Terminal Sterilization and Potential for Parametric Release

S tcrility of a drug product, in the strictest sense, is defined as "complete absence of microorganisms in the product." However, the test for sterility as described in the Pharmacopoeias [I], is not a test on which any strong reliance can be based tor sterility assurance of the product. Due to limitations in testing [2]. the test for sterility is not a suitable release test to verify that a product complies with its release specifications for sterility. On the contra1y, it is primarily intended as a shelf life test. Hence, release of a sterile product should not solely rely on a sterility test. Release criteria should include the conditions under which a product was manufactured, critical parameters of sterilization processes, data about presterilization bioburden and environmental conditions of manufacturing and subsequent aseptic processing. The sterility assurance level (SAL) of each batch of drug product is defined in probabilistic terms, where the likelihood of a contaminated unit or anietc is acceptably remote (a 10" probability of nonstcrility (PNS) or a maximum of I non-sterile unit in a total of I million units is considered to be the minimally acceptable PNS). Terminal sterilization involves filling of formulation in prima1y packaging containers followed by thermal, ionizing, or chemical modes of sterilization. Terminally sterilized products are typically released on the basis of compliance with sterility test results and a review of the sterilization cvcle records. Te~inally sterilized products represent the lowest risk category of sterile pharmaceutical products. Unlike products aseptically manufactured in a microbiologically controlled environment, terminally sterilized products are subjected to a sterilization process the microbiological lethality of which can be quantified. When the mode of sterilization is very well understood and the physical parameters of processing are well defined, predictability, measurability, and the lethality of the cycle has been microbiologically validated, the release of terminally sterilized batches or lots of sterile products, parametric release [3,4], without having to perform the requirements under Sterility Tests [ l] is a possibility. However, the use of parametric release jiJr sterilization processes requires prior FDA approval. This artlcle contains an overview of the infonnation in USP on terminal sterilization, and parametric release. The reader is directed to the jixt that references to USP-NF contain "official" text. while references to Pharmacopeia[ Forum (Pf), contains "proposed" text.