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ASEPTIC PROCESS SIMULATION/ MEDIA FILL

ASEPTIC PROCESS

Aseptic process is the manufacturing of sterile drug product using aseptic techniques with the sterile product coming in contact with only sterile components and exposed to only in sterile environment.
ASEPTIC PROCESS SIMULATION
Aseptic process simulation is simulation /mimics the aseptic processing as closely as possible, while sterile media is using instead of drug product.
PURPOSE OF ASEPTIC PROCESS SIMULATION
•       A media fill run is done to validate the aseptic techniques and aseptic process which is to be carried out during routine production.
•       To evaluate the aseptic process is capable to produce the sterile product.
•       To qualify the operators and asses their aseptic techniques.
MEDIA USED FOR ASEPTIC PROCESS SIMULATION
Generally soybean casein digest medium is used for media fill, because SCDM is a good growth medium for common bacteria and fungi. Any possible contaminant in the system or introduced during the aseptic processing is caught up in the media and multiplied, thereafter identified by naked eye  too.  
Why SCDM?
•       Wide range of microorganism growth
•       GPT
•       Solubility
•       Clarity
•       Concentration
•       Filterability
•       Availability
MEDIA FILL FREQUENCY
•       Three consecutive separate successful run during initial qualification, thereafter routine semiannual qualification for each line.
•       Any change to line or process which can affect the aseptic process should be validated through additional media fills, which include
                      I.        Facility modification
                    II.        Equipment modification
                   III.        Line configuration change
                  IV.        OOS environmental monitoring
                    V.        Extended shut downs
                  VI.        Sterility test failure
SIZE OF MEDIA FILL
A generally acceptable starting point for run size is in range of 5,000 to10, 000 units.
•       If the commercial batch size is under 5,000 then the media fill units should be equal to lager batch size.
•       If the commercial batch size is > 5,000 to <10,000 then the media fill units should be NLT 5,000.
•       If the commercial batch size is more than 10,000 then the media fill units should be NLT 10,000 units.
Sandwiching theory:-
Agalloco claims that the USFDA Suggested sandwiching WFI filling in between media fill.
 Example – If the largest commercial batch size is 100000 then media fill can be done by 5000 units with media 90000 units with WFI and end with 5000 units with media.
MEDIA FILL DURATION
As per ISO
“The process simulation run shall be of sufficient duration to cover the most routine manipulations and operation as well as the greatest possible number of permitted interventions”.
As per PDA
“Media fill duration should be of sufficient duration to fill sufficient number of units for proper contamination rate determination”.
LINE SPEED DURING MEDIA FILL
There is no specification available for line speed, but USFDA suggested high speed for processes with high manual interventions and slow speed for product with prolonged exposure of sterile drug.
INTERVENTIONS
•       All the interventions which can harm the sterility of the system /product during the production run are to be simulated in the media fill.
•       Any unplanned intervention should also be recorded
•       The respective units /vials to be labeled accordingly.
INCUBATION OF FILLED UNITS AND ITS EXAMINATION
•       Incubates the media units at 20-25 °c for 7 days and further at 30-35 °c for again 7days.
•       The vials are inverted every third day for maximum exposure of media to inside of vial.
•       All the vials are observed for growth visually by a trained microbiologist, both at the end of incubation at 20-25 °c and after incubation at 30-35 °c
INTERPRETATION OF RESULTS
•       When filling less than 5000 units, no contaminated units should be detected, one contaminated unit is considered cause an investigation following by revalidation.
•       When filling from 5000 to 10000 units,
1. One contaminated unit should result in an investigation including consideration of repeat media fill.
2. Two contaminated units are considered cause for revalidation following an investigation
•       When filling more than 10,000 units,
                          1. One contaminated unit should result in an investigation.
2. Two contaminated units are considered cause for revalidation following an       investigation.
MEDIA FILL FAILURE
•       The filling line is to be shut down immediately.
•       All the bathes filled since the media fill should be kept on hold.
•       The contaminant should be identified till species level.
•       A thorough investigation should be  done to ascertain the source of the contamination as per the protocol for the media fill failure investigation
•       Five production batches filled prior to the media fill should also be kept on hold.
•       All the held batches are subjected to extensive testing as per protocol.
•       Upon identifying the source of contamination, further three successful media fill to be taken.  

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