CTD Open Cefoperazone

HARBIN PHARMACEUTICAL GROUP CO., LTD General Pharm.
Factory
THE COMMON TECHNICAL DOCUMENT 3.2.S FOR THE

REGISTRATION OF PHARMACEUTICALS FOR HUMAN USE:
Sterile Cefoperazone Sodium

Open part
HARBIN PHARMACEUTICAL GROUP CO., LTD.

General Pharma. Factory
11
20
2011
CTD Module 3.2.S for Sterile Cefoperazone Sodium

HARBIN PHARMACEUTICAL GROUP CO., LTD General Pharm. Factory
3.1
3.2
3.2.S
3.2.S.1
3.2.S.1.1
3.2.S.1.2
3.2.S.1.3
3.2.S.2
3.2.S.2.1
3.2.S.2.2
3.2.S.2.3
3.2.S.2.4
3.2.S.2.5
3.2.S.2.6
3.2.S.3
3.2.S.3.1
3.2.S.3.2
3.2.S.4
3.2.S.4.1
3.2.S.4.2
3.2.S.4.3
3.2.S.4.4
3.2.S.4.5
3.2.S.5
3.2.S.6
3.2.S.7
3.2.S.7.1
3.2.S.7.2
3.2.S.7.3
TABLE OF CONTENTS OF MODULE 3

BODY OF DATA
DRUG SUBSTANCE
General Information
Nomenclature
Structure
General Properties
Manufacture
Manufacturer(s)
Description of Manufacturing Process and Process Controls
Control of Materials
Control of Critical Steps and Intermediates
Process Validation and/or Evaluation
Manufacturing Process Development
Characterization
Elucidation of Structure and other Characteristics
Impurities
Control of Drug Substance
Specification
Analytical Procedures
Validation of Analytical Procedures
Batch Analyses
Justification of Specification
Reference Standards or Materials
Container Closure System
Stability
Stability Summary and Conclusions
Post-approval Stability Protocol and Stability Commitment
Stability Data

3.2
BODY OF DATA
3.2.S
DRUG SUBSTANCE
3.2.S.1 General Information

3.2.S.1.1 Nomenclature
General remark
This Drug Master File has been compiled to provide the necessary information for the evaluation
of suitability of the bulk substance of CEFOPERAZONE SODIUM manufactured by Harbin
Pharmaceutical Group CoLtd
It is used as active substance for medicinal products(dosage forms) which are blended with
sulbactam sodium generally. The structure of the document represents the section 3.2.S of the
module 3 of the Common Technical Document(CTD)Thusit is appropriate to be integrated in the
quality part of an application for marketing authorization
The content of this Active Substance Master File is property of Harbin Pharmaceutical Group Co
Ltd. and thereforeit is confidentialThis document should not be disclosed no matter if in whole
or in part Not any parties other than customers and government employees required for
regulatory purposes are authorized to have access to its content
The manufacture of cefoperazone sodium is performed according to the presented dossier and to
theGood Manufacturing Practice of the Peoples Republic of China.
On request of relevant authorities and customers the inspection regarding the manufacture of
cefoperazone sodium is possible
Cefoperazone sodium is an antibiotic compound of the third generation of cephaIosporins It
shows a high resistance against -lactamase And because sulbactam can strengthen the
antibacterial activity of it, cefoperazone sodium has been often blended with sulbactam sodium to
comply the requirements of customers.

The active ingredient is commonly known under the name

perazone sodium
Cefo
Cefoperazone
This term is used in the compendial title of the monograph of the European Pharmacopoeia
published in its current edition The cefoperazone sodium produced by Harbin Pharmaceutical
Group CoLtdNangang DistrictChina corresponds to the quality standard of this monograph
ChemicaI names
Sodium
Sodium(6R,7R)-7-[[(2R)-2-[[(4-ethyl-2,3-dioxopiperazin-1-yl)carbonyl]amino]-2-(4-hydroxyphenyl)
acetyl]amino]-3-[[(1-methyl-1H-tetrazol-5-yl)sulphanyl]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct2-ene-2-carboxylate.
(EP 6.0)
5-Thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid,
7-[[[[(4-ethyl-2,3-dioxo-1-piperazinyl)carbonyl]amino](4-hydroxyphenyl)acetyl]amino]-3-[[(1-methyl
-1H-tetrazol-5-yl)thio]methyl]-8-oxo-, monosodium salt, [6R-[6 ,7 (R*)]]-.
(USP 32)
Sodium
(6R,7R)-7-[(R)-2-(4-ethyl-2,3-dioxo-1-piperazinecarboxamido)-2-(p-hydroxyphenyl)acetamido-3-[[
(1-methyl-H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate
(USP 32)
CAS-Registry-Number
[62893-20-3]

3.2.S.1.2 Structure
The chemical structure of cefoperazone sodium is exhibited below.
perazone sodium
Cefo
Cefoperazone
Molecular formula
C25H26N9NaO8S2
Relative molecular mass
668

3.2.S.1.3 General Properties

Appearance
A white or slightly yellow powder
Hygroscopicity
Hygroscopic
pka-value
The pH of the solution is 4.5 to 6.5.
Infrared absorption spectrophotometry
Examine by infrared absorption spectrophotometry (2.2.24), comparing with the Ph. Eur. reference
spectrum of cefoperazone sodium.
Solubility
Freely soluble, in water, soluble in methanol, slightly soluble in alcohol.
Polymorphism
If crystalline, it shows polymorphism.

3.2.S.2 Manufacture

3.2.S.2.1 Manufacturer(s)
The name and address of the manufacturing site of the active ingredient manufacturer is:
HARBIN PHARMACEUTICAL GROUP CO., LTD. General Pharm. Factory
No. 109 Xuefu Road
Nangang Dist.
Harbin, Peoples Republic of China
Tel: 0086-0451-86665134
Fax: 0086-0451-86662959
E-mail: hpfinpex@public.hr.hl.cn

3.2.S.2.2 Description of Manufacturing Process and Process Controls

A. Synthetic route
Cefoperazone acid
Preparation of TZA
Dissolve of TZA
H2N
O
CH2 S
COOH
CH3
N
N
N N
H2N
BSA
CH3CN
CH3
N
N
CH2 S
N
COOSi(CH3)3 N N
Acyl chloride reaction

Acyl
Acylation
Acylation
O O
C2H5 N
O
N C NH CH COCl + H2N
O
CH3
N
N
CH2 S
N
COOSi(CH3)3 N N
S
OH

O O
C2H5 N
O
O H
N C NH CH C N
O
CH3
N
N
CH2 S
N
COOSi(CH3)3 N N
S
OH
hydrolysis
hydrolysis
O O
O
O H
N C NH CH C N
C2H5 N
CH3
N
N
CH2 S
N
COOSi(CH3)3 N N
S
OH
O O
C2H5 N
O
O H
N C NH CH C N
O
S
N
CH2 S
COOH
CH3
N
N
N N
OH
Cefoperazone Sodium
H2O


3.2.S.2.3 Control of Materials

In the following starting materials will be presented which are mentioned in the description of the
manufacturing process in section 3.2.S.2.2:

Acetonitrile
Molecular formula
formula:: CH 3CN
Molecular weight
weight:: 41.05

BF3-Acetonitrile
Molecular formula
formula:: C 2 H 3 N B F 3
Molecular weight
weight:: 109
Structure:

5-mercapto-1-methyltetrazole
Molecular formula
formula:: C2H4N4S
Molecular weight
weight:: 116.14
Structure:

7-ACA
Molecular formula
formula:: C 1 0 H 1 2 N 2 O 5 S
Molecular weight
weight:: 27 2 . 2 7
Structure:

Ammonia Water (refined)

Molecular formula: NH4OH or NH3 H2O
Molecular weight: 35.10

Acetone
Molecular formula
formula: C3H6O
Molecular weight
weight: 58.08
Structure
Structure:

6% sulfurous acid
Molecular formula
formula: H 2SO 3
Molecular weight
weight: 82.08

N,O-Bis(trimethylsilyl)acetamide (BSA)
Molecular formula
formula: C8H21NOSi2
Molecular weight
weight: 203.43
Structure
Structure:

