3.2.S.4.2 — Analytical Procedures

Description of analytical procedures used for testing drug substance

Requirements by Phase

IND Phase 1: basic IND Phase 2: basic IND Phase 3: basic NDA: validated

Content (NCE/Small Molecule)

• Description of analytical procedures used for testing the drug substance

Content (Biotech)

• Description of analytical procedures including biological/immunological/biochemical test methods

Expected Deliverables

• Analytical procedures descriptions

ICH Guidelines: Q2A, Q6B

Regulatory Requirements (FDA IND PHASE 1)

• [Phase 1] Proposed acceptable limits supported by simple analytical data (e.g., IR spectrum to prove the identity, and HPLC chromatograms to support the purity level and impurities profile) of the clinical trials material should be provided.

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] Validated stability-indicating analytical procedures should be applied for drug substance stability studies.
• [Pre-approval] Analytical procedures for drug product stability studies should be fully validated and stability indicating.

Regulatory Requirements (ICH Q1B)

• [Development, Registration] The analytical procedures used should be suitably validated.

Regulatory Requirements (ICH Q3AR2)

• [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.
• [Registration] The registration application should include documented evidence that analytical procedures are validated and suitable for detection and quantification of impurities (refer to ICH Q2A and Q2B).
• [Development, Commercial] Differences in analytical procedures used during development and those proposed for commercial product should be discussed.
• [Commercial] The quantitation limit for the analytical procedure should be not more than (≤) the reporting threshold.
• [Commercial] Analytical assumptions (e.g., equivalent detector response) for acceptance criteria and procedures for identified/unidentified impurities should be discussed.
• [Development, Commercial] Analytical results should be provided for all batches used for clinical, safety, stability testing, and representative commercial batches.
• [Development, Commercial] Any impurity > reporting threshold and total impurities should be reported with analytical procedures indicated.
• [Development] When analytical procedures change during development, reported results should be linked to the procedure used, with validation information.
• [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] For unusually potent or to produce toxic or unexpected pharmacological effects, the quantitation/detection limit of the analytical procedures should be commensurate with the level at which the impurities should be controlled.
• [Commercial] Specified, unidentified impurities should be referred to by an appropriate qualitative analytical descriptive label.
• [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.
• [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.

Regulatory Requirements (ICH Q5B)

• [Development, Registration] Analytical methodologies should be validated for the intended purpose of confirmation of sequence.
• [Development, Registration] Analytical data derived from both nucleic acid analysis and evaluation of the final purified protein should be evaluated to ensure the quality of a recombinant protein product.

Regulatory Requirements (ICH Q5C)

• [Specification Setting] Limits of acceptable degradation should be derived from the analytical profiles of batches of the drug substance and drug product used in the preclinical and clinical studies.
• [Stability Studies] The use of relevant physicochemical, biochemical and immunochemical analytical methodologies should permit a comprehensive characterisation of the drug substance and/or drug product (e.g., molecular size, charge, hydrophobicity) and the accurate detection of degradation changes that may result from deamidation, oxidation, sulfoxidation, aggregation or fragmentation during storage.
• [Stability Program Design] For substances that cannot be properly characterised or products for which an exact analysis of the purity cannot be determined through routine analytical methods, the applicant should propose and justify alternative testing procedures.
• [Stability Studies] Studies under accelerated conditions may provide useful support data for establishing the expiration date, provide product stability information for future product development, assist in validation of analytical methods for the stability program, or generate information which may help elucidate the degradation profile of the drug substance or drug product.

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.

Regulatory Requirements (ICH Q6B)

• [All] 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.
• [All] The purity of the drug substance and drug product is assessed by a combination of analytical procedures.
• [Submission] At the time the application is submitted to the regulatory authorities, applicants should have validated the analytical procedures used in the specifications in accordance with the ICH Harmonised Tripartite Guidelines "Validation of Analytical Procedures: Definitions and Terminology” and “Validation of Analytical Procedures: Methodology".
• [All] Pharmacopoeias contain important requirements pertaining to certain analytical procedures and acceptance criteria which, where relevant, are part of the evaluation of either the drug substance or drug product.
• [Development] The choice and optimization of analytical procedures for drug substance purity should focus on the separation of the desired product from product-related substances and from impurities.
• [Development, Submission] Acceptance criteria and analytical procedures should be developed and justified, based upon previous experience with the drug product, to measure changes in the drug substance during the manufacture and/or storage of the drug product.
• [Development] The choice and optimization of analytical procedures for drug product purity should focus on the separation of the desired product and product-related substances from impurities including degradation products, and from excipients.

Source: ICH Q2(R2)