Nudelman ChemTox
Consulting
Nitrosamines
Risk of formation assessments
This service evaluates the potential for nitrosamines to form during the manufacturing process of the drug substance (API) or drug product (formulated product), storage, or within the product lifecycle. Key aspects include:
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Identifying nitrosamine precursors, such as secondary or tertiary amines, and nitrosating agents in raw materials, reagents, intermediates, and excipients.
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Assessing manufacturing processes of drug substance synthesis and drug product formulation, including conditions like pH, temperature, and moisture, that may promote nitrosamine formation.
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Providing strategies to minimize risk, such as modifying formulations, selecting alternative raw materials, or optimizing production parameters.
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These assessments are essential for meeting regulatory expectations, such as those outlined by the FDA and EMA for nitrosamine mitigation in drug products.
Setting acceptable intake (AI) limits
This service determines safe exposure levels for nitrosamines to ensure product safety and regulatory compliance. Key components include:
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Utilizing default regulatory thresholds, such CPCA (carcinogenicity potency categorization approach)-derived AIs
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Derivation of AIs by extrapolation from carcinogenicity data for individual nitrosamines.
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Clear and scientifically justified AI limits help protect public health and prevent regulatory delays during product approvals.
Recommendations for studies to support increased AIs
In cases where standard AI limits may not be practical, this service supports clients in justifying higher limits by:
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Proposing additional toxicological studies, such as in vitro mutagenicity (e.g. enhanced Ames test (EAT)) and in vivo mutagenicity studies (e.g. TGR or duplex sequencing), to provide compound-specific safety data, and coordinate and monitor such studies.
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Read-across techniques to set AIs for nitrosamines that lack specific mutagenicity of carcinogenicity data by structure comparison to similar nitrosamines that have more available data.
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Conducting (via third party) quantum mechanical (QM) calculations and cytochrome P450 binding evaluations.
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Recommending pharmacokinetic studies to determine exposure levels and refine safety margins.
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Guiding the design of studies to ensure they meet regulatory requirements for submission and acceptance. These recommendations aim to facilitate product development while maintaining a robust safety profile and meeting regulatory demands.