MFR of Nimesulide 100 mg and Paracetamol 325 mg Tablets
TABLE OF CONTENTS
|3.0||LIST OF EQUIPMENTS|
|MANUFACTURING PROCESS DETAILS|
1.0 PRODUCT DETAILS:
|Product Name||Nimesulide and Paracetamol Tablets|
|Product Description||Yellow color biconvex oval shape, uncoated tablet having one side mid break line and other side plain|
|Strength||Nimesulide 100 mg and Paracetamol 325 mg|
|Each uncoated tablet contains:
Nimesulide BP – 100 mg
Paracetamol IP – 325 mg
|Batch Size||3,00,000 Tablets|
|Average Weight||580 mg|
|Shelf Life||24 months|
|Storage||Store in a cool, dry and dark place below 25 0C|
|Drug Category||Non-steroidal Anti-Inflammatory Drug|
2.0 MANUFACTURING FORMULA:
|Material Name||Grade||Category||Quantity per Unit (In mg)||Batch Qty.
|Nimesulide||BP||API||100 mg||30.000 kg|
|Paracetamol||IP||API||325 mg||97.500 kg|
|Starch||IP||Binder||66.14 mg||19.842 kg|
|MCCP Plain||IP||Diluent||47.00 mg||14.100 kg|
|Tartrazine Supra Color||IP||Color||0.177 mg||0.053 kg|
|PVPK-30||IP||Binder||5.8 mg||1.740 kg|
|Sodium Benzoate||IP||Preservative||1.16 mg||0.348 kg|
|Starch||IP||Binder||13.13 mg||3.938 kg|
|Purified Water||IP||Diluent||0.160 ml||48.000 liter|
|Talcum||IP||Anti-caking agent||8 mg||2.400 kg|
|Sodium Starch Glycolate||IP||Disintegrant||5.8 mg||1.740 kg|
|Cross Carmilose Sodium||IP||Disintegrant||5.8 mg||1.740 kg|
|Magnesium Stearate||IP||Anti- adherent||2 mg||0.600 kg|
3.0 LIST OF EQUIPMENTS:
|Sr. No.||Machineries/equipments||Capacity||Equipment ID.|
|1.||Weighing Balance||300 kg|
(with SS Sieves No’s 16,20,30,60 and 100 )
|3.||Paste Kettle with stirrer||60 liter|
|4.||Stirrer for binder preparation||—|
|5.||Multi-Mill (screen size 8 mm and 2 mm)||—|
|6.||Rapid Mixer Granulator (RMG )||160 liter|
|7.||Fluid Bed Dryer (FBD)||120 kg|
|8.||Octagonal Blender||500 liter|
|9.||Compression Machine||27 Station|
|10.||SS Containers with lid||10 liter ( 04 No’s)||—|
|11.||Halogen Moisture Balance||—|
|12.||Poly-lined HDPE Containers with lid||30 liter (11 No’s)||—|
4.0 MANUFACTURING INSTRUCTIONS:
- All the manufacturing activities shall be performed under controlled conditions (temperature NMT 25 0C and relative humidity NMT 60%).
- When working with Active Ingredients and drug product or mixture of Active Ingredients and Excipients, wear gloves and mask to avoid exposure and contact with any body parts.
5.0 GENERAL PRECAUTIONS:
- Before working with Nimesulide and Paracetamol, read Material Safety Data Sheet of Active Ingredients.
- In case of skin contact (Irritants), wash skin with soap and water for at least 15 minutes. Cold water may be used.
- To protect the eyes, use goggles and in case of infection wash the eyes thoroughly with running water.
- General reported side effects: Nausea, Indigestion, Headache, Allergic skin reactions such as Itching and Rash.
- MANUFACTURING PROCESS DETAILS:
STEP – I (SIFTING):
- Check Sieve Integrity (before sifting and after sifting).
