CIP & SIP OF MANUFACTURING TANK, HOLDING TANK,PRODUCT LINE, FILTER ASSEMBLY & FFS MACHINE
1.0 PURPOSE
To establish the procedure for CIP & SIP of manufacturing tanks, holding tank, Product line, filter assembly & FFS machine.
2.0 SCOPE
This SOP is applicable for CIP & SIP of manufacturing tanks, holding tank, FFS machine & filter assembly at facility of Relax Pharmaceuticals Pvt. Ltd. Unit-I.
| Equipment Name | Equipment ID | Location | Make |
3.0 REFERENCE(S) & ATTACHMENTS
3.1 REFERNCES (S)
3.1.1. WHO-TRS 961 Guidelines
3.1.2. cGMP guide lines & (21 CFR part 11)
3.1.3. FDA guide lines on sterile drug products produced by aseptic processing
3.2 CROSS REFERENCE DOCUMENTS
3.2.1. Filter Integrity of Product/Hydrophilic Filter
3.2.2. Batch preparation of SVP products
3.2.3. Cleaning, operation, precaution, monitoring & mould change procedure of FFS Machine
3.3 ATTACHMENTS
3.3.1. Attachment/Annexure/Format
Attachments No. I : Mfg. tanks, holding tank & FFS machine CIP & SIP Record
3.3.2. Label
3.3.2.1 NA
4.0 DEFINITION & ABBREVIATION(S)
4.1 DEFINITION
4.1.1. CIP : CIP stands for “ Cleaning In Place”. CIP is the method of cleaning of Interior surface tanks, pipes, filters assembly, interior associate fittings without disassembly. Due to the use of CIP system, cleaning is faster, less labor intensive, more repeatable & poses less of exposure risk. CIP has started as manual practice involving tanks, centrifugal pump & connection to the system being cleaned. CIP has evolved now fully automated system operate by PLC, multiple balance tanks, sensors, controllers & specially designed spray nozzle system.
4.1.2. SIP : SIP stands for “Sterilization In Place”. SIP is the method of sterilization of production equipment (interior surface tanks, pipes, filters assembly, interior associate fittings without disassembly). SIP system is used in that area where germ reduction play a decisive role.
Sterilization is carried out with pure steam of above 121ºC over a period of more than or equal to 30 minutes. the duration varies according to application and system type.
4.2 ABBREVIATIONS
SOP : Standard Operating Procedure
QA : Quality Assurance
PROD. : Production
C.C. No. : Change Control Number
SS : Stainless Steel
WFI : Water For Injection
CIP : Cleaning In Place
SIP : Sterilization In Place
FFS : Form Fill Seal
SFS : Sterile Filter Space
HMI : Human Machine Interface
QC : Quality Control
PLC : Programing Logic Control
WHO : World Health Organization
CFR : Code of federal Regulations
5.0 RESPONSIBILITY
5.1 Originating department shall be responsible:
5.1.1. Preparation of the SOPs.
5.1.2. To provide the final draft copy to Quality Assurance.
5.1.3. To follow the described here in.
5.1.4. To perform the operation/activity as per respective SOP.
5.1.5. To impart the training to concerned personal as well as operators before effective date of SOPs.
5.1.6. Co-ordinate with engineering person for utility & maintenance/breakdown.
5.1.7. To maintain online documentation, records & log books.
5.1.8. Initiation of change control to revise or modify the SOPs.
5.2 Head of Originating department/designee shall be responsible for:
- Ensure that sub-ordinate, operators are trained before performing any task or operation.
- To check the SOP for proper contents/technical parameter as per the equipment.
- To get the SOP approval from Quality Assurance or designee.
- To provide the training of SOP to the concerned personnel before effective date of the SOP.
5.2.5. To ensure implementation of the SOP on effective date.
- To maintain the controlled copies of the SOPs at required location.
- To ensure the compliance of SOP.
