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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.
The concepts of "clean-hold time" and "dirty-hold time" have been part of cleaning validation since its inception. Clean hold time is generally considered to be the time between the completion of cleaning and the initiation of the subsequent manufacturing operation. Dirty hold time can begin when the clean equipment is initially soiled, but more often is defined as the time between the end of manufacturing and the beginning of the cleaning process. Intuitively, it makes sense to be concerned about both hold times. Dirty equipment is harder to clean the longer the hold time, and clean equipment has a greater chance of becoming soiled as hold time increases.
In its Guide to Inspection of Validation of Cleaning Processes, the US Food and Drug Administration considers identifying and controlling the length of time between the end of processing and each cleaning step to be critical elements of the cleaning processes (1). FDA also expects pharmaceutical companies to demonstrate that routine cleaning and storage of equipment does not allow for microbial proliferation. The European Union expects companies to provide a validation master plan with clearly defined and documented validation program elements (2). Health Canada looks for companies to describe the interval between the end of production and the beginning of the cleaning procedures as well timeframes and conditions for the storage of clean equipment that do not allow for microbial proliferation (3). Finally, the Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-operation Scheme (PIC/S) guideline looks for documentation of both dirty- and clean-hold times (4). The general practice among industry is to routinely document and track equipment-hold times to ensure ongoing compliance.
Although regulatory agencies expect manufacturers to document and address hold times, they do not describe a process for establishing hold times. In this validation study, a dirty-hold time was established but ongoing implications were not examined (5). Several articles define both clean- and dirty-hold times and how to establish them but do not mention a strategy to guide the experiments (6, 7). A more recent article, which referred to hold-time studies as "the lost parameter for cleaning validation," explored several issues associated with hold-time studies (8). Issues included storage conditions, test locations, testing methodology, and the length of hold-time studies.
The concern with clean-hold times is that clean equipment will not stay clean indefinitely despite using appropriate storage conditions. Holding soiled equipment makes it more difficult to remove pharmaceutical soil and allows biological contamination to proliferate. To address these concerns, the author extended clean-hold time testing for more than 2 yrs and extended dirty-hold time studies for up to 9 days. After identifying clean- and dirty-hold time, ongoing control of the hold times became difficult. Every time a piece of equipment is used, the operator needs to confirm and document that the actual clean-hold time does not exceed the established clean-hold time. And before washing a piece of equipment, the washer needs to confirm and document that the actual dirty-hold time does not exceed the established dirty-hold time.
This study suggests that if clean- and dirty-hold time issues are addressed during the validation study that the severity of exceeding the established hold times diminishes to a near-acceptable level.
Table I: Dry granulation equipment train-dirty-hold validation (Acceptable residue limit [ARL] = 100 Âµg/swab)
As part of the cleaning-validation study in a pilot plant (5), soiled equipment was held after processing for an extended period of time before cleaning. The hold times for the three validation trials held ranged from 2 h–217 h or 9 days. Data from the validation study including dirty-hold times are shown in Tables I, II, and III. The results include data from a typical dry-granulation equipment train and a wet-granulation equipment train. The majority of the data (187 of 231 swabs) showed no detectable residue. All results were far below the acceptable residue limit (ARL) of 100 µg/swab. The tests showed that over the time span examined, the dirty-hold time had no discernable impact on the ability of the cleaning process to effectively remove the soil from the manufacturing equipment.
Table II: Wet granulation equipment train-dirty-hold validation (Acceptable residue limit [ARL] = 100 Âµg/swab)
The clean-hold time validation study was conducted independently. After cleaning, the equipment was wiped or sprayed with alcohol to remove residual water, dried, and covered to prevent any dust or particulate accumulation. The validation study consisted of three trials; one trial extended the clean-hold time. The clean-hold times for the three trials ranged from same-day cleaning to a hold time of 2 yrs and 5 mo. Storage conditions included both the clean-equipment hold area in the pilot plant and a storage room outside the pilot plant but in the same building. Data from the clean-hold time study are shown in Tables IV, V, and VI. The majority of the data (128 of 180 swabs) showed no detectable bioburden and all results were far below the ARL of 100 colony forming units (cfu)/swab. The results include data from a typical dry-granulation equipment train and a wet granulation equipment train. The results demonstrate that bioburden was not present immediately after cleaning and was not a cause for concern during storage of properly cleaned, dried, and covered equipment.
Table III: Equipment dirty-hold time
Cleaning-validation studies have established equipment dirty-hold times and clean-hold times for pharmaceutical manufacturing equipment. The ongoing expectation is that equipment cleaning documentation verifies compliance with the validated hold times. A conservative approach uses either the established time for each group of equipment, which makes recordkeeping difficult, or the shortest established extended hold time for all equipment. Using this approach, the dirty-hold time is limited to 7 days and the clean-hold time to several weeks. A more aggressive approach uses the longest hold-time data. This gives a maximum dirty-hold time of 9 days and a clean-hold time of more than 2 yrs.
Table IV: Dry 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 V: Wet granulation equipment train-clean-hold validation (Acceptable residue limit [ARL] = 100 cfu/swab)
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.
Table VI: Equipment clean-hold time
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 1. High-shear granulator prepared for cleaning. (FIGURES ARE COURTESY OF THE AUTHOR)
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.
Figure 2. Granulator exit chute prepared for cleaning.
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, email@example.com
Submitted: Nov. 16, 2007. Accepted: Dec. 20, 2007.
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.