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APPLICANT’S PART
(OPEN PART)
APPLICANT’S PART
MODULE-3: QUALITY
MARCH, 2014
TABLE OF CONTENTS
APPLICANT’S PART
MODULE-3: QUALITY
MARCH, 2014
TABLE OF CONTENTS
SECTION CONTENTS
ANNEX-I Analytical method validation report and chromatograms of Related
Substances by HPLC
ANNEX-II Analytical method validation report and chromatograms of Assay by
HPLC
ANNEX-III Analytical method validation report and chromatograms of Residual
Solvents by GC
ANNEX-IV Analytical method validation report and chromatograms of Forced
Degradation Study
ii
3.2.S DRUG SUBSTANCE
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3.2 BODY OF DATA
3.2.S DRUG SUBSTANCE
3.2.S.1.1 NOMENCLATURE
3.2.S.1.1.1 Recommended International Nonproprietary Name (rINN)
Amlodipine besilate
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3.2.S.1 GENERAL INFORMATION
3.2.S.1.2 STRUCTURE
3.2.S.1.2.1 Structural Formula:
H
H3C N NH2
O
O O CH3 SO3H
H 3C .
O H O
Cl
and enantiomer
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3.2.S.1 GENERAL INFORMATION
3.2.S.1.3.2 Solubility
Slightly soluble in water, freely soluble in methanol, sparingly soluble in ethanol,
slightly soluble in 2-propanol
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3.2.S.2 MANUFACTURE
3.2.S.2.1 MANUFACTURER
NAME AND ADDRESS OF MANUFACTURER
Please send all correspondence to the manufacturer’s address mentioned below.
CADILA PHARMACEUTICALS LTD.,
294, G.I.D.C. Industrial Estate,
Ankleshwar - 393 002,
Gujarat, INDIA.
Tel. No.: +91 -2646 -252626, 251519
Fax No.: +91 -2646 -250051
Contact Person: Mr. Rangaraju Kakarlapudi
Vice President - Quality
E-mail: k.rangaraju@cadilapharma.co.in
Note: All steps of the manufacturing process (i.e. chemical synthesis, purification,
analysis and packaging) are carried out at this manufacturing site.
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3.2.S.2 MANUFACTURE
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3.2.S.2 MANUFACTURE
ROUTE OF SYNTHESIS
O
NCH 2 CH 2OH O
NaH
O
+ Cl CH 2 C CH 2 COOC 2 H5
O
O
O
Ethyl-4-[ 2-(phthalimido)ethoxy] acetoacetate (PHEMAA)
M.W. 319
CHO O
NH2 O
Cl
O
o- Chloro benzaldehyde Methyl-3-amino crotonate Ethyl-4-[ 2-(phthalimido)ethoxy] acetoacetate (PHEMAA)
M.W. 140. 5 M.W. 115 M.W. 319
H
H 3C N N
O
O O CH3 O
H 3C
H
O O
Cl
Phthaloyl amlodipine
M.W. 537
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3.2.S.2 MANUFACTURE
H
H 3C N N
O
O O CH3 O
H 3C
H
O O
Cl
Phthaloyl amlodipine
M.W. 537
O O CH3
H 3C
H
O O
Cl
Amlodipine base
M.W. 408
SO 3 H
H
H 3C N NH2
O
O O CH3 SO 3 H
H 3C
H
O O ,
Cl
AMLODIPINE BESILATE
M.W. 567
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3.2.S.2 MANUFACTURE
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3.2.S.2 MANUFACTURE
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3.2.S.2 MANUFACTURE
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3.2.S.2 MANUFACTURE
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3.2.S.3 CHARACTERIZATION
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3.2.S.3 CHARACTERIZATION
H
H3C N NH2
O
O O CH3 SO3H
H 3C .
O H O
Cl
and enantiomer
3. 2980.0 2981.0 ib i
Due to Sulphonic acid
4. 3138.0 3138.0 -NH stretching
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IR Spectrum of Amlodipine besilate working standard 1AMLO070
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IR Spectrum of Amlodipine besilate batch no. 2AMLO001
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3.2.S.3 CHARACTERIZATION
1
H NMR Spectroscopy
The proton NMR spectrum of batch no. 9AD072 shows similar protons, which are
present in Amlodipine besilate working standard WRS/AMD/004.
1
H NMR spectra were recorded on a Bruker Avance-300 Spectrometer in DMSO
containing TMS as the internal standard. Chemical shifts are given in parts per
million (ppm) down field from TMS.