Dimethylacetamide (DMAC)
Molecular formula
formula: CH 3 CON(CH 3 ) 2
Molecular weight
weight: 87.12
Structure
Structure:

Phosphorus oxychloride
Molecular formula
formula: POCl 3
Molecular weight
weight: 153.33

Active carbon #767

Molecular formula: C

Sodium Bicarbonate
Molecular formula: NaHCO3

3.2.S.2.4 Controls of Critical Steps and Intermediates

With reference to section 3.2.S.2.2 it is obvious from the description of the manufacturing
process that during this process cefoperazone acid, as an isolated intermediate, is
obtained. This cefoerazone acid is still nonsterile. For this reason a separate
inprocess control of the key intermediate cefoperazone acid takes place and the
analytical tests are described. The reasonable inprocess specification ensures that the
finished active substance meets the specification.
Preparation of TZA
Process
Control point
Specification
Treatment
Temperature
121
Control the
temperature
Assay of 7-ACA
after reaction.
< 2.0 mg/ml
pH
3.1 ~ 3.3
Control using
ammonia water
Temperature
91
Control the
temperature
Process
Control point
Specification
Treatment
Dissolve of TZA
Temperature
20 ~23
Control using hot

water
Acyl chloride
reaction
Temperature
-25 ~ -30
Control using liquid

nitrogen
Temperature
-302
Control using liquid

nitrogen
Assay of TZA after

acylation.
<2%
Assay of
Cefoperazone
side-chain acid < 3
mg/ml after
crystallization.
< 3.0 mg/ml
Condensation
reaction
Crystallization
Cefoperazone acid
Acylation
Crystallization

Cefoperazone Sodium
Process
Control point
Specification
Treatment
Forming
sodium
salt reaction
Temperature
20 ~ 25
pH
6.0 ~ 7.0
Control the temperature

using ethylene glycol in
mezzanine.
Adjust using NaHCO3
slowly.
Temperature
26 2
How long the acetone dropping
For 4.5 hours
Crystallization
Centrifugalization
and washing
Turns when transfer crystallization 600 50 rpm

solution
Turns when add washing solution
600 50 rpm
Turns when centrifugalization
900 300 rpm
Drying
Temperature
Water
60 2
Control the temperature

using ethylene glycol in
mezzanine.
Adjust
mins.
the
turns
per
Hot water circulation

Evacuate during drying

3.2.S.2.5 Process Validation and/or Evaluation

Documentation on process validation is given in the Restricted Part of the Active
Substance Master File and is submitted directly to registration authorities on request.

3.2.S.2.6 Manufacturing Process Development

Not applicable.

3.2.S.3 Characterization

3.2.S.3.1 Elucidation of Structure and other Characteristics

Chemical structure analysis of Cefoperazone sodium
I. Name of compound
Drug name (English): Cefoperazone Sodium
Chemical name (English):
Sodium
(6R,7R)-3-[[(1-methyl-H-tetrazol-5-yl)thio]methyl]-7-[(R)-2-(4-ethyl-2,3-dioxo-1-piperazinecarboxa
mido)-2-(phydroxy phenyl)acetamido]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-carboxylate
II. Molecular formula and molecular weight and chemical structure formula
Molecular formula: C25H26N9NaO8S2
Structure formula:
III. Ultravilet absorption spectrum

Apparatus:Cary 1E violet-visible spectrophotometer,America
Conditions:With 10g/ml and 12g/ml of test solution concentration respectively and 190-600nm
of scanning width.
1. Ultraviolet absorption spectrum
a.Ultraviolet absorption spectrum of RS
b.Ultraviolet absorption spectrum of test sample
2.Ultraviolet absorption spectrum data of reference standard
For methanol solution,1=200, 2=229,3=269
3. Ultraviolet absorption spectrum data of test sample

For methanol solution,1=200, 2=229,3=269

4.Conclusion: There exists -* and n-* band absorption in UV,which shows that the
compound contains the structure replacing the phenyl and carbonyl.
IV.Elements analysis
Apparatus model:EA 1112E element analyzer,Flash company,Italia.
Test condition:Left oven temperature of reactor:950 C;Right oven temperature of reactor:
22C;Gas:High purity He and O2;Chromatographic column temperature: 75C.
Test data list of test sample:
Theoretical value
C%
H%
N%
S%
Test value
44.97
3.93
18.88
9.61
Test I
Test II
Test III
43.37
4.27
18.76
9.23
43.41
4.33
18.72
9.41
43.39
4.30
18.74
9.32
V. Infrared absorption spectrum(IR)

Apparatus model:FTS-135 Fourier transform infrared spectrometer,BIO-RAD company,America.
Test condition:Adopt KBr pellet method
1.Infrared spectrogram
a. Infrared spectrogram of RS
b.Infrared spectrum of test sample
2. Infrared spectrum test data table of test sample

Note:strength:
vs:
extremely strong,s:strong,m:medium,w:weak

3. IR Spectrum analysis
a.Wide and strong absorption centered at ~3400cm-1 is originated from OH stretching
vibration;Strong absorption entrapped in low wave number side of 1610 cm-1 and 1514cm-1 is
originated from benzene ring vibration(Vring);The OH changing angular vibration at 1365cm-1 and
C-O stretching vibration at 1174cm-1 is originated from phenol;The absorption at 841cm-1 is
originated from outside changing angular viabration of C-H
exists
b.Wide
side.All these data show that there
structure in the molecule.

and
strong
absorption
at
cm-1
3287
is
originated
from
NH
stretching
vibration(vNH);1680cm-1 is originated from amid I band;Absorption entrapped in 1514cm-1 is

originated from absorption on amid II band;Amid III band is at 1282cm-1 ;806cm-1 and 753cm-1 is
originated separately from amid V band and IV band;576cm-1 is originated from amid VI
band.Appearance of all these bands is connective with the amid structure
c.Stretching virbration with high wave number C=O(vC=O) appearing at 1762 cm-1 is
characterization of
structure.
d.1716cm-1 and 1670cm-1 (entrapped in the low wave number side of

originated from stretching vibration of two carbonyls in
that characteristic vibration of CH2-CH2- appears at
1610 cm-1)is separatedly
structure ,together considering

753cm-1
and CH stretching vibration
(vas CH2)of CH2 at 2940cm-1 and changing angular vibration of CH2 at 1463cm-1 ,all these prove
that
there exists
e.Addtionally,absorption
1514cm-1
,1365cm-1

band
at
,1282cm-1
1610cm-1
involves
and 1109cm-1
N=N
stretching
is originated from stretching vibration of
ring,showing that there exists this structure in the molecule.697cm-1
can be classified as C-S stretching vibration,which is consistent with

structure
vibration,while
and 618cm-1
CH2-S- and
f.Absorption about at 1540cm-1
entrapped in the high frequency side of 1514cm-1
js

antisymmetry
stretching vibration of carboxylic radical COO-(vas COO-).Together with the
symmetry stretching vibration(vas COO-)at 1392cm-1 ,all these prove there exists carboxylic
radical conjugating with C=C in the molecule.
g.IR spectrum of the test sample is consistent with that of the reference standard.
VI.1H NMR
Apparatus: Unity-400 nuclear magnetic resonance spectrometer,Varian,America.
Solvent:Deuterated
dimethyl
sulfoxide
DMSO-d6
standard
reference
displacement:TMS=0.00;heavy water(D2O),reference displacementD20=4.7

i. One-dimensional 1H NMR test
1. One-dimensional 1H NMR test
a. 1H NMR spectrum of reference standard
b. Heavy water exchange 1H NMR spectrogram of reference standard
c. 1H NMR spectrum of test sample
d. Heavy water exchange 1H NMR spectrogram of test sample
2. 1H NMR test data table of test sample
Serial no. of Chemical shift Multiplicity
peak
1
9.93
bs
2
9.72
d
3
9.30
d
4
7.20
d
5
6.74
d
6
5.56
dd
7
5.51
d
8
4.87
d
9
4.41
d
10
4.21
d
11
3.91
s
12
3.71-3.32
m
13
1.08
t
Coupling
constant(Hz)
6.8
8.0
7.8
8.0
6.8,4.4
7.2
4.4
12.0
12.0
7.2
Proton
number
1
1
1
2
2
1
1
1
1
1
3
8
3
Corresponding
proton
-OH
>NH
>CH
=CH=CH>CH>CH>CH-CH2-CH2-CH3
-CH2-CH3
ii. Two-dimensional 1H-1H correlated NMR test(1H-1H COSY)

