MFR of Azithromycin 500 Tablets IP
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 | ||
| 6.4 | BRAND DETAILS | ||
1.0 PRODUCT DETAILS:
| Product Name | Azithromycin Tablets IP |
| Product Description | White color elongated biconvex, film coated tablet having one side mid break line and 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 | 700 mg (Uncoated tablets) 714 mg (Film coated tablets) |
| Shelf Life | 24 months |
| Storage | Store in a cool, dry and dark place below 250C |
| Drug Category | Macrolide Antibiotics |
2.0 MANUFACTURING FORMULA:
| Material Name | Grade | Category | Quantity per Unit (In mg) | Overages | Batch Qty.
(In kg) |
| Dry Mixing | |||||
| Azithromycin | IP | API | 500 mg | 5 % | 105.000 kg |
| MCCP Plain | IP | Diluent | 50 mg | —- | 10.000 kg |
| Binder | |||||
| PVPK-30 | IP | Binder | 4 mg | —- | 0.800 kg |
| Sodium Benzoate | IP | Preservative | 1.4 mg | —- | 0.280 kg |
| Sodium Starch Glycolate | IP | Binder | 20 mg | —- | 4.000 kg |
| Purified Water | IP | Diluent | 0.26 ml | —- | 52.000 liter |
| Lubricants | |||||
| Talcum | IP | Anti-caking agent | 14 mg | —- | 2.800 kg |
| MCCP PH-102 | IP | Diluent | 54.6 mg | —- | 10.920 kg |
| Cross Carmillose Sodium | IP | Disintegrant | 14 mg | —- | 2.800 kg |
| Crospovidone XL | IP | Disintegrant | 7 mg | —- | 1.400 kg |
| Aerosil | IP | Glidant | 3 mg | —- | 0.600 kg |
| Calcium Stearate | IP | Anti-Adherent | 7 mg | —- | 1.400 kg |
3.0 LIST OF EQUIPMENTS:
| Sr. No. | Machineries/Equipments | Capacity | Equipment ID. |
| 1. | Weighing Balance | 100 kg | |
| 2. | Vibro Sifter (with SS Sieves No’s 14,18,20, 40 and 60) | 30” | |
| 3. | Paste Kettle with stirrer | 100 liter | |
| 4. | Portable Stirrer | ||
| 5. | Multi Mill (screen size 2 mm and 8 mm) | — | |
| 6. | Rapid Mixer Granulator (RMG) | 160 liter | |
| 7. | Fluid Bed Dryer (FBD) | 120 kg | |
| 8. | Double Cone Blender | 400 liter | |
| 9. | Halogen Moisture Balance | — | |
| 10. | Compression Machine | 27 Station | |
| 11. | SS Containers | 10 liter, 20 liter,70 liter (,100 liter | — |
| 12. | Poly-lined HDPE Containers with lid | 65 liter | — |
| 13. | Polybags | 1.0 kg,2.0 kg,5.0 kg,20 kg |
4.0 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 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 from QA before starting the manufacturing operation during batch to batch and product to product change over.
- Do not overwrite any 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 and sieve the Dispensed Materials as per Sieve Sizes mentioned below:
| Material Name | Std. Qty. (kg) | Sieve No. |
| Dry Mixing | ||
| Azithromycin IP | 105.000 kg | 18 # |
| MCCP Plain IP | 10.000 kg | 60 # |
| Binder | ||
| PVPK-30 IP | 0.800 kg | 20 # |
| Sodium Benzoate IP | 0.280 kg | 20 # |
| Sodium Starch Glycolate IP | 4.000 kg | 60 # |
| Lubricant | ||
| Talcum IP | 2.800 kg | 60 # |
| MCCP PH-102 IP | 10.920 kg | 40 # |
| Cross Carmillose Sodium IP | 2.800 kg | 60 # |
| Crospovidone XL | 1.400 kg | 60 # |
| Aerosil IP | 0.600 kg | 14 # |
| Calcium Stearate IP | 1.400 kg | 60 # |
- 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) in two equal parts for LOT-I and LOT-II (5.000 kg each) and collect in two above Poly-lined HDPE Containers (capacity: 65 liter 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 liter) in Paste Kettle (capacity: 100 liter), heat the purified water to 350
- Take purified water (5.000 liter, at temperature 350C) from 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 upto 800C of Step-II (a) (37.000 liter) in Paste Kettle.
