Use of the TTC vs calculating an ADE

Here at Affygility, we often get asked " Can't I just apply the TTC to all compounds instead of determining ADEs (PDEs) for each compound?"

The short answer is "no" and the longer, more detailed answer is as follows:

First, it is important to understand the purpose of the threshold of toxicological concern (TTC). As indicated in Dolan, DG, Naumann, BD, Sargent EV, et la (2005) the purpose of the TTC is for estimating acceptable daily exposure (ADE) [at that time call acceptable daily intake values] limits for compounds where there is little or no toxicity information. This was further elaborated in the International Society of Pharmaceutical Engineers' Risk-MaPP document, where it said in Section 5.3.5.3 "The temporary use of the TTC concept to support preliminary ADE values should be an interim strategy until a formal ADE value can be established."

The use of the TTC was never intended to be a permanent value. It was intended to only be used as an interim value, until there is enough data to provide a permanent value.

Second, there are many limitations to applying the TTC, including:

• The TTC is limited to the database it is built on. If you are applying the TTC to a different "chemical space" it may not represent your compound;
• Chemical cohorts of concern such as highly potent carcinogens are not covered by the TTC. N-nitrosamine (NDMA) is a good example here, the ADE for NDMA is a lot lower than the lowest TTC value;
• Metals are not covered by the TTC;
• Biologics are not covered by the TTC;
• The TTC is a conservative estimate based on a database of compounds. It should not be assumed to be a precise number. It is typically lower than the true limit;
• The TTC can mean a lot of things and it can be confusing for those not knowing what they are doing.  For example, there is a TTC for mutagens, non-carcinogenic compounds based on the Cramer classification, active pharmaceutical ingredients, oncology products, etc.
• The TTC cannot cover immune hypersensitivity, with the exception of skin sensitization; and
• The TTC can be specific to a route of administration.

Thirdly, the use of the TTC can be used with compounds with limited or no data, but as mentioned in Section 6.3.2.3 in ISPE's Risk-MaPP document, it is only a temporary strategy and should be used with caution. Lower than necessary cleaning acceptance limits increase the risk of cleaning failure. It is expected that companies will have robust cleaning processes that provide as large of a safety margin as possible, especially where existing data indicates the ability to clean to very low residue limits.

Forth, there are many compounds, that when calculated on actual compound-specific data, have ADEs significantly lower than the TTC. A good example for this would be topotecan. According to one of the manufacturer's SDS (a reputable big pharma company), and based on compound-specific data, the OEL is 0.03 ug/m3. Therefore, assuming that the ADE is somewhere between 5-10 times the OEL, the ADE can reasonably be estimated at 0.15 - 0.3 ug/day.

The end result is that if you have either a late-stage compound in clinical development or a marketed product, the ADE should be calculated and documented based on the specific compounds dataset. The cost of a product-specific OEL/ADE monograph is much lower than the ongoing costs of the additional controls and cleaning procedures required to achieve the TTC limits.