The EU GMP (good manufacturing practice) Guideline Part IV “GMP Requirements for ATMP (advanced therapy medicinal products)” and Annex 1 ”Manufacture of Sterile Medicinal Products” specify the validation of aseptic manufacturing processes by means of a process simulation. This is an elementary component of process validation.
The aseptic process is simulated by filling a suitable, sterile, microbial growth medium (media fill). In addition to the routine process, the media fill should also take into account worst-case conditions and possible interventions performed during the process. In the case of producing different ATMPs, a matrix and/or bracketing approach may be used.
The procedure for performing the media fill must be described in detail in specification documents (including validation plan, manufacturing instructions, SOP) and documented in protocols in a GMP-compliant manner for proof during regulatory inspections or other audits.
For initial validation or after significant process changes (e.g., changes to the air-conditioning system, plants, process, or number of shifts), the media fill must be successfully performed in three consecutive runs per shift. Thereafter, the media fill must be repeated at least once every six months or twice a year per shift and per process. Frequency can be adjusted on an individually risk basis. Since production of ATMPs is not regular, it is possible to perform the media fill directly before ATMP batch production.
The number of containers filled in the media fill must allow a valid evaluation. For small batch sizes, as in the case of ATMPs, the number of containers to be filled should be at least equal to the batch size. The filled containers must be inverted or otherwise agitated at least once to ensure the culture medium wets all surfaces of the container and closure. The standard procedure includes incubating the containers first at 20 to 25°C and then at 30 to 35°C for seven days each. This procedure can be deviated from in justified cases.
The acceptance criterion for successful media fills is “no microbial growth”. If growth is detected, a timely root cause analysis and subsequent revalidation must be performed. In addition, it must be checked whether previously produced batches must be suspended or recalled.