Batch Manufacturing Record(BMR)

Product Name: Atorvastatin  calcium equivalent to Atorvastatin 10 mg
Batch Size:2000000 tablets

Composition

Each film-coated tablet contains: Atorvastatin  calcium equivalent to Atorvastatin 10 mg

Checklist of BMR

1. Check Points
2. Batch release and composition
3. Checklist of BMR
4. General instruction
5. Line clearance check for  dispensing
6. Dispensing sheet of Raw Material
7. Dispensing sheet of Coating Material
8. Calculation of Material
9. General instruction for manufacturing
10. Equipment required for manufacturing

Manufacturing  Process

1. Line clearance of granulation
2. Affix dispensing label
3. Manufacturing process
4. Line clearance check for blending
5. Blending
6. Weight and reconciliation record of blend
7. Analysis requisition sheet for blend analysis

Compression Process

1. Compression general  instruction
2. Line clearance  for compression
3. Initial checks  for compression parameters & metal detector  performance record
4. Start-up checks
5. In-process checks(RH.S)
6. In-process checks(L.H.S.)
7. Uniformity of  weight
8. Weight record of compressed tablets. Reconciliation
9. Analysis requisition sheet

Coating process

1. Line clearance for the coating process
2. Affix coating material dispensing label
3. Coating process & parameter record
4. Weighing record of coated tablet. Reconciliation of coated tablet
5. Analysis  Requisition sheet
6. Tablet inspection
7. Reconciliation of inspected tablet
8. Documentation reconciliation

General Instructions

Dispensing of Raw material

1.  Use a nose mask and hand gloves during the operation.
2. Check for line clearance, and cleanliness of the area  equipment and record the observations
3. Check the temperature %RH  & differential pressure  of  dispensing area (20-25°c , 50±20%  NLT 1.2 mm of water)
4. Check for qc approved label and necessary details (material name, item code, manufacturer’s name, B.no, MFG, EXP, A.R No, retest date, etc.) on the raw material container before weighing.
5. Check and transfer the raw material required for the batch near the dispensing booth.
6. Operate dispensing booth as per current SOP. Dispense the excipients first, and remove them from the dispensing area prior to active ingredient dispensing.
7. Make necessary entries in the manufacturing work order and the  store ledgers
8. Attach the duly filled dispensed material label to the dispensed raw material and transfer the dispensed material to dispensed material quarantine area.

Line clearance check for Dispensing of Raw Materials 

1. Is the temperature 20-25°c? Actual Temperature
2. Is the Humidity 50±20%RH?
3. Is the pressure differential NLT actual 1.2
4. Is the room clean where the material to be dispensed kept?
5. Is the LAF table cleaned and switched on at least 15 minutes before starting dispensing?
6. Are all the materials of the previous batch/ product been completely removed including dust bins?
7. Is the balance clean and calibrated?
8. Do all the materials to be dispensed have approved status?
9. Are all the dispensing devices clean & ready for use?
10. Are polybags of various sizes required for dispensing materials available?
11. Is the copy of said BMR relevant to dispensing available?

Sr.No	Ingredients	Spec.	Std. qty
									Polyvinyl Pyrrolidone  K 30(Kollidon K 30)	EP/BP	1.000
	Isopropyl Alcohol	EP/BP	8.00
Lubricant
	Colloidal Anhydrous  Silica (Aerosol 200)	USP	1.000
	Croscarmellose sodium (Ac-di-SD-711)	USP	1.400
	Magnesium Stearate	EP/BP	0.600

Coating material issue note:

Sr.No	Ingredients	Spec.	Std. qty
									Opadry pink	IH	1.000
	purified water	EP/BP	5.00

Water contents shall be compensated on the basis of the actual %of water in API.  If the assay of the API is more than 100%  the standard quantity of Atorvastatin calcium shall be taken Atorvastatin calcium should be micronized& the particle size of Atorvastatin calcium should be d90 below 50 microns.

