Validation of Integrated line by Media Fill Test Seminar On Validation of Integrated line by Media Fill Test

INDEX Introduction Validation What is media fill test ? Principle of media fill test Protocol Validation Objectives Scope Responsibilities Pre-requisites Equipment/ system description Study design Procedure 23 April 2017

Media Fill Test

What is Media Fill Test ? Aseptic media fill test is used to quantify the aseptic technique of compounding personnel or processes and to insure that the processes used are able to produce a sterile product without microbial contamination During this test microbiological growth medium such as Soybean Casein Digest Medium (SCDM) is substituted for the actual drug product to simulate admixture compounding The final container is then incubated and checked for turbidity which indicate the microbial contamination 23 April 2017

Principles of Media Fill Why the validation of aseptic process is required by pharmaceutical regulations? A “sterile product” is defined as “free of viable organisms” As it is not practical examine every unit for confirmation of sterility. All efforts are made to minimise the risk of contamination (finishing, HVAC, pressure differentials, cleaning procedure, monitoring programme) 23 April 2017

Principles of Media Fill Despite of such measures, contamination is an ever-present danger because aseptic processing is a process being operated in a controlled –but not sterile- environment and sample numbers are too small; so that only gross contamination is likely to be detected So the sterility of the product is major requirement, But the sterility test of the whole batch is not possible to check whole batch because it is destructive method. It is better to validate the integrated line by media fill test 23 April 2017

Media Fill Protocol Number and frequency of runs Medium culture (to replace the product) Number of units filled Container (vial) size Fill volume Line speed (or filling speed) Duration of fill Operators shifts Monitoring activities Interventions –both routine and non-routine Incubation method Acceptance criteria 23 April 2017

Validation of Integrated line by Media Fill test

OBJECTIVE The Objective of validation protocol is to establish documented evidence that the process employed for aseptic processing of Parenterals liquid/Ophthalmic solution will produce the desired results consistently, within the specified acceptance limits, when performed as per the latest Standard Operating Procedures. SCOPE The Validation protocol describes the procedure for the total Process Simulation (Media Fill) for integrated line. 23 April 2017

RESPONSIBILITIES Sr. no . Responsibility Name of the department 1 Preparation of Protocol QC 2 Provision of qualified personnel to assist in the protocol preparation and execution QC, QA, Production and Maintenance 3 Verification of Protocol QC and Production 4 Approval of protocol QA 5 Final determination of System Acceptability 6 Review and assembling of data into a final report 23 April 2017

PREREQUISITES PREREQUISITES PREREQUISITES PREREQUISITES PRE-REQUISITES Approved Soybean casein digest broth Environmental Monitoring of manufacturing areas by Plate Exposure, Air sampling and surface monitoring procedures and its SOP’s. Qualified and validated manufacturing equipments, system facility (i.e. HVAC, water, compressed gases) CIP and SIP procedures. Trained operating personnel’s. Approved BMR for media fill trial. 23 April 2017

EQUIPMENT / SYSTEM DESCRIPTION: Location :Manufacturing Area integrated line ( Mixing room and filling room) Equipments :Mixing Tank, Holding Tank, Filtration housings, connected product line and FFS machines 23 April 2017

IDENTIFICATION OF CRITICAL CONTROL MONITORING PARAMETER Check and ensure that- The equipment and system facility is validated. The HVAC system, compressed air, CIP and SIP procedures are qualified. All operations, cleaning/sanitization procedures are established and operating personnel are trained. Media used for Process Simulation is passed for GPT The WFI used for preparation of batch is complied to USP/IP 23 April 2017

STUDY DESIGN Worst Case Consideration Frequency, Duration, Number of runs & Fill Volume  Environmental Consideration  Media  Incubation and examination of filled units Interpretation of Test Result: 23 April 2017

STUDY DESIGN Worst Case Consideration Allow maximum number of personnel in the aseptic processing area , including the maintenances and house keeping personnel   Increased the time period to start the filling operation Increase the Duration of the media fill trial than that required for routine manufacturing operation. Simulating Process / Power breakdown during the process simulation test  Shift changes and breaks 23 April 2017

STUDY DESIGN Frequency, Duration, Number of runs & Fill Volume 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 . Filled units in Media Fill run should be 10,000 units or more. Fill minimum 3000 units in each production shift. 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 steps  Fill volume for Media Fill run for SVP is 10 ml. 23 April 2017

STUDY DESIGN Environmental conditions Cleaning of Area must be done by using routine cleaning agent and disinfectant solution, as per latest SOP Microbiological Environmental Monitoring should be carried out by - Settle plate Air sampling Swab test and personnel monitoring as per the latest SOP. 23 April 2017

STUDY DESIGN   Media: Soybean Casein Digest Medium, manufactured by Hi Media Laboratories should be used for Media fill trial The media must be passed the test for GPT as per SOP No. APL/QC/SOP/185 to promote the growth of gram-negative and gram-positive bacteria and yeast and molds For anaerobic microbs Fluid Thioglycollate Medium (FTM) is used 23 April 2017

