There has been some misunderstanding of a statement in the Health Canada guideline GUI-0028 (dated June 29, 2021) about the use of HBEL values (such as PDE or ADE) in setting limits. The sentences of concern in Section 6.1.a are:
“It should be noted that there may be multiple worst case products. For example, an insoluble product with a high HBEL value may be the most difficult product to clean but not necessarily worst case compared to a partially soluble product with a low HBEL value.”
Some have interpreted those sentences to mean either:
OR
Before I discuss why these two are misunderstandings, let me clearly state that the sentences in 6.1.a are correct and accurate. Note that the first sentence reads “there may be multiple worst case products” [emphasis added], not that there always are multiple worst case products. A distinction should be made here between the “worst case as the product most-difficult-to-clean (acronym MDTC)” and the “worst case as the representative product to be used in a protocol to represent other products in the group”. Note that the distinction is why I prefer to avoid the use of the term “worst case” as applied to the selection of the product to be used for the protocol. I prefer using the term “MDTC” to refer to the product that is physically/chemically most likely to leave residues at the end of the cleaning process, and use the term “representative” to refer to the product selected for a grouping protocol to cover successful validation of all products in the group in a single protocol (typically with three runs). Now I fully realize that most of you will continue to “worst-case product” to refer to either situation; I fully realize that I will meet resistance from many because the “worst-case product” terminology is used in many guidance documents as well as in your corporate documents.
As for misinterpretation “A” above dealing with ranking criteria, note that the approach here is still one product with an associated residue limit where one protocol successfully covers all other products in the group. My primary contention is that a low HBEL is not related to the difficulty of cleaning. Yes, a lower HBEL will generally (but not always) result in a lower limit, so in that sense it makes getting acceptable results more difficult. However, the approach I have advocated for years is to select the MDTC product absent any inclusion of HBEL values, and for that MDTC product perform the cleaning validation protocol using the lowest L4 limit of any product in the group. In this way I am addressing both the difficulty of cleaning and the lowest limit in one protocol.
The approach I recommend (see the Cleaning Memo of May 2017) avoids the example given in Section 6.1.a of GUI-0028 in which, based on the relative weight given to the HBEL and the “difficulty of cleaning” criteria, there may be situations where certain product are not adequately protected from unacceptable residue transfer (see the Cleaning Memo of November 2017 for more, including examples, of this problematic situation).
As for misinterpretation “B”, this is the approach that was commonly used in the early days of cleaning validation, where for a group one protocol (three runs) was performed on the most difficult to clean product and then another protocol (three runs) was performed using the “most toxic” product (see the July 2001 Cleaning Memo). “Most toxic” initially referred to the product with the lowest limit, and then later was modified to refer to the product with the lowest PDE (or ADE). The main concern with this approach is that while for a given grouping of products it may adequately provide protection for all products in the group, there may be other groupings of products where that is not true. Please refer to Example 3 in the May 2017 Cleaning Memo for a more on possible pitfalls of such an approach like “B”. This is another reason why for a grouping approach I prefer to select the MDTC product absent any inclusion of HBEL values, and for that MDTC product perform the cleaning validation protocol using the lowest L4 limit of any product in the group. In this way I am addressing both the difficulty of cleaning and the lowest limit in one protocol and making sure no other product “falls through the cracks”.
Finally, let me emphasize that everyone should carefully read this Health Canada guidance document. When read in its entirety, my preferred approach is consistent with the principles given in GUI-0028. Here is a more complete statement from Section 6.1.a.
“Examples of factors that can be included in the assessment of worst case products include:
It should be noted that there may be multiple worst case products. For example, an insoluble product with a high HBEL value may be the most difficult product to clean but not necessarily worst case compared to a partially soluble product with a low HBEL value.”
Please read through this carefully and thoughtfully, referring to the various cited Cleaning Memos where further clarifications or examples might help. Note that my preferred approach captures the concerns about HBEL (as given the first bullet point above) and the difficulty of cleaning (related to the last four bullet points).
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