PHARMA SCIENCE MONITOR AN INTERNATIONAL JOURNAL OF ... · vibratory sifter, and pass the over sized granules through 1.2 mm ss screen through Oscillating granulator. 5.0 Lubrication

Vol-3, Issue-3, July-2012 ISSN: 0976-7908 Yadav et al

www.pharmasm.com IC Value – 4.01 29

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/cm2-5.0kg/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



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 pre-

determine. 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:



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)

Binding:

A. Binder preparation:

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

Top Left (1) Top Right (2)

Bottom Left (4)

Bottom Right (5)

Middle (3)

Fig:1 Rapid Mixer Granulator (RMG)

COMPOSITE SAMPLE (6) TOP LAYER

COMPOSITE SAMPLE (8) BOTTOM LAYER

COMPOSIT SAMPLE (7) MIDDLE LAYER



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.

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:

Fig:2 FLUIDISED BED DRYER (FBD)

Top left(1)

Top right(2)

Bottom left (4)

Bottom Right(5)

Middle (3)



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.

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

Fig:3 OCTAGONAL BLENDER

å ç é

è ê ë



Table;1 parameters of compression stage

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

(after strip packing)

: Appearance of tablet should match as per description of

tablet.[5-14]

RESULTS & DISCISSION

The Manufacturing of paracetamol Tablet-500mg is validated successfully considering

the following Parameter.

S. No. Tablet Parameter Set value

1 Appearance White round, flat, uncoated tablets with break line on one side.

2 Average weight of tablet 590 mg ± 2% [578.2 mg to 601.8 mg]

3 Weight of 20 tablet 11.800 gm ± 2 % [11.564 gm to 12.036 gm]

4 Uniformity of weight ± 5 % of Average weight

5 Dimension 13.55 X 4.20 ±0.2 mm

6 Thickness 4.0 to 4.4 mm

7 Hardness 3.0 –5.0 Kg /cm2

8 Friability NMT 1.0 % w/w

9 Dissolution NLT 80 %.



S.No. Process stage Observation

1.0 Dry mixing : Dry mixing performed in RMG for 15 min.

2.0 Wet mixing

and Binding

: 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.

3.0 Drying : 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.

4.0 Sifting and

sizing of dried

granules

: 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.

5.0 Lubrication : 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.

6.0 Compression : Compression performed on single rotary press at

30 ± 5 [25 to 35] RPM.

7.0 Blister strip : 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:



To be used in manufacturing of Paracetamol Tablet-500mg shall be described as

per the following table:

Table: 2 Status of Qualification

S. No. Name of the Equipment Qualified (Yes / No)

1. Vibratory sifter YES

2. Rapid Mixer Granulator YES

3. Steam Kettle 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 Name of the Equipment Preventive maintenance Status

1. Vibratory sifter Conforms

2. Rapid Mixer Granulator Conforms

3. Steam Kettle Conforms

4. Multi mill Conforms

5. Fluid Bed Dryer Conforms

6. Oscillating Granulator Conforms

7. Octagonal Blender Conforms

8. Compression Machine Conforms

9. Blister strip Machine Conforms



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. No

Measuring Device Calibration Status

1. Weigh Balance (Granulation) Calibrated

2. Thermo Hygrometer (Granulation) Calibrated

3. FBD outlet Temperature gauge Calibrated

4. FBD inlet Temperature gauge Calibrated

5. IR Moisture balance Calibrated

6. Thermo Hygrometer (Compression) Calibrated

7. Balance (IPQC) Calibrated

8. Vernier Calipers Calibrated

9. Hardness Tester Calibrated

10. Friability Apparatus Calibrated

11. Disintegration Test Apparatus Calibrated

12. Dissolution Calibrated

13. Thermo Hygrometer (Blister packing) Calibrated

14. Blister strip Machine Temperature gauge Calibrated

15. Blister strip Machine Pressure gauge Calibrated

Manufacturing process observation and Analytical Results:

Table: 5 Dry mixing stage observation

Equipment : Rapid Mixer Granulator (RMG)

Dry mixing Time : 15 min

Speed : At slow speed

Batch No. X Y Z

From To From To From To

Total Mixing Time

10:40 10:55 16:10 16:25 10:20 10:35

15 min. 15 min. 15 min.



