Month: October 2021

MFR of Rabeprazole Sodium 20 mg Tablets

TABLE OF CONTENTS 

 1.0 PRODUCT DETAILS:

2.0 MANUFACTURING FORMULA:

3.0 LIST OF EQUIPMENT:                         

4.0 GENERAL PRECAUTIONS:

• API Description: A white to light yellow, crystalline powder. (Hygroscopic and Light Sensitive)
• 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 products or a mixture of Active Ingredients and Excipients, wear gloves and a mask to avoid exposure and contact with any body parts.
• Use Sodium Lamp and Black Poly-bags at every Step.

5.0 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 a correct entry.

6.0 MANUFACTURING PROCESS DETAILS:

6.1 GRANULATION:

 NOTE: Turn ON the sodium lamp and switch OFF all lights before starting the operation and use black polybags to store the materials.

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:

NOT

• After sifting divide the sifted Rabeprazole Sodium IP (10.500 kg), in two equal parts  for LOT-I and LOT-II (5.250 kg each) and collect in two Black Poly-Bags (capacity : 50 kg each).
• After sifting divide the sifted Magnesium Oxide IP (77.500 kg) in two equal parts for LOT-I and LOT-II (38.750 kg each) and collect in the above two Black Poly-Bags (capacity : 50 kg each) with Rabeprazole.
• After sifting divide the sifted Croscarmellose Sodium IP (6.000 kg) in two equal parts for LOT-I and LOT-II (3.000 kg each) and collect in the two Black Polybags (capacity: 50 kg each) with Rabeprazole and Magnesium Oxide.
• Collect sifted PVPK-90 IP (5.625 kg) in one Poly bag (capacity: 10 kg).
• Collect sifted Talcum IP (1.000 kg), Croscarmellose Sodium IP (6.675 kg), Crospovidone XL IP (5.000 kg), Aerosil IP (0.750 kg) into one Poly-Bags (capacity : 20 kg)
• Collect the sifted Calcium Stearate IP (2.950 kg) in one Poly-Bags (capacity: 5 kg)

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

Take Dichloromethane USP (70.000 liter) in SS Container (capacity: 100 liter) and add PVPK-90 IP

(5.625 kg) in it. Mix together by Portable Stirrer continuously stirring till dissolved properly in MDC.

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

Divide the solution (Qty. 75.625 liter) into two equal parts for Lot-I (37.812 liter) and Lot-II (37.812 liter) and store in SS Container (capacity: 65 liter each).

STEP – III (DRY MIXING): FOR LOT-I:

Transfer the sifted Rabeprazole Sodium IP, Magnesium Oxide USP and Cross Carmillose Sodium IP in Mass Mixer (capacity: 100 liter) and dry mix the materials till uniform mixing achieved.

Mixing Time: 10 minutes.(To be validated in next batch)

Mixing Speed: 36 RPM

Paddle (Blades) Timing: 05 minutes in clockwise direction & 05 minutes in anti-clockwise direction.

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

Slowly add the binder for LOT-I of Step-II in dry mix materials of Step-III and mix for 10 minutes till uniform binding and after binding, collect the wet mass into sixteen Trays (capacity: 3.000 kg each).

Mixing Time: 10 minutes (To be validated in next batch).

Mixing Speed: 36 RPM

Paddle (Blades) Timing: 05 minutes in clockwise direction & 05 minutes in anti-clockwise direction

NOTE:

FOR LOT – II: Please follow the same procedure of LOT – I of dry mixing and binding.

STEP –V (DRYING):

Dry the wet mass of Step –IV for LOT-I and LOT-II as follows:

Load in thirty-two trays in Tray Dryer.

First airs dry the granules for 30 minutes in Tray Dryer. Ensure that heaters are in OFF mode. After air drying Switch ON the heaters and dry the granules at 35^oC in Tray Dryer until the LOD of granules is between 1.0 to 1.5% at 105^oC checked by Halogen Moisture Balance.

Air Drying Time: 30 minutes (Heaters should be OFF).

Drying Time: 04 to 05 Hours (To be validated in next batch)

Drying Temperature: 35⁰C (After Air Drying)

Raking Frequency: After every 20 minutes.

STEP-VI (SIZING/MILLING):

Check Screen Integrity (before sifting and after sifting).

Mill the dried material of Step -V through Multi Mill using screen size 2.0 mm and collect milled material in two Poly-lined HDPE Containers (capacity :30 liter each ) and weigh and record the milled granules weight.

Blade Type: Both (Knife blades/Scraping blades)

Rotor Speed: 2000 RPM

STEP – VII (PRE –LUBRICATION):

Load the milled granules of Step-VI  in Double Cone Blender (capacity : 400 liter) and add sifted Talcum IP, Croscarmellose Sodium IP, Crospovidone XL IP and Aerosil IP, mix properly till uniform mixing of sized material with Pre-Lubricating Material.

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

Mixing Speed: 10 RPM

STEP – VIII (LUBRICATION):

Add the sifted Calcium Stearate IP in Pre- Lubricated Materials of Step-VII and mix properly till uniform mixing of materials with Calcium Stearate IP.

Mixing Time: 05 minutes. (clockwise direction)

Mixing Speed: 10 RPM.

STEP- IX (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 – XI:

• 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 Container.
• Batch Yield of Lubricated granules:

Theoretical Batch Yield: 116.00 kg (100 %)

Actual Batch Yield Limit NLT 114.840 kg (NLT 99 %) (To be established in next batch)

STEP – XII:

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

6.2   COMPRESSION:

NOTE: Turn ON sodium lamp and switch OFF all lights before starting compression and use black polybags to store the tablets.

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 35 stations (B-Tooling) Compression Machine of 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 three Poly-lined HDPE Containers (capacity: 45 liter each) 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: 116.000 kg (100 %)

Actual Batch Yield Limit NLT 114.840 kg (NLT 99 %) (To be established in next batch)

STEP – IV:

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

NOTE: For this product, the lot size of 500000 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 100000 tablets for coating in this MFR.

6.3 COATING: FOR 1, 00,000 Tablets

NOTE: Switch ON the Sodium lamp and switch OFF all lights and use black polybags to store the 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 SEAL COAT DETAILS):      

STEP – II (COATING MATERIALS ENTERIC COATING DETAILS):      

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):

STEP – IV (PREPARATION OF SEAL COAT SOLUTION):

• Take Isopropyl Alcohol IP (1.322 liter) and Dichloromethane USP (3.085 liter) and add Instacoat Sol. Trans IC-S-1643 (0.232 kg) in SS Container (capacity 10 liter), mix together by Portable Stirrer continuously stirring properly 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: 10 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 COAT OF TABLETS):

NOTE: Use Sodium lamps and switch OFF all lights and use black polybags to store the tablets.

