What is Media Fill
The Media fill or Broth fill technique is one in which a liquid microbiological nutrient growth medium is prepared and filled in a simulation of normal manufacturing operation.
The microbiological growth medium such as Soybean Casein Digest Medium (SCDM) is processed and handled in a manner which simulates “normal” manufacturing process with same exposure and possible contamination.
The final container is then incubated and checked for turbidity which indicate the microbial contamination.
- The medium should be able to support the growth of a wide range of microorganisms.
- The medium should be suitable from a process perspective to perform as product (e.g. it should be filterable, if the product is normally also filtered).
- The medium should be clear in order to be able to observe any turbidity caused by growth.
- The medium should be prepared according to manufacturer’s instructions.
- Medium tested on House Flora Meaning: House Flora determined as a prerequisite
- Growth Promotion Property tests with the correct amount of microorganisms (10 – 100 or less CFU/unit)
- GPP test performed either after processing or in parallel; growth within 5 days
Area General Principles :
- Media fills should be performed in the same areas as product fills (this includes being in and out a freeze-‐dryer, if applicable!).
- If the same process is carried out in another clean room, this should also be validated.
- Each filling line to be validated twice per year
- Bracketing principles can be applied to reduce number of fills.
- Worst case principles can be applied to reduce number of fills.
Filling Equipment’s General Principles :
- The same equipment that is used for product fills should be used for media fills.
- If inert gases are normally used in the process, filtered air should be applied during media fills not to prohibit growth of microorganisms. (If anaerobic microorganisms are found during routine E.M., the use of inert gases should also be considered.)
- All aseptic holding vessels should be part of a regular process simulation test, unless a validated pressure hold or vacuum hold test is routinely performed.
Process General Principles :
- The media fills should simulate the complete product fill situation as far as equipment, processes, Environmental Monitoring, personnel involved, areas and time taken for both filling and holding.
- The media fill should represent a “worst case” situation compare to a normal fill with respect to manipulations and interventions.
- If filling takes place for over 24 hours, the media fills should extend to the same time, unless the validity of the media fill is not compromised by running the fill for less time.
- Media fills should include all interventions normally expected during product filling.
- Unplanned interventions should reﬂect actual experience with the filling process.
- Simulating interventions defines the validated envelope– Excursions outside validated envelope, batch failure as default
- Normal actions associated with the process, e.g. stopper bowl filling
- Normal occurrences, e.g. needle exchange, line stoppage
- Abnormal occurrences determined from deviations noted during previous runs
- Operator versus allowable interventions by him/her to be defined
- During normal operation, after intervention: removal of possible contaminated vials; that is allowable for Media Fill as well.
- Only discarding of vials as it is usually done.
Media Fills Duration :
- ISO: “sufficient duration to cover most manipulations”
- EU: “sufficient to enable a valid evaluation”
- PIC: “Over the whole of the standard filling period”
- FDA: “Duration of commercial aseptic process best and preferred for larger simulations
PRIMARY PACKAGING COMPONENTS – GENERAL PRINCIPLES
- Primary packaging components should be prepared as for regular production.
- When normally opaque containers are used, these should be used for media fills as well. The examination of growth though should be performed by transferring the whole contents.
PRIMARY PACKAGING COMPONENTS – Point to consider
- Primary packaging components should be the same as for normal production runs (amber vs clear vials?)
- Primary packaging components should be prepared the same as for normal production runs (washing and sterilisation)
- Media fill volume should be sufficient to cover, when the vial is inverted, the whole inner surface.
- Start-‐up simulation is applicable to new processes, new equipment or after critical changes to environment, equipment, process or significant personnel changes.
- Start-‐up simulation should consist of three consecutive, satisfactory runs with the same shift of people.
- Ongoing simulations should happen normally twice a year per shift and per process (unless there were changes to the product process or action limits exceeded).
The Outcome :
- Incubation is normally 14 days at 20 – 25ºC or sometimes 7 days at 20 – 25ºC followed by 7 days at a higher temperature (<35º C).
- When inspecting for growth, a known sterile container should be used as comparison.
- Alert and actions limits should be previously established.
- Even if not alert nor action limit was exceeded, microorganisms should be identified.
Media Fills – OOS
- There are not detailed indications from regulations, except:
- Each contamination must be investigated.
- Repeat media fill or repeat validation, after investigation, depending on the level of contamination and the run size.
- There is not distinction between initial validation and routine revalidation
Media Fills—Points to consider in Summary :
- Duration of longest run
- Worst case environmental conditions
- Number and type of interventions, stoppages, adjustments, transfers
- Aseptic assembly of equipment
- Number and activities of personnel
- Number of aseptic additions
- Shift breaks, changes, multiple gownings
- Number/type of aseptic equipment disconnections and connections
- Aseptic samples
- Line speed/configuration
- Manual weight checks
- Operator fatigue
- Container/Closure types run on the line
- Temp/Relative humidity extremes
- Conditions permitted before line clearance