3.2.P.5.5 — Characterisation of Impurities

Identification and characterization of degradation products in the drug product

Requirements by Phase

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

Content (NCE/Small Molecule)

• Characterisation of impurities in the drug product (if not addressed in 3.2.S.3.2)
• Degradation products characterization
• Leachables from container closure (if applicable)

Content (Biotech)

• Product-related impurities (aggregates, degradation products)
• Process-related impurities
• Leachables characterization

Expected Deliverables

• Drug product impurity characterization report

ICH Guidelines: Q3B, 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)

• [Commercial] The impurity profile of drug substance batches for marketing should be compared with those used in development, and any differences discussed.
• [Commercial] Any impurity at a level > identification threshold in any batch manufactured by the proposed commercial process should be identified.
• [Development, Commercial] If identification of an impurity is not feasible, a summary of unsuccessful laboratory efforts should be included.
• [Commercial] Reference standards for impurity control should be evaluated and characterised according to their intended uses.
• [Development, Commercial] Any impurity > reporting threshold and total impurities should be reported with analytical procedures indicated.
• [Registration] The applicant should ensure complete impurity profiles (e.g., chromatograms) of individual batches are available, if requested.
• [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] A general acceptance criterion of not more than (≤) the identification threshold (Attachment 1) for any unspecified impurity and an acceptance criterion for total impurities should be included.
• [Commercial] Where there is no safety concern, impurity acceptance criteria should be based on data generated on batches of the new drug substance manufactured by the proposed commercial process, allowing sufficient latitude to deal with normal manufacturing and analytical variation and the stability characteristics of the new drug substance.
• [Commercial] The new drug substance specification should include: Each specified identified impurity, Each specified unidentified impurity, Any unspecified impurity with an acceptance criterion of not more than (≤) the identification threshold, Total impurities, Residual Solvents, Inorganic Impurities.
• [Commercial] The applicant should provide a rationale for establishing impurity acceptance criteria that includes safety considerations.
• [Development] Any new impurity observed in later stages of development should be identified if its level is greater than (>) the identification threshold given in Attachment 1.
• [Development, Commercial] The qualification of the impurity should be considered if its level is greater than (>) the qualification threshold given in Attachment 1.
• [Development, Commercial] Safety assessment studies to qualify an impurity should compare the new drug substance containing a representative amount of the new impurity with previously qualified material.
• [Development] The study duration for general toxicity studies should be based on available relevant information and performed in the species most likely to maximise the potential to detect the toxicity of an impurity.

Regulatory Requirements (ICH Q6A)

• [Marketing Approval] A specification is defined as a list of tests, references to analytical procedures, and appropriate acceptance criteria, which are numerical limits, ranges, or other criteria for the tests described.
• [Marketing Approval] Specifications are critical quality standards that are proposed and justified by the manufacturer and approved by regulatory authorities as conditions of approval.
• [Marketing Approval] Specifications should focus on those characteristics found to be useful in ensuring the safety and efficacy of the drug substance and drug product.
• [Marketing Approval] This guideline addresses specifications (tests, procedures, and acceptance criteria) for new drug substances and new drug products at release and during shelf life.
• [Marketing Approval] This guideline may be applicable to synthetic and semi-synthetic antibiotics and synthetic peptides of low molecular weight.
• [Post-approval (generally)] Periodic or skip testing, the performance of specified tests at release on pre-selected batches and/or at predetermined intervals, should be justified and approved by the regulatory authority prior to implementation.
• [Post-approval] Any failure to meet acceptance criteria for a periodic test should be handled by proper notification of the appropriate regulatory authority(ies), and routine testing should be reinstated if data demonstrate a need.
• [Marketing Approval] The concept of different acceptance criteria for release vs. shelf-life specifications applies to drug products only, allowing for more restrictive criteria at release.
• [Manufacturing] In-process tests are performed during manufacture and are not part of the formal battery of tests conducted prior to release, unless the acceptance criterion is identical to or tighter than the release requirement and validated.
• [Development, Marketing Approval] Excluding or replacing certain tests may be proposed based on development data, such as microbiological testing for solid dosage forms shown not to support microbial viability or growth.
• [Development, Marketing Approval] Dissolution testing for immediate release solid oral drug products made from highly water soluble drug substances may be replaced by disintegration testing if consistently rapid drug release characteristics have been demonstrated.
• [Marketing Approval, Post-approval] Initially approved tests and acceptance criteria should be reviewed and potentially modified as more information is collected post-approval, focusing on safety and efficacy at filing.
• [Marketing Approval] Parametric release, an operational alternative to routine release testing, can be used for drug products (e.g., sterility testing for terminally sterilized products) when approved by the regulatory authority, based on satisfactory monitoring of specific parameters.
• [Marketing Approval] When parametric release is performed, the attribute indirectly controlled (e.g., sterility) and a reference to its associated test procedure should still be included in the specifications.
• [Marketing Approval] Alternative analytical procedures may be used if they control the quality of the drug substance or drug product to an extent comparable or superior to the official procedure, but the official procedure should still be used to demonstrate compliance during shelf-life.

Source: ICH Q3B(R2)