Standard Operating Procedure (SOP) for Media Fill Validation in Sterile facility. A “media fill” (sometimes known as a “process simulation”) is the performance of an aseptic manufacturing procedure using a sterile microbiological growth medium in place of the drug solution.
The microbiological growth medium is used in place of the drug solution during media fills to test whether the aseptic procedures are adequate to prevent contamination during actual drug production.
A media fill is one part of the validation of an aseptic manufacturing process.
SOP for Media Fill Validation
1.0 PURPOSE:
- To lay down the procedure to challenge the aseptic techniques used for sterile drug product processing using media fill.
2.0 SCOPE:
- This SOP is applicable for media fill operation to be carried out for aseptic processing using a dry powder filling machine at the sterile/aseptic drug manufacturing plant.
3.0 RESPONSIBILITY – MEDIA FILL VALIDATION:
- Production Department shall be responsible for:
- Perform media fill as per the defined frequency and procedure.
- Simulate all routine and possible non-routine interventions during media fill as per the defined procedure.
- To ensure each operator working in the aseptic area shall participate in the media fill once in a year.
- Quality Assurance Department shall be responsible for :
- To ensure that media fill activity is performed as per the frequency and procedure described in the SOP.
- Monitor media fill operation and review the documentation.
- To evaluate the results of the media fill and conduct investigation resulting from the media fills failure (if any) in consultation with production.
- Quality Control (Microbiology) Department shall be responsible for:
- To provide sterile media powders for media fill activity
- Perform microbiological monitoring for the environment, personnel, and surface during media fill as specified in the protocol.
- To collect different samples for sterility, BET, particulate matter, and bioload as per the media fill protocol.
- Utility Department shall be responsible for:
- To ensure that each person handling aseptic area maintenance activities in the aseptic area shall participate in the media fill once in a year.
- To participate and co-ordinate in taking the intervention.
4.0 DEFINITION (S):
- Media fill: Method of evaluating an aseptic process using a microbial growth medium. (Media fills are understood to be synonymous to simulated product fills, broth trials, broth fills, etc.).
5.0 PROCEDURE – MEDIA FILL VALIDATION:
| 5.1 | Initial validation of an aseptic process: |
| 5.1.1 | Each new type of aseptic process shall be validated with media fills prior to regular production. This includes but is not limited to; new container closure systems, new filling lines, the introduction of new operating shifts. |
| 5.1.2 | For new facilities, pre-qualification media fill runs may be performed. This is for the verification of the machine performance and fine-tuning of the facility. |
| 5.1.3 | At least three successive successful media fills for each vial size are required to ensure that the results are consistent and meeting acceptance criteria. |
| 5.2 | Scheduled revalidation of an aseptic process: |
| 5.2.1 | Media fill activity shall be repeated every six months ± 1 month with all operating shift with maximum and minimum vial size. |
| 5.2.2 | The smallest and the biggest size of the container filled on a particular line shall be challenged to demonstrate bracketing of the container sizes. |
| 5.2.3 | During media fill, an empty run (Dummy / mock run) shall be performed for verification of online particle counter performance with all sensors running conditions. |
| 5.3 | Revalidation other than scheduled revalidation: |
| 5.3.1 | Revalidation shall be performed in case of any of the below-mentioned activities has been carried out. |
| 5.3.1.1 | Facility and/or equipment modification. |
| 5.3.1.2 | Changes in the process. |
| 5.3.1.3 | Anomalies in environmental monitoring result. (Continuous out of trend found during the environmental monitoring). |
| 5.3.1.4 | Failure in sterility test. |
| 5.3.1.5 | As per recommendation during any incident or investigation. |
| 5.3.1.6 | The container size of the new product is out of the container size bracketed for the filling line. |
| 5.3.1.7 | Failure of initial validation and routine media fill. |
| 5.4 | Planned interventions during media fill: |
| 5.4.1 | The representative number of all routine interventions and possible non-routine interventions shall be simulated in all media fill tests as per respective protocol, which includes but not limited to: |
| 5.4.1.1 | Removing vials for weight variation. |
| 5.4.1.2 | Adjustment of fill weight. |
| 5.4.1.3 | The setting of compressed air and vacuum supply. |
| 5.4.1.4 | Failure of power supply. |
| 5.4.1.5 | Removal of fallen vials from the turntable |
| 5.4.1.6 | Presence of maximum persons in the filling area. |
| 5.4.1.7 | The entry of QA and Production person |
| 5.4.1.8 | Change of operator |
| 5.4.1.9 | Charging of seals |
| 5.4.1.10 | Minimum, optimum, and maximum filling speed. |
| 5.4.1.11 | Charging of rubber stopper in the hopper. |
| 5.4.1.12 | Charging of sterile powder in the hopper |
| 5.4.1.13 | Removal of loosely fitted plugged vials with forceps |
| 5.4.1.14 | Stoppage of filling machine |
| 5.4.1.15 | Cleaning of spilled powder |
| 5.4.1.16 | Adjustment of the bung pressure rocker arm |
