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COMMENTARY
Setting Alert/Action Limits for Environmental Monitoring Programs
JAMES D. WILSON
Pharmaceutical Systems, Incorporated, Mundelein, Illinois
The principle purposes of an environmental monitoring
program are to provide an assessment of the general
microbiological cleanliness of an operation and to assess the
state of environmental systems control. Being cognizant of
the numbers and kinds of microbes present, a microbiologist
can assist in designing an effective control system(s);
however, no environmental monitoring program, regardless
of its design, can provide the level of confidence desired
without subsystem management which is accomplished by
adherence to current good manufacturing practices, facility
design control, effective supervision, sound corrective ac-
tion steps, and proper employee training.
An environmental program is comprehensive. One impor-
tant component of an environmental surveillance system is
the establishment of alert and action levels. It is dangerous to
consider alert/action limits independently of other compo-
nents of the system. The setting of absolute numerical limits
for microbiological monitoring, from either published re-
ports or guidelines, should be approached with caution due
to the diversity of operations and inherent variability of
sampling/testing methodologies, notwithstanding statistical
implications.
There are several methods in use for establishment of
alert/action levels. There is no clear consensus among
pharmaceutical/device manufacturers on a preferred method.
Challenges to microbiologists apparently occur when wide
ranges in results are observed or when limited data are
available. The challenge for the microbiologist is exacer-
bated by the adoption of arbitrary limits imposed by some
Food and Drug Administration (FDA) investigators.
If historically based alert/action levels are desired, accept-
able microbial levels must be established based on sound
statistical surveys of historical data that have been collected
on a consistent basis using identical methods. Historically,
environmental data have been treated as means ± 2 or 3 SD,
cumulative frequencies, log transformations, etc., but these
methods can ultimately lead to levels that may not represent
the actual process capability and/or an understanding of the
same.
Setting alert/action levels using standard statistical tools
such as means ± 2 or 3 SD, while providing a method of
identifying out-of-limit trends, can be misleading because
(1) these methods are based on a normal distribution and (2)
these methods are based on two-tail probability. In practice,
environmental data are usually not normally distributed;
environmental data histograms generally resemble poisson
Received January 25, 1997. Accepted for publication April 10, 1997.
Correspondence address: Pharmaceutical Systems, Inc., 102 Terrace Dr.,
Mundelein, IL 60060-3826.
Vol. 51, No. 4 / July-August 1997
or negative exponential distributions. Regardless of the
method employed, however, a special concern is how one
deals with outliers and clusters of unusual results in the data.
Including data taken from a period of unusually high counts,
where the process was out of control, will lead to inappropri-
ately high alert/action limits. Such clusters of obviously out
of control data should be excluded before alert/action limits
are calculated. For example, suppose a plot of the data
versus date showed that counts from July and August were
about twice as high as typical. An investigation showed that
a new technician had been using poor technique and was
retrained at the end of August. If this out of control period is
left in, the alert/action limits will be calculated inappropri-
ately high. The out of control period is not part of the
underlying process capability and should not be used in
calculating limits.
Several ways to identify unusually high clusters of data
include (1) plots of the data over time; (2) histograms; and
(3) statistical process control charts. The data should always
be plotted versus date for separate physical locations to help
identify unusual data points.
Once the data have been cleaned up by removing obvious
out of control points, the underlying process capability can
be determined. Several methods may then be used to
determine appropriate alert/action limits on the cleaned up
data:
1. Direct calculation of percentiles
If there are enough data points (perhaps 100 or more),
the action level may be set to equal the 99th percentile
of the data; the alert level may be set to equal the 95th
percentile. This method is probably the most desirable
because it does not make any assumption about the
shape of the distribution of the data.
2. Poisson
Counts often follow the poisson distribution. If the
data appear to be Poisson distributed, the estimated
99th and 95th percentiles may be calculated with
tables of the Poisson distribution or available software.
3. Negative Exponential Distribution
Although microbial counts are not continuous data, the
exponential distribution may provide a reasonable ap-
proximation. The estimated 99th and 95th percentiles
may be calculated by multiplying the mean by 4.6 (for
the 99th percentile) or 3.0 (for the 95th percentile).
4. Other Distributions
If the data appear to be approximated by the normal
distribution, which does not often occur with microbial
data, the upper one-sided 99th and 95th percentiles
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may be approximated by the mean ± 2.326 SD (99th)
and by the mean ± 1.645 SD (95th). Sometimes taking
a transformation of the data, such as square root or
logarithm, will normalize the data. Other distributions.
such as the Weibull, may also be used.
It is advisable to compare the alert/action limits obtained
with a histogram of the data. If something is dramatically
wrong with the method used, it will be obvious when
locating where the alert/action limits are on the histogram.
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This deficiency can happen when the method and distribu-
tion used does not match the actual distribution of the data.
This approach provides a reference point for adopting
official or corporate alert/action levels by using a sound
scientific rationale.
Acknowledgment
The valuable assistance of Mark Varney is gratefully
acknowledged.
PDA Journal of Pharmaceutical Science & Technology