INTERNATIONAL JOURNAL OF UNIVERSAL PHARMACY ...

International Standard Serial Number (ISSN): 2319-8141 International Journal of Universal Pharmacy and Bio Sciences 2(3): May-June 2013

INTERNATIONAL JOURNAL OF UNIVERSAL

PHARMACY AND BIO SCIENCES

Pharmaceutical Sciences Research Article……!!!

Received: 02-06-2013; Accepted: 10-06-2013

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PPaallllaavvii JJoosshhii**,, NNiiddhhii AAsswwaall ,, AAllkkaa NN.. CChhoouuddhhaarryy

QQuuaalliittyy AAssssuurraannccee DDeeppaarrttmmeenntt LLaabboorraattoorryy,, DDiivviissiioonn OOff PPhhaarrmmaacceeuuttiiccaall SScciieennccee,,

SSGGRRRRIITTSS,, PPaatteell NNaaggaarr,, DDeehhrraadduunn,, UUttttaarraakkhhaanndd,, IInnddiiaa.. PPiinn CCooddee-- 2244000011..

KEYWORDS:

Manufacturing Process,

Process Validation,

Rosuvastatin Tablets.

For Correspondence:

PPaallllaavvii JJoosshhii**

Address:

QQuuaalliittyy AAssssuurraannccee

DDeeppaarrttmmeenntt LLaabboorraattoorryy,,

DDiivviissiioonn ooff

PPhhaarrmmaacceeuuttiiccaall SScciieennccee,,

SSGGRRRRIITTSS,, PPaatteell NNaaggaarr,,

DDeehhrraadduunn,, UUttttaarraakkhhaanndd,,

IInnddiiaa.. PPiinn CCooddee-- 2244000011..

ABSTRACT

Validation is the most basic and important step for maintaining

the quality of any pharmaceutical product. Process validation

ensures that a process consistently produces a product that meets

its specifications. Each validated step of any process ensure about

the fine quality of that final product. It is the collection and

evaluation of data from the each process throughout the

procedure. In this research article three batch of rosuvastatin

calcium are taken. They all have same size, same quantity,

equipment, method and validation criteria. This process consist

of dry mixing, lubrication, compression parameters and then

evaluation of manufactured tablets of each batch. The outcome

states that this process validation gives a higher degree of quality

assurance. All batches fulfill the requirements of given criteria.

501 Full Text Available On www.ijupbs.com

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International Standard Serial Number (ISSN): 2319-8141

INTRODUCTION:

Process Validation is defined as the collection and evaluation of data, from the process design stage

throughout production, which establishes scientific evidence that a process is capable of consistently

delivering quality products.

A validation manufacturing process is one, which has been proved to do what it purports to is

represented to do. The proof of validation is obtained through the collection and evaluation of data,

preferably, beginning from the process development phase and continued through into the

production phase, validation necessarily includes process qualification, but it also includes the

control of the entire process for repeated batches or runs [1].

The development of a drug product is a lengthy process involving drug discovery, laboratory testing,

animal studies, clinical trials and regulatory registration. To further enhance the effectiveness and

safety of the drug product after approval, many regulatory agencies such as the United State Food

and Drug Administration (USFDA) also require that the drug product be tested for its identity,

strength, quality, purity and stability before it can be released for use. For this reason pharmaceutical

validation and process controls are important in spite of the problems that may be encountered [2-3].

A successful validation program depends upon information and knowledge from product and

process development. This knowledge and understanding is the basis for establishing an approach to

control of the manufacturing process results in products with the desired quality attributes [4-5].

Prospective Validation:

Prospective validation means validation, which is done during the product development stage. When

we develop a new manufacturing process each step in the new process is required to be established

that it will give us the desired results, in the routine processing. In this stage the limits of variations

of the process parameters are identified and it is shown that within these variation the output product

will still be within the quality specification defined. It is defined as the established documented

evidence that a system does what it purports to do based on a pre-planned protocol. This validation

usually carried out prior to distribution either of a new product or a product made under a revised

manufacturing process. Performed on at least three successive production-sizes. Every aspect from

laboratory scale to commercial scale is documented on record of the prospective validation carried

out [6-8].

Essentials of Validation:

There are two main reasons for validating a process. The first is to reduce production costs of

sorting and rework due to the manufacture of non-conforming products [products that do not meet

their specification(s)]. The second is to meet regulatory requirements. Regulatory bodies, such as the

FDA, may require process validation.




