Last month we discussed options for validating the maximum Dirty Hold Time (DHT). We’ll start this year off by covering options for extending the maximum DHT for an already validated (shorter) maximum DHT. That is, we will assume that in the past a maximum DHT has been validated. Now, we want to extend that maximum validated time, for example, from four days (allowing for a three-day weekend) to a maximum of five days (to allow for the possibility of a four-day weekend).
Certainly one approach is to do the same amount of work that was previously done for the validation of the maximum time of four days (see the December 2022 Cleaning Memo). However, that may involve a lot of extras work adding very little value to my overall cleaning validation efforts. Is there another approach?
Glad you asked! It may be possible to utilize an approach not unlike what I have suggested for extending a campaign length (see Cleaning Memo of March 2022). Here is what is involved in applying the approach. First, the general principle is that I will do a new one-run validation protocol with a five-day DHT using the same product, the same equipment, the same cleaning SOP, the same sampling method, and the same analytical method. I then compare the measured values (such as M4b – see the Cleaning Memo of June 2022 for a discussion of what I call “M” values) in the five-day protocol with measured values in the original four-day protocol. If the values are essentially the same, I can conclude that extension of the maximum DHT from four days to a maximum of five days has no significant effect on the difficulty of cleaning as the DHT is increased in this way, and therefore my maximum DHT is now validated for five days.
Note that in this example, the extension was just by one day. However, the general principle applies whether the increase is from one day to four days, from two days to three days or from three days to seven days. However, the shorter the extension time, the more likely I will get acceptable values at the extended time. For example, I am more likely to have a success if the maximum DHT is increased from two days to three days as compared to an increase from two days to six days. Furthermore, the greater the absolute value of the initial (original) maximum DHT, the more likely I will get acceptable data at the extended time. For example, I am more likely to be successful if the maximum time is increased from four days to five days as compared to an increase from one day to two days. In both cases the increase is only one day; however, as the product dries, I am more likely to see the difficulty of cleaning to increase in going from one day to two days as compared to going from four days to five days. The reason for this is drying of liquid products. For solid products, there may never be a change in difficulty of cleaning within the typical maximum DHTs used in the industry, with the possible exception of hygroscopic products, which might become more difficult to clean as they pick up moisture from the air.
How is the equivalence of data established as the maximum DHT is extended? How “equivalence” is determined should be defined in a high level Cleaning Validation Master Plan, and if not in that higher level document it should be specified in the protocol itself (that is, in the protocol to establish the extended maximum DHT). One way to do that is using a two-stage criteria something like this:
The data on the extended DHT one-run protocol should be no more than 50% of the calculated carryover limit for each individual sample. In that case, the protocol is successful and the extended time is validated. If any sample exceeds that first criterion, the individual sample data values for higher samples for the extended DHT protocol shall be compared to the corresponding individual sample data values for the original maximum DHT protocol; if each of those values is no more than 150% of the value for the corresponding individual sample in the original protocol, then the protocol is successful and the extended time is validated.
Note that for the second-stage criterion, one could also use equivalent terminology by saying “no more than 50% greater than the corresponding individual sample of the original protocol”.
If the first stage is met, there is no need to go to the second stage. If the first stage is not met, then the criterion in the second stage must be met. Here are examples for how these “staged” criteria might work. In each case given below, we will consider possible data for individual swab samples for the sample locations in the original three validations runs as well as the data for the same location in the extended DHT one-run protocol. Presented are three possible sets of residue data (given as examples below, assuming an L4b carryover limit of 12.3 ppm). In these examples, I am giving only the data for one swab sample location. In real life it is likely that there will be multiple swab sample locations, so that the two-stage criteria given above should be applied to each sample location.
| Case I | Case II | Case III | |
| 1-day DHT original run 1 | 1.4 ppm | 1.4 ppm | 1.4 ppm |
| 1-day DHT original run 2 | 1.9 ppm | 1.9 ppm | 1.9 ppm |
| 1-day DHT original run 3 | 1.3 ppm | 1.3 ppm | 1.3 ppm |
| 3-day extended DHT protocol | 1.6 ppm | 5.0 ppm | 7.3 ppm |
For Case I the result of 1.6 ppm after the 3-day DHT one-run protocol meets the first stage (it is below 50% of the residue limit of 12.3 ppm). It is not necessary to go to the second stage. Additionally, in this case it appears that the cleaning process I designed is so robust that even at the extended maximum DHT my data may be close to my LOQ for the analytical method. So, I am happy.
For Case II, the result of 5.0 ppm after the 3-day DHT one-run protocol meets the first stage criterion (it is below 50% of the residue limit of 12.3 ppm). Even though the “stage two” criterion would not be met if it were applied, it is not necessary to go to that second stage. I am happy (even though I might prefer to see the Case I result for the extended DHT).
For Case III, the result of 7.3 ppm after the 3-day DHT one-run protocol does not meet the first stage (it is below 50% of the residue limit of 12.3 ppm). Therefore, I should evaluate the second stage criterion; in this case the value for the extended DHT is greater than the 150% of the original data, so I would not accept this one run protocol by itself as adequate to validate the extended maximum DHT of three days.
If I really were in a situation where the DHT had to be extended to three days for Case III, I could possibly try two additional protocol runs using the same cleaning SOP at the extended time (which if they met the acceptance criterion of 12.3 ppm, might be satisfactory to extend the DHT). Another option might be to improve the robustness of the cleaning process (increased times or higher concentration of the cleaning agent, for example) and perform a three-run cleaning validation protocol for what is essentially a new cleaning process using the approach covered in the December 2022 Cleaning Memo. In either of these options, the strategy should be specified in the initial version of the protocol for the one-run extended maximum DHT.
While one possible criterion for extending the maximum DHT has been presented, it is certainly possible to use other criteria for showing equivalence, or to modify the acceptable percentages (either up or down) for the criterion presented above based on an individual company’s risk analysis and risk profile.
It also should be remembered in an extended time one-run protocol that if the equipment is not visually clean, the extended time is not validated even though the analytical data itself may be acceptable (unless, of course, there is a root cause to establish a reason for the visually soiled equipment, such as a failure in maintaining a required process parameter – for example, temperature, cleaning agent concentration and time – in the cleaning SOP).
For clarification in the three cases above, only one data value is given. In actual fact for most real life situations, there will be multiple values in each protocol run (for different swab locations, for example). Based on that fact, additional considerations will be necessary if values for different swab locations vary significantly.
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