Interesting shift in responsibilities from market authorization holders to manufacturers and applicants. Some manufacturers were previously willing to pass the buck entirely before this change.
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Section II “Scope” states, “This guidance also applies to prescription and OTC drug products in clinical development.”
Does this suggest that compliance to the new document may be expected at IND submission? Or are they describing previously-approved drugs that are in clinical trails for new indications?
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Great and Thanks for sharing
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Dear @x.h.yao , It’s a relevant question, and I believe others may arise in this regard. For this very reason, the guide itself states:
"the predicted carcinogenic potency categorization and resulting recommended AI limit approach described in this guidance should not be applied to NDSRIs in circumstances in which FDA otherwise recommends an AI limit (e.g., based on compound-specific assessments or read-across analysis from a surrogate) (…)
When FDA communicates a recommended AI limit based on compound-specific assessments or read-across analysis from a surrogate, manufacturers and applicants should apply that recommended AI limit rather than using the predicted carcinogenic potency categorization approach in this guidance to identify a recommended AI limit.
(…) In corresponding with certain manufacturers and applicants, FDA previously recommended that certain NDSRIs, for which there is no compound-specific data and no suitable surrogate for a read-across analysis, be controlled at levels that do not exceed a conservative AI limit of 26.5 ng/day. For these NDSRIs, we now recommend that manufacturers and applicants use the framework recommended in this guidance to determine an appropriate predicted carcinogenic potency category and corresponding recommended AI limit."
The guide also states: "FDA recognizes that the AI limits recommended by the Agency and those generated by manufacturers and applicants may evolve with advances in the science and generation of data for nitrosamines. As industry groups and consortia perform investigations that provide insights into mutagenicity and carcinogenicity risks of nitrosamine impurities, FDA encourages sharing such information to help expand the available knowledge base.
I hope I’ve helped you.
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非常感谢您的回复，这对我有很大的帮助，实际上也告诉了我答案。
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My contributions to the highlights of the guidance:
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Overall, the U.S. FDA approach is harmonized with the EMA’s guidance on NDSRI detection and mitigation. The updated EMA guidance introduces a new Carcinogenic Potency Categorization Approach (CPCA), which is a basis of the new approach both regulators are taking to determine the AI of a given NDSRI and aid in risk assessment for various APIs.
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Manufacturers of approved or marketed drug products should, if they have not done so already, evaluate NDSRI risk within 3 months of the August 4, 2023 publication of the guidance, with a “recommended completion date” of November 1, 2023. If an NDSRI is detected, confirmatory testing with “sensitive and appropriately validated methods” should start immediately for products at high risk. If NDSRI levels are detected over the AI limit for the CPCA category, then manufacturers should work toward design approaches and control strategies, as appropriate, to bring the NDSRI level for that product to levels at or below the AI limit. Moving forward, confirmatory testing for approved products should be completed by August 1, 2025. By this date, “manufacturers and applicants should ensure that any NDSRIs in their drug products meet the FDA-recommended AI limit.” In this section, the FDA acknowledges the many steps required to meet this timeline, including a root cause investigation, identifying changes that may need to occur at any stage along the supply, formulation, and manufacturing process, and confirming that any proposed changes will minimize the presence of NDSRIs without otherwise adversely affecting drug product quality. However, the FDA may even ask for an expedited risk assessment or other actions from the manufacturer, depending on findings for a particular product. Reformulation of an approved product to bring NDSRI AI to within acceptable limits will likely be considered a major change and will require a prior approval supplement (PAS).
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NDSRI detection at or below FDA-recommended AI limits for an approved product still triggers a need for the manufacturer to “develop an appropriate control strategy;” here, the FDA says that applicants who do need to make changes to an approved application should report them.
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For products at the pre-submission stage, applicants should conduct the NDSRI risk assessment and, as appropriate, confirmatory testing before submitting an original application. If assessment and confirmatory testing, along with any changes to the drug master file, are not available at the time of original submission, they may be submitted as an amendment. This should be done “as quickly as possible” to minimize adverse impact on the review timeline.
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For applications already pending with the FDA, applicants should finish risk assessment “expeditiously,” and notify the agency of any NDSRI levels above the recommended AI levels, amending the application “as appropriate.” The FDA promises to “work with the applicant in an effort to review issues during the review cycle,” citing its intention to adhere to the timelines the agency agreed to in the commitment letters for the latest Prescription Drug User Fee Act (PDUFA VII) and Generic Drug User Fee Amendments (GDUFA III) reauthorizations.
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FDA wants to be contacted immediately if products in distribution have NDSRI levels above the AI limit and recalls or changes are likely to lead to disruption in the drug supply . The agency will then work on a case-by-case basis to determine whether to temporarily lift the AI limit for a given product. If a manufacturer or applicant wants to propose or justify an alternative AI limit for their product, they should provide the FDA with a “scientifically justified rationale,” and the FDA provides examples of alternative approaches such as working from compound-specific data or data from a suitable surrogate. For mutagenicity testing, the FDA, is recommending enhanced testing conditions for the Ames test, and is investigating other conditions to improve Ames test sensitivity for NDSRIs.
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Great work ! , efforts are highly appreciated.
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Thanks for all the contributions… following the trend of the replies.
What else is missing or not considered??
Hi @Naiffer_Host
It’s amazing that this is released - and so quickly after Europe - shows that there is real collaboration going on in the background between regulatory authorities.
The multiple NDSRIs is not missing, but it is weak. It doesn’t look like the alternative approach from the EMA etc has been taken into consideration, where it is possible to justify immediately higher levels if you have category 5 and category 1 NSDRIs present in a formulation. Which in itself seems a little odd as for certain drug substances where there are multiple potential nitrosamines the FDA themselves have set different limits for some of the different nitrosamines, so if both we present you could be complying with one allowed limit, but failing overall.