Validation is required for the following reasons:

a) To design or built the quality, safety, and efficacy into the product.

b) Each step of a manufacturing process is controlled to assure that the finished product meets

all design characteristics and quality attributes including specifications.

c) To assure the quality merely by in-process and finished product inspection [9-10].

MATERIAL AND METHOD:

Methodology

Validation procedure:

a) Three batches of 100 tablets batch size to be manufactured as described in the batch

manufacturing record.

b) Current version of standard operating procedures to be followed.

c) Record the observations at every stage in the below specified data sheets.

d) Record the results after compression.

e) Evaluation of formulated rosuvastatin tablet is done and the results are recorded.

Materials:

Rosuvastatin was used as a active ingredient. Sodium Alginate used as a disintegrant. Lactose

worked as diluents to increase the bulk. Stabilizing agent magnesium hydroxide was added. And for

the lubrication magnesium state was used [11]. Amount of ingredient used is given in table 1.

Machineries:

For the validation mortar pestle was used for mixing. Weighing machine was used to weight the

ingredients and for weight variation. Single punch machine was used for compression method. For

hardness testing Monsanto apparatus was used. Roche friability apparatus was used for friability

testing. Dissolution and disintegration apparatus was taken. For the assay method Double Beam

Ultraviolet Spectroscopy was used.

Process of Tablet Manufacturing:

The critical process considered during the process validation of Rosuvastatin 10 mg tablets were-

1. Dry Mixing

2. Lubrication

3. Compression

Dry Mixing:

The dry-mixing step involves mixing of active ingredients with other additives using mortar pestle.

The content of Rosuvastatin in the dry mix was tested, to validate dry mixing process. In dry mixing

stage 3 batches like Batch A, Batch B, Batch C were considered for validation. Each sides sampled

from Location 1 (A1, A2, A3), Location 2 (B1, B2, B3), Location 3 (C1, C2, C3) of mortar pestle in

self sealing bags for QC analysis of assay.




Lubrication:

This step involves mixing of Lubricating agent with drug & other additives material. The purpose of

mixing was to get a uniform distribution of drug powder and lubricating agent. This was followed by

mixing of the drug powder rosuvastatin with lubricant magnesium stearate to get good flow and anti-

adhesion property of the mixer.

Compression of Tablets:

The sample was filled in the dies of single punch machine where the powder mixer were compressed

in to tablets. Compression carried out as per batch manufacturing recorded. Collect the sample at

various, i.e. at start, middle and end of compression process and carry out testing of content

uniformity and evaluated for physical parameters such as hardness, thickness, friability etc. In

compression stage three batches were considered for validation.

Tablets were compressed using round Punch, Upper punch & lower Punches plain. Each 100 mg

tablet contains 10mg Rosuvastatin.

Evaluation parameter of tablet in process validation:

1. Content uniformity

2. Weight variation

3. Thickness

4. Hardness

5. Friability

6. Assay

Content Uniformity: After the compression method the content uniformity of tablets was tested.

The assay method was followed to check the content uniformity.

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 not more than two of the individual tablet weight deviate from the

average weight.

Thickness: Twenty tablets were randomly selected from each batch and thickness was measured by

using digital vernier caliper

Hardness: The crushing strength Kg/cm2 of prepared tablets was determined for 10 tablets of each

batch by using Monsanto tablet hardness tester. The average hardness and standard deviation was

determined.

Friability: Twenty tablets were weighed and placed in the Roche friabilator and apparatus was

rotated at 25 rpm. After revolutions the tablets were deducted and weighed again. The percentage

friability was measured using the formula,




% F = {1-(Wt/W)} ×100

Where, % F = friability in percentage

W = Initial weight of tablet

Wt = weight of tablets after revolution [1-14].

Assay:

Standard solution preparation: Standard solution of Rosuvastatin was prepared by dissolving

20.10 mg of Rosuvastatin in 200ml of methanol to obtain a solution containing 0.1mg/ml. Further

diluted 5ml to 50ml with same solvent to obtain a solution containing 10 μg/ml.

Sample solution preparation: Twenty tablets of Rosuvastatin were weighed and powdered.

Amount of powdered equivalent to 20 mg taken into a 200ml volumetric flask, 140 ml methanol

added to dissolve the drug, cooled the flask up to the room temperature and methanol was added to

make up the volume up to the mark, centrifuged at 4000 RPM for 10mins, Further diluted 5ml to

50ml with same solvent to obtain a solution containing 10 μg/ml. [15]

Abs sample Conc. Of Std Potency

Practical yield = ------------------- x ------------------- x ----------------x Avg wt.