Table: 6 Analytical results

Paracetamol content in dry mix : Acceptance criteria : 98.0 % to 102.0%

Sample Identification

Sample Location Batch No.

X Y Z

Sample (S1) Top Left 99.1 99.0 98.4 Sample (S2) Top Right 99.1 99.8 99.2 Sample (S3) Middle 99.2 99.6 99.7 Sample (S4) Bottom Left 99.0 99.5 99.8 Sample (S5) Bottom Right 99.4 99.6 99.6

Sample (S6) Composite Top

Layer 99.4 99.8 100.5

Sample (S7) Composite Middle

Layer 99.2 99.5 101.0

Sample (S8) Composite Bottom

Layer 99.1 99.9 99.7

Average --- 99.19 99.59 99.74 RSD --- 0.15 0.28 0.78

Table: 7 Inprocess checks for Binder

S. No.

Parameter Observation

Batch No. X Y Z

1. Transfer of starch slurry Done Done Done

2. Addition and dissolution of Povidone K

30 Done Done Done

Inprocess checks for wet mixing and binding stage observation:

Table: 8 Inprocess checks for wet mixing and binding

S. No.

Parameter Batch No.

Observation X Y Z From To From To From To

1 Wet Mixing at slow

speed for 20 - 22 min. 11:10 11:30 16:30 16:50 10:40 11:00

Satisfactory 2

Keeping chopper ON at slow speed for 3 - 4

min. 11:35 11:38 16:55 16:58 11:05 11:08

3 Quantity of extra Purified water (If

required) - - - Satisfactory

4

Ampere load at the end point of granulation

(For data Collection)

38.4 37.7 35.8 Satisfactory



Milling stage Observation:

Table: 9 Milling stage Observation

Equipment Screen

size

Observation Batch No.

X Y Z

CO – Mill 15.0 mm

Passed the wet mass through co-

mill using 15.0 mm screen.

Passed the wet mass through co-

mill using 15.0 mm screen.

Passed the wet mass through co-mill using 15.0 mm

screen.

Drying stage Observation:

Table: 10 Drying stage Observation

Batch No.

Initial Drying at Ambient Temperature

15 min.

Inlet Temp. (40 – 500C)

*Out let Temp.

Final Drying for 25 – 50 min. Remark

From TO Time From TO Time

X 12:20 12:35 15

min. 450c 290c

12:45 13:05

13:00 13:30

15 min 25 min

Satisfactory

Y 17:15 17:30 15

min. 450c 280c

17:35 18:00

17:50 18:20

15min 20 min

Satisfactory

Z 11:30 11:45 15

min. 450c 290c 11:55 12:35 40 min Satisfactory

Water content result after drying:

Table: 11 Water content result after drying

Loss on drying of dried Granules Acceptance criteria : 1.0 – 2.0 %

Batch No. Top Left

Top Right

Middle Bottom

Left Bottom Right

% RSD (for

information)

X 1.34% 1.38% 1.36% 1.41% 1.40% 0.506

Y 1.54% 1.51% 1.58% 1.61% 1.59% 0.516

Z 1.43% 1.42% 1.51% 1.55% 1.49% 0.606

Granules sifting and sizing observation:



Table: 12 Granules sifting and sizing observation

Equipment Process Sieve /

Screen size

Observation Batch No.

X Y Z

Vibratory sifter

Sifting 16

Sift the dried material

through 16 mesh using

vibratory sifter.



vibratory sifter.



vibratory sifter.

Oscillating Granulator

Sizing 1.5 mm

Passed the retention

through OG using 1.5 mm

ss screen.



ss screen.



ss screen.

Table: 13 Water content results after sifting and sizing

S.

No.

Test to be performed

(composite sample) Limit

Results (for information) Batch No.

X Y Z

1 Loss on drying 1.0 – 2.0 % 1.41% 1.54% 1.49%

Table: 14 Lubrication Stage Observation

Equipment : Octagonal Blender

Process stage

Batch No. X Y Z

From To From To From To

Unlubricated granules mix for 5 min.

10:20 1025 12:40 12:45 16:50 16:55

Lubricated granules mix for 15 min.

