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International Journal of Universal Pharmacy and Bio Sciences 6(2): March-April 2017

INTERNATIONAL JOURNAL OF UNIVERSAL

PHARMACY AND BIO SCIENCES IMPACT FACTOR 2.96***

ICV 6.16***

Pharmaceutical Sciences RESEARCH ARTICLE …………!!!

“PROCESS VALIDATION & DESIGN SPACE STUDY OF CAPTOPRIL

TABLETS 50 MG”

Komal Kaneria1, Samarth Shihora

2

Department of Quality Assurance, Parul Institute of Pharmacy, Vadodara.

KEYWORDS:

Captopril Tablets,

Concurrent process

Validation, Design Space

study.

For Correspondence:

Komal P. Kaneria*

Address:

Department of Quality

Assurance, Parul Institute

of Pharmacy, Vadodara.

ABSTRACT

The Aim of this work was to perform Concurrent process

validation & Design Space Study of Captopril Tablets. Three

consecutive process validation batches of same size, Method,

Equipment and Validation criteria were taken and subjected to

validation. The critical parameters involved in sifting, granulation,

drying, blending and compression were identified and evaluated as

per validation master plan. At the stage of granulation, mixing for

5-15 minutes was required to achieve the blend uniformity which is

within the limit. % LOD of dried granules was found to be within

limit (1.5 % - 2.5% w/w) at inlet temperature 50˚C, at the stage of

lubrication. The compression data of all the three batches were

indicated that compression speed would be 12 rpm.



1. INTRODUCTION:

In the mid 1970’s , Food and Drug Administration (FDA) officials, Ted Byers and Bud Loftus first

proposed the concept of validation in order to improve the quality of pharmaceuticals. Validation is

a work of demonstrating and documenting that any process, procedure and activity will consistently

lead to the expected results. Validation is a concept that has been evolving continuously since its

first formal appearance in the United States in 1978. [1-5]

“Validation is act of demonstrating and documenting that any procedure, process and Activity will

consistently lead to the expected results.”[6]

Design space study is a relationship between process inputs (material attributes & process

parameters) and Critical Quality Attributes (CQA’s). It is also called as “challenge testing” with

respective to process & equipment functioning. Working with Design Space is not consider as

change, movement out of Design space to be a change and would normally initiate regulatory post

approval change process. If design spaces are accurately developed and all essential aspects of the

manufacturing process are within the design space, the Critical quality attributes are assured of

being acceptable.[7-9]

IUPAC name: 2S)-1-[(2S)-2-methyl-3-sulfanylpropanoyl] pyrrolidine-2-carboxylic acid

1. Empirical formula: C9H15NO3S

2. Molecular weight: 217.285 gm/mol

3. Solubility: Freely soluble in water

4. Melting Point: 106 °C

5. Pharmacological class: Antihypertensive Agents Angiotensin-converting Enzyme Inhibitors

6. Uses: treatment of hypertension

7. Storage: Captopril should be stored at 25˚c temperature and away from moisture.

8. Mechanism of Action: Captopril is a potent, competitive inhibitor of angiotensin-converting

enzyme (ACE), the enzyme responsible for the conversion of angiotensin I (ATI) to angiotensin II

(ATII). ATII regulates blood pressure and is a key component of the renin-angiotensin-aldosterone

system (RAAS).



9. pKa (strongest acidic): 4.02

(Strongest basic): -1.2[10]

2. MATERIALS AND METHOD:

Anti-Hypertensive Captopril tablets are currently manufacturing at S Kant Healthcare Ltd Vapi. So

at the time of manufacturing Captopril Tablets, it became necessary to validate the whole process of

Captopril tablets from dispensing to packing.

Process validation was performed on the three batches of Captopril Tablet. The three consecutive

batches were labelled as (Batch A, Batch B, Batch C).The protocol includes list of raw materials,

list of equipments used, process flow diagram, critical process parameters, standard specification

and acceptance criteria & sampling plan as given below. During the manufacturing process samples

were collected and sent for analysis to Q.C. department.

