MFR of Trypsin 48 mg, Bromelain 90 mg, Rutoside Trihydrate 100 mg with Diclofenac Sodium 50 mg Tablets
TABLE OF CONTENTS
| S.NO. | TITLE | Page No. | |
| 1.0 | PRODUCT DETAILS | 2 of 11 | |
| 2.0 | MANUFACTURING FORMULA | 2 of 11 | |
| 3.0 | LIST OF EQUIPMENTS | 3 of 11
|
|
| 4.0 | MANUFACTURING INSTRUCTIONS | 3 of 11 | |
| 5.0 | GENERAL PRECAUTIONS | 3 of 11 | |
| 6.0
|
MANUFACTURING PROCESS DETAILS | ||
| 6.1 | GRANULATION | 3 of 11 | |
| 6.2 | COMPRESSION | 6 of 11 | |
| 6.3 | COATING | 7 of 11 | |
| 6.4 | BRAND DETAILS | 11 of 11 | |
1.0 PRODUCT DETAILS:
| Product Name | Trypsin, Bromelain, Rutoside Trihydrate with Diclofenac Sodium Tablets |
| Product Description | Pink color biconvex, round shape, enteric coated tablets having both side plain |
| Strength | Trypsin BP 48 mg
Bromelain 90 mg Rutoside Trihydrate BP 100 mg Diclofenac Sodium IP 50 mg |
| Label claim
|
Each enteric coated tablet contains:
Trypsin BP 48 mg Bromelain 90 mg Rutoside Trihydrate BP 100 mg Diclofenac Sodium IP 50 mg |
| Batch Size | 2,00,000 Tablets |
| Average Weight | 540 mg (Uncoated tablets)
594 mg (Enteric coated tablets) |
| 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) | Overages | Batch Qty.
(In kg) |
| Dry Mixing – I | |||||
| Diclofenac Sodium | IP | API | 50 mg | 2 % | 10.200 kg |
| MCCP PH -102 | IP | Diluent | 50 mg | – | 10.000 kg |
| Binder | |||||
| Ethyl cellulose | IP | Binder | 0.05 mg | – | 0.010 kg |
| Isopropyl Alcohol (IPA) | IP | Solvent | 0.090 liter | 18.000 liter | |
| Lubricant | |||||
| Trypsin | BP | API | 48 mg | 25 % | 12.000 kg |
| Bromelain | NA | API | 90 mg | 20 % | 21.600 kg |
| Rutoside Trihydrate | BP | API | 100 mg | 12 % | 22.400 kg |
| MCCP PH-112 | IP | Diluent | 109.95 mg | 21.990 kg | |
| Talcum | IP | Anti caking agent | 15 mg | 3.000 kg | |
| Sodium Starch Glycolate | IP | Disintegrant | 12 mg | – | 2.400 kg |
| Crospovidone XL 10 | IP | Disintegrant | 10 mg | – | 2.000 kg |
| Cross Carmellose Sodium | IP | Disintegrant | 10 mg | – | 2.000 kg |
| Magnesium Stearate | IP | Anti -adherent | 2 mg | – | 0.400 kg |
3.0 LIST OF EQUIPMENTS:
| Sr. No. | Machineries/Equipments | Capacity | Equipment ID. |
| 1. | Weighing Balance | 100 kg | SC/PD/WBL/03 |
| 2. | Vibro Sifter
(with SS Sieves No’s 30 and 60 ) |
30 inch dia | SC/PD/SFT/01
SC/PD/SFT/02 |
| 3. | Mass Mixer with Propeller | 100 Liter | SC/PD/MSM/01,SC/PD/MSM/02 |
| 4. | Portable Stirrer | – | SC/PD/STR/01 |
| 5. | Tray Dryer | 48 Trays | SC/PD/TRD/01,SC/PD/TRD/02
SC/PD/TRD/03,SC/PD/TRD/04 |
| 6. | Double Cone Blender | 400 liter | SC/PD/GR/O3 |
| 7. | Halogen Moisture Balance | — | SC/QC/007 |
| 8. | Compression Machine | 27 Station | SC/PD/CPM/03,SC/PD/CPM/05 |
| 9. | SS Containers with lid | 30 liter (02 No’s) | — |
| 10. | Poly-lined HDPE Containers with lid | 45 liter (10 No’s) | — |
| 11. | Polybags | 01 kg (01 No.),
50 kg (01 No.) |
GENERAL PRECAUTIONS:
- Trypsin API Description: A white or almost white crystalline powder.