- Take purified water separately (10.000 liter, at room temperature) in SS Container (capacity: 20 liter) and add Sodium Starch Glycolate IP (4.000 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.
(f) Add Step -II (b) solution with continuously stirring to Step-II (c) till final paste is ready.
(g) Transfer the ready paste by tilting the Paste Kettle in one SS Container (capacity: 100 liter). Cool
the paste upto 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 liter each).
STEP – III (DRY MIXING): FOR LOT-I:
Transfer the sifted Azithromycin IP and MCCP Plain IP in Rapid Mixer Granulator (capacity: 160 liter) running at 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 in dry mix materials of Step – III in Rapid Mixer Granulator running at slow speed impeller for 5 minutes till binder addition. After binder addition run impeller and chopper both at slow speed for 08 min and finally run both chopper and impeller on fast speed 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-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 liter) and after screening transfer 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) 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 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-VII of LOT-I and LOT-II in Double Cone Blender (capacity: 400 liter) 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 |
| 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 % 1.0 % to 1.5 % To be established in next batch To be established in next batch To be established in next batch To be established in next batch |
STEP – X:
- Take Tare Weight of four 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: 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.
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.
| Sr. 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 | 17.5 mm x 8.0 mm with break line | —– | —– |
| 6. | Lower Punch Size | 17.5 mm x 8.0 mm | —– | —– |
| 7. | Length of Tablets | 17.5 mm | —– | —– |
| 8. | Width of Tablets | 8.0 mm | 6/Individual | 2 hours |
| 9. | Thickness of Tablets | 5.6 mm ±.2 mm | 6/Individual | 2 hours |
| 10. | Weight of 20 Tablets | 14.000 gm. ± 2% | 20/Composite | 30 minutes |
| 11. | Tablets for Dissolution | 700 mg ± 2% | 20/Composite | —– |
| 12. | Dissolution | NLT 80 % | —– | —– |
| 13. | Product Description | White color elongated, biconvex, uncoated tablet having one side mid break line and other side plain | 20/Composite | 30 minutes |
| 14. | 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 |
| 15. | Standard Average Weight of Tablets | 700 mg ± 2 % | 20/Individual | 30 minutes |
| 16. | Hardness | NLT 4 kg/cm2 | 6/Individual | 30 minutes |
| 17. | Disintegration Time | NMT 15 min | 6/Composite | 01 hour |
| 18. | 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 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 status label and after confirmation continue for tablet coating.
STEP – I (COATING MATERIALS DETAILS):
| Sr. No. | Material Name | Batch Quantity |
| 1. | Instacoat White Aq.III | 2.800 kg. |
| 2. | Purified Water IP | 16.800 liter |
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-II (LIST OF EQUIPMENTS FOR COATING):
| Sr. No. | Machineries/Equipments | Capacity/Size | Equipment ID. |
| 1. | Coating Pan and Coating Machine | 42″ | |
| 2. | Spray Gun | 02 | — |
| 3. | Filter Cloth 100 # | 0.5 mm | — |
| 4. | Portable Stirrer | — | — |
| 5. | SS Containers | 15 liter and 20 liter | — |
| 6. | Poly-lined HDPE Containers with lid | 45 liter (04 No’s) | — |
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 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:
- Coating will be done in two lots, divide total compressed tablets into two equal quantities for LOT -I and LOT -II (70.000 kg tablets for each lot).
- Load the tablets in 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.
| Parameter | Specification |
| No. of Baffles in coating pan | 06 |
| No. of Guns | 02 |
| Inlet Temperature | 60°C to 65°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 | 1.5 to 2.0 % |
| Coating Time | 2-3 Hour each (To be validated in next batch) |
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 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 (LOT) completion |
| 2 | Weight of 20 Tablets
after coating |
14.280 gm. ± 2 % | 20 No. | |
| 3 | Average Weight after coating | 714 ± 2% | 20 No. | |
| 4 | Individual Tablets Weight Variation | ± 3% | 20 No. | |
| 5 | Thickness | 5.61 mm ± 0.2 mm | 6 No. | |
| 6 | Disintegration | NMT 30 min. | 6 No. |
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).