MFR of Trypsin 48 mg, Bromelain 90 mg and Rutoside Trihydrate 100 mg Tablets

TABLE OF CONTENTS

 

S.NO. TITLE Page No.
1.0 PRODUCT DETAILS 02 of 09
2.0 MANUFACTURING FORMULA 02 of 09
3.0 LIST OF EQUIPMENTS 02 of 09

 

4.0 GENERAL PRECAUTIONS 03 of 09
5.0 MANUFACTURING INSTRUCTIONS 03 of 09
6.0

 

 

 

MANUFACTURING PROCESS DETAILS
6.1 GRANULATION 03 of 09
6.2 COMPRESSION 05 of 09
6.3 COATING 06 of 09
6.4 BRAND DETAILS 09 of 09

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

1.0 PRODUCT DETAILS:

Product Name Trypsin, Bromelain and Rutoside Trihydrate Tablets
Product Description Pink color, round shape, biconvex, enteric coated tablets having both side plain
Strength Trypsin BP                          48 mg

Bromelain                           90 mg

Rutoside Trihydrate  BP    100 mg

Label claim

 

Each enteric coated tablet contains:

Trypsin BP                          48 mg

Bromelain                           90 mg

Rutoside Trihydrate  BP    100 mg

Batch Size 2,00,000 Tablets
Average Weight 500 mg (Uncoated tablets)

550 mg (Enteric coated tablets)

Shelf Life 24 months
Storage Store in a cool, dry and dark place below 25 0C
Drug Category Analgesic, Anti-Inflammatory Drug

2.0 MANUFACTURING FORMULA:

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

(In kg)

Dry Mixing – I
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 40 mg 8.000 kg
MCCP PH -102 IP Diluent 143.50 mg 28.700 kg
Lubricant
Talcum IP Anti caking agent 10 mg 2.000 kg
Sodium Starch Glycolate IP Disintegrant 7.5 mg 1.500 kg
Crospovidone XL IP Disintegrant 7.5 mg 1.500 kg
Cross Carmellose Sodium IP Disintegrant 7.5 mg 1.500 kg
Magnesium Stearate IP Anti -adherent 4 mg 0.800 kg

3.0 LIST OF EQUIPMENTS:                         

 Sr. No. Machineries/Equipments Capacity Equipment ID.
1. Weighing Balance 100 kg SC/PD/WBL/03
2. Vibro Sifter

(with SS Sieves No’s 24, 40 and 60 )

30 inch dia SC/PD/SFT/01

SC/PD/SFT/02

3. Double Cone Blender 400 liter SC/PD/GR/O3
4. Halogen Moisture Balance SC/QC/007
5. Compression Machine 27 Station SC/PD/CPM/03,SC/PD/CPM/05
6. Poly-lined HDPE Containers with lid 45 liter (09 No’s)
7. Polybags 01 kg (01 No.),

10 kg (01 No.)

  • GENERAL PRECAUTIONS:
  • API Description Trypsin: A white or almost white crystalline powder.
  • API Description Bromelain: Off white to pale brown color powder.
  • API Description Rutoside Trihydrate: Yellow or greenish yellow color crystalline powder.
  • All the Manufacturing Activities shall be performed under controlled conditions (temperature NMT 250C and relative humidity NMT 40%).
  • When working with Active Ingredients and drug product or mixture of Active Ingredients and Excipients, wear gloves and 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 for every machine 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 single line with sign & date and make 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
Trypsin BP 12.000 kg 24 #
Bromelain 21.600 kg 24 #
Rutoside Trihydrate   BP 22.400 kg 24 #
MCCP PH -112 IP 8.000 kg 40 #
MCCP PH -102 IP 28.700 kg 40 #
Lubricants
Talcum IP 2.000 kg 60 #
Sodium Starch Glycolate IP 1.500 kg 60 #
Crospovidone XL IP 1.500 kg 60 #
Cross Carmellose Sodium IP 1.500 kg 60 #
Magnesium Stearate 0.800 kg 60 #

 

  • Collect sifted Trypsin BP (12.000 kg), Bromelain (21.600 kg), Rutoside Trihydrate BP (22.400 kg), MCCP PH-112 IP (8.000 kg) and MCCP PH-102 IP (28.700 kg) in three Poly-lined HDPE Containers (capacity: 45 liter each).
  • Collect sifted Talcum IP (2.000 kg), Sodium Starch Glycolate IP (1.500 kg), Crospovidone XL IP (1.500 kg) and Cross Carmellose Sodium IP (1.500 kg) in one Polybag (capacity: 10 kg).
  • Collect the sifted Magnesium Stearate IP (0.800 kg) in one Polybag (capacity: 1 kg).

