Azithromycin 250 mg Tablets IP
TABLE OF CONTENTS
| S.NO. | TITLE | Page No. | |
| 1.0 | PRODUCT DETAILS | ||
| 2.0 | MANUFACTURING FORMULA | ||
| 3.0 | LIST OF EQUIPMENT | ||
| 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 | Azithromycin Tablets IP |
| Product Description | White color, round shape, biconvex, film-coated tablets having both side plain |
| Strength | 250 mg |
| Label claim
|
Each film-coated tablet contains:
Azithromycin(As Dihydrate) equivalent to Azithromycin Anhydrous – 250 mg |
| Batch Size | 2,00,000 Tablets |
| Average Weight | 347mg (Uncoated tablets)
354 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 | 250 mg | 5 % | 52.500 kg |
| MCCP Plain | IP | Diluent | 25 mg | — | 5.000 kg |
| Binder | |||||
| PVPK-30 | IP | Binder | 2.0 mg | — | 0.400 kg |
| Sodium Benzoate | IP | Preservative | 0.7 mg | — | 0.140 kg |
| Sodium Starch Glycolate | IP | Binder | 10.00 mg | — | 2.000 kg |
| Purified Water | IP | Solvent | 0.13 ml | — | 26.000 liter |
| Lubricant | |||||
| Talcum | IP | Anti-caking agent | 7.0 mg | — | 1.400 kg |
| MCCP PH-102 | IP | Diluent | 25 mg | — | 5.000 kg |
| Cross Carmellose Sodium | IP | Disintegrant | 7.0 mg | — | 1.400 kg |
| Crospovidone XL | IP | Disintegrant | 3.5 mg | — | 0.700 kg |
| Aerosil | IP | Glidant | 1.5 mg | — | 0.300 kg |
| Calcium Stearate | IP | Anti-Adherent | 3.5 mg | — | 0.700 kg |
3.0 LIST OF EQUIPMENT:
| Sr.No. | Machinery/Equipment | Capacity | Equipment ID. |
| 1. | Weighing Balance | 100 kg | |
| 2. | Vibro Sifter
(with SS Sieves No’s 14,18,20, 40 , 60) |
36 inch dia | |
| 3. | Paste Kettle with stirrer | 100 liter | |
| 4. | Portable Stirrer | — | |
| 5. | Rapid Mixer Granulator (RMG) | 120 liter | |
| 6. | Fluid Bed Dryer (FBD) | 120 kg | |
| 7. | Multi Mill (screen size 2 mm and 8 mm) | — | |
| 8. | Bin Blender | 150 liter | |
| 9. | Halogen Moisture Balance | — | |
| 10. | Compression Machine | 37 Station | |
| 11. | SS Containers | 10 liter (02 No’s),
70 liter (01 No.) 100 liter (02 No’s) |
— |
| 12. | Double Poly-lined HDPE Containers with lid | 45 liter( 08No’s)
65 liter (01 No.) |
— |
| 13. | Polybags | 1.0 kg (03 No’s)
5.0 kg (01 No.), 10 kg (01 No.) |
4.0 GENERAL PRECAUTIONS:
- API Description Azithromycin: 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 the entry. In case of mistake, cancel the entry by single line with sign & date and make correct entry.
6.0 MANUFACTURING PROCESS DETAILS:
6.1 GRANULATION:
STEP – I (SIFTING):
- Check Sieve Integrity (before and after sifting).
- Set the Vibro Sifter (capacity: 36 inch dia) and sieve the Dispensed Materials as per Sieve Sizes mentioned below:
| Material Name | Std. Qty. (kg) | Sieve No. |
| Dry Mixing | ||
| Azithromycin IP | 52.500 kg | 18 # |
| MCCP Plain IP | 5.000 kg | 60 # |
| Binder | ||
| PVPK-30 IP | 0.400 kg | 20 |
| Sodium Benzoate IP | 0.140 kg | 20 |
| Sodium Starch Glycolate IP | 2.000 kg | 60 # |
| Lubricant | ||
| Talcum IP | 1.400 kg | 60 # |
| MCCP PH-102 IP | 5.000 kg | 40 # |
| Cross Carmellose Sodium IP | 1.400 kg | 60 # |
| Crospovidone XL | 0.700 kg | 60 # |
| Aerosil IP | 0.300 kg | 14 # |
| Calcium Stearate IP | 0.700 kg | 60 # |
- Collect sifted Azithromycin IP (52.500 kg) and MCCP Plain IP (5.000 kg) in one Poly-lined HDPE Container (capacity: 65 liter).
