Process Validation For Atorvastatin Tablet - Article

Indo American Journal of Pharmaceutical Research, 2013 ISSN NO: 2231-6876
INDO AMERICAN
Journal home page: JOURNAL OF
http://www.iajpr.com/index.php/en/ PHARMACEUTICAL
RESEARCH
PROCESS VALIDATION OF ATORVASTATIN TABLETS 10MG
Vinod J1, Yogalaksmi K2, Vidyasagar V3

1
Dept. of Pharmaceutical Chemistry, Arulmigu Kalasalingam College of Pharmacy, Srivilliputtur, Tamilnadu, India.
2
Dept. of Pharmaceutical Chemistry, Manonmaniam Sundarnar University, Tirunelveli, Tamilnadu, India
3
Quality Assurance Department, Surien Pharmaceuticals (P) Ltd, Kovur, Chennai, Tamilnadu
ARTICLE INFO ABSTRACT

Article history The present research work focused on concurrent process validation for Atorvastatin tablets
Received 09/12/2013 10mg. The tablets were manufactured by wet granulation method. Since the dose is 10mg,
Available online uniform distribution of the drug in the tablet is critical which can influence the content
30/12/2013 uniformity, assay and dissolution of the tablets. The critical parameters selected for process
validation were drymixing, blending and compression. Uniformity of dry mixing was found
to be excellent after 20 minutes because %RSD was less than 1.0%. The content uniformity
after 20 minutes of blending was satisfactory since the % RSD was less than 1.0%. Physical
parameters and assay at compression stage, i.e different turret speeds (20, 25 and 30 rpm),
Keywords different hopper levels (Full hopper, half hopper and quarter hopper) and different time
Drymixing, intervals (Initial, Middle and End) were within limits. Based on results at each critical stage
Atorvastatin Tablets, for the specified parameters, it is concluded that the wet granulation method can ensure
Granulation Method. uniform distribution of Atorvastatin and the tablets can be effectively manufactured with
the desired specifications & reproducible quality standards.
Corresponding author
Vinod J
Department of Pharmaceutical Chemistry
Arulmigu Kalasalingam College of Pharmacy
Anand Nagar, Krishnankoil
Srivilliputtur taluk-626126
Tamilnadu, India
E-Mail: vinoddivien2001@yahoo.com
(M): 09566811941
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Please cite this article in press as Vinod J et al.Process validation of atorvastatin tablets 10mg.Indo American Journal Of Pharm
Research.2013:3(12).
Copy right © 2013 This is an Open Access article distributed under the terms of the Indo American journal of Pharmaceutical
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Research, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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Vol 3, Issue 12, 2013. Vinod J, et. al. ISSN NO: 2231-6876
INTRODUCTION
The basic principle of quality assurance is that a drug should be produced that is fit for its intended use [1]. In order to meet
this principle, a good understanding of the processes and their performance is important. Quality cannot be adequately assured by in-
process and finished product inspection and testing, but it should be built into the manufacturing processes. These processes should be
controlled in order that the finished product meets all quality specifications. One of the major problems that affect product quality is
the non-uniform distribution of drug in the dosage form. Non-uniform distribution of drug can affect critical parameters like assay,
content uniformity and dissolution. The purpose of the present study is to ensure uniform distribution of the drug in the dosage form,
which is manufactured by wet granulation method by concurrent process validation approach. The validation study was performed on
three batches.
Process validation is establishing documented evidence which provides high degree of assurance that a specific process
consistently produced a product meeting its predetermined specifications and quality characteristics [2]. Process validation is intended
to establish that the proposed manufacturing process is a suitable one and yields consistently a product of the desired quality. i.e. that
the process is suitable and under control[3].
The main advantages to be obtained from process validation are
1. Expanded real time monitoring and adjustment of process.
2. Enhanced ability to statistically evaluate process performance and product variables.
3. Increased confidence about process reproducibility and product quality.
4. Improved ability to set target parameters and control limits for routine production.
5. Enhanced reporting capability[4].
Options of process validation are (a) Prospective validation (b) Concurrent Validation
(c) Retrospective validation [5] .
Prospective process validation is done prior to manufacture of commercial batches. Using this well defined process, a series
of batches (generally considered acceptable that three consecutive batches/runs within the finally agreed parameters) should be
produced which would give desired quality product and constitute a proper process validation.
Concurrent validation is a practical approach under certain circumstances which includes (a) When a previously validated
process transferred to a third party contract manufacturer or to another manufacturing site, (b) Where the product is a different
strength of a previously validated product (c) When the number of lots evaluated under the Retrospective Validation were not
sufficient to obtain a high degree of assurance demonstrating that the process is fully under control, (d) When the number of batches
produced are limited (e.g. orphan drugs).
Retrospective validation is applicable to processes that are stable and in routine use which have not undergone a formally
documented validation process. Documentary evidence for the validity of the processes can be provided by utilizing the historical
data. Retrospective validation is only acceptable approach for well established detailed processes that include operational limits for
each critical step of the process and will be inappropriate where there is a change in operating procedures, product formulation,
equipment and facility. Data from a minimum of ten consecutive batches produced will acceptable for retrospective validation.
Process re-validation provides the assurance that changes in a process and /or the process environment that are introduced do
not adversely affect process characteristics and product quality. Some planned or unplanned changes that may require re-validation
under following situations (a) Changes in raw materials (b) Changes in the source of active raw material manufacturer, (c) Changes in
packaging material (d) Changes in process (e) Changes in the equipment (f) Changes in the plant/facility, (g) Variations revealed by
trend analysis .
MATERIALS AND METHODS