10:40 10:55 13:40 13:55 17:20 17:35

Total mixing time 20 min. 20 min. 20 min.



Analytical Results:

Table: 15 Analytical Results of samples after lubrication

Paracetamol content in Lubricated Granules :

Acceptance criteria: 98.0 % to 102.0%

Sample No. Sample ID Batch No.

X Y Z

Sample 1(S1) Top Left 99.5 99.8 99.9 Sample 2 (S2) Top Center 99.7 99.7 99.6

Sample 3 (S3) Top Right 99.5 99.7 99.6 Sample 4 (S4) Middle Left 99.6 99.9 99.5

Sample 5 (S5) Middle Center

99.8 99.5 99.6

Sample 6 (S6) Middle Right 100.0 99.2 99.4 Sample 7 (S7) Bottom Left 98.4 99.4 99.5

Sample 8 (S8) Bottom Center

99.7 99.8 99.5

Sample 9 (S9) Bottom Right 99.4 100.0 99.3 Average --- 99.51 99.67 99.54

RSD (NMT 2%)

--- 0.46 0.26 0.17

Table: 16 Test Results after lubrication

Process Stage

Tests on Composite sample

criteria Results

Batch No. X Y Z

After Lubrication

Bulk Density in gm / ml

Untapped For

Information 0.5 g/ml 0.5 g/ml 0.5 g/ml

Tapped For

Information 0.7 g/ml 0.7 g/ml 0.7 g/ml

Sieve analysis in %

# 20 For

Information 70.7% 71.1% 71.8%

# 40 For

Information 49.0% 49.5% 52.2%

# 60 For

Information 38.7% 41.7% 41.6%

# 80 For

Information 33.5% 35.1% 34.4%

# 100 For

Information 29.7% 30.7% 29.0%

Water content 1.0 – 2.0 % 1.45% 1.61% 1.59% Assay 98 % to 102 % 99.0% 99.9% 99.5%



Observation and Results of Uncoated Tablets:

Different time

Table: 17 Observations for Physical Parameter of Batch X (Uncoated)

[A] Batch No. : X

Physical parameters

Acceptance criteria

Initial Middle End Date : 11/01/11 Date : 11/01/11 Date : 11/01/11

Time : 09:40 Time : 12:15 Time : 15:10 RHS LHS RHS LHS RHS LHS

1-Appearance :

* Conforms Conforms - Conforms - Conforms -

2-**Wt of Tablet in gm.

[11.80/20 Tabs.]

11.564 gm to 12.036 gm

11.820 - 11.800 - 11.800 -

3-Average weight

590 mg ± 2% [11.564 gm

to12.036 gm] 591.0 590.0 - 590.0 -

4-Uniformity of weight :

± 5% of Average weight

590 - 584 - 582 - 588 - 590 - 595 - 593 - 589 - 594 - 595 - 596 - 592 - 597 - 593 - 586 - 587 - 592 - 582 - 588 - 597 - 592 - 593 - 588 - 586 - 587 - 596 - 592 - 590 - 587 - 591 - 593 - 584 - 592 -

594 - 594 - 597 -

587 - 586 - 580 - 594 - 583 - 588 - 587 - 593 - 583 - 595 - 590 - 592 - 591 - 591 - 598 - 592 - 587 - 588 - 583 - 584 - 587 - 592 - 596 - 594 -

- - - - - - - - - - - - - - - - -



- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -

Minimum 583 - 584 - 580 - Maximum 597 - 597 - 598 -

Wt. Variation ± % -1.35 - -1.70 - - - 1.02 - 1.18 - 1.36 -

Physical parameter &

Test procedure No.

