MFR of Aceclofenac 100 mg, Paracetamol 325 mg and Trypsin-Chymotrysin 50,000 armour units Tablets

MFR of Aceclofenac 100 mg, Paracetamol 325 mg and Trypsin-Chymotrypsin 50,000 armor units Tablets

TABLE OF CONTENTS                                                                                                                         

 1.0 PRODUCT DETAILS:

2.0 MANUFACTURING FORMULA:

3.0 LIST OF EQUIPMENTS:

4.0 GENERAL PRECAUTIONS:

• API Description Aceclofenac: A white or almost white crystalline powder.
• API Description Paracetamol: A white crystals or a white crystalline powder.
• API Description Trypsin-Chymotrypsin: A white or a white crystalline powder.
• All the Manufacturing Activities shall be performed under controlled conditions (temperature NMT 25 ⁰C and relative humidity NMT 60%).
• 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.

5.0 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.
• 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:

• After sifting divide the sifted Aceclofenac IP (30.000 kg) in two equal parts for LOT-I and LOT-II (15.000 kg each) and collect in four Poly-lined HDPE Containers (capacity: 45 liter each).
• After sifting divide the sifted Paracetamol IP (97.500 kg) in two equal parts for LOT-I and LOT-II (48.750 kg each) and collect in above Poly-lined HDPE Containers (capacity: 45 liter each) with Aceclofenac.
• After sifting divide the sifted Starch (15.000 kg) in two equal parts for LOT-I and LOT-II (7.500 kg each) and collect in above Poly-lined HDPE Containers (capacity: 45 liter each) with Aceclofenac and Paracetamol.
• After sifting divide the sifted MCCP Plain IP (11.034 kg) in two equal parts for LOT-I and LOT-II (5.517 kg each) and collect in above Poly-lined HDPE Containers (capacity: 45 liter each) with Aceclofenac, Paracetamol and Starch.
• Collect sifted Trypsin & Chymotrypsin (6.720 kg) in one Polybag (capacity: 10 kg)
• Collect sifted PVPK-30 IP (0.900 kg) in Polybag (capacity: 1 kg).
• Collect sifted Sodium Benzoate IP (0.348 kg) in one Polybag (capacity: 1 kg).
• Collect sifted Starch IP (4.875 kg) in one Polybag (capacity: 5 kg)
• Collect sifted Talcum IP (3.000 kg), MCCP-PH-102 IP (5.023 kg) and Sodium Starch Glycolate IP (2.400 kg) in one Polybag (capacity: 20 kg)
• Collect the sifted Magnesium Stearate IP (1.800 kg) in one Polybag (capacity: 2 kg)

STEP – II – (BINDER PREPARATION-I): FOR LOT-I:

• Take purified water (50.00 liter) in Paste Kettle (capacity: 100 liter), heat the purified water to 35⁰
• Take purified water (5.00 liter, at temperature 35⁰C) from Paste Kettle  of Step-II (a) in SS Container (capacity: 10 liter) and add sifted Sodium Benzoate IP (0.348 kg) and PVPK-30 IP (0.900 kg) and mix one by one with Stirrer till dissolved properly in water and make a solution.
• Heat the remaining purified water (45.000 liter) upto 80⁰C of Step-II (a) in Paste Kettle and add Gelatin (0.900 kg) and mix properly with continuously stirring till the Gelatin properly dissolved in heated water.
• Take purified water separately (10.000 liter, at room temperature) in SS Container (capacity: 20 liter) and slowly add Starch (4.875 kg) continuously stirring till uniform solution is ready.
• Add above solution of Step-II (d) to heated purified water of Step-II (c) in Paste Kettle with continuously stirring till uniform paste is ready.
• Add Step-II (b) solution with continuously stirring into Step-II (c) till final paste is ready.
• Transfer the ready paste by tilting the Paste Kettle in one SS Container (capacity: 100 liter). Cool the paste up to 35⁰C to 40⁰
• Divide paste (Qty.67.123 kg) into two equal parts (Qty.33.561 kg) for LOT-I and LOT-II in SS Containers (capacity: 70 liter each).

STEP – III (DRY MIXING): FOR LOT – I:

Transfer the sifted Aceclofenac IP, Paracetamol IP, Starch IP and MCCP Plain in Rapid Mixer Granulator (capacity: 160 liter) running at slow speed impeller (0.820 ampere) and dry mix the materials till uniform mixing.

Mixing Time: 05 minutes (To be validated in next batch)

Mixing Speed: 05 minutes at slow speed.

