3.2.S.2.2 — Manufacturing Process and Controls

Flow diagram and narrative description of manufacturing process with critical steps identified

Requirements by Phase

IND Phase 1: minimal IND Phase 2: minimal IND Phase 3: expanded NDA: full

Content (NCE/Small Molecule)

• Flow diagram of the synthetic process with molecular formulae, weights of reagents, yield ranges
• Chemical structures of starting materials, intermediates, reagents, and product
• Stereochemistry notation at each step
• Sequential procedural narrative at representative commercial batch scale
• Quantities of raw materials, solvents, catalysts, and reagents
• Identification of critical steps and process controls
• Equipment and operating conditions (temperature, pressure, pH, time)
• In-process tests and acceptance criteria
• Alternate processes described at same level of detail
• Reprocessing steps identified and justified

Content (Biotech)

• Flow diagram from cell bank through cell culture, harvest, purification, modification reactions, filling, storage, and shipping
• Description of each process step including scale, buffers, reagents, and equipment
• Batch numbering system and pooling information
• Identification of critical steps
• Reprocessing criteria and procedures

Expected Deliverables

• Manufacturing process flow diagram
• Procedural narrative document
• Critical process parameters table
• In-process controls table

ICH Guidelines: Q5A, Q5B, Q6B, Q7, Q11

Regulatory Requirements (FDA IND PHASE 1)

• [Phase 1] A brief description of the manufacturing process, including a list of the reagents, solvents, and catalysts used, should be submitted.
• [Phase 1] A diagrammatic presentation and a brief written description of the manufacturing process should be submitted, including sterilization process for sterile products.

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 Q1AR2)

• [Pre-approval] The manufacturing process used for primary batches of drug product should simulate that to be applied to production batches and should provide product of the same quality and meeting the same specification as that intended for marketing.

Regulatory Requirements (ICH Q3AR2)

• [Registration] For each batch, the report should include batch identity/size, date/site of manufacture, manufacturing process, individual/total impurity content, use of batches, and reference to analytical procedure.
• [Commercial] Acceptance criteria should be set no higher than the level that can be justified by safety data, and should be consistent with the level achievable by the manufacturing process and the analytical capability.

Regulatory Requirements (ICH Q3C)

• [Manufacturing] Higher amounts of Class 3 solvents may also be acceptable provided they are realistic in relation to manufacturing capability and good manufacturing practice (GMP).

Regulatory Requirements (ICH Q6A)

• [Marketing Approval] Inorganic impurities: The need for tests and acceptance criteria for inorganic impurities (e.g., catalysts) should be studied based on manufacturing process knowledge, following pharmacopoeial precedents for sulfated ash/residue on ignition.
• [Marketing Approval] Microbial limits: Microbial limit testing is generally advisable for drug products unless components are tested and the manufacturing process is validated not to carry a significant risk of contamination or proliferation.
• [Marketing Approval] Microbial limits: Microbial limit testing is generally advisable for drug products unless components are tested and the manufacturing process is validated not to carry a significant risk of contamination or proliferation.

Regulatory Requirements (ICH Q6B)

• [Manufacturing] When a correlation exists between quantity and biological assay values, it may be appropriate to use measurement of quantity rather than the measurement of biological activity in manufacturing processes, such as filling.
• [Development, Validation] Data obtained during development and validation runs should provide the basis for provisional action limits to be set for the manufacturing process.
• [Manufacturing] Process-related impurities in the drug substance should be minimized by the use of appropriate well-controlled manufacturing processes.

Note: IND P1: brief. NDA: full with validation

Source: ICH Q7; ICH Q11