Pharma Science Monitor An International Journal Of

Vol-3, Issue-3, July-2012

ISSN: 0976-7908

Yadav et al

PHARMA SCIENCE MONITOR
AN INTERNATIONAL JOURNAL OF PHARMACEUTICAL SCIENCES

PROCESS VALIDATION OF PARACETAMOL TABLET
Surendra Nath Yadav*1, Aarti Zanwar1, Jitesh Katewa2, A.K. Seth1
1Department of Pharmacy, Sumandeep Vidyapeeth, Pipariya, Vadodara (Gujarat)- 391760 2Combitic Global Caplet Pvt.Ltd.Sonipet (Harayana)-131001
ABSTRACT In present work, concurrent process validation of Paracetamol Tablet 500 mg, good release tablets was carried out to monitor process parameters in current production batches. In-process quality monitoring of all critical processing steps was done for three production batches, End product testing of current production batches was done to provide documented evidence that manufacturing process is in state of control. Assay for drug content was within the limit of 98%-102% at the dry mixing stage. LOD for the dried granules after wet granulation was within 1.30-1.80%. Assay after lubrication was within the specified limit at different corners in the blender, indicating blend uniformity. Physical parameters like average weight of tablet was found to be 589.5mg-592.5mg, thickness was found to be between 4.0mm-4.4mm, hardness was found to be 3.0kg/cm25.0kg/cm2, %friability was between 0.25%-0.41%. disintegration time was 3min -4min, assay of tablets 99.4%-100.0 % for all the three batches of compressed tablets. Temperature monitoring was done throughout the process. Dissolution occurred in buffer up to 30 min. at-50 rpm. , drug release in buffered medium was within the limit of 95%98% within 30 min. Thickness was 4.09mm-4.24 mm. Uniformity of dosage forms which is found to be (98 % to 102%). Blister strip packing was carried out for the tablets. During packing operation each pack size was checked for physical appearance and sealing quality and found satisfactory. All the tests were found to have satisfactory results. Thus process validation of paracetamol tablet 500mg was successfully completed and found within the specifications. Keywords: Paracetamol Starch, Pyrolidone cellulose Magnesium Stearate & Talcum having Good Release property, Process validation, Concurrent validation INTRODUCTION
A process is a series of interrelated function and activities using a variety of
specified action and equipment which is defined to produce a define result. To validate
the reproducibility and consistency of a process, the full defined process is carried out
using validated equipment, under the established procedure usually at least 3 times.
The process must successfully meet all acceptance criteria each time to consider a
validated process. In many cases, “worst cases” conditions are used for validation to
ensure that process is acceptable in the extreme cases. Sometimes worst condition for the

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Vol-3, Issue-3, July-2012

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Yadav et al

system can only really be tested overtime & hence must be evaluated using a rigorous long term monitoring programme.
Each of these categories may apply to several distinct processes in manufacturing facilities. Each process to be validated must be specific process clearly described in the master formula or in the SOP. All the equipment and the process parameter and the specification in each step must be detailed. Complete description of identity code number, construction operating capacity, and actual operating range must be defined for the equipment.
The processing parameter for all step must be sufficiently detailed to permit complete Reproducibility of the process each time it is performed, such as time period, pH, volume, temperature, measurement specification, acceptable range etc. The controls and test and their specification must be defined. The purity profile for the product process must be defined for the each step.
To be considered validated, the process must consistently meet all the specification at all stage throughout the procedure at least three times consecutively. It is very important that the specification for the process undergoing validation be predetermine. It is also important that all the critical processing parameter for which specification has been set; there must be equipment to measure all those parameter for which specification has been set.
Process validation studies examine a process under normal operating condition to prove that the process is in control. Once the process has been validated, it is expected that it remain in control, provided no change are made.
In the event that modification to the process is made, problem occurs or equipment, or systems, involved in the process are changed, the validation of the process would be required. Very often validation studies require more measurement than that required for the routine process. The validation must prove the consistency of the process, & therefore must assess the efficacy and effectiveness of each step to produce its intended outcome. [1-4]
MATERIALS AND METHOD
Granulation Raw Material:

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Paracetamol ,Lactose, Pregelatinized Starch ,Polyvinyl Pyrrolidone (Povidone K30),Purified water Lubrication Raw Material: Microcrystalline cellulose,Talcum,Sodium Starch, Glycolate, Colloidal Silicon Dioxide (Anhydrous) (Aerosil 200), Magnesium Stearate (Veg. Grade)

Manufacturing procedure and schematic diagram of sample location: Dry Mixing:
Add Paracetamol, Pregelatinized starch, Lactose and Polyvinyl Pyrrolidone previously weighed and sifted, sequentially in RMG & mixed for 15 min. at slow speed. Withdraw 2 gm samples by sampling thief at 8 different locations Top left, Top right, middle, bottom left & bottom right then collected three composite sample from top layer , middle layer & bottom layer ( Sample No. 6, 7 & 8 ) as shown in below diagram from RMG after 15 min. mixing interval. Send the sample to Q.C. department for assay analysis. (Total 8 sample)

