3.2.P.5.1 — Drug Product Specification

Drug product release and shelf-life specifications

Requirements by Phase

IND Phase 1: preliminary IND Phase 2: preliminary IND Phase 3: preliminary NDA: final

Content (NCE/Small Molecule)

• Drug product specification including tests, analytical procedures, and acceptance criteria

Expected Deliverables

• Drug product specification table

ICH Guidelines: Q3B, Q6A, Q6B

Regulatory Requirements (FDA IND PHASE 1)

• [All] Any questions sponsors have about potential large scale IND clinical trials or potential marketing application manufacturing requirements or specifications should be directed to the appropriate division in the CDER Office of New Drug Chemistry, or the appropriate CBER division with responsibility for the product, for clarification and discussion.
• [Phase 1] For some well-characterized, therapeutic biotechnology-derived products, preliminary specifications and additional validation data may be needed in certain circumstances to ensure safety in Phase 1.
• [Phase 1] For well-characterized, therapeutic, biotechnology-derived products, adequate assessment of bioactivity and preliminary specifications should be available.

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 Q1B)

• [Registration] For both options 1 and 2, a pharmaceutical manufacturer/applicant may rely on the spectral distribution specification of the light source manufacturer.
• [Registration] When evaluating the results of photostability studies to determine whether change due to exposure to light is acceptable, it is important to consider the results obtained from other formal stability studies in order to assure that the product will be within proposed specifications during the shelf life.

Regulatory Requirements (ICH Q3AR2)

• [Commercial] The need for inclusion or exclusion of inorganic impurities in the new drug substance specification should be discussed.
• [Commercial] The specification for a new drug substance should include a list of impurities.
• [Commercial] Selection of impurities in the specification should be based on impurities found in batches manufactured by the proposed commercial process.
• [Commercial] A rationale for inclusion or exclusion of impurities in the specification should be presented.
• [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.

Regulatory Requirements (ICH Q3C)

• FDA's guidance documents do not establish legally enforceable responsibilities; they describe the Agency's current thinking and are recommendations, unless specific regulatory or statutory requirements are cited.
• The use of the word 'should' in Agency guidances means that something is suggested or recommended, but not required.
• [Manufacturing] Solvents in Class 1 (Table 1) should not be employed in the manufacture of drug substances, excipients, and drug products.
• [Manufacturing] Solvents in Class 2 (Table 2) should be limited in pharmaceutical products.
• [Analytical Development] Precision should be determined as part of the validation of the method for Class 2 solvents.
• [Manufacturing] Amounts of Class 3 residual solvents of 50 mg per day or less (corresponding to 5,000 ppm or 0.5 percent under Option 1) would be acceptable without justification.
• [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).
• [Manufacturing, Regulatory Submission] Manufacturers should supply justification for residual levels of solvents listed in Table 4 in pharmaceutical products.

Regulatory Requirements (ICH Q5C)

• [Post-Approval] Where pilot-plant scale batches were submitted to establish the dating for a product and, in the event that product produced at manufacturing scale does not meet those long-term stability specifications throughout the dating period or is not representative of the material used in preclinical and clinical studies, the applicant should notify the appropriate regulatory authorities to determine a suitable course of action.
• [Stability Program Design] The protocol should include all necessary information which demonstrates the stability of the biotechnological/biological product throughout the proposed expiration dating period including, for example, well-defined specifications and test intervals.
• [Specifications] Each product should retain its specifications within established limits for safety, purity, and potency throughout its proposed shelf-life.
• [Specification Setting] These specifications and limits should be derived from all available information using the appropriate statistical methods.
• [Specification Setting] The use of different specifications for release and expiration should be supported by sufficient data to demonstrate that clinical performance is not affected as discussed in the tripartite guideline on stability.

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)

• [New Marketing Applications] This guidance document provides general principles on the setting and justification, to the extent possible, of a uniform set of international specifications for biotechnological and biological products to support new marketing applications.
• [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.
• [Approval] Specifications are critical quality standards that are proposed and justified by the manufacturer and approved by regulatory authorities as conditions of approval.
• [Development, Approval] Specifications are chosen to confirm the quality of the drug substance and drug product rather than to establish full characterization and should focus on those molecular and biological characteristics found to be useful in ensuring the safety and efficacy of the product.
• [All] The principles outlined in this document apply to proteins and polypeptides, their derivatives, and products of which they are components (e.g., conjugates) produced from recombinant or non-recombinant cell-culture expression systems.
• [Development] To determine applicability to other product types such as proteins and polypeptides isolated from tissues and body fluids, manufacturers should consult with the appropriate regulatory authorities.
• [Development] Characterization of a biotechnological or biological product by appropriate techniques is necessary to allow relevant specifications to be established.
• [Development, Submission] Acceptance criteria should be established and justified based on data obtained from lots used in preclinical and/or clinical studies, data from lots used for demonstration of manufacturing consistency and data from stability studies, and relevant development data.
• [Submission] At the time of submission, the product should have been compared with an appropriate reference standard, if available.
• [Submission] At the time of submission, the manufacturer should have established appropriately characterized in-house reference materials which will serve for biological and physicochemical testing of production lots.
• [Development] A physicochemical characterization program will generally include a determination of the composition, physical properties, and primary structure of the desired product.
• [Development] The manufacturer should define the pattern of heterogeneity of the desired product and demonstrate consistency with that of the lots used in preclinical and clinical studies.
• [Development] If a consistent pattern of product heterogeneity is demonstrated, an evaluation of the activity, efficacy and safety (including immunogenicity) of individual forms may not be necessary.
• [Lot Release] For the purpose of lot release (section 4), an appropriate subset of physicochemical methods should be selected and justified.
• [Development, Submission] A valid biological assay to measure the biological activity should be provided by the manufacturer.

Source: ICH Q6A/Q6B