In September 2015 I wrote about “duration specific” PDE values as a possible basis for cleaning validation limits. While the basic principles and/or consequences of that Cleaning Memo have not changed, I have significantly revised how that approach should be presented.
First, I will just review the basic principle, which is if the product containing a carryover residue was to be only administered for a short time (not a life time), is it possible to be less stringent in setting limits. For clarification, in a limits calculation the “product” referred to is not the cleaned product (often called “Product A”), but rather is the next manufactured product, (often called “Product B”).
So what change have I moved to? In that 2015 Cleaning Memo I suggested changing the PDE value (increasing it) based on ICH M7. While that M7 document discusses changing TTC (Threshold of Toxicological Concern) values for mutagenic impurities based on the duration of treatment, I believe that a relative change from a value for lifetime exposure (1.5 mcg/day) to higher values for shorter durations can be reasonably applied to most residue limits for cleaning validation purposes.
Now I no longer suggest revising the PDE values upward. Instead the PDE should be included in the carryover equation as it was originally established for a lifetime exposure, and then a “correction factor” (which might be called a “duration correction factor”) should be added to the carryover equation to account for the limited duration exposure.
How is that correction factor determined? Here is a summary table of how the possible increases in TTC values (for shorter durations) are given in M7.
| Duration of treatment | ≤ 1 month | >1 – 12 months | >1 – 10 years | >10 years to lifetime |
| Safe daily intake (µg/day) | 120 | 20 | 10 | 1.5 |
The relative “safe daily intake” correction factors can be calculated by dividing the safe daily intake value for as given duration by the lifetime safe daily intake of 1.5 mcg/day. Using that same type of relative changes, here are the resulting correction factors. Again note that the duration of treatment is for the product containing the residues (and not the cleaned product).
| Duration of treatment | ≤ 1 month | >1 – 12 months | >1 – 10 years | >10 years to lifetime |
| Correction Factor | 80.00 | 13.33 | 6.66 | N.A. |
These correction factors given are factors that should appear in the numerator of a carryover calculation, most typically in determining the L1 (limit in the next product). That can be critical if your company also uses the most stringent of a calculated L1 value and a “default” L1 value of 10 ppm; if the correction factor is applied to only at a later stage (such as to L2, L3 or L4), situations may present in which the L1 value might actually be above 10 ppm.
If you adopt this approach, it is something that should not be unilaterally adopted by a validation department; agreement should be obtained from your toxicology and/or pharmacology department. And if this approach is adopted, it should be clearly specified with the relevant rationale in a master plan or high level SOP.
Now, the reason for modifying the way these adjustments are made is one of perception or optics. In the approach I had previously suggested, the PDE value used in calculations may be different. In a case where the next product is given for a lifetime, the PDE may be 5 mcg/day, while in another case where the next product is given only for a few years, the PDE value may be 33 mcg, even though is for the same active (the active of the cleaned product). Reviewers or auditors taking a look at both sets of calculations may question why the PDE values appear to be changing or inconsistent. You can certainly explain why, but it is better to just focus on the rationale for the newer approach rather than allowing others to think your manner of calculating PDE values has changed. This approach of keeping any documentation of a PDE as one based on a lifetime exposure is also consistent with the generally accepted definition that PDE values are for a lifetime exposure.
Note also that while this approach may be applicable to most residue types where the toxic effect can only be measured by cumulative exposure, it may not be applicable for residues where the toxicity effect is immediately apparent. An extreme example of this is trying to adjust a PDE for sodium hydroxide (NaOH) based on possible tissue damage due to a short term exposure. These types of examples may be rare, but caution should be applied in addressing them.
As a final caveat (and as most of you are aware), I am not a toxicologist or pharmacologist. However, my contention is that this approach is a reasonable utilization of scientific principles.
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