• Coating will be done in one lot (For 1,00,000 tablets), take total compressed tablets for coating (23.200 kg)

• Load the tablets in coating pan (Capacity: 24″), start the hot air blower, set the supply 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 Coat.
• Set the coating parameter as given in below table and start the coating process by starting coating spray from gun.
• After completion of Seal Coating, calculate the weight gain by using below Formula in the table.

STEP – V: PREPARATION OF ENTERIC SOLUTION:

• Take Isopropyl Alcohol IP (13.224 liter) and Dichloromethane USP (30.856 liter) and add Instacoat EN Sol.Wht.IC-EN-001 (2.320 kg) in SS Container (capacity: 65 liter), and mix together by Portable Stirrer continuously stirring properly till uniform mixing achieved.

Speed of stirrer: Constant.

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

• After uniform mixing add color Yellow oxide of iron IP (0.047 kg) in the above solution and mix for 05 minutes with stirrer till uniform mixing achieved.
• Filter the coating solution with Filter Cloth 100 # in one SS Container (capacity: 65 liter)
• Keeps the solution, after completion of Seal Coat, proceed for Enteric coating process.

STEP – VI (COATING PROCEDURE FOR ENTERIC COATINFG):

• Set the coating parameter for Enteric Coating as given in below table and start the enteric coating process by starting coating spray through gun.

• After completion of Enteric Coating, take weight of 100 enteric coated tablets and record the weight in BMR and calculate the weight gain by using Weight Gain Formula given in above table of Step-VI.

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

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

STEP –VII:

• Send the composite sample of coated tablets (Qty.30 tablets) to QC department for analysis.

STEP – IX:

• Take Tare Weight of one Poly-lined HDPE Containers (capacity: 30 liter ), record the Tare Weight in BMR and transfer the coated tablets in Poly-lined HDPE Containers (capacity: 30 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: 25.500 kg (100 %)

Actual Batch Yield Limit NLT 25.245 kg (NLT 99 %) (To be established in next batch).

MFR of Calcium Citrate 1000 mg, Magnesium Hydroxide 100 mg Vitamin D3 200 IU and Zinc Sulphate 4 mg Tablets

TABLE OF CONTENTS 

 1.0 PRODUCT DETAILS:

2.0 MANUFACTURING FORMULA:

3.0 LIST OF EQUIPMENTS:

4.0 GENERAL PRECAUTIONS:

• API Description Calcium Citrate: A white odorless crystalline powder.
• API Description Magnesium Hydroxide: A bulky white powder.
• API Description Vitamin D3: A white powder.
• API Description Zinc Sulphate: A white or almost white crystalline powder or colorless transparent crystals.
• 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 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.

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:

• Collect the sifted Zinc Sulphate Monohydrate IP (1.650 kg) in one Polybag (capacity: 2 kg).
• After sifting divide the sifted Calcium Citrate IP (168.00 kg) in two equal parts for LOT-I and LOT-II (84.000 kg each) and collect in five Poly-lined HDPE Containers (capacity: 45 liter each).
• After sifting divide the sifted Magnesium Hydroxide IP (36.600 kg) in two equal parts for LOT-I and LOT-II (18.300 kg each) and collect in above Poly-lined HDPE Containers (capacity: 45 liter each) with Calcium Citrate.
• Collect the sifted PVPK-30 IP (0.750 kg) in Polybag (capacity: 1 kg).
• Collect the sifted Sodium Benzoate IP (0.378 kg) in one Polybag (capacity: 1 kg).
• Collect the sifted Starch IP (2.520 kg) in one Polybag (capacity: 5 kg)
• Collect the sifted Talcum IP (3.000 kg), Sodium Starch Glycolate IP (2.550 kg) and Aerosil (0.500 kg) in Polybag (capacity: 10 kg)
• Collect the sifted Calcium Stearate IP (0.750 kg) in Polybag (capacity: 2 kg)0

STEP-II (BINDER PREPARATION):

(a) (PREPARATION OF BINDER TO COAT ZINC SULPHATE):

Take Isopropyl Alcohol IP (5.250 liter) in SS Container (capacity: 10 liter) and add Ethyl Cellulose IP (0.008 kg) in it. Mix together by Portable Stirrer continuously stirring till Ethyl Cellulose IP is dissolved properly in IPA.

Mixing Time: 10 minutes.

Filter it with filter cloth 100 # in SS container (capacity: 10 liter).

(b) (COATING OF ZINC SULPHATE):

Transfer the sifted Zinc Sulphate Monohydrate (1.650 kg) in SS Container (capacity: 10 liter) and slowly add the coating solution of Step-II (a) and coat the API manually with coating solution till uniform coating. After coating transfer the material into one SS Tray (capacity: 3.000 kg).

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

(c) (DRYING OF COATED GRANULES OF ZINC SULPHATE):

Dry the wet material of Step-II (c) as follows:

Load one Tray in Tray dryer.

First air dry the granules 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 Temperature: 35°C (After Air Drying)

Drying Time: 03 hours (To be validated in next batch).

Raking Frequency: After every 20 minutes.

(d) (SIZING/MILLING):

Check Sieve Integrity (before sifting and after sifting).

Set the Vibro Sifter and fix the sieve 40 # and sieve the dried material of Step-II (d). Collect the sized granules in one Polybag (capacity: 2 kg).

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

• Take purified water (60.500 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 (0.378 kg) and PVPK-30 IP (0.750 kg) and mix one by one with Stirrer till dissolved properly in water and make a solution.
• Heat the remaining purified water (55.500 liter) upto 80⁰C of Step-II (a) in Paste Kettle.
• Take purified water separately (7.000 liter, at room temperature) in SS Container (capacity: 10 liter) and add Starch (2.520 kg) slowly 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 upto 35⁰C to 40⁰C
• Divide paste (Qty.71.148 kg) into two equal parts (Qty.35.574 kg) for LOT-I and LOT-II in SS Containers (capacity: 70 liter each).

STEP – IV- (DRY MIXING): FOR LOT – I:

Transfer the sifted Calcium Citrate IP and Magnesium Hydroxide IP 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.

Mixing Speed: 05 minutes at slow speed.

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

Slowly add the binder of Step – III (h) in dry mix materials of Step – IV 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.

