Aseptic filling process can be validated using microbiological growth medium in place of the product. This process of validation also known as a media fill validation, normally includes exposing the microbiological growth medium to product contact surface of equipment, container closure system, and critical environments to closely simulate the same exposure that the product itself will undergo at the time of processing or filling. The sealed containers after filling with the medium are incubated to detect microbial growth for contamination at optimum temperature.
The objective of the validation is to establish documented evidence that the process for aseptic processing of parenterals liquid/ophthalmic solution will pass the acceptance criteria consistently, when performed as per the Standard Operating Procedures.
The Validation protocol provides the procedure for the Process Simulation (Media Fill) for SVP line.
Name of the Department
Preparation of Protocol
|Verification of Protocol||QC and Production|
Approval of protocol
Final determination of System Acceptability
Review and assembling of data into a final report
Production and Engg.
1. Approved (Sterile) Soybean casein digest broth
2. Aseptic area gowning and entry & exit procedures into sterile areas.
3. Environmental Monitoring of manufacturing areas by Plate Exposure, Air sampling and surface monitoring procedures and its SOP’s. Personnel Monitoring by Finger Dab & Swab Test Method & its SOPs.
4. Qualified and validated manufacturing equipments, system facility (i.e. HVAC, water, compressed gases) CIP and SIP procedures.
5. Trained operating personnel’s.
6. Approved BMR for media fill Validation.
6.0 EQUIPMENT / SYSTEM DESCRIPTION:
Location : Manufacturing Area
Equipments : Mixing Tank, Holding Tank, Filtration housings, connected product line and FFS machines
7.0 IDENTIFICATION OF CRITICAL CONTROL MONITORING PARAMETER
7.1 Critical control parameters were identified and it should be considered and recorded during validation program, following are the critical points-
· Check all the equipment and system facility is validated.
· Check and ensure that the HVAC system, compressed air, CIP and SIP procedures are qualified.
· Check and ensure that all operations, cleaning/ sanitization procedures are established and operating personnel are trained.
· Check the Media used for Process Simulation is passed for GPT
· Check and ensure that the WFI used for preparation of batch is complied to USP/IP
7.2 Environmental monitoring should cover three operational shifts, by following methods –
· Settle plate method
· Air sampling
· Swab testing
· And Personnel monitoring
8.0 STUDY DESIGN
8.1 Worst Case Consideration:
8.1.1 Allowed maximum number of personnel in the Aseptic Processing Area, including the maintenance and housekeeping personnel
8.1.2 Simulating routine machine parts assembling / disassembling, equipment / system setups, in between minor maintenance jobs
8.1.3 Increased the time period to start the filling operation
8.1.4 Duration of the media fill trial was more than that required for routine manufacturing operation.
8.1.5 Simulating Process / Power breakdown during the process simulation test
8.1.6 Shift changes and breaks
8.2 Frequency, Duration, Number of runs & Fill Volume:
8.2.1 Media fill trials must be performed on semi-annual basis for each aseptic process and additional media fill trials should be performed in case of any change in procedure, practices or equipment configuration.
8.2.2 Filled units in Media Fill run should be 10,000 units or more. Fill minimum 3000 units in each production shift.
8.2.3 The duration of Media Fill run must cover all the three operational shifts in each run turn by turn including worst cases as stated in step No. 9.1.
8.2.4 Fill volume for Media Fill run for SVP is 10 ml.
8.3 Environmental Consideration:
8.3.1 Cleaning of Area must be done by using routine cleaning agent and disinfectant solution, as per latest SOP
8.3.2 Microbiological Environmental monitoring should be carried out to cover the entire media fill program for manufacturing area by Settle plate, Active Air sampling, Swab test and personnel monitoring as per the latest SOP.
8.4.1 Soybean Casein digest Medium, manufactured by Hi Media Laboratories should be used for Media fill trial.
8.4.2 The media must be passed the test for GPT as per SOP to promote the growth of gram-negative and gram-positive bacteria and yeast and molds.