2.1 Material used:

Table 1.1 List of Raw materials

Name of Ingredient Unit Formula (mg) Batch Formula (kg)

Dry Mixing

Captopril USP 50.00 25.00

Maize Starch BP 170.00 85.00

Lactose Anhydrous BP 194.82 97.410

Sodium Starch Glycolate BP 10.00 5.00

Wet Granulation

Purified Water BP Q.S Q.S

Methyl Hydroxybenzoate BP 0.4 0.2

Propyl Hydroxybenzoate BP 0.08 0.040

Maize Starch BP 13.7 6.850

Lubrication

Purified Talc BP 4.00 2.00

Sodium Starch Glycolate BP 5.00 2.50

Magnesium Stearate BP 2.00 1.00

Maize starch(Additional) BP 18.37 9.185



2.2 Sampling Plan

2.2.1 Sample label:

Each Sample was labelled with Product Name, Batch No, Batch Size, Mfg. Date, Exp. Date, Stage,

Sample Quantity, Sample No, Sampled By/Date as Follows. For Three Batches.

2.2.1. (A) Dry Mix: RMG

Table 1.2 Sampling Plan for RMG

Stage Sample Location Sample

Quantity

Test To Be

Performed Label Detail

Dry mixing:

RMG

5 Points from TOP of bed,

5 points from Bottom of bed,

1 point from middle of bed

From of RMG

Approx.

1100 mg /each

location

Blend

uniformity

Dry-mixing

powder

Drying : FBD From 4 corner & 1 center of

FBD Dryer 5 gm LOD Dried granules

Lubrication :

RMG

Dry mixing

5 Points from TOP of bed,

5 points from Bottom of bed,

1 point from middle of bed

From of RMG

Approx.

1100 mg /each

location

Blend

uniformity

Dry-mixing

powder

2.3 Compression:

Table 1.3 Compression Machine Setting & Operation Details

Compression

Parameter Specification Tablet Parameter Specification

Compression

Machine

Double rotary (35

station) Appearance

white colour, circular, flat,

beveled edge, Uncoated Tablet

having a Central break line on 1

side & plain on other sides

Punch Size 11.30 mm Average weight 450.0 mg

Punch Shape Circular Flat

punches Weight of 20 tablets 450.0 mg± 2%

Upper Punch

(11.30 mm)

With central break

line

Diameter 11.30mm±0.2mm

Lower Punch (11.30 mm)

Plain Thickness 3.60mm±0.2 mm

Dies 11.30mm

Hardness NLT 40 N

Friability NMT 1 % w/w

Disintegration time NMT 15 min



Withdraw samples as per the required quantity as per below mentioned respective column. Quantity

of IPQC tests will be double in case of LHS & RHS

Table 1.4 Sampling Plan for Compression

1.4 Sampling Procedure:

2.4.1 At Dry Mixing Stage

By using SS sampling rod sample was withdrawn from each sampling point as shown in the RMG

sampling (Figure2.1) after 5, 10, 15 minute. Each sample quantity should be at least equivalent to

one to three times of the dosage unit. Average weight of single dosage unit is 425.0 mg. sample

quantity to be taken is about 1100.0 mg of dry mix for each location to check uniformity of mixing.

Figure 2.1:Sampling Location forRMG

2.4.2 At Drying Stage

Withdraw Sample from the FBD bowl as shown in the FBD sampling (Figure 2.2) and collect about

5.0 gm of dried granules from each location to check loss on drying.

Stage Run Sample Quantity Label Detail

Compression

Minimum, Optimum,

Maximum Speed 3x100 Nos.

Compressed Tablet

(uncoated)

Optimum Speed (Initial) 150 Nos.

Optimum Speed (Middle) 150Nos

Optimum Speed (End) 150Nos

Composite Sample 150Nos



Figure 2.2: Sampling Locations for FBD

2.4.3 At Lubrication Stage

By using SS sampling rod sample was withdrawn from each sampling point as shown in the RMG

sampling (Figure 2.1) after 5, 10, 15 minute. Each sample quantity should be at least equivalent to

one to three times of the dosage unit. Average weight of single dosage unit was 425.0 mg. sample

quantity to be taken is about 1100.0 mg of dry mix for each location to check uniformity of mixing.

2.4.4 At Compression Stage

Samples of approximately 150 nos. tablets each from LHS & RHS was collected at the initial,

middle and end of compression. 150 Nos. Make a composite sample of 150 Nos. tablets. Tablets

were to be tested for description, average weight, weight uniformity, diameter, thickness, friability,

hardness.

2.5 Testing Procedure:

2.5.1 Identification:

A. By Thin Layer chromatographic Identification Test:

Test Solution: Transfer a portion of powdered tablets, equivalent to about 100 mg of Captopril, to a

conical flask. Add 25 ml methanol, stir for 30 minutes using a magnetic stirrer and centrifuge. Use

the clear supernatant.