4'
5' 3'
2'
6'
1' Cl
-
4 H SO3
H3COOC 5 COOCH2CH3
14 13 10 11 12
3 1''
6 6'' 2''
+
2
H3C N CH2OCH2CH2NH3 .
1 7 8 5'' 3''
15 9
H 4''
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3.2.S.3 CHARACTERIZATION
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1
HNMR of Amlodipine besilate working standard WRS/AMD/004
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1
HNMR of Amlodipine besilate batch no. 9AD072
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3.2.S.3 CHARACTERIZATION
13
C NMR Spectroscopy
13
The C NMR spectrum of batch no 9AD072 shows similar carbons, which are
present in Amlodipine besilate working standard WRS/AMD/004
13
The C NMR spectra were recorded on a Bruker Avance-300 Spectrometer in
DMSO containing TMS as the internal standard. Chemical shifts are given in parts
per million (ppm) down field from TMS.
. 4'
5' 3'
2'
6'
1' Cl
-
4 H SO3
H3COOC COOCH2CH3
5
14 13 10 11 12
3 1''
6 6'' 2''
+
2
H3C N CH2OCH2CH2NH3 .
1 7 8 5'' 3''
15 9
H 4''
13
C NMR Spectra of Amlodipine besilate working standard WRS/AMD/004 is
consistent with the spectrum of batch no- 9AD072 are given below.
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3.2.S.3 CHARACTERIZATION
13
From these assignments, we concluded that C NMR data of batch no. 9AD072
and working standard WRS/AMD/004 confirms the structure of Amlodipine
Besilate as delineated above.
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13
C NMR of Amlodipine besilate working standard WRS/AMD/004
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13
C NMR of Amlodipine besilate batch no. 9AD072
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3.2.S.3 CHARACTERIZATION
Mass Spectroscopy
The Mass spectrometer used for this analysis was an applied biosystems MDC
SCIEX, QTRAP LC/MS/MS system.
The Mass spectra of Amlodipine besilate indicated a very prominent peak of pseudo
molecular ion [M ++1] at m/z 409.2 (molecular wt 567.1, where M.+= Amlodipine)
as the major component. Sample spectrum of batch no. 9AD072 and working
standard WRS/AMD/004 are attached.
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Mass Spectra of Amlodipine Besilate working standard WRS/AMD/004
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Mass spectra of Amlodipine Besilate batch no. 9AD072
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3.2.S.3 CHARACTERIZATION
The X-RAY Diffraction pattern of Amlodipine besilate batch no. 3AM001 is given
below.
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X-Ray Diffractogram of Amlodipine besilate batch no. 3AM001
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3.2.S.3 CHARACTERIZATION
Cadila has defined water content and Sulphated Ash limit as not more than 0.50 %
w/w and not more than 0.20 % w/w respectively in specification of Amlodipine
besilate drug substance as a control test for anhydrous form.
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3.2.S.3 CHARACTERIZATION
3.2.S.3.2 IMPURITIES
3.2.S.3.2.1 FOLLOWING ARE THE POTENTIAL PROBABLE IMPURITIES IN OUR
AMLODIPINE BESILATE .
A) POSSIBLE ORGANIC IMPURITIES IN AMLODIPINE BESILATE
1. Impurities possible from starting materials:
No impurities are possible from starting materials.
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3.2.S.3 CHARACTERIZATION
B) INORGANIC IMPURITY
1. Catalysts and Reagents
No catalysts are used in the manufacturing process of Amlodipine Besilate.
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3.2.S.3 CHARACTERIZATION
O
H
H3C N N
O
O CH3 O
O
H3 C
O H O
Cl
and enantiomer
b. Impurity B:
Chemical Name: 3-ethyl 5- methyl (4RS)-4-(2- chlorophenyl)-6-methyl-2-[[2-[[2-
(methylcarbamoyl) benzoyl] amino]-ethoxy] methyl-1, 4-dihydropyridine-3, 5-
dicarboxylate.
Structure:
O
NHCH3
H H
H3C N N
O
O CH 3 O
O
H3 C
O H O
Cl
and enantiomer
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3.2.S.3 CHARACTERIZATION
O O CH3
H3C H
O O
Cl
and enantiomer
d. Impurity E:
Chemical Name: Diethyl (4RS)-2-[(2-aminoethoxy) methyl]-4-(2-chlorophenyl) -
6-methyl-1,4-dihydropyridine-3,5-dicarboxylate.
