Drugsformulations

Cefazolin Sodium for Injection 1000mg

GENERAL INSTRUCTIONS:

• Good manufacturing practices should be followed during the entire process of manufacturing including sampling and dispensing.
• All the containers and equipment used for manufacturing shall be properly cleaned as per the relevant SOP of the current version.
• All the equipment and containers should have a proper status label with Product name, Batch No., Mfg. Date, Exp. Date., etc.
• All the equipment should be operated as per the relevant current version SOPs only.
• All the measuring equipment and containers should be calibrated irrespective of the activity and use within the date of calibration as per the calibration schedule.
• Weights of all the materials should be cross-checked by production personnel against dispensing labels and dispensing sheets before being taken up for manufacturing.
• Overwriting in BPR shall be strictly avoided.
• All the activities should be carried out according to the respective BPR only. All the operations shall be carried out in a clean and orderly manner.
• Any deviation in the process shall be brought to the knowledge of the QA In charge and prior approval of the QA In charge should be taken.
• Critical parameters like temperature, Relative Humidity, and pressure differences should be checked and monitored during all manufacturing stages.
• In-process controls should be carried out throughout manufacturing operations as per relevant BPR and relevant current version SOPs.
• Ensure that all materials like raw materials, in-process materials, and finished products should be placed in respective areas with the proper status labels.
• Attach additional sheets wherever required.
• Attach system-generated data recording sheets wherever applicable.
• Gowning should be as per the current version SOP while processing.
• Masks and hand gloves should be used during processing.
• Check for line clearance, cleanliness of the area, and equipment.
• Calibrated weighing scales shall be used while processing.
• Attach printouts wherever applicable.
• Avoid direct product contact.
• In the checklist write OK if complies, not OK if not complies, and write NA if the step is not applicable.
• Do not perform any cleaning activity if the area is under manufacturing process.

LABEL CLAIM  :

Each vial contains:

Cefazolin Sodium USP

Eq. to Cefazolin ……………..1000mg

Storage Condition – Store in a cool dry place. Protect from light

Shelf Life –  36 Months 

Brand Name

Product Manufactured For

Work Order Number

Batch Size:

Mfg. Date:

Exp. Date:

Market

License No.

Type and Size of Vial

Colour of Vial

M.R.P. (Inclusive of All Taxes)

Final Batch Yield

NUMBER OF PERSONNEL INVOLVED IN BATCH MANUFACTURING:

Note: The person which is involved in the whole process from Dispensing to Final Packing, enter her/his name, Emp. Code, Department, and Sign and Date in the below table.

EQUIPMENT DETAILS:

API CALCULATION:-

Detail of API Stock use for Batch

Factor Calculation

Mol wt of Cefazolin Sodium:476.5

Mol wt of Cefazolin: 454.5

Factor  = 476.5/454.5 = 1.048gm

The calculation for Target Fill Weight:

Quantity required as per AR No. 1 = Label Claim in gm. X Factor X 100 X 100 X Batch Size in no of vials

Assay X (100 – LOD) X 1000

                             X 1.048 X 100 X 100 X                                 .          =____________ Kg.

X (100 –__________ ) X 1000

Required as per AR1 – Stock of AR1 =  Required from AR2 as per AR1

____________ Kg. – ___________ Kg. =____________ Kg.    (Required from AR2 as per AR1)

Required from AR2:

Required from AR2 as per AR1 X Assay of AR1X (100 – LOD of AR1)   = ____________ Kg

Assay of AR2 X (100 – LOD of AR2)

                                     X                          X (100 –                        )      = ____________ Kg

_____________X (100 – ____________)

Required as per AR2 –Stock of AR2 =  Required from AR3 as per AR2

____________ Kg. – ___________ Kg. =____________ Kg.    (Required from AR3 as per AR2)

Required from AR3:

Required from AR3 as per AR2 X Assay of AR2X (100 – LOD of AR2)   = ____________ Kg