- Collect sifted PVPK-30 IP (0.400 kg) in one Polybag (capacity: 1.0 kg).
- Collect sifted Sodium Benzoate IP (0.140 kg) in one Polybag (capacity: 1.0 kg).
- Collect sifted Sodium Starch Glycolate IP (2.000 kg) in one Polybag (capacity: 5.0 kg).
- Collect sifted Talcum IP (1.400 kg), MCCP PH-102 IP (5.000 kg), Cross Carmellose Sodium IP (1.400 kg), Crospovidone XL IP (0.700 kg), Aerosil IP (0.300 kg) in one Polybag (capacity:10 kg).
- Collect sifted Calcium Stearate IP (0.700 kg) in one Polybag (capacity: 1.0 kg).
STEP – II (BINDER PREPARATION):
- Take purified water (21.00 liter) in Paste Kettle (capacity: 100 liter), heat the purified water up to 350
- Take purified water (3.000 liter, at temperature 350C) from Paste Kettle of Step-II(a) in SS Container (capacity: 10 liter) and add Sodium Benzoate IP (0.140 kg) and PVPK-30 IP (0.400 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) (18.000 liter) in Paste Kettle.
- Take purified water separately (5.000liter, at room temperature) in SS Container (capacity: 10 liter) and add Sodium Starch Glycolate IP (2.000 kg) slowly continuously stirring till uniform solution is ready.
- Add above solution of Step – II (d) to heated purified water of Step -III (c) in Paste Kettle with continuously stirring till uniform paste is ready.
- Add Step -II (b) solution with continuously stirring to Step-II (c) till final paste is ready.
- Transfer the ready paste by tilting the Paste Kettle in one SS Container (capacity: 70 liter). Cool the paste upto 35°C to 40°C.
STEP – III (DRY MIXING):
Transfer the sifted Azithromycin IP and MCCP Plain IP in Rapid Mixer Granulator (capacity: 120 liter) running at slow speed impeller (0.82 ampere) and dry mix the materials till uniform mixing.
Mixing Time: 05 minutes.
Mixing Speed: 05 minutes at slow speed.
Ampere Load of Impeller: 0.82 ampere.
STEP –IV (BINDING OF DRY MIX MATERIAL):
Slowly add the binder of Step-II (g) in dry mix materials of Step -III in Rapid Mixer Granulator running at
slow speed impeller (1.02 ampere)for 05 minutes till binder addition. After binder addition run impeller and
chopper both at slow speed (0.63 ampere) for 05 minutes and finally run both impeller and chopper 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: 12 minutes
Ampere Load of Impeller: 0.62 to 1.02 ampere.(To be validated in next batch)
STEP-V (WET SCREENING):
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 that transfer the wet material in a FBD bowl.
STEP –VI (DRYING):
Dry the wet material of Step-V in FBD (capacity: 120 kg) until the LOD of granules is achieved between
- to 1.5 % at 105°C checking by Halogen Moisture Balance and after drying unload the material in two
Poly-lined HDPE Containers (capacity : 45 liter each).
Inlet Temperature: 65°C
Outlet Temperature: 45°C
Raking Frequency: After 30 minutes.
Drying Time: 02 Hours.
STEP-VII (SIZING/MILLING):
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 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.
STEP – VIII (PRE –LUBRICATION):
Load the sized granules of Step-VII in Bin Blender (capacity: 150 liter) and add sifted Talcum IP,
MCCP PH-102 IP, Cross Carmillose Sodium IP, Crospovidone XL and 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 Material 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 free flowing granular powder
90 % to 110 % 95 % to 105 % 1.0 % to 1.5 % 0.6250 gm/ml 0.7500 gm/ml 16.667 % 1.2000 |
STEP – XI:
- Take Tare Weight of two Double Poly-lined HDPE Containers (capacity: 45 liter each), record the Tare Weight in BMR and unload the above blended material from Bin Blender in Double 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: 100 %
Actual Batch Yield Limit 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.
- Set the 37 stations (D-Tooling) Compression Machine. Compress the blend as per below parameters and In Process checks and take a sample for Dissolution (Qty. 20 tablets) and send to QC Department for Dissolution Analysis.
