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 Noes)	—
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 the 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 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
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 liters) 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

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 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: 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 the result continues the compression 27 stations (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	12.5 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 sides 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 liters 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 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: 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 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 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 EQUIPMENT 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 liters (02 Noes)	—
6.	Poly-lined HDPE containers with lid	45 liter (01 No.)	—

STEP – IV (PREPARATION OF SEAL COATING SOLUTION):

Take Isopropyl Alcohol IP (1.425 liters) and Dichloromethane USP (3.325 liters) in SS Container (capacity: 15 liters) and add Instacoat Moistshield White IC-MS 2398 (0.250 kg). 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 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 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 (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 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 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 liters) and Dichloromethane USP (33.250 liters) in SS Container (capacity: 65 liters) 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 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 coating 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	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 the weight of 10 Enteric coated tablets and record the weight in BMR, and calculated the weight gain by using the 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 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 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: 27.500 kg (100 %)
Actual Batch Yield Limit NLT 27.225 kg (NLT 99 %) (To be established in next batch).

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