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