• MFR of Diclofenac Potassium 50 mg and Serratiopeptidase 10 mg Tablets

TABLE OF CONTENTS FOR Diclofenac Potassium

1.0 PRODUCT DETAILS FOR Diclofenac Potassium :

2.0 MANUFACTURING FORMULA FOR Diclofenac Potassium:

3.0 LIST OF EQUIPMENT FOR Diclofenac Potassium:                         

4.0 GENERAL PRECAUTIONS FOR Diclofenac Potassium:

• API Description Diclofenac Potassium: A white or slightly yellowish, slightly hygroscopic crystalline powder.
• API Description Serratiopeptidase (Plain): A greyish white to pale brown powder with a characteristic odor.
• All the Manufacturing Activities shall be performed under controlled conditions (temperature NMT 25 ⁰C and relative humidity NMT 50%).
• 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.

5.0 MANUFACTURING INSTRUCTIONS FOR Diclofenac Potassium:

• All activities shall be performed as per current SOPs.
• Take the line clearance for all equipment 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 a single line with sign & date and make a correct entry.

6.0 MANUFACTURING PROCESS DETAILS FOR Diclofenac Potassium:

6.1 GRANULATION FOR Diclofenac Potassium:

STEP – I (SIFTING) FOR Diclofenac Potassium :

• 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:

NOT

• Collect sifted Diclofenac Potassium IP (25.000 kg) and MCCP PH-102 IP (13.700 kg) into two Poly-Bags (capacity: 25 kg each).
• Collect sifted PVPK-30 IP (0.400 kg) in one Polybag (capacity: 1 kg) for Part-I.
• Collect sifted Serratiopeptidase IP (6.000 kg) and MCCP-PH-102 IP (5.000) into one Poly-Bag (capacity: 20 kg).
• Collect sifted PVPK-30 IP (0.100 kg) in one Polybag (capacity: 1 kg) for Part-II.
• Collect the sifted Talcum IP (1.250 kg), Cross Carmillose Sodium IP (1.000 kg), Crospovidone XL IP (1.100 kg), Sodium Starch Glycolate IP (1.250 kg) and Aerosil IP (0.500 kg) into one Poly-Bag (capacity : 10 kg).
• Collect the sifted Magnesium Stearate IP (0.700 kg) into one Poly-Bag (capacity: 1 kg).

STEP – II (BINDER PREPARATION): PART-I:

• Take Isopropyl Alcohol IP (21.310 liter) in SS Container (capacity: 30 liter) and add PVPK-30 IP (0.400 kg) in it. Mix together by Portable Stirrer continuously stirring till PVPK-30 IP dissolved properly in IPA.
• Mixing Time: 10 minutes (To be validated in the next batch).
• Filter it with 100# filter cloth in SS Container (capacity: 30 liters).

STEP – III (DRY MIXING): FOR PART-I:

• Transfer the sifted Diclofenac Potassium BP and MCCP PH-102 IP in Mass Mixer (capacity: 100 liters) and dry mix the materials till uniform mixing.
• Mixing Time: 10 minutes
• Mixing Speed: 36 RPM.
• Paddle (Blades) Timing: 05 minutes in a clockwise direction and 05 minutes in the anti-clockwise direction.

STEP –IV (BINDING OF DRY MIX MATERIAL): FOR PART-I:

• Slowly add the binder 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 thirteen Trays (capacity: 3.000 kg each).
• Mixing Time: 10 minutes
• Mixing Speed: 36 RPM.
• Paddle (Blades) Timing & Direction = 5 minutes in clockwise direction & 5 minutes in anti-clockwise direction 

STEP –V (DRYING):  FOR PART-I:

• Dry the wet mass of Step -IV as follows:
• Load these thirteen Trays of PART-I in the Tray Dryer.
• First air dries the granules for 30 minutes in a Tray Dryer. Ensure that heaters are in OFF mode. 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: 03 Hours. (To be validated in the next batch).
• Drying Temperature: 35⁰C (After Air Drying).
• Raking Frequency: After every 30 minutes.

