validation refers to establishing documented evidence that a process or system, when operated within established parameters, can perform effectively and reproducibly to produce a medicinal product meeting its pre-determined specifications and quality attributes
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 III: Equipment dirty-hold time
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.
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.