Assay of AR3 X (100 – LOD of AR3)

                                     X                          X (100 –                        )      = ____________ Kg

_____________X (100 – ____________)

Required as per AR3 –Stock of AR3 =  Required from AR4 as per AR3

____________ Kg. – ___________ Kg. =____________ Kg.    (Required from AR4 as per AR3)

Required from AR4:

Required from AR4 as per AR3 X Assay of AR3X (100 – LOD of AR3)   = ____________ Kg

Assay of AR4 X (100 – LOD of AR4)

                                     X                          X (100 –                        )      = ____________ Kg

_____________X (100 – ____________)

Target Filled weight = [(AR1 + AR2+ AR3+AR4)/Batch size in Numbers] x 1000000

=[(              +                +              +                )/____________] x1000000 = _____________ mg/ vials

LINE CLEARANCE FOR DISPENSING AREA USED FOR RM DISPENSING:

Note:  Warehouse personnel shall write in the observation column whether OK or not OK and NA if the step is not applicable and IPQA personnel shall verify the same.

DISPENSING OF RAW MATERIAL :

Note: An intact container shall be issued to production. The detail of Weight verification shall be verified and written inside the Dispensing and sampling booth present near the filling area under RLAF. After completion of filling the tare weight and net weight shall be checked by production and verified by IPQA.

LINE CLEARANCE FOR DISPENSING AREA USED FOR PRIMARY PACKING MATERIAL:

Warehouse personnel shall write in the observation column weather OK or not OK and NA if the step is Not applicable and IPQA personal shall verify the same.

• DISPENSING OF PRIMARY PACKAGING MATERIAL
  • PACKING MATERIAL REQUISITION SHEET: (Production Copy)

                        Requisitioned By Prod. (Sign. /Date):_____________________

       Batch Size: ____________ (Nos)                                                                  Date: __________________                         

MANUFACTURING

Instruction:

• Ensure all the received shipper have Approved label has been affixed.
• Received Shipper pack of the Vials shall be De- shippered in material Receiving Area (Lift Area)
• De-shippered, Vials shrink pack shall keep into the Bottle Loading Area by using Trolley.
• Ensure and check for the damaged shrink pack (if any damage shrink pack found returned it to Warehouse department for replacement).
• Load the Vials on Loading table and check for the Defects as per respective SOP , Title: Decartoning and empty Vial Inspection, if any Defects are found place them in to the rejection Bin provided.

Line Clearance Check-list for Vial De-cartoning & Inspection

• Check and ensure the cleanliness of area, inspection table & waste bin
• Area is free from any remnants of previous activity and batch materials.
• Check and ensure that the log book of area and equipment are completed and signed off.
• Ensure the type and size of the issued vials
• Check and ensure that the quantity of the vials issued is available.
• Details on equipment / Containers status labels match with BPR details.
• Check and ensure that the status labels in the area are maintained.
• Check & ensure that the rejection tray with status is available.

Vial De-cartoning Procedure

• De-pack / de-carton the shippers / cartons as per Respective SOP.
• Load vials on the inspection table. Inspect the vials visually and pass them to vial washing machine through swing conveyor.

De-Cartoning And Inspection of Empty Vials Record:

Total Rejection ___________________________

Issued quantity from store – Total  Rejection = Total transfer quantity for washing

VIALS WASHING, VIAL STERILIZATION & DE-PYROGENATION

Line Clearance Check-list for Vial Washing

• Line properly identified.
• Floor and surrounding area neat and clean.
• All equipment clean and free from foreign material.
• Status Label is filled with current batch details.
• Details on equipment / Containers status labels match with BPR details.
• Washing nozzles are working properly.
• Pump and air pressure of water and air is satisfactory.
• Check and ensure the cleanliness of area and Vial Sterilization & Depyrogenation Tunnel
• Check and ensure the batch entries (batch no., mfg. date, exp. date, vial type) are correct as per respective batch.
• Check and ensure that the BPR is completed till the activity
• Check and ensure that the calibration and validation status of all equipment is within validity periods
• Check and ensure PLC set parameters for the vial type to be sterilized are as per the required size of vials
• Details on equipment / Containers status labels match with BPR details.
• Check and ensure that internal cleaning of the tunnel has been done as per the predefined frequency and no previous product is present.
• Check & ensure the DP in the Magnehelic gauge is within the limit