Abs Standard Conc. of Smp 100

Practical yield

% Assay as per L.C. = ------------------------ x 100

Theoretical yield

RESULTS AND DISCUSSION:

Process of Tablet Manufacturing: The rosuvastatin tablets were formulated and the results of

every step were recorded. The results of process validation of rosuvastatin of each batch in every

stage is as follow:

Dry Mixing Process: The dry-mixing step involves mixing of active ingredients with other

additives using mortar pestle. In dry mixing stage 3 batches like Batch A, Batch B, Batch C were

considered for validation. Each sides sampled from Location 1 (A1, A2, A3), Location 2 (B1, B2,

B3), Location 3 (C1, C2, C3) layer of mortar pestle were taken in self sealing bags for QC analysis

of assay. The results of dry mixing are shown in table 2.

All the % assay were under the acceptable criteria of standards. So the content uniformity was

acceptable for manufacturing of tablets.

Lubrication Stage: This step involves mixing of Lubricating agent with drug & other additives

material. The purpose of mixing was to get a uniform distribution of drug powder and lubricating

agent. This was followed by mixing of the drug powder with lubricant to get good flow and anti-

adhesion property of the mixer. The results of lubrication process are given in table 3.




Compression Process: The sample was filled in the dies of single punch machine where the powder

mixer were compressed in to tablets. Compression carried out as per batch manufacturing recorded.

Results of compression are shown in table 4.

Evaluation Parameters: The formulated tablets were evaluated as according to parameters. Weight

variation, thickness and hardness were checked and the obtained data was recorded.

Weight Variation: The manufactured tablets were evaluated on the weight variation test. The

results are shown below in table 5.

Thickness: The tablets were evaluated on the basis of their thickness. The results of the thickness

test are shown in the table 6.

Hardness: Hardness of the 10 tablets of each batch is checked. And the results are shown in the

table 7.

CONCLUSION:

In process validation of Rosuvastatin the tablet manufacturing process was followed. Then the

evaluation of formulated tablets had been done. The manufactured tablets of each batch passed the

acceptable criteria of evaluation parameters (i.e. content uniformity, weight variation, thickness,

friability, hardness, dissolution and disintegration). And there were negligible variations between the

process validation results of each batch which were under acceptable criteria.

ACKNOWLEDGEMENT:

Author take this pleasant opportunity to express her deep sense gratitude to this holiness Mahant

Shri Devendra Daas Ji Maharaj, for providing the required the facilities for research work.

Tables:

Table no.-1 Chemical Used In Formulation

Ingredients

Pharmacopial

status

Theoritical

Quantity

(mg)/tab

Actual

quantity

(mg)/tab

Quantity per

batch

(gm)

Rosuvastatin Active

Pharmaceutical

ingredient

10 mg 10mg 1

Sod. Alginate Disintegrant 4.5mg 4.5mg 0.45

Lactose Diluent 40.5mg 40.5mg 4.05

Microcrystalline

cellulose

Binder 22.5mg 22.5mg 2.25

Magnisium

hydroxide

Stabilizer 21.6mg 21.6mg 2.16

Magnesium sterate Lubricant 0.9mg 0.9mg 0.09




Table no.- 2 Results after dry mixing

Table 3: Lubrication Stage Results


BATCH A

BATCH B

BATCH C

Assay result after

completion of

mixing process

Location 1

98.68%

98.56%

101.4%

99.4%

99.32%

99.83%

98.12%

98.34%

99.59%

Location 2

98.02%

99.65%

98.48%

98.4%

100.01%

99.73%

98.76%

98.58%

100.76%

Location 3

99.82%

98.09%

98.55%

100.93%

98.37%

99.63%

98.10%

99.48%

98.35%

SD % 0.91 0.64 0.97

% Assay

After 20 min After 25 min After 30 min

Location 1 Batch A Batch B Batch C Batch A Batch B Batch C Batch A Batch B Batch C