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

STEP –VI – (DRYING): FOR LOT- I:

Dry the wet material of Step-IV in FBD (capacity: 120 kg) until the LOD of granules is achieved between  to 1.0 % at 105°C checking by Halogen Moisture Balance and after drying unload the material in five Poly-lined HDPE Container (capacity : 45 liter each).

Inlet Temperature: 80°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): FOR LOT – I:

Check Sieve & Screen Integrity (before and after sifting & screening).

Set the Vibro Sifter and fix the Sieve 20 # and sieve the dried material of Step-VI and collect in five Poly-lined HDPE Containers (capacity: 45 liter each) and remaining retention after sieving, pass through the Multi-Mill using screen size 1.5 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 (PRE –LUBRICATION):

Load  the sized granules of  Step VI, Step-XI of LOT- I and LOT – II in Octagonal Blender (capacity: 500 liter) and add sifted Vitamin D3,  Talcum IP, Sodium Starch Glycolate IP and Aerosil, 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 – IX (LUBRICATION):

Add the sifted Calcium Stearate IP in Step-VIII of Pre- Lubricated Material in Octagonal Blender and mix properly till uniform mixing of materials with Magnesium Stearate IP and Calcium Stearate IP.

Mixing Time: 05 minutes (clockwise direction).

Mixing Speed: 10 RPM. 

STEP- X (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 – XI:

• Take Tare Weight of six 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 Container.
• Batch Yield of Lubricated granules:

Theoretical Batch Yield: 216.750 kg (100 %)

Actual Batch Yield Limit NLT 214.582 kg (NLT 99 %) (To be established in next batch)

STEP – XII:

• 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 of 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 six 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 six 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: 216.750 kg (100 %)
• Actual Batch Yield Limit NLT 214.582 kg (NLT 99 %) (To be established in next batch) 

STEP – IV:

• After completion of compression clean the Compression Machine as per cleaning SOP.
  • COATING:
• Verify the Net Weight of the received compressed tablets for coating as per status label and after confirmation continue for tablet coating.

STEP-II (COATING MATERIAL DETAILS):

STEP-III (LIST OF EQUIPMENTS FOR COATING):

STEP – IV (PREPARATION OF COATING MATERIAL): FOR LOT –I, LOT- II & LOT-III:

• Take Purified Water IP (21.750 liter) in SS Container (capacity: 30 liter) and add Instacoat White Aqueous.III (4.335 kg) in SS Container (capacity: 30 liter). 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)
• Keep the solution for 15 minutes to let it the foam settle down. Thereafter proceed with coating process.
• Divide the coating solution equally into three parts for LOT – I, LOT – II and LOT-III in SS Container (capacity: 30 liter each).

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

• Coating will be done in three lots, divide total compressed tablets into three equal quantities for LOT -I, LOT –II and LOT-III (72.250 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 up the tablets, take weight of 100 warmed tablets and also take weight of 100 tablets and record the weight in BMR for calculation of weight buildup of tablets.
• Set the coating parameter as given in below table and start the coating process by starting coating spray through gun.

• After completion of Film Coating, take weight of 100 Film coated tablets and record the weight in BMR and calculate the weight gain by using above Weight Gain Formula.

NOTE:

FOR LOT – II & LOT – III (COATING PROCEDURE):

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

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 six 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: 220.950 kg (100 %)

Actual Batch Yield Limit NLT 218.740 kg (NLT 99 %) (To be established in next batch).

Levocetirizine 5 mg Tablets IP

Levocetirizine Tablet belongs to a group of medicines called antihistamines. It is used to treat various allergic conditions such as hay fever, conjunctivitis, some skin reactions such as eczema, hives, and reactions to bites and stings. It also relieves watery eyes, runny nose, sneezing, and itching.

Levocetirizine tablets can be taken with or without food. The dose required by you may vary depending on what you are taking it for. Levocetirizine is usually taken in the evening, but follow the advice of your doctor on how to take it. You may need Levocetirizine tablet only on days you have symptoms, but if you are taking it to prevent the symptoms then you should take it regularly. If you miss doses or stop taking them earlier than advised, your symptoms may come back.

Levocetirizine is generally very safe. The most common side effects include feeling sleepy or dizzy, dry mouth, fatigue, and headache. These are usually mild and go away after a couple of days as your body adjusts to it. Consult your doctor if any of the side effects persist or worry you.

Levocetirizine is an antihistamine used to relieve allergy symptoms such as watery eyes, runny nose,  itching eyes /nose, and sneezing. It is also used to relieve itching and hives. It works by blocking a certain natural substance (histamine) that your body makes during an allergic reaction.

Before taking it, tell your doctor if you have any kidney problems or epilepsy (seizures). Your dose may need to be modified or Levocetirizine may not suit you. Some other medicines can interact with Levocetirizine so let your healthcare team know what else you are taking. You should also talk to your doctor before using Levocetirizine if you are pregnant or breastfeeding, although it is not thought to be harmful.

Mechanism of action:

Levocetirizine, the (R) enantiomer of cetirizine, is a potent and selective antagonist of peripheral H1-receptors.

Binding studies revealed that levocetirizine has a high affinity for human H1-receptors (Ki = 3.2 nmol/l). Levocetirizine has an affinity 2-fold higher than that of cetirizine (Ki = 6.3 nmol/l). Levocetirizine dissociates from H1-receptors with a half-life of 115 ± 38 min. After single administration, levocetirizine shows a receptor occupancy of 90% at 4 hours and 57% at 24 hours.

Pharmacodynamic studies in healthy volunteers demonstrate that, at half the dose, levocetirizine has comparable activity to cetirizine, both in the skin and in the nose.

Pharmacodynamic effects

The pharmacodynamic activity of levocetirizine has been studied in randomized, controlled trials:

In a study comparing the effects of levocetirizine 5mg, desloratadine 5mg, and placebo on histamine-induced wheal and flare, levocetirizine treatment resulted in significantly decreased wheal and flare formation which was highest in the first 12 hours and lasted for 24 hours, (p<0.001) compared with placebo and desloratadine.

The onset of action of levocetirizine 5 mg in controlling pollen-induced symptoms has been observed at 1-hour post-drug intake in placebo-controlled trials in the model of the allergen challenge chamber.

In vitro studies (Boyden chambers and cell layers techniques) show that levocetirizine inhibits eotaxin-induced eosinophil transendothelial migration through both dermal and lung cells. A pharmacodynamic experimental study in vivo (skin chamber technique) showed three main inhibitory effects of levocetirizine 5 mg in the first 6 hours of pollen-induced reaction, compared with placebo in 14 adult patients: inhibition of VCAM-1 release, modulation of vascular permeability and a decrease in eosinophil recruitment.