1.Two-dimensional 1H-1H correlated
NMR spectrogram of reference standard
2. Two-dimensional 1H-1H correlated
NMR spectrogram of test sample
3. Two-dimensional 1H-1H correlated
NMR test data table of test sample
Serial no.
Chemical shift
Correlated peak shift Crossing peak intensity

1
9.72
5.51
2
9.30
5.56
3
7.20
6.74
4
6.74
7.20
5
5.56
9.30
6
5.51
9.72
7
4.41
4.21
8
4.21
4.41
9
3.37
1.08
10
1.08
3.37
iii. Proton NMR spectrum analysis of test sample
m
w
s
s
w
m
s
s
s
s
1. For 26 protons observed in the 1H NMR spectrum of DMSO-d6 solvent of this product,three
groups of peak at low field
will disappear in heavy water,the other peak will become
apparently and part of them have shifted.
The amount and type of hydrogen atom of
wider
the
test sample is consistent with that of the chemical structural formula of Cefoperazone sodium.
2. 9.72 and9.30 at low field is separately weakly coupled with5.51 and5.53 in COSY
spectrum,with the coupling constant separately being 6.8Hz and 8.0Hz,but they will disappear
in the heavy water spectrum.Obviously,the two above-mentioned peaks belong to NH3,which
shows that there exist NHCH structure in this compound.
3. Both7.20 and6.74 belong to d desintegration,and JHH equals to 8Hz.Both peaks correspond
to 2 protons,which produce strong coupling information in COSY spectrum and belong to para
substitution benzene proton contribution.
4. 1.08
at
high
field
corresponds
to
proton
disintegration,which produces coupling information
contribution,and
belongs
to
triple
with 3.37 in COSY spectrum and
belongs to CH3 proton contribution.All these show that there exist CH2CH3 structure. 3.91 is
a single peak and its signal strength corresponds to 3 proton resonance,which falls within
lowest field and belongs to NCH3 proton contribution.
5. Two groups of peaks of 4.41 and4.21 constitute d disintegration with same coupling
constant,which produce strong coupling information in COSY spectrum.The two groups of
peaks constitute quadri peaks which show high inside and low outside,and is represented as
typical AB self-rotating system.
6.
H NMR spectrum of the test sample is consistent with that of the reference standard.
VII.13C NMR
Apparatus: Unity-400 nuclear magnetic resonance spectrometer

Solvent:Deuterated water(D2O), reference standard:DMSO=39.5

i. One-dimensional 13C NMR test
1. One-dimensional 13C NMR test
a.13C NNE NMR spectrum of reference standard
b. 13C DEPT NMR spectrum of reference standard
c. 13C NNE NMR spectrum of test sample
d. 13C DEPT NMR spectrum of test sample
2.13C NMR test data table of test sample
Serial no. of
peak
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
Chemical shift
Multiplicity
Amount of C
Correponding type of C
171.28
166.53
163.25
159.03
155.78
155.67
153.04
151.94
129.81
127.85
126.68
117.62
115.04
57.84
57.03
56.60
42.34
39.70
35.47
33.14
25.70
10.44
s
s
s
s
s
s
s
s
s
d
s
s
d
d
d
d
t
t
t
q
t
q
1
1
1
1
1
1
1
1
1
2
1
1
2
1
1
1
2
1
1
1
1
1
>C=O
=C<
>C=O
>C=O
>C=O
>C=O
>C=O
=C<
=C<
=CH=C<
=C<
=CH>CH>CH>CH-CH2-CH2-CH2-CH3
-CH2-CH3
ii. Two-dimensional 13C-1H HETCOR
1Two-dimensional 13C-1H heteronuclear correlated NMR spectrogram of test sample

2Two-dimensional 13C-1H correlated NMR test data table of test sample
Serial no.
1
2
3
Chemical shift
127.85
115.04
57.84
Correlated peak shift

7.20
6.74
5.56
Crossing peak intensity

s
s
w

4
57.03
5.51
5
56.60
4.87
6
42.34
3.64
7
39.70
3.40
8
35.47
4.41,4.21
9
33.14
3.91
10
25.70
3.37
11
10.44
1.08
13
iii. C NMR spectrum analysis of test sample
1. 22 spectral lines are observed from
13
w
m
m
w
w
s
m
s
NMR spectrum depending on the relative strength of
spectrum peak,among which three spectral lines all correspond to two proton carbon
contribution.Therefore,This product contain
25 carbon atoms,including two methyl carbons,
five -CH3 ,seven quaternary carbons and eleven tertiary carbons,which is consistent with the
amount and type of carbon atoms of chemical structural formula of Cefoperazone sodium.
2.Both 127.85 and115.04 peak in the aromatic carbon district represent contribution of two
proton aromatic carbons respectively. 115.04 displace to high field as result of the shielding
effect of the ortho-oxigen substituent.Therefore,both peaks belong to resonance absorption
signal of proton carbon of oxygen para orientation benzene,which proves that there exists
structure in this compound.
3. 9.30 is coupled with5.56 in 1H-1H COSY spectrum ,while5.56 is relative with4.87,and the
carbon chemical shift connecting with5.56 and4.87 fall within57.84 and 56.60.The two
above mentioned peaks and CH2 of 25.70 and
alkene carbon peak of 129.81 and 117.62,together with the 163.25 at low field,all these
prove that there exist a joint-heterocycle
structure
of
in this
cephalosporin compound.
4. 42.34 belongs is overlapping peak
and has a relative wide peak form,which belong to CH2
contribution and fall within nitrogen-carbon district,so this compound constitue a NCH2CH2N
structure. 42.34 is methyl carbon and has a comparative
big chemical shift value.The proton
peak also fall within lower field 3.91,which belong to NCH3 methyl carbon contribution.
5.There are totally 8 spectrum peak with chemical shift value exceeding150.00 in the low field of
13
C NMR spectrum,and all them belong to tertiary carbon contribution.According to the


chemical shift theory,this test sample belong to
multicarbonyl compounds.
6. 13C NMR spectrum of the test sample is consistent with that of the reference standard.
VIII. 23Na NMR
Apparatus: Unity-400 nuclear magnetic resonance spectrometer
Solvent:Deuterated water(D2O), reference standard:NaCl=0.00
1.
23
Na NMR test
a. 23Na NMR spectrogram of reference standard

b. 23Na NMR spectrogram of test sample
2.Test data of
23
Na NMR
Reference standard:-2.13,test sample: -2.09

IX. Complete structure attribution of Cefoperazone sodium
1. Chemical structural formula of skeleton atom identification number
2. Chemical structure-Complete attributiton of NMR spectrum

Serial no.
1
2
3
4
5
6
7
8
9
10
11
12
Chemical shift of Correlated peak shift

13C
Of 1H
171.28
166.53
163.25
159.03
155.78
155.67
153.04
151.94
129.81
127.85
7.20
126.68
117.62
Structure
number
20
15
4
11
38
39
24
31
8
29,33
28
7
identification

13
115.04
14
57.84
15
57.03
16
56.60
17
42.34
18
39.70
19
35.47
20
33.14
21
25.70
22
10.44
X. Mass spectrum
6.74
5.56
5.51
4.87
3.64
3.40
4.41,4.21
3.91
3.37
1.08
30,32
5
22
2
35,36
41
13
26
6
42
Apparatus:LCQ Electro-Spray Mass Spectrometry

Conditions:LCQ electro-spraying ion source;spraying voltage: 4.5KV;atomization vapor is Nitrogen
gas N2;the temperature of Metal capillary tube is
2000C;dissolved in methanol;sample injection
by flow injection pump

1. Mass spectrum of Cefoperazone sodium
a. LCQ positive ion electro-spraying mass spectrum of reference standard
b. LCQ positive ion electro-spraying mass spectrum of test sample
2. Mass spectrum test data of test sample(EI-MS data)
m/z
relative abundance(%)
690
100
574
21
548
25
432
32
3. Lytic pathway

4. MS spectrum analysis
a. m/z690 peak in the positive ion electro-spraying mass spectrum is a quasi-molecular ion peak
[M+Na]+peak of the test sample with 667 of molecular weight.
b. m/z548 peak is a fragment peak which is obtained after the quasi-molecule ion peak lost
,and m/z574 peak is a fragment peak which is obtained after the quasi-molecular
ion peak lost
c. m/z432 peak is a fragment peak which is obtained after m/z 432 peak lost
m/z432 peak is a fragment peak after m/z548 lost
,and
d.From the MS spectrogram,quasi-molecular ion peak and breaking rule of this sample is proved

to be consistent with the reference standard,so this product is Cefoperazone sodium.

