A temporary AI (t-AI) of 178 ng/day (total nitrosamines) - EMA

Last October EMA updated “Questions and answers for marketing authorisation holders/applicants on the CHMP Opinion for the Article 5(3) of Regulation (EC) No 726/2004 referral on nitrosamine impurities in human medicinal products”

Question #21. What is the approach to control the presence of nitrosamines until a substance specific AI is established?

To protect public health, to inform decisions on required market actions while ensuring at the same time availability of medicines while a formal AI is established, a temporary AI (t-AI) of 178 ng/day (total nitrosamines) can be adopted by the relevant authorities for marketed medicines identified to
contain one or more nitrosamines exceeding the TTC of 18ng/day.
This t-AI has been derived using TD50 values calculated in the Lhasa carcinogenic potency database and is based on a probabilistic approach that there is a 33% risk that the “true” AI is below the t-AI. It is expected that the t-AI would be used for a period of less than 12 months, as an exposure over this period of time is not expected to increase the theoretical overall lifetime risk above 1:100,000.

My non-toxicologist question: Where did the 33% comes from? @LATAM_Community


Just my preliminary assumption…

  1. Is there any chance that 33% risk has to do with MTD 33% set by Storer (1989)?

“The maximal tolerated dose (MTD) is conceptually the highest dose that most patients can tolerate, usually producing grade 3 or greater toxicity in less than 33% of patients”

  1. In addition, “A Tiered Approach to Threshold of regulation” (Cheeseman et al. 1999) also mentioned 66% and 33% risk.

" The results in Fig. 2 can also be used for each of the three data sets to estimate the likelihood that a substance would be a potent carcinogen (i.e. one that would result in an upper-bound risk of greater than one in a million when present in the daily diet at 0.5 ppb). For example, when one extrapolates from an ALV of 5.91 (this ALV corresponds to the specific potency that would result in a upper bound risk of one in a million if the substance were present in the daily diet at 0.5 ppb) to the curve corresponding to the 709 cohort, the point of intersection occurs at 66% of the data set. This means that 66% of the 709 carcinogens would have potencies that would result in less than one in a million upper-bound risk when present in the diet at 0.5 ppb, while the remaining 33% would have potencies that would result in greater than one in a million upper-bound risk."

At first I thought that it is calculated using LTL approach (as @Yosukemino said), since 26.5 ng/day (NDEA) x 6.6 (life time vs 1-10 yrs) = 177 ng/day and this value is pretty close to 178 ng/day

I’m sorry for misleading you, @heajin. I did not mean that the temporary AI was calculated from the LTL approach. 18ng/day is less than 95% of AIs for all known nitrosamines. And 187ng/day is less than 67%. And I am not sure how to calculate the risk of use in less than 12 months, except for the LTL approach.
I hope further information will be published in the NIOG meeting in November.


@Yosukemino Thank you for correcting my misunderstanding and your kind explanation! : )

Dear sir,

Can you please tell if this concept of t-AI(178ng) is applicable for USFDA also?
If t-AI is not acceptable then is there any other way relax the limits except for SAR approach?

Thank you in advance :smiley:

With FDA you need to contact them and explain your case. Better if you come with a proposal of an AI, evidence, etc.


Thank you for enlightening me :smiley:

As per my knowledge, FDA currently not accepting LTL and t-AI approaches.

Nevertheless, an attempt can be made and let us know the outcome

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