Acceptance criteria

Initial Middle End

RHS LHS RHS LHS RHS LHS

5-Thickness :

4.0 – 4.4 mm

4.11 - 4.22 - 4.25 - 4.32 - 4.15 - 4.13 - 4.21 - 4.26 - 4.32 - 4.32 - 4.27 - 4.18 - 4.11 - 4.34 - 4.26 - 4.24 - 4.13 - 4.15 - 4.15 - 4.12 - 4.31 - 4.12 - 4.21 - 4.22 - 4.34 - 4.35 - 4.23 - 4.13 - 4.13 - 4.12 -

Range in mm 4.11– 4.34 mm 4.12 – 4.35 mm 4.12 – 4.32 mm

6-Hardness :

3.0 – 5.0 Kg / cm 2

4.1 3.1 3.2 3.6 4.2 4.3 4.2 4.8 3.6 4.4 3.4 4.5 4.8 3.5 4.4 4.2 3.6 3.2 3.3 4.3 3.5 4.1 - 3.6 - 3.4 - 3.5 - 4.7 - 4.5 - 3.6 - 3.5 - 3.8 -

Range in Kg / cm 2 3.3 – 4.8Kg/cm2 3.1 – 4.8Kg/cm2 3.2 – 4.5Kg/cm2

7-Friability : Wt. of 12

Tablets before Friability

7.080. - 7.092 - 7.068 -



Wt. of Tablets after Friability

7.052 - 7.074 - 7.044 -

Wt. of Loss in gm.

0.28 - 0.018 - 0.024 -

NMT 1.0 % w/w

0.40% - 0.25% - 0.34% -

8-Disintegration

Time :

NMT 15 min.

7’38” – 10’10” 08’05” – 11’20” 07’55” – 11’05”

9-Assay: 98 % to 105 % 99.4% 99.1% 100.3%

Dimension check at the initial stage during compression :

10-

Dimension:

13.55 x

4.20 mm

13.52x4.28 13.53x4.23 13.55x4.23 - - -

13.54x4.28 13.52x4.25 13.54x4.31 - - -

13.52x4.35 13.52x4.22 - - - -

3.52x4.27 13.55x4.26 - - - -

13.54x4.35 13.54x4.24 - - - -

13.56x4.28 13.56x4.25 - - - -

13.52x4.26 13.52x4.23 - - - -

13.55x4.34 13.53x4.23 - - - -

13.52x4.25 13.53x4.21 - - - -

Range in mm 13.52x4.21 - 13.56x4.34

**Equal to no. of punches

* Conforms – White round flat uncoated tablets with break line on one side. Free

from rough surface, Hairline cracks, sticking, mottling, chipped edges

etc.



Table: 18 observations for Physical Parameter of Batch Y (Uncoated)

[B] Batch No. : Y

Physical parameters

Acceptance criteria



1-Appearance :



[11.84/20 Tabs.]

11.566 gm to 12.032 gm

11.840 - 11.820 - 11.780 -

3-Average weight

590 mg ± 2% [11.566

to12.032 gm] 592.0 - 591.0 - 589.0 -



594 - 590 - 591 - 590 - 583 - 592 - 593 - 589 - 588 - 584 - 593 - 586 - 596 - 596 - 581 - 590 - 584 - 593 - 591 - 598 - 586 - 590 - 586 - 590 - 596 - 593 - 598 - 591 - 596 - 586 - 601 - 587 - 590 - 588 - 591 - 593 - 588 - 590 - 588 - 596 - 583 - 586 - 593 - 594 - 587 - 594 - 587 - 593 - 590 - 588 - 590 - 594 - 592 - 588 - 590 - 596 - 589 - 591 - 584 - 586 -

- - - - - - - - - - - - - - - - - - - - -



- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -

Minimum 584 - 583 - 581 - Maximum 601 - 598 - 598 -

Wt. Variation ± % -1.35 - -1.35 - -1.36 - 1.52 - 1.18 - 1.52 -

Physical parameter &

Test procedure No.

Acceptance criteria

Initial Middle End

RHS LHS RHS LHS RHS LHS

5-Thickness :

4.0 – 4.4 mm

4.24 - 4.32 - 4.25 - 4.13 - 4.16 - 4.37 - 4.31 - 4.21 - 4.19 - 4.12 - 4.35 - 4.22 - 4.30 - 4.26 - 4.38 - 4.23 - 4.22 - 4.12 - 4.35 - 4.33 - 4.14 - 4.30 - 4.21 - 4.21 - 4.14 - 4.14 - 4.28 - 4.26 - 4.23 - 4.31 -