STUDY DESIGN Incubation and examination of filled units: 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 . 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 . Each media filled unit should be examined by trained Microbiologist after 3rd day, 7th day, 10th day and 14th day. All suspect units identified during the observation should be brought to the immediate attention of the QC Microbiologist. 23 April 2017

STUDY DESIGN Interpretation of Test Result: Any contaminated unit should be considered objectionable and investigated. The microorganism should be identified to species level. The investigation should survey the possible causes of contamination. When filled units up to 10000, one contaminated unit should result in an investigation, including consideration of a repeat test. 23 April 2017

VALIDATION PROCEDURE Main steps for the Validation of the integrated line by media fill test Cleaning of the line Dispensing of Soybean Casein Digest Medium for 150 L batch size Batch Preparation 150 L Filling And Sealing Incubation and Examination of Media Filled Units  Interpretation of Results 23 April 2017

VALIDATION PROCEDURE Cleaning of the SVP line Carry out cleaning of SVP mixing tank and holding tank along with product line and bottle pack machine as per respective SOP for CIP. 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.   After getting approval report from QC, affix status label on the tank “READY FOR STERILIZATION”. Immediately carry out the sterilization of SVP holding tank along with final filter and product line of bottle pack machine as per respective SOP. 23 April 2017

VALIDATION PROCEDURE Dispensing of Soybean Casein Digest Medium for 150 L batch size Enter to dispensing room as per SOP for entry exit procedure to dispensing area. 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. Check the availability of clean containers, pressure differentials, and temperature & humidity should be not more than 250C and 45 to 60% RH respectively. 23 April 2017

VALIDATION PROCEDURE Calibrate the balance as per SOP of Balance Calibration. 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. 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. Close the dispensed material, affix the weighing tag and transfer the material in dispensed material storage room. 23 April 2017

VALIDATION PROCEDURE Batch Preparation 150 L: After dispensing, put “OFF” the balance and LAF. Clean the surrounding area, balance and spray with 70% IPA solution. Reseal the original container and shift to their original place. Batch Preparation 150 L: Ensure that the area and product line is clean and free from the traces of previous product. Recheck 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. 23 April 2017

VALIDATION PROCEDURE 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. Send the entry point sample of WFI from the user point to QC department for testing along with BMR. On approval of WFI sample from QC department, affix a status board on the Mixing tank “UNDER MANUFCTURING” with Product name and B. No. Collect approx 50 L water for injection at 80 to 850C in a manufacturing tank fitted with stirrer. Start the stirrer and add SCDM through the mainhole of the tank. 23 April 2017

VALIDATION PROCEDURE Continue stirrer for complete dissolution of ingredients. Stop the stirrer. Make up the volume to the 150 L with water for injection. Start the stirring for complete dissolution of SCDM and homogeneous bulk solution (generally required 10 minutes). 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. After getting clearance of bulk analysis from Quality Control, start the filtration from mixing tank to Holding tank of line with the help of pump. 23 April 2017

VALIDATION PROCEDURE Filling And Sealing: After getting clearance of bulk analysis from Quality Control, start the filtration from mixing tank to Holding tank of line with the help of pump. Perform the bubble point test of the final filter after holding tank as per SOP of Bubble point test. Filling And Sealing: Start the filtration from holding tank to FFS machine using pump. 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. 23 April 2017

VALIDATION PROCEDURE Check online cartridge filter integrity test as per its respective SOP. Start Machine line and discard initial 15 shots. Collect first cassette of vials from next shot and send the sample with written information to QC for testing. Arrange the out coming cassettes of vials sequentially in vacuum chamber tray and verify the results of testing from QC department. Now start the filling and sealing continuously as per SOP for Filling and sealing. 23 April 2017

VALIDATION PROCEDURE Collect the filled and sealed containers coming out of the filling area in plastic crates. During filling operation keep the filled ampoules separately for each breakdown, shift change, power breakdown, stoppage etc and assign lot number. 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. After leak test, transfer the goods vials in the clean plastic crates horizontally in cassette from one above the other, lot wise separately 23 April 2017

VALIDATION PROCEDURE Incubation and examination of filled units: 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 . 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 . Each media filled unit should be examined by trained Microbiologist after 3rd day, 7th day, 10th day and 14th day. All suspect units identified during the observation should be brought to the immediate attention of the QC Microbiologist. 23 April 2017

VALIDATION PROCEDURE Interpretation of Results: When filling fewer than 5,000 units, no contaminated units should be detected.  When filling 5,000 to 10,000 units : One contaminated unit should result in an investigation, including consideration of a repeat media fill Two contaminated units are considered cause for revalidation, following investigation. When filling more than 10,000 units : One contaminated unit should result in an investigation; Two contaminated units are considered cause for revalidation, following investigation.  23 April 2017

REFERENCES Syed Imtiaz Haider, “ Validation Standard Operating Procedures ” 314-321 R. A. Nash and A. H. Wachter “Pharmaceutical Process validation”; Third edition Agalloco James, Carleton J. Fredric “Validation of Pharmaceutical Processes”; Third edition Pharmaguideline.blogspot.com www.milipore.com www.nsdl.niscair.res.in/bitstream 23 April 2017

23 April 2017