ASEPTIC PROCESSING: TWO - Risk Management Applications in Pharmaceutical and Biopharmaceutical Manufacturing - page 259

bioburden, which can be linked to true product risk. Flow-cytometric-based mea-
surement platforms are commercially available and are being validated within
aseptic manufacturing facilities. This technology does allow us to apply actual
bioburden data to describe hazard magnitude and when combined with transfer
coefficients permit calculation of the quantitative risk (transfer of bioburden into
vulnerable product) to product. Application of true quantitative values of risk is
far superior to the employment of surrogate descriptors. The second strategy is
the use of population distributions to describe the risk factors. This does require
some empirical data to enable the definition of the risk factor in terms of the
likely minimum and maximum mode and shape of distribution. Environmental
monitoring data lend itself especially well to this form of describing the magni-
tude of bioburden as a risk factor. With a high level of assurance, we can say that
in controlled aseptic manufacturing environments the level of resident bioburden
is a population between less than one and a maximum value (identifiable from
environmental monitoring program data), is non-normally distributed at a value
close to one (again identifiable from the environmental monitoring program data).
The difficulty with using population distribution data in quantitative risk analysis
is the necessity for a sophisticated software program to interpolate the data.
10.8.2 Culture-Based Microbial Test Methods are Inadequate
Measurements of Product Quality
The sterility test is currently mandated within 211.165 of the Code of Federal
Regulations (CFRs) and therefore presently constitutes one of the requisite tests
implicit in a sterility assurance program. There remains a common belief or
perhaps a convenient reliance on the sterility test as a definitive test of product
sterility for an aseptically processed product. The purpose of the sterility test is to
provide proof of absence of microorganisms (sterility); however, the absence of
evidence of microorganisms by a sterility test is not adequate evidence of absence
of microorganisms. A credible risk to the patient population likely accompanies
our reliance on the sterility test; the risk of permitting the release of a microbially
contaminated product may be described as a Type II error (false negatives). Type
II errors in any testing or analysis of sterility has the potential for the disposition
of nonsterile items into the market.
Fallibility of the sterility test to identify the presence of microorganisms within
a product can be attributed to numerous factors, all potentially contributing to a
Type II error. Generally, these factors contribute to two main categories, which
are (i) the inability of the sterility test to grow microorganisms and (ii) the small
sample size of this end product consuming test.
A microorganism may not grow or replicate by virtue of (a) debilitating
injury (lethal or sublethal), (b) physiological prerogative (microbial dormancy),
or (c) the mere fact that the nutritional and physicochemical conditions are
not conducive. It has been estimated that only 1-5% of all microbial species
have been successfully cultured [52,53]. With many aseptic processes involving
human manipulation and intervention, the “culturability” of the human microflora