- Bromelain API Description: Off white to pale brown color powder.
- Rutoside Trihydrate API Description: Yellow or greenish yellow color crystalline powder.
- Diclofenac Sodium API Description: A white or off white powder.
- All the Manufacturing Activities shall be performed under controlled conditions (temperature NMT25 0C and relative humidity NMT 40%).
- 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.
MANUFACTURING INSTRUCTIONS:
- All activities shall be performed as per current SOPs.
- Take the line clearance of every machine from QA before starting the manufacturing operation during batch to batch and product to product change over.
- Do not overwrite the entry. In case of mistake, cancel the entry by single line with sign & date and make correct entry.
6.0 MANUFACTURING PROCESS DETAILS:
6.1 GRANULATION:
STEP – I (SIFTING):
- Check Sieve Integrity (before sifting and after sifting).
- Set the Vibro Sifter (capacity: 30 inch dia) and sieve the Dispensed Materials as per Sieve Sizes mentioned below:
| Material Name | Std. Qty. (kg) | Sieve No. |
| Dry Mixing-I | ||
| Diclofenac Sodium IP | 10.200 kg | 30 # |
| MCCP PH -102 IP | 10.000 kg | 30 # |
| Binder | ||
| Ethyl Cellulose IP | 0.010 kg | NA |
| Isopropyl Alcohol (IPA) | 18.000 liter | NA |
| Lubricants | ||
| Trypsin BP | 12.000 kg | 30 # |
| Bromelain | 21.600 kg | 30 # |
| Rutoside Trihydrate BP | 22.400 kg | 30 # |
| MCCP PH -112 IP | 21.990 kg | 30 # |
| Talcum | 3.000 kg | 60 # |
| Sodium Starch Glycolate IP | 2.400 kg | 60 # |
| Crospovidone XL IP | 2.000 kg | 60 # |
| Cross Carmellose Sodium IP | 2.000 kg | 60 # |
| Magnesium Stearate | 0.400 kg | 60 # |
- Collect sifted Diclofenac Sodium IP (10.200 kg) and MCCP PH IP -102 (10.000 kg) in one Polybag (capacity: 50 kg each).
- Collect sifted Trypsin BP (12.000 kg), Bromelain (21.600 kg), Rutoside Trihydrate BP (22.400 kg), MCCP PH-112 (21.990 kg), Talcum IP (3.000 kg), Sodium Starch Glycolate IP (2.400 kg), Crospovidone –XL IP (2.000 kg) and Cross Carmillose Sodium IP (2.000 kg) in three Poly-lined HDPE Container (capacity: 45 liter each).
- Collect the sifted Magnesium Stearate IP (0.400 kg) in one Polybag (capacity: 1 kg).
STEP – II (BINDER PREPARATION):
- Take Isopropyl Alcohol IP (18.000 liter) in SS Container (Capacity: 30 liter) add Ethyl Cellulose IP (0.010 kg) in it. Mix together by Portable Stirrer continuously stirring till Ethyl Cellulose IP is dissolved properly in IPA.
- Mixing Time: 10 minutes. (To be validated in next batch)
- Filter it with filter cloth 100# in SS container (capacity 30 liter).