STEP-VI (SIZING/MILLING): FOR PART-I:

• Check Screen Integrity (before sifting and after sifting).
• Mill the dried material of Step –V and pass through Multi Mill using screen size 1.5 mm and  collect milled material into one Poly-lined HDPE Containers (capacity:45 liters)
• Blade Type: Both (Knife blades/Scraping blades)
• Rotor Speed: 2000 RPM

STEP – VII (BINDER PREPARATION): FOR PART-II:

• Take Isopropyl Alcohol IP (6.050 liters) in SS Container (capacity: 10 liters) and add PVPK-30 IP (0.100 kg) in it. Mix together by Portable Stirrer continuously stirring till PVPK-30 IP dissolved properly in IPA.
• Mixing Time: 10 minutes (To be validated in next batch)
• Filter it with 100# filter cloth in SS Container (capacity: 10 liters).

STEP – VIII (DRY MIXING): FOR PART-II:

• Transfer the sifted Serratiopeptidase IP and MCCP PH-102 IP in SS Container (capacity: 30 liters) and dry mix the materials manually till uniform mixing.
• Mixing Time: 10 minutes (manually) (To be validated in the next batch).

STEP –IX (BINDING OF DRY MIX MATERIAL): FOR PART-II:

• Slowly add the binder PART-II of Step-VII in dry mix materials of Step-VIII and mix manually for 15 minutes till uniform binding and after binding, collect the wet mass into four Trays (capacity: 3.000 kg each).
• Mixing Time: 15 minutes (manually) (To be validated in next batch)

STEP –X (DRYING): FOR PART-II:

• Dry the wet mass of Step -IX as follows:
• Load these four Trays of PART-II in the Tray Dryer.
• First air dries the granules for 30 minutes in a Tray Dryer. Ensure that heaters are in OFF mode. 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 (To be validated in next batch)
• Drying Time: 03 Hours. (To be validated in the next batch).
• Drying Temperature: 35⁰C (After Air Drying).
• Raking Frequency: After every 30 minutes.
• Rotor Speed: 2000 RPM 

STEP-XI (SIZING/MILLING): FOR PART-II:

• Check Sieve Integrity (before sifting and after sifting).
• Set the Vibro Sifter and fix the sieve 30 # and sieve the dried material of Step-X. Collect the sized material in one Poly-lined HDPE Container (capacity: 30 liters).

STEP – XII (PRE –LUBRICATION):

• Load the milled granules of Step-VI (PART-I) and sized granules of Step-XI (PART-II) in Double Cone Blender (capacity: 200 liters) and add sifted Talcum IP, Cross Carmellose Sodium IP, Crospovidone XL IP, Sodium Starch Glycolate IP, and Aerosil IP, mix properly till uniform mixing of milled and 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 – XIII (LUBRICATION):

• Add the sifted Magnesium Stearate IP in Pre- Lubricated Material of Step-XII and mix properly till uniform mixing of materials with Magnesium Stearate IP.
• Mixing Time: 05 minutes. (clockwise direction)
• Mixing Speed: 10 RPM.

STEP- XIV (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:

STEP – XV:

• Take Tare Weight of two Poly-lined HDPE Containers (capacity: 30 liters each), record the Tare Weight in BMR and unload the above-blended material from Double Cone Blender in Poly-lined HDPE Containers (capacity: 30 liters 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 the 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: 56.000 kg (100 %)

Actual Batch Yield Limit: 55.440 kg (NLT 99 %) (To be established in next batch).

STEP – XVI:

• Clean all equipment used in the granulation as per respective equipment cleaning SOP.

6.2 COMPRESSION:

STEP – I:                                

• After receiving QC approval for the blend, verify the Net Weight of the received blend as per the status label in Granules Day Store.
• After confirmation continue the compression with 35 stations (B-Tooling) Compression Machine. Compress the blend as per the following parameters and In-Process checks under controlled environmental conditions. 