Manufacturing Procedure of Levocetirizine 5 mg Tablets IP

TABLE OF CONTENTS 

• PRODUCT DETAILS
• MANUFACTURING FORMULA
• LIST OF EQUIPMENT
• GENERAL PRECAUTIONS
• MANUFACTURING INSTRUCTIONS
• MANUFACTURING PROCESS DETAILS
• GRANULATION
• COMPRESSION
• COATING

PRODUCT DETAILS:

Product Name: Levocetirizine Dihydrochloride Tablets IP

Product Description: White color round shape, biconvex, film-coated tablet having both sides plain.

Strength: 5 mg

Label claim: Each film-coated tablet contains: Levocetirizine Dihydrochloride  IP – 5 mg

Average Weight: 102 mg (Film-coated tablets)

Shelf Life:24 months

Storage: Store in a cool, dry, and dark place below 25 ⁰C

Drug Category: Anti-histamine Drug

MANUFACTURING FORMULA:

LIST OF EQUIPMENT:  

• Weighing Balance
• Vibro Sifter
• Mass Mixer with propeller
• Portable Stirrer
• Tray Dryer
• Double Cone Blender
• Halogen Moisture Balance
• Compression Machine
• SS Containers with lid
• Filter Cloth 100 #

GENERAL PRECAUTIONS:

• API Description: A white or almost white 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 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 from QA before starting the manufacturing operation during batch-to-batch and product-to-product changeover.
• Do not overwrite any entry. In case of a mistake, cancel the entry by a single line with a sign & date and make the correct entry.

MANUFACTURING PROCESS DETAILS:

GRANULATION:

STEP – I (SIFTING):

Check Sieve Integrity (before sifting and after sifting).

Set the Vibro Sifter  and sieve the Dispensed Materials as per Sieve Sizes mentioned below:

Collect the sifted Levocetirizine Dihydrochloride IP (2.525 kg), MCCP PH-102 IP (5.075 kg), Starch IP (2.500 kg), and Cross Carmillose Sodium IP (0.625 kg) in one Polybag (capacity: 20 kg).

Collect the sifted Talcum IP (1.500 kg), MCCP PH-102 IP (35.650 kg), Cross Carmillose Sodium IP (0.625 kg) and Aerosil IP (0.500 kg) in one Polybag (capacity: 50 kg).

Collect the sifted Calcium Stearate IP (1.000 kg) in one Polybag (capacity: 2.0 kg).

STEP – II (BINDER PREPARATION):

Take Isopropyl Alcohol IP (10.800 liters) in SS Container (capacity: 20 liters) and add Ethyl Cellulose IP (0.010 kg) to it. Mix together by Portable Stirrer continuously stirring till Ethyl Cellulose IP is dissolved properly in IPA.

Mixing Time: 10 minutes.

Filter it with filter cloth 100 # in an SS container (capacity: 20 liters).

STEP – III (DRY MIXING):

Transfer the sifted material Levocetirizine Dihydrochloride IP, MCCP PH-102 IP, Starch IP, and Cross Carmillose Sodium IP in Mass Mixer ( capacity: 100 liters) and dry mix the materials till uniform mixing.

Mixing Time: 10 minutes.

Mixing Speed: 36 RPM

Paddle (Blades) Timing: 5 minutes in a clockwise direction and 5 minutes in the anti-clockwise direction.

STEP –IV (BINDING OF DRY MIX MATERIAL):

Slowly add the binder of Step-II to the dry mix material of Step-III and mix for 10 minutes till uniform binding after binding, collect the wet mass in four Trays  (capacity: 3.000 kg each).

Mixing Time: 10 minutes.

Mixing Speed: 36 RPM.

Paddle (Blades) Timing: 5 minutes in a clockwise direction and 5 minutes in an anti-clockwise direction.

STEP –V (DRYING):                                                                

Dry the wet material of Step IV as follows:

Load these four Trays in a Tray dryer.

First air dry the granules 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.

Drying Temperature: 35°C (After Air Drying)

Drying Time: 03 hours (To be validated in the next batch).

Raking Frequency: After every 20 minutes.

STEP-VI (SIZING/MILLING):

Check Sieve Integrity (before sifting and after sifting).

Set the Vibro Sifter and fix the sieve 40 # and sieve the dried material of Step-V. Collect the sized granules in one Poly-lined HDPE Container (capacity: 30 liters).

STEP – VII (PRE –LUBRICATION):

Load the sized granules of Step-VI in Double Cone Blender (capacity: 200 liters) and add sifted Talcum IP, MCCP PH-102 IP, Cross Carmillose Sodium IP, and Aerosil IP, mix properly till uniform mixing of sized material with Pre-Lubricating Materials.

Mixing Time: 40 minutes (20 minutes clockwise direction and 20 minutes anti-clockwise direction).

Mixing Speed: 10 RPM.

STEP – VIII (LUBRICATION):

Add the sifted Calcium Stearate IP in Pre- Lubricated Materials of Step-VII in a Double Cone Blender and mix properly till uniform mixing of materials with Calcium Stearate IP.

Mixing Time: 05 minutes (clockwise direction).

Mixing Speed: 10 RPM.

STEP- IX (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

The appearance of the blend -White free-flowing granular powder

Blend Uniformity: 90 % to 110 %

Blend Assay:98 % to 103 %

LOD: 1.0  % to 1.5 %

STEP – X:

Take the Tare Weight of two Poly-lined HDPE Containers (capacity: 30 liters each), record the Tare Weight in BMR and unload the above-blended material from Double Cone Blender in Poly-lined HDPE Containers (capacity: 30 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: 50.000 kg (100 %)

Actual Batch Yield Limit: 49.500 kg (NLT 99 %) (To be established in next batch).

STEP – XI:

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

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.

Set the 35 stations (B-Tooling) Compression Machine. Compress the blend as per the below parameters and In Process checks and take a sample for Dissolution (Qty. 20 tablets) and send it to QC Department for Dissolution Analysis.

After confirmation of the Dissolution result continue the compression with the blend as per the following parameters and In Process checks under controlled environmental conditions. 

Collect the compressed tablets in SS Container (capacity: 20 liters each on both sides), when SS containers are filled with tablets, transfer the tablets to two Poly-lined HDPE Containers as given in below Step-III.

STEP – II:

Send the sample of compressed tablets (Qty. 30 tablets) to the QC department for analysis.