STEP – III (DRY MIXING):
- Transfer the sifted material Diclofenac Sodium IP and MCCP PH-102 IP in Mass Mixer (capacity: 100 liter) and dry mix the materials till uniform mixing.
- Mixing Time: 10 minutes.(TO be validated in next batch)
- Mixing Speed: 36 RPM.
- Paddle (Blades) Timing: 05 minutes in clockwise direction and 05 minutes in anti- clockwise direction.
STEP – IV (BINDING OF DRY MIX MATERIAL):
- Slowly add the binder of Step – II in dry mix material of Step –III and mix for 10 minutes till uniform binding and after binding , collect the wet mass in seven SS Trays ( capacity :3.000 kg each).
- Mixing Time: 10 minutes,
- Mixing Speed 36 RPM.
- Paddle (Blades) Timing: 05 Minutes in clockwise direction and 05 minutes in anti– clockwise direction.
STEP – V (DRYING):
- Dry the wet materials of Step – IV as follow:
- Load these seven trays in Tray Dryer.
- First air dry the wet material for 30 minutes in Tray Dryer. Ensure that heaters are in OFF mode during air drying. After 30 minutes of air drying, Switch ON the heaters and set the temperature at 35°C and dry the granules, until the LOD of granules is achieved between 1.0 to 1.5% at 105°C checking by Halogen Moisture Balance.
- Air Drying Time: 30 minutes (Heaters should be OFF)
- Drying Time: 02 hours (To be validated in next batch).
- Drying Temperature: 35°C (After Air Drying)
- Raking Frequency: After every 20 minutes.
STEP – VI (SIZING /MILLING):
- Check Sieve Integrity (before and after sifting)
- Set the Vibro Sifter and fix the sieve 40# and sieve the dried material of Step –V. Collect the sized materials in one Poly-lined HDPE Container (capacity: 45 liter).
STEP – VII (PRE –LUBRICATION):
- Load the sized granules of Step-VI in Double Cone Blender (capacity: 400 liter) and add sifted Trypsin BP, Bromelain, Rutoside Trihydrate BP, MCCP PH 112 IP, Talcum IP, Sodium Starch Glycolate IP, Crospovidone XL IP, Cross Carmellose Sodium and mix properly till uniform mixing of sized material with Trypsin BP, Bromelain, Rutoside Trihydrate BP and Pre-Lubricating Materials.
- Mixing Time: 30 minutes (15 minutes clockwise direction and 15 minutes anti-clockwise direction
- Mixing Speed: 10 RPM.
STEP – VIII (LUBRICATION):
- Add the sifted Magnesium Stearate IP in Double Cone Blender with Step-VII of Pre-Lubricated Material and mix properly till uniform mixing of materials with Magnesium Stearate IP.
- Mixing Time: 05 minutes (clockwise direction)
- Mixing Speed: 10 RPM.
STEP- 1X (BLEND SAMPLE ANALYSIS):
- After completion of lubrication, collect the composite blend sample (Qty. 10 gm) and send to QC for analysis according to the table below:
| Test | Specification |
| Appearance of blend
Blend Uniformity Blend Assay LOD Bulk Density Tapped Density Compressibility Index Hausner Ratio
|
Yellow color free flowing granular powder
90 % to 110 % 98 % to 103 % 1.0 % to 1.5 % 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 – X:
- Take Tare Weight of three Poly-lined HDPE Containers (capacity: 45 liter each), record the Tare Weight in BMR and unload the above blended material from Double Cone Blender in Poly-lined HDPE Containers (capacity: 45 liter each) and weigh the material with containers and record the Gross Weight of the material and calculate the Net Weight of the material as per given formula:
Net Weight = Gross Weight – Tare weight
- Affix the status label with following details – Product Name, Batch No., Batch Size, Mfg. Date, Exp. Date, Tare Weight, Gross Weight and Net Weight on the Poly-lined HDPE Containers.
