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Quality, safety and regulatory · Nitrosamines

“The authority wants to see our nitrosamine risk assessment, and we don't know whether our API can form an NDSRI.”

Nitrosamine risk assessment: identify and justify NDSRIs

Nitrosamines and nitrosamine drug substance related impurities (NDSRIs) are on the question list for every submission and every variation. CovaSyn checks API, intermediates and excipients for nitrosatable structures, assigns possible NDSRIs to potency categories and compiles the justification. Your expert reviews the result and signs it off.

Starting point

When you need this

  • The API contains a secondary or tertiary amine, and nobody has checked yet whether it can form an NDSRI.
  • An authority or a sponsor requests the risk assessment for a product that has been on the market for years.
  • An excipient or API supplier changes, and nitrite or amines newly enter the process.
  • No limit is listed by the authorities for a possible NDSRI, and its classification is open.

If nothing changes

What it costs when the case stays open

  • The submission or variation stays on hold until the assessment is complete.
  • An audit finding or an authority question that takes weeks of rework to answer.
  • In the worst case, batches are blocked or recalled because the risk has not been ruled out with evidence.

Result

What you get

  • Structure check for nitrosatable groups

    API, intermediates, degradation products and excipients checked for amines and other groups that can form a nitrosamine, with the possible nitrosamine structure.

  • Potency category assignment

    For every possible NDSRI, the assignment under the Carcinogenic Potency Categorisation Approach (CPCA), with the structural features behind the category and the resulting limit in ng per day.

  • Risk assessment along the process

    Where nitrite, amines and acidic conditions can meet in synthesis, formulation and packaging, and which points need a confirmatory measurement.

  • Report with justification for sign-off

    Input data, assessment steps and conclusions are laid out traceably in the report, so your toxicologist or QP can check the result and defend it to the authority.

How it works

From an open case to a signed-off report

  • 1. Describe the case

    In the initial call, 30 minutes on Microsoft Teams. We tell you honestly whether we can solve your problem.

  • 2. Send the data

    Confidential from the start. We run the evaluation, typically within 5 working days once we have your data.

  • 3. Sign off the report

    You receive the result with reasoning and input data. Your expert reviews and approves it.

CovaSyn

What we evaluate for this

Every number is calculated, not estimated. Every evaluation is documented with its input data and reasoning, so your expert can review and sign it off.

  • Nitrosamine formation recognised from structure

    Recognition of nitrosatable amines and the nitrosamines they form, including complex APIs with several nitrogen centres.

  • ICH M7 assessment

    Structural alerts, a mutagenicity estimate with an applicability domain check and a proposed ICH M7 class.

  • Potency category and limit justified

    Assignment of possible NDSRIs to potency categories with a justification per structural feature and a comparison with published limits.

Audience

Who it is for

For regulatory affairs, QA, analytical and CMC teams at generics manufacturers, CDMOs and marketing authorisation holders who need to create or update nitrosamine risk assessments for new or existing products.

What the computation does not replace

  • We do not run lab measurements. Where the assessment cannot rule out a risk, a confirmatory test with a sufficiently sensitive method is needed.
  • The acceptable intake comes from authority lists or the potency category assignment. Your expert has to confirm the value applied.
  • The assessment prepares your decision. Release stays with your QP or toxicologist, and the assessment does not replace evaluation by the authority.

Insights

Read on

Questions

Common questions

What is an NDSRI?

An NDSRI is a nitrosamine impurity formed from the API itself, usually from a secondary or tertiary amine in its structure. Unlike small nitrosamines such as NDMA, every NDSRI is a distinct substance, and often no limit is listed for it by the authorities.

How do I set a limit for an NDSRI without data?

The authorities provide the Carcinogenic Potency Categorisation Approach (CPCA) for this: structural features around the nitroso group lead to a category and from that to a limit in ng per day. CovaSyn assigns the category and shows every feature, so your expert can follow and confirm it.

Which steps does a nitrosamine risk assessment include?

First the risk evaluation of whether nitrosamines can form or be introduced, then confirmatory testing if a risk exists, and measures if something is found. CovaSyn takes on the first step with a structure check and justification and shows where a measurement is needed.

Do products that have been approved for a long time need an assessment too?

Yes. Authorities in the EU and the US expect the assessment for all authorised human medicines, regardless of how old the authorisation is. Older products in particular often lack a documented justification.

Who can prepare our nitrosamine risk assessment?

CovaSyn does this as Done-for-You: you describe API and process in the initial call, we agree on scope, and you typically receive the report within 5 working days once we have your data. Handled confidentially from the start.

Quality, safety and regulatory

Related problems we solve

Next step

Tell us about your API and your process.

30 minutes on Microsoft Teams with the CovaSyn team. If it is not a fit, we will say so.