The Myth Called "Sterility" - Pharmaceutical Technology

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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.


Pharmaceutical Technology
Volume 34

EM has been increasing as a consequence of regulatory pressure for at least 20 years, but there is never any consideration of diminishing return or even patient risk arising from EM-related interventions. Quite simply, it is not possible to monitor quality into product (something we've known since the very origins of validation in the 1970s) and it will never be possible to use EM to prove sterility. EM is neither sensitive nor accurate enough to pinpoint when intervention might put a patient at risk. EM has significant and inherent, technical limitations and we have likely passed the point of diminishing return on it within even manned cleanrooms. This is an acknowledged fact that's never contemplated in current regulation.

The need foranewdirection. The absolutist thinking regarding sterility assurance plays a significant role in standards development. Both industry and regulatory authorities would benefit from a serious dialogue about the nature of aseptic processing regulation. Intensity and length of effort cannot alone ensure sterility. Monitoring, even if continuous, and smoke tests, even if comprehensive, cannot ensure sterility. Unfortunately, subjective evaluation of such data can result in regulatory observations that are not pertinent and may be irrelevant.

The authors are raising this issue now because we believe that evolving aseptic-processing technology has rendered the traditional evaluative methods less useful. These more advanced processes consistently operate below the limits of detection for the presently available microbiological assays.

As processes have improved and "zero" results have become the norm, the regulatory reaction has been to multiply the test and in-process workload which, while intuitively logical, is scientifically inappropriate and, unfortunately, valueless. We suggest that rapid microbiology, drawing increasing attention by industry, only provides the same imprecise information about the aseptic process we already have, albeit somewhat sooner. The use of that "information" is what the authors are concerned about, not the time it takes to obtain it. Rapid microbiology is very useful technology, but it cannot overcome the sampling limitations that exist. No analytical method (microbiological, chemical, or physical), regardless of how advanced and sensitive, can measure the complete absence of something. Sterility is, by definition, the complete absence of viable contamination.

The authors seek to highlight the increasingly arduous regulatory spiral into which we have been drawn. The most practical way forward is to carry out honest and detailed dialogue between all stakeholders. In many technical endeavors, there's a time at which paradigm shifts are required. Discipline of aseptic processing is now at such a point. Continuing to follow the same path of the past two decades will neither improve end-user safety nor the economics of manufacture.

A process-centric approach for superior performance

To successfully manufacture sterile products by aseptic means, it's necessary to redefine the process controls essential for success. Central to the authors' suggested approach is the use of the Akers-Agalloco (A-A) method for aseptic-processing risk analysis to support the evaluation and selection of the specific means for aseptic-process design and execution (1,2). Our preference for this over other methodologies is based upon the absence of inference from EM results. Katayama et al, in their review of aseptic-processing risk models, identified the A-A method as having the closest correlation to the operational performance evidenced for a variety of different installations (3).


Figure 1: Influences on aseptic processing (Adapted from L. Mastrandrea, Ref. 9).
Central to aseptic processing is the understanding that there are numerous factors that can influence the outcome (see Figure 1).

The authors believe it's the decisions, selections, and approaches—made with respect to each of the factors depicted in Figure 1—that have the greatest effect on results. Poor choices, regardless of the monitoring outcomes associated with them, must be acknowledged as unsound. Our approach differs from those derived from EM expectations because of our focus on personnel and their impact on contamination levels. The rankings in the A-A method devolve from a singular focus on the operator. From that perspective, the authors established the following basic precepts to the A-A risk method and the recommendations outlined below (4, 5):

  • Interventions are to be avoided at all times in aseptic processing
  • Interventions always mean increased risk to the patient
  • There is no truly safe intervention
  • The "perfect" intervention is the one that doesn't happen.


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