- Batch Yield of Lubricated granules:
- Theoretical Batch Yield: 108.00 kg (100 %)
- Actual Batch Yield Limit NLT 106.920 kg (NLT 99 %) (To be established in next batch)
STEP – XI:
- Clean all equipments used in the granulation as per respective equipment cleaning SOP.
6.2 COMPRESSION:
STEP – I:
- After receiving of QC approval for the blend, verify the Net Weight of the received blend as per status label in Granules Day Store.
- After confirmation of result continue the compression 27 station (D-Tooling) Compression Machine. Compress the blend as per the following parameters and In Process checks under controlled environmental condition.
| S.No. | Parameters | Standard | No. of Tablets | In-Process Frequency |
| 1. | Feed frame alignment and adjustment | Should be satisfactory | —– | —– |
| 2. | Lower Weight Assembly | Should be satisfactory | —– | —– |
| 3. | Hydraulic Pressure | 5 -7 Tones | —– | —– |
| 4. | Machine Speed | 12 RPM to 15 RPM | —– | —– |
| 5. | Common Name of Die | Big Para Coated | ||
| 6. | Upper Punch Size | 12.5 mm | —– | —– |
| 7. | Lower Punch Size | 12.5 mm | —– | —– |
| 8. | Die | 12.85 mm | 6/Individual | 2 hours |
| 9. | Diameter of the tablet | 12.85 mm | 6/Individual | 2 hours |
| 10. | Thickness of Tablets | 4.95 mm ±0.2 mm | 6/Individual | 2 hours |
| 11. | Weight of 20 Tablets | 10.80 gm. ± 2% | 20/Composite | 30 minutes |
| 12. | Product Description | Yellow color biconvex, round shape, uncoated tablets having both side plain | 20/Composite | 30 minutes |
| 13. | Uniformity of Weight | NMT 02 tablets out of 20 deviate from the standard average weight by more than 3 % and no single tablet deviates from the standard average weight by more than 5 % | 20/Composite | 01 hour |
| 14. | Standard Average Weight of Tablets | 540 mg ± 2 % | 20/Individual | 30 minutes |
| 15. | Hardness | NLT 4 kg/cm2 | 6/Individual | 30 minutes |
| 16. | Disintegration Time | NMT 15 min | 6/Composite | 01 hour |
| 17. | Friability | NMT 1% | 20/Composite | 01 hour |
- Collect the compressed tablets in SS Containers (capacity: 20 liter each on both sides), when SS containers are filled with tablets, transfer the tablets in three Poly-lined HDPE Containers as given in below Step-III.
STEP – II:
- Send the composite sample of compressed tablets (Qty. 30 tablets) to QC department for analysis.
STEP – III:
- Take Tare Weight of three Poly-lined HDPE Containers (capacity: 45 liter each), record the Tare Weight in BMR and transfer the compressed tablets in Poly-lined HDPE Containers (capacity: 45 liter each) and weigh the compressed tablets with containers and record the Gross Weight of the compressed tablets and calculate the Net Weight of the material as per given formula:
Net Weight = Gross Weight – Tare weight
- Affix the status label with following details – Product Name, Batch No., Batch Size, Avg. Weight Mfg. Date, Exp. Date, Tare Weight, Gross Weight and Net Weight on the Poly-lined HDPE Container.
- Batch Yield of Compressed Tablets:
- Theoretical Batch Yield: 108.00 kg (100 %)
- Actual Batch Yield Limit NLT 106.920 kg (NLT 99 %) (To be established in next batch)
STEP – IV:
- After completion of compression of the tablets, clean the Compression Machine as per cleaning SOP.
NOTE: For this product the lot size of 200000 tablets is taken which is divided into different sub lots (batches of different quantities) as per the order of the customers.
In order to standardized the Coating Procedure we are taking the Batch Size of 50000 tablets for coating in this MFR.
6.3 COATING: (FOR 50,000 tablets):
- Verify the Net Weight of the received compressed tablets for coating as per status label and after confirmation continue for tablet coating.