XI. TGA test
Apparatus model:TGA 7,PE company
Test conditions:20~750C,raising temperature at 10 C/min of rate.
1. TGA of reference standard
a.TGA graph
b.Break under 204.7C
2. TGA of test sample
a.TGA graph
b.Break under 206.8C
3. TGA of test sample is consistent with that of reference standard
XII. X-ray diffraction test
Apparatus model: D/max-IIB- X-ray diffractometer
Test conditions:CuKa radiation source;operating voltage:40Kv;working current:20mA
1.X-ray diffraction test
a.X-ray diffractogram of reference standard
b.X-ray diffractogram of test sample
2. For 20 data sheet,see the attached graph.
3. Test data of X-ray diffraction test show that the crystal form of the test sample is consitent with
that of the reference standard.
XIII. Analysis summarization
1. m/z690 peak in the positive ion electro-spraying mass spectrum of Cefoperazone sodium is a
quasi-molecular ion peak [M+Na]+peak,the molecular weight of this compound is 667. From the
MS spectrogram,quasi-molecular ion peak and breaking rule of this sample is proved to be
consistent with the reference standard,so this product is Cefoperazone sodium.
2. For 26 protons observed in the 1H NMR spectrum of DMSO-d6 solvent of this product,three
groups of peak at low field
will disappear in heavy water,the other peak will become
apparently and part of them have shifted. 22 spectral lines are observed from
13
wider
NMR
spectrum depending on the relative strength of spectrum peak,among which three spectral lines
all correspond to two proton carbon contribution.Therefore,This product contain
25 carbon

atoms,including two methyl carbons,
five -CH3 ,seven quaternary carbons and eleven tertiary
carbons.From the proton spectrum and
13
C NMR spectrum,the amount and type of proton and
carbon of this product is consistent with chemical structural formula of Cefoperazone sodium.
3. 1716cm-1 and 1670cm-1 (entrapped in the low wave number side of
1610 cm-1)in the IR
spectrum is separatedly originated from stretching vibration of two carbonyls in

structure,together considering that characteristic vibration of CH2-CH2- appears at
753cm-1
and CH stretching vibration (vas CH2)of CH2 at 2940cm-1 and changing angular vibration of CH2
at 1463cm-1 ,all these prove that
there exists
4.. 1.08 at high field of 1H NMR corresponds to 3 proton contribution,and belongs to triple
disintegration,which produces coupling information
with 3.37 in COSY spectrum and belong
to CH3 proton contribution.All these show that there exist CH2CH3 structure. 3.91 is a single
peak and its signal strength corresponds to 3 proton resonance,which falls within lowest field,all
these prove that there exist NCH3.
5. Stretching virbration with high wave number C=O(vC=O) appearing at 1762 cm-1 in the IR
spectrum is characterization of
structure. 397cm-1 and 618cm-1 can be summarized as
stretching vibration and 9.30 is coupled with 5.56 in the COSY spectrum ,while5.56 is
relative with 4.87,and the carbon chemical shift connecting with5.56 and4.87 fall
within57.84 and 56.60.The two above mentioned peaks and CH2 of 25.70 and alkene
carbon peak of 129.81 and 117.62,together with the 163.25 at low field,all these prove that
there exist a joint-heterocycle structure of
in this cephalosporin compound.
6. There are totally 8 spectrum peak with chemical shift value exceeding150.00 in the low field of
13
C NMR spectrum,and all them belong to tertiary carbon contribution.According to the chemical
shift theory,this test sample belong to
multicarbonyl compounds.
7. Wide and strong absorption centered at ~3400cm-1 in the IR spectrum is originated from OH
stretching vibration;Strong absorption entrapped in low wave number side of 1610 cm-1 and
1514cm-1 is originated from benzene ring vibration(Vring);The OH changing angular vibration at

1365cm-1 and C-O stretching vibration at 1174cm-1 is originated from phenol;The absorption at
841cm-1 is originated from outside changing angular viabration of C-H
and115.04 peak in the aromatic carbon district in the
13
side. Both 127.85
C NMR spectrum
represent
contribution of two proton aromatic carbons respectively. 115.04 displace to high field as result
of the shielding effect of the ortho-oxigen substituent.Therefore,both peaks belong to resonance
absorption signal of proton carbon of oxygen para orientation benzene,which proves that there
exists
structure
8. Summarizing from all spectrum,the chemical structure of the test sample is consistent with that
of the reference standard.

3.2.S.3.2 Impurities
According to Ph.Eur.5.0
Related substances.
Examine by liquid chromatography (2.2.29) as prescribed under Assay. Inject 20 l of reference
solution (b) and adjust the sensitivity of the system so that the height of the principal peak in the
chromatogram obtained is at least 50 per cent of the full scale of the recorder. Inject 20 l of test
solution (b). Continue the chromatography for at least 2.5 times the retention time of the principal
peak. In the chromatogram obtained with test solution (b): the area of any peak, apart from the
principal peak, is not greater than 1.5 times the area of the principal peak in the chromatogram
obtained with reference solution (b) (1.5 per cent); the sum of the areas of any such peaks is not
greater than 4.5 times the area of the principal peak in the chromatogram obtained with reference
solution (b) (4.5 per cent). Disregard any peak with an area less than 0.1 times the area of the
principal peak in the chromatogram obtained with reference solution (b).
A.
(5aR,6R)-6-[[(2R)-2-[[(4-ethyl-2,3-dioxopiperazin-1-yl)carbonyl]amino]-2-(4-hydroxyphenyl)acetyl]
amino]-5a,6-dihydro-3H,7H-azeto[2,1-b]furo[3,4-d][1,3]thiazine-1,7(4H)-dione,
B.
(6R,7R)-7-[[(2R)-2-[[(4-ethyl-2,3-dioxopiperazin-1-yl)carbonyl]amino]-2-(4-hydroxyphenyl)acetyl]a
mino]-3-[(4-methyl-5-thioxo-4,5-dihydro-1H-tetrazol-1-yl)methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]o
ct-2-ene-2-carboxylic acid,

C. 1-methyl-1H-tetrazole-5-thiol,
D.
(6R,7R)-7-amino-8-oxo-3-[(1H-1,2,3-triazol-4-ylsulphanyl)methyl]-5-thia-1-azabicyclo[4.2.0]oct-2ene-2-carboxylic acid (7-TACA),
E. (6R,7R)-3-[(acetyloxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic
acid (7-ACA),

F.
(6R,7S)-7-[[(2R)-2-[[(4-ethyl-2,3-dioxopiperazine-1-yl)carbonyl]amino]-2-(4-hydroxyphenyl)acetyl]
amino]-3-[[(1-methyl-1H-tetrazol-5-yl)sulphanyl]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene2-carboxylic acid.

Residual solvents
In the course of manufacture of the active substance cefoperazone sodium acetone is used which
are mentioned in the monograph of the European Pharmacopoeia.
The solvent is mentioned and classified in the following table:
Solvent
Class
Acceptance limit according to

Ph. Eur. 5.0
Acetone
III
n. m. t. 2.0%
For description of the method and for validation results please refer to section 3.2.S.4.

Agents transmitting spongiform encephalopathies

With reference to the general chapter 5.2.8 of the European Pharmacopoeia "Minimising the Risk
of Transmitting Animal Spongiform Encephalopathy Agents via Medicinal Products" HARBIN
Pharmaceutical Group & Co., Ltd. confirms that during the manufacturing steps no starting
materials, solvents or fermentation media of animal origin are used.

