To demonstrate your aseptic manufacturing is free from contamination,  a worst case simulation must be performed as part of the process validation and also on a bi-annual basis once routine manufacturing has commenced.


What is simulation?

In place of the actual drug substance, a broth medium is used which will easily detect any microbial contamination throughout the aseptic manufacturing process.


The media selected for media fill runs should be capable of growing a wide spectrum of microorganisms and of supporting microbiological recovery and growth of low numbers of microorganisms, i.e. 100 CFU/unit or less. Normally media fills are conducted with Casein Soybean Digest medium (CSD).


Examples for worst-case simulations are:

  • Use of materials, components, closures that have remained in the aseptic processing area for the maximum acceptable period.
  • Increase of the fill staff to include mechanics and QC personnel to the maximum number of people acceptable in the room.
  • Evaluate the worst case for the product and process – for example, this may be to fill the smallest units at the fastest speed (handling difficulty) and the largest units at the slowest speed (maximum exposure).
  • Perform planned interventions at the maximum number acceptable per number of filled vials (e.g. weight adjustments, container / closure or product re-supply, sampling or environmental monitoring).
  • Perform non-planned interventions at the maximum number and with the highest degree of intrusion acceptable (e.g. corrections for container breakage or tip-over, corrections for leakage of fluid, corrections for stopper jams).
  • Perform a shift change and continue filling (where applicable).
  • Shifts, including night shifts should be included (where applicable).
  • Operator breaks during filling.

 

Note: Interventions in the routine process are only defendable to the extent that they have been simulated or occurred during the simulation test (media fill test).