Proving System Closure? - Integrity is Insufficient

The other speakers and I were pleased so many attendees had chosen our session. Even this exceptionally large room seemed full. Perhaps it was the clever session headline; “Caging the Tiger: Managing the Risk of Contamination”, or the challenge implicit in my presentation’s title “INTEGRITY IS INSUFFICIENT”, a (hopefully) clever play on words that would entice attendees to hear a different perspective on Proving System Closure.

I was passionate about the topic, having spent most the prior year co-authoring the article, Proof of Closure: Life Cycle of Closed Systems (Sept/Oct PE Magazine). My co-authors and I found the definitions of ‘functionally closed’, ‘briefly open’, and ‘externally closed’ somewhat confusing, and wanted to convey a more holistic approach to proving closed systems were fit for use.

A key concept was that a focus on integrity is insufficient. Systems must also be clear of residue (clean) and have appropriate bioburden levels. All three must be under control to declare a system ‘closed’.

System closure = ƒ (bioburden, cleanliness, integrity)

Creating and maintaining these three attributes occurs both before, during, and after processing, so a detailed accounting of the important procedures, tests, and validations is essential to defending system closure.

There are direct measures of closure, such as a pressure hold test, visual (cleanliness) inspections, or an in-process bioburden sample, and these provide a great deal of confidence about fit for use. But there are also indirect measures such as (normal) cell culture growth rates, or verification that a cleaning cycle was completed within validated limits. Finally, there are multiple Quality System activities critical to proving closure. For example, Cleaning and Sanitization Qualification for stainless systems, and Quality Agreements with single-use vendors. This portfolio of measures and activities, taken together, form a web of confidence and sufficient proof that a system is closed. Our article presented a method to succinctly tally these closure related activities and noted it was a great precursor and tool for completing a risk assessment, defending during an audit, or facilitating investigations.

There’s a big focus on the integrity of the system boundary, rightfully so, but wholly insufficient. A gap big enough to pass a microbe is too small to detect with a pressure hold test. Pressure holds, and other integrity measures are one of many activities that taken together form a web of confidence and sufficient proof that a system is sufficiently close.

I had a well-practiced presentation complete with colorful graphics and animation, all designed to maintain people’s attention and precisely convey our article’s concepts. In 20 minutes it was over, and upon returning to my seat on the stage I enjoyed the post-presentation sense of relief and accomplishment. Imagine my disappointment when an attendee noted his inability to convince quality organization that their integrity test parameters insured system closure. I patiently replied, “Integrity is Insufficient……”