ASEPTIC PROCESSING: TWO - Risk Management Applications in Pharmaceutical and Biopharmaceutical Manufacturing - page 258

of thoroughly documenting the primary sources, vectors, and potential routes of
microbial transfer within aseptic environments as the foremost and pivotal step of
any risk assessment. Assessment of risk to a product is dependent on the compre-
hensive identification and inclusion of all those salient contributors to risk and
concomitantly on a thorough knowledge of the process, product, and environ-
ment. Brainstorming and application of mind maps clearly assist and are useful
tools [5,24]. Fishbone tools (see previously) and the methodical determination of
all means by which microbial hazards can generate a risk in aseptic manufacture
(essentially a failure mode analysis) permit the comprehensive inventory of all
risks. An organization's design history files, process flows, and change controls
associated with the aseptic manufacturing process must be used to detail the pro-
cess flow and assist in the identification of all vulnerabilities permitting microbial
hazard ingress, proliferation, or retention. As with any assessment of risk, the
accuracy of the magnitude of the hazard contributes to the level of certainty of
the predicted risk. Historically, comprehensive monitoring of the environment has
adopted growth-based technologies to recover a variable and uncertain portion
of the bioburden hazard present [49]. Sutton [50] exemplifies this and points out
that the limit of detection of an agar plate is 1 but the limit of quantification is
25! Uncertainty and variability implicit to traditional growth-based measurement
of the magnitude of microbial hazards likely diminish the accuracy of predicted
risk and confound the effectiveness of any assessment, irrespective of its specific
objective.
Any evaluation of the environmental levels of microbial hazards with the
objective of determining adequacy of control and product impact is most usually
arbitrary in nature. Measurement uncertainty and variability restrict evaluation
of the control of microorganisms in the environment, which at best can only
be judged in terms of trend analysis or with respect to levels perceived to rep-
resent adequate environment of control [51]. Furthermore, there is routinely no
data linking the magnitude of a microbial hazard in the immediate or extended
environmental vicinity to product quality and the risk of product contamination.
Moreover, to the author's knowledge there has been no detailed published data
that strictly links environmental levels of microbial hazard to nonsterility of a
product. However, constrained by measurement uncertainty and the absence of
a correlation between the magnitude of microbial hazard and product impact,
environmental (facility, personnel, equipment) levels of the microbial hazard are
universally considered as key parameters to facilitate the disposition of an asep-
tically processed product. The rigor and objectivity of such analysis for product
disposition is profoundly opportune for improvement via a truly quantitative risk
assessment, which necessarily captures and considers associated measurement
uncertainty and variability. Two strategies can be used to reduce measurement
uncertainty and variability. First, more accurate and rapid microbial measuring
technologies permit a realistic determination of the magnitude of the microbial
hazard in the aseptic manufacturing environment. Quantification of the levels of
microorganisms in the same time frame of filling and associated with each step
of aseptic manufacture generates an accurate assessment of the magnitude of the