Atorvastatin calcium was procured from Dr.Reddys Laboratories.
Experiment/ Methodology
Table1: Product profile of Atorvastatin tablets 10mg
Product Name Atorvastatin tablets 10 mg

Dosage form Tablet
Label claim Each film coated tablet contains Atorvastatin calcium equivalent to Atorvastatin 10 mg
Batch size 3,00,000 Tablets
Shelf life 36 months
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The manufacturing formula for batch size of 3,00,000 tablets is given below:
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Table 2: Compostion of Atorvastatin tablets
S.No Ingredients Mg/tablet Kg/Batch

Core
1. Atorvastatin calcium 11.000 3.300
2. Starch 29.916 8.975
3. Lactose 10.000 3.000
4. Sodium starch glycollate 6.000 1.800
5. Microcrystalline cellulose 15.000 4.500
6. Povidone 9.000 2.700
7. Isopropyl alcohol* Q.S 20.000
8. Purified talc 2.000 0.600
9. Magnesium stearate 2.000 0.600
10. Colloidal anhydrous silica 1.000 0.300
11. Croscarmellose sodium 10.000 3.000
12. Sodium Lauryl sulphate 2.000 0.600
13. Ponceau 4R 0.084 0.0252
Core weight 98.000 29.400
Film coating**
14. Hydroxy propyl methyl cellulose 1.000 0.360
15. Purified talc 0.250 0.090
16. Titanium dioxide 0.250 0.090
17. Iron oxide red 0.020 0.007
18. Ponceau 4R 0.250 0.090
19. Polysorbate 80 0.230 0.083
20. Isopropyl alcohol* Qs 1.700
21. Methylene Chloride* Qs 1.700
Coated tablet weight 100.000 30.000
Evaporated during drying process
Inclusive of 20% overages to compensate process loss.
Flowchart for the manufacturing process
Sifting
Dispensing Atrovastatin Calcium 40#
Starch 40 #
Lactose 40 #
Sodium starch glycollate 40#
Microcrystalline cellulose powder 40 #
Binder solution preparation Povidone 40 #
Dissolve povidone in Iso Isopropyl alchohol
propyl alcohol under stirring Purified talc 40 #
to form a clear solution Magnesium Stearate 40#
Collidal silicon dioxide 40#
Croscarmellose Sodium 40 #
Sodium lauryl sulphate 40 #
Ponceau 4R 40 #
Drymixing & Granulation

Assay of Atorvastatin
Charge sifted Microcrystalline cellulose, Lactose,
Sodium starch glycollate, Ponceau & Atorvastatin Calcium (After 10, 15,
calcium in RMG. Dry mix for 20 mins at slow speed. 20 mins)
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Add binder solution at slow speed (2 min) and mix at

high speed (5 min) and continue till the required
consistency is achieved.
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Drying
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Sizing
Blending Assay of Atorvastatin

Load sized granules, Colloidal silicon dioxide,
calcium after 10, 15 and
Croscarmellose sodium, Ponceau 4R and sodium
lauryl sulphate into mixer and blend for 20 minutes. 20 minutes
Lubrication Assay of Atorvastatin

