More and more I am thinking that that companies can improve their cleaning validation program by making improvements not necessarily in the cleaning validation activities, but rather in the cleaning process (cleaning procedure) design and execution. When you stop and look at your overall program, is it better to have a well-designed cleaning procedure or to have well designed cleaning validation activities. Of course, it is best to have both; this is also consistent with the fact that is a life cycle cleaning validation programs, the design and development of the cleaning procedure is usually one of the first steps. So don’t get me wrong; I am not saying that the cleaning procedure is more important than the cleaning validation protocols. However, it is the first step to make sure when you get to the protocols and routine execution on an ongoing basis that you are on more solid ground. Many companies will benefit by paying some additional attention to the design of the cleaning procedure. This month’s Cleaning Memo, on the issue of the “dirty hold time” (DHT), is one such area where improvements may be possible.
A typical industry approach is to establish a DHT of at least three days. This accounts for the possibility (or likelihood) of manufacturing being completed on a Friday afternoon, and the equipment remaining dirty (that is, uncleaned) until the following Monday morning. So as a challenge in the validation protocols, at least one protocol run is performed at the maximum DHT of three days. Now I can fully understand that rationale. However, if in that scenario cleaning can be started on Friday afternoon (perhaps with some overtime), and the equipment is easier to clean after a DHT of a few hours as opposed to a DHT of 3 days, are there possible benefits?
Well, the answer depends to some extent on the other specific factors. For example, perhaps the situation is such that the difficulty of cleaning does not change with increased time. This might be the case with certain process steps of oral solid dosage form manufacturing. In that situation where one is just processing dry powder, it is not expected that the equipment becomes more difficult to clean with increasing DHT. If the OSD manufacturing step is wet granulation, then it is likely that the equipment will be easier to clean after a DHT of a few hours as compared to after three days. The reason for that is as the wet product dries on surfaces during the DHT, the product may become more difficult to clean. A second situation might be where a “dry” powder might pick up moisture (from the air) during the DHT, and therefore become more difficult to clean.
On the other hand, for liquid products it is reasonable that the liquid product may dry out in some equipment locations and thereby become more difficult to clean with time. Liquid products are clearly situations where the likelihood of more difficult cleaning with increased DHT requires more attention. Certainly setting a DHT of three days is possible (although some companies may select a DHT of four days to deal with situations where there is a Monday holiday). An alternative is to initiate cleaning in as short a DHT as practical. If possible three or four hours could be the goal. To do so would require more planning to have the cleaning team prepared and available to start within that shorter time.
What is the advantage of this approach (if it can be implemented consistently)? Assuming the cleaning process is not modified from the cleaning process used for the previous, longer DHT time, the main advantage is that I am more likely not to have situations where the cleaning process is ineffective (either due to visual failures or to analytical failures). The reason for this is that if my cleaning process was previously validated for a DHT of three days, and I have reduced the DHT to one day, my cleaning process is likely to be more effective because the liquid drug product will not dry out to the same extent with the shorter DHT.
Of course, some may object that with a shorter DHT, I am more likely to exceed the DHT and therefore be in a “deviation” situation. While that is possible, if it is rare it may be possible to handle it by appealing to the effectiveness of the previous validation done at the longer DHT. In such a situation, it may be possible not to open a formal deviation, but just to record and trend such occurrences. If it is likely that controls cannot be put in place to more consistently follow the shorter DHT, it makes little sense to try this approach.
Note that while it may be possible to modify the cleaning SOP to account for a shorter DHT, that approach is not likely to be economically feasible considering the cost of revalidating what, in essence, is a new cleaning process and situation. The exception to this is when I am forced (for other reasons) to modify the cleaning SOP such that entirely new validation protocols would be required.
If the approach of shortening the DHT and keeping the same cleaning SOP is to be successfully implemented, it is important to consider whether a shorter DHT can be consistently adhered to with the existing staff and existing procedures. Changes that may be needed include training operators on the rationale for the change as well as changed procedures to assure compliance. Changed procedures may include a more formal “time” procedure to make sure cleaning is started within the DHT. This might include an “early warning notice” so that, for example, when 12 hours have passed there is a visible or audible signal that cleaning must begin within 12 hours.
Another option to consider for situations where there may be significant drying during a longer DHT is to introduce a “pre-flush” (with ambient temperature water) immediately after manufacture, but allow the equipment to be “idle” for up to three days before the previously validated cleaning process is utilized. The idea here is that this pre-flush will reduce the drug product load, thus making cleaning “easier” when the previously validated cleaning process is utilized at a later time. In addition to reducing the drug product load, the pre-flush will also leave the drug product at a lower “solids” level, thus slowing down the time for drying to occur. A balancing consideration is that after the pre-flush, the more dilute drug product remaining may be more likely to result in microbial growth during the extended DHT.
Note that in most cases adding a pre-flush as part of an existing process should not be considered “precleaning” as discussed in Question #8 of the FDA’s “Questions and Answers on Current Good Manufacturing Practice Requirements – Equipment”. A pre-flush of this type is not separate from the cleaning SOP, but should be defined as part of the cleaning SOP. This change should be made as part of the company’s change management process. However, there should be a limited need to repeat the more formal (and more complete) cleaning validation protocols. In a sense, this added pre-flush is not unlike a pre-flush is done in biotechnology cleaning processes; the purpose of the pre-flush there is to improve the efficiency of a subsequent application of a hot, caustic cleaning solution. The pre-flush in biotechnology manufacturing is considered an integral part of the cleaning procedure (the SOP).
I should also point out one downside to modifying a cleaning procedure with a shorter DHT without repeating a more complete protocol. That downside is related to what might be done for repeating a run of the original validation on a regular basis. In this situation, the repeat of the original validation should be done at the longer (original) DHT and/or the any added pre-flush. This is probably not like the situation for campaign length extension where I can do a data comparison for a more difficult cleaning situation (see the Cleaning Memo of March 2022). In the present situation of shortening the DHT, I am making the cleaning process easier, so the two situations are not comparable.
There are probably other things to focus on to make a cleaning process more robust. These may be the focus of future Cleaning Memos.
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