3.2.P.5.6 — Justification of Specification

Scientific rationale for drug product specification and acceptance criteria

Requirements by Phase

NDA: required

Content (NCE/Small Molecule)

• Justification for the proposed drug product specification
• Linkage of acceptance criteria to clinical, nonclinical, and stability data

Expected Deliverables

• Drug product specification justification document

ICH Guidelines: Q3B, Q6A, Q6B

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 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 Q6A/Q6B