Trypsin, Bromelain, Rutoside Trihydrate with Diclofenac Sodium 50 mg Tablets

Trypsin 48 mg, Bromelain 90 mg, Rutoside Trihydrate 100 mg with  Diclofenac Sodium 50 mg Tablets

TABLE OF CONTENTS 

 1.0 PRODUCT DETAILS:

2.0 MANUFACTURING FORMULA:

3.0 LIST OF EQUIPMENT:                         

• GENERAL PRECAUTIONS:
• Trypsin API Description: A white or almost white crystalline powder.
• Bromelain API Description: Off white to the 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 NMT 25 ⁰C and relative humidity NMT 40%).
• 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.

• 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 the 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:

• 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 liters) in SS Container (Capacity: 30 liters) 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 an SS container (capacity 30 liters).

STEP – III (DRY MIXING):

Transfer the sifted material Diclofenac Sodium IP and MCCP PH-102 IP in Mass Mixer (capacity: 100 liters) 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 a clockwise direction and 05 minutes in the 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 a clockwise direction and 05 minutes in an anti-clockwise direction.

STEP – V (DRYING):

Dry the wet materials of Step – IV as follow:

Load these seven trays in Tray Dryer.

First air dries the wet material for 30 minutes in a 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 the 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 liters).

STEP – VII (PRE –LUBRICATION):

Load the sized granules of Step-VI in Double Cone Blender (capacity: 400 liters) 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:

 STEP – X:

• Take Tare Weight of three Poly-lined HDPE Containers (capacity: 45 liters each), record the Tare Weight in BMR and unload the above-blended material from Double Cone Blender in Poly-lined HDPE Containers (capacity: 45 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: 108.00 kg (100 %)

Actual Batch Yield Limit NLT 106.920 kg (NLT 99 %) (To be established in next batch)

STEP – XI:

• 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 of the 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 conditions. 

• Collect the compressed tablets in SS Containers (capacity: 20 liters 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 the QC department for analysis.

STEP – III:

• Take Tare Weight of three Poly-lined HDPE Containers (capacity: 45 liters each), record the Tare Weight in BMR and transfer the compressed tablets in Poly-lined HDPE Containers (capacity: 45 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 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 standardize 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 continues for tablet coating.

 STEP – I (COATING MATERIALS DETAILS FOR SEAL COATING):

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

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 (1.540 liters) and Dichloromethane USP (3.590 liters) in SS Container (capacity: 15 liters) and add Instacoat Moistshield White IC-MS 2398 (0.270 kg). Mix together by Portable Stirrer properly continuously stirring till uniform mixing is achieved.

Speed of Stirrer: Constant

Mixing Ti9me: 20 minutes (To be validated in the next batch).

• Filter the coating solution with Filter Cloth 100 # in SS Container (capacity: 15 liters).
• Keep the solution for 10 minutes and after 10 minutes start the Seal coating process with the Seal coating solution.

STEP – V (COATING PROCEDURE FOR SEAL COATING OF TABLETS):

• The 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 the weight of 100 warmed 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.
• Set the coating parameter as given in the below table and start the coating process by starting coating spray through 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 (15.450 liters) and Dichloromethane USP (36.043 liters) in SS Container (capacity: 65 liters) 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 is 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 liters).
• 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 the below table and start the enteric coating process by starting the Enteric coating solution spray through the gun.

• 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 the 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 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: 45 liters), record the Tare Weight in BMR and transfer the coated tablets in Poly-lined HDPE Containers (capacity: 45 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: 29.700 kg (100 %)

Actual Batch Yield Limit NLT 29.403 kg (NLT 99 %) (To be established in next batch).