Page 84 - Assurance of Sterility for Sensitive Combination Products and Materials

70 Assurance of sterility for sensitive combination products and materials

may be present in the aseptic process. Aseptic process simulations should be
long enough to properly challenge the process the duration of the aseptic
process simulation will also depend on the length of commercial produc-
tion runs and should capture operator shift changes.
Although a full duration (or longer) aseptic process simulations may be
of value in some cases, a risk evaluation may demonstrate that full or longer
duration aseptic process simulations are not necessary. In these cases, longer
duration aseptic process simulations may lead to a false sense of security and
resources could be used more effectively to identify the process risks.
In other cases, longer duration aseptic process simulations may be effec-
tive to probe duration-related process variables and conditions that cannot
be easily evaluated by any other means. The determination of the duration
should be based on scientific, risk-based, and logical evaluation of the ob-
jective of the study. The aseptic process simulation should not be used as
proof of the acceptability of poor process practices or conditions.
Understanding the objective of the study will aid in determining the du-
ration. For example, if the question is “what is the value of running a full
duration aseptic process simulation?” One answer is that the full duration is re-
quired to determine the maximum length of time the production run. By dig-
ging deeper, it may be possible to understand how the duration of the aseptic
process simulation meet provides confidence that the process will be reliable.
Two variables that one may try to address with a long duration fill are
(1) whether the environment remains suitable for aseptic processing during
the entire length of the fill and (2) whether human fatigue becomes an issue.
Clean room environmental deterioration: The concern is that the clean room
environment may deteriorate over the course of the fill and may no longer
be suitable for the aseptic process. Since the aseptic process simulation is a
secondary output relying on the probability of increased bioburden making
its way into the fill, and the fill being properly incubated to detect microbial
growth, it is not an effective way to determine or uncover this condition.
A much more effective direct measure would be monitoring of the clean
room, process, and HVAC system, along with environmental monitoring
of viable and total particulate. Since the aseptic process simulation output
is a low probability event, is not sensitive enough to determine if the clean
room environment has changed sufficiently enough to pose an unaccept-
able risk to product quality. The aseptic process simulation is not designed
to monitor or judge the condition of the environment. The environmental
monitoring program will likely indicate that a properly designed and oper-
ated clean room environment will remain in control over time. If the clean