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

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

TABLE OF CONTENTS 

S.NO. TITLE Page No.
1.0 PRODUCT DETAILS
2.0 MANUFACTURING FORMULA
3.0 LIST OF EQUIPMENTS
4.0 GENERAL PRECAUTIONS
5.0 MANUFACTURING INSTRUCTIONS
 

 

 

6.0

 MANUFACTURING PROCESS DETAILS
6.1 GRANULATION
6.2 COMPRESSION
6.3 COATING

 1.0 PRODUCT DETAILS:

Product Name Calcium Citrate, Magnesium Hydroxide, Vitamin D3 and Zinc Sulphate Tablets
Product Description White, elongated, biconvex shape, film coated tablet having one side mid break line and other side plain
Strength Calcium Citrate USP – 1000 mg, Magnesium Hydroxide IP 100 mg

Vitamin D3 IP – 200 IU and Zinc Sulphate Monohydrate IP 4 mg
Label claim

 

 Each film coated tablet contains:

Calcium Citrate USP – 1000 mg

Magnesium Hydroxide IP

Equivalent to Magnesium – 100 mg

Vitamin D3 IP – 200 IU

Zinc Sulphate Monohydrate IP

Equivalent to Elemental Zinc – 4 mg
Batch Size 1,50,000 Tablets
Average Weight 1445 mg (Uncoated Tablet)

1473.9 mg (Film Coated Tablet)
Shelf Life 24 months
Storage Store in a cool, dry and dark place below 250C
Drug Category Minerals-Supplement

2.0 MANUFACTURING FORMULA:

Material Name Grade Category Quantity per Unit (In mg) Overages Batch Qty. (In kg)
Coat of API          
Zinc Sulphate Monohydrate IP API 4 mg eq. to 11 mg —- 1.650 kg
Binder-I
Ethyl Cellulose IP Binder 0.053 mg —- 0.008 kg
Isopropyl Alcohol IP Solvent 0.035 ml —- 5.250 liter
Dry Mixing          
Calcium Citrate USP API 1000 mg 12 % 168.000 kg
Magnesium Hydroxide IP API 100 mg eq. to 240 mg 1.66 % 36.600 kg
Binder-II
PVPK-30 IP Binder 5 mg —- 0.750 kg
Sodium Benzoate IP Preservative 2.52 mg —- 0.378 kg
Starch IP Binder 16.8 mg —- 2.520 kg
Purified Water IP Solvent 0.450 ml —- 67.500 liter (To be validated in next batch)
Lubricant
Vitamin D3(850 IU/mg)-kg IP API 200 IU 30 % 0.044 kg
Talcum IP Anti-caking agent 20 mg —- 3.000 kg
Sodium Starch Glycolate IP Disintegrants 17 mg —- 2.550 kg
Aerosil IP Glidant 3.33 mg 0.500 kg
Calcium Stearate IP Anti- Adherent 5 mg —- 0.750 kg

3.0 LIST OF EQUIPMENTS:

Sr. No. Machineries/equipments Capacity Equipment ID.
1.  Weighing Balance 300 kg,100 kg
2. Vibro Sifter (with SS Sieves No’s -14,20,40,60 and 100 ) 30 inch dia
3. Paste Kettle with stirrer 100 liter
4. Portable Stirrer —
5. Multi-Mill (screen size 1.5 mm) —
6. Rapid Mixer Granulator (RMG ) 160 liter
7. Fluid Bed Dryer (FBD) 120 kg
8. Octagonal Blender 500 liter
9. Compression Machine 27 Station
10. SS Containers 10 liter ,30 liter,70 liter and 100 liter —
11. Halogen Moisture Balance —
12. Poly-lined HDPE Containers with lid 45 liter (22 No’s) —
13. Polybags 1 kg ,2 kg,5 kg,10 kg

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:
Material Name Std. Qty. (kg) Sieve No.
Coat of API
Zinc Sulphate Monohydrate 1.650 kg 60 #
Binder- I
Ethyl Cellulose IP 0.008 kg
Isopropyl Alcohol IP 5.250 liter
Dry Mixing
Calcium Citrate IP 168.00 kg 24 #
Magnesium Hydroxide IP 36.600 kg 24 #
Binder-II
PVPK-30 IP 0.750 kg 20 #
Sodium Benzoate IP 0.378 kg 20 #
Starch IP 2.520 kg 100 #
Lubricant
Vitamin D3 (850 IU/mg) 0.044 kg
Talcum IP 3.000 kg 60 #
Sodium Starch Glycolate IP 2.550 kg 60 #
Aerosil IP 0.500 kg 14 #
Calcium Stearate IP 0.750 kg 60 #
  • 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:
Test Specification
Appearance of blend