Standard Solution: 4 mg/ml in methanol. (40mg 10ml)

Application volume: 50µL, as streaks.

Developing Solvent System: a mixture of toluene, glacial acetic acid, and methanol (75:25:1)

Procedure: Locate the spots on the plate by lightly spraying with a freshly prepared mixture of 1

volume of ammonium hydroxide and 6 volumes of a solution of 0.04% 5, 5’dithiobis (2-

nitrobenzoic acid) in methanol.

The solvent front has moved about three-fourths of the length of the plate. Remove the plate from

the developing chamber, mark the solvent front, and allow the solvent to evaporate. Unless



otherwise directed in the individual monograph, locate the spots on the plate by examination under

short-wavelength UV light.

Observation: The Rf value of the principle spot obtained from the test solution corresponds to that

obtained from the Standard solution.

2.5.2 Average weight:

Select 20 tablets randomly from the analytical sample and weigh find out the average weight of a

tablet.

2.5.3 Uniformity of weight:

This test was performed on 20 tablets. Using a calibrated and suitable balance.

Individual 20 tablets weights from the average weight by more than ± 5.0% and none deviates by

more than ± 10.0%.

2.5.4 Diameter

Measure the diameter of 10 tablets using Vernier calipers record minimum, maximum and reports

average value.

2.5.5 Thickness:

Measure the thickness of 10 tablets using Vernier calipers record minimum, maximum and reports

average value.

2.5.6 Hardness:

Check the hardness of the ten tablets with hardness tester and record minimum, maximum and

report average value.

2.5.7 LOD:

LOD of the powder was checked by placing 5 g of sample in I.R. moisture balance which was

previously calibrated and recording the % LOD at 55˚C.

2.5.8 Bulk density and tapped density:

Bulk density was measured by weighing powder of approximately 10 grams and poured in 100 ml

glass cylinders, the initial volume occupied by material (in ml) was noted and volume occupied by

material after 100 taps in the bulk density apparatus was noted (in g/ml), then bulk density and

tapped density was calculated by using the following formula

Bulk density = weight of the material taken (in gm) / volume occupied by the

Material (in ml)

Tapped density = weight of the material taken (in gm) / volume occupied by

Material (in ml) after tapping.



2.5.9 Dissolution: (UV Absorption)

(a) Dissolution medium: 0.01 N Hydrochloric acid, 900 ml.

(Note: Completely deaerate the Dissolution medium to minimize exposure of Captopril to air, and

analyze the samples immediately).

Apparatus: Basket

RPM: 50 rpm

Test time: 20 minutes.

(b) Standard Solution:

Dissolve accurately weighed 55.0 mg of Captopril WS in 100 ml volumetric flask, and dilute with

dissolution medium. Take 2 ml of this solution dilute with 100 ml dissolution medium (55 mg

100 ml 2 ml 100 ml).

(c) Sample Preparation:

1 Tablet 900ml with dissolution medium.

Withdraw 10 ml of aliquot at the specified time interval and filter. Take a 10 ml filtrate in a 50 ml

volumetric flask & Dilute up to mark with dissolution medium.

(1 tablet 900 ml 10 ml 50 ml)

(d) Procedure:

Determine the amount of Captopril dissolved by employing UV absorption at the wavelength of

maximum absorbance at about 205 nm on filtered portion of the solution under test, suitably diluted

with dissolution having a known concentration of Captopril WS in the same amount of medium.

Calculate the % of Captopril dissolved in 20 min.

Sample Abs. Std. Wt. (mg) 2 900 50 Std. potency 100

= ------------------ x------------------x---- x ------x ----- x-----------------x ------------------

Std. Abs. 100 100 1 100 100 Label amount

2.5.10 Friability Test (%)

This test was performed on a sample of whole tablets weight of 6.5 g tablets.

The tablets should be carefully dedusted prior to testing. Accurately weigh the tablet sample and

place the tablets in the drum. Rotate the drum 100 times & remove the Tablets. Remove any loose

dust from the tablets as before, and accurately weigh.

Loss in weight x 100

% Friability = ----------------------------------------------

Wt. of whole tablets (about 6.5 g)



2.6 Deviation (If Any) From Protocol

The protocol shall be followed. Planned changes of the approved protocol must receive QA

approval prior to implementation. The proposed change to the protocol shall be provided with

justification and scientific rationale for change.