| 5.4.1.17 | Pushing vials in channels by forceps |
| 5.4.1.18 | A sampling of Vials, bungs, seals, WFI, and SCDM from filling line. |
| 5.5 | Unplanned interventions during media fill: |
| 5.5.1 | All unplanned interventions/breakdown shall be immediately reported to Head QA and same shall be documented in media fill validation report |
| 5.6 | Fill Volume: |
| 5.6.1 | The fill volume of media should be sufficient to wet the entire surface including the closures and to allow easy inspection. A volume of at least greater than 50 % of the total container volume is recommended. |
| 5.6.2 | Fill weight of SCDM and W.F.I. should be adjusted in such a way that the concentration of SCDM remains a minimum of 3% in each vial. |
| 5.7 | Duration of media filling: |
| 5.7.1 | Media filling activity shall be performed to cover three operating shifts. |
| 5.7.2 | At least one run should cover all the operating shifts for each type of vials. |
| 5.7.3 | The duration of the run shall adequately mimic worse case operating conditions and cover all interventions that are performed in the actual processing operation. |
| 5.8 | Size of runs: |
| 5.8.1 | A generally acceptable starting point for run size is in the range of 5, 000 to 10, 000 units. |
| 5.8.2 | The size of the run should be sufficient to cover all the representative numbers of planned/Un-planned Interventions and desired filling duration. |
| 5.8.3 | The number of vials filled shall be sufficient to reflect the effect of potential operator fatigue, as well as the maximum number of interventions. |
| 5.9 | Sample preparation for negative and positive control: |
| 5.9.1 | Media filled vials shall be checked against negative and positive control vials used as a reference. |
| 5.9.2 | Microbiologist shall prepare negative and positive control separately in the microbiology testing area. The required quantity of media is taken aseptically in the sterilized conical flask and adds the required quantity of sterile water for injection and dissolves completely. Pour aseptically in dehydrogenated vials. The prepared vials shall be incubated at 20 to 25°C for 7 days and 30 to 35°C for the next 7 days. If no growth observed, the vials shall be considered as a negative control for checking media filled vials. Negative control shall prepare before 2 weeks of media fill activity. |
| 5.9.3 | During validation, the positive control shall be prepared. Prepare the vials containing sterile media is as per procedure mentioned in step no. 5.9.2. Add 10-100 cfu culture of the different organisms in the vials and incubate the vials at respective temperatures to get luxuriant growth. These vials shall be used as a positive control for media fill vials. The positive control vials shall be used within 15 days after incubation. |
| 5.9.4 | The positive and negative control vials shall be prepared for each vial size and kept in the microbiology lab and shall be used during a visual inspection of media filled vials as a reference. |
| 5.10 | Personnel involvement during media fill: |
| 5.10.1 | During media fill the personnel involved should include Operator, supervisor, QA, production, microbiologist, and engineering. |
| 5.10.2 | Each person participating in the media fill should perform his normal job function for that process. |
| 5.11 | Issuance of media fill Protocol and BMR: |
| 5.11.1 | BMR for media fill shall be prepared and issued as per SOP. |
| 5.11.2 | Carryout the media fill as per the steps mentioned in the protocol and BMR. |
| 5.12 | Choice Of Sterile Soyabean Casein Digest Medium For Simulation: |
| 5.12.1 | Sterile Soyabean casein digest medium powder is selected for media fill activity because of the following reasons: |
| 5.12.2 | Low selectivity of media i.e. it supports the growth of a wide range of organisms including bacteria and fungi. |
| 5.12.3 | Good growth-promoting the property. |
| 5.12.4 | Flow-ability of Sterile Soyabean casein digest medium through hopper and dosing wheel is good. |
| 5.12.5 | Sterile Soyabean casein digest medium is easily soluble in water for injection. |
| 5.12.6 | Clarity of the media to observe the turbidity if present. |
| 5.13 | Filtration of WFI: |
| 5.13.1 | Filter WFI through 0.2-micron filter and collect the filtrate in pre-sterilized pressure vessel through sterile silicon tube as per SOP. |
| 5.14 | Blending : |
| 5.14.1 | Sterile SCDM shall be blended in blender bin before use in filling operation, blending shall be carried out as per respective media fill BMR. |
| 5.15 | Filling: |
| 5.15.1 | Sterilized SCDM shall be used for filling. |
| 5.15.2 | First WFI will be filled in vials through the additional filling assembly. |
| 5.15.3 | After that SCDM will be filled in vials through powder hopper. |
| 5.15.4 | During media, filling simulates all the possible interventions as described in Protocol. |
| 5.15.5 | All interventions including unplanned interventions must be documented as part of the media fill record. |
| 5.15.6 | Carry out the in-process testing as mentioned in the BMR and protocol, which includes but not limited to checking the weight of sterile powder i.e. SCDM, volume verification for sterile WFI, color, and clarity test, Seal integrity test of filled vials. |
| 5.15.7 | Microbiologist shall perform environmental monitoring, surface monitoring, and personnel monitoring as per respective SOP’s. |
| 5.15.8 | Carryout non-viable particle count monitoring before media fill validation as per SOP. |