3.2.S.4 Control of Drug Substance

3.2.S.4.1 Specification
In the following the release specification for the active pharmaceutical ingredient cefoperazone
sodium produced by Harbin Pharmaceutical Group Co., Ltd. is given.
The parameters to be investigated as well as the defined acceptance criteria are in full compliance
with the requirements of the monograph cefoperazone sodium (1404) published in the currently
valid edition of the European Pharmacopoeia.

Product Specification
perazone sodium (European Pharmacopoeia 6.0
Cefo
Cefoperazone
6.0))
Manufacturer: HARBIN Pharmaceutical Group Co., Ltd. General Pharma, Factory
Test
Specification
Pharmacopoeial reference
Appearance
white or slightly yellow, hygroscopic powder.
Ph.Eur.6.0
Solubility
freely soluble in water, soluble in methanol,slightly

soluble in ethanol (96 per cent).
Ph.Eur.6.0
Identification
A. Infrared absorption spectrophotometry

B. Examine the chromatograms obtained in the
assay.
C. It gives reaction (a) of sodium
Ph.Eur.6.0 (2.2.24).
Ph.Eur.6.0
Appearance of solution
The solution is clear (2.2.1) and its absorbance

(2.2.25) at 430 nm is not greater than 0.15.
Ph.Eur.6.0 (2.2.25)
pH
4.5 to 6.5
Ph.Eur.6.0 (2.2.3)
Related substances
Any peak 1.5%

The sum of the impurities peak 4.5%
Ph.Eur.6.0 (2.2.29)
Ph.Eur.6.0 (2.2.29)
Acetone
2.0%
Ph.Eur.6.0 (2.4.24, System B)
Heavy metals
5 ppm
Ph.Eur.6.0 (2.4.8)
Water
5.0 percent, determined on 0.200 g.
Ph.Eur.6.0 (2.5.12)
Bacterial endotoxin
<0.20EU/mg
Ph.Eur.6.0 (2.6.14)
Assay
95.0 to 102.0% (anhydrous substance).
Ph.Eur.6.0 (2.2.29).
Ph.Eur.6.0 (2.3.1).

3.2.S.4.2 Analytical Procedures

perazone sodium (EP 6.0-0
1/
2008:1404
Cefo
Cefoperazone
6.0-01/
1/2008:1404
2008:1404))
DEFINITION
Sodium(6R,7R)-7-[[(2R)-2-[[(4-ethyl-2,3-dioxopiperazin-1-yl)carbonyl]amino]-2-(4-hydroxyphenyl)
acetyl]amino]-3-[[(1-methyl-1H-tetrazol-5-yl)sulphanyl]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct2-ene-2-carboxylate
Semi-synthetic product derived from a fermentation product.
Content : 95.0 per cent to 102.0 per cent (anhydrous substance).
CHARACTERS
Appearance: white or slightly yellow, hygroscopic powder.
Solubility : freely soluble in water, soluble in methanol,slightly soluble in ethanol (96 per cent).
If crystalline, it shows polymorphism (5.9).
IDENTIFICATION
A. Infrared absorption spectrophotometry (2.2.24).
Preparation: dissolve the substance to be examined in methanol R and evaporate to dryness.
Examine the residue.
Comparison: Ph. Eur. reference spectrum of cefoperazone sodium.
B. Examine the chromatograms obtained in the assay.
Results: the principal peak in the chromatogram obtained with test solution (a) is similar in
retention time and size to the principal peak in the chromatogram obtained with reference solution
(a).
C. It gives reaction (a) of sodium (2.3.1).
TESTS
solution. The solution is clear (2.2.1) and its absorbance (2.2.25) at 430 nm is not
greater than 0.15.
Dissolve 2.5 g in water R and dilute to 25.0 ml with the same solvent.
pH (2.2.3) : 4.5 to 6.5.
Dissolve 2.5 g in carbon dioxide-free water R and dilute to 10 ml with the same solvent.
Related substances
substances. Liquid chromatography (2.2.29).Prepare the solutions immediately before
use.
Test solution (a). Dissolve 25.0 mg of the substance to be examined in the mobile phase and
dilute to 250.0 ml with the mobile phase.
Test solution (b). Dissolve 25.0 mg of the substance to be examined in the mobile phase and

Reference solution (a). Dissolve 25.0 mg of cefoperazone dihydrate CRS in the mobile phase and
Reference solution (b). Dilute 5.0 ml of reference solution (a) to 100.0 ml with the mobile phase.
Column:
size: l = 0.15 m, = 4.6 mm;
stationary phase: end-capped octadecylsilyl silica gel for chromatography R (5 m).
Mobile phase: mix 884 volumes of water R, 110 volumes of acetonitrile R, 3.5 volumes of a 60 g/l
solution of acetic acid R and 2.5 volumes of a triethylammonium acetate solution prepared as
follows : dilute 14 ml of triethylamine R and 5.7 ml of glacial acetic acid R to 100 ml with water R.
Flow rate: 1ml/min.
Detection: spectrophotometer at 254 nm.
Injection: 20 l of test solution (b) and reference solutions (a) and (b).
Run time: 2.5 times the retention time of cefoperazone.
Retention time: cefoperazone = about 15 min.
System suitability : reference solution (a) :
number of theoretical plates : minimum 5000, calculated for the principal peak; if necessary,
adjust the content of acetonitrile R in the mobile phase;
symmetry factor: maximum 1.6 for the principal peak; if necessary, adjust the content of
acetonitrile R in the mobile phase.
Limits:
any impurity : for each impurity, not more than 1.5 times the area of the principal peak in the
chromatogram obtained with reference solution (b) (1.5 per cent) ;
total : 4.5 times the area of the principal peak in the chromatogram obtained with reference
solution (b) (4.5 per cent) ;
disregard limit : 0.1 times the area of the principal peak in the chromatogram obtained with
reference solution (b) (0.1 per cent).
Acetone (2.4.24, System B) : maximum 2.0 per cent.
Sample solution: Dissolve 0.500 g of the substance to be examined in water R and dilute to 10.0
ml with the same solvent.
Solvent solution: Dissolve 0.350 g of acetone R in water R and dilute to 100.0 ml with the same
solvent. Dilute 10.0 ml of this solution to 100.0 ml with water R.
Prepare each of 4 injection vials as shown in the table below:

Static head-space conditions which may be used:

equilibration time: 15min;
transfer-line temperature: 110 C.
Temperature:
Column: 40 C for 10min.
Heavy metals (2.4.8) : maximum 5 ppm.
2.0 g complies with test C. Prepare the reference solution using 1 ml of lead standard solution (10
ppm Pb) R.
Water (2.5.12) : maximum 5.0 per cent, determined on 0.200 g.
Bacterial endotoxins (2.6.14) : less than 0.20 IU/mg, if intended for use in the manufacture of
parenteral dosage forms without a further appropriate procedure for the removal of bacterial
endotoxins.
ASSAY
Liquid chromatography (2.2.29) as described in the test for related substances with the following
modifications.
Injection: test solution (a) and reference solution (a).
System suitability : reference solution (a) :
repeatability : maximum relative standard deviation of 1.0 per cent after 6 injections.
Calculate the percentage content of cefoperazone sodium by multiplying the percentage content
of cefoperazone by 1.034.
STORAGE
In an airtight container, protected from light, at a temperature of 2 C to 8 C. If the substance is
sterile, store
in a sterile, airtight, tamper-proof container.
IMPURITIES

A.(5aR,6R)-6-[[(2R)-2-[[(4-ethyl-2,3-dioxopiperazin-1-yl)-carbonyl]amino]-2-(4-hydroxyphenyl)acet
yl]amino]-5a,6-dihydro-3H,7H-azeto[2,1-b]furo[3,4-d][1,3]thiazine-1,7(4H)-dione,
B.(6R,7R)-7-[[(2R)-2-[[(4-ethyl-2,3-dioxopiperazin-1-yl)-carbonyl]amino]-2-(4-hydroxyphenyl)acety
l]amino]-3-[(4-methyl-5-thioxo-4,5-dihydro-1H-tetrazol-1-yl)methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]
oct-2-ene-2-carboxylic acid,
C. 1-methyl-1H-tetrazole-5-thiol,

D.(6R,7R)-7-amino-8-oxo-3-[(1H-1,2,3-triazol-4-ylsulphanyl)methyl]-5-thia-1-azabicyclo[4.2.0]oct2-ene-2-carboxylic acid (7-TACA),
E. (6R,7R)-3-[(acetyloxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic
acid (7-ACA),
F.(6R,7S)-7-[[(2R)-2-[[(4-ethyl-2,3-dioxopiperazine-1-yl)-carbonyl]amino]-2-(4-hydroxyphenyl)acet
yl]amino]-3-[[(1-methyl-1H-tetrazol-5-yl)sulphanyl]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en
e-2-carboxylic acid.