5.3 Quality Assurance department shall be responsible for:
5.3.1 To check the draft sops for regulatory and cGMP compliance.
5.3.2 To maintain the approved master copy of the SOP of all department for document control.
5.3.3. To issue the required number of controlled copies to the departments and document the same.
5.3.4. Issuance of change control form required for SOP revision.
5.4 Head Quality Shall be responsible for:
5.4.1. Review of draft SOP regulatory and cGMP compliance.
5.4.2. Final approval of new or revised SOP by signing off as approved by.
5.4.3. To ensure the implementation of the defined system.
5.5 Engineering person shall be responsible for:
5.5.1. Co-ordinate with production person for schedule preventive maintenance or breakdown maintenance of equipment.
5.5.2. Perform maintenance of equipment or system as per schedule.
5.5.3. Provide utility as per co-ordination with production.
5.6 Plant head shall be responsible for
5.6.1. To approve new or revised SOP.
5.6.2 To ensure the implementation of defined system.
6.0 PROCEDURE
6.1 SAFETY/PRECAUTION/EHS
6.1.1. Don’t touch the hot WFI & steam line, tanks during CIP & SIP.
6.1.2. Always check on routine basis the gasket & clamps of all utilities line.
6.1.3. During CIP don’t be in direct contact of hot water for injection.
6.1.4. Always check the main hole gasket of tanks before SIP.
6.1.5. Be sure that tanks pressure should not go above 2.0 bar.
6.1.6. Before SIP jacket of tank should be empty to avoid creating vacuum in tank.
6.1.7. During SIP don’t open main hole of the tank, clamps or gasket of product line as well as filtration skid.
6.1.8. Be care full that electrical panel, HMI should not be moistened to avoid mal functioning.
6.1.9. Don’t start batch processing during batch preparation.
6.2 CHECK POINTS PRIOR TO CIP & SIP PROCESS
6.2.1. Ensure availability of BMR with approved check list.
6.2.2. Ensure manufacturing area with corresponding air locks is properly clean and sanitized before start batch preparation with schedule disinfectant solution.
6.2.3. Ensure environmental condition (temp./humidity, differential pressure, non-viable & viable particle count are within permissible limit.
6.2.4. Ensure product filters, vent filters are passed in filter integrity test.
6.2.5. Ensure WFI availability, temperature of WFI maintained above 80ºC & release from QC for chemical & microbiological analysis.
6.2.6. Ensure availability of pure steam.
6.2.7. Ensure all the gauges, sensors are calibrated.
6.2.8. Ensure HMI is properly working.
6.2.9. Ensure manufacturing tanks, holding tank is empty before performing the CIP & SIP.
6.2.10. Gowning procedure is properly followed.
6.2.11. Line clearance of the area & the machine.
6.2.12. Verify the clamps & gasket for tightness.
6.3 CIP & SIP OF MANUFACTURING TANKS (500 LITERS) WITH FILTER ASSEMBLY
6.3.1. CIP of manufacturing tanks, holding tank, product line & FFS machine shall be performed as per operating manual with semi-automatic process.
6.3.2. Hot water for injection above 80ºC will be used in CIP.
6.3.3. After filtration of product perform post integrity of product filter as per SOP & collect 100 liters of WFI in 500 liters manufacturing tank through spray ball.
6.3.4. Switch “ON” first stirrer of tank & run for 5 minutes, then start transfer pump with HMI & circulation of WFI with transfer pump, filter assembly, product line up to holding vessel for 5 minutes & drain out the WFI from the bottom of tank.
6.3.5. Again second time collect 100 liters in the tank through the spray ball & perform same process for stirring & circulation for 5 minutes & drain out from the bottom of tank by opening of the diaphragm valve & check the pH & conductivity in the display of HMI of tank.
6.3.6. Again third time repeat the same step as 6.2.5 & verify the pH & conductivity in the HMI of tank, if the conductivity is within limit (below 1.3 µS) then drain out the water.