Blend Uniformity

Blend Assay

LOD

Bulk Density

Tapped Density

Compressibility Index

Hausner Ratio

 White color free flowing granular powder

90 % to 110 %

98 % to 103 %

1 %

To be established in next batch

To be established in next batch

To be established in next batch

To be established in next batch

STEP – 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. 
S.No Parameters Standard No. of Tablets In-Process Frequency
1.        Feed frame alignment and adjustment Should be satisfactory —– —–
2.        Lower Weight Assembly Should be satisfactory —– —–
3.        Hydraulic Pressure 6 -8 Tones —– —–
4.        Machine Speed 15 RPM to 18 RPM ­—– —–
5.        Upper Punch Size 20.5 mm x 9.0 mm with break line ­—– —–
6.        Lower Punch Size 20.5 mm x 9.0 mm —– —–
7.        Length of Tablets. 20.5 mm —– —–
8.        Width of Tablets 9.0 mm 6/Individual 2 hours
9.    Thickness of Tablets 6.70 mm ± 0.2 mm 6/Individual 2 hours
10.    Weight of 20 Tablets 28.900 gm. ± 2% 20/Composite 30 minutes
11.    Product Description White, elongated, biconvex shape, uncoated tablet having one side mid break line and other side plain 20/Composite 2 hours
12.    Uniformity of Weight NMT 02 tablets out of 20 deviate from the standard average weight by more than 3 % and  no single tablet deviates from the standard average weight by more than 5 % 20/Composite 01 hour
13.    Standard Average Weight of Tablets 1445 mg ± 2 % 20/Individual 30 minutes
14.    Hardness NLT 5 kg/cm2 6/Individual 30 minutes
15.    Disintegration Time NMT 15 min 6/Composite 01 hour
16.    Friability NMT 1% 20/Composite 01 hour
  • 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):

Sr. No. Material Name Batch Quantity (In kg)
1. Instacoat White Aqueous.III 4.335 kg
2. Purified water IP 21.750 liter

STEP-III (LIST OF EQUIPMENTS FOR COATING):

Sr. No. Machineries/Equipments Capacity Equipment ID.
1. Coating Machine and Coating Pan 42″
2. Spray Gun 02 —
3. Filter Cloth 100 # 0.5 meter —
4. Portable Stirrer — —
5. SS Container 30 liter (05 No’s) —
6. Poly-lined HDPE Containers with lid 45 liter (06 No’s) —

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.
Parameter Specification
No. of Baffles in coating pan 06
No. of Guns 02
Inlet Temperature 70°C to 75°C (To be validated in next batch)
Peristaltic Pump Speed 2- 4 RPM (To be validated in next batch)
Atomization 2.5 to 3.0 kg/cm2
Gun to Tablet Bed Distance 8 inch
BED Temperature 400C to 45 0C (To be validated in next batch)
Pan RPM 13 to 15 RPM
% Weight Gain (1 % to 1.5 %) Weight of Film Coated Tablets – Weight of Uncoated Tablets x 100 / Weight of Film Coated Tablets
 Film Coating Time 04 Hours (To be validated in next batch)
  • 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:
Sr.No. Parameters Standard No. of Tablets In-Process Frequency
1 Product Description White color, elongated  biconvex, film coated tablet having one side mid break line and other side plain 20 No.  

 

 

After batch completion
2 Weight of 20 Tablets after  seal coating  29.478 gm. + 3 % 20 No.
3 Average Weight after coating  1473.9 mg + 3 % 20 No.
4 Individual Tablets Weight Variation NMT 02 tablets out of 20 deviate from the standard average weight by more than 3 % and  no single tablet deviates from the standard average weight by more than 5 % 20 No.
5 Thickness 6.74 mm ± 0.2 mm 6 No.
6 Disintegration NMT 30 min. 6 No.

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).