3.2.S.4.3. Validation of Analytical Procedures

This document has to demonstrate that all analytical procedures used in characterisation of the
active substance are suitable for their intended purpose.
As mentioned in section 3.2.S.4.2 the analytical methods applied in the course of release testing
of the active substance are those described in the monograph cefoperazone sodium (1404) of the
currently valid edition of the European Pharmacopoeia. These methods are followed without any
deviation. It is generally agreed and accepted that the analytical procedures published in the
known pharmacopoeias such as European Pharmacopoeia (EP) comply with the requirements for
validation of analytical methods as laid down in the Note for Guidance on Validation of Analytical
Procedures: Methodology (CPMP/ICH/281/95). For this reason additional validation studies to be
performed by the manufacturer of the active substance are not required.

3.2.S.4.4 Batch Analyses

In order to demonstrate that the produced batches of cefoperazone sodium are in full compliance
with the demands of the release specification certificates of analysis of the finished product tested
according to the analytical procedures of section 3.2.S.4.2 are given on the following pages.

Harbin Pharmaceutical Group Co., Ltd. General Pharm. Factory

Certificate of Analysis
Product name
Cefoperazone sodium
Manufacturer
HPGC-GPF
Batch No.
050522380
Manufacturing date
2005-05-22
Packing
5Kgs/drum
Testing date
2005-05-23
Batch size
100.000Kg
Reporting date
2005-06-07
Reference
Ph.Eur.5.0
Re-test date
May 2008
Parameter
Acceptance criteria
Results
CHARACTERS
Characters
Solubility in
water
methanol
alcohol
A white or slightly yellow powder, A white crystalline powder

hygroscopic.
Meet the requirements.
Freely soluble
Soluble
Slightly soluble
IDENTIFICATION
Cefoperazone sodium
CRS
The spectrum of the

substance to be examined
and of a qualified reference
substance are comparable
Meet the requirement.
Cefoperazone dihydrate
CRS
The retention time and size of the Meet the requirement.

principal peak in
the chromatogram obtained with test
solution (a) are
approximately the same as those of
the
principal
peak
in
the
chromatogram
obtained
with
reference solution (a).
Sodium
Positive
Appearance of
solution
(conc. 10 %)
Clear, absorbance at
430 nm not greater than
0.15
<0.15
pH-value
4.5-6.5
5.5
Related substances
Any impurity peak, apart from the

principal peak, is not greater than
1.5 ;
Sum of the any impurity peak is not
greater than 4.5 %.
0.28%
TESTS
0.74%

Acetone
Not more than 2.0 per cent
1.36%
Heavy metal
Not more than 5ppm
5ppm
Water
Not more than 5.0%
3.79%
Bacterial endotoxins
Less than 0.20 IU/mg,
95.0%-102.0%
97.1%
Assay
Content of cefoperazone
sodium
Reported by
Rechecked by
QC manager
Wang Caiyan
Zhang Baiwen
Han Dongmei


Product name
Cefoperazone sodium
Manufacturer
HPGC-GPF
Batch No.
050530383
Manufacturing date
2005-05-30
Packing
5Kgs/drum
Testing date
2005-06-01
Batch size
100.000Kg
Reporting date
2005-06-16
Reference
Ph.Eur.5.0
Re-test date
May 2008
Parameter
Acceptance criteria
Results
CHARACTERS
Characters
Solubility in
water
methanol
alcohol

hygroscopic.
Freely soluble
Soluble
Slightly soluble
IDENTIFICATION
Cefoperazone sodium
CRS
The spectrum of the

CRS

principal peak in
solution (a) are
the
principal
peak
in
the
chromatogram
obtained
with
Sodium
Positive
Appearance of
solution
(conc. 10 %)
0.15
<0.15
pH-value
4.5-6.5
5.2
Related substances

1.5 ;
greater than 4.5 %.
0.74%
TESTS
1.1%

Acetone
1.30%
Heavy metal
Not more than 5ppm
5ppm
Water
Not more than 5.0%
3.38%
95.0%-102.0%
97.7%
Assay
sodium
Reported by
Rechecked by
QC manager
Wang Caiyan
Zhang Baiwen
Han Dongmei


Product name
Cefoperazone sodium
Manufacturer
HPGC-GPF
Batch No.
050530387
Manufacturing date
2005-05-30
Packing
5Kgs/drum
Testing date
2005-06-01
Batch size
100.000Kg
Reporting date
2005-06-16
Reference
Ph.Eur.5.0
Re-test date
May 2008
Parameter
Acceptance criteria
Results
CHARACTERS
Characters
Solubility in
water
methanol
alcohol

hygroscopic.
Freely soluble
Soluble
Slightly soluble
IDENTIFICATION
Cefoperazone sodium
CRS
The spectrum of the

CRS

principal peak in
solution (a) are
the
principal
peak
in
the
chromatogram
obtained
with
Sodium
Positive
Appearance of
solution
(conc. 10 %)
0.15
<0.15
pH-value
4.5-6.5
5.2
Related substances

1.5 ;
greater than 4.5 %.
0.46%
TESTS
0.82%

Acetone
1.40%
Heavy metal
Not more than 5ppm
5ppm
Water
Not more than 5.0%
3.30%
95.0%-102.0%
98.3%
Assay
sodium
Reported by
Rechecked by
QC manager
Wang Caiyan
Zhang Baiwen
Han Dongmei

3.2.S.4.5 Justification of Specification

The release specification implemented in section 3.2.S.4.1 of this documentation consists of the
test parameters defined in the currently valid monograph of cefoperazone sodium published in the
European Pharmacopoeia.

3.2.S.5
Reference Standards or Materials
The primary reference standard used in the mentioned in the monograph cefoperazone sodium
release investigation of cefoperazone sodium (1404) is given in the European Pharmacopoeia.
In case of the active ingredient cefoperazone dihydrate CRS is used as reference standard.
The substance is purchased from the European Directorate for the Quality of Medicines (EDQM)
in Strasbourg, France.
The reference substances are stored in a dry and cool place protected from light and moisture.

3.2.S.6 Container Closure System

The European Pharmacopoeia has defined in its monograph cefoperazone sodium (1404) a
recommendation for storage which says:
Storage:
In an airtight container, protected from light, at a temperature of 2 C to 8 C. If the substance is
sterile, store in a sterile, airtight, tamper-proof container.
Labeling
The label states, where applicable, that the substance is free from bacterial endotoxins.
The primary packaging material used by Harbin Pharmaceutical Group Co., Ltd, fulfils the
pharmacopoeial requirements and is described hereafter. The medicinal aluminium bottles are
used in pre-sterilized status.