STEP – III:

Take the Tare Weight of two Poly-lined HDPE Containers (capacity: 30 liters each), record the Tare Weight in BMR and transfer the compressed tablets to Poly-lined HDPE Containers (capacity: 30 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 Containers.

Batch Yield of Compressed Tablets:

Theoretical Batch Yield: 50.000 kg (100 %).

Actual Batch Yield Limit: 49.500 kg (NLT 99 %) (To be established in next batch).

STEP – IV:

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

COATING:

Verify the Net Weight of the received compressed tablets for coating as per the status label and after confirmation continues for tablet coating.

 STEP – I (COATING MATERIALS DETAILS):

STEP-II (LIST OF EQUIPMENT FOR COATING):

• Coating Machine and Coating Pan
• Spray Gun
• Filter Cloth 100 #
• Portable Stirrer
• SS Container
• Poly-lined HDPE Containers with lid

STEP – III (PREPARATION OF COATING SOLUTION):

Take Purified Water IP (6.000 liters at room temperature) in SS Container (capacity: 10 liters) and add Instacoat White Aq.III (1.000 kg) and mix together with Portable Stirrer continuously stirring till uniform mixing is achieved.

Speed of Stirrer: Constant.

Mixing Time: 15 minutes.

Filter the coating solution with Filter Cloth 100 # in SS Container (capacity: 10 liters).

Keep the solution for 15 minutes to let it the foam settle down. Thereafter proceed with the coating process.

STEP – IV (COATING PROCEDURE):

Coating will be done in one lot, take total compressed tablets for coating (50.000 kg).

Load the tablets in the 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 40°C to 45°C.

After warming up the tablets, take weight of 100 warmed tablets and record the weight in BMR for calculation of weight buildup of tablets after coating.

Set the coating parameter as given in below table and start the coating process by starting coating spray through gun.

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

STEP – VI:

Send the composite sample of coated tablets (Qty. 30 tablets) to the QC department for analysis.

STEP – VII:

Take the Tare Weight of two Poly-lined HDPE Containers (capacity: 30 liters each), record the Tare Weight in BMR and transfer the coated tablets to Poly-lined HDPE Containers (capacity: 30 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: 51.000 kg (100 %)

Actual Batch Yield Limit NLT 50.490 kg (NLT 99 %) (To be established in next batch).

Reference: Levocetirizine 5 mg film-coated 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).

MFR of Aceclofenac 100 mg and Paracetamol 325 mg Tablets

TABLE OF CONTENTS 

 1.0 PRODUCT DETAILS:

2.0 MANUFACTURING FORMULA:

3.0 LIST OF EQUIPMENTS:

4.0 MANUFACTURING INSTRUCTIONS:

• Aceclofenac API Description: A white or almost white crystalline powder.
• Paracetamol API Description: A white crystals 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 GENERAL PRECAUTIONS:

• All the Activity shall be performed as per current SOPs.
• Follow the GMP compliance throughout the manufacturing process
• Take the line clearance from QA before starting the manufacturing operation during batch to batch and product to product change over.
• Do not overwrite the entry, in case there is correction, 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 Sifter and sieve the Dispensed Materials as per Sieve Sizes mentioned below:

• Collect the sifted Aceclofenac IP (30.000 kg), Paracetamol IP (97.500 kg), Starch IP (15.000 kg) and MCCP Plain IP (18.477 kg) into four Poly-lined HDPE Container (capacity: 45 liter each) two equal parts for LOT I and LOT II.
• Collect the sifted Starch IP (4.875 kg) in SS Container (capacity: 10 liter)
• Collect the sifted Talcum IP (3.000 kg) and Sodium Starch Glycolate IP (2.400 kg) in Poly-lined SS Container (capacity : 10 liter)
• Collect the sifted Magnesium Stearate IP (0.600 kg) in Poly-lined SS Container (capacity: 10 liter)
• Divide the sifted material Aceclofenac IP (30.000 kg), Paracetamol IP (97.500 kg), Starch IP (15.000 kg) and MCCP Plain IP (18.477 kg) in two equal parts for LOT-I and LOT-II. 

STEP – II (DRY MIXING): FOR LOT – I:

Transfer the sifted Aceclofenac IP (15.000 kg ), Paracetamol IP (48.750 kg ), Starch IP (7.500 kg) and MCCP Plain ( 9.238 kg ) in RMG ( capacity : 160 liter) and dry mix the materials till uniform mixing.

Mixing Time = 8 minutes.

Mixing Speed: 03 minutes at slow speed and 05 minutes at fast speed.

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

(a) Take purified water (42.00 liter) in Paste Kettle, heat the purified water at 80⁰C and add Gelatin IP (0.900 kg).

(b) Take purified water (5.00 liter, at temperature 25⁰C) in SS Container (capacity: 30 liter) and add Starch IP (4.875 kg) slowly with continuously stirring till uniform solution is ready.

(c) Add the above solution of Step – III (b) in solution of Step – III (a) in Paste Kettle with continuously stirring till uniform paste is ready.

(d) Take purified water (1.000 liter, at temperature 35°C) separately in SS Container (capacity: 10 liter) and add 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 then add to Step – III (c) and continuously stirring till final paste is ready and cool the paste to 35°C to 40°C.

(e) Divide paste into two equal parts for LOT – I and LOT – II in SS Containers (capacity: 30 liter each).

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

Slowly add the binder of Step-III in dry mix materials of Step – II in Rapid Mixer Granulator (capacity: 160 liter) with running at slow speed impeller (13 ampere) for 5 minutes. Then run impeller and chopper both at medium speed (15 ampere) for 10 min and finally run both chopper and impeller on fast speed (19 ampere) for 3 minutes till uniform mixing. Unload the material in SS Container (capacity: 100 liter) from RMG.

Mixing Time: 18 minutes

Ampere Load of Impeller: 13 to 19 ampere. 

STEP-V (WET SCREENING) : FOR LOT – I:

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

STEP –VI – (DRYING) : FOR LOT- I:

Dry the wet material of Step-V in FBD (capacity: 120 kg) till the LOD of granules is achieved between 2.5 to 3.0 % at 105°C checking by Halogen Moisture Balance.

Inlet Temperature: 55°C.

Outlet Temperature : To be established

Bed Temperature: To be established

Raking Frequency: After 30 minutes

Drying Time: 2 hours.

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

Check Screen Integrity (before sifting and after sifting).

