Sterilization Validation INTRODUCTION

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 manufacture of a sterile product is absolute absence of microbial contamination.
The emphasis of this chapter will be the validation of the sterilization
processes responsible for achieving this goal.
Unlike many dosage form specifications, the sterility specification is an
absolute value. A product is either sterile or nonsterile. Historically, judgment
of sterility has relied on an official compendial sterility test; however, endproduct
sterility testing suffers from a myriad of limitations [1–4]. The most
obvious limitation is the nature of the sterility test. It is a destructive test; thus,
it depends on the statistical selection of a random sample of the whole lot.
Uncertainty will always exist as to whether or not the sample unequivocally
represents the whole. If it were known that one unit out of 1000 units was
contaminated (i.e., contamination rate = 0.1%) and 20 units were randomly sampled
out of those 1000 units, the probability of that one contaminated unit being
included in those 20 samples is 0.02 [5]. In other words, the chances are only
2% that the contaminated unit would be selected as part of the 20 representative
samples of the whole 1000-unit lot.
Even if the contaminated unit were one of the 20 samples selected for the
sterility test, the possibility still exists that the sterility test would fail to detect the contamination. The microbial contaminant might be at too low a concentration
to be detectable during the incubation period or might not grow rapidly
enough or at all because of media and incubation insufficiencies.
If microbial growth is detected in a sterility test, this may reflect a falsepositive
reading because of the problem of accidental contamination of the culture
media while performing the sterility test. The problem of accidental contamination
is a serious yet unavoidable limitation of the sterility test.
The Food and Drug Administration (FDA) published guidelines pertaining
to general principles of process validation [6]. General concepts and key elements
of process validation considered acceptable by the FDA were outlined. A
major point stressed in the guidelines was the insufficiency of relying solely on
end-product sterility testing alone in ascertaining the sterility of a parenteral of
a sterile product lot. Greater significance should be placed on process validation
of all systems involved in producing the final product.
These major limitations demonstrate that reliance on end-product sterility
testing alone in ascertaining the sterility of a parenteral product may lead to
erroneous results. One purpose of validation in the manufacture of sterile products
is to minimize this reliance on end-product testing. Three principles are
involved in the validation process for sterile product.
1. To build sterility into a product
2. To demonstrate to a certain maximum level of probability that the
processing and sterilization methods have established sterility to all
units of a product batch
3. To provide greater assurance and support of the results of the endproduct
sterility test
Validation of sterile products in the context of this chapter will refer to the
confirmation that a product has been exposed to the appropriate manufacturing
processes and especially to the appropriate sterilization method yielding a batch
of product having a known degree of nonsterility.