MFR of Rabeprazole Sodium 20 mg Tablets

MFR of Rabeprazole Sodium 20 mg Tablets

TABLE OF CONTENTS 

S.NO.TITLEPage No.
1.0PRODUCT DETAILS
2.0MANUFACTURING FORMULA
3.0LIST OF EQUIPMENTS
4.0GENERAL PRECAUTIONS
5.0MANUFACTURING INSTRUCTIONS
6.0

 

 

 

MANUFACTURING PROCESS DETAILS
6.1GRANULATION
6.2COMPRESSION
6.3COATING
6.4BRAND DETAILS

 1.0 PRODUCT DETAILS:

Product NameRabeprazole Sodium Tablets IP
Product DescriptionYellow 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 Size5,00,000 Tablets
Average Weight232 mg (Uncoated tablets)

255 mg (Enteric-coated tablets)

Shelf Life24 months
StorageStore in a cool, dry, and dark place below 250C
Drug CategoryProton-Pump Inhibitors

2.0 MANUFACTURING FORMULA:

Material NameGradeCategoryQuantity per Unit (In mg)OveragesBatch Qty.

 (In kg) without

Dry Mixing
Rabeprazole Sodium IPAPI20 mg5 %10.500 kg
Magnesium OxideUSPDiluent155 mg—-77.500 kg
Cross Carmillose SodiumIPDisintegrant12  mg6.000  kg
Binder
PVPK-90IPBinder11.25 mg—-5.625 kg
DichloromethaneUSPSolvent 0.140 ml—-70.000 liter
Lubricant
TalcumIPAnti-caking agent2  mg—-1.000 kg
Cross Carmillose SodiumIPDisintegrant  13.35 mg—-6.675 kg
Crospovidone XLIPDisintegrant10 mg—-5.000 kg
AerosilIPGlidant1.5 mg—-0.750 kg
Calcium StearateIPAnti-adherent 5.9 mg—-2.950 kg

3.0 LIST OF EQUIPMENT:                         

Sr. No.Machinery/EquipmentCapacityEquipment ID.
1.Weighing Balance100 kg
2.Vibro Sifter

(with SS Sieves  No’s 14,20,30, 40 and 60)

30”
3.Mass Mixer with propeller100 liter
4.Portable Stirrer
5.Tray Dryer48 Trays
6.Multi-Mill (screen size 2.0 mm)
7.Double Cone Blender200 liter
8.Halogen Moisture Balance
9.Compression Machine35 Station
10.SS Containers with lid100 liter,65 liter
11.Poly-lined HDPE Containers with lid30  liter, 45 liter
12.Filter Cloth 100 #0.5 Meter
13.Polybags05 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 IP10.500 kg40 #
Magnesium Oxide IP77.500 kg40 #
Croscarmellose Sodium IP6.000 kg60 #
Binder
PVPK-90 IP5.625 kg20 #
Dichloromethane USP70.000 literNA
Lubricant
Talcum IP1.000 kg60 #
Croscarmellose Sodium IP6.675 kg60 #
Crospovidone XL5.000 kg60 #
Aerosil IP0.750 kg14 #
Calcium Stearate2.950 kg30 #

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:

TestSpecification
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.

ParametersStandardNo. of TabletsIn-Process Frequency
1.       Feed frame alignment and adjustmentShould be satisfactory—–—–
2.       Lower Weight AssemblyShould be satisfactory—–—–
3.       Hydraulic Pressure5 -6 Tones—–—–
4.       Machine Speed18 RPM -20 RPM—–—–
5.       Common Name of DieHimosin
6.       Lower Punch Size9.5  mm—–—–
7.        Diameter of the tablet9.5 mm6/Individual2 hours
8.       Thickness of Tablets2.82 mm ± 0.2 mm6/Individual2 hours
9.   Weight of 20 Tablets4.640 gm. ± 2%20/Composite30 minutes
10.   Product DescriptionOff white color round shape, biconvex, uncoated tablets having both side plain20/Composite30 minutes
11.   Uniformity of WeightNMT 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 Tablets232 mg ± 2 %20/Individual30 minutes
13.   HardnessNLT 3.0 kg/cm26/Individual30 minutes
14.   Disintegration TimeNMT 15 min6/Composite01 hour
15.   FriabilityNMT 1%20/Composite01 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. NoMaterial NameBatch Quantity
1.Instacoat  Sol. Trans IC-S-16430.232 kg
2.Isopropyl Alcohol IP1.322 liter
3.Dichloromethane USP3.085 liter

STEP – II (COATING MATERIALS ENTERIC COATING DETAILS):      

1.Instacoat EN Sol. Wht.IC-EN-0012.320 kg
2.Isopropyl Alcohol IP13.224 liter
3.Dichloromethane USP30.856 liter
4.Yellow oxide of iron0.047 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/EquipmentsCapacityEquipment ID.
1.Coating  Machine and Coating Pan24″
2.Spray Gun01
3.Filter Cloth 100 #0.5 Meter
4.Portable Stirrer
5.SS Containers10 liter (02 No’s)

65 liter (02 No’s)

6.Poly-lined HDPE Containers with lid30 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.
ParameterSpecification
No. of Baffles in coating pan03
No. of Guns01
Inlet Temperature60°C to 65°C (To be validated in next batch)
Peristaltic Pump Speed2 – 4 RPM (To be validated in next batch)
Atomization2.5 to 3.0 kg/cm2
Gun to Tablet Bed Distance10 inch
BED Temperature300C to 35 0C (To be validated in next batch)
Pan RPM13 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 Time01 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.
ParameterSpecification
No. of Baffles in coating pan03
No. of Guns01
Inlet Temperature60°C to 65°C (To be validated in next batch)
Peristaltic Pump Speed2 – 4 RPM (To be validated in next batch)
Atomization2.5 to 3.0 kg/cm2
Gun to Tablet Bed Distance10 inch
BED Temperature300C to 35 0C (To be validated in next batch)
Pan RPM13 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 Time06 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.ParametersStandardNo. of TabletsIn-Process Frequency
1Product DescriptionYellow color, round shape, biconvex, enteric coated tablet having both side plain20 No. 

 

 

 

 

 

 

After batch completion

2Weight of 20 Tablets after coating5.100 gm.(8 % to 10 % weight gain)20 No.
3Average Weight after coating255 mg .(8 % to 10 % weight gain)20 No.
4Individual 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.
5Thickness3.10 mm ± 0.2 mm6 No.
6Disintegration Time (Acid Medium)In 0.1M HCl – Should not crack in two hours6 No
7Disintegration Time (In Phosphate Buffer)Should disintegrate within one hour in mixed phosphate buffer pH = 6.8
8Dissolution in Acid Medium (Gastro Resistance)Rabeprazole Sodium (as Enteric Coated tablet)

Should be dissolved less than 15 %

 

20 No.
9Dissolution in Phosphate BufferRabeprazole 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).

 

 

 

About ABHA

Abha is the Author  of pharmaceutical guidance, she is a pharmaceutical professional having more than 22 years of rich experience in pharmaceutical field. During her career, she works in the quality assurance department with multinational companies i.e Zydus Cadila Ltd, Unichem Laboratories Ltd, Indoco remedies Ltd. During his experience, she faces many regulatorily audits i.e. USFDA, MHRA, ANVISA, MCC, TGA, EU –GMP, WHO –Geneva, ISO 9001-2008 and many ROW Regularities Audit i.e.Uganda, Kenya, Tanzania, Zimbabwe. She is currently leading a regulatory pharmaceutical company as a Head Quality. You can join him by Email, Facebook, Google+, Twitter, and YouTube

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