STEP – I (COATING MATERIALS DETAILS FOR SEAL COATING):
| Sr. No | Material Name | Batch Quantity |
| 1. | Instacoat Moistshield White (IC-MS 2398) | 0.270 kg. |
| 2. | Isopropyl Alcohol IP | 1.540 liter |
| 3. | Dichloromethane USP | 3.590 liter |
STEP – II (COATING MATERIALS DETAILS FOR ENTERIC COATING):
| Sr. No | Material Name | Batch Quantity |
| 1. | Instacoat EN Solution White (IC-EN-001) | 2.710 kg |
| 2. | Isopropyl Alcohol IP | 15.450 liter |
| 3. | Dichloromethane USP | 36.043 liter |
| 4. | Ponceau 4R | 0.135 kg (To be validated according to the reference sample of products) |
NOTE:
Color: As per packing material /according to the brands/products. The color and quantity of color to be used may vary from product to product as per the reference sample.
STEP-III (LIST OF EQUIPMENTS FOR COATING):
| Sr. No. | Machineries/Equipments | Capacity | Equipment ID. |
| 1. | Coating Machine and Coating Pan | 36″ | SC/PD/COT/02 |
| 2. | Spray Gun | 01 | — |
| 3. | Filter Cloth 100 # | 0.5 meter | — |
| 4. | Portable Stirrer | — | — |
| 5. | SS Containers | 15 liter (02 No’s) ,65 liter (02 No’s) | — |
| 6. | Poly-lined HDPE containers with lid | 45 liter (01 No.) | — |
STEP – IV (PREPARATION OF SEAL COATING SOLUTION):
- Take Isopropyl Alcohol IP (1.540 liter) and Dichloromethane USP (3.590 liter) in SS Container (capacity: 15 liter) and add Instacoat Moistshield White IC-MS 2398 (0.270 kg). Mix together by Portable Stirrer properly continuously stirring till uniform mixing achieved.
- Speed of Stirrer: Constant
- Mixing Ti9me: 20 minutes (To be validated in next batch).
- Filter the coating solution with Filter Cloth 100 # in SS Container (capacity: 15 liter).
- Keep the solution for 10 minutes and after 10 minutes start the Seal coating process with Seal coating solution.
STEP – V (COATING PROCEDURE FOR SEAL COATING OF TABLETS):
- Coating will be done in one lot for 50,000 tablets, take total compressed tablets for coating (27.000 kg).
- Load the tablets in coating pan (capacity: 36″), start the hot air blower, set the inlet air temperature at 60°C to 65°C and start the exhaust fan & warm the tablets bed 30°C to 35°C.
- After warming up the tablets, take weight of 100 warmed tablets and also take weight of 100 tablets after Seal coating and record the weight in BMR for calculation of weight buildup of tablets after Seal Coating.
- Set the coating parameter as given in below table and start the coating process by starting coating spray through gun.
- After completion of Seal Coating, calculate the weight gain by using below Formula in the table.
| Parameter | Specification |
| No. of Baffles in coating pan | 03 |
| No. of Guns | 01 |
| Inlet Temperature | 60°C to 65°C(To be validated in next batch) |
| Peristaltic Pump Speed | 2 to 4 RPM (To be validated in next batch) |
| Atomization | 2.5 to 3.0 kg/cm2 |
| Gun to Tablet Bed Distance | 8 inch |
| BED Temperature | 300C to 35 0C (To be validated in next batch) |
| Pan RPM | 13 to 15 RPM |
| % Weight Gain
(Upto 1 %) |
Weight of tablets after Seal Coating – Weight of Uncoated warmed tablets x 100
Weight of tablets after Seal Coating |
| Seal Coating Time | 02 Hour (To be validated in next batch)
|
STEP – VI (PREPARATION OF ENTERIC COATING SOLUTION):
- Take Isopropyl Alcohol IP (15.450 liter) and Dichloromethane USP (36.043 liter) in SS Container (capacity: 65 liter) and add Instacoat EN Solution White (IC-EN-001) (2.710 kg) and add color Ponceau4R (0.135 kg) in it. Mix together by Portable Stirrer properly continuously stirring till uniform mixing achieved.