Theoretically, 10.85 mg of Atorvastatin calcium is equivalent to 10 mg of Atorvastatin.

Quantity of Microcrystalline Cellulose to be adjusted based on  actual assay & % w/w  water content of Atorvastatin calcium

Calculation of material required for a single A.R no for the standard batch size 

Calculation of Atorvastatin  calcium(For Single A.R.No)

A.R.No of Atorvastatin  calcium ,Assay on Dried Basis (ODB)——-%w/w ,LOD——–%w/w

The standard quantity of Atorvastatin calcium for batch on 100% Basis(Q)in Kgs i.e. 2.17 Kgs for 200000 tablets batch size as per BMR.

Actual Quantity to be issued  Std Qty (Q) *100*100

against of Atorvastatin  calcium (Q1)in Kgs  =  Assay on (ODB)*(100-LOD)

Note: if the quantity of Atorvastatin calcium is insufficient for the batch then proceed with under mentioned calculation.

Calculation of material required if the material available is not sufficient from one Batch or Lot, then the calculation of the next  Lot/Batch shall be performed as under.

From first A.R No. quantity of batch available (Q1) which is insufficient for the batch & in this case remaining quantity shall be taken from another batch A.R No along with Q1 for 100% assay basis by the following expression.

A.R No of  Atorvastatin  calcium, Assay on Dried basis (ODB) ——%w/w, LOD——-% w/w

Quantity available Atorvastatin  calcium =  Kg

Available Quantity on 100% basis  of Atorvastatin   =  Quantity available * 100*100/Assay (ODB)*(100-LOD)

calcium in Kgs(Q1)————————————— = Kgs

Further, use the following  expression to calculate the quantity of additional Atorvastatin  calcium quantity required from the next batch or Lot 

A.R No. of Atorvastatin calcium ————– Assay on Dried basis (ODB) ——%w/w LOD——-% w/w

Quantity required of Atorvastatin calcium another lot or batch at 100% basis in Kgs (Y)=Std. Quantity reqd. for the batch – Quantity for 1st  lot/batch. = ———-Kgs.

Available Quantity to be

issued against Atorvastatin   = Std. quantity (Y)*100*100

calcium (Y1)in Kgs                           ————————————— = Kgs

Assay on (ODB)*(100-LOD)

Total Quantity issued in Kgs

Note: if more than two batches are required then the calculation follows these steps.

Adjustment or statement batch size in Kgs. 

The actual quantity of Atorvastatin calcium is to be calculated on the basis of assay and water of the drug and the quantity is to be compensated with microcrystalline cellulose (Avicel PH101).

The actual quantity of Atorvastatin  calcium – Standard quantity of Atorvastatin  calcium = Kgs

Standard  qty. of microcrystalline cellulose -quantity =Kgs

General instruction for Manufacturing 

During the operation, all personnel of the manufacturing area should wear clean uniforms, caps, nose masks, and hand gloves.

Check the relative humidity, temperature, and pressure difference and record where ever necessary & should be Temp 20-25ºc  & RH 50±20%, PD -NLT 1.2 mm water.

Check the line clearance, cleanliness of the area, and equipment.

Cross-check the weight of the material before taking it up to manufacturing against the dispensing label and status label.

In case of any deviations in the process, intimate to the QA and take approval from the QA  for the same.

Whenever there is a machine breakdown during processing, rectify the machine and take again line clearance from QA before starting the operation.

Holding time

Dispensed materials: 15 days from the date of dispensing.

Blend: Compression to be completed within 15 days from the date of quality control approval.

Compressed tablets: To be coated within 30 days from the date of compressed tablets’ approval by QC.

Coated tablets: Packing is to be completed within 45 days from the date of approval by QC.