Milled the dried material of Step -VI through Multi Mill using screen size 2 mm and collect milled material in one SS Containers (capacity :100 liter ). After milling transfer the milled material into four Poly-lined HDPE Containers (capacity: 30 liter each) and weight and record the milled granules weight.

Blade Type: Both (Knife blades/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 (PRE –LUBRICATION):

Load the milled granules of Step-VII of LOT- I and LOT – II in Octagonal Blender (capacity: 500 liter) and add sifted Talcum IP (3.000 kg) and Sodium Starch Glycolate IP (2.400 kg), mix properly till uniform mixing of Pre-Lubricating Material.

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

Mixing Speed: 10 RPM

STEP – IX (LUBRICATION):

Add the sifted Magnesium Stearate IP (0.600 kg) in Step-VIII 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- X (BLEND SAMPLE ANALYSIS):

After completion of lubrication, collect the composite blend sample and send to QC for analysis according to the table below:

STEP – XI:

Unload the above blended material and weight and store in seven Poly-lined HDPE Containers (capacity: 30 liter each).

STEP – XII:

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

• COMPRESSION:

STEP – I:

After receiving QC approval for blend, compress the blend as per the following parameters and In-Process checks under controlled environmental condition. 

 STEP – II:

Send the sample of compressed tablets to QC department for analysis.

STEP – III:

Weight the compressed tablets and store into seven Poly-lined HDPE Containers with lid (capacity: 30 liter each) with proper status label till next step tablet packing.

STEP – IV:

Clean the Compression Machine as per cleaning SOP.

COATING:

STEP – I (COATING MATERIALS DETAILS):

STEP-II (LIST OF EQUIPMENTS FOR COATING):

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

• Take Purified Water IP (17.400 liter) and mix Sheffcoat PVA Orange 5Y02059 (4.350 kg) in SS Container (capacity: 30 liter) and mix properly with stirrer till uniform mixing achieved.

Speed of stirrer: Constant.

• Filter the coating solution with Nylon Filter Cloth 100# (0.5 mm).
• Keep the solution for 30 minutes and after 30 minutes proceed for coating process.
• Divide the coating solution equally into two parts for LOT – I and LOT – II in SS Container (capacity: 30 liter each)

STEP – IV (COATING PROCEDURE 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 (87.000 kg tablets for each lot).
• Load the tablets of LOT – I (87.000 kg) in coating pan (capacity: 42″), start the hot air blower, set the supply air temperature at 60°C to 65°C and start the exhaust fan & warm the tablets bed 40°C to 45°C.
• After warm up of tablets, take weight of 100 warm tablets for calculation of weight buildup of tablets after coating.
• Set the coating parameter as given in below table and start the coating process by starting coating spray from gun.

STEP – V (COATING IN-PROCESS CHECK PARAMETERS): FOR LOT- I:

NOTE:

FOR LOT – II (COATING PROCEDURE): Please follow the same procedure of LOT – I of coating from Step-IV and Step -V.

STEP – VI:

Send the composite sample of coated tablets of LOT- I and LOT – II to QC department for analysis.

STEP – VII:

Weigh the coated tablets and store the coated tablets into seven Poly-lined HDPE Containers with lid (capacity: 30 liter each) with proper status label till next step tablet packing.

Azithromycin 500 Tablets IP

Azithromycin 500 Tablet is an antibiotic used to treat various types of bacterial infections of the respiratory tract, ear, nose, throat, lungs, skin, and eyes in adults and children. It is also effective in typhoid fever and some sexually transmitted diseases like gonorrhea.

Azithromycin 500 Tablet is taken orally, preferably one hour before or 2 hours after a meal. It should be used regularly at evenly spaced time intervals as prescribed by your doctor. Do not skip any doses and finish the full course of treatment even if you feel better. Stopping the medicine too early may lead to the return or worsening of the infection.

Commonly seen side effects with Azithromycin 500  tablet include vomiting, nausea, stomach pain, and diarrhea. These are usually temporary and subside with the completion of treatment. Consult your doctor if you find these side effects worry you or persist for a longer duration.

Uses of Azithromycin 500 mg Tablets

Treats mild to moderate susceptible infections caused by bacteria and other micro-organisms which include chest, throat, and nasal infections (such as bronchitis, pneumonia, tonsillitis, sore throat, and sinusitis)

Treats ear infections and skin & soft tissue infections (such as an abscess/boil) in affected individuals

Treats sexually transmitted diseases such as cervicitis (caused by organisms such as Chlamydia trachomatis/ Neisseria gonorrhea) in affected individuals

HOW AZITHROMYCIN 500 TABLET WORKS

Azithromycin 500 mg Tablets works by inhibiting bacterial protein synthesis (essential for the bacteria to grow) that results in its destruction thus preventing its growth and spread of infection in affected individuals.

DIRECTIONS FOR USE

Take Azithromycin 500 mg Tablets as advised by your physician. Swallow the medicine with a glass of water. Do not crush or chew the medicine. Your doctor will decide the correct dose and duration for you depending on your age, body weight, and disease condition.

Manufacturing Procedure of Azithromycin 500 mg Tablets

TABLE OF CONTENTS 

• PRODUCT DETAILS
• MANUFACTURING FORMULA
• LIST OF EQUIPMENT
• GENERAL PRECAUTIONS
• MANUFACTURING INSTRUCTIONS
• MANUFACTURING PROCESS DETAILS
• GRANULATION
• COMPRESSION
• COATING

PRODUCT DETAILS:

Product Name:
Azithromycin Tablets IP
Product Description:
White color elongated biconvex, film-coated tablet having one side mid-break line and the other side plain
Strength: 500 mg

Label claim:

Each film-coated tablet contains:

Azithromycin Dihydrate IP

equivalent to  Azithromycin Anhydrous – 500 mg

Batch Size: 2,00,000 Tablets
Average Weight: 714 mg 
Shelf Life: 24 months
Storage: Store in a cool, dry, and dark place below 25⁰C
Drug Category: Macrolide Antibiotics

MANUFACTURING FORMULA:

LIST OF EQUIPMENT:    

Weighing Balance
Vibro Sifter
Paste Kettle with stirrer
Portable Stirrer
Multi Mill (screen size 2 mm and 8 mm)
Rapid Mixer Granulator (RMG)
Fluid Bed Dryer (FBD)
Double Cone Blender
Halogen Moisture Balance
Compression Machine                     

GENERAL PRECAUTIONS:

API Description: A white or almost white color powder. Protected from moisture during storage.

All the Manufacturing Activities shall be performed under controlled conditions (temperature NMT 25⁰C and relative humidity NMT 60%).

