ASEPTIC PROCESSING: ONE - Risk Management Applications in Pharmaceutical and Biopharmaceutical Manufacturing - page 227

for real-world application. In effect, while the guiding principles are correct,
utilizing this method would rely on estimates of these values. As noted early
in this chapter, the reliability and precision of microbial monitoring methods in
the most critical environments are severely limited, and thus these risk analysis
methods must be considered more theoretical than anything else. The greatest
value in Dr. Whyte's work is as an indication to others of where the risks lie,
and that quantification of those risks may be possible.
The concepts in Dr. Whyte's work were adapted for application in conjunction
with a Monte Carlo simulation of contamination derived from microbial levels
in aseptic processing operations by Tidswell and McGarvey from Eli Lilly & Co
[27]. The potential for microbial ingress onto sterilized items was considered in
a case study process sequence consisting of the following:
1. filling line setup;
2. vial transfer from depyrogenation tunnel to accumulator;
3. conveying empty vials to filling;
4. emptying stoppers into stopper bowl;
5. stopper handling in stopper bowl and conveying to stoppering;
6. filling;
7. stoppering;
8. conveying stoppered vials to accumulator;
9. loading accumulator with stoppered vials;
10. conveying stoppered vials to capping; and
11. capping of stoppered vials.
In this model, the potential contributions in the early steps are weighted by
a number of factors, and, as might be expected, only minimal increased risk
is associated with the steps subsequent to stoppering. The data utilized to
develop this model was drawn from a specific operational facility, and thus
is not transferable to a different facility or process design. A Monte Carlo
estimation was applied to the environmental monitoring results from the
evaluated facility to estimate the contamination potential. This model assesses
relative risk within a specific process, but does not appear to be well suited
for comparison of different aseptic operations or consideration of design
alternatives.
The work done by Tidswell and McGarvey served as the basis for a sterility
assurance risk management model developed in 2009 by G. Berrios, also from
Lilly. Berrios redefined the approach taken in the earlier model and developed
a risk assessment method that is suitable for use in any manufacturing facility
or process design. In the revised method, the risk of microbial, endotoxin, or
particulate contamination is evaluated by ranking the following:
• amount of challenge;
• likelihood of the challenge's ingress into the product stream;