CRED Getting the CMC Dossier Right 2024

28/08/2024

Starting Materials: Global Acceptance?

Data from IQ consortium on 110 SMs by 19 companies

Data identical pre and post ICH Q11 Q&A

Main reason stated by HAs - Not enough steps under GMP

Main reasons for rejection after analysis of data: - Impurities that impact DS - Number of solid isolation steps

https://doi.org/10.1021/acs.oprd.4c00033

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N -Nitrosamines

Since 2020, registration dossiers need to include a comprehensive N -nitrosamine risk assessment

The risk assessment needs to be comprehensive: DS manufacturing process, input materials, cross contamination, DP manufacturing process, DP during shelf life, packaging

Critical to the assessment is the establishment of Acceptable Intakes as the potency of nitrosamines spans many orders of magnitude, with some nitrosamines being non-toxic. Agencies published a simple framework (CPCA) for assigning Acceptable Intakes for nitrosamines. Other methods are also available such as read across, Ames testing (using an enhanced protocol, or EAT) and in-vivo mutagenicity assays.

Key Guidances:

Emea-Article 5(3)-assessment-report Emea-Article 5(3)-Q&A FDA Guidance on Nitrosamines

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