Structure:
H
H3C N NH2
O
C2H5 O O C2H5
O H O
Cl
and enantiom er
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e. Impurity F:
Chemical Name: Dimethyl (4RS)-2-[(2-aminoethoxy) methyl]-4-(2-chlorophenyl)
-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate.
Structure:
H
H3C N NH 2
O
CH 3O O CH 3
O H O
Cl
and enantiomer
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3.2.S.3 CHARACTERIZATION
From the above results, it is evident that Cadila’s Amlodipine besilate is meeting
the predefined specification.
None of the individual impurity was observed to be greater than 0.10 %. Therefore,
no characterization study of impurities was carried out.
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3.2.S.3 CHARACTERIZATION
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3.2.S.4 CONTROL OF DRUG SUBSTANCE
3.2.S.4.1 SPECIFICATION
Finished drug substance specification for ‘Amlodipine besilate’ is provided in this
section.
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3.2.S.4 CONTROL OF DRUG SUBSTANCE
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3.2.S.4 CONTROL OF DRUG SUBSTANCE
3.2.S.4.3 VALIDATION OF ANALYTICAL PROCEDURES
3.2.S.4.3.1 RELATED SUBSTANCES
The analytical procedure used for detection of related substances is EP method.
This method is validated for attributes Specificity, Limit of Detection, Limit of
Quantitation and Linearity. The method validation report for the mentioned related
substance method is provided as ANNEX-I.
3.2.S.4.3.2 ASSAY
The analytical procedure used for detection of assay of Amlodipine Besilate is EP
method. This method is validated for attributes Specificity and Linearity. The
method validation report for the mentioned assay method is provided as ANNEX-
II.
Validation report and its supporting chromatograms are provided as ANNEX- III.
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3.2.S.4 CONTROL OF DRUG SUBSTANCE
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3.2.S.4 CONTROL OF DRUG SUBSTANCE
3.2.S.4.5 JUSTIFICATION OF SPECIFICATION
List of all the tests along with specifications and justifications and references is
given below.
1. Characters
Specification : Appearance: White or almost white powder.
Justification : As per Ph. Eur. monograph.
Specification : Solubility: Slightly soluble in water, freely soluble in methanol,
sparingly soluble in ethanol, slightly soluble in 2-propanol.
Justification : As per Ph. Eur. monograph.
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5. Water content (By KF)
Specification : Not more than 0.50 % w/w
Justification : As per Ph. Eur. monograph.
6. Sulphated Ash
Specification : Not more than 0.20 % w/w
Justification : As per Ph. Eur. monograph.
Additional Test
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3.2.S.5 REFERENCE STANDARDS OR MATERIALS
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3.2.S.6 CONTAINER CLOSURE SYSTEM
This section describes the acceptance criteria for the Packaging Materials used in
the packing of the Amlodipine besilate, also includes packaging and labeling
procedures for finished product
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3.2.S.6 CONTAINER CLOSURE SYSTEM
Label issuance
Strict control is exercised over labels issued for use. Exact number of labels,
sufficient for the number of containers to be labeled and one specimen label are
issued for each batch. Labeling materials issued for a batch, are carefully examined
for identity and conformity to the labels specified in Master/Batch Process Records.
Only one batch is labeled at a time.
STORAGE CONDITIONS
Store in tightly closed container.
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PACKING MATERIAL SPECIFICATIONS
Specifications and test methods of packing materials together with Food grade
certificate are provided in this section.
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3.2.S.6 CONTAINER CLOSURE SYSTEM
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3.2.S.7 STABILITY
OBSERVATIONS
There are no significant changes observed in the physical and chemical properties
during accelerated and long-term stability studies.
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3.2.S.7 STABILITY
Assay
It contains not less than 97.0 % w/w and not more than 102.0 % w/w. All the values
are within the specified limits. All results are within the acceptance limits.
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CONCLUSIONS
Based on 60 month stability study data, Cadila propose the expiry date for
Amlodipine besilate to be 5 years when stored under recommended storage
conditions as given on the product label, “Store in tightly closed container”
Annually one batch of product will be placed for long-term stability, if a batch is
manufactured that year.
FORCED DEGRADATION
Forced degradation studies is carried out for Amlodipine Besilate under stress
conditions of Acid, Alkali, Oxidation, water, heat and Sunlight. From the results of
3-point peak purity of degradations.
Validation report and its supporting chromatograms are provided as ANNEX-IV.
