For decades, two different approaches have been used to manufacture sterile products. The most common approach, aseptic processing, relies upon separating potential microbial contaminants from the product through a combination of filtration of the product stream, individual sterilization of product-contact packaging components, and environmental controls. Terminal sterilization relies on a more limited contamination control of the product, components, equipment, and environment followed by a lethal sterilization process applied to the fully assembled dosage form. From a macro perspective, these two approaches have been treated as equivalent means to the same end, but they have never been considered equal in terms of process capability. In the jargon of sterile-product manufacturing, they are not considered fully equivalent in terms of sterility assurance.
The world's regulatory authorities have long expressed a preference for terminal sterilization, but have rather inexplicably set up expectations that provide little real benefit to firms that implement terminal sterilization. The foremost shortcoming is requiring firms to make a regulatory filing to delete the compendial sterility test as a requirement for product release, a practice known as parametric release. Regulatory pressure exists to manufacture products for terminal sterilization in ways increasingly similar to aseptic processing. This change involves added facility controls, stricter gowning requirements, and substantial environmental monitoring that further deteriorate any financial benefit that would accrue to firms using terminal sterilization. In Europe and to a lesser extent in the United States, another blow against terminal sterilization has been the increasingly commonly enforced idea that terminal sterilization should require lethalities in the range of F° ≥15 min. (F° refers to lethality in moist-heat sterilization; by convention, F° is equal to 1 min of exposure to moist heat at 121.1 °C.)In Japan, a different and far more scientifically logical approach has evolved and is undergoing further refinement. The idea is that with reasonable control of presterilization bioburden, lower levels of lethality can afford high levels of patient safety. Specifically, for reasonably heat-stabile products F° values of 2 min or less can provide levels of end-user safety substantially higher than those attainable in aseptic processing. The logic of this approach is irrefutable as can be shown by simple microbiology.
Although spore-bearing gram-positive rods with substantial heat resistance are used to develop and validate sterilization cycles, the most common human and animal pathogens are bacteria, mold, and virus with substantially lower heat resistance than these spore-bearing organisms. Protein, a key structural and functional component of microorganisms, is typically denatured in vegetative mold, bacteria, and virus at temperatures only slightly greater than 56 °C. Unsurprisingly, these organisms die quite readily at temperatures in the range of 65–75 °C. This difference means that substantial increases in user safety could accrue at temperatures that are substantially lower than those at which spore killing begins and at which F° begins to accumulate, which is in the range of 100–105 °C. Thus, the vast majority of medically significant organisms would be dead well before a postassembly heat process reached F° = 0.1 min. The improved patient safety that this approach could add to moderately heat-stable products is so obvious that one wonders why it is so steadfastly ignored. In fact, a process need not get to 100 °C to add substantial safety, five minutes or less at 70 °C or so would be appropriate.
One used to applying the common pharmaceutical approach to sterilization might ask whether a process that did not kill spores had value? Aseptic processing is a completely nonlethal process and yet is widely accepted. Of course, a moist-heat sterilization of F° = 2 min would effeciently kill many spores of many spore-bearing species, including those known to produce human or animal disease. (The recommended means to deliver this process is at temperature less than 121 °C, whereby more uniform conditions can be delivered through the use of a much shorter time at an elevated temperature). Most spores isolated from industrial environments have D121 values of < 0.2 min. (D121 is the time required to reduce a microbial population by 90% when exposed to moist heat at 121 °C.) Given the conservative assumption that the presterilization bioburden following an aseptic processing would be no more than one organism per container and the organisms present had a D121 value of 0.2 min, a process yielding an F° = 2 min would produce a probability of nonsterility of 10-9. In medical terms, this calculation dramatically understates the actual safety because the majority of the bioburden (especially those considered human pathogens) would be non-spore forming and would therefore be dead while the process was still in heat-up mode.