Range in mm 4.12 – 4.34 mm 4.14 – 4.35 mm 4.12 – 4.38 mm

6-Hardness : 3.0 – 5.0 Kg /

cm 2

3.6 - 3.4 - 3.5 - 3.2 - 4.2 - 3.8 - 3.5 - 4.7 - 3.5 - 4.1 - 4.5 - 4.5 - 3.5 - 3.6 - 4.1 - 4.4 - 3.8 - 3.5 - 3.2 - 3.4 - 3.5 - 3.3 - 3.5 - 4.6 - 3.6 - 3.6 - 3.8 - 3.8 - 4.5 - 4.5 -

Range in Kg / cm 2 3.2 – 4.4Kg/cm2 3.4 – 4.7Kg/cm2 3.5 – 4.6Kg/cm2

7-Friability :

Wt. of 12 Tablets before

Friability 7.104 - 7.092 - 7.080 -

Wt. of Tablets after Friability

7.078 - 7.063 - 7.043 -

Wt. of Loss in gm.

0.026 - 0.029 - 0.037 -



NMT 1.0 % w/w

0.37% - 0.41% - 0.52% -

8-Disintegration

Time :

NMT 15 min.

06’45” – 07’15” 05’56” – 06’40” 06’15” – 07’15”

9-Assay: 98.0 % to 102.0

% 99.6% 100.5% 99.7%


10-

Dimension:

13.55 x

4.20 mm

13.53x4.22 13.56x4.24 13.52x4.24 - - -

13.56x4.31 13.56x4.28 13.53x4.25 - - -

13.52x4.23 13.52x4.23 - - - -

13.54x4.25 13.57x4.29 - - - -

13.56x4.31 13.56x4.27 - - - -

13.53x4.23 13.53x4.22 - - - -

13.55x4.24 13.51x4.30 - - - -

13.53x4.24 13.54x4.21 - - - -

13.51x4.23 13.56x4.25 - - - -

Range in mm 13.51x4.2 1– 13.57x4.31


* Conforms – White round flat uncoated tablets with break line on one side. free


etc.



Table: 19 observations for Physical Parameter of Batch Z (Uncoated)

[C] Batch No. : Z

Physical parameters

Acceptance criteria



1-Appearance :



[11.82/20 Tabs.]

11.562 gm to 12.034 gm

11.800 - 11.780 - 11.820 -

3-Average weight

590 mg ± 2% [11.562

to12.034 gm] 590 - 589 - 591 -



580 - 592 - 592 - 594 - 588 - 590 - 595 - 590 - 587 - 598 - 594 - 590 - 585 - 598 - 591 - 592 - 590 - 588 - 582 - 589 - 593 - 586 - 592 - 590 - 578 - 590 - 592 - 590 - 600 - 590 - 588 - 582 - 591 - 598 - 588 - 588 - 586 - 589 - 594 - 595 - 590 - 591 - 585 - 585 - 592 - 600 - 589 - 589 - 594 - 580 - 592 - 601 - 584 - 598 - 582 - 588 - 594 -

593 - 582 - 592 -

- - - - - - - - - - - - - - - - - -



- - - - - - - - - - - - - - - - - - - - - - - - - - -

Minimum 578 - 580 - 587 - Maximum 601 - 600 - 598 -

Wt. Variation ± % -2.03 - -1.53 - -0.68 - 1.7 - 1.87 - 1.18 -

Physical parameters

Acceptance criteria

Initial Middle End RHS LHS RHS LHS RHS LHS

5-Thickness :

4.0 – 4.4 mm

4.36 - 4.12 - 4.30 - 4.22 - 4.24 - 4.13 - 4.38 - 4.29 - 4.12 - 4.21 - 4.17 - 4.22 - 4.12 - 4.32 - 4.37 - 4.13 - 4.11 - 4.31 - 4.31 - 4.20 - 4.20 - 4.31 - 4.12 - 4.17 - 4.20 - 4.36 - 4.15 - 4.29 - 4.20 - 4.27 -

Range in mm 4.12 – 4.38 mm 4.11 – 4.36 mm 4.12 – 4.37 mm

6-Hardness :

