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

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

TABLE OF CONTENTS 

S.NO. TITLE Page No.
1.0 PRODUCT DETAILS
2.0 MANUFACTURING FORMULA
3.0 LIST OF EQUIPMENT
4.0 MANUFACTURING INSTRUCTIONS
5.0 GENERAL PRECAUTIONS
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, Rutoside Trihydrate with Diclofenac Sodium Tablets
Product Description Pink color biconvex, round shape, enteric coated tablets having both side plain
Strength Trypsin BP                          48 mg

Bromelain                           90 mg

Rutoside Trihydrate  BP    100 mg

Diclofenac Sodium  IP       50 mg
Label claim

 

 Each enteric-coated tablet contains:

Trypsin BP                          48 mg

Bromelain                           90 mg

Rutoside Trihydrate  BP    100 mg

Diclofenac Sodium  IP       50 mg
Batch Size 2,00,000 Tablets
Average Weight 540 mg (Uncoated tablets)

594 mg (Enteric-coated tablets)
Shelf Life 24 months
Storage Store in a cool, dry, and dark place below 25 0C
Drug Category Non-Steroidal Anti-Inflammatory Drug

2.0 MANUFACTURING FORMULA:

Material Name Grade Category Quantity per Unit (In mg) Overages Batch Qty.

(In kg)
Dry Mixing – I
Diclofenac Sodium IP API 50 mg 2 % 10.200 kg
MCCP PH -102 IP Diluent 50 mg – 10.000 kg
Binder
Ethyl cellulose IP Binder 0.05 mg – 0.010 kg
Isopropyl Alcohol (IPA) IP Solvent 0.090 liter 18.000 liter
Lubricant
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 109.95 mg 21.990 kg
Talcum IP Anti-caking agent 15 mg 3.000 kg
Sodium Starch Glycolate IP Disintegrant 12 mg – 2.400 kg
Crospovidone XL 10 IP Disintegrant 10 mg – 2.000 kg
Cross Carmellose Sodium IP Disintegrant 10 mg – 2.000 kg
Magnesium Stearate IP Anti -adherent 2 mg – 0.400 kg

3.0 LIST OF EQUIPMENT:                         

 Sr. No. Machinery/Equipments Capacity Equipment ID.
1. Weighing Balance 100 kg
2. Vibro Sifter

(with SS Sieves No’s 30 and 60 )

 30-inch dia
3. Mass Mixer with Propeller 100 Liter
4. Portable Stirrer –
5. Tray Dryer 48 Trays
6. Double Cone Blender 400 liter
7. Halogen Moisture Balance —
8. Compression Machine 27 Station
9. SS Containers with lid 30 liter (02 No’s) —
10. Poly-lined HDPE Containers with lid 45 liter (10 No’s) —
11. Polybags 01 kg (01 No.),

50 kg (01 No.)
  • 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:
Material Name Std. Qty. (kg) Sieve No.
Dry Mixing-I
Diclofenac Sodium IP 10.200 kg 30 #
MCCP PH -102 IP 10.000 kg 30 #
Binder
Ethyl Cellulose IP 0.010 kg NA
Isopropyl Alcohol (IPA) 18.000 liter NA
Lubricants
Trypsin BP 12.000 kg 30 #
Bromelain 21.600 kg 30 #
Rutoside Trihydrate   BP 22.400 kg 30 #
MCCP PH -112 IP 21.990 kg 30 #
Talcum 3.000 kg 60 #
Sodium Starch Glycolate IP 2.400 kg 60 #
Crospovidone XL IP 2.000 kg 60 #
Cross Carmellose Sodium IP 2.000 kg 60 #
Magnesium Stearate 0.400 kg 60 #

 

  • 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:

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 %

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 – 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. 
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.        Common Name of Die Big Para Coated
6.        Upper Punch Size 12.5 mm ­—– —–
7.        Lower Punch Size 12.5 mm —– —–
8.        Die 12.85 mm 6/Individual 2 hours
9.        Diameter of the tablet 12.85 mm 6/Individual 2 hours
10.    Thickness of Tablets 4.95 mm ±0.2 mm 6/Individual 2 hours
11.    Weight of 20 Tablets 10.80 gm. ± 2% 20/Composite 30 minutes
12.    Product Description Yellow color biconvex, round shape,  uncoated tablets having both side plain 20/Composite 30 minutes
13.    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
14.    Standard Average Weight of Tablets 540  mg ± 2 % 20/Individual 30 minutes
15.    Hardness NLT 4 kg/cm2 6/Individual 30 minutes
16.    Disintegration Time NMT 15 min 6/Composite 01 hour
17.    Friability NMT 1% 20/Composite 01 hour
  • 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):

Sr. No Material Name Batch Quantity
1. Instacoat Moistshield White (IC-MS 2398) 0.270 kg.
2. Isopropyl Alcohol IP 1.540 liter
3. Dichloromethane USP 3.590 liter

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

Sr. No Material Name Batch Quantity
1. Instacoat EN Solution White (IC-EN-001) 2.710 kg
2. Isopropyl Alcohol IP 15.450 liter
3. Dichloromethane USP 36.043 liter
4. Ponceau 4R 0.135 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 EQUIPMENT FOR COATING):

Sr. No. Machinery/Equipment Capacity Equipment ID.
1. Coating Machine and Coating Pan 36″ SC/PD/COT/02
2. Spray Gun 01 —
3. Filter Cloth 100 # 0.5 meter —
4. Portable Stirrer — —
5. SS Containers 15 liter (02 No’s),65 liters (02 No) —
6. Poly-lined HDPE containers with lid 45 liter (01 No.) —

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.
Parameter Specification
No. of Baffles in a 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 (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.
Parameter Specification
No. of Baffles in a 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 250C to 30 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 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
S.No. Parameters Standard No. of Tablets In-Process Frequency
1 Product Description Pink color, round shape, biconvex, enteric-coated tablet having both sides plain 20 No.  

 

 

After batch completion
2 Weight of 20 Tablets after coating  11.880 gm.(8 % to 10 % weight gain) 20 No.
3 Average Weight after coating 594 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 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) 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).