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Sterilization: How to Validate Novel and Non-Traditional Processes

In addition to using BIs, sterilization validation also makes use of a Process Challenge Device (PCD). The PCD is designed to protect BIs, so that it is more difficult to sterilize the BIs than the product. The design of PCDs is somewhat of an art, but some companies simply place the BIs in the same packaging that is used for the product and then place that packaging inside another layer of packaging (i.e., triple-layer packaging).

Another approach is to design small containers with a “torturous path” (e.g., a pouch within a pouch with openings facing in opposite directions) for gas sterilants to navigate. Often, these containers will have a cap that can be adjusted to have a larger or smaller opening for the gas sterilant to enter. The design of these containers may appear to be easy to copy, but the specifications for the materials and dimensions are critical to the proper function of a PCD. A microbiologist must also develop a validated incubation process for the BIs to ensure that BI testing does not result in “false negatives.”

Overkill & Half-Cycles

When you validate a sterilization process, you typically need to quantify and characterize the average bioburden present on the packaged devices. ISO 11737-1:2006 describes the method for determining the population of microorganisms on a product. You also need to verify that the sterilization process chosen is effective for the types of organisms present. After bioburden is counted and characterized, you need to determine the minimum amount of sterilant that is required to kill those organisms. BIs will have a known concentration of the resistant organism that exceeds one million cells—much higher than the native population. This serves to ensure that the resulting process has a Sterility Assurance Level (SAL) of 10-6 (i.e., the minimum requirement for “Sterile” products).

In order to determine the minimum dose required, a fractional cycle is typically performed. If the process is UV light, you want to determine the minimum length of exposure during your Operational Qualification (OQ). During the OQ, you also want to determine the impact of distance between the light source and the device, because the effectiveness of light diminishes rapidly as distance increases. If the process is a gas sterilant, you want to inject doses that are a fraction of the regular full-dose for a cycle. For fractional cycles, BIs will be placed with the product in the product packaging, and PCDs will be used.

The goal of this testing is to demonstrate that you have identified a fractional dose in which BIs packaged with product are killed, but BIs in the PCD survive the sterilization process. This testing demonstrates that you have identified a dose that results in a 6-log reduction in resistant organisms (i.e., a reduction from 106 to 100). The regular cycle must be sufficient to kill the BIs in the PCDs. The information gathered for fractional cycles is also valuable if you perform an incubation reduction study in order to reduce the incubation time for sterility testing from seven days to 48 hours.

A UV light process would simply increase the duration of exposure by two-fold, but gas processes are more complex. If the fractional cycle is one cycle of the maximum injection volume, and the regular cycle is three cycles of the maximum injection volume, then the required number of cycles for the production process will be two-times greater (i.e., six cycles).

The number of regular cycles is doubled because the half-cycle method is used for process validation. During half-cycle validation, companies will place BIs within product packaging and place PCDs throughout the same sterilization load. If none of the BIs are positive for growth, then three cycles provide greater than a 6-log reduction in the resistant organism and six cycles provide greater than a 12-log reduction (i.e., SAL of 10-6).


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