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

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

TABLE OF CONTENTS

 

S.NO.TITLEPage No.
1.0PRODUCT DETAILS2 of 11
2.0MANUFACTURING FORMULA2 of 11
3.0LIST OF EQUIPMENTS3 of 11

 

4.0MANUFACTURING INSTRUCTIONS3 of 11
5.0GENERAL PRECAUTIONS3 of 11
6.0

 

 

 

MANUFACTURING PROCESS DETAILS
6.1GRANULATION3 of 11
6.2COMPRESSION6 of 11
6.3COATING7 of 11
6.4BRAND DETAILS11 of 11

 

1.0 PRODUCT DETAILS:

Product NameTrypsin, Bromelain, Rutoside Trihydrate with Diclofenac Sodium Tablets
Product DescriptionPink color biconvex, round shape, enteric coated tablets having both side plain
StrengthTrypsin 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 Size2,00,000 Tablets
Average Weight540 mg (Uncoated tablets)

594 mg (Enteric coated tablets)

Shelf Life24 months
StorageStore in a cool, dry and dark place below 25 0C
Drug CategoryNon-Steroidal Anti-Inflammatory Drug

2.0 MANUFACTURING FORMULA:

Material NameGradeCategoryQuantity per Unit (In mg)OveragesBatch Qty.

(In kg)

Dry Mixing – I
Diclofenac SodiumIPAPI50 mg2 %10.200 kg
MCCP PH -102IPDiluent50 mg10.000 kg
Binder
Ethyl celluloseIPBinder0.05 mg0.010 kg
Isopropyl Alcohol (IPA)IPSolvent0.090 liter18.000 liter
Lubricant
TrypsinBPAPI48 mg25 %12.000 kg
BromelainNAAPI90 mg20 %21.600 kg
Rutoside TrihydrateBPAPI100 mg12 %22.400 kg
MCCP PH-112IPDiluent109.95 mg21.990 kg
TalcumIPAnti caking agent15 mg3.000 kg
Sodium Starch GlycolateIPDisintegrant12 mg2.400 kg
Crospovidone XL 10IPDisintegrant10 mg2.000 kg
Cross Carmellose SodiumIPDisintegrant10 mg2.000 kg
Magnesium StearateIPAnti -adherent2 mg0.400 kg

3.0 LIST OF EQUIPMENTS:                         

 Sr. No.Machineries/EquipmentsCapacityEquipment ID.
1.Weighing Balance100 kgSC/PD/WBL/03
2.Vibro Sifter

(with SS Sieves No’s 30 and 60 )

30 inch diaSC/PD/SFT/01

SC/PD/SFT/02

3.Mass Mixer with Propeller100 LiterSC/PD/MSM/01,SC/PD/MSM/02
4.Portable StirrerSC/PD/STR/01
5.Tray Dryer48 TraysSC/PD/TRD/01,SC/PD/TRD/02

SC/PD/TRD/03,SC/PD/TRD/04

6.Double Cone Blender400 literSC/PD/GR/O3
7.Halogen Moisture BalanceSC/QC/007
8.Compression Machine27 StationSC/PD/CPM/03,SC/PD/CPM/05
9.SS Containers with lid30 liter (02 No’s)
10.Poly-lined HDPE Containers with lid45 liter (10 No’s)
11.Polybags01 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 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 NMT25 0C 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 of 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
Diclofenac Sodium IP10.200 kg30 #
MCCP PH -102 IP10.000 kg30 #
Binder
Ethyl Cellulose IP0.010 kgNA
Isopropyl Alcohol (IPA)18.000 literNA
Lubricants
Trypsin BP12.000 kg30 #
Bromelain21.600 kg30 #
Rutoside Trihydrate   BP22.400 kg30 #
MCCP PH -112 IP21.990 kg30 #
Talcum3.000 kg60 #
Sodium Starch Glycolate IP2.400 kg60 #
Crospovidone XL IP2.000 kg60 #
Cross Carmellose Sodium IP2.000 kg60 #
Magnesium Stearate0.400 kg60 #

 

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

STEP – III (DRY MIXING):

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

STEP – V (DRYING):

  • Dry the wet materials of Step – IV as follow:
  • Load these seven trays in Tray Dryer.
  • First air dry the wet material for 30 minutes in 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 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 liter).

