3.2.S.2.3 — Control of Materials

Quality and control of starting materials, reagents, solvents, catalysts

Requirements by Phase

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

Content (NCE/Small Molecule)

• List of all materials used in manufacture (raw materials, starting materials, solvents, reagents, catalysts)
• Identification of where each material is used in the process
• Quality specifications and control information for each material
• For biologically-sourced materials: compliance with standards for adventitious agents

Content (Biotech)

• Control of source and starting materials of biological origin
• Viral safety information for biological source materials
• Cell substrate source, history, and generation details
• Cell banking system description, characterization, and testing

Expected Deliverables

• Materials list table with specifications
• Material quality specifications
• Cell bank characterization report (biotech)

ICH Guidelines: Q5A, Q5B, Q5C, Q5D, Q6A, Q6B

Regulatory Requirements (FDA IND PHASE 1)

• [Phase 1] Reasons for concern (that may lead to clinical hold) may include: 1) a product made with unknown or impure components; 2) a product possessing chemical structures of known or highly likely toxicity; 3) a product that cannot remain chemically stable throughout the testing program proposed; or 4) a product with an impurity profile indicative of a potential health hazard or an impurity profile insufficiently defined to assess a potential health hazard; or 5) a poorly characterized master or working cell bank.

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.

Regulatory Requirements (ICH Q5B)

• [Development, Registration] Segments of the expression construct should be analysed using nucleic acid techniques in conjunction with other tests performed on the purified recombinant protein for assuring the quality and consistency of the final product.
• [Development, Registration] Analysis of the expression construct at the nucleic acid level should be considered as part of the overall evaluation of quality.
• [Development, Registration] The purpose of analysing the expression construct is to establish that the correct coding sequence of the product has been incorporated into the host cell and is maintained during culture to the end of production.
• [Development, Registration] Analytical methodologies should be validated for the intended purpose of confirmation of sequence.
• [Development, Registration] The validation documentation should at a minimum include estimates of the limits of detection for variant sequences.
• [Development, Registration] This should be performed for either nucleic acid or protein sequencing methods.
• [Development, Registration] Information should be supplied regarding the characterisation of the expression construct during the development and validation of the production system.
• [Development, Registration] The manufacturer should describe the origin of the nucleotide sequence coding for the protein.
• [Development, Registration] This description should include identification and source of the cell from which the nucleotide sequence was originally obtained.
• [Development, Registration] Methods used to prepare the DNA coding for the protein should be described.
• [Development, Registration] The steps in the assembly of the expression construct should be described in detail.
• [Development, Registration] This description should include the source and function of the component parts of the expression construct (e.g., origins of replication, antibiotic resistance genes, promoters, enhancers, whether or not the protein is being synthesised as a fusion protein).
• [Development, Registration] A detailed component map and a complete annotated sequence of the plasmid should be given, indicating those regions that have been sequenced during the construction and those taken from the literature.
• [Development, Registration] Other expressed proteins encoded by the plasmid should be indicated.
• [Development, Registration] The nucleotide sequence of the coding region of the gene of interest and associated flanking regions that are inserted into the vector, up to and including the junctions of insertion, should be determined by DNA sequencing of the construct.

Regulatory Requirements (ICH Q6B)

• [All] The principles outlined in this document apply to proteins and polypeptides, their derivatives, and products of which they are components (e.g., conjugates) produced from recombinant or non-recombinant cell-culture expression systems.

Source: ICH Q7