Any deviations like deviations from the protocol, batch record, or sampling plan shall be reported

to the Validation team and QA. These deviations shall be managed through deviation handling

system and a systematic, documented investigation and CAPA shall be performed and shall be

closed and approved by QA. The reference of the deviation shall be given in the protocol.

2.7 Design Space Study of Captopril Tablets

During manufacturing of Captopril Tablets Speed of machine is major variable. So Design Space

Study is performed on this variable. Content Uniformity is determined for Speed Challenge Study.

Parameters Checked during Speed Challenge Test Study Are:

Appearance

Average weight

Diameter

Thickness

Hardness

Friability

Disintegration

Hardness of Tablet is also important variable. It will indirectly affect the dissolution of the tablets.

So Dissolution is performed for hardness Challenge Study.

Thus Design Space Study of Captopril Tablets was performed on below parameters:

A) Machine Speed

B) Hardness of Tablets

2.8 RESULTS AND DISSCUSSION:

2.8.1 Process Validation Report:

Process Validation Report of Captopril Tablet USP was as Follows:

This report describes results obtained during the different processing steps to evaluate and qualify

the acceptability of the manufacturing process of Captopril Tablets. This report was also been

evident the reproducibility of process and results with consecutiveness.

2.8.2 Dry Mixing

Dry mixing was carried out in Rapid Mixer Granulator for 05, 10, 15 minutes and Samples were

collected from 11 different locations to test the content Uniformity. The results are as follows:



Table 1.5 Content uniformity after dry mixing

Batch Time Average SD %RSD Acceptance criteria

Batch A

5 99.74 1.70 1.70

Content Uniformity

Should be 85 % -

115 % and % RSD

is NMT 3 %

10 98.54 2.53 2.56

15 98.95 2.11 2.13

Batch B

5 99.83 1.72 1.72

10 99.76 1.59 1.29

15 100.13 1.29 1.28

Batch C

5 99.87 1.22 1.22

10 98.49 0.98 0.98

15 98.81 1.29 1.29

2.8.3 Evaluation:

%RSD of Captopril for all three validation batches were found within the limit of acceptance criteria.

It was evident that the dry mixing was in proper manner throughout the sampling locations.

2.8.4 Wet Mixing & Drying

2.8.4. a Wet Mixing:

Granulate the material at slow speed of impeller with chopper off and binder solution was added

slowly. Then start impeller at fast speed and chopper at slow/fast speed. Granulate the mass till dough

like consistency is formed and record the time for wet mixing.

Table 1.6 Wet Mixing Time Record

2.8.4. b Drying

Drying was performed at inlet temperature (at 55˚C) and samples were collected from 5 different

locations and % LOD is check. The results are as follow.

Batch Start End Duration Impeller

Speed

Chopper

Speed

Additional

Water

(if any)

Granulation

End Point

Batch A

16:30 16:32 2 min Slow Off NA (Impeller)

26.0Ampere

(Chopper) --

16:32 16:33:30 1 min. 30

sec. Slow Slow NA

16:33:30 16:36:30 3 min. Fast Slow NA

Batch B


26.1 Ampere

(Chopper) --

13:27 13:28:30 1 min. 30

sec. Slow Slow NA

13:28:30 13:31:30 3 min. Fast Slow NA

Batch C


25.8 Ampere

(Chopper) --

9:52 9:53:30 1 min. 30

sec. Slow Slow NA

9:53:30 9:56:30 3 min. Fast Slow NA



Table 1.7 Results of % LOD

2.8.4. c Evaluation:

% LOD of dried granules of Captopril were within the range for all three validation batches, which

were within the limit of specification.

2.8.5 Milling

Mill the dried granules through Sifter using 1.50 mm screen.

Table 1.8 Parameters of wet mixing, drying, sifting and sizing process

Sample Location % LOD Acceptance

Criteria Batch A Batch B Batch C

Left 2.05% 2.10% 2.28% % LOD of dried

granules at 50°

c

Should be 1.5 %

- 2.5% w/w

Right 2.10% 1.98% 2.20%

Centre 2.12% 2.01% 2.10%

Front 2.11% 2.10% 2.15%

Back 2.10% 2.10% 2.08%

Stage Results

Wet mixing

Batch A Batch B Batch C

Additional Quantity of Purified Water

Added NA NA NA

Total Quantity of Purified Water

Added 58.85 Lit. 58.85 Lit 58.85 Lit

Duration

of

Wet

Mixing

Impeller slow without

Chopper 2 min. 2 min 2 min.

