Page 83 - Assurance of Sterility for Sensitive Combination Products and Materials

Aseptic processing 69

The rationale for the selection of worst-case conditions for the ascetic
process summation should be documented in the validation protocol or
document that would be subject to quality review. Worst case in the context
of aseptic process simulations does not necessarily mean the worst possible
case. It refers to the process parameters and conditions that are most likely
to uncover weakness or variability in the process. The worst-case conditions
should be used in the process simulation studies to gain the greatest scien-
tific understanding of the process. It can be surmised that if these conditions
are challenged in the aseptic process simulations, then conditions represent-
ing less than worst case should represent a conservative condition.
In theory, using worst-case conditions is an effective and efficient
method to design aseptic process simulations. Unfortunately, defining the
actual worst-case parameters and conditions may not always be simple. For
example, would the worst case be the maximum or minimum number of
operators in the clean room? On the one hand, the maximum number of
operators represents the larger source of microbial bioburden, while on the
other, the minimum number of operators may mean that operator move-
ment is increased, and their focus on aseptic behavior decreased. Both may
represent worst case for different reasons.
Another example would be container size which might be the worst
case—the largest container or smallest container. The largest container
would have the larger opening, affording more opportunity for contamina-
tion to enter, while the small container may be less stable during the trans-
port and filling process. Again, it might not be clear which represents worst
case. A final example would be slowest vs fastest fill speed. Slower fills rep-
resent longer fill times and a greater opportunity for contamination prior
to sealing, however, faster fills may represent more mechanical movement,
larger airflow disruption, human activity, and unstable container transport.
Without sound justification to identify the worst case from two or more
sets of parameters or conditions, then all the potential worst-case configu-
rations should be included in the process simulations study.

4.27 How long should the aseptic process simulation be?

The duration of the aseptic process simulation should be long enough to
capture all activities, interventions, and actions relevant to the maintenance of
aseptic process performance and product sterility. This will enable it properly
to challenge the process to discover any flaws, weakness, or under-addressed
variables into the process that can pose a risk to process performance and
product sterility. The aseptic process simulations should be long enough to
fill sufficient units to capture the low-frequency contamination events that