Add Magnesium stearate and talc and lubricate
calcium
for 5 minutes
Group weight
Weight variation
Compression Hardness
Friability
Disintegration time
Assay
Film coating
The rationale for selection of critical process steps for validation is given below:
Drymixing
This step involves mixing of Atorvastatin Calcium with other excipients. Mixing speed and time are critical variables in this
process. Since speed of the RMG is constant, proper mixing time shall be determined. Mixing is a critical step as less mixing time will
result in non-uniform distribution of drug whereas more mixing time will result in de-mixing, leading to non-uniform distribution of
drug and increase in disintegration time [6]. Proper mixing shall be established by checking content uniformity of drug at all the time
intervals mentioned in protocol.
Blending
Blending involves mixing of granules with other extragranular ingredients[7]. The purpose is to get a uniform distribution of
Atorvastatin Calcium with other ingredients. Blending speed and time are critical variables in this process. Since speed of the blender
is constant, proper blending time shall be determined. Blending is critical as less blending will result in non-uniform distribution of
drug whereas more blending will result in de-mixing, leading to non-uniform distribution of drug and increase in disintegration time.
Proper blending shall be established by checking content uniformity of drug at all the time intervals mentioned in protocol.
Lubrication
This step involves mixing of blended granules with lubricant to achieve good flow and antiadherent properties to aid
satisfactory compression parameters [8]. Lubrication time and speed are critical variables in this process. Since speed of the blender is
constant, proper lubrication time shall be determined. Proper lubrication shall be established by checking content uniformity of drug
and physical parameters of lubricated granules.
Compression
This step involves conversion of lubricated granules into tablets as per specifications. Speed of machine and hopper levels are the
major variables. So, following parameters are to be checked to establish the above-mentioned variables at regular intervals:
1. Weight variation (group and individual)
2. Hardness
3. Thickness
4. Friability
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5. Disintegration time
6. Assay
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Table 3: Process control steps for validation
Sl. No. Process Step Control Variable Measured Response

1. Dry mixing a) Mixing time (10, 15, 20 min) a)Assay of Atorvastatin
b) Mixing speed
2. Blending a) Blending time (10, 15, 20 min)
b) Speed a)Assay of Atorvastatin Calcium
a) Assay
3. Lubrication
a) Lubrication time
b) Speed
4. Compression a) Machine speed (20, 25, 30 rpm) a)Group weight

b) Initial, middle, end of compression b)Individual weight
c) Full hopper, half hopper, quarter c)Hardness
hopper levels d)Friability
e)Disintegration time
f)Assay
Table 4: Sampling and testing plan
Stage Sample Location Sample size Test

5 positions from Rapid Mixer Approximately one to
Dry Mixing Granulator after 10, 15 and 20 minutes three unit dose withdrawn Assay
of Dry mixing. in triplicate
Approximately one to
10 positions from paddle mixer after Assay
Blending three unit dose withdrawn
10, 15,20 minutes of blending
in triplicate
Composite sample from center of the

Lubrication top, middle & bottom level of paddle Approx. 150 g Assay
mixer
1.Group weight
After each interval (From RHS and 2.Individual
LHS) weight
30, 60,90&120 minutes 3. Hardness.
Compression 160 tablets
RPM: 20. 25. 30 4. Assay
Full hopper, Half Hopper, Quarter 5.Disintegration
hopper time
6.Friability
The sampling positions are shown in figures 1-2.

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Figure 1 : Sampling position of Rapid Mixer Granulator
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Figure 2: Sampling position of Paddle mixer
Method of analysis
The method of analysis of samples taken at various process steps is given below:
Weight variation
Twenty tablets were randomly selected from each batch and individually weighed. The average weight and standard
deviation of 20 tablets was calculated. The batch passes the test for weight variation test if none of the individual tablet weight deviate
from the average weight by more than the 7.5 % of the average weight.
Hardness
The crushing strength in Kg/cm2 of tablets was determined for 10 tablets of each batch by using Monsanto tablet hardness
tester. The average hardness and standard deviation was determined.
Friability
Ten tablets were weighed and placed in the Electrolab friabilator and apparatus was rotated at 25 rpm for 4 minutes. After
revolutions the tablets were deducted and weighed the percentage friability was measured using the formula: % F = {1-(Wt/W)}
×100 where
% F = friability in percentage
W = Initial weight of tablets
Wt = weight of tablets after revolution
Disintegration
6 tablets were placed in beaker containing water in electrolab disintegration tester with disc and the time to disintegrate was
recorded.
ASSAY[9]
Chromatographic system:
Mode: LC
Detector: UV 244 nm
Column: 4.6-mm x 25-cm; 5-mm packing L7
Column temperature: 35°
Flow rate: 1.5 mL/min
Injection volume: 20 µL
Mobile Phase:
Time (min) Solution A % Solution B %

