Numerous points of special emphasis in the regulation of sterile products have come and gone over the past three decades,
but by and large the trajectory of regulatory change has remained the same. The dominant regulatory philosophy is well known
to all stakeholders, and in general involves an ongoing reduction of allowable environmental-control levels with an emphasis
on the quantitative aspects of microbiological monitoring (1–4). Along the way, new parallel points of emphasis have been
added, including the evaluation of airflow patterns (chiefly by smoke study testing), emphasis on high-efficiency particulate
air filter integrity, and increasing attention to nonviable particle excursions. Not surprisingly, given this direction, regulators
recently have spoken about expanding the correlation between particulate-air quality, room or zone classification, and microbiological
The emphasis on reducing microbial contamination has worked, although it is possible to debate whether this progress was the
result of regulatory emphasis or of ongoing technological advancement. Much of the improvement likely was inevitable, unrelated
to regulatory pressure, and purely technological. The increase of automation dramatically reduces the need for human operators
to intervene in the process. Examples include automatic weight checking, sterilizing or cleaning in place after equipment
setup, depyrogenation tunnels, automatic parts feeding, and automatic lyophilizer loading. The cumulative effect of these
advances has been to reduce the number of human operators required in aseptic-processing areas. Because humans are the major
source of contamination, automation directly reduces microbial levels.
It is also clear that improved cleanroom garments and cleanroom undergarments have played significant roles in reducing human-borne
contamination of aseptic processing environments. An often overlooked reason for improved environmental control is that modern
aseptic fill rooms have far higher air-exchange rates than they did two or three decades ago, a fact that deserves emphasis.
Clean-air dilution rates have not received the same amount of regulatory attention as have air direction evaluated by smoke
tests, and transient and low-amplitude particulate excursions.
Aligning philosophy with metrology
Regulators' increased emphasis on microbiological monitoring has fostered the implementation of advanced processing technology
and better cleanroom designs. The effort to "push down counts" was inarguably effective at focusing industry's attention on
improving the science and engineering of aseptic processing. Interestingly though, other industries have unquestionably evolved
faster in environmental contamination control without similar levels of regulatory emphasis on monitoring. The aseptic beverage
industry has already moved beyond using human operators and gone to highly automated and fully enclosed aseptic processing
systems. And, of course, the microelectronics industry operates at levels of environmental control well beyond those employed
for the aseptic processing of healthcare products. These industries were motivated largely by commercial opportunity and advantage.
Modern biopharmaceutical manned aseptic processing ISO 5 critical zones generally produce contamination recovery rates of
substantially less than 1%. A review of data from these cleanrooms confirms that this low-level contamination does not follow
any discernible pattern. Small deviations in rate are apparent, but statistical trends are not. In addition, the long relied-upon
alert-and-action-level trending approach now has little scientific merit in ISO 5 or cleaner environments. The limit of detection
of the monitoring methods is not zero, and, in fact, that limit is necessarily unclear. Analytically, it is not possible to
know that zero means no contamination, although it is reasonable in a manned cleanroom to assume that it doesn't. No meaningful
difference exists between a plate with one colony forming unit (CFU) and one with three or four CFU, but current regulatory
philosophy forces us to pretend that it does. Those required to investigate a normal and completely routine environmental
recovery from a manned environment generally understand the utter futility of their exertions, but those who require them
to do this busywork apparently fail to grasp that it is a waste of human resources. The resulting lack of mutual understanding
is just the sort of thing that breeds cynicism, and ultimately frustration.
The authors believe that unless human operators are made to wear hermetically sealed suits with filtered inlet and exhaust
air, the industry has approached the contamination-control baseline in state-of-the-art manned cleanrooms. The substantial
improvements observed before the 1990s are no longer possible. As a result, the industry is operating at the ragged edge of
method capability.* Put another way, we are operating at the edge of our limit of detection at all times. People often express
a need for better monitoring technology to continue on the current regulatory trajectory, but this is quite simply fool's
gold. Ultimately, industry must accept the fact that where human-scale aseptic processing is concerned, it can no longer measure
the incremental improvements using monitoring approaches that worked well when process capability was substantially lower.
Random, low-level counts, essentially at background levels, are common. Manned rooms will always and inevitably have a background
level of microbial count. Conducting investigations, then, into background-level recoveries is a meaningless activity that
is unrelated to the assessment or reduction of risk.
Monitoring in the assessment of risk has another drawback in that, more than ever, it requires a significant increase in interventions
into the ISO 5 aseptic-processing critical zone. Greater implementation of automation has reduced risk largely by eliminating
interventions and reducing the human population within aseptic fill suites. Increasing the intensity of monitoring will reverse
this positive trend by requiring more interventions to perform air and surface sampling. In the research that led to the publication
of the Akers-Agalloco risk-analysis method, the authors found that monitoring activities were the largest single type of intervention
in many modern cleanrooms (5). Operators thus were creating risk in an effort to measure risk.