- Speed of stirrer: Constant.
- Mixing Time: 20 minutes (To be validated in next batch)
- Filter the coating solution with Filter Cloth 100# in SS Container (65 liter).
- Keeps the solution, after completion of Seal Coating, proceed for Enteric coating process with Enteric coating solution.
STEP – VII (ENTERIC COATING PROCEDURE OF TABLETS):
- Set the coating parameter as given in below table and start the enteric coating process by starting Enteric coating solution spray through gun.
| Parameter | Specification |
| No. of Baffles in coating pan | 03 |
| No. of Guns | 01 |
| Inlet Temperature | 60°C to 65°C (To be validated in next batch) |
| Peristaltic Pump Speed | 2 to 4 RPM (To be validated in next batch) |
| Atomization | 2.5 to 3.0 kg/cm2 |
| Gun to Tablet Bed Distance | 8 inch |
| BED Temperature | 250C to 30 0C (To be validated in next batch) |
| Pan RPM | 13 to 15 RPM |
| % Weight Gain
(8 to 10 %) |
Weight of Enteric Coated Tablets – Weight of Seal Coated Tablets x 100
Weight of Enteric Coated Tablets |
| Enteric Coating Time | Coating Time: 06 Hours (To be validated in next batch)
|
- After completion of Enteric coating, take weight of 10 Enteric coated tablet and record the weight in BMR and calculated the weight gain by using Weight Gain Formula given in above table of Step-VII.
STEP – VIII (ENTERIC COATING IN-PROCESS CHECK PARAMETERS):
- After completion of Enteric Coating perform the In Process checks as per below parameters
| S.No. | Parameters | Standard | No. of Tablets | In-Process Frequency |
| 1 | Product Description | Pink color, round shape, biconvex, enteric coated tablet having both side plain | 20 No. |
After batch completion |
| 2 | Weight of 20 Tablets after coating | 11.880 gm.(8 % to 10 % weight gain) | 20 No. | |
| 3 | Average Weight after coating | 594 mg .(8 % to 10 % weight gain) | 20 No. | |
| 4 | Individual Tablets Weight Variation | NMT 02 tablets out of 20 deviate from the standard average weight by more than 3 % and no single tablet deviates from the standard average weight by more than 5 % | 20 No. | |
| 5 | Thickness | 5.29 mm ± 0.2 mm | 6 No. | |
| 6. | Disintegration Time
(Acid Medium) |
In 0.1M HCl – Should not crack in two hours | ||
| 6 | Disintegration Time
(In Phosphate Buffer) |
Should disintegrate within one hour in mixed phosphate buffer pH = 6.8 | – |
STEP – IX:
- Send the composite sample of coated tablets (Qty. 30 tablets) to QC department for analysis.
STEP – X:
- Take Tare Weight of one Poly-lined HDPE Containers (capacity: 45 liter), record the Tare Weight in BMR and transfer the coated tablets in Poly-lined HDPE Containers (capacity: 45 liter each) and weigh the coated tablets with containers and record the Gross Weight of the coated tablets and calculate the Net Weight of the material as per given formula:
Net Weight = Gross Weight – Tare weight.
- Affix the status label with following details – Product Name, Batch No., Batch Size, Avg. Weight, Mfg. Date, Exp. Date, Tare Weight, Gross Weight and Net Weight on the Poly-lined HDPE Containers.
- Batch Yield of Coated Tablets:
- Theoretical Batch Yield: 29.700 kg (100 %)
- Actual Batch Yield Limit NLT 29.403 kg (NLT 99 %) (To be established in next batch).