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The responsibility begins at the NDA, ANDA, etc., not INDA. However, one should go into formulation with their eyes open to the inherent risks.
Any commercial product has to go through the process. Any new submission has to go through the process.
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Additional information…
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FDA guidance quotes "'Additionally, the predicted
carcinogenic potency categorization approach does not apply to NDSRIs where the N-nitroso group is within an aromatic ring (e.g., nitrosated indoles).
Does this imply that NDSRIs are not required to be monitored or a divergent approach other than CPCA is recommended for these class of molecules? .
Any thought process on this.
RAPs published the article on the FDA’s new guidance.
Dear @RCREDDYP, as mentioned by @David in the article Strategies for Assessing Acceptable Intakes for Novel N-Nitrosamines Derived from Active Pharmaceutical Ingredients, similar to tert-butyl groups, aromatic side chains lack the α-hydrogen required for metabolic activation.
However, the available toxicity data for compounds of this nature does not exhibit the same consistent negative trend as that observed with tert-butyl groups. A matter of particular concern upon initial analysis is the discovery that N-nitrosodiphenylamine (NDPhA) demonstrates carcinogenicity in rodents and genotoxicity in the Salmonella Ames assay, even though it lacks an α-carbon oxidation site.
These findings imply that an alternate mechanism, such as trans-nitrosation of DNA base(s) as observed with NDPhA, is likely responsible for DNA reactivity in this case.
3-substituted-N-nitrosoindoles are mutagenic in the Salmonella Ames test in the absence of CYP activation
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NDPhA, while an important argument for the potential non-CoC positive results of the Ar-NN=O substructure due to transnitrosation (or indeed denitrosative formation of a hydroxylamine, following the aromatic amine pathway subsequently, as we describe here Tennant et al, Ponting and Foster - we only found this after writing the referenced Ponting et al), isn’t quite the right argument for the nitrosoindoles.
Should note that it is for the nitrosoindolines, where the N-containing ring is not aromatic, and these can be classified as CPCA and will be class 4 or 5 depending on whether the 3-position is substituted (class 4 because (0,2) and in a 5-ring is 5 points, you’d need to add both activating features to get to less than 4)
Returning to nitrosoindoles: As you note, they are positive without S9; this is because the pyrrole-type nitrogen behaves a lot like an aromatic carbon (with a bit more electronegative character). The relevant analogues for nitrosated pyrroles and indoles are therefore C-nitroso aromatic rings (such, ironically, as that formed by the transnitrosation of NDPhA, though not of course NDPhA itself where the amine is not in an aromatic ring), which reduce to the hydroxylamine via innate bacterial metabolism and follow the aromatic amine pathway from there. They should as far as I am concerned be treated as normal, non-CoC, potentially mutagenic impurities, though do flag them as an N-nitroso compound you have thought about rather than hiding anything…
Ultimately I think the HAs haven’t been particularly clear with their nomenclature here; I would say pyrroles and indoles are not amines and thus don’t form nitrosamines per se, rather ‘N-nitroso aromatic systems’
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In this case I would second the idea that this nitroso-compounds should be evaluated in a different assessment that the one from nitrosamines. Nevertheless, evaluated as this compounds goes inside the ICH M7 that is an harmonized guideline and go inside the characterization of impurities evaluation in you API or FP dossier.
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I have doubt, whether presence of a secondary amine in an API is enough in your Nitrosamine risk assessment to perform confirmatory testing with the calculated AI limit ?
There are cases, for an API manufacturer, that the API or its impurities are having secondary amine group but there is no source of nitrite used anywhere in the manufacturing process. In such cases, are we still supposed to do confirmatory testing by developing & validating an appropriate analytical method ? Or mere paper risk assessment can suffice.
Also, can water be considered as a source of nitrite even if it is meeting the WHO standards of water with limit 0.9mg/L of Nitrite nitrogen ? If yes, then request you to throw some light on the calculation part.
(One cae: If water is used before API formation.
another case: If water is used during and after API molecule formation)
When it comes to API risk assessment, one needs to consider not just the main reaction steps but also the chemistry involved in the reagents, solvents, and impurities for both Amines and Nitrosating agents sources. Before jumping to conduct confirmatory testing purge calculations can be performed to measure the true risk of nitrosamines forming.
In the post below, Schlingemann et al (@schlinjo1975) clearly utilize these tools and validate their results for the API risk assessment evaluation
Good discussions to help you navigate and answer your question related to water.
Hi experts,
Could anyone share some literatures regarding to
" …such as fluid bed drying at an elevated temperature and jet milling because these can create favorable conditions in which nitrogen oxides can react with at-risk APIs."
Many thanks!
Hi, @arim416,
You can find a description in the following paper, Formation of N-Nitrosamine Drug Substance Related Impurities in Medicines: A Regulatory Perspective on Risk Factors and Mitigation Strategies.
https://pubs.acs.org/doi/10.1021/acs.oprd.3c00153
Identifying the source (and exact speciation) of nitrosating agent in excipients is of critical importance as it would enable the rational implementation of corrective measures. For example, if nitrogen oxides formed during hot-air drying unit operations are indeed involved, their concentration could theoretically be reduced by the use of lower temperatures and/or nitrogen-enriched gas stream instead of air.
And Dr. Grahek’s presentation provides useful insights into the phenomenon.
The risk posed by NOx gas in the air should be reviewed carefully, especially for API containing secondary/ tertiary amines.
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