The maintenance of product attributes may require the use of sterilizing conditions that are less aggressive and sterilization equipment, cycles, and validation methods adapted to these more restricted circumstances. The substantial variations in equipment designs and methods for terminal sterilization preclude a singular description of a typical cycle. All terminal sterilizers heat the load, but they accomplish this in varying ways: saturated steam; steam–air mixtures, steam–air–water mixtures, and superheated water. Air over-pressure for maintenance of container integrity and cooling containers and water for heating/cooling of the load may be present depending upon the autoclave size, throughput expectations, and container.

In-process fluids are used for pH adjustment, dilution to a specified volume, lubrication, and other purposes. In many instances these liquids are sterilized in conjunction with items that must be sterilized by direct steam contact, and the sterilization process must ensure that all items are adequately sterilized.

Laboratory media often are sterilized in standard steam autoclaves with minor adaptations. Provision for slow exhaust (to reduce stress on container integrity and minimize boil over) and jacket cooling can help improve the basic steam sterilizer design and operation to better accommodate the materials. The sterilization process may be specific for media containers or a combination of both liquid-filled containers and hard goods. This process may resemble the methods used for terminally sterilized products (see above). The sterilization of laboratory media may entail the processing of a number of different containers that contain different materials. Manufacturers should be aware of the potential for under- and over-processing across the load and must consider container size, container contents, and position. When liquid-filled containers are combined in the same load with hard goods, manufacturers must consider the unique concerns of each to ensure all items are properly sterilized. Because laboratory media are considered self-indicating with respect to sterility, the use of internal biological indicators during validation is not required.

The sterilization of biowaste in sealed containers from laboratory or production use is similar to parts sterilization. The process is defined to ensure a minimum time–temperature exposure or attainment of a specified F0 value throughout all items of the load. Depending on the potential contaminants present, the autoclave design may incorporate condensate collection/sterilization or sterilizable exhaust filters to ensure that pathogens are adequately contained. Because the objective of biowaste sterilization is to render the materials safe for contact and disposal, the overkill method described in Steam Sterilization by Direct Contact 1229.1 is employed.

In most respects the BB method is similar to the BB/BI indicator method. The difference lies in the isolation and characterization of the most-resistant bioburden microorganism. The worst-case isolate is used as the biological indicator in the evaluation of the process. For use in this manner, it must be cultured to produce a suitable challenge population. When this method is used, the bioburden of each process cycle must be closely controlled with respect to population and must be monitored for resistance.

Process equipment for terminal sterilization typically is controlled by calibrated and pressure sensors in/on the chamber/equipment. During the exposure portions of the cycle, attainment of a minimum dwell time at a predefined temperature is used to support process lethality. Cycle lethality for terminal sterilization customarily is measured using F0, which is defined as an actual exposure time at a variable process temperature that is equivalent to an exposure at 121 based on an ideal microorganism with a z-value of 10. This can include lethality delivered during the heat-up and cooling phases of the sterilization process. A z-value is defined as the number of degrees of temperature change necessary to change the D-value by a factor of 10. The F0 approach is used to evaluate to a single standard sterilization processes that are operated at varying temperature conditions. The process lethality at temperatures other than 121 can be calculated to determine lethality equivalent to that provided at 121. Sterilizer control systems for terminal sterilization deliver conditions within a predefined time–temperature or F0 range to avoid over-processing.

Simple mathematics can be used to calculate the total lethality over the course of the process. For the specific reference temperature of 121 and a z-value of 10.0, the F0 calculation can be determined by Equation 2:

Summing the instantaneous lethality contributions over the entire sterilization process allows the calculation of the overall process lethality or F0 delivered over the course of the entire process at varying conditions.

As previously noted, the preferred method for steam sterilization is the overkill method as defined in Sterilization of Compendial Articles 1229 and Steam Sterilization by Direct Contact 1229.1. However, when the processed materials are susceptible to damage by moist heat at the overkill conditions, the BB/BI method is better suited because it results in reduced heat input while affording the same degree of process efficacy but with different controls. As noted above, terminal sterilization processes require greater consideration of the effects of the treatment on material properties. This has implications for many of the elements of the qualification and validation exercises as indicated below. The validation requirements for the BB/BI and BB methods are more rigorous than those associated with the overkill method. Although the overkill method can be confidently used without detailed consideration of the presterilization bioburden, application of the BB/BI and BB methods require continued monitoring and control of the bioburden, specifically the population and resistance. This is accomplished by testing of filled containers just before sterilization and measuring the number of colony-forming units per container and confirming the absence of resistant BB isolates. When resistant isolates are found, their thermal resistance in the fluid should be determined.

Proof of cycle efficacy is provided by replicate studies in which the BIs perform as expected and the physical measurements correspond to the expected values of time and temperature or F0. If the microbial and physical measurements do not correlate, an investigation is in order, and corrective action must be taken to rectify the discrepancy. Samples from the hottest regions of the load are used for evaluation of material stability and quality.

All sterilization processes should be subject to formalized practices that maintain them in a controlled state. The practices outlined in Sterilization of Compendial Articles 1229 include the general requirements appropriate for all sterilization systems. This is accomplished by a number of related practices that are essential for continued use of the process over an extended period of time. The practices include: calibrartion, physical measurements, physicochemical integrators, indicators for sterilization, monitoring of bioburden, ongoing process control, change control, preventive maintenance, periodic reassessment, and training.

The use of parametric release is common in the terminal sterilization of finished product containers. This subject is addressed in Terminally Sterilized Pharmaceutical Products—Parametric Release 1222