COMPOSITE SAMPLE (6) TOP LAYER

Top Left (1)
Bottom Left (4)

COMPOSIT SAMPLE (7) MIDDLE LAYER
Middle (3)
COMPOSITE SAMPLE (8) BOTTOM LAYER

Top Right (2) Bottom Right (5)

Binding:

Fig:1 Rapid Mixer Granulator (RMG)

A. Binder preparation:

1. Take 15.0 Lt. purified water in to cleaned SS vessel.

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2. Add starch slurry and dissolved Povidone K 30 in above solution under continuous stirring and heat to prepare starch paste. B. Binding: 1. Start RMG containing dry mixed powder at slow speed, Add binder into RMG. 2. Mixed under slow speed for 20 - 22 minutes. Rinse the binder vessel with 0.5 Lt.
of purified water and added to RMG, ran the chopper during the mixing at slow speed for 3 - 4 minutes. Till granulation end point is reached to get required consistency of dough mass. C. Wet Milling: Passed the wet mass through conical mill using 15.0 mm screen. Collected the milled granules in to FBD bowl.
Drying: Performed drying in FBD: Loaded the wet mass of respective lot in FBD bowl. Dried the wet mass at ambient temperature for 15 min. Rack the mass of the bowl. Then dried at 40°C - 50°C inlet temperature with intermittent raking till water content of granules obtained must not be more than 7.0 – 4.0 %. After drying collected 5 gm by sampling thief sample at 5 different locations from the FBD bowl as per given below.

Top left(1)

Top right(2)

Middle (3)

Bottom left (4)

Bottom Right(5)

Fig:2 FLUIDISED BED DRYER (FBD)
After drying sifted the granules through # 18 sieves using vibratory sifter and over
size granules passed through oscillating Granulator using 1.2 mm S.S. screen.
After sifting and sizing loaded the Granules in octagonal Blender.

Lubrication:

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Yadav et al

Loaded the granules in octagonal blender and mix for 5 min. collecedt the composite sample by sampling thief from 5 different locations and check LOD. Add all lubricants previously weighed and sifted (except Magnesium Stearate) & mix for 15 minute mixing. Add sifted Magnesium Stearate & continue mixing for 3 min.

Œ • Ž • • ‘

Fig:3 OCTAGONAL BLENDER

Sample Position: Sample location for Lubrication stage

Left

Center

Right

Top Layer

1

2

3

Middle layer

4

5

6

Bottom Layer

7

8

9

Sample locations for lubrication stage Collected 2 gm samples by sampling thief from 9 different locations from
octagonal blender shown above after 15 min. mixing (Without addition of Magnesium stearate) & after addition of Magnesium stearate mix for 3 min. collected one composite Sample (approx. 100 gm) from 9 different locations. For analysis of loss on drying, Bulk density and sieve analysis (for information) after lubrication unloaded the granules in SS IPC.

Compression: Set the Compression Machine on following parameter and compressed the tablet

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Table;1 parameters of compression stage

S. No. 1
2
3 4 5 6 7 8 9

Tablet Parameter Appearance
Average weight of tablet
Weight of 20 tablet Uniformity of weight Dimension Thickness Hardness Friability Dissolution

Set value White round, flat, uncoated tablets with break line on one side. 590 mg ± 2% [578.2 mg to 601.8 mg]
11.800 gm ± 2 % [11.564 gm to 12.036 gm]
± 5 % of Average weight 13.55 X 4.20 ±0.2 mm 4.0 to 4.4 mm 3.0 –5.0 Kg /cm2 NMT 1.0 % w/w
NLT 80 %.

Blister strip Packing Machine setting and operation details : Set the machine as per standard operating procedure. After seating the machine, operate on selected temperature & speed. Following parameters checking during striping.

• Appearance of strips : Aesthetically good legible over coding, no colors

smudging of strips.

• Sealing and cutting : Proper sealing, uniform cutting.

• Cut pocket

: Free from hollow pocket, no damage pocket.

• Leak test

: No one pocket should wet.

• Appearance of tablet : Appearance of tablet should match as per description of

(after strip packing)

tablet.[5-14]

RESULTS & DISCISSION
The Manufacturing of paracetamol Tablet-500mg is validated successfully considering the following Parameter.

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S.No. 1.0 2.0 3.0 4.0 5.0
6.0 7.0

Process stage Dry mixing

Observation : Dry mixing performed in RMG for 15 min.