0 100 0
40 100 0
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70 20 80
85 0 100
Solution A: Acetonitrile, stabilizer-free tetrahydrofuran and Buffer (21:12:67)

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Solution B: Acetonitrile, stabilizer-free tetrahydrofuran and Buffer (31:12:27)

Buffer: 3.9 g/L of ammonium acetate in water. Adjust with glacial acetic acid to a pH of 5.0.
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Sample Preparation:
Weigh and powder 20 tablets. Transfer accurately weighed quantity of powder equivalent to about 10 mg in 50 ml volumetric
flask. Dilute with methanol. Sonicate for 20 minutes. Then cool and filter. Dilute 2ml of filtrate to 100 ml with methanol.
Standard Preparation:
Weigh and transfer accurately 25 mg of Atorvastatin Calcium in 50 ml volumetric flask. Make up with methanol. Then
dilute 2ml to 100 ml with methanol in 100 ml volumetric flask. Calculate the percentage of atorvastatin calcium (C 66H68CaF2N4O10) in
the portion of Atorvastatin Calcium taken: (rU/rS) x (CS/CU) x 100
rU = peak response from the Sample solution
rS = peak response from the Standard solution
CS = concentration of USP Atorvastatin Calcium RS in the Standard solution (mg/mL)
CU = concentration of Atorvastatin Calcium in the Sample solution (mg/mL)
Dissolution
Dissolution studies were performed according to United States Pharmacopoeia (USP XXVIII), paddle method. The stirring
speed used was 50 rpm, and the temperature was maintained at 37 ± 0.1°C. Each test was carried out in 900 ml of 0.05 M Phosphate
buffer, pH 6.8 then 4 ml of aliquot samples were withdrawn in certain time intervals and filtered using 0.11 μm nylon syringe filter. At
each sampling time, an equal volume of the test medium was replaced. Filtered samples were appropriately diluted with methanol and
assayed for drug concentration by HPLC
Chromatographic system:
Detector: PDA detector 240 nm
Column: C18 Inertsil ODS 3V column (250 mm, 5 μm)
Column temperature: 35°
Flow rate: 1.0 mL/min
Injection volume: 20 µL
Mobile phase system: Reservoir A (0.01 M ammonium acetate buffer, pH 5.0–acetonitrile; 90:10) and Reservoir B (0.01 M
ammonium acetate buffer, pH 5.0– acetonitrile; 5:95) and Reservoir C (0.01 M ammonium acetate buffer, pH 5.0–methanol; 10:90)
RESULTS AND DISCUSSION

