Media Fill Validation Procedure & Guideline

A media fill is the performance of an aseptic manufacturing procedure using a sterile microbiological growth medium, in place of the drug solution, to test whether the aseptic procedures are adequate to prevent contamination during actual drug production.

Media Fill Validation / Aseptic Process  Simulation

1.0   OBJECTIVE

• • 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 operations to be carried out for aseptic processing using an injection filling machine at the pharmaceutical drug manufacturing plant.

3.0   RESPONSIBILITY – MEDIA FILL OPERATIONS

• • The production department shall be responsible to:

• • 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.

• • Ensure each operator working in the aseptic area shall participate in the media fill once a year.

• • The Quality Assurance department shall be responsible 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.

• • Evaluate the results of the media fill and conduct investigation resulting from the media fill failure (if any) in consultation with production.

• • Quality Control (Microbiology) department shall be responsible 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 media fill protocol.

• • To collect different samples for sterility, BET, particulate matter, and bio load as per the media fill protocol.

• • Utility Department department shall be responsible to:

• • To ensure that each person handling aseptic area maintenance activities in the aseptic area shall participate in the media fill once a year.

• • To participate and coordinate in taking the intervention.

Definition of Media fill: Method of evaluating an aseptic process using a microbial growth medium. (Media fills are understood to be synonymous with simulated product fills, broth trials, broth fills, etc.).

5.0   PROCEDURE – MEDIA FILL OPERATIONS

• • Initial validation of an aseptic process (Medial Fill) :

• • 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, and the introduction of new operating shifts.

• • 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.

• • At least three successive successful media fills for each vial size are required to ensure that the results are consistent and meet acceptance criteria.

• • Scheduled revalidation of an aseptic process:

• • Media fill activity shall be repeated every six months ± 1 month with all operating shifts with maximum and minimum vial size.

• • The smallest and the biggest size of the container filled on a particular line shall be challenged to demonstrate bracketing of the container sizes.

• • During media fill, an empty run (Dummy / mock run) shall be performed for verification of online particle counter performance with all sensors running condition.

• • Revalidation other than scheduled revalidation:

• • Revalidation shall be performed in case any of the below-mentioned activities have been carried out.

• • • Facility and/or equipment modification.

• • • Changes in the process.

• • • Anomalies in environmental monitoring result. (Continuous out-of-trend found during the environmental monitoring).

• • • Failure in sterility test.

• • • As per recommendation during any incident or investigation.

• • • The container size of the new product is out of the container size bracketed for the filling line.
    • Failure of initial validation and routine media fill.

• • Planned interventions during media fill:

  • A 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 is not limited to:

• • • Removing vials for weight variation.

• • • Adjustment of fill weight.

• • • The setting of compressed air and vacuum supply.

• • • Failure of power supply.

• • • Removal of fallen vials from the turntable.

• • • Presence of maximum persons in filling area.

• • • Entry of QA and Production person.

• • • Change of operator.

• • • Charging of seals.

• • • Minimum, optimum, and maximum filling speed.

• • • Charging of rubber stopper in the hopper.

• • • Charging of sterile powder in hopper.

• • • Removal of loosely fitted plugged vials with forceps.

• • • Stoppage of filling machine.

• • • Cleaning of spilled powder.

• • • Adjustment of the bung pressure rocker arm.

• • • Pushing vials in channels by forceps.

• • • A sampling of Vials, bungs, seals, WFI, and SCDM from the filling line.

• • Unplanned interventions during media fill:

  • All unplanned interventions/breakdowns shall be immediately reported to Head QA and the same shall be documented in the media fill validation report.

• • Fill Volume:

• • 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.

• • The 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.

• Process & Interventions duration of media filling:

• • Media filling activity shall be performed to cover three operating shifts.

• • At least one run should cover all the operating shifts for each type of vial.

• • The duration of the run shall adequately mimic worst-case operating conditions and cover all interventions that are performed in the actual processing operation.

• • Size of Media Fill runs:

• • A generally acceptable starting point for run size is in the range of 5, 000 to 10, 000 units.

• • The size of the run should be sufficient to cover all the representative numbers of planned/Un-planned Interventions and desired filling duration.

• • The number of vials filled shall be sufficient to reflect the effect of potential operator fatigue, as well as the maximum number of interventions.

• • Sample preparation for negative and positive control:

• • Media-filled vials shall be checked against negative and positive control vials used as references.

• • Microbiologists 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 is for injection and dissolves completely. Pour aseptically into 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 is 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.

• • During media fill validation the positive control shall be prepared. Prepare the vials containing sterile media as per the procedure mentioned in the above step.  Add 10-100 cfu cultures 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.