Wet mixing : and Binding

Drying

:

Sifting and :

sizing of dried

granules

Lubrication

:

Compression :

Blister strip

:

Wet mixing performed for 20 - 22 minute at slow speed, keeping the chopper ON for 3 - 4 min. Wet milling done through Co mill using 15.0 mm screen. Drying performed in fluid bed dryer. Initial drying at ambient Temperature for 15 min. Final drying at 40 - 50º C Temperature for 25 – 50 min. Dried granules sifted through 16 mesh sieve using vibratory sifter, and pass the over sized granules through 1.2 mm ss screen through Oscillating granulator. Lubrication performed in Octagonal Blender. Unlubricated granules mixed for 5 min. Lubricated granules mixed without Magnesium Stearate for 15 min. Lubricated granules mixed with Magnesium Stearate for 3 min. Compression performed on single rotary press at 30 ± 5 [25 to 35] RPM. Blister Strip sealing : ( For 47525) Blister forming roller Temperature Observed between 120 ± 20 º C and Counter sealing roller Temp. Observed between 220 ± 20 º C at speed 40 ± 10 cuts/ min. Blister Strip sealing : ( For 35950) Blister forming roller Temperature Observed between 150 ± 20 º C and Counter sealing roller Temp. observed between 220 ± 20 º C at speed 40 ± 10 cuts/ min.

Status of Qualification:

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To be used in manufacturing of Paracetamol Tablet-500mg shall be described as per the following table: Table: 2 Status of Qualification

S. No. 1. 2. 3.

Name of the Equipment Vibratory sifter
Rapid Mixer Granulator Steam Kettle

Qualified (Yes / No) YES YES YES

4.

Multi mill

YES

5.

Fluid Bed Dryer

YES

6.

Oscillating Granulator

YES

7.

Octagonal Blender

YES

8.

Compression Machine

YES

9.

Blister strip machine

YES

10.

PLC validation of Critical equipment

YES

Status of Preventive Maintenance: The status of the preventive maintenance of various equipment shall be described as per the following table: Table: 3 Status of Preventive maintainance

S. No 1. 2. 3. 4. 5. 6. 7. 8. 9.

Name of the Equipment Vibratory sifter
Rapid Mixer Granulator Steam Kettle Multi mill
Fluid Bed Dryer Oscillating Granulator
Octagonal Blender Compression Machine Blister strip Machine

Preventive maintenance Status Conforms Conforms Conforms Conforms Conforms Conforms Conforms Conforms Conforms

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Status of Calibration: The status of calibration of different gauges, thermometer, sensors, balances, etc. shall be described as per the following table:

Table: 4 Status of Calibration

S. Measuring Device
No

1.

Weigh Balance (Granulation)

2.

Thermo Hygrometer (Granulation)

3.

FBD outlet Temperature gauge

4.

FBD inlet Temperature gauge

5.

IR Moisture balance

6.

Thermo Hygrometer (Compression)

7.

Balance (IPQC)

8.

Vernier Calipers

9.

Hardness Tester

10.

Friability Apparatus

11.

Disintegration Test Apparatus

12.

Dissolution

13.

Thermo Hygrometer (Blister packing)

14.

Blister strip Machine Temperature gauge

15.

Blister strip Machine Pressure gauge

Calibration Status
Calibrated Calibrated Calibrated Calibrated Calibrated Calibrated Calibrated Calibrated Calibrated Calibrated Calibrated Calibrated Calibrated Calibrated Calibrated

Manufacturing process observation and Analytical Results:

Table: 5 Dry mixing stage observation

Equipment : Rapid Mixer Granulator

(RMG)

Speed :

At slow speed

X

From

To

Total Mixing 10:40

10:55

Time

15 min.

Dry mixing Time : 15 min

Batch No.

Y

From

To

16:10

16:25

15 min.

Z

From

To

10:20

10:35

15 min.

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Yadav et al

Table: 6 Analytical results

Paracetamol content in dry mix :

Sample Sample Location
Identification

Sample (S1) Sample (S2) Sample (S3) Sample (S4) Sample (S5) Sample (S6)
Sample (S7)
Sample (S8)
Average RSD

Top Left Top Right
Middle Bottom Left Bottom Right Composite Top
Layer Composite Middle
Layer Composite Bottom
Layer -----

Acceptance criteria : 98.0 % to 102.0%

Batch No.

X

Y

Z

99.1

99.0

98.4

99.1

99.8

99.2

99.2

99.6

99.7

99.0

99.5

99.8

99.4

99.6

99.6

99.4

99.8

100.5

99.2

99.5

101.0

99.1
99.19 0.15

99.9
99.59 0.28

99.7
99.74 0.78

Table: 7 Inprocess checks for Binder

S.

Parameter

No.

1.

Transfer of starch slurry

2. Addition and dissolution of Povidone K 30

X Done
Done

Observation Batch No. Y Done
Done

Z Done
Done

Inprocess checks for wet mixing and binding stage observation: Table: 8 Inprocess checks for wet mixing and binding

Batch No.

S.

Parameter

X

Y

Z

Observation

No.

From To From To From To

1 Wet Mixing at slow 11:10 11:30 16:30 16:50 10:40 11:00 speed for 20 - 22 min.

Keeping chopper ON

Satisfactory

2 at slow speed for 3 - 4 11:35 11:38 16:55 16:58 11:05 11:08

min.

Quantity of extra

3

Purified water (If

-

-

-

Satisfactory

required)

Ampere load at the

4

end point of

38.4

37.7

35.8

Satisfactory

granulation

(For data Collection)

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