MFR of Rabeprazole Sodium 20 mg Tablets
TABLE OF CONTENTS
| S.NO. | TITLE | Page No. | |
| 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 | Rabeprazole Sodium Tablets IP |
| Product Description | Yellow color, round shape, biconvex, enteric-coated tablets having both side plain |
| Strength | Rabeprazole 20 mg |
| Label claim
|
Each enteric-coated tablet contains:
Rabeprazole Sodium IP 20 mg |
| Batch Size | 5,00,000 Tablets |
| Average Weight | 232 mg (Uncoated tablets)
255 mg (Enteric-coated tablets) |
| Shelf Life | 24 months |
| Storage | Store in a cool, dry, and dark place below 250C |
| Drug Category | Proton-Pump Inhibitors |
2.0 MANUFACTURING FORMULA:
| Material Name | Grade | Category | Quantity per Unit (In mg) | Overages | Batch Qty.
(In kg) without |
| Dry Mixing | |||||
| Rabeprazole Sodium | IP | API | 20 mg | 5 % | 10.500 kg |
| Magnesium Oxide | USP | Diluent | 155 mg | —- | 77.500 kg |
| Cross Carmillose Sodium | IP | Disintegrant | 12 mg | 6.000 kg | |
| Binder | |||||
| PVPK-90 | IP | Binder | 11.25 mg | —- | 5.625 kg |
| Dichloromethane | USP | Solvent | 0.140 ml | —- | 70.000 liter |
| Lubricant | |||||
| Talcum | IP | Anti-caking agent | 2 mg | —- | 1.000 kg |
| Cross Carmillose Sodium | IP | Disintegrant | 13.35 mg | —- | 6.675 kg |
| Crospovidone XL | IP | Disintegrant | 10 mg | —- | 5.000 kg |
| Aerosil | IP | Glidant | 1.5 mg | —- | 0.750 kg |
| Calcium Stearate | IP | Anti-adherent | 5.9 mg | —- | 2.950 kg |
3.0 LIST OF EQUIPMENT:
| Sr. No. | Machinery/Equipment | Capacity | Equipment ID. |
| 1. | Weighing Balance | 100 kg | |
| 2. | Vibro Sifter
(with SS Sieves No’s 14,20,30, 40 and 60) |
30” | |
| 3. | Mass Mixer with propeller | 100 liter | |
| 4. | Portable Stirrer | ||
| 5. | Tray Dryer | 48 Trays | |
| 6. | Multi-Mill (screen size 2.0 mm) | — | |
| 7. | Double Cone Blender | 200 liter | |
| 8. | Halogen Moisture Balance | — | |
| 9. | Compression Machine | 35 Station | |
| 10. | SS Containers with lid | 100 liter,65 liter | — |
| 11. | Poly-lined HDPE Containers with lid | 30 liter, 45 liter | — |
| 12. | Filter Cloth 100 # | 0.5 Meter | |
| 13. | Polybags | 05 kg,10 kg,20 kg |
4.0 GENERAL PRECAUTIONS:
- API Description: A white to light yellow, crystalline powder. (Hygroscopic and Light Sensitive)
- 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 products or a mixture of Active Ingredients and Excipients, wear gloves and a mask to avoid exposure and contact with any body parts.
- Use Sodium Lamp and Black Poly-bags at every Step.
5.0 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 from batch to batch and product to product change over.
- Do not overwrite the entry. In case of mistake, cancel the entry by a single line with sign & date and make a correct entry.
6.0 MANUFACTURING PROCESS DETAILS:
6.1 GRANULATION:
NOTE: Turn ON the sodium lamp and switch OFF all lights before starting the operation and use black polybags to store the materials.
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 | ||
| Rabeprazole Sodium IP | 10.500 kg | 40 # |
| Magnesium Oxide IP | 77.500 kg | 40 # |
| Croscarmellose Sodium IP | 6.000 kg | 60 # |
| Binder | ||
| PVPK-90 IP | 5.625 kg | 20 # |
| Dichloromethane USP | 70.000 liter | NA |
| Lubricant | ||
| Talcum IP | 1.000 kg | 60 # |
| Croscarmellose Sodium IP | 6.675 kg | 60 # |
| Crospovidone XL | 5.000 kg | 60 # |
| Aerosil IP | 0.750 kg | 14 # |
| Calcium Stearate | 2.950 kg | 30 # |
NOT
- After sifting divide the sifted Rabeprazole Sodium IP (10.500 kg), in two equal parts for LOT-I and LOT-II (5.250 kg each) and collect in two Black Poly-Bags (capacity : 50 kg each).