Impeller slow with Chopper

slow 1 min. 30 sec. 1 min 30 sec 1 min. 30 sec.

Impeller fast with Chopper

slow 3 min. 3 min 3 min.

Additional mixing with

addition of additional water NA NA NA

End Point Value (Ampere)

Impeller :

26.0

Chopper : Off

Impeller : 26.1

Chopper : Off

Impeller :

25.8

Chopper : Off

Drying

Total Drying Time 170 min. 175 min. 175 min.

Inlet Temp. of FBD (50-55)˚C 50˚C 50˚C 50˚C

Outlet Temp. of FBD 38˚C 38˚C 38˚C

Sizing

Size of screen used for milling through

1.50mm 1.5 mm 1.5 mm 1.5 mm

Duration of sizing 30 min. 25 min. 25 min.



2.5.8.a Evaluation:

All the Parameters during Milling Stage were found satisfactory and were within Limit of

specification.

2.5.9 Lubrication

Blending was carried out in Rapid Mixer Granulator for 05, 10, 15 minutes and samples were

collected from 11 different locations to test the Blend Uniformity. Once composite Sample was

collected, loss on drying, and physical properties determination tests were performed on it. The

results are as follow

Table 1.9 Analytical Data for Lubricated Blend

2.5.9. aEvaluation:

% RSD of Captopril for all three validation batches were found within specification limit, it was

evident that there was no segregation or demixing occurs in the RMG and mixing is homogeneous

throughout the sampling locations for all three batches.

The physical parameter such as description, bulk density, tapped density, Angle of repose, and

particle size distribution for three validation batches were satisfactory and found consistent.

Significant observation related to the flow of the blend was observed throughout the compression

activity. Assay of Composite Blend for three validation batches was within the specification.

2.5.10 Compression

During compression, samples from compression machine at minimum speed, Maximum speed, and

Optimum speed were collected. At the initial, middle and end of compression from all the three

consecutive batches, samples were collected to test various in-process checks i.e. description,

Process Parameters &

Quality Attributes Batch A Batch B Batch C

Pre lubrication Time 5 min. 5 min. 5 min.

Lubrication Time 3 min. 3 min. 3 min.

Average of content uniformity 101.32% 99.96% 101.21%

%RSD (NMT 3 %) 1.31% 1.58% 1.55%

Composite Sample

Description(white coloured powder) Complies Complies Complies

Bulk Density(Untapped) 0.678gm/ml 0.678 gm/ml 0.678 gm/ml

Bulk Density(Tapped) 0.73 gm/ml 0.74 gm/ml 0.75 gm/ml

Angle of Repose 23.55 23.55 23.55

Loss on Drying 2.50% 2.24% 2.03%

Sieve Analysis

Pass thru. 20# 98.43% 98.44% 97.95%

Pass thru. 60# 74.88% 74.79% 74.79%

Pass thru. 80# 69.19% 68.20% 66.20%

Pass thru. 100# 58.69% 58.68% 58.72%

Assay (97.0 to 105.0%) 100.1% 100.3% 100.6%



average weight, Uniformity of weights, thickness, hardness, friability, and disintegration test. QC

test parameter like Assay was also performed. The results are as follows,

A. Inprocess check Results of physical Parameter at various speed

Table 1.10 Inprocess check Results of Physical parameter at various speed

Test Acceptance

Criteria

Observation

10 RPM

(Minimum)

12 RPM

(Optimum)

15 RPM

(Maximum)

