The inadequate validation of dirty equipment hold time (DEHT) is a common health agency observation. A deficient DEHT validation impacts cleaning effectiveness, allowing residues to remain on equipment surfaces after cleaning, leading to cross-contamination. DEHT is the time between the end of product manufacturing and the beginning of the cleaning process [1]. There’s a common misconception that the cleaning process and DEHT validation are separate entities performed under two separate cleaning validation studies. This memo aims to clarify the role of DEHT in validating your cleaning process and how the two are intrinsically linked.
Without challenging the DEHT during validation, we do not know if our cleaning process is robust enough to remove residues after the hold time. As the process residues dry after manufacturing, the residue’s composition may change, and affect its cleanability. We see this in our everyday life: sauce on a plate only takes a simple rinse to remove when wet, but if left overnight, we must bring out the sponge and use some elbow grease. In addition to changes in residue cleanability, there is a concern that microbes can proliferate unchecked due to the potentially rich food source provided by the process residues. Changes in residue cleanability and bioburden accumulation can directly impact the effectiveness of the cleaning process, and increased levels of contaminants may remain on equipment surfaces after cleaning if DEHT is not appropriately challenged during cleaning validation.
Let's discuss an example, residue buildup was observed on an auto coater marked as clean. Sampling of the buildup revealed the presence of multiple drug substances, and the bioburden specification was exceeded. As part of the deviation investigation, the documentation of the validated cleaning process was reviewed, and it was found that the auto coater cleaning validation did not include challenging the DEHT. During validation, the auto coater was held for less than two hours before the cleaning process began across all three runs. A DEHT of 10 days was established for all equipment in a separate study with a single run on a fluid bed dryer (FBD).
There are multiple issues with this validation approach. The first is that one run cannot demonstrate consistency or repeatability [A]. The second is that the validation approach for DEHT inappropriately allows for the grouping of equipment with different equipment designs and different cleaning procedures. The third is that the cleaning process for the auto coater was not challenged at the DEHT during validation.
To remediate the cross-contamination concern identified, the site will need to revise the procedure related to cleaning validation requirements to require the establishment of the DEHT during cleaning validation with no less than three runs, and that equipment may only be grouped for validation if they are of similar or identical design, mode of operation, and are cleaned by the same cleaning procedure [1]. Next, they will need to execute revalidation of the cleaning process for the auto coater with DEHT. In addition, a gap analysis should be performed to determine what equipment was incorrectly grouped for DEHT validation or an inadequate number of runs was performed to support the DEHT validation claims, in all these situations, revalidation is required.
In preparation for revalidation, a target DEHT should first be identified and then specified in the cleaning validation protocol. The target DEHT should be liberal enough to allow for atypical holding of equipment, but conservative enough so as not to adversely impact the manufacturing schedule. Factors to consider may include routine time equipment is not in use between batches and average time experienced for delays, (e.g., maintenance activities or emergency repairs). This should give a manageable DEHT that accounts for the inevitable delays but does not keep production tied up too long during validation.
Setting a target DEHT such as 10 days may not be ideal. Allowing equipment to remain soiled for several days not only takes up valuable time that could be used for production but also increases the risks of cross-contamination and microbial proliferation. A target DEHT of 10 days will extend the cleaning validation execution to a minimum of 30 days for all three runs.
The validated DEHT will be the shortest hold time of the three validation runs. During revalidation, if our target DEHT is 72 hours, the equipment must be held in a soiled state for at least 72 hours before the cleaning can begin for all three runs. If our equipment was held for 72 hours for run one, 75 hours for run two, and 80 hours for run three, our validated DEHT is 72 hours.
There are certain situations and residue types where DEHT is not a factor as cleanability is not impacted over time, such as a completely dry powder in a dry environment. However, this must be well documented and scientifically demonstrated under actual manufacturing conditions including environmental considerations. Even small amounts of environmental moisture absorbed by a dry powder can change its cleanability.
Regulatory agencies unequivocally require that a validated DEHT is established [2,3,4,5,6] and expect that cleaning validation demonstrates that the cleaning process when challenged at the established DEHT will adequately remove process residues. Thus, DEHT is inextricably linked to the validation of the cleaning process as an input parameter, and separation of the DEHT from the cleaning validation is not a compliant practice. We cannot show the repeatability, effectiveness, or robustness of the cleaning process without the inclusion of DEHT.
[A] For further reading, see the MQ memo One Data Point is Not Enough
References-
PDA. (2012). Technical Report No. 29 (Revised 2012). Points to Consider for Cleaning Validation.
FDA. (1993). Guide to Inspection of Validation of Cleaning Processes
Health Canada. (2021). GUI0028: Cleaning Validation Guidelines.
WHO. (2019). Annex 3, Appendix 3. Good Manufacturing Practices: Guidelines on Validation
PIC/S. (2023). PE009-17, Annex 15, Qualification of Validation
ICH. (2016). Q7. Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients
FDA. 21 C.F.R. Part 211.67
Contributors: Alec Fufidio, Joanna Joseph, and Jenna Carlson