Ampere Load of Impeller: 0.820 ampere. (To be validated in next batch).

STEP –IV (BINDING OF DRY MIX MATERIAL): FOR LOT-I:

Slowly add the binder LOT-I of Step – II (h) (33.561 kg) in dry mix materials of Step – III in Rapid Mixer Granulator running at slow speed impeller (1.02 ampere) for 5 minutes till binder addition. After binder addition run impeller and chopper both at slow speed (0.63 ampere) for 08 min and finally run both chopper and impeller on fast speed (0.97 ampere) for 02 minutes till uniform mixing. Unload the material in SS Container (capacity: 100 liter) from RMG by opening the discharge point with running impeller.

Mixing Time: 15 minutes (To be validated in next batch)

Mixing Speed: 05 minutes (Impeller on slow speed), 08 minutes (Impeller and chopper at slow speed) and 02 minutes (Impeller and chopper at fast speed)

Ampere Load of Impeller: 0.62 to 1.02 ampere. (To be validated in next batch).

STEP-V (WET SCREENING): FOR LOT – I:

Check Screen Integrity (before screening and after screening)

Take wet material from SS Container and pass through Multi-Mill with screen size 8 mm and collect the wet material in SS Container (capacity: 100 liter) and after screening transfer the wet material in a FBD bowl. 

STEP –VI – (DRYING-I): FOR LOT- I:

Dry the wet material of Step-V in FBD (capacity: 120 kg) until the LOD of granules is achieved between 2.5 to 3.0 % at 105°C checking by Halogen Moisture Balance and after drying unload the material in  two Poly-lined HDPE Container (capacity : 45 liter each).

Inlet Temperature: 55°C. (To be validated in next batch).

Outlet Temperature: 40°C to 45°C (To be validated in next batch)

Raking Frequency: After 30 minutes.

Drying Time: 01 to 1.5 hours. (To be validated in next batch).

STEP-VII- (SIZING/MILLING-I): FOR LOT – I:

Check Screen Integrity (before screening and after screening).

Set the Vibro Sifter and fix the Sieve 18 # and sieve the dried material of Step-VI and collect in two Poly-lined HDPE Containers (capacity: 45 liter each) and remaining retention after sieving, pass through the Multi-Mill using screen size 2 mm. After screening keep the screened material with sized material in above Poly-lined HDPE Containers. Weigh and record the sized/milled granules quantity.

Blade Type: Both (Knife blades and Scraping blades).

Rotor Speed: 2000 RPM.

NOTE:

FOR LOT – II: Please follow the same procedure of LOT – I of dry mixing, binding of dry mix material, wet screening, drying and sizing/ milling.

STEP-VIII – (PREPARATION OF ENTERIC COATED GRANULES OF TRYPSIN & CHYMOTRYPSIN):

(a) (BINDER PREPARATION FOR ENTERIC COATING OF TRYPSIN & CHYMOTRYPSIN):

Take Isopropyl Alcohol IP (2.500 liter) and Dichloromethane USP (2.500 liter) in SS Container (capacity: 10 liter) and add Cellulose Acetate Phthalate IP (0.500 kg) in it. Mix together by Portable Stirrer continuously stirring till Cellulose Acetate Phthalate IP dissolved properly in IPA & MDC.

Mixing Time: 30 minutes (To be validated in next batch).

Filter the solution with 100 # filter cloth in SS Container (capacity: 10 liter).

(b) (ENTERIC COATING OF TRYPSIN & CHYMOTRYPSIN):

Transfer the sifted Trypsin & Chymotrypsin in SS Container (capacity: 20 liter) and slowly add the enteric coating solution of Step-VIII (a) and coat the API manually with enteric coating solution till uniform coating.

Mixing Time: 05 minutes (manually) (To be validated in next batch)

(c) (WET SIZING OF ENTERIC COATED GRANULES OF TRYPSIN & CHYMOTRYPSIN):

Check Sieve Integrity (before sieving and after sieving)

Take wet material from SS Container of Step-VIII (b) and pass through sieve size 10 # manually and collect the wet material in three Trays (capacity: 3.000 kg each).

(d) (DRYING OF ENTERIC COATED GRANULES OF TRYPSIN & CHYMOTRYPSIN):

Dry the wet mass of Step-VIII (c) as follows:

Load these three Trays in Tray Dryer.

First air dry the granules for 30 minutes of Step- VIII (c) 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: 01 Hour. (To be validated in next batch)

Drying Temperature: 35⁰C (After Air Drying).

Raking Frequency: After every 15 minutes.

