CRED Getting the CMC Dossier Right 2024

29/08/2024

Common deficiencies: Starting materials

⚫ Examples

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short synthetic route

▪ potentially multiple synthetic routes to B ➢ each could result in a different impurity profile ➢ changes can be made without regulatory oversight ▪ pre-starting material - steps not subject to GMP ▪ no confidence that process is under control ➢ Lifecycle management issue

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few isolated intermediates – limited purification opportunities

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multiple telescoped steps ➢ high number of variables and potential interdependencies discussion of impurities often inadequate ➢ Control of process must be demonstrated

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Common deficiencies: Starting materials

⚫ Exemplary MO

● The active substance manufacturer should redefine the starting material X to an earlier point in the synthesis. – All manufacturers of the redefined starting material must be listed with names and addresses. Additional suppliers can only be added by means of a variation. – All syntheses of GMP starting materials from all suppliers should be briefly described from simple starting materials where all reagents, catalysts and solvents are indicated for each step. – Suitable specifications and batch analysis data should be provided for the redefined starting materials. – The carry-over of reactants, solvents, catalysts, intermediates and related substances should be discussed thoroughly. Supportive data should be provided, as applicable. – The redefined GMP steps should be fully described and supported by in-process controls and relevant specifications. – The previously assigned starting material should be considered as an intermediate and a suitable specification and documentation should be provided for this material. – The QP declarations for GMP compliance of the drug substance manufacturing site should be amended accordingly.

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