MFR of Trypsin, Bromelain and Rutoside Trihydrate Tablets
TABLE OF CONTENTS
| S.NO. | TITLE | |
| 1.0 | PRODUCT DETAILS | |
| 2.0 | MANUFACTURING FORMULA | |
| 3.0 | LIST OF EQUIPMENTS | |
| 4.0 | GENERAL PRECAUTIONS | |
| 5.0 | MANUFACTURING INSTRUCTIONS | |
| 6.0
|
MANUFACTURING PROCESS DETAILS | |
| 6.1 | GRANULATION | |
| 6.2 | COMPRESSION | |
| 6.3 | COATING | |
| 6.4 | BRAND DETAILS | |
1.0 PRODUCT DETAILS:
| Product Name | Trypsin, Bromelain and Rutoside Trihydrate Tablets |
| Product Description | Pink color, round shape, biconvex, enteric coated tablets having both side plain |
| Strength | Trypsin BP 48 mg
Bromelain 90 mg Rutoside Trihydrate BP 100 mg |
| Label claim
|
Each enteric coated tablet contains:
Trypsin BP 48 mg Bromelain 90 mg Rutoside Trihydrate BP 100 mg |
| Batch Size | 2,00,000 Tablets |
| Average Weight | 500 mg (Uncoated tablets)
550 mg (Enteric coated tablets) |
| Shelf Life | 24 months |
| Storage | Store in a cool, dry and dark place below 25 0C |
| Drug Category | Analgesic, Anti-Inflammatory Drug |
2.0 MANUFACTURING FORMULA:
| Material Name | Grade | Category | Quantity per Unit (In mg) | Overages | Batch Qty.
(In kg) |
| Dry Mixing – I | |||||
| 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 | 40 mg | — | 8.000 kg |
| MCCP PH -102 | IP | Diluent | 143.50 mg | — | 28.700 kg |
| Lubricant | |||||
| Talcum | IP | Anti caking agent | 10 mg | 2.000 kg | |
| Sodium Starch Glycolate | IP | Disintegrant | 7.5 mg | — | 1.500 kg |
| Crospovidone XL | IP | Disintegrant | 7.5 mg | — | 1.500 kg |
| Cross Carmellose Sodium | IP | Disintegrant | 7.5 mg | — | 1.500 kg |
| Magnesium Stearate | IP | Anti -adherent | 4 mg | — | 0.800 kg |
3.0 LIST OF EQUIPMENTS:
| Sr. No. | Machineries/Equipments | Capacity | Equipment ID. |
| 1. | Weighing Balance | 100 kg | |
| 2. | Vibro Sifter (with SS Sieves No’s 24, 40 and 60 ) | 30 inch dia | |
| 3. | Double Cone Blender | 400 liter | |
| 4. | Halogen Moisture Balance | — | |
| 5. | Compression Machine | 27 Station | |
| 6. | Poly-lined HDPE Containers with lid | 45 liter (09 No’s) | — |
| 7. | Polybags | 01 kg (01 No.),
10 kg (01 No.) |
- GENERAL PRECAUTIONS:
- API Description Trypsin: A white or almost white crystalline powder.
- API Description Bromelain: Off white to pale brown color powder.
- API Description Rutoside Trihydrate: Yellow or greenish yellow color crystalline powder.
- All the Manufacturing Activities shall be performed under controlled conditions (temperature NMT 250C 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 for 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 | ||
| Trypsin BP | 12.000 kg | 24 # |
| Bromelain | 21.600 kg | 24 # |
| Rutoside Trihydrate BP | 22.400 kg | 24 # |
| MCCP PH -112 IP | 8.000 kg | 40 # |
| MCCP PH -102 IP | 28.700 kg | 40 # |
| Lubricants | ||
| Talcum IP | 2.000 kg | 60 # |
| Sodium Starch Glycolate IP | 1.500 kg | 60 # |
| Crospovidone XL IP | 1.500 kg | 60 # |
| Cross Carmellose Sodium IP | 1.500 kg | 60 # |
| Magnesium Stearate | 0.800 kg | 60 # |
- Collect sifted Trypsin BP (12.000 kg), Bromelain (21.600 kg), Rutoside Trihydrate BP (22.400 kg), MCCP PH-112 IP (8.000 kg) and MCCP PH-102 IP (28.700 kg) in three Poly-lined HDPE Containers (capacity: 45 liter each).
