A common practice for the Clean Hold Time (CHT) is to consider it as the time from the end of the cleaning process to the beginning of the subsequent use of a specified vessel. This month’s Cleaning Memo is on how to define (or establish) those two “boundaries” for the CHT just like last month’s on the DHT (Dirty Hold Time). If you have not read the January 2024 Cleaning Memo, you might want to consider reading it before you read the current one. Many of the same principles apply, although the specifics of how those principles might apply are different for the CHT. So, how do we set clear boundaries for the DHT?
We’ll start with the end of the cleaning process (the start of the CHT). Note that the end of the cleaning process should mean the end of manufacture on a specific equipment item, and not just the completion of all processes on a given batch. Let’s say I am cleaning with an aqueous cleaning solution. It is not just the end of that final rinsing step that defines the end of the cleaning process. I also need to consider any subsequent step(s) such as drying or application of a sanitizing agent. Drying may be just an ambient temperature drying time, or may be with heated air or nitrogen, or may be using cleanroom wipers, or may be the use of 70/30 IPA/water. In a cleaning validation protocol, swab sampling is typically done on dry equipment, so any microbial data representing the “time zero” for the CHT should be measured after the drying step. This is based on the fact that the major concern for the CHT is microbial proliferation, so that the baseline (time zero) data for that proliferation should be data for dry equipment. If the baseline data were taken before drying, then it is likely that any drying step would further reduce microbial values, thus making any change in microbial levels difficult to evaluate.
Similar concerns are present with the use of a sanitizing step, such as a final application of an oxidizing sanitizer, a quaternary ammonium sanitizer, or use of 70/30 IPA/water as sanitizing agent (in addition to alcohol’s drying properties). That is, the beginning of the CHT should be at the completion of the sanitizing step, as well as after the end of any drying step following the use of a sanitizer. Note also that if the sanitizer leaves a residue that may inhibit re-growth of microorganisms, this fact should be considered (or the impact reduced); otherwise the data at the end of the CHT may not be meaningful (unless any change in microbial levels is due to external contamination rather than proliferation of bioburden that was present at the start of the CHT).
So the next issue is to establish the ending time for the CHT. What constitutes the “next use”? If the next use is manufacture of another product (which may be a different product or another batch of the same product), there may be variations. The simplest is to specify the time when the first component (which may be water, an individual chemical compound, or a chemical mixture) is added to the equipment for processing. If any steps are taken prior to processing of the next product, then the ending CHT time could be defined as the beginning of such a step. An example of such a step is a hot water flush. If the next “use” of the equipment is a validated sterilization cycle, then the beginning of that sterilization cycle time should be used as the ending CHT time. Something like the time at which steam is first introduced into the equipment might be an appropriate end time.
Some may question why the CHT does not extend to the end of the sterilization cycle. The main reason is that if bioburden were sampled at the end of the sterilization cycle, there should be no bioburden measured; so there is no reason to measure bioburden after that sterilization cycle. Note further that the maintenance of sterility following a sterilization cycle should be evaluated as part of what could be called the “sterility hold time” (SHT). That SHT (I probably should have chosen a different acronym) answers the question of how long the sterile equipment can be held in an unused state before manufacturing a drug product using that equipment. This is not typically done by opening up the equipment to sample it for bioburden. A more practical approach is to state that provided the equipment is closed and maintained under positive pressure that is continuously measured and recorded, the sterile state should be maintained. While this conceivably could be an indefinite time, it is generally the practice that some reasonable time is specified before it is required to perform the sterilization cycle again. If the concern related to loss of sterility is more than just the elapsed time, then it also may be appropriate to clean the equipment before performing sterilization again.
For clarification, sampling at the “end time” should be done immediately before that subsequent use (and not during that subsequent use).
Below are some additional considerations for the CHT.
As with the DHT, realize that the design of a robust cleaning process with challenges for the CHT in the design/development phase may be a more preferable way to simplify CHT issues.
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