In calculating Permitted Daily Exposure (PDE) about cleaning validation, can anyone explain about adjustment factor especially F4?
F4 about a factor that may be applied in cases of severe toxicity.
Value of F4
1 = for fetal toxicity associated with maternal toxicity
5 = for fetal toxicity without maternal toxicity
5 = for a teratogenic effect with maternal toxicity
10 = for a teratogenic effect without maternal toxicity
can anyone explain to me why teratogenic effect without material toxicity got a higher point than teratogenic effect with material toxicity?
Hello Nyoman, I think you mean 'maternal' instead of 'material'. To answer your question, whether it is toxicity or teratogenicity, if the effects are seen in the presence of maternal toxicity then it is possible that the foetal effects were secondary to the effects on the mother. In the case when no toxic effects were observed in the mother, then it demonstrates a toxic mechanism that is specific to the development process in the foetus. Furthermore, there is generally more concern about teratogenic effects than for general toxicity, mainly because of the hangover from the thalidomide experience many decades ago.
I hope you got your answer from Peter who has explained well. Just to add, if the compound is toxic to fetus in addition to mother, then it might be a secondary effect as the toxicity to mother (e.g. weight loss) would have resulted in fetal toxicity which is easily predictable and the compound can be labeled in a less severe category. On the other hand, if the compound is only causing fetotoxicity with no noticeable effects in mother, then it is serious as one can't easily predict it beforehand and it can cause malformations/deaths in fetuses. This was the case with thalidomide which was used to treat morning sickness in pregnant mothers and lead to fetal malformations.
I have provided my justifications below,
1. In simple concept, a factor of 10 is the most conservative factor that you can chose in case of severe toxicity. Eventually, when you notice teratogenic effect at a dose, and you consider a factor of 10 for that even if it has no maternal t, your factor of 10 covers up all possible considerations for toxicity which includes fetal, maternal and developmental toxicity. This is the reason why a factor of 10 is provided for a teratogenic effect alone without maternal toxicity.
2. A factor of 10 shall be used only in case of effects seen in a LOAEL. An NOAEL is provided only when there are no drug related effects seen. And hence, under NOAEL when you consider either a factor of 5 or 10, you cover all possible effects of the drug on basis of conservatism.
In my opinion, when there are no effects reported at all or an NOEL is given I use a F4 of 1 to calculate PDE. Only in LOAEL we consider 10.
Hope this is clarifying. But the factor consideration for PDE calculation is always a debatable topic. But one idea is very clear when there are no effects seen at a dose, lesser factor considerations (3 and less) should not cause any considerations.
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