The Myth Called "Sterility"

The authors propose a process-centric approach for carrying out aseptic-processing and suggest further dialogue. This articles contains bonus online-exclusive material.
Mar 01, 2010

There's been a steady stream of compliance documents from global regulatory authorities concerning aseptic processing. These regulations require the healthcare and pharmaceutical industries to do the impossible—unequivocally establish the sterility of the materials we produce. Although this goal seems logical and laudable to the ill-informed, it defies available, real-scientific capabilities. The expectation seems to be based either on personal opinion or untested hypothesis, discounting the realities that such proof might entail.


A common perspective underlying regulatory documents that call for a "proof" of sterility is the belief that industry can somehow use microbiological analysis and other select and, often-subjective, tests to prove that sterility has been attained. Such proof does not technically exist and is not scientifically possible. There are dangers implicit in regulatory authorities requiring industry to attempt to prove the unprovable. These misguided efforts create circumstances in which industry can never truly accomplish the intended objective and, as such, can always be found to have made insufficient efforts to support sterility-assurance programs.

Users of isolation technology, for example, have been asked to increase environmental monitoring (EM) to extreme levels because existing monitoring programs established for manned cleanrooms cannot detect contamination. Scientifically and legally, these standards have left industry with both feet firmly planted in mid-air. The result, as evidenced from recent inspections, is that if an inspector wishes to use these documents to insist that a firm lacks "sterility assurance," then there is virtually no way the manufacturing firm can defend itself.

It is always possible to start an inspection report with the following statement, "The firm failed to demonstrate sterility assurance in that...." It's impossible to objectively prove or disprove this allegation. Sterility is an absolute concept, and its presence cannot be proven, regardless of the effort to do so.

Examples of unprovable regulatory citations include claims of inadequate air visualization (smoke studies), claims regarding the conduct of media fills, the acceptability (or not) of a specific aseptic intervention, and charges regarding the adequacy of environmental monitoring. Metrics for smoke-test success are absent. This test is strictly an eye-ball exercise in which one party may see one thing and another sees something quite different. Although smoke tests are valuable for fine-tuning certain elements of critical-zone performance, they rarely lead to real performance improvements.

Airflow is another example. Airflow in cleanrooms is some-times incorrectly called "laminar," but in practice, laminarity cannot be achieved. No matter how well-designed or qualified an isolator or cleanroom is, there always will be turbulence and eddy currents. There is no objective standard for the point at which adequacy no longer exists or at which turbulence might affect sterility assurance, if it ever does.

Media-fill conduct is yet another issue without an endpoint. In recent years, regulators have required larger and longer media fills and placed an increased emphasis on using media fills as long as the longest production run. However, change does not enable proof of sterility. No media fill, no matter how large or intensive, can ever prove sterility. New conditions can always be added to a media-fill program, even if those conditions are atypical. Recently, FDA has expected that the production and filter sterilization of media parallel the compounding and filtration of product. Yet, media and product are two very different materials with different attributes. The most obvious of these differences is that media will amplify the presence of contamination, which the majority of products will not do. Also, media may contain insoluble particu-late in quantities not seen with most aqueous formulations which means prefiltration is a must. There is nothing to be gained from ever larger media fill tests with activities that really don't relate to process simulation being required

Another prevailing notion is that some aseptic processing interventions are inherently bad. There's no question that heroic efforts during aseptic processing should be avoided. But what makes a particular intervention good or bad? We have no useful metrics, to assess the difference, yet such categorization is all too swift and final. Furthermore, media-fill tests, no matter how intensive, cannot reliably demonstrate (or validate) that an intervention is low-risk, nor can they unequivocally prove that an intervention is bad. Neither media-fill or eyeball tests are inherently sound arbiters of sterility assurance. In absolute terms, they are both inadequate for such a task. Destroying a batch because an intervention is arbitrarily assumed to be "bad" is not much different than accepting a different batch made with a series of "good" interventions.