Equipment Required

1. S.S Scoops & Inprocess plastic containers
2. Dispensing cabinet
3. Vibratory sifter
4. Fluid bed processor
5. Conta blender
6. Tablet compression machine
7. Deduster
8. Metal Detector
9. Dust collector
10. Lifting & positioning device
11. Friability Apparatus
12. Digital hardness tester
13. Disintegration test apparatus
14. Vernier  caliper
15. Balance
16. Auto coater machine
17. Solution preparation tank
18. Colloidal mill
19. Tablet inspection machine

Line Clearance for Granulation

1. is the temperature 20-25°c? Actual Temperature
2. is the Humidity 50±20%RH actual
3. is the pressure differential NLT 1.2 Actual
4. is the room clean, where the material to be processed is kept & where the processing is to be done?
5. Does all the equipment have cleaned status labels & is the cleaning in the validity periods?
6. Are all the materials of the previous product/batch been removed including the dust bin
7. Are all the documents /papers  for the previous product/batch been removed
8. Is the BMR for the same product & required batch available?
9. Are all the materials issued of the required batch & product only?

Manufacturing Process

Sifting

Sievesintegrity checked (Before sifting) Set sifter with 40 sieves and sift & mix Atorvastatin Calcium Micronized Standard Quantity 2.17 kg Calcium Carbonate (PPT)(Calopake extra light) Standard Quantity 1.000 kg

Set the sifter  with 40 # sieves & mix with Microcrystalline Cellulose (Avicel PH 101) Standard Quantity 10.93kg

Lactose Monohydrate (Pharmatose 200M)

Standard Quantity 10.93kg

Collect sifted material in a polyline container and Check the sleeve integrity # 40 after sifting

Preparation of binding solution

Collect in a SS vessel

Isopropyl Standard Quantity 8.00kg

Add slowly into isopropyl alcohol following material under stirring Polyvinyl Pyrrolidone K 30(Kollidon K 30)___Kgs

Standard Quantity 1.000kg

Stir the solution until the Polyvinyl Pyrrolidone K 30(Kollidon K 30) is completely dissolved

Granulation

Set FBP & load in top spray product container,sifted materials from 10 min at 20 rpm

Mixing starting at Mixing over at Blower speed

Set the parameters as given in the following table

Parameters	Set
Inlet temperature	30°-65°c
Bed temp.	20°-35°c
Blower speed	20-40Hz
Peristaltic pump speed	20-80 rpm

Granulate material by spraying with binder and with continuous drying. Dry the granules till the LOD of the granules is NMT 3.0% by halogen moisture balance

Granulation Time

From________To_____________

LOD(NMT 3.0%)

Upload the dried granules in polyline containers

Line clearance for Blending

1. is the temperature 20-25°c? Actual Temperature
2. is the Humidity 50±20%RH actual
3. is the pressure differential NLT 1.2 Actual
4. is the room clean, where the material to be processed is kept & where the processing is to be done?
5. Does all the equipment have cleaned status labels & is the cleaning in the validity periods?
6. Are all the materials of the previous product/batch been removed including the dust bin?
7. Are all the documents /papers  for the previous product/batch been removed
8. Is the BMR for the same product & required batch available?
9. Are all the materials issued of the required batch & product only?

Blending

Set sifter with 40# sleve for lubricant and sift Colloidal Anhydrous Silica____Kgs

Croscarmellose  sodium__________________________Kgs

Set sifter with 60# sleve and sift Magnesium Stearate ___________ Kgs

Collect sifted material in a polyline container and Check the sleeve integrity # 40 after sifting

Blending

Fit IPC container to Conta Blender.

Load dried granules & lubricants in conta blender. Mix it for 15 minutes at 9 RPM speed.

Total Blending time(Std time 15 min.)