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 from QA before starting the manufacturing operation during batch-to-batch and product-to-product changeover.

Do not overwrite any entry. In case of a mistake, cancel the entry by a single line with a sign & date and make the correct entry.

MANUFACTURING PROCESS DETAILS:

GRANULATION:

 STEP – I (SIFTING):

Check Sieve Integrity (before sifting and after sifting).

Set the Vibro Sifter and sieve the Dispensed Materials as per the Sieve Sizes mentioned below:

After sifting divide the sifted Azithromycin IP (105.000 kg) in two equal parts for LOT-I and LOT-II (52.500 kg each) and collect in two Poly-lined HDPE Containers (capacity: 65 liter each).

After sifting divide the sifted MCCP Plain IP (10.000 kg) into two equal parts for LOT-I and LOT-II (5.000 kg each) and collect in two above Poly-lined HDPE Containers (capacity: 65 liters each) with Azithromycin.

Collect sifted PVPK-30 IP (0.800 kg) in one Polybag (capacity: 1.0 kg).

Collect sifted Sodium Benzoate IP (0.280 kg) in one Polybag (capacity: 1.0 kg).

Collect sifted Sodium Starch Glycolate IP (4.000 kg) in one Polybag (capacity: 5 kg)

Collect the sifted Talcum IP (2.800 kg), MCCP PH-102 IP (10.920 kg), Cross Carmillose Sodium IP (2.800 kg), Crospovidone XL (1.400 kg), and Aerosil IP (0.600 kg) in  one Polybag (capacity: 20 kg)

Collect sifted Calcium Stearate IP (1.400 kg) in Polybag (capacity: 2.0 kg).

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

Take purified water (42.00 liters) in Paste Kettle (capacity: 100 liters), heat the purified water to 35⁰

Take purified water (5.000 liter, at temperature 35⁰C) from the Paste Kettle of Step-II (a) in SS Container (capacity: 10 liter) and add sifted Sodium Benzoate IP (0.280 kg) and PVPK-30 IP (0.800 kg) and mix one by one with stirrer till dissolved properly in water and make a solution.

Heat the remaining purified water to 80⁰C of Step-II (a) (37.000 liters) in a Paste Kettle.

Take purified water separately (10.000 liters, at room temperature) in an SS Container (capacity: 20 liter) and add Sodium Starch Glycolate IP (4.000 kg) slowly continuously stirring till a uniform solution is ready.

Add the above solution of Step-II (d) to the heated purified water of Step–II (c) in a Paste Kettle with continuous stirring till uniform paste is ready.

(f)  Add Step -II (b) solution with continuous stirring to Step II (c) till the final paste is ready.

(g) Transfer the ready paste by tilting the Paste Kettle in one SS Container (capacity: 100 liters). Cool the paste up to 35°C to 40°C.

(h) Divide paste (Qty.57.080 kg) into two equal parts (Qty. 28.540 kg each) for LOT- I and LOT- II SS Containers (capacity: 70 liters each).

STEP – III (DRY MIXING): FOR LOT-I:

Transfer the sifted Azithromycin IP and MCCP Plain IP in Rapid Mixer Granulator (capacity: 160 liters) running at a slow speed impeller and dry mix the materials till uniform mixing.

Mixing Time: 05 minutes.

Mixing Speed: 05 minutes at slow speed.

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

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

Slowly add the binder of Step – II to dry mix materials of Step – III in Rapid Mixer Granulator running at a slow speed impeller for 5 minutes till binder addition. After binder addition run the impeller and chopper both at slow speed for 08 min and finally run both chopper and impeller at fast speed for 02 minutes till uniform mixing. Unload the material in SS Container (capacity: 100 liters) from RMG by opening the discharge point with a running impeller.

Mixing Time: 15 minutes.

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 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 liters) and after screening transfer the wet material in an FBD bowl.

STEP –VI (DRYING): FOR LOT –I:

Dry the wet material of Step-V in FBD (capacity: 120 kg) until the LOD of granules is achieved between 1.0 to 1.5 % 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: 60°C. (To be validated in next batch).

Outlet Temperature: To be established.

Raking Frequency: After 30 minutes.

Drying Time: 02 hours. (To be validated in next batch). 

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

Check Sieve & Screen Integrity (before and after sifting & screening).

Set the Vibro Sifter and fix the Sieve 18 # and sieve the dried material of Step-VI and collect in three 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 the 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 as LOT – I of dry mixing, binding of dry mix material, wet screening, drying, and sizing/ milling.

STEP – VIII (PRE –LUBRICATION):

Load the sized granules of Step-VII of LOT-I and LOT-II in Double Cone Blender (capacity: 400 liters) and add sifted Talcum IP, MCCP PH-102 IP, Cross Carmillose Sodium IP, Crospovidone XL, Aerosil IP, 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 – IX (LUBRICATION):

Add the sifted Calcium Stearate IP in Pre- Lubricated Materials of Step-VIII and mix properly till uniform mixing of materials with Calcium Stearate IP.

Mixing Time: 05 minutes. (Clockwise direction).

Mixing Speed: 10 RPM.

STEP- X (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

The appearance of the blend: White color free-flowing granular powder

Blend Uniformity:90 % to 110 %

Blend Assay:98 % to 103 %

LOD:1.0 % to 1.5 %

STEP – X:

Take the Tare Weight of four 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 Container.

Batch Yield of Lubricated granules:

Theoretical Batch Yield: 140.00 kg (100 %)

Actual Batch Yield Limit NLT 138.600 kg (NLT 99 %) (To be established in next batch)

STEP – XI:

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 the status label in Granules Day Store.

After confirmation continue the compression with 27 stations (D-Tooling) Compression Machine of the blend as per the following parameters and In Process checks under controlled environmental conditions. 

Collect the compressed tablets in SS Container (capacity: 20 liters each on both sides), when SS containers are filled with tablets, transfer the tablets to four 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 four 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: 140.00 kg (100 %)

Actual Batch Yield Limit NLT 138.600 kg (NLT 99 %) (To be established in next batch)

STEP – IV:

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

COATING:

Verify the Net Weight of the received compressed tablets for coating as per the status label and after confirmation continues for tablet coating.

 STEP – I (COATING MATERIALS DETAILS):

Material Name:

Instacoat White Aq.III: 2.800 kg.

Purified Water IP:16.800 liter

STEP-II (LIST OF EQUIPMENT FOR COATING):

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

Take Purified Water IP (16.800 liter, at room temperature) in SS Container (capacity: 20 liter) and add Instacoat White Aq.III (2.800 kg and mix together by Portable Stirrer continuously stirring till uniform mixing achieved.