98 .81 98.01 100.1 98.85 98.45 98.54 99.36 100.87 98.83

99.08 98.56 101.56 99.47 99.47 99.49 98.74 99.97 99.05

99.47 98.38 99.7 99.68 98.39 98.38 99.47 101.5 98.98

Location 2 101.2 99.59 98.02 99.97 99.36 99.29 99.43 99.12 99.43

99.36 99.38 98.28 100.01 98.35 101.46 98.93 98.83 98.04

99.27 98.29 99.37 102.32 99.86 98.73 98.26 99.26 99.35

Location 3 98.67 100.87 98.47 99.79 98.37 99.47 100.59 98.49 98.47

99.94 99.18 98.95 99.73 98.43 99.7 99.3 98.75 99.37

99.29 102.26 99.25 98.6 99.36 98.57 98.47 99.54 99.96

SD% 0.70 1.43 1.09 1.00 0.67 0.91 0.64 0.95 0.71

RSD % 0.70 1.43 1.09 1.00 0.68 091 065 0.95 0.72



Table 4- Compression stage observation

Parameter Critaria Batch A Batch B Batch C Inference

Appearance

Ok

Ok

Ok

White colored powder,

round shaped, plain on

both side.

Weight variation

(mg)

Max 100.1 100.7 101

Not less or more than 5%

from average Min 99 99.2 99.2

Avg 99.7 99.8 99.95

Thickness (mm)

Max 2.8 2.8 2.8

2.4mm to 2.8mm Min 2.4 2.4 2.4

Avg 2.7 2.7 2.6

Hardness(kg/cm2)

Max 4 4 4

From 2 to 5 kg/cm sq Min 2 3 3

Avg 3.3 3.4 3.5

Friability (%)

Max 0.58 0.49 0.41

Not more than 1% w/w Min 0.39 0.35 0.27

Avg 0.47 0.41 0.35

Disintegration(min)

Max 3.57 3.12 3.13

Not more than 15 min Min 2.64 2.23 1.85

Avg 3.14 2.72 2.35

Dissolution (%)

Max 91.5 93.65 92.98

Not less than 80% Min 85.4 84.47 86.94

Avg 89.37 90.75 88.82

Assay %

Max 100.93 100.01 101.76

98% to 105% Min 98.02 98.09 98.35

Avg 98.91 98.93 99.59




Table 5: Weight variation of compressed tablets


Sample No. Batch A (mg) Batch B (mg) Batch C (mg)

1 99.6 100 99.4

2 99.8 100.2 99.7

3 99.8 99.7 101

4 99.7 99.5 100.9

5 99.6 99.7 100.5

6 99.9 99.3 99.7

7 100.1 99.8 99.4

8 100 99.2 99.9

9 99.8 99.9 99.5

10 99.7 100 99.9

11 99.9 99.4 99.6

12 99 99.9 100

13 99.3 100.3 100

14 99.7 100.2 99.8

15 99.2 99.7 99.8

16 99.5 99.8 100.7

17 99.9 99.2 99.4

18 99.6 100 99.9

19 100 100.6 99.5

20 99.4 99.8 100

Maximum 100.1 100.7 101

Minimum 99 99.2 99.2

Average 99.7 99.8 99.95



Table 6: Thickness of compressed tablets

Sample

no.

Batch A (mm) Batch B (mm) Batch C (mm)

1 2.5 2.8 2.6

2 2.6 2.7 2.5

3 2.6 2.5 2.5

4 2.5 2.6 2.6

5 2.4 2.5 2.7

6 2.6 2.7 2.5

7 2.6 2.6 2.8

8 2.8 2.7 2.7

9 2.4 2.5 2.6

10 2.6 2.4 2.5

11 2.5 2.7 2.4

12 2.7 2.5 2.8

13 2.7 2.4 2.8

14 2.8 2.5 2.8

15 2.6 2.4 2.5

16 2.7 2.6 2.3

17 2.5 2.8 2.6

18 2.4 2.7 2.7

19 2.6 2.7 2.8

20 2.4 2.5 2.6

Maximum 2.8 2.8 2.8

Minimum 2.4 2.4 2.4

Average 2.7 2.7 2.6

Table 7: Hardness of compressed tablets

Sample no. Batch A Batch B Batch C

1 4 3 3

2 3 4 4

3 2 3 4

4 3 3 3

5 4 3 3

6 4 4 3

7 3 4 4

8 3 3 4

9 3 4 3

10 4 3 4

Maximum 4 4 4

Minimum 2 3 3

Average 3.3 3.4 3.5




Fig 1: Comparison of weight variation for three batches

Weight Of Tablets

Samples

Fig 2: Comparison of thickness of three batches:

Fig 3: Comparison of hardness of three batches:

Hardness

Sample




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