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Regulatory agencies expect companies to establish and monitor clean equipment- and dirty equipment-hold times for manufacturing equipment as part of their cleaning validation program.
An examination of the clean-hold time data supports the more aggressive approach. The data were consistent for both the wet-
and dry-granulation equipment. The average bioburden level for the 180 samples taken was 1.1 cfu/swab. There were 128 samples
with no detectable bioburden and only nine with a bioburden greater than 10 cfu/swab. Although the majority of samples were
taken shortly after cleaning, samples were taken at 1, 2, 5, and 8 mo and at 2 yrs, 5 mo with no discernable increase in bioburden.
With a bioburden limit of 100 cfu/swab, clean-hold time is not an issue for cleaned equipment that is dried, covered, and
stored appropriately.
Table VI: Equipment clean-hold time
The dirty-hold-time study needed to answer two questions. Does the soil become harder to clean the longer it sits, and what
is the possibility of microbial proliferation on soiled equipment? Soils can be more difficult to clean when they are wet
and allowed to dry onto the surface, or when the soil is hygroscopic and transforms into a pasty material or subsequently
dries. A high-shear granulator is the only equipment that carries out wet granulation at the conclusion of unit operation.
The dirty-hold time for the high-shear granulator (196 h) was lengthy enough to allow any wet material to dry. The controlled
humidity of the pilot plant prevented any moisture uptake by residual granulation. All other equipment in the validation studies
resulted in a dry granulation at the conclusion of unit operation. Microbial proliferation was not a realistic possibility,
which was corroborated by the clean-hold time data.
Figure 1. High-shear granulator prepared for cleaning. (FIGURES ARE COURTESY OF THE AUTHOR)
Subsequent to the validation studies, the gross cleaning of the equipment, including scraping and vacuuming the equipment
was shifted from the equipment-cleaning process to the manufacturing process, which effectively shortened dirty-hold times.
Because of environmental considerations for residue disposal, equipment operators scrape and vacuum accumulated residue from
equipment surfaces. Operators then wipe equipment surfaces with alcohol to remove as much of the residue as possible to minimize
the amount of residue discharge to the municipal sewer system. An example of a typical soiled equipment surface prepared for
cleaning is shown in Figures 1 and 2. The steps taken for environmental concerns effectively shorten the dirty-hold time.
The alcohol wipe dries within minutes, leaving no wet material to dry and become harder to clean. The dry soiled surfaces
do not have sufficient water activity to support microbial proliferation. There is no sufficient residue remaining for hygroscopic
residues to be a concern. The dirty-hold time data, which measured cleaning effectiveness out to 9 days, demonstrated a worst-case
scenario for the pilot plant facility. The dirty-hold time is not of significant concern for soiled equipment awaiting cleaning.
Figure 2. Granulator exit chute prepared for cleaning.
Under the operating conditions tested as part of the cleaning validation studies, the clean- and dirty-hold times have little
impact on the ongoing operations of the pilot-plant facility. In addition, routine verification of adherence to these parameters
adds little value to a firm's ability to produce quality formulations. The risk, therefore, tied to not monitoring hold times should be low for validated cleaning and storage conditions.
Richard J. Forsyth is an associate director of worldwide GMP quality with Merck & Co., Inc, WP53C-307, West Point, PA. 19486, tel. 215.652.7462, fax 215.652.7106.
Articles by Richard J. Forsyth
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