1. Aluminum drum drawing

drawing::
2. Medicinal aluminum barrel specification

pecification::
Unit: mm
Dimension
Type
Basal size
Limit deviation
d1
230
1.00
d2
154
0.60
d3
140
0.40
h1
380
3.00
h2
0.40
h3
25
--------
d4
149
1.00
d5
135
0.20
h4
17
0.50
d6
155
h5
13
0.50
d7
134
0.50
d8
150
0.50
d9
129.5
0.50
d10
118
1.00
h6
18
0.30
h7
0.10
15L
Size
Barrel body
Inner cap
Outer cap
0.30
-0.20

3.2.S.7 Stability

3.2.S.7.1 Stability Summary and Conclusions

In order to demonstrate stability of the active pharmaceutical ingredient, Harbin Pharmaceutical
Group Co.,Ltd has initiated a stability program with cefoperazone sodium which is in accordance
with the Note for Guidance on Stability Testing: Stability of Existing Active Substances and Related
Finished Products (CPMP/QWP/122/02).
The stability study has been designed in accordance with the requirements of the Note for
Guidance mentioned above.
The storage conditions were set as follows:
Long-term stability testing
Temperature:
62
Relative humidity:
60%5%
Accelerated stability testing
Temperature:
252
Relative humidity:
75%5%
Three representative production scale batches for each of both storage conditions have been
selected to take part in the stability study of the active substance.
All batches have been produced in full compliance with the manufacturing procedure described in
section 3.2.S.2 of this documentation.
The key-information on the batches investigated according to the condition of long-term and
accelerated stability testing is summarized in the following table.
Batch no.
Date of
manufacture
Date of sampling
Sample Size
Batch Size
020510232
May 10, 2002
May 12, 2002
400 vials
(approx.1.5g/vial)
200.0kg
020511233
May 11, 2002
May 12, 2002
400 vials
(approx.1.5g/vial)
200.0kg
020512234
May 12, 2002
May 12, 2002
400 vials
(approx.1.5g/vial)
200.0kg

As pre-sterilized aluminium bottles of suitable size for the stability samples are not commercially
available Harbin Pharmaceutical Group Co.,Ltd. Has decided to use pre-sterilized glass vials (5ml
and 10ml volume) closed with a butyl-rubber stopper fixed with an aluminium cap. The vials were
placed in an upright position in the climatic chambers in order to prevent artificial effects due to a
contact of the active substance with the rubber stopper. Glass containers are considered as
suitable to serve as a substitute for the aluminium containers actually used for shipment since both
materials are considered to provide a high level of chemical inertness.
The determination of the quality of the active substance during the stability study was performed
using the analytical methods of the European Pharmacopoeia valid at the respective time of
investigation.
The specification applied in the stability study is in accordance with that exhibited in section
3.2.S.4.1 of this documentation.
The test schedule for long-term stability testing at the condition of 62 and 60%5% rel.
humidity is exhibited in the following table:
Test points
Batch no.
020510232
020511233
020512234
Initial test
3 months
6 months
9 months
12 months
18 months
24 months
36 months
Corresponding to this table the test schedule for accelerated stability testing at 252 and
75%5% relative humidity is exhibited in the following table:
Test points
Batch no.
020510232
020511233
020512234
Initial test
30 days
60 days
90 days
120 days
150 days
180 days

The stability results are summarized in tabular form in chapter 3.2.S.7.3. The data reveal that the
substance is in full compliance with the demands of the release specification under any condition
at every time point. On this basis Harbin Pharmaceutical Group Co.,Ltd. Has defined a re-test
period of 36 months for this active substance.

3.2.S.7.2 Post-approval Stability Protocol and Stability Commitment

As in the course of initial stability testing 3 production scale batches for long-term and accelerated
conditions have been investigated. Any further stability studies are not required unless any
significant change in manufacture, primary packaging material or quality specification takes place.

3.2.S.7.3 Stability Data

In the following the parameters which were investigated at long-term stability testing and
accelerated stability testing are given in tabular form their respective specifications.
Parameter
Acceptance criteria
CHARACTERS
Characters
A white or slightly yellow powder, hygroscopic.
IDENTIFICATION
Cefoperazone sodium
CRS
The IR spectrum of the substance to be examined and

of a qualified reference substance are comparable
CRS
The retention time and size of the principal peak in

the chromatogram obtained with test solution (a) are
approximately the same as those of the principal peak
in the chromatogram obtained with reference solution
(a).
Sodium
Positive
TESTS
Appearance of solution (conc. 10 %)
Clear, absorbance at 430 nm not greater than 0.15
pH-value
4.5-6.5
Related substances
Any impurity peak, apart from the principal peak, is

not greater than 1.5 ;
Sum of the any impurity peak is not greater than 4.5
%.
Water
Not more than 5.0%
Less than 0.20 IU/mg
Assay
Content of cefoperazone sodium
95.0%-102.0%

Stability Report

Stability report (Long-term Stability Testing)

Storage conditions: 62/60%5% Relative humidity
Batch number: 020510232
Date of manufacture: May 10, 2002
Batch size: 200.0kg
Date of sampling: May 12, 2002
Primary packaging material: rubber stoppered glass vial (upright position)
Number of samples: 200 vials
Months
Items
Initial
3 months
6 months
9 months
12 months
18 months
24 months
36 months
Characters
White
White
White
White
White
White
Slightly yellow
Slightly
yellow
Meet
the
requirements.
Meet
the
requirements.
Meet
the
requirements.
Meet
the
requirements.
Meet
the
requirements.
Meet
the
requirements.
Meet
the
requirements.
Meet
the
requirements
.
Clear, <0.15
Clear, <0.15
Clear, <0.15
Clear, <0.15
Clear, <0.15
Clear, <0.15
Clear, <0.15
Clear, <0.15
5.2
5.3
5.3
5.2
5.4
5.4
5.3
5.3
Related substances
Any peak
Sum
0.48%
0.82%
0.48%
0.85%
0.46%
0.85%
0.49%
0.83%
0.43%
0.82%
0.48%
0.80%
0.47%
0.80%
0.48%
0.81%
Water
3.30%
3.32%
3.32%
3.35%
3.33%
3.30%
3.30%
3.31%
Less than 0.20

IU/mg
Less than 0.20

IU/mg
Less than 0.20

IU/mg
Less than 0.20

IU/mg
Less than 0.20

IU/mg
Less than 0.20

IU/mg
Less than 0.20

IU/mg
Less
than
0.20 IU/mg
98.2%
98.9%
98.6%
98.0%
97.7%
97.9%
97.2%
97.2%
Identification
Appearance of
solution
pH
Bacterial endotoxin
Assay


Batch size: 200.0kg
s
Month
Months
Items
Initial
3 months
6 months
9 months
12 months
18 months
24 months
36 months
Characters
White
White
White
White
White
White
Slightly yellow
Slightly yellow
Meet
the
requirements
.
Meet
the
requirements
.
Meet
the
requirements
.
Meet
the
requirements
.
Meet
the
requirements
.
Meet
the
requirements
.
Meet
the
requirements.
Meet
the
requirements.
Clear, <0.15
Clear, <0.15
Clear, <0.15
Clear, <0.15
Clear, <0.15
Clear, <0.15
Clear, <0.15
Clear, <0.15
5.2
5.3
5.3
5.2
5.4
5.4
5.3
5.3
Related substances
Any peak
Sum
0.48%
0.82%
0.48%
0.85%
0.46%
0.85%
0.49%
0.83%
0.43%
0.82%
0.48%
0.80%
0.47%
0.80%
0.48%
0.81%
Water
3.30%
3.32%
3.32%
3.35%
3.33%
3.30%
3.30%
3.31%
Less
than
0.20 IU/mg
Less
than
0.20 IU/mg
Less
than
0.20 IU/mg
Less
than
0.20 IU/mg
Less
than
0.20 IU/mg
Less
than
0.20 IU/mg
Less than 0.20

IU/mg
Less than 0.20

IU/mg
98.2%
98.9%
98.6%
98.0%
97.7%
97.9%
97.2%
97.2%
Identification
Appearance of
solution
pH
Bacterial endotoxin
Assay


Batch size: 200.0kg
s
Month
Months
Items
Initial
3 months
6 months
9 months
12 months
18 months
24 months
36 months
Characters
White
White
White
White
White
White
Slightly yellow
Slightly yellow
Meet
the
requirements
.
Meet
the
requirements
.
Meet
the
requirements
.
Meet
the
requirements
.
Meet
the
requirements
.
Meet
the
requirements
.
Meet
the
requirements.
Meet
the
requirements.
Clear, <0.15
Clear, <0.15
Clear, <0.15
Clear, <0.15
Clear, <0.15
Clear, <0.15
Clear, <0.15
Clear, <0.15
5.2
5.3
5.3
5.2
5.4
5.4
5.3
5.3
Related substances
Any peak
Sum
0.48%
0.82%
0.48%
0.85%
0.46%
0.85%
0.49%
0.83%
0.43%
0.82%
0.48%
0.80%
0.47%
0.80%
0.48%
0.81%
Water
3.30%
3.32%
3.32%
3.35%
3.33%
3.30%
3.30%
3.31%
Less
than
0.20 IU/mg
Less
than
0.20 IU/mg
Less
than
0.20 IU/mg
Less
than
0.20 IU/mg
Less
than
0.20 IU/mg
Less
than
0.20 IU/mg
Less than 0.20