• Collect the compressed tablets in SS Container (capacity: 20 liters each on both sides), when SS containers are filled with tablets, transfer the tablets in two Poly-lined HDPE Containers as given below in Step-III.

STEP – II:

• Send the sample of compressed tablets (Qty. 30 tablets) to QC department for analysis.

STEP – III:

• Take Tare Weight of two Poly-lined HDPE Containers (capacity: 30 liters each), record the Tare Weight in BMR and transfer the compressed tablets in Poly-lined HDPE Containers (capacity: 30 liters 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 the 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 Compressed Tablets:
• Theoretical Batch Yield: 56.000 kg (100 %).
• Actual Batch Yield Limit: 55.440 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)

• 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 FOR SEAL COATING DETAILS):      

STEP – II (COATING MATERIALS FOR ENTERIC COATING DETAILS):      

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):

STEP – IV (PREPARATION OF SEAL COATING SOLUTION):

• Take Isopropyl Alcohol IP (0.640 liter) and Dichloromethane USP (1.490 liter) in SS Container (capacity: 10 liter) and add Instacoat Solution Transparent IC-S-1643 (0.112 kg). Mix together by Portable Stirrer properly continuously stirring till uniform mixing is achieved.

Speed of stirrer: Constant.

Mixing Time: 15 minutes (To be validated in next batch)

• Filter the Seal coating solution with Filter Cloth 100 # in SS Container (capacity: 10 liters) and proceed for Seal coating with the seal coating solution.

STEP – V (COATING PROCEDURE FOR SEAL COATING):

• The coating will be done in one lot for 1,00,000 tablets, take total compressed tablets for coating (11.200 kg)

• Load the tablets in coating pan (Capacity: 24″), 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 the weight of 100 warm tablets and also take the weight of 100 tablets after Seal Coating and record the weight in BMR for calculation of weight buildup of tablets after Seal Coating of tablets.
• Set the coating parameter as given in the below table and start the coating process by starting coating spray from the gun.
• After completion of Seal Coating, calculate the weight gain by using the below Formula in the table.

STEP – VI (PREPARATION OF ENTERIC COATING SOLUTION):

• Take Isopropyl Alcohol IP (6.384 liters) and Dichloromethane USP (14.896 liters) in SS Container (capacity; 30 liters) and add Instacoat EN Solution White IC-EN-001(1.120 kg), mix together by Portable Stirrer properly continuously stirring till uniform mixing achieved.

Speed of stirrer: Constant.

Mixing Time: 15 minutes (To be validated in next batch)

• After uniform mixing add color Yellow oxide of iron IP (0.055 kg) in the above solution and mix for 05 minutes with stirrer till uniform mixing is achieved.
• Filter the Enteric coating solution with  Filter Cloth 100 # in one SS Container (capacity: 30 liters)
• Keep the solution, after completion of Seal Coating, start the enteric coating process with the enteric coating solution.

STEP – VII (COATING PROCEDURE FOR ENTERIC COATING TABLETS):

• Set the coating parameter as given in the below table and start the enteric coating process by starting coating spray through the gun.

• After completion of Enteric coating, take the weight of 100 Enteric-coated tablets and record the weight in BMR, and calculate the weight gain by using the above Weight Gain Formula.

STEP – VIII (COATING IN-PROCESS CHECK PARAMETERS):

• After completion of Enteric Coating, perform the In Process checks as per the below parameters.

STEP – IX:

• Send the composite sample of coated tablets (Qty.30 tablets) to the QC department for analysis.

STEP – X:

• Take Tare Weight of one Poly-lined HDPE Containers (capacity: 30 liters), record the Tare Weight in BMR and transfer the coated tablets in Poly-lined HDPE Containers (capacity: 30 liters 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 the 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: 12.320 kg (100 %)

Actual Batch Yield Limit NLT 12.197 kg (NLT 99 %) (To be established in next batch).

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