8.5 Incubation and examination of filled units:
8.5.1 Incubate all media filled units in normal position after leak test at of 20 to 250C for 7 days. Incubation temperature should be maintained within 22.5 ± 2.50C .
8.5.2 After completion of 7 days Incubation at 20 to 250C, invert the units and incubate them at 30-350C for next 7 days. Incubation temperature should be maintained within 32.5±2.50C .
8.5.3 Each media filled unit should be examined by trained Microbiologist after 3rd day, 7th day, 10th day and 14th day.
8.5.4 All suspect units identified during the observation should be brought to the immediate attention of the QC Microbiologist.
8.6 Interpretation of Test Result:
8.6.1 Any contaminated unit should be considered objectionable and investigated. The microorganism should be identified to species level.
8.6.2 The investigation should survey the possible causes of contamination.
8.6.3 When filled units up to 10000, one contaminated unit should result in an investigation, including consideration of a repeat media fill.
9.0 VALIDATION PROCEDURE
9.1 CIP and SIP for SVP:
9.1.1 Carry out cleaning of SVP mixing tank and holding tank along with product line and bottle pack machine 3012 as per respective SOP for CIP.
9.1.2 At the end of cleaning, collect last rinses sample from sampling point and send to QC department with written information for testing of previous product traces.
9.1.3 After getting approval report from QC, affix status label on the tank “READY FOR STERILIZATION”.
9.1.4 Immediately carry out the sterilization of SVP holding tank along with final filter and product line of bottle pack machine as per respective SOP.
9.1.5 After Sterilization, affix a status label on the SVP line.
9.2 Dispensing of Soybean Casein Digest Medium for 150 L batch size:
9.2.1 Give raw material requisition slip in duplicate to store (either computerized or manual) duly signed by Production Officer and Authorized by HOD (Production)
9.2.2 Enter to dispensing room as per SOP for entry exit procedure to dispensing area.
9.2.3 Check for the clearance of the area from any unwanted materials. Check for the cleanliness of the area, LAF, weighing pan as per checklist. Put “ON” the reverse LAF unit 15 minutes before dispensing of material.
9.2.4 Check the availability of clean containers, SS scoops, pressure differentials, and temperature & humidity should be not more than 250C and 45 to 60% RH respectively.
9.2.5 Check the balance spirit level is within the circle and then calibrate the balance as per SOP of Balance Calibration.
9.2.6 Take the Approved Soybean Casein Digest Medium in pre-dispensing room, place on SS pallet and check the label of container for correctness and Approval of material.
9.2.7 Transfer the material to Dispensing room, place the empty clean container on the balance and record the tare weight. Press “ZERO” of the balance and weigh the required quantity of material, note the weighed material and then remove the container from balance and press Zero.
9.2.8 Close the dispensed material, affix the weighing tag and transfer the material in dispensed material storage room.
9.2.9 After dispensing, put “OFF” the balance and LAF. Clean the surrounding area, balance and spray with 70% IPA solution.
9.2.10 Reseal the original container and shift to their original place.
9.3 Batch Preparation 150 L:
9.3.1 Ensure that the area and product line is clean and free from the traces of previous product.
9.3.2 Recheck the tag and gross weight of Soybean casein digest medium (SCDM) to be used for manufacturing and ensure that they match as per entries made in the BMR weighing sheet.
9.3.3 Check the status board affixed on the tank “READY FOR USE”, also verify the records and ensure that the bottom outlet valve of the mixing tank is closed.
9.3.4 Send the entry point sample of WFI from the user point to QC department for testing along with BMR.
9.3.5 On approval of WFI sample from QC department, affix a status board on the Mixing tank “UNDER MANUFCTURING” with Product name and B. No.