6.3.7. Finally collect 100 liters WFI & after stirring & circulation production person will first collect the sample from bottom of tank & check the pH, conductivity, if both are within limit (pH= 5.5-7.0 & conductivity= below 1.3 µs). production person in presence of QA will collect the first sample (300 ml) in a clean & dried screw cap glass bottle from sampling valve incorporated bottom of tank & second sample (300 ml) also in clean & dried screw cap second bottle after 0.22 micron cartridge filter housing sampling valve.
6.3.8. During sampling first rinse the bottle & cap from same sample solution twice & discard the sample in drain. Afterwards sampling will be performed & immediately closed the bottle from screw cap to avoid any contamination.
6.3.9. QA person will send the CIP sample to QC for chemical analysis (pH, conductivity, previous product residue & TOC) against CIP intimation slip.
6.3.10. If the sample released by QC proceed for further process.
6.3.11. If sample not release by QC raise the incident & verify the root cause with CAPA & repeat the step 6.2.5 & again send the sample until all the parameters complies & meet the specification.
6.3.12. After CIP perform filter integrity of final product filter (0.22 micron) installed in filtration skid & FFS machine, mfg./holding tank vent filter (0.22 micron), buffer air & support air filter (0.22 micron) of FFS machine.
6.3.13. For SIP process empty out the tank & jacket of tank.
6.3.14. Check the main hole gasket for any damage, if gasket damage replace with new one &perform CIP again.
6.3.15. Close the main hole of manufacturing tanks tightly & close all the opening of tank & vent filter valve of mfg. tank.
6.3.16. Start the SIP process by pressing SIP icon on the HMI of the tank.
6.3.17. Open the pure steam valve in the tank and drain valve of tank will be open for1-2 minutes to remove starting condensate of the line & close the same as the steam start.
6.3.18. As the SIP process start steam trap of the tank will automatic open & slowly slowly temperature & pressure in the tank rise.
6.3.19. Check the temperature & pressure of the tank with temperature sensor & pressure Transmitter displayed on HMI.
6.3.20. Also pressure of the tank can be measure with calibrated pressure gauge mounted the tank.
6.3.21. As the temperature in the tank reach more than 110 º & pressure reach more than 1.0 kg/cm2 open the product line & filter assembly manual diaphragm valve.
6.3.22. Steam travel from tank to filtration skid, check the temperature of the filtration skid on HMI & pressure with calibrated pressure gauge mounted on filter housings.
6.3.23. As the temperature of tank & filtration skid displayed on HMI above 121.0ºC & pressure shows above 1.5 bar, SIP process start.
6.3.24. Hold the temperature for 30 minutes & SIP process continue & elapse SIP time will be displayed on the screen.
6.3.25. As the set SIP time complete, manually close pure steam inlet diaphragm valve.
6.3.26. Slightly open the vent filter valve to drain out the steam from the tanks & filters & pressure & temperature of the tanks reduce, as the tanks pressure on the gauge become zero, drain valve & steam trap will close.
6.3.27. Allow the tank to cool up to room temperature & take the per minute SIP printout to measure the temperature & pressure of the tanks & enclose with BMR.
6.4 CIP & SIP OF HOLDING TANKS (300 LITERS) & FFS WITH MACHINE
6.4.1. CIP & SIP of holding tank & FFS machine is performed together with hot WFI & pure steam.
6.4.2. To start CIP & SIP assemble the mendral hood in the FFS machine.
6.4.3. CIP to be performed with hot WFI (above 80ºC), collect 75 litres of WFI in
300 litres holding tank through spray ball & start circulation through product line for 5 minutes & drain out from the tank.
6.4.4. Repeat the same process of step 6.3.3 thrice.
6.4.5. Finally collect 75 litres WFI & after stirring & circulation collect the 300 ml sample From the sampling point of tank in a clean & dried glass bottles.