• • The positive and negative control vials shall be prepared for each vial size and kept in the microbiology lab and shall be used during the visual inspection of media-filled vials as a reference.

• • Personnel involvement during media fill:

• • During media fill the personnel involved should include the Operator, supervisor, QA, production, microbiologist, and engineering.

• • Each person participating in the media fill should perform his normal job function for that process.

• • Issuance of media fills Protocol and BMR:

• • BMR for media fill shall be prepared and issued.

• • Carry out the media fill as per the steps mentioned in the protocol and BMR.

• • Choice Of Sterile Soyabean Casein Digest Medium For Simulation:

• • Sterile Soyabean casein digests medium powder is selected for activity because of the following reasons:

• • Low selectivity of media i.e. it supports the growth of a wide range of organisms including bacteria and fungi.

• • Good growth promoting property.

• • The flowability of the Sterile Soyabean casein digest medium through the hopper and the dosing wheel is good.

• • Sterile Soyabean casein digest medium is easily soluble in water for injection.

• • Clarity of the media to observe the turbidity if present.

• • Filtration of WFI:

• • Filter WFI through the 0.2-micron filter and collect the filtrate in a pre-sterilized pressure vessel through a sterile silicon tube.

• • Blending :

• • Sterile SCDM shall be blended in a blender bin before use in the filling operation, blending shall be carried out as per respective BMR.

• • Media Fill Filling process:

• • Sterilized SCDM shall be used for filling.

• • First WFI will be filled in vials through the additional filling assembly.

• • After that SCDM will be filled in vials through a powder hopper.

• • During media, filling simulates all the possible interventions as described in Protocol.

• • All interventions including unplanned interventions must be documented as part of the media fill the record.

• • Carry out the in-process testing as mentioned in the BMR and protocol, which includes but is not limited to checking the weight of sterile powder i.e. SCDM, volume verification for sterile WFI, color and clarity test, and Seal integrity test of filled vials.

• • Microbiologists shall perform environmental monitoring, surface monitoring, and personnel monitoring.

• • Carry out non-viable particle count monitoring before validation.

• • The activity shall be performed with frequent interventions, which we come across during routine production to simulate actual conditions.

• • The vials filled during each intervention shall be collected in suitable trays/boxes.

• • The trays/boxes shall be marked with the name of the intervention and no. of vials.

• • Cleaning and sanitization after media fill:

• • After completion of the run, clean the entire area.

• • Visual inspection & training:

• • Visual inspection of media-filled vials shall be performed three times:

• • • Before incubation.

• • • After 7 days of incubation

• • • After 14 days of incubation

• • 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.

• • Visual inspection of media-filled vials shall be supervised by the microbiology & QA department.

• • Visual inspection before incubation:

• • Sort out and reject those vials having obvious breaches of container/closure integrity (Non-integral vials) such as cracked containers, broken containers, and Containers with missing stoppers. Record tray-wise quantity of good containers to be incubated on the tray label as well as BMR.

• • Empty containers with container closure integrity shall be rejected.

• • Good vials shall be stored in trays in the inverted position.

• • Record tray-wise quantity of good vials and integral rejected vials to be incubated in the protocol as well as in BMR.

• • Media Fill Vial Incubation:

• • All good vials shall be incubated.

• • Incubate media-filled vials for not less than 336 hours (14 days).

• • After 7 days of incubation observe the vials for any microbial contamination and record the observation.

• • Transfer the vials at 30-35°C for another 7 days.

• • Observe and record the temperature of the incubation room on daily basis in the protocol.

• • Visual Inspection during & after incubation:

• • 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.

• • Growth promotion test of media-filled vials:

• • 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.

• • Collect the samples of container for the growth promotion test as per protocol and send to QC Micro department along with intimation.

• • A growth promotion test shall be performed.

• • 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

• • Failure of GPT shall be investigated and if required media fill shall be repeated.

• • Acceptance criteria of Aseptic Process Simulation :

• • Action to be taken in case of media fill failure:

• • Failure investigation to be carried out as per SOP.

• • If the out of specification confirms the following action is to be taken:

• • Root cause analysis is 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 runs. Based on the success of the repeat media fill production activity to be taken.

• • Disposal of media filled Containers:

• • 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 into the container, having 5 % Savlon solution. The vial shall be kept in another container having 5 % savlon solution.

• • Rubber stoppers and seals shall be kept in the container having 5% savlon solution.

• • Give the contact time of 1 hour, then discard the media in the drain, and vials, bungs, and seals shall be sent to the scrap yard for destruction

• • Resuming Production after simulation:

• • Batches manufactured after media fill shall be released by QA only after the successful media fill results. & closure of investigation report (if any).

7.0      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.

• • WHO Technical report series, No. 957,