- Set the Sifter and sieve the Dispensed Materials as per Sieve Sizes mentioned below:
|Material Name||Std. Qty. (kg)||Sieve No.|
|Nimesulide BP||30.000 kg||16 #|
|Paracetamol IP||97.500 kg||16 #|
|Starch IP||19.842 kg||100 #|
|MCCP Plain IP||14.100 kg||60 #|
|Tartrazine Supra Color IP||0.053 kg||100 #|
|PVPK-30 IP||1.740 kg||20 #|
|Sodium Benzoate IP||0.348 kg||20 #|
|Starch IP||3.938 kg||100 #|
|Talcum IP||2.400 kg||60 #|
|Sodium Starch Glycolate IP||1.740 kg||60 #|
|Cross Carmillose Sodium||1.740 kg||60 #|
|Magnesium Stearate IP||0.600 kg||30|
- Collect the sifted Nimesulide BP (30.000 kg), Paracetamol IP (97.500 kg), Starch IP (18.842 kg), and MCCP Plain IP (14.100 kg) in seven Poly-lined HDPE Container (capacity: 30 liter each)
- Collect the sifted Starch IP (3.938 kg) in one SS Container (capacity: 10 liter)
- Collect the sifted Talcum IP (2.400 kg), Sodium Starch Glycolate IP (1.740 kg) and Cross Carmillose Sodium IP (1.740 kg) in one Poly-lined SS Container (capacity :10 liter)
- Collect the sifted Magnesium Stearate IP (0.600 kg) in one Poly-lined SS Container (capacity:10 liter)
- Geometrically mix Tartrazine Supra Color IP (0.053 kg) with Starch IP (1.000 kg) and sieve through 100 # and divide in two equal parts LOT- I and LOT- II.
- Divide sifted materials, Nimesulide BP (30.000 kg), Paracetamol IP (97.500 kg), Starch IP (18.842 kg), MCCP Plain IP (14.100 kg) and Tartrazine Supra Color (0.053 kg) in two equal parts for LOT I and LOT- II.
STEP – II (DRY MIXING) FOR LOT – I:
Transfer the sifted Nimesulide IP (15.000 kg ), Paracetamol IP (48.750 kg ), Starch IP (9.421 kg), MCCP Plain ( 7.050 kg ) and Tartrazine Supra Color IP (0.0265 kg) with Starch IP (0.500 kg) in RMG ( capacity : 160 liter) and dry mix the materials till uniform mixing.
Mixing Time = 8 minutes.
Mixing Speed: 03 minutes at slow speed and 05 minutes at fast speed.
STEP – III – (BINDER PREPARATION) FOR LOT –I & II:
(a) Take purified water (42.00 liter) in Paste Kettle, heat the purified water at 800C .
(b) Take purified water (5.00 liter, at temperature 25°C) in SS Container (capacity: 30 liter) and add Starch IP (3.938 kg) slowly with continuous stirring till uniform solution is ready.
(c) Add above solution of Step – III (b) in Step – III (a) in Paste Kettle with continuously stirring till uniform paste is ready.
(d) Take purified water (1.000 liter, at temperature 35°C) in SS container (capacity: 10 liter) and add Sodium Benzoate IP (0.348 kg) and PVPK-30 IP (1.740 kg) and mix with stirrer till dissolved properly in water and then add to Step – III (c) and continuously stirring till final paste is ready and cool the paste to 35°C to 40°C.
(e) Divide paste into two equal parts for LOT – I and LOT – II in SS Containers (capacity: 30 liter each)
STEP –IV (BINDING OF DRY MIX MATERIAL) FOR LOT – I:
Slowly add the binder of Step-III in dry mix materials of Step-II in Rapid Mixer Granulator (capacity: 160 liter) with running at slow speed impeller (13 ampere) for 5 minutes. Then run impeller and chopper both at medium speed (15 ampere) for 10 min and finally run both chopper and impeller on fast speed (19 ampere) for 3 minutes till uniform mixing. Unload the material in SS Container (capacity: 100 liter) from RMG.
Mixing Time: 18 minutes
Ampere Load of Impeller: 13 to 19 ampere.
STEP-V (WET SCREENING) : FOR LOT – I:
Take wet material from SS Container (capacity: 100 liter) and pass through Multi-Mill with 8 mm screen and collect the wet material in a FBD bowl.
STEP –VI – (DRYING) FOR LOT – I:
Dry the wet material of Step-V in FBD (capacity: 120 kg) till the LOD of granules is achieved between 2.5 to 3.0 % at 105°C checking by Halogen Moisture Balance.
