When we first developed our risk analysis model, we shared it with a limited number of our peers. They were helpful in its
development, and we incorporated nearly all their suggestions as we progressed toward completion. While we awaited its publication
and after that as well, we discussed the model with many other individuals, and it became evident that it needed some modifications.
The present article summarizes the changes made to the analysis model, the underlying thinking behind the revision, and to
a lesser extent, the original effort. Before proceeding further, readers should review the earlier publication if they are
not already familiar with it (1).
We received considerable comments about the inclusion of the background environment as a separate factor in the analysis.
As we endeavored to explain our rationale for its inclusion, we found our support for its inclusion eroding. If the true emphasis
was to be on the aseptic process, and even more narrowly on the human interventions performed, the effect of these background
issues had to be minimal. Moreover, we included at the end of the analysis a further consideration of the primary processing
technology used, and so in effect, we were addressing the same concern in two separate places. Thus in this article, we removed
consideration of the background environment as a separate section and restricted consideration of the facility choice to the
immediate proximity of the filling operation.
Because aseptic compounding and lyophilization might not use the same environmental control practices as the filling operation,
the overall environmental factor was repositioned. Instead of applying it at the end of the analysis, the environmental factor
is included separately for compounding, filling (including setup), and lyophilization.
Using the Akers–Agalloco model
We also altered the risk determination associated with thermocouple placement in lyophilizers. For consistency with the intervention
risk associated with filling, we changed the multiplier for this practice to "per thermocouple."
These changes enabled us to eliminate what was termed the "aseptic processing factor" from the model. We added this factor
to the model as we neared completion because without it, the largely human-supported activities were weighted too lightly.
Call it a "fudge factor" if you will, but it was merely a means to ensure that the contributions from the various parts of
the model were evaluated. By eliminating the background environmental section in its entirety and allowing for differing technologies
in compounding and filling, the "aseptic processing factor" is eliminated in this simplified analysis method.
Some perspective on the effectiveness of high-efficiency particulate air (HEPA) filters
The initial version of this article contended that the majority of microbial contamination in aseptic processing was derived
from personnel. Several references were included to support that position (2, 3). As we revised the method, we reflected on
the industry's growing tendency to attribute microbial contamination to microorganisms that have presumably penetrated HEPA
filters, thereby resulting in detectable levels in the environment (4). We found no scientific evidence that such penetration
occurs in integral HEPA filters. Extensive data are available that support HEPA-filter retention at not less than 99.97% of
particles larger than 0.3 μm. With that type of retention capability, the penetration of microorganisms is nearly impossible.
Suggestions that it has occurred are suspicious in the absence of confirming data supporting that contention. The detection
of microorganisms downstream of a HEPA filter is most likely the result of human activity in the preparation, placement, and
recovery of microbial samples from the tested environment. The activities associated with environmental monitoring are carried
out by aseptically garbed personnel, and there is no reason to believe that these individuals are capable of "perfect interventions"
any more than a production operator would be. To suggest that integral HEPA filters contribute meaningfully to the microbial
presence in aseptic processing ignores available data about human contributions and grossly overestimates the potential for