Weigh the material. Affix the label on the IPC. Transfer it to blend hold room

Lubricant Granules Reconciliation 

1. Theoretical weight of the lubricated granules
2. Actual weight of granules
3. QC samples
4. In-process check loss
5. Process loss
6. Actual percentage yield B*100/A  =   —–  =    ——  Kgs
7. Reconciliation yield (B+C+D)*100/A  = —– = —— %

Send dully filled analysis requisition to QC Department to collect the sample  for analysis

Blend Analysis Test Report

A.R No

Test	Standard Specification
Description	White color granule powder
Essay	Atorvastatin  calcium 95-105% of LC
Report	The sample complies/does not comply with the specification number

Compression

1. Bring approve blend into the Compression area
2. Attach metal detector unit after de-duster of compression M/C at both sides (LHS & RHS). Check the performance of the metal detector at every start of the operation & every 4 hours during compression using 0.2 mm ferrous & 0.4 mm Non-ferrous blocks & record the observation.
3. Compress the blend using upper punches 7.0 mm round, standard, concave embossed with «10» & lower punch 7.0 mm round, standard, concave plain.Set the parameters of compressed tablets as per the parameter mentioned below

Destroy the compressed tablets of the initial two rotations

Carry out the initial checks before starting the operations as specified in the specification given.

Check and enter the individual weight of 37/45 tablets from RHS & LHS separately   in the formats provided

Check the record of the Thickness  & Hardness, DT, Friability, and group wt of 20 tablets.

Check and enter the uniformity weight of 20 tablets from LHS  as well as  RHS in the prescribed format.

Collects the tablets in a double polythene cover-lined, tightly closed, container. weigh each container & record the weight in the given format

Line Clearance Checks for Compression Process 

1. is the temperature 20-25°c? Actual Temperature
2. is the Humidity 50±20%RH actual
3. is the pressure differential NLT 1.2 Actual
4. is the room clean, where the material to be processed is kept & where the processing is to be done?
5. Does all the equipment have cleaned status labels & is the cleaning in the validity periods?
6. Are all the material of the previous product/batch been removed including the dust bin
7. Are all the documents /papers  for the previous product/batch been removed
8. Is the BMR for the same product & required batch available?
9. Are the bags fixed to dust collectors’ dedicated ones
10. Do the bins containing granules for the compression are of the relevant product/batch number and do bins have released status?
11. Are the metal detector challenged?
12. Is the startup test as per BMR?

Initial Checks

Description	White to off-white, round-shaped coated tablets embossed with «10» on one side and plain on another side.
Weight of 20 tablets	2.90gm /±3.0%
Average weight	145.00mg ±3.0%
Thickness	3.60mm±0.2mm
Diameters	7.10 mm
Hardness	NLT 20Kgs
Disintegration time	NMT 15 min
Friability	NMT 1%

Performance Checks for Metal Detector 

Frequency: at every start of the operation & every 4 hours during compression

Size of Metal Block : 0.2 mm (ferrous) & 0.4 mm (Non ferrous)

In-process Check records 

Limit	2.90gm±3.0%(2.813-2.97)	3.60±0.2mm (3.40-3.80mm)	NLT 2.0 Kgs (4.48kp)	NMT 1%	NMT 15 min
Frequency	½hourly	hourly	2hourly	2 hourly	2 hourly

Uniformity of Weights 

	Limit of variation from the average weight ± 7.5%
Individual Weight	To be checked after 2 hour

Reconciliation of compressed Tablet

1. Stage
2. Theoretical
3. Weight of granules received for compression
4. Weight of the compressed tablet
5. Tablets send to Quality Control
6. In process sample
7. Loss during compression
8. Actual percentage yield
9. Reconciliation percentage yield
10. Reconciled by (Production)

Send dully filled analysis requisition to Q.C Department to collect the sample for analysis
Requisition analysis sheet sent by

Coating  Process

1. is the temperature 20-25°c? Actual Temperature
2. is the Humidity 50±20%RH actual
3. is the pressure differential NLT 1.2 Actual
4. is the room clean, where the material to be processed is kept & where the processing is to be done?
5. Does all the equipment have cleaned status labels & is the cleaning in the validity periods?
6. Are all the materials of the previous product/batch been removed including the dust bin
7. Are all the documents /papers  for the previous product/batch been removed
8. Is the BMR for the same product & required batch available?
9. Ensure that the container containing tablets for coating has released status
10. Is the startup test as per BMR?

