CRED Getting the CMC Dossier Right 2024

28/08/2024

N Nitrosamines • Originally identified as a result of detection of simple dialkyl N-Nitrosamines in the active the issue has expanded and is now dominated by complex API like Nitrosamines – referred to as Nitrosamine Drug Substance related impurities (NDSRIs). Drug Substance – Quality Attributes

• NDSRIs form where the drug is a secondary amine through interaction with nitrites present in common excipients

• Cannot eliminate nitrites in excipients

• Unlike the initial simple di-alkyl N-Nitrosamines for which there is considerable carcinogenicity data that allows limits to be set – there are no carcinogenicity data for NDSRIs.

• Recently an entirely new concept and process has been established to address this problem

• Despite this issues remain

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Drug Substance – Quality Attributes

Mutagenic Impurities (ICH M7)

“ Threshold of Toxicological Concern” (TTC) based on a 10 -5 cancer life time risk

Impurities assessment in drug substance and product

Hazard Assessment/classification of impurity structures • Role of QSAR and Ames

Risk characterisation • Limits MIs to 1.5  g / day for >10years dosing (plus higher durational limits) • Compound specific limits (see ICH M7 addendum) • Multiple MI’s

Control strategy •

Multiple options for control strategy in API • Including; specifications (API/intermediates/SM), IPCs/processing parameters, implicit in design of manufacturing process • Purge factors • Quantitative assessment of potential carry-over of a MI (Based on understanding of physicochemical properties of the MI relative to the process conditions. Covers both clinical and marketed products

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