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Sterility and the Micro QC lab – is Zero really Zero?

Posted by Admin User on March 14, 2011

I was recently speaking to one of my colleagues about an interesting presentation given at the PDA Global Conference on Microbiology in October 2009. The presentation, given by Dr James E Akers, was titled Urban Myths in Pharmaceutical Microbiology – The 0 and 1 myth.  Dr. Akers also wrote a more in-depth article on the subject called, “The Myth of Sterility”. I was theorizing with my colleague about what it would have been like to have been part of the audience during the presentation.  Given the topic, I would have expected facial expressions of the audience to range from bewilderment to frustration to understanding.  It is indeed a complex discussion  that I’m sure, when delivered to a room full of industry minds probably drove a mixed reaction. I know my facial expressions ran the gamut, but I’ll keep my computer monitor the only thing privy to that.  I think the topic of sterility, and proving the absence of anythingis intriguing, and Dr. Akers gave me a lot to chew on.

Defining sterility

The term sterility, I admit, waxes philosophical in nature before entering the battling worlds of quality assurance and microbiological testing. Anyone that goes to a hospital, or watches hospital dramas has a very specific view of what sterile is. We microbiologists though take the general public’s concept to a much deeper level, although with a grain of salt. Akers makes the point that sterility in Pharma quality is the “complete absence of microorganisms”, and by extension, an “absolute” that is seemingly impossible to prove scientifically. How do you prove the presence of nothing, as though this “Nothing” is actually a physically defined state (Although well envisioned in The NeverEnding Story)?  This is where it gets interesting.

Proving “Nothingness” where n approaches infinity

Imagine if I asked you to prove the presence of nothing in the air in the area between your nose the computer screen (If there is no space between the two, it may be time to visit the optometrist.) Take a moment to look cross-eyed at that space. (Not too long or your eyes will get stuck that way). How would you begin to design a test method to absolutely prove that there’s nothing there? How big of a sample would you need? At what sampling rate?

For the mathematicians reading, your n (number of samples) size almost instantly approaches infinity, as there are infinite possibilities for there to be 1 of “something” there over time. As your n increases to infinity, your sampling rate has gone running wildly off into infinity too. As the higher n to sample you create, the rate of sampling said nmust increase to accommodate an ever continuous amount. I hope you brought extra batteries for your air sampler! Such is the paradox introduced when trying to prove sterility (nothingness) in Pharma. Now, a statistician reading this may disagree with me in that there is a statistically feasible volume to sample to prove at X% confidence that the remaining volume is sterile. In the end, this still remains a statistical assumption, not a true claim of sterility. Quite simply, there is just too much space to cover to be sure you’ve covered everything.

Don’t cancel your sterility program yet

So, should we just throw out our air monitoring systems and do away with clean rooms all together? Dr. Akers and I agree; of course not. Pharma quality is looking at finite procedures on concrete products in defined areas, such as media fills for in-process batches in ISO rated clean rooms. However, the caveat still remains that to absolutely prove the presence of zero contaminants in an entire batch of product, whether bacterial, viral, or viable but not culturable, one must test and consume the entire product!  But where’s the business model in that? Nonetheless, the public demands safe products and regulatory and QA must still be able to claim sterility assurance based on a heaping compilation of in-process and environmental monitoring data for that specific batch. What is lost in translation is the philosophical impacts.

The solutions to this conundrum seem limitless, as does the amount of stuff to test in the air-in-front-of-nose model I so eloquently provided earlier. To test more volumes, more of the time, seems the only logical solution, given that an entire societal shift in perspective on sterility and consumer safety is out of the question.  

Can rapid micro methods help?

Dr. Akers and I disagree on the value of rapid methods to sterility.  Hey says, “…rapid microbiology, drawing increasing attention by industry, only provides the same imprecise information about the aseptic process we already have, albeit somewhat sooner.”  I think that rapid micro testing methods provide the best case solution to these issues, save for a cultural awakening to true “sterility”. It’s a very prudent response to deliver information sooner rather than later (assuming the RMM selected is as accurate as the current method). Unfortunately, philosophy must give way to practicalities.  Your manufacturing master scheduler likely won’t accept a 14 day sterility test reported result of: “Might be sterile, but who’s to say really?” for a batch of product that has already moved downstream and into holding.   

Akers goes on in his article to talk about approaches to improving sterility by increased scrutiny in manufacturing personnel, aseptic processing, and reduction of interventions based on sterility test failures. I think these are all excellent ways of passively improving production and lessening a sterility failure event.  But, I think everyone would agree that if a product, clean room area, or raw material is grossly contaminated, it’s better to know today than it is to know tomorrow. And RMM is the way of doing so.

Balancing philosophy with practicality

There’s no doubt that the idea of truly proving sterility is indeed an urban myth, and that to prove the presence of nothing is not the same as proving the presence of something. While you can’t test your way to absolute sterility, it’s frankly impossible both statistically and philosophically, as well as business-ally (yes I made that word up), Pharma has a responsibility to deliver on the expectations of consumers that their food, medicine, or product is safe. We can work on better methods improving aseptic technique but also faster detection at the same time. You be the judge.

Sahil Parikh
Senior Research Assistant, R&D Microbiology
Rapid Micro Biosystems