A common practice for the Dirty Hold Time (DHT) is to consider it as the time from the end of manufacture to the beginning of cleaning in a specified vessel. This month’s Cleaning Memo will cover how we define (or how we establish) those two “boundaries” for the DHT. Just like boundaries for land or property, we don’t say something like “from this tree to that rock”; we generally try to have a survey done to address any potential disputes on where the boundary line is. So, how do we set clear boundaries for the DHT?
We’ll start with the end of manufacture (the start of the DHT). Note that the end of manufacture 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 doing liquid processing. Is the end of manufacture the end of the mixing step in blender, or is the end of manufacture the time when the blender is “evacuated”? Why is this distinction relevant? One reason is that if the liquid batch is allow to stay in the mixer for an extended time (for example, overnight) before it is moved to the next equipment, it may be possible for product to “dry out” and accumulate at the air/liquid interface, thus creating a more difficult-to-clean situation with the formation of a “bathtub ring”. There are at least two possible ways to address this.
Option 1: Define the start of the DHT as the time that mixing ends. Therefore the DHT includes both the extended time the batch stays in the mixer without any mixing action as well as the additional extended time the blender is empty, all up to the time of the start of the cleaning process. In this case, the challenge for the DHT evaluation is a situation in which both those times are included in worst-case evaluation.
Here is a possible example for Option 1. Suppose the maximum time (which I will call Time J) the product will be in the blender before it is transferred to the storage vessel is 48 hours. Furthermore, suppose the maximum time (which I will call Time K) from the end of the transfer to the beginning of cleaning is 72 hours. I would then do a protocol in which the equipment was cleaned both after a maximum of 48 hours before transfer and a maximum of 72 hours after the blender is emptied. That is, the evaluation should see a total time of 120 hours (the sum of the two times). Note that I cannot just say the DHT is 120 hours, because that might be interpreted to mean that if the product was immediately transferred out of the blender, I could wait 120 hours before the cleaning process is started. Clearly the evaluation suggested (48 hours for Time J and 72 hours for Time K) are two distinct parameters, where each parameter (Time J, Time K) might be different in terms of making the product in the equipment more difficult to clean.
Option 2: Define the start of the DHT as the time that the equipment is emptied (that is, the product is transferred out of the equipment). Therefore the DHT does not include Time J, but only includes Time K (the extended time the blender is empty up to the time of the start of the cleaning process). This is the more typical use for a DHT. Using the same time parameters as given in the example for Option 1, the DHT would be only 72 hours. So, in this option how would I deal with Time J? Time J here would not be part of the DHT, but a maximum time should be specified and recorded in the manufacturing process batch record as a challenge to the cleaning process.
Now, you might look at these two options and say “As a practical matter for performing the protocol, isn’t Option 2 exactly the same as for Option 1.” And in one sense you would be correct. However, the definitions of terms that we use are significant for careful implementation. For example, in these two situations a risk assessment may be done to simplify things. It would be preferable to keep the conventional definition of DHT as being from the time equipment is emptied until the time the cleaning process begins, and then just add (if appropriate) the maximum Time J as a challenge to the cleaning process in the protocol.
Furthermore, there may be differences in applying these two options to liquid products and to dry products. If scientific judgment and/or data can be used to maintain that for dry products there is no change in difficulty of cleaning with time, then it may be possible that with a reasonable maximum for the DHT, it may not be necessary to include that maximum time as a challenge in a protocol. Note that for final dry product, it may be that for the DHT (either under Option 1 or Option 2) it probably is still required to challenge the maximum times (either in a validation protocol or in a design/development study) for situations where in earlier process steps, wet processing is involved (such as in wet granulation equipment).
Another situation where this distinction of terminology is important would be liquid filling, where a liquid product is transferred to the filling equipment over a significant period of time. In that situation, it may be that there is significant drying of the liquid product on the upper portions of the holding vessel as the product is somewhat slowly transferred to the filler.
It may also be desirable to set a plus/minus range for such maximum times, such as 72 hours ± 2 hours.
Some final comments are related to how to specify things like the time of the end of the mixing, the time that the equipment is emptied, and the time of the beginning of the cleaning process. These should be established, but unless there is something unusual about your manufacturing process, it is not necessary to get bogged down in slight time differences. Here are examples.
The end of mixing is the time at which the agitator is turned off. [Sure there still may be some liquid movement after that, but in most cases it is not significant.]
The end of emptying a vessel is the time when the discharge valve is closed.
The beginning of the cleaning process is the time at which the cleaning solution is first introduced into the soiled vessel (or perhaps the time at which the water pre-rinse is introduced into the soiled vessel). Note further that complications may arise for manual cleaning where the start of cleaning for certain segments of large equipment may vary depending on the times of first exposure to the cleaning solution; in this situation, consider a worst case time as most relevant challenge for determining the maximum time.
Realize further that the design of a robust cleaning process with challenges for the DHT in the design/development phase may be a more preferable way to simplify DHT issues.
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