- After sifting divide the sifted Magnesium Oxide IP (77.500 kg) in two equal parts for LOT-I and LOT-II (38.750 kg each) and collect in the above two Black Poly-Bags (capacity : 50 kg each) with Rabeprazole.
- After sifting divide the sifted Croscarmellose Sodium IP (6.000 kg) in two equal parts for LOT-I and LOT-II (3.000 kg each) and collect in the two Black Polybags (capacity: 50 kg each) with Rabeprazole and Magnesium Oxide.
- Collect sifted PVPK-90 IP (5.625 kg) in one Poly bag (capacity: 10 kg).
- Collect sifted Talcum IP (1.000 kg), Croscarmellose Sodium IP (6.675 kg), Crospovidone XL IP (5.000 kg), Aerosil IP (0.750 kg) into one Poly-Bags (capacity : 20 kg)
- Collect the sifted Calcium Stearate IP (2.950 kg) in one Poly-Bags (capacity: 5 kg)
STEP – II (BINDER PREPARATION): FOR LOT-I and LOT-II:
Take Dichloromethane USP (70.000 liter) in SS Container (capacity: 100 liter) and add PVPK-90 IP
(5.625 kg) in it. Mix together by Portable Stirrer continuously stirring till dissolved properly in MDC.
Filter the solution with filter cloth 100 # in SS Container (capacity: 100 liter).
Divide the solution (Qty. 75.625 liter) into two equal parts for Lot-I (37.812 liter) and Lot-II (37.812 liter) and store in SS Container (capacity: 65 liter each).
STEP – III (DRY MIXING): FOR LOT-I:
Transfer the sifted Rabeprazole Sodium IP, Magnesium Oxide USP and Cross Carmillose Sodium IP in Mass Mixer (capacity: 100 liter) and dry mix the materials till uniform mixing achieved.
Mixing Time: 10 minutes.(To be validated in next batch)
Mixing Speed: 36 RPM
Paddle (Blades) Timing: 05 minutes in clockwise direction & 05 minutes in anti-clockwise direction.
STEP –IV (BINDING OF DRY MIX MATERIAL): FOR LOT-I:
Slowly add the binder for LOT-I of Step-II in dry mix materials of Step-III and mix for 10 minutes till uniform binding and after binding, collect the wet mass into sixteen Trays (capacity: 3.000 kg each).
Mixing Time: 10 minutes (To be validated in next batch).
Mixing Speed: 36 RPM
Paddle (Blades) Timing: 05 minutes in clockwise direction & 05 minutes in anti-clockwise direction
NOTE:
FOR LOT – II: Please follow the same procedure of LOT – I of dry mixing and binding.
STEP –V (DRYING):
Dry the wet mass of Step –IV for LOT-I and LOT-II as follows:
Load in thirty-two trays in Tray Dryer.
First airs dry the granules for 30 minutes in Tray Dryer. Ensure that heaters are in OFF mode. After air drying Switch ON the heaters and dry the granules at 35oC in Tray Dryer until the LOD of granules is between 1.0 to 1.5% at 105oC checked by Halogen Moisture Balance.
Air Drying Time: 30 minutes (Heaters should be OFF).
Drying Time: 04 to 05 Hours (To be validated in next batch)
Drying Temperature: 350C (After Air Drying)
Raking Frequency: After every 20 minutes.
STEP-VI (SIZING/MILLING):
Check Screen Integrity (before sifting and after sifting).
Mill the dried material of Step -V through Multi Mill using screen size 2.0 mm and collect milled material in two Poly-lined HDPE Containers (capacity :30 liter each ) and weigh and record the milled granules weight.
Blade Type: Both (Knife blades/Scraping blades)
Rotor Speed: 2000 RPM
STEP – VII (PRE –LUBRICATION):
Load the milled granules of Step-VI in Double Cone Blender (capacity : 400 liter) and add sifted Talcum IP, Croscarmellose Sodium IP, Crospovidone XL IP and Aerosil IP, mix properly till uniform mixing of sized material with Pre-Lubricating Material.