IU/mg
Less than 0.20

IU/mg
98.2%
98.9%
98.6%
98.0%
97.7%
97.9%
97.2%
97.2%
Identification
Appearance of
solution
pH
Bacterial endotoxin
Assay

Stability report (Accelerated Stability Testing)

Batch size: 200.0kg
s
Month
Months
Items
Initial
1 months
2 months
3 months
4 months
5 months
6 months
Characters
White
White
White
White
White
White
Slightly yellow
Meet
the
requirements
.
Meet
the
requirements.
Meet
the
requirements
.
Meet
the
requirements.
Meet
the
requirements.
Meet
the
requirements.
Meet
the
requirements.
Clear, <0.15
Clear, <0.15
Clear, <0.15
Clear, <0.15
Clear, <0.15
Clear, <0.15
Clear, <0.15
5.2
5.3
5.3
5.2
5.4
5.4
5.3
Related substances
Any peak
Sum
0.48%
0.82%
0.48%
0.85%
0.46%
0.85%
0.49%
0.83%
0.43%
0.82%
0.48%
0.80%
0.47%
0.80%
Water
3.30%
3.32%
3.32%
3.35%
3.33%
3.30%
3.30%
Less
than
0.20 IU/mg
Less than 0.20

IU/mg
Less
than
0.20 IU/mg
Less than 0.20

IU/mg
Less than 0.20

IU/mg
Less than 0.20

IU/mg
Less than 0.20

IU/mg
98.2%
98.9%
98.6%
98.0%
97.7%
97.9%
97.2%
Identification
pH
Bacterial endotoxin
Assay


Batch size: 200.0kg
s
Month
Months
Items
1 months
2 months
3 months
4 months
5 months
6 months
White
White
White
White
White
White
Slightly yellow
Meet
the
requirements
.
Meet
the
requirements.
Meet
the
requirements
.
Meet
the
requirements.
Meet
the
requirements.
Meet
the
requirements.
Meet
the
requirements.
Clear, <0.15
Clear, <0.15
Clear, <0.15
Clear, <0.15
Clear, <0.15
Clear, <0.15
Clear, <0.15
5.2
5.3
5.3
5.2
5.4
5.4
5.3
Related substances
Any peak
Sum
0.48%
0.82%
0.48%
0.85%
0.46%
0.85%
0.49%
0.83%
0.43%
0.82%
0.48%
0.80%
0.47%
0.80%
Water
3.30%
3.32%
3.32%
3.35%
3.33%
3.30%
3.30%
Less
than
0.20 IU/mg
Less than 0.20

IU/mg
Less
than
0.20 IU/mg
Less than 0.20

IU/mg
Less than 0.20

IU/mg
Less than 0.20

IU/mg
Less than 0.20

IU/mg
98.2%
98.9%
98.6%
98.0%
97.7%
97.9%
97.2%
Characters
Identification
pH
Bacterial endotoxin
Assay
Initial


Batch size: 200.0kg
s
Month
Months
Items
Initial
1 months
2 months
3 months
4 months
5 months
6 months
Characters
White
White
White
White
White
White
Slightly yellow
Meet
the
requirements
.
Meet
the
requirements.
Meet
the
requirements
.
Meet
the
requirements.
Meet
the
requirements.
Meet
the
requirements.
Meet
the
requirements.
Clear, <0.15
Clear, <0.15
Clear, <0.15
Clear, <0.15
Clear, <0.15
Clear, <0.15
Clear, <0.15
5.2
5.3
5.3
5.2
5.4
5.4
5.3
Related substances
Any peak
Sum
0.48%
0.82%
0.48%
0.85%
0.46%
0.85%
0.49%
0.83%
0.43%
0.82%
0.48%
0.80%
0.47%
0.80%
Water
3.30%
3.32%
3.32%
3.35%
3.33%
3.30%
3.30%
Less
than
0.20 IU/mg
Less than 0.20

IU/mg
Less
than
0.20 IU/mg
Less than 0.20

IU/mg
Less than 0.20

IU/mg
Less than 0.20

IU/mg
Less than 0.20

IU/mg
98.2%
98.9%
98.6%
98.0%
97.7%
97.9%
97.2%
Identification
pH
Bacterial endotoxin
Assay

Conclusion
As shown in the test result, Cefoperazone Sodium meets the requirements defined in the monographs of
Cefoperazone Sodium in EP for 6 months of the accelerated stability testing conditions of temperature of
25 2 and humidity of 75 5RH, and 36 months in the storage conditions of temperature 6 2
and humidity 60 5RH.
In this respect we think in advance that Cefoperazone Sodium is capable of keeping a quality not
exceeding the requirements for 3 years re-test period under the designed storage conditions and
packing conditions such as temperature of 2-8, protecting from light and sterile airtight, tamper-proof
pure aluminum container.

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HARBIN PHARMACEUTICAL GROUP CO., LTD General Pharm.

THE COMMON TECHNICAL DOCUMENT 3.2.S FOR THE

Sterile Cefoperazone Sodium

HARBIN PHARMACEUTICAL GROUP CO., LTD.

CTD Module 3.2.S for Sterile Cefoperazone Sodium

TABLE OF CONTENTS OF MODULE 3

CTD Module 3.2.S for Sterile Cefoperazone Sodium

CTD Module 3.2.S for Sterile Cefoperazone Sodium

CTD Module 3.2.S for Sterile Cefoperazone Sodium

The active ingredient is commonly known under the name

CTD Module 3.2.S for Sterile Cefoperazone Sodium

CTD Module 3.2.S for Sterile Cefoperazone Sodium

3.2.S.1.3 General Properties

CTD Module 3.2.S for Sterile Cefoperazone Sodium

CTD Module 3.2.S for Sterile Cefoperazone Sodium

CTD Module 3.2.S for Sterile Cefoperazone Sodium

3.2.S.2.2 Description of Manufacturing Process and Process Controls

Acyl chloride reaction

CTD Module 3.2.S for Sterile Cefoperazone Sodium

CTD Module 3.2.S for Sterile Cefoperazone Sodium

CTD Module 3.2.S for Sterile Cefoperazone Sodium

3.2.S.2.3 Control of Materials

CTD Module 3.2.S for Sterile Cefoperazone Sodium

CTD Module 3.2.S for Sterile Cefoperazone Sodium

CTD Module 3.2.S for Sterile Cefoperazone Sodium

CTD Module 3.2.S for Sterile Cefoperazone Sodium

CTD Module 3.2.S for Sterile Cefoperazone Sodium

Ammonia Water (refined)

CTD Module 3.2.S for Sterile Cefoperazone Sodium

CTD Module 3.2.S for Sterile Cefoperazone Sodium

CTD Module 3.2.S for Sterile Cefoperazone Sodium

CTD Module 3.2.S for Sterile Cefoperazone Sodium

CTD Module 3.2.S for Sterile Cefoperazone Sodium

CTD Module 3.2.S for Sterile Cefoperazone Sodium

Active carbon #767

CTD Module 3.2.S for Sterile Cefoperazone Sodium

CTD Module 3.2.S for Sterile Cefoperazone Sodium

3.2.S.2.4 Controls of Critical Steps and Intermediates

< 2.0 mg/ml

Control using hot

Control using liquid

Control using liquid

Assay of TZA after

< 3.0 mg/ml

CTD Module 3.2.S for Sterile Cefoperazone Sodium

Control the temperature

How long the acetone dropping

For 4.5 hours

Turns when transfer crystallization 600 50 rpm

CTD Module 3.2.S for Sterile Cefoperazone Sodium

Control the temperature

Hot water circulation

3.2.S.2.5 Process Validation and/or Evaluation

CTD Module 3.2.S for Sterile Cefoperazone Sodium

3.2.S.2.6 Manufacturing Process Development

CTD Module 3.2.S for Sterile Cefoperazone Sodium

CTD Module 3.2.S for Sterile Cefoperazone Sodium

3.2.S.3.1 Elucidation of Structure and other Characteristics

III. Ultravilet absorption spectrum

For methanol solution,1=200, 2=229,3=269

V. Infrared absorption spectrum(IR)

2. Infrared spectrum test data table of test sample

CTD Module 3.2.S for Sterile Cefoperazone Sodium