 

STEP – II (DRY MIXING):

Transfer the sifted Trypsin BP, Bromelain, Rutoside Trihydrate BP, MCCP PH-112 IP and MCCP PH-102 IP in Double Cone Blender (capacity: 400 liter) and dry mix the materials till uniform mixing.

Mixing Time: 20 minutes (10 minutes clockwise and 10 minutes anticlockwise direction).

(To be validated in next batch)

Mixing Speed: 10 RPM.

STEP – III (PRE –LUBRICATION):

Add the sifted Talcum IP, Sodium Starch Glycolate IP, Crospovidone XL IP and Cross Carmellose Sodium in Double Cone Blender with Step-II and mix properly till uniform mixing of sifted  materials 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 – IV (LUBRICATION):

Add the sifted Magnesium Stearate IP in Double Cone Blender with Step-III 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- V (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 %

To be established in next batch

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 – VI:

  • 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 Containers.
  • Batch Yield of Lubricated granules:

Theoretical Batch Yield: 100.000 kg (100 %).

Actual Batch Yield Limit NLT 99 .000 kg (NLT 99 %) (To be established in next batch).

STEP – VII:

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

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 of 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 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 -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 12.5 mm 6/Individual 2 hours
9.        Diameter of the tablet 12.5 mm 6/Individual 2 hours
10.    Thickness of Tablets 4.95 mm ±0.2 mm 6/Individual 2 hours
11.    Weight of 20 Tablets 10.000 gm. ± 2% 20/Composite 30 minutes
12.    Product Description Yellow color, round shape, biconvex, 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 500  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 liter each on both sides), when SS containers are filled with tablets, transfer the tablets in three Poly-lined HDPE Containers 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: 100.00 kg (100 %).

Actual Batch Yield Limit NLT 99.000 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 standardized 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 continue for tablet coating.

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

Sr. No Material Name Batch Quantity
1. Instacoat Moistshield White (IC-MS 2398) 0.250 kg.
2. Isopropyl Alcohol IP 1.425 liter
3. Dichloromethane USP 3.325 liter

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

Sr. No Material Name Batch Quantity
1. Instacoat EN Solution White (IC-EN-001) 2.500 kg
2. Isopropyl Alcohol IP 14.250 liter
3. Dichloromethane USP 33.250 liter
4. Ponceau 4R 0.125 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 EQUIPMENTS FOR COATING):

Sr. No. Machineries/Equipments 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 liter (02 No’s)
6. Poly-lined HDPE containers with lid 45 liter (01 No.)

STEP – IV (PREPARATION OF SEAL COATING SOLUTION):

  • Take Isopropyl Alcohol IP (1.425 liter) and Dichloromethane USP (3.325 liter) in SS Container (capacity: 15 liter) and add Instacoat Moistshield White IC-MS 2398 (0.250 kg). Mix together by Portable Stirrer properly continuously stirring 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: 15 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 COATING OF TABLETS):

  • Coating will be done in one lot for 50,000 tablets, take total compressed tablets for coating (25.000 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 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 Coating.
  • Set the coating parameter as given in below table and start the coating process by starting coating spray through 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 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 (14.250 liter) and Dichloromethane USP (33.250 liter) in SS Container (capacity: 65 liter) and add Instacoat EN Solution White (IC-EN-001) (2.500 kg) and add color Ponceau 4R (0.125 kg) in it. Mix together by Portable Stirrer properly continuously stirring 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 (65 liter).
  • 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 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 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

(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 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 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 side plain 20 No.  

 

 

 

 

After batch completion

2 Weight of 20 Tablets after coating 11.000 gm (8 % to 10 % weight gain) 20 No.
3 Average Weight after coating 550 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 No.
7 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 of each Lot) to QC department for analysis.

STEP – X:

  • Take Tare Weight of one Poly-lined HDPE Containers (capacity: 45 liter), record the Tare Weight in BMR and transfer the coated tablets in Poly-lined HDPE Containers (capacity: 45 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: 27.500 kg (100 %)

Actual Batch Yield Limit NLT 27.225 kg (NLT 99 %) (To be established in next batch).

 

 

 

By iamraj