Inlet Temperature: 55°C
Outlet Temperature: To be established
Bed Temperature: To be established
Drying Time: 2 hours.
Raking Frequency: After 30 minutes
STEP-VII- (SIZING/MILLING) FOR LOT – I:
Check screen integrity (before sifting and after sifting).
Mill the dried material of Step -VI through Multi Mill using screen size 2 mm and collect milled material in two SS Containers (capacity :100 liter ). After milling transfer the milled material into four Poly-lined HDPE Containers (capacity: 30 liter each) and weight and record the milled granules quantity.
Blade Type: Both (Knife blades/Scraping blades)
Rotor Speed: 2000 RPM
FOR LOT – II: Please follow the same procedure of LOT – I of dry mixing, binding of dry mix material, wet screening, drying and sizing/ milling.
STEP – VIII (PRE –LUBRICATION):
Load the milled granules of Step-VII of LOT- I and LOT – II in Octagonal Blender and add sifted Talcum IP (2.400 kg) and Sodium Starch Glycolate IP (1.740 kg), Cross Carmillose Sodium IP (1.740 kg) and mix properly till uniform mixing of Pre-Lubricating Material.
Mixing Time: 30 minutes (15 minutes clockwise direction and 15 minutes anti-clockwise direction)
Mixing Speed: 10 RPM
STEP – IX (LUBRICATION):
Add the sifted Magnesium Stearate IP (0.600 kg) in Pre- Lubricated Material of Step-VIII and mix properly till uniform mixing of materials with Magnesium Stearate.
Mixing Time: 05 minutes. (clockwise direction)
Mixing Speed: 10 RPM.
STEP- X (BLEND SAMPLE ANALYSIS):
After completion of lubrication, collect the composite blend sample and send to QC for analysis according to the table below:
|Appearance of blend
|Yellow color free flowing granular powder
90 % to 110 %
98 % to 103 %
2.0 % to 3.0 %
To be established in next batch
To be established in next batch
To be established in next batch
To be established in next batch
STEP – XI:
Unload the above blended material and weight and store in five Poly-lined HDPE Containers (capacity: 45 liter each)
STEP – XII:
Clean all equipments used in the granulation as per respective equipment cleaning SOP.
STEP – I:
After receiving QC approval for blend, compress the blend as per the following parameters and In-Process checks under controlled environmental condition.
|Parameters||Standard||No. of Tablets||In-Process Frequency|
|1.||Feed frame alignment and adjustment||Should be satisfactory||—–||—–|
|2.||Lower Weight Assembly||Should be satisfactory||—–||—–|
|6 -8 Tones (D-Tooling, 27station Compression Machine)||—–||—–|
|4.||Machine Speed||15 RPM to 18 RPM||—–||—–|
|5.||Upper Punch Size||16.7 mm x 8.3 mm with break line||—–||—–|
|6.||Lower Punch Size||16.7 mm x 8.3 mm||—–||—–|
|7.||Length of Tablets.||16.7 mm||—–||—–|
|8.||Width of Tablets||8.3 mm||6/Individual||2 hours|
|9.||Thickness of Tablets||5.33 mm ±.2 mm||6/Individual||2 hours|
|10.||Weight of 20 Tablets||11.600 gm ± 3%||20/Composite||30 minutes|
|11.||Product Description||Yellow color, biconvex oval shape, un-coated tablet having one side mid break line and other side plain||20/Composite||2 hours|
|12.||Uniformity of Weight||NMT 02 tablets out of 20 deviate from the average weight by more than 3 % and no single tablet deviates from the average weight by more than 5 %||—–||01 hour|
|13.||Average Weight of Tablets||580 mg ± 2 %||20/Individual||30 minutes|
|14.||Hardness||NLT 4 kg/cm2||6/Individual||30 minutes|
|15.||Disintegration Time||NMT 15 min||6/Composite||01 hour|
|16.||Friability||NMT 1%||20/Composite||01 hour|
STEP – II:
Send the sample of compressed tablets to QC department for analysis.
STEP – III:
Weight the compressed tablets and store into seven Poly-lined HDPE Containers with lid (capacity: 30 liter each) with proper status label till next step tablet packing.
STEP – IV:
Clean the Compression Machine as per cleaning SOP.