Let Patient Safety Frame Our Definitions of 'Sterile'

Sterility is absolute. Like pregnancy, it either is or it isn’t.

Given the difficulties of demonstrating sterility in the absolute sense, why shouldn’t patient safety guide the discussion? After all, the essential concern is that patients incur no added risk of infection.

When we think in terms of safety, rather than in the unconditional sense of sterility, the means to attain that state can become more flexible.

Now, consider the question of whether or not to use terminal sterilization to ensure sterility of manufactured product.

The choices of sterilization method boil down to either aseptic processing or terminal sterilization. Terminal sterilization of the final product minimizes the risk of any contamination remaining in the product (for this discussion, I’m talking about heat methods, although a parallel argument could be made for radiation).

Unfortunately, many products may not be able to undergo terminal sterilization and still maintain all their essential attributes. In such cases, aseptic processing is used, and product components are sterilized separately and assembled under well controlled conditions, into the final product.

However, an essential question remains: What time-temperature or F0 target should be the minimum requirement for the process to be considered acceptable as sterilization?

Currently, the industry’s expectation for pharmaceutical materials is somewhat bipolar. The European Medicine Agency’s decision tree takes a position that a product must deliver an F0 >8 and a Sterility Assurance Level (SAL) of 10-6 in order to be considered terminally sterilized. This sets the minimum process bar rather high.

Setting the bar this high often results in the increased use of aseptic processing for products that cannot withstand the desired minimum terminal process and maintain their essential quality attributes. In attempting to increase the sterility assurance of any prospective lethal process, EMA’s decision tree may actually result in the use of a less effective aseptic process!

If one considers this from the perspective of patient safety, current practices seem completely upside down.

The fault in the EMA sterilization process selection lies in unstated assumptions about what the process is being asked to accomplish and why. Why is an F0 >8 required? How is the SAL of 10-6 to be calculated? The situation in the US is no different; the most recent mention of an FDA preference for terminal sterilization can be found in the FDA’s aseptic processing guidance with no indication whatsoever regarding process expectations.

The correct answer to "what process to use?" is rather simple: one that has the best chance of delivering a safer medication to the patient. The subject of sterility and how to deliver it must be approached with a willingness to consider methods that transcend conventional wisdom, which is laden with overly conservative thinking.