Coating Process

Parameters	Limits
Room Temperature	20-25°c
Pressure Differential	NLT 1.2
Relative Humidity	50±20%

Preparation of Solution

In the solution preparation tank add and prepare the solution of the following materials

• Opadry Pink
• Std. Qty. 1.000 Kgs
• Purified water
• Std. Qty. 5.00 Kgs
• Stir the solution for 1 hour

Coating

Load the tablets in a coating pan. Start the hot water blower, and set the supply air temperature at 65 -80°c. Start the exhaust fan, and warm the tablet bed to 45°c.

When the exhaust temp reaches 45°c, adjust the spray gun, and start the peristaltic pump with the coating solution. Spray the solution on a rolling tablet bed; simultaneously keep on drying the tablets. continue coating till the solution gets exhausted.

Continue coating as per the following parameters

S.no	Parameters	Specification
1	Pan speed	3-6 rpm
2	Peristaltic pump	6-15 min
3	inlet temperature	65°c-80°c
4	Exhausted temperature	45°c-55°c

Upload the tablet in a polyline container and weigh it. Check  & record the above parameters of coated tablets

Parameters: 
Description: Pink, circular, biconvex film-coated tablets with«10» embossed on one side and plain on another side.
Weight of 20 tablets:3.00±3.0%(2.91-3.09 gms)
Average tablet:150 mg± 3.0%
Thickness:3.70±2.0mm
Disintegration Test: NMT 30 min

Reconciliation of  Coated Tablet

1. Stage
2. Theoretical
3. Tablet received for coating
4. QC sample
5. In the process check the loss
6. Loss during coating
7. Actual percentage yield
8. Reconciliation percentage yield
9. Reconciled by (Production)

Send dully filled analysis requisition to Q.C Department to collect the sample for analysis

The requisition analysis sheet was sent by t Inspection

1. Use a nose mask and hand gloves during the operation.
2. Check for line clearance, and cleanliness of the area  equipment and record the observations
3. Transfer the coated tablet into the tablet inspection area.
4. Transfer the required qty. of tablets into the hopper of the tablet inspection machine
5. Inspect each tablet for any defects and segregate the goods and rejected one
6. Keep the inspected tablets in a double polyethylene bag lined drum, weigh and record

Line clearance (Tablet Inspection)

• is the temperature 20-25°c? Actual Temperature
• is the Humidity 50±20% RH actual
• is the pressure differential NLT 1.2 Actual
• is the room clean, where the material to be processed is kept & where the processing is to be done?
• Does all the equipment have cleaned status labels & is the cleaning in the validity periods?
• Are all the materials of the previous product/batch been removed including the dust bin
• Are all the documents /papers  for the previous product/batch been removed
• Are the remnants of the previous batch/product removed?
• Is the area clean & dirty?
• Are relevant status labels affixed?
• Equipment clean (check visually or wash water reports)?

Tablet Inspection Record

Container No
Weight of tablets
Wt. of tablets after inspection
Rejected tablets

Reconciliation of inspected tablets

• Stage
• Theoretical
• Tablet received for inspection
• Inspected tablets
• Rejection Tablets
• Actual percentage yield
• Checked by

Document  Reconciliation

No. of BMR pages
No. of additional pages
No. dispensing labels

BATCH RELEASE 

REMARKS: All content of the batch record has been checked, reviewed & found to comply/not compiling with the proper requirements .as per in-process check records & analytical data submitted by quality control the product complies/does not comply with specifications. Hence the batch can/cannot be released for further manufacturing stage.

 QA Head