STEP – VII (PRE –LUBRICATION):

  • Load the sized granules of Step-VI in Double Cone Blender (capacity: 400 liter) 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:
TestSpecification
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 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: 108.00 kg (100 %)
  • Actual Batch Yield Limit NLT 106.920 kg (NLT 99 %) (To be established in next batch)

STEP – XI:

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

6.2 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.ParametersStandardNo. of TabletsIn-Process Frequency
1.       Feed frame alignment and adjustmentShould be satisfactory—–—–
2.       Lower Weight AssemblyShould be satisfactory—–—–
3.       Hydraulic Pressure5 -7 Tones—–—–
4.       Machine Speed12 RPM to 15 RPM—–—–
5.       Common Name of DieBig Para Coated
6.       Upper Punch Size12.5 mm­—–—–
7.       Lower Punch Size12.5 mm—–—–
8.       Die 12.85 mm6/Individual2 hours
9.       Diameter of the tablet12.85 mm6/Individual2 hours
10.   Thickness of Tablets4.95 mm ±0.2 mm6/Individual2 hours
11.   Weight of 20 Tablets10.80 gm. ± 2%20/Composite30 minutes
12.   Product DescriptionYellow color biconvex, round shape,  uncoated tablets having both side plain20/Composite30 minutes
13.   Uniformity of WeightNMT 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/Composite01 hour
14.   Standard Average Weight of Tablets540  mg ± 2 %20/Individual30 minutes
15.   HardnessNLT 4 kg/cm26/Individual30 minutes
16.   Disintegration TimeNMT 15 min6/Composite01 hour
17.   FriabilityNMT 1%20/Composite01 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 in below 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: 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 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. NoMaterial NameBatch Quantity
1.Instacoat Moistshield White (IC-MS 2398)0.270 kg.
2.Isopropyl Alcohol IP1.540 liter
3.Dichloromethane USP3.590 liter

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

Sr. NoMaterial NameBatch Quantity
1.Instacoat EN Solution White (IC-EN-001)2.710 kg
2.Isopropyl Alcohol IP15.450 liter
3.Dichloromethane USP36.043 liter
4.Ponceau 4R0.135 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 EQUIPMENTS FOR COATING):

Sr. No.Machineries/EquipmentsCapacityEquipment ID.
1.Coating Machine and Coating Pan36″SC/PD/COT/02
2.Spray Gun01
3.Filter Cloth 100 #0.5 meter
4.Portable Stirrer
5.SS Containers15 liter (02 No’s) ,65 liter (02 No’s)
6.Poly-lined HDPE containers with lid45 liter (01 No.)

STEP – IV (PREPARATION OF SEAL COATING SOLUTION):

  • Take Isopropyl Alcohol IP (1.540 liter) and Dichloromethane USP (3.590 liter) in SS Container (capacity: 15 liter) and add Instacoat Moistshield White IC-MS 2398 (0.270 kg). Mix together by Portable Stirrer properly continuously stirring till uniform mixing achieved.
  • Speed of Stirrer: Constant
  • Mixing Ti9me: 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 (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 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.
ParameterSpecification
No. of Baffles in coating pan03
No. of Guns01
Inlet Temperature60°C to 65°C(To be validated in next batch)
Peristaltic Pump Speed2 to 4 RPM (To be validated in next batch)
Atomization2.5 to 3.0 kg/cm2
Gun to Tablet Bed Distance8 inch
BED Temperature300C to 35 0C (To be validated in next batch)
Pan RPM13 to 15 RPM
% Weight Gain

(Upto 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 liter) and Dichloromethane USP (36.043 liter) in SS Container (capacity: 65 liter) 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 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 Enteric coating solution spray through gun.
ParameterSpecification
No. of Baffles in coating pan03
No. of Guns01
Inlet Temperature60°C to 65°C (To be validated in next batch)
Peristaltic Pump Speed2 to 4 RPM (To be validated in next batch)
Atomization2.5 to 3.0 kg/cm2
Gun to Tablet Bed Distance8 inch
BED Temperature250C to 30 0C (To be validated in next batch)
Pan RPM13 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.ParametersStandardNo. of TabletsIn-Process Frequency
1Product DescriptionPink color, round shape, biconvex, enteric coated tablet having both side plain20 No. 

 

 

After batch completion

2Weight of 20 Tablets after coating 11.880 gm.(8 % to 10 % weight gain)20 No.
3Average Weight after coating594 mg .(8 % to 10 % weight gain)20 No.
4Individual 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.
5Thickness5.29 mm ± 0.2 mm6 No.
6.Disintegration Time

(Acid Medium)

In 0.1M HCl – Should not crack in two hours
6Disintegration 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 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: 29.700 kg (100 %)
  • Actual Batch Yield Limit NLT 29.403 kg (NLT 99 %) (To be established in next batch).

 

 

 

About ABHA

Abha is the Author  of pharmaceutical guidance, she is a pharmaceutical professional having more than 22 years of rich experience in pharmaceutical field. During her career, she works in the quality assurance department with multinational companies i.e Zydus Cadila Ltd, Unichem Laboratories Ltd, Indoco remedies Ltd. During his experience, she faces many regulatorily audits i.e. USFDA, MHRA, ANVISA, MCC, TGA, EU –GMP, WHO –Geneva, ISO 9001-2008 and many ROW Regularities Audit i.e.Uganda, Kenya, Tanzania, Zimbabwe. She is currently leading a regulatory pharmaceutical company as a Head Quality. You can join him by Email, Facebook, Google+, Twitter, and YouTube

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