CRED Getting the CMC Dossier Right 2024

29/08/2024

Common deficiencies: Starting materials

⚫ One of the most frequent MOs – Abridged and NAS applications

⚫ The issue:

● short synthetic routes

● custom- synthesized starting materials; in fact “intermediates’’

● minimal synthetic steps (esterification, salt formation, protection/ deprotection)

● Information insufficient – to assess the suitability of SM specification / analytical controls – to provide reassurance on the impact of amendment to the upstream synthesis to the quality of final drug substance ● Information on key synthetic steps from structural precursors and isolation of intermediates omitted or SM defined late stage beyond significant chemical transformations

The Organisation for Professionals in Regulatory Affairs

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Common deficiencies: Starting materials

⚫ The issue (contd.):

● Lack of information on introduction and removal of potential impurities and those that carry over into the drug substance ● Potential impurities – related substances, catalysts, potential genotoxic impurities, solvents ● Limited number of steps under GMP; concerns with lack of sufficient control/regulatory oversight ● Major Objection raised requesting re-definition to an earlier stage in the synthesis ● Major problem for the Applicant as manufacturing decisions already taken – supply chain etc. ● Often unable to re-define SMs without long delays & requiring significant 3.2.S dossier changes

The Organisation for Professionals in Regulatory Affairs

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