The tailing factor must not be greater
than 1.5 [0120] Theoretical plates number must not be less than
10000
3. Inject Sample Solution
[0121] 4. Inject System Suitability Solution and check for tailing
factor and theoretical plate number for CXA-101 peak. [0122] The
tailing factor must not be greater than 1.5 [0123] Theoretical
plates number must not be less than 10000 5. Identify the peaks of
Related Substances in the Sample chromatogram based on the
reference chromatogram.
E. Calculations
[0124] I. Report for each related substance its amount as expressed
by area percent.
C i = A i .times. 100 A t + .SIGMA. A i ##EQU00001##
[0125] wherein:
[0126] C.sub.i=Amount of related substance i in the Sample, area
%
[0127] A.sub.i=Peak area of related substance i in the Sample
chromatogram
[0128] A.sub.t=Area of CXA-101 peak in the Sample chromatogram
[0129] A.sub.t+.SIGMA.A.sub.i=Total peaks area in the Sample
chromatogram
[0130] Consider as any Unspecified Impurity, each peak in the
chromatogram except CXA-101, peaks from 1 to 11 and every peak
present in the blank chromatogram and report the largest.
II. Report the total impurities content as expressed by the
following formula:
C T = A i .times. 100 A t + .SIGMA. A i ##EQU00002##
[0131] wherein:
[0132] C.sub.T=total impurities content in the Sample, area %
[0133] A.sub.t=area of CXA-101 peak in the sample chromatogram
[0134] .SIGMA. A.sub.i=total peak areas of impurities in the sample
chromatogram
* * * * *
References