Speed of stirrer: Constant.

Mixing Time: 15 minutes.

Filter the coating solution with Filter Cloth 100 # in one SS Container (capacity: 20 liter).

Keep the solution for 15 minutes to let the foam settled down. Thereafter proceed with the coating process.

Divide the coating solution equally into two parts for LOT – I and LOT – II in SS Container (capacity: 15 liter each).

STEP – IV (COATING PROCEDURE): FOR LOT-I:

The coating will be done in two lots, dividing the total compressed tablets into two equal quantities for LOT -I and LOT -II (70.000 kg tablets for each lot).

Load the tablets in the coating pan (Capacity: 42″), 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 40°C to 45°C.

After warming the tablets, take weight of 100 warmed tablets and record the weight in BMR for calculation of weight buildup of tablets after coating.

Set the coating parameter as given in below table and start the coating process by starting coating spray through gun.

NOTE:

FOR LOT – II (COATING PROCEDURE):

Please follow the same procedure of LOT – I of coating from Step IV. 

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

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

STEP – VI:

Send the composite sample of coated tablets (Qty. 30 tablets of each Lot) to QC department for analysis.

STEP – VII:

Take Tare Weight of four 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: 140.00 kg (100 %)

Actual Batch Yield Limit NLT 138.600 kg (NLT 99 %) (To be established in next batch).

Blister Packing:

Shift the inspected tablets to the blister section and blister pack them using the Triple Track Blister Packing Machine by operating it.

IN-PROCESS CONTROLS: 

The following in-process controls should be maintained during the processing:

Check Raw materials used for manufacturing purposes are all approved materials and have ‘Released’ labels fixed on them.

All weighed Raw materials should be counter-checked by the Manufacturing Chemist. If any discrepancy is noticed, it should be immediately brought to the notice of the Production and QC/QA Manager.

Physical characteristics of Raw materials like color, odor, and consistency are checked before compounding.

Humidity and temperature should be maintained during the compression of thermolabile products.

A sample of dried granules should be sent to the Quality Control Department for the determination of Moisture content.

The total weight of blended powder should be checked in the presence of the Manufacturing Chemist and recorded the same in the Batch Manufacturing Record.

Bulk samples should be sent for analysis to the Quality Control Department before starting the compression of tablets.

Weight Variation: I) Intermittently weight variation of compressed tablets should be checked at 30 minutes intervals by the Assistant Manufacturing Chemist and a record for the same should be kept in the Batch Manufacturing Record

Out-of-limit tablets should be checked by the Weight Variation Method.

Take the average weight of 20 tablets on the calibrated balance and calculate the upper and lower limit as per below by IP/BP/USP:

Take the weight of individual tablets and check if all the tablets are lying within the limits.

Select the tablets only if no more than two tablets are out of the percentage limit and if no tablet differs by more than two times the percentage limit, otherwise reject the tablets.

Adjust the desired weight of the tablets in the Compression Machine by moving the weight adjustment cam clockwise or anticlockwise accordingly as per the Standard Operating Procedure of the Compression Machine.

Re-check the weight of tablets for further adjustment, if any.

The thickness of Tablets: The thickness of the tablets should be determined using the vernier caliper. The thickness of the tablet should be checked whenever weight adjustments are made.

Hardness of the tablets: The equipment used is the ‘Monsanto’ type hardness tester. The hardness of the compressed tablets should be checked at regular intervals to determine the need for pressure adjustments on the tableting machine.

The hardness of tablets varies between 2-4 Kg/cm².

Friability:

Roche Friabilator is used for measuring the Friability. The instrument is designed to evaluate the ability of the tablet to withstand abrasion in packaging, handling, and shipping.

Adjust the instrument to 25 RPM before adding the tablets.

Weigh 20 Tablets on a calibrated balance. Transfer the tablets to the plastic chamber. Close the drum tightly.

Switch on the apparatus. Operate the Friabilator for 100 revolutions.

De-dust and reweigh the tablets. Loss in weight indicates the ability of tablets to withstand wear.

Take 10 tablets to check the friability, when the average weight of the tablet is 1g or more than 1g.

 Friability Limit  = Less than 1.0%

Disintegration Test:

Disintegration is the time required for the group of tablets to disintegrate into the particles. Disintegration Test should be carried out at regular intervals of 1 hour by using the Disintegration Test Apparatus.

The tube assembly unit is removed from the glass beaker and from each tube the plastic discs are removed.

Place the tablets in each of the 6 tubes along with a plastic disc over the tablets.

The glass beaker is filled with water. The water in the beaker is retained at the temperature of 37+1˚C throughout the test by suitably setting the thermostat.

Introduce a tube assembly unit into a glass beaker in such a way that the wire mesh at the base of each tube is at least 2.5cm below the surface of the liquid when the basket is at its highest position.

Switch on the apparatus to move the basket assembly containing the tablets up and down through a distance of 5 to 6 cm at a frequency of 28 to 32 cycles per minute. Start the stopwatch.

When the tablets have disintegrated i.e. when no particles remain on the wire mesh at the bottom of the tube, stop the stopwatch. Note the time taken for the disintegration of the tablets and record the same in the Batch Manufacturing Record.

If one or two tablets fail to disintegrate, the test is to be repeated using 12 tablets

Disintegration Time of uncoated tablets= Not more than 15 minutes

Disintegration Time of coated tablets= Not more than 30 minutes

Tablets taken for testing and In-process control should not be added to the bulk batch to avoid mix-ups and cross-contamination.

Inspection and sorting of rejected tablets should be done.

The strips and cartons should be checked thoroughly for proper batch coding.

The Manufacturing Chemist and Production should randomly check that the correct no. of strips are being packed in each carton and also the number of cartons in each shipper is the same as that shown in the proof.

Intimation should be sent to the Quality Control Department for finished product sampling and testing.

After the completion of labeling and packaging, the coded cartons should be accounted for, and rejected printed material should be destroyed in the presence of the QC/QA Manager. Fill out the destruction sheet and attach the same in the Batch Manufacturing Record.

It will be ensured that filling or packaging equipment has been properly cleaned after the completion of the batch.

Filling or packaging of the next product should not commence until the IPQA has given the ‘Line Clearance’

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

TABLE OF CONTENTS 

 1.0 PRODUCT DETAILS:

2.0 MANUFACTURING FORMULA:

3.0 LIST OF EQUIPMENT:                         

• 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:

• 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:

 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.