“I see – but not by sight alone” – a discussion of FDA’s final guidance, Recommended Acceptable Intake Limits for Nitrosamine Drug Substance-Related Impurities (NDSRIs)

Home Blog
  • December 22, 2024

“I see—but not by sight alone” – a discussion of FDA’s final guidance, Recommended Acceptable Intake Limits for Nitrosamine Drug Substance-Related Impurities (NDSRIs)

Aloka Srinivasan, Ph.D.
Principal and Managing Partner

So, on 4th August, just when I am boarding my Alaskan Cruise Ship in Vancouver, I hear a ping on my phone and guess what, a notification on FDA’s publication of the finalized guidance shows up, “Recommended Acceptable Intake Limits for Nitrosamine Drug Substance-Related Impurities (NDSRIs)”. You can all understand how the onboarding went after this 😀, totally distracted, I was giving incoherent answers to the questions and the Celebrity Millenium staff looked at me strangely for rest of the trip. I was peeking into the guidance the entire trip and trying to read and interpret what the agency may have intended to communicate and see if there was anything beyond what the eyes meet. And here is a summary of what I perceived. Please look and let me know what you think:

  • The guidance is well laid out and easier to read than the EMA guidance but contains the same CPCA information up to page 12.
  • The FDA also calls out nitrosamides, nitrosoureas, guanidine, and any NDSRI where a nitroso group is part of an aromatic ring as not being part of this guidance.
  • They state that they worked with other international regulatory authorities to develop this guidance. So, there is light at the end of the tunnel when it comes to things that FDA has not mentioned, but EMA and HC may have accepted.
  • Page 12 – Implementation of Recommended AI Limits……
    • They discuss the timeline – it is as if this guidance resets previous timelines by a few years. “FDA recommends that if NDSRIs were not considered in previous risk assessments, applicants must re-evaluate risk within 3 months of publication of this guidance as part of overall risk management..”…if NDSRIs are detected at levels that exceed the AI limit…then FDA recommend the manufacturers develop control strategies…By August 1, 2025 manufacturers should ensure that NDSRIs meet the FDA-recommended AI…” I do think we will need more time than this, but it is a good start.
  • Page 14 – Applications Pending: seem to give some leeway to applications that may have been submitted and can be amended based on these new AIs.
  • Page 14/15 – Not a lot of leeway in general if manufacturers now exceed the new AIs – seems like a recall – unless drug substance is critical to maintaining drug supply. So, Drug Shortage may need to come to the rescue of the industry. We are anyway seeing comments in FDA letters regarding contacting drug shortage group, even when the drug is not in shortage.
  • Page 16 – Looks like if there is disagreement with the agency published AI the manufacturer can submit additional scientific justification for a higher limit based on surrogate approach – not sure why but it is in this same section where a modified Ames is recommended using all the usual requirements and 30% S9 has been provided.
  • The agency also says that they endorse the following surrogate compounds for read across: NDMA, NPIP, NNK, NPYR, and NMOR. Not sure what this means. This statement surprised me the most. The meaning is unclear and the scientific basis of the statement unknown. It may be disadvantageous to the industry when an agency with no specific explanation says that the “read across” will be accepted with a handful of surrogates. While nitrosamines are overall data poor, there are numerous nitrosamines with good data which could be suitable surrogates other than the few mentioned here. I hope the FDA accepts good surrogates when placed before them with good scientific justification. I still find it strange that NDELA is not included in the list, though it is well studied and has an AI that is justified by many studies.

From the information I have seen, it appears more like a quick effort to avoid some of the chaos that was created by the original guidance. But it is still written in haste and the possibility of recalls of is still high as many critical drugs have NDSRIs above 1.5 mcg/day. I don’t exactly see a reason to rejoice yet, but we did or better to say, Agencies did come a long way from 26.5 ng/day. I am hoping that the CAPA proposal that EMA has will be acceptable to the FDA and Drug Shortage group will come to the rescue if needed.

I saw people on the cruise eat bacon and sausage to their heart’s content and worried that they may go home to hear that their favorite medications are being pulled off the market for a few parts per million level of some nitrosamine impurity. As for me, I came back with a COVID and I checked that Paxlovid (Nirmatrelvir) has only “amide” groups and no amines. So, by taking Paxlovid, I ingest only nitrosamides and not nitrosamines at this time. Sounds hilarious!

Acknowledgment: This author acknowledges the valuable inputs of Dr. Charles Lambert for his valuable input