3.2.S — Drug Substance

Drug substance quality information: characterization, manufacture, control, reference standards, stability

Requirements by Phase

IND Phase 1: required IND Phase 2: required IND Phase 3: required NDA: required

Content (NCE/Small Molecule)

• Complete drug substance quality documentation covering nomenclature, manufacture, characterization, control, reference standards, container closure, and stability

Expected Deliverables

• Drug substance quality dossier (Module 3.2.S)

ICH Guidelines: Q6A, Q6B, Q7, Q11

Regulatory Requirements (FDA IND PHASE 2 3 CMC)

• [All] Certain information traditionally submitted in information amendments, identified as corroborating information, can be submitted in an annual report.
• [Phase 2] Limited phase 2 corroborating information recommended in section III need not be submitted before initiation of phase 2 studies and can be generated during phase 2 drug development.
• [Phase 3] Phase 3 corroborating information recommended in section IV need not be submitted before the initiation of phase 3 studies and can be generated during phase 3 drug development.
• [All] Corroborating information and a summary of CMC safety information submitted during a subject-reporting period should be included in the annual report, eliminating the need for general CMC updates at the end of phase 1 or phase 2.
• [All] CMC safety information should be submitted to support the safe use of the drug.
• [Phase 2] The CMC safety information identified in section III (Phase 2 Studies) should be submitted before initiation of the phase 2 studies.
• [Phase 3] The CMC safety information identified in section IV (Phase 3 Studies) should be submitted before initiation of the phase 3 studies.
• [All] When new information becomes available that relates to the safe use of the drug or when there are changes in previously submitted CMC safety information, it should be submitted during IND clinical trials in an information amendment.
• [All] For changes with a significant potential to affect the safety of the product, an information amendment should be submitted describing the changes and containing relevant information at a level of detail sufficient for an adequate review and assessment.
• [Phase 2] Corroborating information specified in section III (Phase 2 Studies) that is generated during phase 1 need not be submitted until the first annual report after initiation of phase 2 studies.
• [Phase 2] Corroborating information specified in section III (Phase 2 Studies) that is generated during phase 2 studies should be submitted in the next annual report after the information becomes available.
• [Phase 3] Corroborating information specified in section IV (Phase 3 Studies) that is generated earlier during phase 1 and phase 2 need not be submitted until the first annual report after initiation of phase 3 studies.
• [Phase 3] Corroborating information specified in section IV (Phase 3 Studies) that is generated during phase 3 studies should be submitted in the next annual report after the information becomes available.
• [Phase 2] Updates on the brief description of the drug substance and a more detailed description of the configuration and chemical structure for complex organic compounds should be provided.
• [Phase 2] The addition, deletion, or change of any manufacturer of the drug substance from that specified during phase 1 should be reported.

Source: ICH Q7; ICH Q11; 21 CFR 312.23(a)(7)(i)