(e) (SIZING/MILLING):

Check Sieve Integrity (before sifting and after sifting).

Set the Vibro Sifter and fix the sieve 18 # and sieve the dried granules of Step- VIII (d). Collect the sieved material in Polybag (capacity: 10 kg).

STEP – IX (PRE –LUBRICATION):

Load the sized/ milled granules of Step-VII of LOT- I and LOT – II and sized granules of Step-VIII (e) in Octagonal Blender (capacity: 500 liter) and add sifted Talcum IP, MCCP-PH-102 and Sodium Starch Glycolate, mix properly till uniform mixing of sized material with Pre-Lubricating Materials.

Mixing Time: 30 minutes (15 minutes clockwise direction and 15 minutes anti-clockwise direction).

Mixing Speed: 10 RPM.

STEP – X (LUBRICATION):

Add the sifted Magnesium Stearate IP in Step-IX 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- XI (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 – XII:

• Take Tare Weight of five Poly-lined HDPE Containers (capacity: 45 liter each), record the Tare Weight in BMR and unload the above blended material from Octagonal 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: 180.000 kg (100 %)

Actual Batch Yield Limit NLT 178.200 kg (NLT 99 %) (To be established in next batch)

STEP – XIII:

• 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 continue the compression with 27 stations (D-Tooling) Compression Machine. Compress the blend as per the following parameters and In Process checks under controlled environmental condition.

• Collect the compressed tablets in SS Container (capacity: 20 liter each on both sides), when SS containers are filled with tablets, transfer the tablets in five 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 five 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: 180.00 kg (100 %)

Actual Batch Yield Limit NLT 178.200 kg (NLT 99 %) (To be established in next batch)

STEP – IV:

• After completion of compression clean the Compression Machine as per cleaning SOP.

6.3 COATING:

• 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 COAT

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

STEP-III (LIST OF EQUIPMENTS FOR COATING): FOR LOT-I & LOT-II:

STEP – IV (PREPARATION OF SEAL COAT SOLUTION) FOR LOT -I & LOT- II:

• Take Isopropyl Alcohol IP (10.200 liter) and Dichloromethane USP (24.000 liter) in SS Container (capacity: 45 liter) and add Instacoat Solution White (ICS-223) Non Aqueous (1.800 kg), mix together by Portable Stirrer continuously stirring till uniform mixing achieved.

Mixing Time: 20 minutes (To be validated in next batch)

Speed of Stirrer: Constant

• Filter the coating solution with Filter Cloth 100# in SS Container (capacity : 45 liter)
• Divide the solution (36.000 liter) equally into two parts (18.000 liter) for LOT-I and LOT-II in SS Container (capacity: 30 liter each and proceed for Seal Coating.

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

• Coating will be done in two lots, divide total compressed tablets into two equal quantities for LOT -I and LOT -II (90.00 kg tablets for each lot).
• Load the tablets in coating pan (Capacity: 42″), start the hot air blower, set the inlet air temperature at 70°C to 75°C and start the exhaust fan & warm the tablets bed 40°C to 45°C.
• After warming 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 Coat.
• Set the coating parameter as given in below table and start the coating process by starting coating spray through gun by using Seal coating solution for LOT-I

 STEP – VI (PREPARATION OF FILM COATING SOLUTION) FOR LOT -I & LOT- II:

• Take Purified Water IP (18.000 liter) in SS Container (capacity: 30 liter) and add Sheffcoat PVA Orange 5Y02059 (4.500 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 (capacity: 30 liter)
• Keeps the solution, after completion of Seal Coat, proceed for Film coating process.
• Divide the coating solution (22.500 liter) equally into two parts (11.250 liter) for LOT – I and LOT – II in SS Container (capacity: 30 liter each)

STEP – VII (COATING PROCEDURE FOR FILM COATING OF TABLETS): FOR LOT- I:

• Set the coating parameter for Film Coating as given in below table and start the Film Coating process by starting coating spray through gun by using Film coating solution for LOT-I

• After completion of Film coating, take weight of 100 Film 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.

NOTE:

FOR LOT – II (COATING PROCEDURE):

 Please follow the same procedure of LOT – I of coating from Step-V to Step-VII.

STEP – VIII (COATING IN-PROCESS CHECK PARAMETERS):

• After completion of Film coating perform the In Process checks as per below parameters:

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 five Poly-lined HDPE Containers (capacity: 45 liter each), 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: 185.400 kg (100 %)

Actual Batch Yield Limit NLT 183.546 kg (NLT 99 %) (To be established in next batch).