Average

Weight 450.0 mg± 2 %

452.3 mg –

448.3 mg

450.5 mg –

541.8 mg

449.7 mg - 450.8

mg

Uniformity

of weight

450 mg ± 3

%

Min. 443 mg – 442

mg

442 mg - 443

mg 441 mg – 443 mg

Max. 460 mg - 458

mg

457 mg - 460

mg 458 mg – 460 mg

Diameter 11.30 mm

± 0.2 mm

Min. 11.31 mm -

11.29 mm

11.30 mm -

11.31 mm

11.29 mm – 11.31

mm

Max. 11.38 mm -

11.37 mm

11.39 mm –

11.40 mm

11.37 mm – 11.39

mm

Hardness NLT

40 N

Min. 49.20 N – 60.3

N 50.3 N – 60.3 N 51.7 N – 54.8 N

Max. 70.6 N – 76.4 N 72.4 N – 80.1 N 69.3 N - 73.4 N

Avg. 59.3 N – 68.3 N 62.3 N – 69.4 N 60.4 N – 63.5 N

Thickness 3.60 mm±

0.2mm

Min. 3.52 mm – 3.60

mm

3.57 mm – 3.59

mm

3.59 mm – 3.60

mm

Max. 3.64 mm - 3.70

mm

3.62 mm – 3.69

mm

3.63 mm – 3.69

mm

Friability NMT 1.0% w/w Nil – 0.01% Nil - 0.01% Nil – 0.01%

Disintegrati

on NMT 15 minute

2 min. 31 sec. –

2 min. 51 sec.

2 min. 37 sec. –

3 min. 12 sec.

2 min. 28 sec. – 3

min. 28 sec.



2.5.10. a Evaluation:

The Results of all Physical parameters and Uniformity of weight at different speed of machine (10-

15RPM) were found within the limit of acceptance criteria for all three batches. Hence at the

specified machine speed the compression stage is validated.

2.5.11 Finished Product Specification:

Table 1.11 Finished Product Test and Observation

Test Parameter Observation Acceptance

Criteria Batch-A Batch-B Batch-C

Identification By TLC

The Rfvalue of

the principle spot

obtained from the

test solution

corresponds to

that obtained

from the Standard

solution.

The Rfvalue of

the principle spot

obtained from the

test solution

corresponds to

that obtained

from the Standard

solution.

The Rfvalue of

the principle spot

obtained from the

test solution

corresponds to

that obtained

from the Standard

solution

The Rfvalue of the

principle spot

obtained from the

test solution

corresponds to that

obtained from the

Standard solution

Average weight 450.1 mg 452.3 mg 452.0 mg 450.0 mg ± 5 %

Uniformity of

Weight

Min. -1.38% -1.30% -1.55% ± 5% of Average

Wt. Max. +2.13% +1.13% +1.33%

Diameter Min. 11.40 11.38 11.39 11.30 mm ± 0.2

mm Max. 11.45 11.44 11.45

Thickness Min. 3.55 3.60 3.56 3.60 mm ±

0.2 mm Max. 3.75 3.73 3.73

Hardness Min. 45.2 48.9 56.0

NLT 40 N Max. 62.8 56.1 79.6

Dissolution Min. 88.1 88.4 88.5

NLT 80%(Q)(i.e.

85%) of labelled

amt. release in 20

minutes Max. 96.6 95.3 96.2

Disintegration 6 min 30 sec 6 min 30 sec 6 min 50 sec NLT 40 N

Friability 0.13% 0.18% 0.15% NMT 1.0%

Uniformity of Dosage 5.6 6.9 6.1

Acceptance Value

NMT 15.0 for first

Dosage units(L1)

Limit of Captopril

Disulfide 0.495% 0.488% 0.324% NMT 3.0%

Assay content of Captopril

USP 50 mg 99.9% 100.3% 100.1%

NLT 90.0% &

NMT 110% of L.A



2.5.11 Design Space Study (Challenge Study) Of Captopril Tablets

2.5.12.aSpeed Challenge Study

Table 1.12 Speed Challenge Study

Test

Parameter

Specification

Low speed

High speed

Machine Speed To be Established 10 rpm 15 rpm

Avg. Wt. 450.0 mg ± 5 % 448.3 mg -

452.3 mg 449.7 mg - 450.3 mg

Diameter 11.30 mm ± 0.2

mm

11.29 to

11.38mm

11.29 to

11.39 mm

Thickness 3.60mm±0.2 mm 3.52 to

3.70 mm

3.59 to

3.69 mm

Hardness NLT 40 N 49.20 to

74.6 N

51.70 to

73.40 N

Disintegration NMT 15 minutes

2 min. 31 sec.

- 2 min. 45

sec

2 min. 30 sec - 2 min. 53 sec

Friability NMT 1.0 % 0.01% 0.01%

2.5.12. b Hardness Challenge Study

Table 1.13 Hardness Challenge Study

Test

Parameter

Specification Low Hardness Hard Hardness

Avg. Wt. 450.0 mg ± 5 % 449.3 mg – 451.1 mg 449.4 mg – 450.1 mg

Diameter 11.30 mm ± 0.2 mm 11.30 to 11.37mm 11.30 to 11.38 mm

Thickness 3.60mm±0.2 mm 3.52 to 3.70 mm 3.56 to 3.68 mm

Hardness NLT 40 N(40- 60N) 49.2 to 50.6 N 62.8 N to 76.6 N

Disintegration NMT 15 minutes 2 min. 40 sec. - 2 min.