- Collect sifted Talcum IP (2.000 kg), Sodium Starch Glycolate IP (1.500 kg), Crospovidone XL IP (1.500 kg) and Cross Carmellose Sodium IP (1.500 kg) in one Polybag (capacity: 10 kg).
- Collect the sifted Magnesium Stearate IP (0.800 kg) in one Polybag (capacity: 1 kg).
STEP – II (DRY MIXING):
Transfer the sifted Trypsin BP, Bromelain, Rutoside Trihydrate BP, MCCP PH-112 IP and MCCP PH-102 IP in Double Cone Blender (capacity: 400 liter) and dry mix the materials till uniform mixing.
Mixing Time: 20 minutes (10 minutes clockwise and 10 minutes anticlockwise direction).
(To be validated in next batch)
Mixing Speed: 10 RPM.
STEP – III (PRE –LUBRICATION):
Add the sifted Talcum IP, Sodium Starch Glycolate IP, Crospovidone XL IP and Cross Carmellose Sodium in Double Cone Blender with Step-II and mix properly till uniform mixing of sifted materials 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 – IV (LUBRICATION):
Add the sifted Magnesium Stearate IP in Double Cone Blender with Step-III 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- V (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 % To be established in next batch 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 – VI:
- 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: 100.000 kg (100 %).
Actual Batch Yield Limit NLT 99 .000 kg (NLT 99 %) (To be established in next batch).
STEP – VII:
- Clean all equipments used in the granulation as per respective equipment cleaning SOP.
- 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. | Upper Punch Size | 12.5 mm | —– | —– |
| 6. | Lower Punch Size | 12.5 mm | —– | —– |
| 7. | Die | 12.5 mm | 6/Individual | 2 hours |
| 8. | Diameter of the tablet | 12.5 mm | 6/Individual | 2 hours |
| 9. | Thickness of Tablets | 4.95 mm ±0.2 mm | 6/Individual | 2 hours |
| 10. | Weight of 20 Tablets | 10.000 gm. ± 2% | 20/Composite | 30 minutes |
| 11. | Product Description | Yellow color, round shape, biconvex, uncoated tablets having both side plain | 20/Composite | 30 minutes |
| 12. | 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 |
| 13. | Standard Average Weight of Tablets | 500 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 |
- 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 below in 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: 100.00 kg (100 %).
Actual Batch Yield Limit NLT 99.000 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) | 0.250 kg. |
| 2. | Isopropyl Alcohol IP | 1.425 liter |
| 3. | Dichloromethane USP | 3.325 liter |
STEP – II (COATING MATERIALS DETAILS FOR ENTERIC COATING):
| Sr. No | Material Name | Batch Quantity |
| 1. | Instacoat EN Solution White (IC-EN-001) | 2.500 kg |
| 2. | Isopropyl Alcohol IP | 14.250 liter |
| 3. | Dichloromethane USP | 33.250 liter |
| 4. | Ponceau 4R | 0.125 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″ | |
| 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 (1.425 liter) and Dichloromethane USP (3.325 liter) in SS Container (capacity: 15 liter) and add Instacoat Moistshield White IC-MS 2398 (0.250 kg). 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 (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 (25.000 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
(Up to 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 (14.250 liter) and Dichloromethane USP (33.250 liter) in SS Container (capacity: 65 liter) and add Instacoat EN Solution White (IC-EN-001) (2.500 kg) and add color Ponceau 4R (0.125 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 coating 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 | 300C to 35 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 | 11.000 gm (8 % to 10 % weight gain) | 20 No. | |
| 3 | Average Weight after coating | 550 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 No. | |
| 7 | 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 of each Lot) 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: 27.500 kg (100 %)
Actual Batch Yield Limit NLT 27.225 kg (NLT 99 %) (To be established in next batch).