ASEPTIC PROCESSING: TWO - Risk Management Applications in Pharmaceutical and Biopharmaceutical Manufacturing - page 251

assessing extrinsic risks from particulate and microbial hazards, the fundamental
risk Equation 10.1 is best applied in two ways.

Risk = Severity of occurrence × Probability of occurrence (10.1)

First, the risk of product contamination from extrinsic particles in the manufactur-
ing environment can be adequately described with the fundamental risk equation
in its previously given form (Eq. 10.1). Here, severity of occurrence, that is to
say the amount of particulates within a product, can acceptably vary from 0
to pharmacopoeia-defined quantities. It is thus appropriate to use a quantitative
value of particulates that might exist within the product as the severity of occur-
rence. In comparison, the loss of sterility by ingress of a single microorganism
is not permissible. Ingress of a single microorganism always results in loss of
sterility, a two-parameter logic system is applied; an item is either sterile or it is
not sterile, that is, it either contains a microorganism or it does not. Hence, the
severity of occurrence can only be nonsterile, it will always be invariable and
therefore the numerical contribution to the overall risk of extrinsic bioburden
contamination will always be unity. Accordingly, the most appropriate means of
applying the fundamental risk equation defining the risk of bioburden ingress is
defined by Equation 10.2:

Risk = Probability of occurrence (10.2)

A wide variety of physical, physiological, and biochemical characteristics make
microbial hazards the most significant of hazards to aseptically manufactured
products. Virtually all known environments possess a resident microflora, with
microorganisms existing as individuals, collectives, or complex social consortia.
The magnitude of the global microflora can be appreciated by the consideration
of a single gram of soil in which there exists 10 8 -10 9 microorganisms; assum-
ing uniform distribution, a microgram of material accessing any clean room or
controlled environment could conceivably carry 1000 microorganisms. Further-
more, 10 14 microorganisms exist in association with the human body compared to
only 10 13 human eukaryotic cells; the biogeography of the bacterial communities
associated with healthy individuals is astoundingly rich [39]. Irrespective of loca-
tion of aseptic manufacture, a variable and uncertain quantity of microorganisms
will unquestionably exist and represent a reservoir of hazard with potential to
access and contaminate the product. Microorganisms are exceptionally adaptive
in both morphological and physiological dimensions, employing phenotypic and
genotypic mechanisms to endure environmental insult, proliferate, replicate, and
perpetuate their existence. Many inherent mechanisms (including their capabil-
ity to swiftly reproduce, some doubling every 20 min or so) permit species of
microorganisms to expediently evolve. New species possessing different char-
acteristics and survival traits evolve quickly to permit survival and successful
population of new and changing environments. The magnitude of microbial