6.4.6. QA person will send the CIP sample to QC chemical analysis(pH, conductivity,previous product residue & TOC) against CIP intimation slip.
6.4.7. If the sample released by QC, transfer the WFI to FFS machine & WFI travel through product line, filter assembly, buffer tank & drain through filling nozzle covered with mendral hood.
6.4.8. Repeat the same process step of 6.3.7 by collecting 75 litres hot WFI in holding tank, Check the pH conductivity in HMI & also with pH & conductivity meter located in mfg. room, if same is with in limit (pH= 5.5-7.0 & conductivity= below 1.3 µs).
6.4.9. Then production will collect the 300 ml sample in clean & dried screw capped glass bottle from mendral hood & QA person will send the CIP sample to QC for chemical analysis(pH, conductivity, previous product residue & TOC) against CIP intimation slip & record the process in BMR.
6.4.10. After CIP perform filter integrity of final filter of 0.22 micron installed in FFS machine.
6.4.11. For SIP process empty out the tank & jacket of tank.
6.4.12. Check the main hole gasket for any damage, if gasket damage replace with new one & perform CIP again.
6.4.13. Close the main hole of manufacturing tanks tightly & close all the opening of tank.
6.4.14. Start the SIP process by pressing SIP icon on the HMI of the tank & FFS machine.
6.4.15. Open the pure steam valve above the holding tank & near FFS machine and drain valve of tank will be open for 1-2 minutes to remove starting condensate of the line & close the same as the steam start.
6.4.16. As the SIP process start steam trap of the tank will automatic open, temperature & pressure in the tank slowly rise.
6.4.17. Check the temperature, pressure of the tank & FFS machine with temperature sensor & pressure transmitter displayed on HMI.
6.4.18. Also pressure of the tank can be measure with calibrated pressure gauge mounted the tank.
6.4.19. As the temperature in the tank reach more than 110 º & pressure reach more than
1.0 kg/cm2 open the product line & filter assembly manual diaphragm valve.
6.4.20. Steam travel from tank to the transfer pump, product line, filtration assembly,buffer tank filling nozzles & drain out through mendral hood.
6.4.21. Check the temperature of the filtration skid on HMI.
6.4.22. As the temperature of tank & filtration assembly, buffer tank, filling nozzles
displayed on HMI above 121.4ºC & pressure shows above 1.5 bar, SIP process start.
6.4.23. Hold the temperature for 30 minutes & SIP process continue & elapse SIP will be displayed on HMI of tank & FFS machine.
6.4.24. As the set SIP time complete, manually close steam valve & slightly open the vent valve to drain out the steam pressure.
6.4.25. Temperature & pressure of the tanks, filters, buffer tank, nozzles reduce & as the tanks pressure in the gauge become zero, drain valve & steam trap will close.
6.4.26. Allow the tank to cool up to room temperature & take the per minute SIP printout to measure the temperature & pressure of the tanks & enclose with BMR.
6.4.27. As the sterilization process in FFS machine complete program will automatically shift to the “FILTER DRYING” stage with the cool air.
6.4.28. Filter drying process will be run up to 45 minutes.
6.4.29. Remove the mendral hood & set the machine in filling position.
6.5 CIP & SIP OF MANUFACTURING TANKS (1500 LITERS) & FFS WITH MACHINE
6.5.1. CIP & SIP of manufacturing tank (1500 liters) & FFS machine is performed together with hot WFI & pure steam.
6.5.2. Attach the mendral hood to the FFS machine to perform CIP & SIP.
6.5.3. Collect 250 litres of WFI in 1500 litres holding tank through spray ball & start circulation through product line for 5 minutes & drain out from the tank.
6.5.4. Repeat the process of step 6.4.3 twice & check the conductivity of WFI in HMI.
6.5.5. Finally collect 250 litres WFI, after stirring & circulation collect the 300 ml sample from tanks in a clean & dried glass bottles.