Mixing Time: 30 minutes (15 minutes clockwise direction and 15 minutes anti-clockwise direction)
Mixing Speed: 10 RPM
STEP – VIII (LUBRICATION):
Add the sifted Calcium Stearate IP in Pre- Lubricated Materials of Step-VII and mix properly till uniform mixing of materials with Calcium Stearate IP.
Mixing Time: 05 minutes. (clockwise direction)
Mixing Speed: 10 RPM.
STEP- IX (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 |
Off white 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 – XI:
- 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 Container.
- Batch Yield of Lubricated granules:
Theoretical Batch Yield: 116.00 kg (100 %)
Actual Batch Yield Limit NLT 114.840 kg (NLT 99 %) (To be established in next batch)
STEP – XII:
- Clean all equipments used in the granulation as per respective equipment cleaning SOP.
6.2 COMPRESSION:
NOTE: Turn ON sodium lamp and switch OFF all lights before starting compression and use black polybags to store the tablets.
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 continue the compression with 35 stations (B-Tooling) Compression Machine of 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 -6 Tones | —– | —– |
| 4. | Machine Speed | 18 RPM -20 RPM | —– | —– |
| 5. | Common Name of Die | Himosin | ||
| 6. | Lower Punch Size | 9.5 mm | —– | —– |
| 7. | Diameter of the tablet | 9.5 mm | 6/Individual | 2 hours |
| 8. | Thickness of Tablets | 2.82 mm ± 0.2 mm | 6/Individual | 2 hours |
| 9. | Weight of 20 Tablets | 4.640 gm. ± 2% | 20/Composite | 30 minutes |
| 10. | Product Description | Off white color round shape, biconvex, uncoated tablets having both side plain | 20/Composite | 30 minutes |
| 11. | 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 % | —– | 01 hour |
| 12. | Standard Average Weight of Tablets | 232 mg ± 2 % | 20/Individual | 30 minutes |
| 13. | Hardness | NLT 3.0 kg/cm2 | 6/Individual | 30 minutes |
| 14. | Disintegration Time | NMT 15 min | 6/Composite | 01 hour |
| 15. | Friability | NMT 1% | 20/Composite | 01 hour |
- Collect the compressed tablets in SS Container (capacity: 20 liter each on both sides), when SS containers are filled with tablets, transfer the tablets in three Poly-lined HDPE Containers (capacity: 45 liter each) 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: 116.000 kg (100 %)
Actual Batch Yield Limit NLT 114.840 kg (NLT 99 %) (To be established in next batch)
STEP – IV:
- After completion of compression of tablets, clean the Compression Machine as per cleaning SOP.
NOTE: For this product, the lot size of 500000 tablets is taken which is divided into different sub lots (batches of different quantities) as per the order of the customers.
In order to standardize the Coating Procedure, we are taking the Batch Size of 100000 tablets for coating in this MFR.
6.3 COATING: FOR 1, 00,000 Tablets
NOTE: Switch ON the Sodium lamp and switch OFF all lights and use black polybags to store the tablets.
- Verify the Net Weight of the received compressed tablets for coating as per status label and after confirmation continues for tablet coating.
STEP – I (COATING MATERIALS SEAL COAT DETAILS):
| Sr. No | Material Name | Batch Quantity |
| 1. | Instacoat Sol. Trans IC-S-1643 | 0.232 kg |
| 2. | Isopropyl Alcohol IP | 1.322 liter |
| 3. | Dichloromethane USP | 3.085 liter |
STEP – II (COATING MATERIALS ENTERIC COATING DETAILS):
| 1. | Instacoat EN Sol. Wht.IC-EN-001 | 2.320 kg |
| 2. | Isopropyl Alcohol IP | 13.224 liter |
| 3. | Dichloromethane USP | 30.856 liter |
| 4. | Yellow oxide of iron | 0.047 kg (To be validated according to the reference sample of product) |
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 EQUIPMENT FOR COATING):
| Sr. No. | Machineries/Equipments | Capacity | Equipment ID. |
| 1. | Coating Machine and Coating Pan | 24″ | |
| 2. | Spray Gun | 01 | — |
| 3. | Filter Cloth 100 # | 0.5 Meter | — |
| 4. | Portable Stirrer | — | — |
| 5. | SS Containers | 10 liter (02 No’s)
65 liter (02 No’s) |
— |
| 6. | Poly-lined HDPE Containers with lid | 30 liter (01 No.) |
STEP – IV (PREPARATION OF SEAL COAT SOLUTION):
- Take Isopropyl Alcohol IP (1.322 liter) and Dichloromethane USP (3.085 liter) and add Instacoat Sol. Trans IC-S-1643 (0.232 kg) in SS Container (capacity 10 liter), mix together by Portable Stirrer continuously stirring properly 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: 10 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 COAT OF TABLETS):
NOTE: Use Sodium lamps and switch OFF all lights and use black polybags to store the tablets.
