Sterile products have several unique dosage form properties,such as freedom from micro-organisms, freedom from pyrogens,freedom from particulates, and extremely high standards of purity and quality; however, the ultimate goal in the manufactureof a sterile product is absolute absence of microbialcontamination.
Unlike many dosage form specifications, the sterility specificationis an absolute value. A product is either sterile or no sterile.Historically, judgment of sterility has relied on an officialcompendial sterility test; however, end product sterility testingsuffers from a myriad of limitations. The most obvious limitation is the nature of the sterility test. It isa destructive test; thus, it depends on the statistical selection of a random sample of the whole lot.
Even if the contaminated unit were one of the 20samplesselected for the sterility test, the possibility still exists that thesterility test would fail to detect the contamination. The microbialcontaminant might be at too low a concentration to bedetectable during the incubation period or might not grow rapidlyenough or at all because of media and incubation insufficiencies.
If microbial growth is detected in a sterility test, this may reflecta false positive reading because of the problem of accidentalcontamination of the culture media while performing the sterilitytest. The problem of accidental contamination is a serious yetunavoidable limitation of the sterility test.
The Food and Drug Administration (FDA) published guidelinespertaining to general principles of process validation. Generalconcepts and key elements of process validation consideredacceptable by the FDA were outlined. A major point stressed inthe guidelines was the insufficiency of relying solely on end-product sterility testing alone in ascertaining the sterility of aparenteral of a sterile product lot. Greater significance should beplaced on process validation of all systems involved in producingthe final product. These major limitations demonstrate thatreliance on end-product sterility testing alone in ascertaining thesterility of a parenteral product may lead to erroneous results.One purpose of validation in the manufacture of sterile productsis to minimize this reliance on end-product testing. Threeprinciples involved are
To build sterility into a product.
To demonstrate to a certain maximum level of probabilitythat the processing and sterilization methods haveestablished sterility to all units of a product batch