TEMPERATURE AND RELATIVE HUMIDITY RECORD

LIMIT: Temperature NMT25°C and Relative Humidity NMT 55% (As Per Area Monitoring SOP). Temperature and Relative Humidity Should be checked during starting of the activity and every 2 hours.

Procedure:

• After tacking line clearance from IPQA personnel, Start the conveyor linker to charge the Turn table with vials.
• Now start the turntable as speed specified in the BPR (CPP column) and Ensure that Turn table is at least half loaded with vials.
• Check the Vial washer parameter as per point No. 8.3 and ensure the parameter are within the specified Limit and record the Observation in 8.3 table for initial set-up.
• Now Start and Operate the Automatic Rotary Vial Washer machine as per respective equipment SOP and align the vial with the machine inlet, and start the washing activity.
• Now Collect the 06 vials to perform Clarity test, add WFI in vial up to neck and check the clarity as per point no. 8.5 and record the observation in respected column, (if any rejections found during the washing Re-Wash the vial and check the clarity, if clarity found OK continue the process).
• After washing, vial shall be go for the sterilization and Depyrogenation process in the tunnel.
• Check the Tunnel Parameters as specified in the point No. 8.8 and record the observation in the respected column.

• Vial Washing Parameter initial Set-up:

• VIAL WASHING RECORD 

In process Clarity Checking of Washed Vials (Frequency: At the start of washing then approx. every 2 hours.)

Vial Washing Parameter In-process Check (Frequency: At the start of washing then approx. every 2 hours).

VIAL STERILIZATION & DEPYROGENATION RECORD

In Process Parameter checks during Sterilization and Depyrogenation:

Frequency: Initial and Approx. Every 1 hour. All the below parameters shall be checked on the HMI screen of the tunnel.

The printed record of Vial Sterilization & Depyrogenation Tunnel to be attached in the BPR.

RUBBER STOPPER (AUTOCLAVE)

Instructions:

1. Set-up and operate the equipments as per SOP.
2. Use cleaned and sterilized Container.
3. Use SS handle to open the door.
4. Place the washed Rubber Plugs/Bungs to the autoclave, after feeding the Rubber Plugs/Bungs close the door.
5. Sterilize the Rubber Plugs/Bungs for 30 minutes at 121.5°C temperature.
6. Send the rinse water sample to the QC lab
7. Attach steam indicator chemical strip.
8. Record the autoclave process in below table and Log Book.

Line Clearance For Rubber Plug/Bung Autoclave Area & Equipment

Check List

• Line properly identified.
• Floor and surrounding area neat and clean.
• All equipment clean and free from foreign material.
• Previous product materials shifted to the respective area.
• Status Label is filled with current batch details.
• Details on equipment / Containers status labels match with BPR details.
• Generated steam is pure.

• Rubber stopper washing and Sterilization Record 

Before going to the next step check the steam indicator chemical strip is attached.

FLIP OFF SEAL WASHING AND AUTOCLAVE

Instructions:

1. Set-up and operate the equipment as per SOP.
2. Use cleaned and sterilized SS vessels.
3. Rinse the flip-off / seal twice with purified water.
4. Finally, wash with WFI.

LINE CLEARANCE FOR FLIP OFF WASHING AREA & EQUIPMENT

Check List

• Line properly identified.
• Floor and surrounding area neat and clean.
• Equipment and accessories are clean and free from foreign material.
• Previous product materials shifted to the respective area.
• Status Label is filled with current batch details.
• Details on equipment / Containers status labels match with BPR details.