- Coating will be done in one lot (For 1,00,000 tablets), take total compressed tablets for coating (23.200 kg)
- Load the tablets in coating pan (Capacity: 24″), start the hot air blower, set the supply 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 Coat.
- Set the coating parameter as given in below table and start the coating process by starting coating spray from 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 – 4 RPM (To be validated in next batch) |
| Atomization | 2.5 to 3.0 kg/cm2 |
| Gun to Tablet Bed Distance | 10 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 tablet after Seal Coat – Weight of uncoated warmed tablets x 100 / Weight of tablet after Seal Coat |
| Seal Coat Time | 01 Hour (To be validated in next batch |
STEP – V: PREPARATION OF ENTERIC SOLUTION:
- Take Isopropyl Alcohol IP (13.224 liter) and Dichloromethane USP (30.856 liter) and add Instacoat EN Sol.Wht.IC-EN-001 (2.320 kg) in SS Container (capacity: 65 liter), and mix together by Portable Stirrer continuously stirring properly till uniform mixing achieved.
Speed of stirrer: Constant.
Mixing Time: 20 minutes (To be validated in next batch)
- After uniform mixing add color Yellow oxide of iron IP (0.047 kg) in the above solution and mix for 05 minutes with stirrer till uniform mixing achieved.
- Filter the coating solution with Filter Cloth 100 # in one SS Container (capacity: 65 liter)
- Keeps the solution, after completion of Seal Coat, proceed for Enteric coating process.
STEP – VI (COATING PROCEDURE FOR ENTERIC COATINFG):
- Set the coating parameter for Enteric Coating 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 – 4 RPM (To be validated in next batch) |
| Atomization | 2.5 to 3.0 kg/cm2 |
| Gun to Tablet Bed Distance | 10 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 Coat Tablets x 100 /Weight of Enteric Coated Tablets |
| Coating Time | 06 Hour (To be validated in next batch) |
- After completion of Enteric Coating, take weight of 100 enteric coated tablets and record the weight in BMR and calculate the weight gain by using Weight Gain Formula given in above table of Step-VI.
STEP – VII (COATING IN-PROCESS CHECK PARAMETERS):
- After completion of Film Coating perform the In Process checks as per below parameters:
| S.No. | Parameters | Standard | No. of Tablets | In-Process Frequency |
| 1 | Product Description | Yellow color, round shape, biconvex, enteric coated tablet having both side plain | 20 No. |
After batch completion |
| 2 | Weight of 20 Tablets after coating | 5.100 gm.(8 % to 10 % weight gain) | 20 No. | |
| 3 | Average Weight after coating | 255 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 8 % and no single tablet deviates from the standard average weight by more than 10 % | 20 No. | |
| 5 | Thickness | 3.10 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 | — | |
| 8 | Dissolution in Acid Medium (Gastro Resistance) | Rabeprazole Sodium (as Enteric Coated tablet)
Should be dissolved less than 15 %
|
20 No. | |
| 9 | Dissolution in Phosphate Buffer | Rabeprazole Sodium (as Enteric Coated tablet)
Should be dissolved more than 75 %
|
— |
STEP –VII:
- Send the composite sample of coated tablets (Qty.30 tablets) to QC department for analysis.
STEP – IX:
- Take Tare Weight of one Poly-lined HDPE Containers (capacity: 30 liter ), record the Tare Weight in BMR and transfer the coated tablets in Poly-lined HDPE Containers (capacity: 30 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: 25.500 kg (100 %)
Actual Batch Yield Limit NLT 25.245 kg (NLT 99 %) (To be established in next batch).