Since the amount of the drug in the tablet is around 5%, the critical process steps that can affect
the distribution of drug in the tablet were evaluated. Non uniform drug distribution can affect the
weight, dissolution and assay. The results are presented below.
Dry mixing
The drymixing of three batches was performed and the samples at the designated locations were drawn after 10, 15, 20
minutes of blending for determining the content uniformity and %RSD values of Atrovastatin calcium. The %RSD values after 20
minutes of mixing was most satisfactory. Hence the drymixing time of 20 minutes was validated. The assay of Atorvastatin calcium in
drymix stage is presented in table 5.
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Table 5: Assay of Atorvastatin calcium in dry mix
Batch number
Time Interval Sample Location
DPV-231 DPV-232 DPV-233
Top 119.93 119.39 119.21
Middle left 77.82 127.28 119.24
10 min Middle 108.61 78.61 108.61
Middle right 119.24 89.42 77.82
Bottom 119.21 119.21 129.17
Mean 108.96 106.78 110.81
%RSD 18.03 21.38 19.82
Top 117.88 89.68 119.33
Middle left 89.61 71.10 129.61
15 min Middle 78.24 129.10 78.24
Middle right 129.61 134.54 89.61
Bottom 119.33 144.56 127.88
Mean 106.93 113.79 108.93
SD 21.85 31.68 23.50
Top 98.34 98.54 98.54
Middle left 99.85 99.98 99.33
Middle 98.61 99.31 98.61
20 min Middle right 99.33 99.85 99.85
Bottom 98.54 99.43 98.34
Mean 98.93 99.42 98.93
SD 0.63 0.56 0.63
Limit 95.0 to 105.0% w/w
Blending
The blending of three batches was performed and the samples at the designated locations were drawn after 10, 15, 20 minutes
of blending for determining the assay and %RSD values of Atrovastatin calcium. The values meet the acceptance criteria after 20
minutes of blending. Hence the blending time of 20 minutes was validated.
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Table 6: Assay of Atorvastatin calcium in blending stage
Batch number
Time Interval Sample Location
DPV-231 DPV-232 DPV-233
S1 119.3 109.9 109.3
S2 129.5 119.7 114.5
S3 126.9 136.8 116.9
S4 106.4 116.8 106.4
S5 109.4 119.2 129.0
S6 119.8 129.6 129.8
10 min
S7 119.4 119.4 139.6
S8 109.3 119.8 149.3
S9 115.9 125.5 125.6
S10 134.6 134.0 144.6
Mean 119.1 123.1 126.5
%RSD 9.26 8.29 14.80
S1 139.6 134.5 119.3
S2 149.3 119.3 129.5
S3 125.6 129.5 126.9
S4 144.6 126.9 106.4
S5 119.3 106.4 109.4
15 min S6 129.5 109.4 139.6
S7 126.9 139.6 149.3
S8 106.4 149.3 125.6
S9 109.4 125.6 144.6
S10 119.6 144.6 109.6
Mean 127.1 128.5 126.1
%RSD 14.22 14.14 15.13
S1 98.3 98.3 98.3
S2 99.5 99.4 99.4
S3 99.6 99.0 99.0
S4 99.1 99.1 99.1
S5 98.3 99.9 98.3
S6 99.4 98.6 99.4
20 min
S7 99.0 98.3 99.0
S8 99.1 99.4 99.1
S9 98.9 99.0 99.1
S10 98.6 99.1 99.0
Mean 98.9 99.0 98.9
%RSD 0.46 0.50 0.38
Limit 95.0 to 105.0% w/w
Lubrication
This step involves mixing of blended granules with lubricant to achieve good flow and antiadherent properties to aid
satisfactory compression parameters. Proper lubrication was established by checking content uniformity of drug and physical
parameters of lubricated granules. The physical parameters and assay of lubricated granules is presented in Table 7.
Table 7: Physical parameters of lubricated granules
Batch Number
TEST Acceptance criteria
DPV-231 DPV-232 DPV-233
Appearance White colored granules White colored granules White colored granules White colored granules
Assay 95.0 to 105.0%w/w 99.71 % 99.67 % 98.55 %
LOD NMT 1.0 w/w 0.89% 0.95% 0.87%
Bulk density For information only 0.561 g/cc 0.571 g/cc 0.554 g/cc
Tapped density For information only 0.687 g/cc 0.674 g/cc 0.680 g/cc
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Particle size distribution Cumulative % retained

20# 15.2% 15.7% 13.5%
30# 26.3% 25.6% 24.3%
40# For information only 37.8% 35.8% 33.7%
60# 49.5% 49.1% 46.5%
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80# 68.2% 64.5% 64.2%

100# 80.5% 78.5% 79.4%
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COMPRESSION
The compression for all the three batches has been validated for different turret speeds (20, 25 and 30 rpm), different hopper
levels (full, half and quarter hopper levels) and different time intervals (initial, middle and end) of compression. The physical
parameters and assay of the tablets were well within the acceptable limits. The results were comparable among all the three batches.
Hence the compression step was validated. The results of different turret speeds at compression stage are presented in table 8.
Table 8: Physical Parameters At Different Turret Speeds
TURRET Batch Number

TEST ACCEPTANCE CRITERIA
RPM DPV-231 DPV-232 DPV-233
A white coloured circular slightly
Appearance biconvex uncoated tablet plain Complies Complies Complies
on both sides.
Av. Weight 98 mg ± 5% 97.3 mg 98.5 mg 98.1 mg
Uniformity of 93.2 to 94.8 to 102.1
± 7.5 % of average weight 95.6 to 100.5 mg
weight 99.2 mg mg
Thickness 2.8 ± 0.3 mm 2.78 mm 2.91 mm 2.85 mm
Friability Not more than 1.0 % 0.23% 0.35% 0.34%
Hardness Not less than 2 Kg/cm2 2.7 Kg/cm2 2.8 Kg/cm2 2.6 Kg/cm2
20 rpm 7 min 30
Disintegration Time Not more than 15 minutes 7 min 25 sec 7 min 45 sec
sec
Assay 95.0 to 105.0 %w/w 99.5% 99.8% 100.2%
on both sides.
Uniformity of 94.8 to 102.1
± 7.5 % of average weight 95.2 to 99.2 mg 95.6 to 101.5 mg
weight mg
25 rpm Thickness 2.8 ± 0.3 mm 2.80 mm 2.85 mm 2.91 mm
Hardness Not less than 2 Kg/cm2 2.8Kg/cm2 2.6Kg/cm2 2.7Kg/cm2
Disintegration Time Not more than 15 minutes 7 min 25 sec 7 min 40 sec 7 min 55 sec
Assay 95.0 to 105.0 %w/w 99.1% 99.5% 99.2%
on both sides.
Av.Weight 98 mg ± 5% 97.3 mg 98.5 mg 98.1 mg
30 rpm ± 7.5 % of average weight 93.2 to 99.2 mg 95.6 to 100.5 mg
weight mg
7 min 30
sec
Assay 95.0 to 105.0 %w/w 99.9% 99.7% 100.2%
The results of different hopper levels at compression stage are presented in table 9.
Table 9: Physical Parameters At Different Hopper Levels
HOPPER Batch Number