6.5.6. Production person will check the pH & conductivity of CIP sample with pH & conductivity meter, if sample is ok then send another 300 ml sample in clean & dried bottles to QC for chemical analysis(pH, conductivity, previous product residue & TOC) against CIP intimation slip & record the process time in BMR & log book.
6.5.7. If the sample released by QC, transfer the WFI to FFS machine & WFI travel through product line, filter assembly, buffer tank & drain through filling nozzle covered with mendral hood.
6.5.8. Repeat the same process step of 6.4.7 by collecting 250 litres hot WFI in manufacturing tank & verify the pH & conductivity.
6.5.9. If pH & conductivity is with in limit then production person will collect the 300 ml sample in clean & dried glass bottle from mendral hood & QA person will send the CIP sample to QC for chemical analysis(pH, conductivity, previous product residue & TOC) against CIP intimation slip & record the process time in BMR & log book.
6.5.10. After CIP perform filter integrity of final filter of 0.22 micron installed in FFS machine.
6.5.11. For SIP process empty out the tank & jacket of tank.
6.5.12. Check the main hole gasket for any damage, if gasket damage replace with new one & perform CIP again.
6.5.13. Start the SIP process by pressing SIP icon on the HMI of the tank & FFS machine.
6.5.14. Open the pure steam valve in the tank & FFS machine and drain valve of tank will be open for1-2 minutes to remove starting condensate of the line & close the same as the steam start.
6.5.15. As the SIP process start steam trap of the tank will automatic start, temperature & Pressure in the tank rise.
6.5.16. Check the temperature & pressure of the tank & FFS machine with temperature sensor & pressure transmitter displayed on HMI.
6.5.17. Also pressure of the tank can be measure with calibrated pressure gauge mounted the tank.
6.5.18. As the temperature in the tank reach more than 110 º & pressure reach more than 1.0 kg/cm2 open the product line & filter assembly manual diaphragm valve.
6.5.19. Steam travel from tank to the transfer pump, product line, filtration assembly, buffer tank filling nozzles & drain out through mendral hood.
6.5.20. Check the temperature of the filtration skid on HMI.
6.5.21. As the temperature of tank & filtration assembly, buffer tank, filling nozzles displayed on HMI above 121.4ºC & pressure shows above 1.5 bar, SIP process start.
6.5.22. Hold the temperature for 30 minutes & SIP process continue & elapse SIP will be displayed on the screen.
6.5.23. As the set SIP time complete, manually close steam valve & open the vent filter valve to drain out the steam from tank.
6.5.24. Temperature & pressure of the tanks, filters, buffer tank, nozzles reduce & as the tanks pressure in the gauge become zero, drain valve & steam trap will close.
6.5.25. Allow the tank to cool up to room temperature & take the per minute SIP printout to measure the temperature & pressure of the tanks & enclose with BMR.
6.5.26. As the sterilization process in FFS machine complete program will automatically shift to the “FILTER DRYING” stage with the cool air.
6.5.27. Filter drying process will be run up to 45 minutes.
6.5.28. Remove the mendral hood & set the machine in filling position.
6.5.29. Take the print out of sterilization process and attach in the BMR.
6.5.30. Maintain the record in log book.
6.6 FREQUENCY
6.6.1. For terminal sterilized same products(SWFI) in continuous operation : CIP & SIP should be required after 72 Hrs.
6.6.2. For terminally sterilized different products: CIP & SIP Should be required after every batch.
6.6.3. For aseptic filling same products (respules/eye drops): CIP & SIP Should be required after every batch.
6.6.4. For aseptic filling different products(respules/eye drops): CIP & SIP Should be required after every batch.
6.6.5. If FFS Machine break down more than 4 hrs. SIP of FFS machine required before start the operation with incident report & CAPA.
6.6.6. If any break down happens in direct product line or product contact part of machine will perform CIP/SIP before start up the machine.
7.0 REVISION HISTORY
| Version No. | 00 | Effective date | |
Detail of revision : New SOP |
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