3.2.S.3.2 — Impurities

Identification, qualification, and control of process-related and degradation impurities

Requirements by Phase

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

Content (NCE/Small Molecule)

• Information on impurities (process-related and degradation products)
• Identified and unidentified impurities
• Impurity classification and qualification thresholds
• Residual solvents
• Elemental impurities assessment

Content (Biotech)

• Process-related impurities (host cell proteins, DNA, etc.)
• Product-related impurities (degradation products, aggregates, etc.)
• Residual solvents

Expected Deliverables

• Impurity profile table
• Impurity characterization report
• Residual solvents analysis

ICH Guidelines: Q3A, Q3C, Q3D, Q5C, 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 M3R2)

• [before Phase 3] Qualification studies for impurities/degradants are generally not warranted before Phase III, unless changes result in a significant new impurity profile.

Regulatory Requirements (ICH Q3AR2)

• [Development, Commercial] The applicant should summarise actual and potential impurities likely to arise during synthesis, purification, and storage of the new drug substance.
• [Development, Commercial] The summary should be based on scientific appraisal of chemical reactions, raw material impurities, and possible degradation products.
• [Development, Commercial] The applicant should summarise laboratory studies conducted to detect impurities, including test results from development and proposed commercial batches, and stress testing results.
• [Commercial] The impurity profile of drug substance batches for marketing should be compared with those used in development, and any differences discussed.
• [Development, Commercial] Studies conducted to characterise the structure of actual impurities present at a level > identification threshold (Attachment 1) should be described.
• [Commercial] Any impurity at a level > identification threshold in any batch manufactured by the proposed commercial process should be identified.
• [Stability] Any degradation product observed in stability studies at recommended storage conditions at a level > identification threshold should be identified.
• [Development, Commercial] If identification of an impurity is not feasible, a summary of unsuccessful laboratory efforts should be included.
• [Development, Commercial] Identification of impurities present at an apparent level of not more than (≤) the identification threshold is generally not considered necessary.
• [Development, Commercial] Analytical procedures should be developed for potential impurities expected to be unusually potent, producing toxic, or pharmacological effects at a level not more than (≤) the identification threshold.
• [Development, Commercial] All impurities should be qualified.
• [Development, Commercial] Inorganic impurities are normally detected and quantified using pharmacopoeial or other appropriate procedures.
• [Development] Carry-over of catalysts to the new drug substance should be evaluated during development.
• [Commercial] The need for inclusion or exclusion of inorganic impurities in the new drug substance specification should be discussed.
• [Commercial] Acceptance criteria for inorganic impurities should be based on pharmacopoeial standards or known safety data.

Regulatory Requirements (ICH Q6A)

• [Marketing Approval] Assay: A specific, stability-indicating procedure (e.g., HPLC) should be included to determine the content of the new drug substance, often also used for impurity quantitation.
• [Marketing Approval] Assay: A specific, stability-indicating assay to determine strength should be included for all new drug products, often using the same procedure as for impurity quantitation.

Note: IND: preliminary. NDA: full qualification

Source: ICH Q3A(R2)