FLIP OFF WASHING RECORD

STERILIZATION OF FLIP-OFF/ SEALS

Instructions:

1. Set-up and operate the equipments as per SOP.
2. Use SS handle to open the door.
3. Place the washed flip off / seal to the autoclave, after feeding the flip off / seal close the door.
4. Sterilize the flip off / seal for 30 minutes at 121°C temperature.
5. Record the autoclave process in below table and Log Book.

• FLIP OFF SEAL STERILIZATION RECORD

STERILIZATION OF MACHINE PARTS AND ACCESSORIES (AUTOCLAVE)

Instructions:

1. Firstly wash the machine parts with hot Purified water, finally, wash with WFI and send the rinse water sample to QC lab, if the results are satisfactory then send the parts for sterilization. Attach steam indicator chemical strip.
2. Machine parts and sterilize in the autoclave at 121.5°C for 30 minutes.

FILLING AND STOPPERING PROCESS

Line Clearance for Filling, Stoppering

Check List

• Line properly identified.
• Floor and surrounding area neat and clean.
• All equipment clean and free of foreign material.
• Previous product materials shifted to the respective area.
• All the workers should wear protective cloth, dust mask and gloves while handling raw materials
• Further check the name of the material and CR No. on the label of dispensed material
• Respective BPR is available with previous stage completed.
• Status Label is filled with current batch details.
• Details on equipment / Containers labels match with BPR details.
• Rinse Water Result and previous stage QC results.
• A.R No.___________________.
• LAF working and pressure within limit.

• Environmental Monitoring: Frequency every 2 hour.

LIMIT: Temperature NMT 25 °C and Relative Humidity NMT 30% (As Per Area Monitoring SOP). Temperature and Relative Humidity Should be checked during starting of the activity and every 2 hours.

PRODUCT INPROCESS SPECIFICATION:

Process: 

• After taken Line clearance From IPQA personnel, Start the Machine.
• On the basis of API Calculation, Set the Standard Individual Fill Weight Variation.
• Now Collect the 08 Filled Vials From Each filling Station (Hopper-1 And Hopper-2) and Check the Fill weight variation on analytical balance.
• Ensure the Fill weight of powder shall within the Acceptance Criteria.
• Production and IPQA personnel both are Check the individual weight variation at the time of initial set-up as per point No. 11.4.1
• After IPQA approval start the filling process.
• Check the In-Process parameters as per the given standard Frequency.

IN-PROCESS RECORD DURING FILLING & BUNGING PROCESS

Initial In-Process Weight Variation Check List for Production and IPQA: 

Remarks: H-1 (Hopper 1) H-2 (Hopper 2)

After IPQA approval Start the machine

In process Checks ( Frequency: Every One Hour alternate by Production and IPQA)

Line Clearance For Vial Sealing Process

Check List

• Line properly identified.
• Floor and surrounding area neat and clean.
• All equipment clean and free of foreign material.
• Previous product materials shifted to the respective area.
• Respective BPR is available with previous stage completed.
• Status Label is Sealing with current batch details.
• Details on equipment / Containers labels match with BPR details.
• Rinse Water Result and previous stage QC results.
• LAF working and pressure within limit.

Procedure:

• After tacking line clearance from IPQA Start the machine for initial Set-up as per respective Equipment SOP.
• Check and ensure that, the environmental condition within the limit.
• Now take 08 Sealed Vials from the sealing machine conveyor and check for the proper sealing.
• Now withdrawn 08 vials for the Leak Test sample and perform the leak test for 100 % No Leakage.
• After complies of Leak test Start the Sealing activity and Record the Observation.

Initial In-Process Check:

Carry out the sealing of the total no of filled vials as per Respective SOP record the In-process details below.

Put [√ ] for OK and [ × ] for NOT OK. 

