Equipment Hold-Time for Cleaning Validation 3

Table V: Wet granulation equipment train—clean-hold validation (Acceptable residue limit [ARL] = 100 cfu/swab)
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.
If clean- and dirty-equipment hold times are established during validation and maintained under properly defined and controlled conditions, the need to monitor clean- or dirty-hold times is not necessary. Avoiding these steps can result in savings of time and resources as well as potential regulatory exposure.
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,
1. FDA, Guide to Inspection of Validation of Cleaning Processes, Division of Field Investigations, Office of Regional Operations, Office of Regulatory Affairs (Rockville, MD), July 1993.
2. EU, Annex 15, European Union Guide to Good Manufacturing Practice, Working Party on Control of Medicines and Inspections, European Commission (Brussels, Belgium), July 2001.
3. Health Canada, Cleaning Validation Guidelines (Guide-0028), Drug GMP Inspection Unit (Ottawa, Ontario) May 2000.
4. "Recommendations on Validation Master Plan Installation and Operational Qualification; Non-Sterile Process Validation; and Cleaning Validation," in proceedings of the PIC/S (PIC/S, July 2004).
5. R. J. Forsyth and D. Haynes, "Cleaning Validation in a Pharmaceutical Research Facility," Pharm. Technol. 22 (9), 104–112, 1998.
6. J. A. Morales Sanchez, "Equipment Cleaning Validation Within a Multi-Product Manufacturing Facility," BioPharm Inter. 31 (2), 38– 49, 2006.
7. A. H. Mollah, "Risk-Based Cleaning Validation in Biopharmaceutical API Manufacturing," BioPharm Inter. 30 (11), 54–68, 2005.
8. T. Fugate, "Hold Time Studies: A Lost Parameter for Cleaning Validation," J. Val. Technol. 13 (3), 206–209, 2007.

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