- After confirmation of Dissolution result continue the compression with 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 | 18 RPM -20 RPM | —– | —– |
| 6. | Upper Punch Size | 11 mm | —– | —– |
| 7. | Lower Punch Size | 11 mm | —– | —– |
| 8. | Avg.- Diameter | 11 mm | 6/Individual | 2 hours |
| 9. | Thickness of Tablets | 3.70 mm ±.2 mm | 6/Individual | 2 hours |
| 10. | Weight of 20 Tablets | 6.940 gm. ± 3% | 20/Composite | 30 minutes |
| 11. | Tablets for Dissolution | 347 mg ± 2% | 20/Composite | Before starting the Compression |
| 12. | Dissolution | NLT 80 % | —- | —- |
| 13. | Product Description | White , round biconvex, uncoated tablets having both 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 | 347 mg ± 2 % | 20/Individual | 30 minutes |
| 16. | Hardness | NLT 3 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 Double Polylined SS Container (capacity: 20 liter each on both sides), when SS containers are filled with tablets, transfer the tablets in two 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 two Double 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: 100 %
Actual Batch Yield Limit 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):
| Sr. No | Material Name | Batch Quantity |
| 1. | Film Coat Aqua White Powder | 1.388 kg. |
| 2. | Purified Water IP | 12.042 liter |
STEP-II (LIST OF EQUIPMENTS FOR COATING):
| Sr. No. | Machineries/Equipments | Capacity | Equipment ID. |
| 1. | Auto coater | 48″ | |
| 2. | Spray Gun | 03 | — |
| 3. | Filter Cloth 100 # | 0.5 mm | — |
| 4. | Portable Stirrer | — | — |
| 5. | SS Containers | 15 liter (02 No’s) | — |
| 6. | Double Poly-lined HDPE Containers with lid | 45 liter (02 No’s) | — |
STEP – III (PREPARATION OF COATING SOLUTION):
- Take Purified Water IP (12.042 liter, at room temperature) in SS Container (capacity: 15 liter) and add Film Coat Aqua White Powder (1.388 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: 15 liter).
- Keep the solution for 15 minutes to let the foam settled down. Thereafter transfer the coating solution in SS tank and proceed with coating process.
STEP – IV (COATING PROCEDURE FOR FILM COATING):
- Coating will be done in one lot (for 2,00,000 tablets), take total compressed tablets for coating (69.400 kg).
- Start the pan, inlet damper and then start exhaust blower to maintain the bed temperature by press the heater “ON” position.
- Press the hot air blower switch to start the hot air blower.
- Start the coating pan and adjust the distance between tablet bed and gun and introduce the spray gun assembly into the coating pan
- Load the tablets in Auto coater (Capacity: 48″), 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 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 | —- |
| No. of Guns | 03 |
| Inlet Temperature | 70°C to 75°C |
| Peristaltic Pump Speed | 2- 4 RPM |
| Atomization | 2.5 to 3.0 kg/cm2 |
| Gun to Tablet Bed Distance | 7 to 10 cm |
| BED Temperature | 400C to 45 0C |
| Pan RPM | 13 to 15 RPM |
| % Weight Gain
(1.5 % to 2.0 %) |
Weight of Film-Coated Tablets – Weight of Uncoated Tablets x 100
Weight of Film-Coated Tablets |
| Coating Time | 2 Hours |
- 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-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, round biconvex, film coated tablet having both side plain | 20 No. |
After batch completion |
| 2 | Weight of 20 Tablets after coating | 7.080 gm. (+2 % Weight Gain) | 20 No. | |
| 3 | Average Weight after coating | 354 mg (+2 % Weight Gain) | 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 | 3.71 mm ± 0.2 mm | 6 No. | |
| 6 | Disintegration | NMT 30 min. | 6 No. |
STEP – VI:
- Send the Composite sample of coated tablets (Qty. 50 tablets) to QC department for analysis.
STEP – VII:
- Take Tare Weight of two Double Poly-lined HDPE Containers (capacity: 45 liter each), record the Tare Weight in BMR and transfer the coated tablets in Double 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, Date, Exp. Date, Tare Weight, Gross Weight and Net Weight on the Poly-lined HDPE Containers.
- Batch Yield of Coated Tablets:
Theoretical Batch Yield: 100 %
Actual Batch Yield Limit NLT 99 % (To be established in next batch).