LEVELS DPV-231 DPV-232 DPV-233
on both sides.
weight mg
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Full hopper Thickness 2.8 ± 0.3 mm 2.79 mm 2.90 mm 2.86 mm

7 min 10
sec
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Assay 95.0 to 105.0 %w/w 100.5% 99.6% 99.2%

Appearance Complies Complies Complies
biconvex uncoated tablet plain
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on both sides.
weight mg
Half hopper Thickness 2.8 ± 0.3 mm 2.85 mm 2.81 mm 2.91 mm
Assay 95.0 to 105.0 %w/w 99.8% 99.2% 99.2%
on both sides.
Uniformity of 93.2 to 100.2 94.8 to 102.1
± 7.5 % of average weight 95.6 to 101.5 mg
weight mg mg
Quarter Thickness 2.8 ± 0.3 mm 2.78 mm 2.91 mm 2.8O mm
hopper Friability Not more than 1.0 % 0.40% 0.55% 0.34%
Hardness Not less than 2 Kg/cm2 2.7 Kg/cm2 2.9Kg/cm2 2.6 Kg/cm2
7 min 30
sec
Assay 95.0 to 105.0 %w/w 99.5% 99.8% 99.8%
The results of different time intervals at compression stage are presented in table 10.
Table 10: Physical parameters at different time intervals
TIME Batch Number

DPV-231 DPV-232 DPV-233
on both sides.
Av. Weight 98 mg ± 5% 98.04 98.0 97.8
Uniformity of
± 7.5 % of average weight 97.1 to 98.4 mg 97.5to 98.2 mg 97.1 to 98.2 mg
weight
Initial Thickness 2.8 ± 0.3 mm 2.90 mm 2.90 mm 2.89 mm
Friability Not more than 1.0 % 0.15 % 0.17 % 0.16 %
Hardness Not less than 2 Kg/cm2 2.5 kg/cm2 2.0 kg/cm2 3.0 kg/cm2
Disintegration Time Not more than 15 minutes 7min19sec 7min2sec 7min20sec
Assay 95.0 to 105.0 %w/w 99.8 99.5 98.9
on both sides.
weight mg
Middle Friability Not more than 1.0 % 0.23% 0.35% 0.34%
7 min 30
sec
Assay 95.0 to 105.0 %w/w 99.5% 99.8% 100.2%
on both sides.
weight mg
End Thickness 2.8 ± 0.3 mm 2.78 mm 2.91 mm 2.85 mm
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Assay 95.0 to 105.0 %w/w 99.8% 99.9% 98.2%
The individual weight variation during compression is presented in table 11.
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Table 11: Individual Weight Variation During Compression (mg)
B.No.DPV-231 B.No.DPV-232 B.No.DPV-233