| 5.15.9 | The activity shall be performed with frequent interventions, which we come across during routine production to simulate actual conditions. |
| 5.15.10 | The vials filled during each intervention shall be collected in suitable trays/boxes. |
| 5.15.11 | The trays/boxes shall be marked with the name of intervention and no. of vials. |
| 5.16 | Cleaning and sanitization after media fill: |
| 5.16.1 | After completion of media fill run, clean the entire area as per respective SOP. |
| 5.17 | Visual inspection & training: |
| 5.17.1 | Visual inspection of media filled vials shall be performed three times: Before incubation. After 7 days incubation After 14 days of incubation. |
| 5.17.2 | Personnel conducting the inspection of media filled vials must have documented training on the following: Basic microbiological concepts. Concepts of media fill. Examples of contaminated vials. |
| 5.17.3 | Visual inspection of media filled vials shall be supervised by the microbiology & QA department. |
| 5.18 | Visual inspection before incubation: |
| 5.18.1 | Sort out and reject those vials having an obvious breach of container/closure integrity (Non-integral vials) such as cracked containers, broken containers, Containers with missing stopper. Record tray wise quantity of good containers to be incubated on the tray label as well as BMR. |
| 5.18.2 | Empty containers with container closure integrity shall be rejected. |
| 5.18.3 | Good vials shall be stored in trays in an inverted position. |
| 5.18.4 | Record tray wise quantity of good vials and integral rejected vials to be incubated in the protocol as well as in BMR. |
| 5.19 | Incubation: |
| 5.19.1 | All good vials shall be incubated. |
| 5.19.2 | Incubate media filled vials for not less than 336 hours (14 days). |
| 5.19.3 | After 7 days of incubation observe the vials for any microbial contamination and record the observation. |
| 5.19.4 | Transfer the vials at 30-35°C for another 7 days. |
| 5.19.5 | Observe and record the temperature of the incubation room on a daily basis in the media fill protocol. |
| 5.20 | Visual Inspection during & after incubation: |
| 5.20.1 | During incubation check, the seal integrity of media filled vials and after 7 days & 14 days of incubation observes the vials for any microbial contamination and record the observations. |
| 5.21 | Growth promotion test of media filled vials: |
| 5.21.1 | The objective of this test is to observe that the media in the filled vial remains growth-promoting up to the end of the incubation period. |
| 5.21.2 | Collect the samples of media fill container for the growth promotion test as per protocol and send to QC Micro department along with intimation. |
| 5.21.3 | Growth promotion test shall be performed as per SOP. |
| 5.21.4 | Media shall be demonstrated to promote the growth of the following microorganisms as well as isolates that have been identified by Environmental monitoring. |
| Pseudomonas aeruginosa ATCC 9027/NCIM2200. Bacillus subtilis ATCC 6633/NCIM-8054 S. aureus ATCC –6538 C. albicans ATCC -10231 A. niger ATCC – 16404 | |
| 5.21.5 | Failure of GPT shall be investigated and if required media fill shall be repeated |
| 5.22 | Acceptance criteria |
| No. Of incubated vials Maximum number of contaminated units for a passing result Additional Investigation Requirement Less than 5,000 0 Not Applicable (Note: 1 contaminated unit is Considered cause for revalidation Following an investigation) 5,000 – 10,000 0 1 contaminated unit should result in an investigation, including consideration of a repeat media fill. (Note: 2 contaminated unit may be considered cause for revalidation Following an investigation) More than 10,000 1 1 contaminated unit requires an investigation. (Note: 2 contaminated unit is Considered cause for revalidation Following an investigation) |
| 5.23 | Action to be taken in case of media fill failure: Media fill failure investigation to be carried out as per SOP. If the out of specification confirms the following action to be taken: Root causes analysis to be performed as per SOP. In view of the failure re-review the environmental monitoring data, personnel monitoring data, and Batch manufacturing data. Impact of the failure to be assessed on previously manufactured batches. Take corrective and preventive action and repeat three consecutive media fill run. Based on the success of the repeat media fill production activity to be taken. |
| 5.24 | Disposal of media filled Containers: |
| 5.24.1 | After completion of incubation and successful growth promotion of media filled vials, destruction of media filled vials shall be done. Open the vials and pour the media in container, having a 5 % Savlon solution. The vial shall be kept in another container having 5 % savlon solution. |
| 5.24.2 | Rubber stoppers and seals shall be kept in the container having a 5% savlon solution. |
| 5.24.3 | Give the contact time of 1 hour, then discard the media in drain and vials, bungs and seals shall be sent to scrap yard for destruction. |
| 5.25 | Resuming Production after media fill: |
| 5.25.1 | Batches manufactured after media fill shall be released by QA only after successful validation results. & closure of the investigation report (if any). |
6.0 REFERENCE (S)
- Guidance for Industry ‘Sterile Drug Products: Produced by Aseptic Processing – Current Good Manufacturing Practice’ by U. S., Department of Health and Human Services. – September 2004.
- WHO Technical report series, No. 957,2010