9.3.6 Collect approx 50 L water for injection at 80 to 850C in a manufacturing tank fitted with stirrer.
9.3.7 Start the stirrer and add SCDM through the manhole of the tank.
9.3.8 Continue stirrer for complete dissolution of ingredients.
9.3.9 Stop the stirrer.
9.3.10 Make up the volume to the 150 L with water for injection.
9.3.11 Start the stirring for complete dissolution of SCDM and homogeneous bulk solution (generally required 10 minutes).
9.3.12 Collect sample of bulk solution in a sterile sampling bottle and send it to QC for testing of color clarity, pH and bioburden along with bulk intimation slip.
9.3.13 After getting clearance of bulk analysis from Quality Control, start the filtration from mixing tank to Holding tank with the help of pump.
9.3.14 Perform the bubble point test of the final filter after holding tank as per SOP of Bubble point test.
10.4 Filling and Sealing:
10.4.1 Start the filtration from holding tank to FFS machine using pump.
10.4.2 Drain one buffer tank approx 1.3 liters of bulk solution from filling nozzle to eliminate any possibility of dilution of bulk by condensates in product line of the machine post SIP.
10.4.3 Check online cartridge filter integrity test as per its respective SOP.
10.4.4 Start Machine and discard initial 15 shots.
10.4.5 Collect first cassette of vials from next shot and send the sample with written information to QC for testing.
10.4.6 Arrange the out coming cassettes of vials sequentially in vacuum chamber tray and verify the results of testing from QC department.
10.4.7 Now start the filling and sealing continuously as per SOP for Filling and sealing.
10.4.8 Collect the filled and sealed containers coming out of the filling area in plastic crates.
10.4.9 During filling operation keep the filled ampoules separately for each breakdown, shift change, power breakdown, stoppage etc and assign lot number.
10.4.10 Arrange the cassettes of vials lot wise in SS trays vertically in vacuum leak testing chamber tray and carry out the leak testing at 650 – 720 mm Hg for 30 minutes. Do not use the leak vials for further media fill study.
10.4.11 After leak test, transfer the goods vials in the clean plastic crates horizontally in cassette from one above the other, lot wise separately.
10.5 Incubation and Examination of Media Filled Units:
10.5.1 Incubate all media filled units in normal position after leak test at 20 to 250C for 7 days. Incubation temperature should be maintained within 22.5 ± 2.50C.
10.5.2 After completion of 7 days Incubation at 20 to 250C, invert the units and incubate them at 30-350C for next 7 days. Incubation temperature should be maintained within 32.5±2.50C.
10.5.3 Each media filled unit should be examined by trained Microbiologist after 3rd day, 7th day, 10th day and 14th day.
10.5.4 All suspect units identified during the observation should be brought to the immediate attention of the QC Microbiologist.
10.5.5 During incubation, if any unit found to be damaged should be recorded in media fill observation format.
10.6 Interpretation of Results:
10.6.1 When filling fewer than 5,000 units, no contaminated units should be detected.
10.6.2 When filling 5,000 to 1,0000 units :
(a) One contaminated unit should result in an investigation, including consideration of a repeat media fill ;
(b) Two contaminated units are considered cause for revalidation, following investigation.
10.6.3 When filling more than 10,000 units:
(a) One contaminated unit should result in an investigation;
(b) Two contaminated units are considered cause for revalidation, following investigation.
10.7 Failure Investigation:
10.7.1 Any contaminated unit should be considered objectionable and investigated. The microorganism should be identified to species level.
10.7.2 The investigation should survey the possible causes of contamination during media fill trials i.e. Environmental, personnel and surface monitoring.
10.7.3 Based on the outcome of the investigation, assign the cause of failure is assignable or not assignable.
10.7.4 If the cause is assignable, then take a corrective and preventive action and record the same in suitable format.
10.7.5 If the cause is not assignable, then the process should be validated, as it is a new process. Consecutive three-process simulation test should be performed to demonstrate consistency and reliability on the sterile formulation manufacturing process to produce acceptable product.
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