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Particle Counting and the FDA
By Joe Gecsey, Product Manager
This article explores the FDA's approach to
monitoring particle contamination and the need to protect particle counters in
humid or washdown environments. The article was compiled frorn conversations
with the FDA and operators of sterile fill lines.
THE IMPACT OF VARIOUS government regulations on actual manufacturing processes
are not always obvious. The current government requirements for monitoring
sterile fin lines in cleanrooms requires a specific method of particle counting
that is somewhat different than Federal Standard 209D. 'Me particle counting
system will have to be compatible with the manufacturing environment, sample the
correct locations at the right size. and fulfill the FDA's requirement for batch
information.
The FDA currently requires the manufacturer to show that the process area was in
control only during the actual filling operation. Continuous monitoring of the
whole filling process is preferred, but not required. Monitoring Is not required
when the room is not in use. It is good practice to monitor during set-up to be
assured of the quality of the air, but it is not required.
If the product or personnel are changed during a shift, a new monitoring program
must be started. The particle counts taken during the morning do not reflect the
operating conditions later in the day if a new product or new personnel have
been introduced. Changing shifts would also require a new verification of the
mom, even if the same product was being made. The monitoring procedure must
occur during the actual filling operation, with the equipment and personnel
operating in their typical modes. This approach makes good sense in a majority
of cleanroom operations.
The monitoring of microorganisms in the product and in the environment is still
the main focus for assuring product sterility: monitoring of particles - living
or not-is useful as an additional indicator of control and as a "real-time" indicator of potential contamination.
Federal Standard 209D
Although the FDA uses Federal Standard 209D as a general basis for their
guidelines. the FS-209D Is not an absolute set of rules for the pharmaceutical
industry. One of the essential differences between the FDA's philosophy and
FS-209D is that FS-209D allows averaging of counts across sample points. During
batch filling, averaging data across multiple sampling points is not acceptable
to the FDA. To keep proper records for a sterile fill area. the particle counts
obtained at each critical point must be maintained as a separate record. The
intent here is to monitor the air approaching the filling line, not to
characterize the general particle level of the room.
The "Guideline on Sterile Drug Products produced by Aseptic
Processing" states that the sample points should be within one foot of the
fill line. The FDA will accept a greater distance if It can be shown that
sampling within one foot will produce erroneous counts due to some processing
condition. such as over spray from a highspeed filling needle or a powder
filling operation.
Also In contrast to FS-209D. the "Guideline ... for Aseptic
Monitoring" requires monitoring at 0. 5 microns: monitoring at other size
ranges, for example 1.0 or 0.3 microns, must be well justified for the
particular filling process. For aseptic areas. the counts at each sample point
must be below 100 counts per cubic foot for all particles 0.5 microns and
larger. Ibis generally equates to an FS 209D "Class 100." but the FDA
specifically requires monitoring at "0.5 micron and larger" sizing.
Using alternate size equivalents is not acceptable unless the manufacturer can
justify an alternate size based on unique processing requirements.
Establishing Quality and Control of the Processing Area Using Trends
At a given sample point, repeated monitoring will provide a typical "baseline" of values during the manufacturing operation.
"Alert" and "Action" levels can be set relative to the
empirically determined baseline count. Using 1 -sigma and 3-sigma points derived
from the baseline count might be appropriate. The FDA is comfortable with
averaging data at a given sample site: that is. each and every sample does not
have to be below the "Alert" level to continue the processing the
batch. However, a consistent trend away from the baseline should be a signal
that the area is out of control.
Selection of Sample Points
Within the sterile fill area. samples must be taken in the immediate vicinity of
the fill heads, and preferably near where the containers enter the sterile area.
In general. you should monitor at points where the product Is exposed to
potential contamination and where an operator might frequently be present.
Outside of the sterile fill area or other "critical" areas. the FDA
recommends frequent monitoring to ensure that the HVAC filtration system is in
order, but the frequency of monitoring can be relaxed to between daily and
once-per-week. Again. the intent of gathering this data is to show that the area
is generally in control.
Tubing Extensions
Short extensions - up to a maximum of roughly 10 feet - from the sample point to
the sensor are generally acceptable, assuming that the tubing has a minimum of
turns or curves and that the curves have a generous radius. Due to the
statistically low number of particles within a sample under "Class
100" conditions, it is best to limit the use of tubing, which causes some
entrapment or fragmentation of particles. If the tubing must be longer than 10
feet. then the loss factor for that given tubing must be determined and a
correction factor must be used to adjust the counts obtained during filling
procedures. In general, the use of manifolds for sampling in extremely clean
areas (e.g. Class 10) Is strongly discouraged by the FDA.
Saving Data
In general. for most sterile products. the particle count data should be saved
for a period extending one year past the expiration date of the product. There
is no restriction on the form of the data storage: it must simply be retrievable
for inspection within a reasonable time.
Equipment Considerations
Sterile fill areas are often aseptically washed. However, particle counters must
be protected from moisture. Since tubing length restrictions require the
particle counter/sensor to be in the washed area, the equipment must be housed
in a moisture and splashproof container. such as a NEMA 4X rated enclosure.
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