CDER is planning to update “Control of Nitrosamine Impurities in Human Drugs”, according to the CDER Guidance Agenda New, Revised Draft and Immediately in Effect Guidances Planned for Publication in Calendar Year 2024(July 2024).
https://www.fda.gov/media/134778/download
We should pay attention to the further information.
Now Control of Nitrosamine Impurities in Human Drugs Guidance for Industry rev.2 is available. Please check the following page.
Specifically, FDA intends to include on this web page updated information on: (1) recommended AI limits for certain nitrosamine impurities, based on their predicted carcinogenic potency categorization (CPCA), including certain recommended AI limits for drug products with a hypothetical risk of forming NDSRIs; (2) recommended AI limits for certain nitrosamine impurities based on compound-specific data from carcinogenicity and mutagenicity data or read-across analysis from a surrogate; (3) recommended interim AI limits for certain nitrosamine impurities; (4) recommended implementation timelines; (5) other emerging scientific and technical issues; (6) recommended analytical methods for confirmatory testing of certain nitrosamines impurities; and (7) recommended safety testing methods for nitrosamine impurities.
Additional documents are also available.
The link in the FDA document doesn’t work currently for me. 
Hi @MarkS,
Now the link to the updated information page is not available, as you pointed out. From the content (1) to (7), it may be similar to the NDSRIs’ page.
The link to the guidance is as follows;
https://www.fda.gov/media/141720/download
In case the link does not work for some folks…
Here is the document:
FDA Nitrosamines Revisoin 2 04.09.2024.pdf (665.0 KB)
Doing a brief look into all the updates (that are huge) it get to my attention the following CDER Nitrosamine Impurity Acceptable Intake Limits | FDA:
For the US an EAT may not be enough, and further in-vitro tests are needed to secure a 1500 ng/day limit, if not a TGR test with -tive results.
Additionally, is now in written that the agency is in awareness that their criteria could differ from other agencies.
Hi @MarkS,
Now the link works correctly. Please check the following.
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/cder-nitrosamine-impurity-acceptable-intake-limits
请问APPENDIX C中，Total nitrosamine包含NDSRI吗？还是仅限于如NDMA、NDEA等 small-molecule nitrosamines?
Has NMPA quietly gone out to a limit of 100 ng/day, based on CPCA, in line with EMA & TGA etc?
Yes, several examples of small nitrosamines where CPCA is now adopted like seen in other territories (NMPA, NMBA, NDIPA, NEIPA).
Also some smaller ones which had temporary limits published on separate webpages which are now integrated based on CPCA (1-methyl-4-nitrosopiperazine, 1-cyclopentyl-4-nitrosopiperazine).
But most remarkable evolution on the small nitrosamine front is N-nitrosopiperazine to N-nitrosopiperidine readacross (1300 ng/day). We haven’t seen that published elsewhere and I’m wondering if it starts to open a door for the re-evaluation of 400 ng/day as class value for category 3.
For our international members, please find attached the translated (Google translation) version of the FDA Nitrosamines Guideline Rev 2.
Spanish:
FDA Nitrosamines Revisoin 2 Spanish.pdf (1.6 MB)
Portugues:
FDA Nitrosamines Revisoin 2 Portugues.pdf (1.6 MB)
French:
FDA Nitrosamines Revisoin 2 French.pdf (1.6 MB)
German:
FDA Nitrosamines Revisoin 2 German.pdf (1.5 MB)
Chinese:
FDA Nitrosamines Revisoin 2 Chinese.pdf (1.8 MB)
Japanese:
FDA Nitrosamines Revisoin 2 Japanese.pdf (1.9 MB)
Korean:
FDA Nitrosamines Revisoin 2 Korean.pdf (1.7 MB)
I think too many sponsors were fighting on this topic, how can a nitrosmaine differ in its level of danger based on regions of the world. This was FDA’s way of saying that they do not have enough data or not legally allowed (possibly more important) to derisk the nitrosamines, that EMA, HC, Anvisa and others could and making requests in this line without enough data would be useless.
Has NMPA quietly gone out to a limit of 100 ng/day, based on CPCA, in line with EMA & TGA etc?
Yes, you are right. 
It includes all nitrosamines including NDSRIs. This is just a repeat of what EMA has had for many months now. Actually, I have helped with submission of some ANDAs with this calculation from EMA since it came out and FDA had accepted it. I think they just wanted to make it official.
According to the guidance, Appendix C does not distinguish between small nitrosamines and NDSRIs. Nitrosamine 1 is a small nitrosamine (NDEA) and Nitrosamine 2 and 3 are NDSRIs in the following table.
APPENDIX C: EXAMPLE OF CONTROL AND SPECIFICATION FOR THE RECOMMENDED ACCEPTABLE INTAKE LIMIT FOR MULTIPLE NITROSAMINES IN ONE DRUG PRODUCT
The following approach can be used to establish specification limits for small-molecule nitrosamines and nitrosamine drug substance-related impurities.
非常感谢您的及时回复，我们也将改变策略。
谢谢@Yosukemino您的热情回复。
The so called metabolic reprogramming of the cancer cell is explained due to the simultaneous actions of many different nitrosamines and ndsris on the future cancer cell: exactly this could be not explained via Ames and CPCA static tests which are applicable for
Bacteria and rodents ! Carcinogenesis is a multi step dynamic process - here some data and expert opinion - as always:
Exactly this explains the descrepnace between the clinic and vitro/ science fiction/ interpretations 
Complete elimination regimes has to be the drastic rule to block the rising cancer incidence
