Thanks @krishmnt - Could you please help in understanding in detail “regulators are establishing acceptable intake values for NDSRIs arbitrarily based on conservative statistical data” What does arbitrarily based on conservative statistical data means specifically refers here
Hi @Naiffer_Host, Thanks for the post and collecting the opinions and also sharing them on this platform.
As I am a regulatory toxicologist with blend of chemistry knowledge - I can only bring 2 challenges/perspectives :
- In regard to NDSRI- NDRIs being complex with chance of more than one amine in its structure- We may end up greater than one NDSRI for one API. How to deal with them - individually or cumulative- because when goes into the patient body the risk is collective.
- No single toxicology test method in picture to arrive an AI for NDSRI. One will agree we cannot sit and start conducting 2-years rodents study and generate TD50s. Regulatory agencies should make an attempt to guide with at least interim assays (like interim AIs) so that we can make sure AI is developed with experimental data and keep evolving with them with time.
Any word in the validity of AMES-negative of NDSRIs? A lot is said about the suitability or not for Nitrosamines testing but my understanding is that is based on very old studies data.
A fantastic editorial by @AndyTeasdale for OPR&D on NDSRIs challenges
Ames test data would be very much valid if conducted according to OECD TG and some appropriate modification related to nitrosamine in consultation with concerned regulators. Regulators (FDA, EMA) are working on multiple in-house and colloborative projects considering different criterias on this area, which may take time (9-12 months). So early 2024, we may have more clarifications or general draft guidance on clear criteria for AMES test for Nitrosamine from requlators.
The biggest safety challenge is the acceptance of the Ames and uncertainty around acceptance of a derived AI.
Another major concern is that there might be very valuable APIs out there which do not make it through development because it is not possible to keep the stringent limit of e.g. 18 ng, as nitrite is everywhere (in traces) and nitrosation cannot be 100% prevented. While the real cancer risk might be negligible.
Thanks @clarkad5 for sharing you perspective. I think efforts going around the globe, one should positively wait for the outcome. I strongly believe Ames assay is still not out of game. It is there!! But the point to note is it not gonna help to derive an AI.
Definitely 18 ng/day is not the savior, that would be the reason EMA came up with t-AI and interim-AI. We may need to wait and watch how these things evolve.
Another important point is, the industries who is engaging in activities to derive AI, should start dialogue with agencies and make strong scientific based justifications to balance safety and availability of drug in market and convince…That could be the pragmatic way deal this issue currently.
Looking forward collecting final comments by end of next week… thanks to all who has provide quite insightful reflections on NDSRIs challenges
Hi Naiffer - the single biggest issue is around establishment of Acceptable intakes (AIs), this is exacerbated by the lack of carcinogenicity data for NDSRIs - necessitating use of read across / surrogate data. Unfortunately the process for doing this is far from agreed and the process used by authorities lacks transparency. This is compounded by the time take to define such AIs.
In the absence of an AI the default limits of 18ng EU (26.5ng US) simply are not achievable from a CMC perspective - this includes through reduction in Nitrite levels in excipients. To put this into context levels would need to be reduced to ppb levels in common excipients
Neither is there a fix from the perspective of Ames testing, allied to other safety studies. For capacity, time and cost reasons transgenic studies cannot realistically be a long term solution, but currently play a key role given uncertainties over acceptance of an Ames test.
Many of the issues described can be resolved but not perhaps in the timescales dictated by current guidance. We need pragmatism and balance to see us through the next 18-24 months if we are to avoid a crisis
- Most important challenge is the for NDSRI is Limit (18 ng is very stringent) and Nitrite source from air. If Nitrosating reagent is not present in manufacturing process till nitrosamine (NDSRI) forming due air contact. ( excluding Hydrazone).
- If Ames test is negative for NDSRs is it possible to treat as regulars impuirty?? or When it will be updated
There are key discussions planned both in US (FDA-HESI meeting) and safety group in EMA over the next few weeks. it is to be hoped that these make some progress in terms of answering your second question.
I totally agree with this, the presence of HCl as salt will create more issues.
@AndyT Is there opportunity to listen to the discussion taking place in EMA? I know that HESI/FDA meeting next week will be open to the public virtually.