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

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).