Page 85 - Assurance of Sterility for Sensitive Combination Products and Materials

Aseptic processing 71

room environment does deteriorate over time, then the proper response is
to provide engineering solutions to address the deterioration and is not to
attempt to show that deterioration is still acceptable.
The effect of human fatigue: Clean room personnel can get tired and fa-
tigued. However, aseptic process simulations are ineffective at monitoring
human fatigue or the effect of fatigue during aseptic processing because of
the difficulty simulating human fatigue. Performing aseptic process simu-
lations for extended periods of time does not probe all the variables asso-
ciated with fatigue, and each of these may or may not result in a microbial
growth. Simply working for extended periods does not consider how much
rest or sleep the operation had the night before, or the presence of any
nonwork-related stress. The fact that the importance of the test is evident,
it also does not probe changes in behavior because the operators are aware
that they are participating in a highly observed test.
The best way to address the process variable of human fatigue is by re-
ducing the risk or potential effect human fatigue may have on the outcome
of the process. In other words, address the issue by eliminating the cause(s)
of work fatigue through better ergonomics, process design, increased rest
breaks, and rotations. Running and passing an aseptic process simulation is
not the solution for human fatigue.
Note that if operator fatigue is thought to be an important process vari-
able that is mitigated by taking rest breaks, then the aseptic process simulation
should include rest breaks. The duration of the aseptic process simulation
should include the time the operator enters the clean room between break
periods and should include the changes of operators during those break
times.
It should also be noted that many global health authorities and regu-
latory agencies, including the US FDA and EMA, have minimum recom-
mendations and expectations for the number of units filled based on the
quantity of commercial batches anticipated. The time it takes to process and
fill these units should be considered in planning the duration of the aseptic
process simulation runs [3, 5].

4.28 What are the aseptic process simulation acceptance
criteria?
The objective of an aseptic process is to produce a sterile product with
the absence of microbiological contamination. It follows that the accep-
tance criteria of the aseptic process simulation should be zero positives.