In process Checks ( Frequency: Every One Hour alternate by Production and IPQA)

*LIMIT: Temperature NMT 25 °C and Relative Humidity NMT 30% (As Per Area Monitoring SOP

In process Checks ( Frequency: Every One Hour alternate by Production and IPQA)

LEAK TEST RECORD 

Carry out the sealed vials for leak test at a one time by each sealing head (8 vials) as per Respective SOP record the In-process details below as per Respective SOP. Check the leak test, initial and after every two hour by production personnel and verified by IPQA using leak test integrity machine the Leak test shall be 100% No leakage. Record the in process details of leak test in below table.

• FILLED AND SEALED VIALS RECORD

OPTICAL INSPECTION RECORD

Procedure:

• After Tacking Line clearance from the IPQA personnel Check and Record the environmental monitoring.
• After Sealing, Inspect the Filled and Sealed vials as per respective Equipment SOP.
• If any rejections are found keep them in the rejection bin provided.

Note: One Visual inspector shall perform the inspection activity only for 2 hours.

Checklist

• Line properly identified.
• Floor and surrounding area neat and clean.
• Inspection table is clean and free from foreign material.
• Previous product materials shifted to the respective area.
• Status Label is filled with current batch details.
• Ensure that the checking table light is working properly
• Ensure that only qualified workers are doing the optical inspections
• Reconstitute the vial with particular solvent as given on product label before starting and after compilation of optical inspection for clarity.

Optical Inspection Record: 

Optical Rejection Record:

Note: Ensure that one Inspector shall perform inspection activity only for 2 hours.

Yield Reconciliation:

Primary Packing Material Reconciliation:

Rejected Material Destruction Record:

Note: Rejected Quantity shall be destroyed in 2% NaOH Solution.

• BATCH TRANSFER DETAILS (For Packing) 

PACKING PROCESS

Instructions:

• All equipment and accessories required for use should be cleaned as per the current approved Standard Operating Procedure.
• All equipment must be properly guarded and earthed.
• Ensure that all the dispensed packing materials are checked for the correct identity on the label and also the  Weight prior to use.
• The temperature and Relative humidity in the packing area should be maintained.
• Necessary preventive measures should be taken to avoid cross-contamination of other products.
• Ear plugs/muffs must be worn during working in high-noise areas/operations.
• All packing operations must be carried out under the supervision of Competent Technical Staff.
• All non-utilizable rejects must be recorded and destroyed as per the current Standard Operating Procedure.

Line clearance Check List

• Cleaning of weighing balance.
• Ensure that previous batch material is traced from the Waste bin
• Calibration status of weighing balance.
• Temperature and Relative Humidity.
• Requisition Slip check for approval.
• Previous product materials shifted to the respective area.
• Check all the document completion.

• DISPENSING OF SECONDARY PACKAGING MATERIAL

OVERPRINTING AREA

Instruction

• Clean the area and the machine and get the Line clearance from IPQA.
• Check the quantity of Label and Cartons received.
• The first Printed Label and Carton should be checked by the Packing and Approved by the IPQA. The approved Label and Cartons have to be attached with the BPR.
• After taken approval from IPQA start the overprinting Process.
• The rejected Over printed materials should be preserved until the batch packing completes and after completion  it has to be destroyed in presence of IPQA and the same has to be recorded.
• Printed materials should be stored properly in the corrugated boxes/Crates.

Line clearance Check List

• Line properly identified.
• Floor and surrounding area neat and clean.
• All equipment clean and free of foreign material.
• Components & Records from previous batch/product removed off the line.
• Approved labels pasted on packing material.
• Status Label is filled with current batch details.
• Respective BPR is available with the previous stage completed.

• STANDARD CARTON OVERPRINTING DETAILS:

CARTON OVERPRINTING RECORD

LABEL OVERPRINTING AREA

LINE CLEARANCE FOR LABEL PRINTING AREA & EQUIPMENT

Line clearance Check List

• Line properly identified.
• Floor and surrounding area neat and clean.
• All equipment clean and free of foreign material.
• Components & Records from previous batch/product removed off the line.
• Approved labels pasted on packing material.
• Status Label is filled with current batch details.
• Respective BPR is available with previous stage completed.