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3.2.S.7 STABILITY
3.2.S.7.2 POST-APPROVAL STABILITY PROTOCOL & STABILITY
COMMITMENT
The stability study of Amlodipine besilate has been initiated at our location in
Dholka, Ahmedabad, INDIA.
PURPOSE
To carry out accelerated & Long-term stability studies of Amlodipine besilate to
determine re-test date of the active pharmaceutical ingredient.
Note: Batch no: 6AD031, 6AD032, 6AD033 upto 36 months stability data station
was analyzed as per old specification and from 48 months onwards stability data
station has been analyzed as per current specification.
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Batch no: 8AD001 upto 24 months stability data station was analyzed as per old
specification and 36 months onwards stability data station has been analyzed as per
current specification.
3.2.S.7 STABILITY
Batch no: 9AD001 upto 12 months stability data station was analyzed as per old
specification and 18 months onwards stability data station has been analyzed as per
current specification.
Batch no: 0AD001 initial stability data station was analyzed as per old specification
and 3 months onwards stability data station has been analyzed as per current
specification.
Batch no: 1AD001, 2AD001, 13AD001 & 14AD001 all stability data stations are
analyzed as per current specification.
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3.2.S.7 STABILITY
Study Required
Packaging Information
Name: Amlodipine besilate
Batch No: 6AD031, 6AD032, 6AD033, 8AD001, 9AD001,
0AD001, 1AD001, 2AD001,13AD001 & 14AD001.
Storage Conditions :
Type of the Study Conditions
Accelerated 40°C±2°C; 75%±5%RH
Long-term 25°C±2°C; 60%±5%RH
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3.2.S.7 STABILITY
Test Parameters & Acceptance Criteria
Test Parameters Acceptance Criteria
Description White or almost white powder.
Sampling Schedule
Accelerated Stability Study
Initial, 1 month, 2 months, 3 months and 6 months.
Long-term Stability Study
Initial, 3 months, 6 months, 9 months, 12 months, 18 months, 24 months, 36
months, 48 months and 60 months.
Reason for Stability Study
To propose and establish re-test date and storage conditions.
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3.2.S.7 STABILITY
STABILITY COMMITMENT
The stability program will be continued till the end of proposed period unless a
significant change is observed during Long-term stability study. Re-test period will
be extended based on the results of Long-term stability study.
A minimum of one commercial batch will be added every year to on going stability
study for long-term conditions.
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3.2.S.7 STABILITY
3.2.S.7.3 STABILITY DATA
The stability data reports of Amlodipine besilate for accelerated and long-term
conditions for the following batches are provided.
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ABBREVIATIONS
o
1. C Degree Centigrade
2. % Percentage
3. µ Micron
4. µL/µl Microlitre
5. µm Micrometer
6. IR Infra-Red
7. A.R. No. Analytical Report Number
8. API Active Pharmaceutical Ingredient
9. Dec December
10. cm Centimeter
11. COA Certificate of Analysis
12. CPL Cadila Pharmaceuticals Limited
13. AM/AD Amlodipine Besilate
14. DMF Drug Master File
15. TIR Test Information Report
16. Exp. Date Expiry Date
17. FPS Finished Product Specification
18. FPT Finished Product Test method
19. g/cc Gram per centimeter cube
20. g/l Gram/ liter
21. GIDC Gujarat Industrial Development Corporation
1
22. H NMR Proton Nuclear Magnetic Resonance
23. GMP Good Manufacturing Practice
24. HPLC High performance liquid chromatography
25. Hrs Hours
26. HSS Head Space Sampler
27. ND Not Detected
28. Inj. Injector
29. Jul. July
30. KF Karl Fisher
31. Km Kilometer
32. GC Gas Chromatography
33. Ltd. Limited
i
ABBREVIATIONS
34. M Months
35. L Liter
36. Kg Kilogram
37. mg Milligram
38. Min Minutes
39. ml Milliliter
40. ml/min. Milliliter/minute
41. mm Millimeter
42. Mol. Wt. Molecular weight
43. mol/L Moles/liter
44. N Normal
45. BDL Below Detection Limit
46. NLT Not Less Than
47. nm Nanometer
48. NMR Nuclear Magnetic Resonance
49. NMT Not More Than
50. No. Number
51. PMS Packing Material Specification
52. ppm Parts Per Million
53. R&D Research And Development
54. RH Relative Humidity
55. RM Raw Material
56. RT Room Temperature
57. SBU Strategic business unit
58. TLC Thin Layer Chromatography
59. WRS Working Standard
60. USP United States Pharmacopoeia
ii