45 sec.

5 min. 20 sec. – 6 min 30

sec

Friability NMT 1.0 % 0.01% 0.01%



2.5.12. b Dissolution For Hardness Challenge Study

Table 1.14 Dissolution for Hardness Challenge Study

Acceptance

Criteria

Dissolution

Batch A Batch B Batch C

Low

Hardness

(NMT 40 N)

High

Hardness

(NLT 60 N)

Low

Hardness

(NMT 40 N)

High

Hardness

(NLT 60 N)

Low

Hardness

(NMT 40 N)

High

Hardness

(NLT 60 N)

NLT

80%(Q) i.e.

85%

dissolved in

20

min

Min. 88.2% 92.0% 92.1% 92.1% 92.0% 97.7%

Max

. 99.7% 99.1% 99.4% 99.4% 99.1% 99.7%

Avg. 95.23% 96.03% 95.15% 96.91% 94.66% 98.81%

2.6 ACKNOWLEDGEMENT:

The authors are thankful to the authorities for providing the facilities to carry out the present work.

2.7 REFERENCES:

1. Nash RA., and Watcher AH. Pharmaceutical Process Validation; 3rd

Edn; Revised and

Expanded Marcel DekkarInc, 2003, New York, pp 20-22.

2. Manohar AP. Pharmaceutical Quality Assurance; 2ndEdn; Nirali Prakashan, 2009, pp 8-20.

3. “Guidelines for Process Validation of Pharmaceutical Dosage Forms Version 2.1”, Oct

2013,www.sfda.sa/NR/rdonlyres/BA1624E9-39E4-4C2C-BCD3

98DCB7E97597/0/GuidelinesforprocessValidationofPharmaceuticalDosageForms.pdf

4. Vasava BY, M.pharm Thesis “Process Validation of Atorvastatin Film Coated Tablets”,

GTU, 2013

5. “The Validation Process”, December 2011, http://www.fda.com/csv/Chapter3.htm

6. FDA , “2011 Process Validation Guidance”, Autumn 2012,

http://www.fda.gov/downloads/AboutFDA/CentersOffices/OfficeofMedicalProductsandTob

acco/CDER/UCM334568.pdf

7. M. Kovalycsik, “Design Space and PAT, Q8 ICH Draft Guidance on Pharmaceutical

Development”, Oct 2013,

www.asqlongisland.org/seminars/Design_Spaceslides_MK_2005.pdf

http://www.sfda.sa/NR/rdonlyres/BA1624E9-39E4-4C2C-BCD3%2098DCB7E97597/0/GuidelinesforprocessValidationofPharmaceuticalDosageForms.pdf

http://www.sfda.sa/NR/rdonlyres/BA1624E9-39E4-4C2C-BCD3%2098DCB7E97597/0/GuidelinesforprocessValidationofPharmaceuticalDosageForms.pdf

http://www.asqlongisland.org/seminars/Design_Spaceslides_MK_2005.pdf



8. Implementation of ICH Q8,Q9, Q10 “Breakout :A Design Space”, Oct 2013,

www.ich.org/fileadmin/Public_Web_Site/Training/ICH_Endorsed_Training_Events

ASEAN_training_on_Q8_Q9_Q10_Guidelines/Breakout_A_DS_Summary.pdf

9. Jakob Christersen, “Design space”, Oct 2013,

www.mit.ida.dk/IDAforum/U0602c/Documents/20121101%20dsk.2012/05%20Jakob%20C

hristensen.pdf

10. Drug Profile of Captopril”, Oct 2013, www.drugbank.ca/drugs/DB01197.

http://www.ich.org/fileadmin/Public_Web_Site/Training/ICH_Endorsed_Training_Events%20ASEAN_training_on_Q8_Q9_Q10_Guidelines/Breakout_A_DS_Summary.pdf

http://www.ich.org/fileadmin/Public_Web_Site/Training/ICH_Endorsed_Training_Events%20ASEAN_training_on_Q8_Q9_Q10_Guidelines/Breakout_A_DS_Summary.pdf

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