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Supporting your complete nitrosamine risk assessment profile

Nitrosamine risk assessment

The discovery of nitrosamine impurities in pharmaceuticals has led to one of the largest exercises in retrospective risk assessment that the pharmaceutical industry has encountered.

Nitrosamines are a concern as they can be mutagenic, genotoxic and potentially carcinogenic.

Human medicine regulatory requirements mean that should the risk of nitrosamine formation be identified, an assessment of potency and result acceptable intake is required.

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Why choose Consult Lhasa?

Consult Lhasa provides expert nitrosamine risk assessments, built on Lhasa Limited science, that are recognised and trusted by industry and regulatory authorities.

Lhasa Limited have been collaborating with industry and regulators to drive nitrosamine risk assessment science. The outcome of this work has influenced, and is referenced in, the latest global nitrosamine regulatory updates.

If you need assistance with your complete nitrosamine risk assessment, Consult Lhasa.

How can our experts help you to assess

Do you need help understanding the nitrosamine formation risk factors relating to your API synthetic route?
Nitrosamines can be formed through a range of pathways, cases where both an amine and nitrosating agent are present are particularly concerning. We can help you to understand if the nitrosamine formation pathways are present in your route of API synthesis.

Do you need help assessing other possible sources of nitrosamine formation, in relation to the manufacturing of your API?
As well as synthetic route assessment, the manufacturing process should also be considered as a potential source of amines or nitrosating agents. Good manufacturing practice (GMP) factors, such as cross contamination and the use of recovered or recycled materials need to be reviewed. We can help you to assess and understand the impact of these factors.

Could the nitrosamine risk be mitigated through a purge factor calculation?
By this point, you know that there is a risk of nitrosamine formation from your API route of synthesis or manufacturing process. We can help you to mitigate the risk associated with these nitrosamines using scientific rationale, to evaluate the process parameters at each stage of the synthesis. We will provide an estimated purge ratio, which can give sufficient confidence that the nitrosamine will be present below the acceptable intake (AI), when used alongside your analytical results.

Are nitrites in your excipients contaminating your final drug product?
It is now well known within the pharmaceutical industry that excipients may be contaminated with levels of nitrites, which can act as nitrosating agent precursors. We can help you to calculate the maximum level of nitrosamine formation, as a function of the nitrite content in the final product.

Do you need help assessing nitrosamine formation risk factors relating to your formulation process?
Aspects of your formulation process – relating to dosage form, conditions such as temperature, and compound characteristics such as amine pKa – can result in significant levels of nitrosamines. We can provide a mechanistic and kinetic evaluation, to assess this risk.

Is your primary packaging inducing a risk of nitrosamine formation?
It is important to consider how your chosen packaging could interact with vulnerable aspects of your final product. We can assess the known composition of your primary packaging and highlight any materials which may be a concern.

Do you need help defining an acceptable intake (AI) strategy?
Only a small amount of carcinogenicity data is available for nitrosamines in the public domain. This data, has been expertly curated by Lhasa Limited. Recent regulatory guidance now allows several methods for determining an AI. We can evaluate your nitrosamine in light of the latest guidance and suggest a suitable AI strategy.

Do you need help evaluating nitrosamine experimental data?
In cases where relevant data exists, the robustness of the data needs to be evaluated before it is used for an AI calculation. Existing data may come from a variety of assays – for example, rodent carcinogenicity, in vivo mutagenicity or the Ames test. We can help you evaluate the suitability of the data for a nitrosamine AI calculation.

Is there a suitable read-across surrogate for your nitrosamine?
Recent guidance has provided the carcinogenic potency categorisation approach (CPCA) as a conservative first-line assessment for a potential nitrosamine. However, guidance permits the use of scientifically robust read-across, in cases where the CPCA-derived limit is not achievable. We can provide an evaluation of potential surrogate structures, using our understanding of relative activity and known experimental data to determine whether a suitable analogue exists. We will provide an expert justification for analogue selection and associated AI.

What if there is no suitable analogue?

If there is no suitable analogue for your nitrosamine and the CPCA, or published limits, are unachievable, we can help you to decide on your next steps. We will review the weight of evidence (WoE) and suggest any additional data that may support the use of a WoE approach.

We provide regulatory support

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For assessing and controlling mutagenic impurities that reside or are reasonably expected to reside, in a final drug substance or product, to limit potential carcinogenic risk. Nitrosamines are covered within ICH M7 as mutagenic impurities, as part of the cohort of concern.
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Other regulations

Widespread formation and potential high potency carcinogenicity of some nitrosamines means that there are additional guidelines to consider from regulators globally, including the EMA, FDA, Health Canada, Swissmedic, Anvisa and MHRA.

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If you are interested in discovering how Consult Lhasa could improve your nitrosamine risk assessments, get in touch.