S.No
Initial Middle End Initial Middle End Initial Middle End
1. 98.2 98.4 97.9 98.1 98.2 98.1 97.5 98.1 98.4
2. 98.4 98.3 97.5 97.7 98.4 97.7 97.4 97.5 98.4
3. 98.0 98.2 98.4 98.0 98.0 98.0 97.9 97.6 98.5
4. 98.1 97.9 98.1 98.1 98.1 98.1 98.2 97.9 98.1
5. 97.9 98.4 97.6 97.5 97.9 97.5 97.9 98.4 97.5
6. 97.3 98.0 97.9 97.6 97.3 97.6 97.6 98.1 97.7
7. 98.3 98.1 97.1 97.9 98.3 97.9 98.2 97.6 97.5
8. 98.1 97.7 97.9 98.1 98.1 97.7 97.5 97.9 97.4
9. 98.4 98.0 98.5 97.7 98.4 98.0 98.2 97.1 98.6
10. 97.5 98.1 98.2 98.0 97.5 98.1 97.1 97.9 97.5
11. 97.4 97.5 98.4 98.1 98.3 97.5 97.3 98.5 97.5
12. 97.9 97.6 98.3 97.5 97.5 97.6 97.9 98.2 98.1
13. 98.2 97.9 98.2 97.6 98.1 97.9 98.1 98.4 97.7
14. 97.9 98.4 97.9 97.9 97.7 98.1 98.1 98.0 98.0
15. 97.6 98.1 98.4 98.1 98.0 97.7 97.7 98.1 98.1
16. 98.2 97.6 98.0 97.7 98.1 98.0 98.0 97.9 97.5
17. 97.5 97.9 98.1 98.0 97.5 98.1 98.1 97.3 97.6
18. 98.2 97.1 97.7 98.1 97.6 97.5 97.5 98.3 97.9
19. 97.1 97.9 97.5 97.5 97.9 97.6 97.6 98.1 98.6
20. 97.3 98.5 97.8 97.6 97.5 97.9 97.9 98.4 97.6
Mean 98.0 98.0 97.9 97.8 97.9 97.8 97.7 97.9 97.9
Maximum 98.4 98.5 98.5 98.1 98.4 98.1 98.2 98.5 98.6
Minimum 97.1 97.1 97.1 97.5 97.3 97.5 97.1 97.1 97.4
%RSD 0.40 0.35 0.36 0.23 0.34 0.22 0.33 0.39 0.41
The results of hardness at compression stage are presented in table 12.
Table 12: results of hardness during compression (kg/cm2)
B.No. DPV 231 B.No. DPV 232 B.No. DPV 233

S.No
Initial Middle End Initial Middle End Initial Middle End
1. 2.5 2.5 2.9 2.5 2.4 2.9 2.6 2.5 2.9
2. 2.8 2.7 2.4 2.8 2.6 2.4 2.8 2.7 2.4
3. 2.2 2.0 2.3 2.2 2.9 2.3 2.2 2.9 2.3
4. 2.5 2.0 2.5 2.5 2.9 2.5 2.5 2.9 2.5
5. 2.5 2.8 2.8 2.5 2.8 2.8 2.5 2.8 2.8
6. 2.5 2.6 2.2 2.6 2.6 2.2 2.6 2.6 2.2
7. 2.6 2.6 2.0 2.5 2.9 2.8 2.8 2.5 2.9
8. 2.5 2.9 2.8 2.9 2.4 2.0 2.9 2.9 2.4
9. 2.9 2.4 2.0 2.5 2.7 2.9 2.7 2.5 2.7
10. 2.5 2.7 2.9 2.8 2.8 2.9 2.6 2.8 2.8
Mean 2.5 2.8 2.9 2.5 2.8 2.9 2.5 2.8 2.9
%RSD 0.5 0.6 0.7 0.5 0.6 0.7 0.5 0.6 0.7
Table 13: Dissolution of tablets
Tablet % Drug dissolved

B.No.DPV-231 B.No.DPV-232 B.No.DPV-233
Tablet 1 95.2 92.4 94.5
Tablet 2 93.5 91.5 97.5
1449
Tablet 3 94.7 95.8 98.2

Tablet 4 96.5 95.4 97.3
Tablet 5 97.8 95.2 95.5
Tablet 6 97.1 92.5 96.4
Page
Mean 95.8 93.8 96.6