LABEL OVERPRINTING RECORD

• VERIFICATION RECORD OF LABEL, CARTON, AND SHIPPER LABEL 

SECONDARY PACKING

Instruction:

• Ensure the area and the equipment is clean.
• Check whether the dispensed secondary packing materials are according to the packing indent.
• Write the Date, Product name, Batch number and the stage of the packing on the display board.
• Check for the absence of packing material/product of previously run product.
• Get the Line clearance from IPQA to start the secondary packing.
• Checks the product/batch details on carton, leaflet and shipper label shall approved by IPQA. The approved carton, leaflet and shipper label  have to be attached with the BPR
• Randomly open the packed shipper (every two hour) and cross check the quantity.

LINE CLEARANCE FOR SECONDARY PACKING AREA & EQUIPMENT

Line clearance Check List

• Area clearance
• Cleaning of weighing balance
• Calibration status of weighing balance
• Next Calibration due date
• Room Temperature
• Ensure whether all the previous batch-packing materials are removed from the area.
• Ensure whether the correct packing materials are brought for packing.
• Respective BPR is available with the previous stage completed.

Input Secondary Packing Material Verification:

Instruction

• Before packing affix the Weight range on Weighing Balance for Weight Variation Limit.
• Prepare the Weight limit.

Calculation of weight limits for carton: 

1. Weigh randomly 10 complete filled carton, filled vial, water ampoule, Leaflet, Empty carton.
2. Find out Minimum & maximum weight all.
3. Find out the Difference between Minimum / Maximum wt. & average wt of all.

1. A) Minimum wt. of Carton

=  Minimum wt. of Empty carton +(Min. wt. of filled vial + Min. wt. of water ampoule + Min. wt. of Leaflet)

      =

1. A) Maximum wt. of Carton

=  Maximum wt. of Empty carton +(Max. wt. of filled vial + Max. wt. of water ampoule + Max. wt. of Leaflet)

SECONDARY PACKING LINE IN-PROCESS CONTROL  (Frequency: Every Hour)

Calculation of weight limits for Outer Carton/Sleeve pack/Shipper:

• Weigh randomly ______ complete Outer Carton/ Sleeve pack and empty shippers.
• Find out Minimum & maximum weight of Outer Carton/ Sleeve pack and empty shippers.
• Difference between Minimum / Maximum wt. & average wt of a Outer Carton/ Sleeve pack and Empty shipper.

1. A) Minimum wt. of Shipper

=    Minimum wt. of Empty shippers + (Minimum wt. of filled Outer Carton/ Sleeve X total No. of Outer

Carton/ Sleeve in a shipper)  

      =

1. A) Maximum wt. of Packed Shipper

=    Max. wt. of Empty shippers + (Max. wt. of filled Outer Carton/ Sleeve X total No. of Outer Carton/ Sleeve

in a shipper) 

      =

PACKING MATERIAL RECONCILIATION:

NOTE: Rejected Label, Carton, WFI, Outer Carton/ Sleeve pack , Shipper,Leaflet should be defaced before sending for disposal.

Reconciliation of Finished Product

TRANSFER OF FINISHED GOODS

• BPR COMPLETION RECORD 

ABHA

Abha is the Author  of pharmaceutical guidance, she is a pharmaceutical professional having more than 22 years of rich experience in pharmaceutical field.
During her career, she works in the quality assurance department with multinational companies i.e Zydus Cadila Ltd, Unichem Laboratories Ltd, Indoco remedies Ltd. During his experience, she faces many regulatorily audits i.e. USFDA, MHRA, ANVISA, MCC, TGA, EU –GMP, WHO –Geneva, ISO 9001-2008 and many ROW Regularities Audit i.e.Uganda, Kenya, Tanzania, Zimbabwe. She is currently leading a regulatory pharmaceutical company as a Head Quality. You can join him by Email, Facebook, Google+, Twitter, and YouTube