3.0 – 5.0 Kg / cm 2

3.1 - 3.2 - 3.2 - 3.5 - 3.6 - 3.6 - 4.2 - 3.2 - 4.1 - 4.5 - 4.2 - 4.5 - 4.1 - 4.8 - 3.9 - 3.5 - 3.7 - 3.4 - 4.1 - 3.7 - 4.1 - 4.6 - 3.2 - 4.2 - 3.8 - 4.2 - 3.7 - 3.4 - 3.5 - 4.1 -

Range in Kg / cm 2 3.1 – 4.6Kg/cm2 3.2 - 4.8 Kg/cm2 3.2 – 4.5 Kg/cm2

7-Friability :

Wt. of 12 Tablets before

Friability

7.104 - 7.080 - 7.056 -

Wt. of Tablets after

Friability 7.077 - 7.047 - 7.036 -



Wt. of Loss in gm.

0.027 - 0.033 - 0.020 -

NMT 1.0 % w/w

0.38% - 0.47% - 0.28% -

8-Disintegration

Time :

NMT 15 min.

05’42” – 07’02” 06’37” – 08’11” 07’04” – 08’32”

9-Assay: 98.0%

to102.0 % 99.5% 99.8% 99.3%


10-

Dimension:

13.55 x

4.20 mm

13.55x4.33 13.54x4.31 13.55x4.30 - - -

13.51x4.27 13.51x4.29 13.56x4.25 - - -

13.53x4.28 13.55x4.28 - - - -

13.55x4.31 13.52x4.25 - - - -

13.54x4.27 13.56x4.31 - - - -

13.51x4.28 13.51x4.27 - - - -

13.55x4.30 13.54x4.25 - - - -

13.57x4.29 13.55x4.25 - - - -

13.52x4.27 13.53x4.27 - - - -

Range in mm 13.51x4.25 – 13.57x4.33


* Conforms – White round flat uncoated tablets with break line on one side. free


etc.



Summary of uncoated tablets:

Table: 20 Summary of uncoated tablets

Parameters Acceptance

criteria Batch No.

X Y Z

Appearance *Conforms Conforms Conforms Conforms

Average weight

590 mg ± 2% [578.2 to 601.8

mg] 590 mg 589 mg 591 mg

Uniformity of weight


560.5 mg to 619.5 mg

559.6 mg to 618.5 mg

561.5 mg to 620.6 mg

Dimension 13.55 X4.20 ±0.2

mm 13.54X4.10mm 13.52X4.09mm 13.57X4.24mm

Thickness 4.0 to 4.4 mm 4.10 mm 4.09 mm 4.24 mm

Hardness 3.0 to 5.0 Kg /

cm 2 3.0 – 4.0 3.5- 4.5 3.0 – 4.5

Friability NMT 1.0 % w/w 0.25 % 0.38 % 0.41 %

Disintegration time

NMT 15 min. 3 min 4min 3min

* Conforms – White round flat uncoated tablets with break line on one side.

Blister strip Packing Machine setting and operation details:

Equipment Name: Blister machine

Acceptance Criteria:

(A)Description: White round flat uncoated tablets with break line on one side.

(B) Leak Test: There should not be any leakage in any of the strips. (Pocket)

Blister Strip packing Inprocess monitoring every two hours from the starting of the

stripping



Table: 21 Blister packing In-process monitoring Parameter

Parameter

Batch No X Y Z

Initial Middle End Initial Middle End Initial Middle End

Blister Forming

Plate Temp. 1280c 1280c 1270c 1280c 1280c 1280c 1660c 1650c 1650c

Counter sealing Roller Temp.

2000c 2000c 2000c 2000c 2000c 2000c 2000c 2000c 2000c

Machine speed in

CPM 40 42 42 40 40 40 40 42 40

Sample taken

(100strips) 100 100 100 100 100 100 100 100 100

Appearance of strips

Ok Ok Ok Ok Ok Ok Ok Ok Ok

Sealing & cutting Quality


Cut Pocket Not

found Not

found Not

found Not

found Not

found Not

found Not

found Not

found Not

found

Leak Test Not

found Not

found Not

found Not

found Not

found Not

found Not

found Not

found Not

found Appearance of Tablets


observations & Inprocess checks of packing operation:



Table: 22 In-process checks of Final Packing Operation

Inprocess parameter

Batch No.