%RSD 1.8 1.5 1.9
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CONCLUSION
Quality cannot be adequately assured by in-process and finished inspections and testing but it should be built in to the
manufacturing process. These processes should be controlled in order that the finished product meets all quality specifications. The
quality system regulation defines process validation by establishing evidence that a process consistently produces a result or product
meeting its predetermined specifications. The goal of quality system is to consistently produce products that are suitable for their
intended use. In this study concurrent process validation was carried out for Atorvastatin Calcium tablets with three batches of same
batch size of 300,000 tablets with same manufacturing process and formula. The entire manufacturing and sampling procedure was
done with the approved validation protocol and sampling plan. The critical process steps like drymixing, wet granulation, drying,
blending, lubrication, compression and coating were validated. Based on the review of critical process parameters and analytical
results for critical process parameters as detailed in results section, it can be concluded that the manufacturing process for Atorvastatin
tablets, described in batch manufacturing record for batch size of 300,000 tablets is validated and can consistently produce the finished
product of Atorvastatin tablets, meeting all pre-determined specification and quality attributes. Furthur research work may be
envisaged on direct compression process.
Authors’ Statements
Competing Interests
The authors declare no conflict of interest.
REFERENCES
1. Pankaj Verma, A Review article on Pharmaceutical Validation and Process Controls, The Pharma Innovation, 2012, 1:7,51.
2. K Kathiresan, An overview of pharmaceutical validation, Research Journal of Pharmaceutical, Biological and Chemical
Sciences, 2010, 1:4,1026-1035.
3. Sharma Tejal Process validation: An essential in the pharmaceutical industry, International journal of pharmaceutical
research and development, 2011, 3:10,133-142.
4. Anurag S.Rathore, Process validation how much to do and when to do it, Biopharm, 2012, 1:1, 18-28.
5. PanditaRachna, Introduction and general overview of pharmaceutical process validation: A review, International research
journal of pharmacy, 2012, 3:6, 60-64.
6. Sharadkumar, Process validation of Azifast 500mg tablet, JAPHR 2011, 1:2,3-9.
7. Onkar J Deshmukh, Prospective process validation of Gliclazide tablet, American Journal of PharmTech Research. 2011, 1:3,
244-254.
8. Md.Saleem, Studies in process validation for Ibuprofen 200mg and methocarbamol 500mg caplets dosage formulation,
IJRPC 2011, 1:4,1075-1081.
9. Narendra Nyola, Simultaneous estimation of cefixime and azithromycin in Api’s and pharmaceutical dosage form by RP-
HPLC, Indo American Journal of Pharmaceutical Research, 2013,2:12,1473-1474.
54878478451001217
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Process Validation For Atorvastatin Tablet - Article

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Indo American Journal of Pharmaceutical Research, 2013 ISSN NO: 2231-6876

PROCESS VALIDATION OF ATORVASTATIN TABLETS 10MG

Vinod J1, Yogalaksmi K2, Vidyasagar V3

ARTICLE INFO ABSTRACT

MATERIALS AND METHODS

Table1: Product profile of Atorvastatin tablets 10mg

Product Name Atorvastatin tablets 10 mg

Table 2: Compostion of Atorvastatin tablets

S.No Ingredients Mg/tablet Kg/Batch

Flowchart for the manufacturing process

Drymixing & Granulation

Add binder solution at slow speed (2 min) and mix at

Blending Assay of Atorvastatin

Lubrication Assay of Atorvastatin

Table 3: Process control steps for validation

Sl. No. Process Step Control Variable Measured Response

4. Compression a) Machine speed (20, 25, 30 rpm) a)Group weight

Table 4: Sampling and testing plan

Stage Sample Location Sample size Test

Composite sample from center of the

The sampling positions are shown in figures 1-2.

Figure 1 : Sampling position of Rapid Mixer Granulator

Figure 2: Sampling position of Paddle mixer

Time (min) Solution A % Solution B %

Solution A: Acetonitrile, stabilizer-free tetrahydrofuran and Buffer (21:12:67)

Solution B: Acetonitrile, stabilizer-free tetrahydrofuran and Buffer (31:12:27)

RESULTS AND DISCUSSION

Table 5: Assay of Atorvastatin calcium in dry mix

Table 6: Assay of Atorvastatin calcium in blending stage

Table 7: Physical parameters of lubricated granules

Particle size distribution Cumulative % retained

80# 68.2% 64.5% 64.2%

Table 8: Physical Parameters At Different Turret Speeds

TURRET Batch Number

Table 9: Physical Parameters At Different Hopper Levels

HOPPER Batch Number

Full hopper Thickness 2.8 ± 0.3 mm 2.79 mm 2.90 mm 2.86 mm

Assay 95.0 to 105.0 %w/w 100.5% 99.6% 99.2%

Table 10: Physical parameters at different time intervals

TIME Batch Number

Table 11: Individual Weight Variation During Compression (mg)

B.No.DPV-231 B.No.DPV-232 B.No.DPV-233

Table 12: results of hardness during compression (kg/cm2)

B.No. DPV 231 B.No. DPV 232 B.No. DPV 233

Table 13: Dissolution of tablets

Tablet % Drug dissolved

Tablet 3 94.7 95.8 98.2

Mean 95.8 93.8 96.6

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