In reviewing the OEL and ADE equations, I see that the lowest therapeutic dose was used as the point of departure rather than the NOEL (no observed effect level) or NOAEL (no observed adverse effect level)
| In reviewing the occupational exposure limit (OEL) and the acceptable daily exposure (ADE) equations, I see that the lowest therapeutic dose (LTD) was used as the point of departure (PoD) rather than the NOEL (no observed effect level) or NOAEL (no observed adverse effect level) that is indicated in the EMA’s Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities. Does Affygility Solutions always use the LTD as the PoD? Furthermore, can you explain your justification? The expert toxicologists don't always use the LTD as the PoD. We perform an adjustment factor analysis of the critical effects from the available human and preclinical data. This is further explained below. While the equation in EMA’s and the PIC/s' Aide-memoire guidance document would lead you to believe that the NOAEL should always be used as the point-‐of-‐departure, the EMA has indicated in stakeholder meetings that was not their intent (1, 2). NOAELs are generally based on animal data, and when setting an OEL or ADE the preference is for good quality human data. This is explained in Section 4.2 of the EMA’s guidance document. In addition, the PDE approach used in the EMA guidance was originally developed for residual solvents or elemental impurities with little human data (2, 3). As you may know, solvents are rarely tested on humans. OEL Fastrac monographs are for active pharmaceutical ingredients that have been on the market for a significant period of time; therefore, a vast amount of good quality human data exists and should be preferred. In addition, when compared to human data; often, the use of PoDs derived from animal model data will result in unnecessarily large uncertainty factors or result in a larger numerical ADE than what is protective. The selection of the PoD should be the data point that is most relevant to humans and results in the lowest numerical ADE value with the least amount of composite uncertainty (also known as adjustment factors). The expert toxicologist performing the adjustment factor analysis decides the appropriate PoD based on calculations of all available PoD (animal NOAELs in different species, lowest therapeutic dose in humans, etc.). The expert toxicologist then selects the most appropriate ADE based on these calculations. This approach is supported in the EMA guidance as follows:
This approach was also emphasized in a recent LinkedIn post by Andreas Flueckiger (former Head, Corporate Health Protection at Roche). Additionally, this is also supported in the recently issued ASTM Standard E3219 Standard Guide For Derivation Of Health Based Exposure Limits (HBELs)
This approach is also supported in the scientific literature (4, 6). Since many people in the regulated community and inspectors are not "expert toxicologists" we have explained this approach to them, and they immediately see that this is the appropriate approach. Finally, the use of the lowest therapeutic dose for establishing OELs is supported in the literature (4). References:
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