FDA - Generic Drug Forum 2022 (Nitrosamine update) 📺

Next April 26/27 will take place FDA’s Generic Drug Forum - The current state of generic drugs

Day 2 - Nitrosamine in Drug Product - An update
by Andre Raw - Senior Science & Policy Advisor

Register here: FDA Generic Drugs Forum 2022 | SBIA Events


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If you participate in Day 2 of Generic Drugs forum 2022. Dr. Andre Raw (Associate Director for Science and Communication) present ‘FDA Overview Control of Nitrosamine Impurities in Human Drugs’

  • Nitrosamine Drug Substance-Related Impurities (NDSRIs) was flagged as risk from synthesis of drug substances

  • Supply Chain nitrosamines - Solvents / How are tankers cleaned? :face_with_raised_eyebrow: Should we expect special attention to cleaning validations related to Nitrosamines?

  • Stability nitrosamines - NDSRIs formed during product manufacturing and/or Shelf-life :face_with_raised_eyebrow: Is this acknowledge of all the concerns related to the withdrawal of the recent products?

  • Processing steps to purge NDSRIs is not possible for those generated in drug products

  • Excipient/Water: Common Source of Nitrite | Possible Nitrite Source: Processing water, processing steps requiring acid titration, bleaching, and oxidation of air as excipient is being heated in a drying process

  • NDSRIs generated in excipient compatibility studies | "N-nitrosation reaction that occurs upon storage of carvedilol- or propranolol-excipient blends in a stability chamber (~60% RH) | Sluggett et al. Artifactual degradation of secondary amine-containing drugs during accelerated stability testing when saturated sodium nitrite solutions are used for humidity control - ScienceDirect

  • Consideration for Risk Mitigation of NDSRIs

    • Work with your excipient supplier to control residual nitrites
    • During Development: Selection of formulation excipients less likely to contain nitrites
    • Formulation design: Formulations with excipients that modify the micro-environment to neutral/basic pH should theoretically be effective in suppressing NDSRI formation
  • NDA/BLA & ANDA meeting package

    • Description of the formulation design strategy
    • Supporting manufacturing information and, at a minimum, three months of accelerated stability data demonstrating control of NDSRI
    • For approved NDAs and ANDAs that require reformulation as part of a mitigation strategy,in vitro or in vivo bioequivalence bridging studies

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Please find attached the presentation…
D2S01-Raw (1).pdf (729.3 KB)

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Interesting to hear from Dr Raw on Nitosamime control/mitigation strategies in dosage forms and emphasis on supplier qualification programme that we discussed here early on as part of risk assessment and mitigation strategies. I liked this talk.

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BIG highlight on excipients evaluation and assessment! “Selection of formulation excipients less likely to contain nitrites”. Looking forward the Q&A panel

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:question: Question from Panel discussion:

  • Does Agency provide any guidance for determining AI on NDSRIs?

  • What is the strategy if secondary amine is present but nitrate is avoided?

  • Do Nitrosamine assessments apply to topicals (Ex: Creams)?

  • If reformulation includes the use of a buffer to control pH, Is there a need for clinical or BE evaluation?

  • If an API contains a secondary amine, should it be considered medium or high risk in my risk assessment?

  • Is it possible that certain APIs containing tertiary amine form NDSRIs? Consider the secondary amine impurities related to APIs

  • Is FDA doing research on Nitrosamines given the impact to generic medications?

  • Will the impact of the antioxidant to mitigate Nitrosamine formation affect the formulation design and manufacturing process?

  • Will FDA meet generic sponsors to discuss various strategies to limit the NDSRIs?

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Yes , it’s being discussed in the community here for quite some time, the session today sort of endorsed it’s importance


@Naiffer_Host am glad our discussion yesterday on the lines of ICH M7 revision made it as the first question today

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You can watch it on youtube with a subtitle anytime you want. It’s marvelous.

18:26-37:09 FDA Overview Control of Nitrosamine Impurities in Human Drugs
54:10- Q&A session

My favorite Q&A is “If I have an API with a secondary amine, should I consider this medium or high risk in my initial risk assessment?”(1:04:27).
We should be careful that not all of the secondary amines are equally reactive to form NDSRI. And we may determine it as low risk after getting more information. I perfectly agree with him.