There are advantages and disadvantages to using model microorganisms in the validation of sterilizing filtration. Although
filtration validation studies may demonstrate the removal of the challenge organisms (whatever they may be), those studies
can only imply that any particular filter used to filter a batch of drug product will yield a sterile filtrate. Successfully
passing a bubble-point test (1) (or multipoint diffusive-flow integrity test), the results of which have been correlated to
successful microbial challenge testing and validation studies, provides additional assurance that a sterile filtrate has been
obtained. The filter manufacturer's quality-management system and production-control program further support the validity
of the sterilizing filtration process. All three elements must be present to predict the successful outcome of a particular
sterile filtration event (2).
Perhaps the best method of determining whether a filter can yield sterile effluent is to subject the drug product to a proper
microbial challenge and to analyze the filtrate for its microorganism content. This method of direct measurement would seem
to be the most reliable way of characterizing a filter's sterilizing ability. Even though an individual filter can be characterized
by a direct microbial challenge, however, the tested filter may not then be used in a processing operation because it has
been contaminated by the test organisms.
In practice, the measurement of a filter's sterilizing capability is derived from a correlation of its degree of bacterial
retention with a characterization of its largest pores, essentially in terms of their width. The latter is obtained by means
of the bubble-point integrity test method (3). It is necessary to confirm this correlative relationship because to assume
it exists could prove a mistake. For instance, two qualities or properties of a filter may so constantly occur together as
to be assumed to be correlated. Actually, they may in fact be two independent but parallel events that are not correlated
(1). For example, single-point air diffusion rates of a filter measured at 5 psi had formerly been thought to correlate with
a bubble point of some 50 psi for that filter, but it was discovered that it was necessary to determine the bubble point by
measurements made at the actual bubble-point pressure. It did not necessarily correlate with the extension of the 5 psi single-point
air diffusion test reading in all cases. So what had seemed to be a correlation turned out to be a case of parallel events.
As a result, the use of single-point diffusive airflows measured at 5 psi was abandoned. In the present instance, extensive
examination by many investigators has established the validity of correlating the bubble point with microbial retention (4).
An inherent assumption
A filter can be characterized by direct microbial challenge as being capable of producing a sterile effluent. Extrapolating
from the properties of the tested filter to other "identical" filters would, however, involve assumptions related to the uniformity
of the filters' manufacture. To investigate this aspect of the filtration picture to a statistically meaningful level would
involve a large number of correlated studies. Moreover, it might well necessitate the disclosure of proprietary information
in a competitive market. This would prove highly impractical. From this one consideration alone, it becomes evident that a
fundamental assumption must be made, namely, that the filter manufacturers can be depended upon to control their manufacturing
processes so that "identical" filters achieve the same level of retention performance.
Factors affecting pore-size ratings
Reliance upon the filter manufacturer is one necessary factor in this action. Identifying the requirements does not ensure
the attainment of sterile effluent.