Stage Quality of strips

Coding of batch details

Over printing on Show

Box

Strips packed

in a Show Box

No. of show box pack in

shipper

Over printing

batch details

on shipper

label

X

Initial S S S

10x10T 100x10x10T S

Middle S S S 10x10T 100x10x10T S

End S S S 10x10T 100x10x10T S

Y

Initial S S S 10x10T 100x10x10T S


End S S S

10x10T 100x10x10T S

Z

Initial S S S 10x10T 100x10x10T S


End S S S 10x10T 100x10x10T S

S = Satisfactory

Observations & Acceptance Criteria of finished products (uncoated tabs.)

Table: 23 Observations & Acceptance Criteria of finished products

S. No

Test Acceptance Criteria Batch No.

X Y Z

1. Appearance White round flat Uncoated tablets with break line on one side.

Conforms Conforms Conforms

2. Identification

In the assay, the test solution shows the maxima as the same wave length as than that of the standard solution.

Conforms Conforms Conforms

3. Average weight

590 mg ± 2 % 590 mg 589 mg 591 mg



4. Uniformity of weight

Within ± 5 % of average weight.

With in limits With in limits

With in limits

5. Friability NMT 1.0 % Conforms Conforms Conforms

6. Dissolution NLT 80 % In 30 min. MT 95.0 % MT 98.0%

MT 97.0%

7. Assay : Paracetamol Tablet 500 mg

98.0 % to 102.0% 100.0% 99.4% 99.8%

CONCLUSION

All the analytical data derived during process validation of Paracetamol Tablet-

500 mg with reference to TMD. (Technical Manufacturing Document)

The results from the analytical data of process validation of Paracetamol tablet

500 mg was excellent and very near to true values. These results prove that the process is

validated.

ACKNOWGEMENT

It gives me an immense pleasure to thank my guide Mrs.Aarti Zanwar and

Industrial Guide Mr. Jitesh Katewa & Dr A.K Seth, Director, Department of Pharmacy,

Sumandeep Vidyapeeth. I am also Thankful to Combitic Global Caplet Pvt.LTd Sonipet

(Harayana) for Providing the facility to Perform my Project Work.

REFERENCES

1. Loftus BT, Berry IR. Pharmaceutical Process Validation, 2nd Edition: Marcel

Dekker, New York, USA; 1993: 1-8.

2. USFDA, Guidelines on General Principles of Validation, Center For Drug

Evaluation and Research (CDER); 1987.

3. Kirrstetter R. Requirement for process validation of biotech active pharmaceutical

ingradients (APIs) . The official J. of ISPE. Vol-22th; 2002: 3.

4. Sharma SK. Validation of pharmaceutical products & process eastern pharmacist.

1999: 39-41.

5. Avallone HE. Retrospective validation. NAPM meeting. Port Chester: new York;

1983.

6. Lingnau J. optimization & validation of manufacturing processes. Drug dev. Ind.

Pharm.15; 1989: 1029-1046.



7. Division of Manufacturing and Product Quality. Guideline on General Principals

of Process Validation. Rockville: Center For Drugs and Biologics; 1987.

8. J.R. Sharp, the problem of process validation as an important element in GMP.

Pharm. J. 236 (1); 1986: 43-45.

9. Snorek SM. On particle size- analysis of drug substances used in oral dosage

forms. J. Pharm Sci. 96(6); 2007: 1451-67.

10. Berman J, blend uniformity & unit dose sampling. Drug dev. Ind.pharm.21 (11);

1995: 1257-1283.

11. Syed Imtiaz Haider. Validation Standard Operating Procedure. Second Edition,

Taylor and Francis Group. Publishers; 2006: 3-9.

12. Savant DA. Pharma Pathway: 4th Edition, Pragati Publisher; 2007: 2.20-2.34,

2.178-2.229.

13. Department Of Health and Human Services. US FDA. Guidelines For Submitting

Samples & Analytical Data For Method Validation. Rockville: Center For Drugs

& Biologics ; 1987.

14. Government Of India. Ministry Of Health and Welfare. Indian Pharmacopoeia

1996: Addendum. Indian Commissions; 2000: 840.

For Correspondence: Surendra Nath Yadav Email: [email protected]

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