3.2.S.7.1 — Stability Summary and Conclusions

Summary of stability studies and conclusions on storage conditions and retest date/shelf life

Requirements by Phase

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

Content (NCE/Small Molecule)

• Types of stability studies conducted and protocols used
• Summary of stability results
• Conclusions on storage conditions and retest date or shelf-life

Expected Deliverables

• Stability summary report
• Proposed storage conditions and retest date

ICH Guidelines: Q1A, Q1B, Q5C

Regulatory Requirements (FDA IND PHASE 1)

• [All phases] Stability data are required in all phases of the IND to demonstrate that the new drug substance and drug product are within acceptable chemical and physical limits for the planned duration of the proposed clinical investigation.
• [Phase 1] A brief description of the stability study and the test methods used to monitor the stability of the drug substance should be submitted.
• [Phase 1] Preliminary tabular data based on representative material for drug substance stability may be submitted.
• [Phase 1] A brief description of the stability study and the test methods used to monitor the stability of the drug product packaged in the proposed container/closure system and storage conditions should be submitted.
• [Phase 1] Preliminary tabular data based on representative material for drug product stability may be submitted.

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 intermediate storage condition has been changed from 30°C ± 2°C/60% RH ± 5% RH to 30°C ± 2°C/65% RH ± 5% RH.
• [Pre-approval] 30°C ± 2°C/65% RH ± 5% RH can be a suitable alternative long-term storage condition to 25°C ± 2°C/60% RH ± 5%.
• [Pre-approval] 30°C ± 2°C/35% RH ± 5% RH has been added as a suitable alternative long-term storage condition to 25°C ± 2°C/40% RH ± 5% for semi-permeable containers.
• [Pre-approval] Mid-stream switch of the intermediate storage condition from 30°C ± 2°C/60% RH ± 5% RH to 30°C ± 2°C/65% RH ± 5% RH can be appropriate.
• [Pre-approval] Registration applications should contain data from complete studies at the intermediate storage condition 30°C ± 2°C/65% RH ± 5% RH.
• [Development] Stability testing should be carried out on a single batch of the drug substance.
• [Development] Stress testing should include the effect of temperatures (in 10°C increments above accelerated testing), humidity (75% RH or greater where appropriate), oxidation, and photolysis on the drug substance.
• [Development] Stress testing should evaluate the susceptibility of the drug substance to hydrolysis across a wide range of pH values when in solution or suspension.
• [Development] Photostability testing should be an integral part of stress testing.
• [Pre-approval] Results from stress studies will form an integral part of the information provided to regulatory authorities.
• [Pre-approval] Data from formal stability studies should be provided on at least three primary batches of the drug substance.
• [Pre-approval] Drug substance batches should be manufactured to a minimum of pilot scale by the same synthetic route as, and using a method of manufacture and procedure that simulates the final process to be used for, production batches.
• [Pre-approval] The overall quality of the batches of drug substance placed on formal stability studies should be representative of the quality of the material to be made on a production scale.
• [Pre-approval] Stability studies should be conducted on the drug substance packaged in a container closure system that is the same as or simulates the packaging proposed for storage and distribution.
• [Pre-approval] Stability studies should include testing of those attributes of the drug substance that are susceptible to change during storage and are likely to influence quality, safety, and/or efficacy.

Regulatory Requirements (ICH Q1B)

• [Registration] The intrinsic photostability characteristics of new drug substances and products should be evaluated to demonstrate that, as appropriate, light exposure does not result in unacceptable change.
• [Registration] Photostability testing is normally carried out on a single batch of material selected as described under Selection of Batches in the Parent Guideline.
• [Registration] Alternative approaches may be used if they are scientifically sound and justification is provided.
• [Registration] A systematic approach to photostability testing is recommended covering, as appropriate, studies such as: i) Tests on the drug substance; ii) Tests on the exposed drug product outside of the immediate pack; iii) Tests on the drug product in the immediate pack; iv) Tests on the drug product in the marketing pack.
• [Registration] The extent of drug product testing should be established by assessing whether or not acceptable change has occurred at the end of the light exposure testing as described in the Decision Flow Chart for Photostability Testing of Drug Products.
• [Registration] The formal labeling requirements for photolabile drug substances and drug products are established by national/regional requirements.
• [Registration] The applicant should either maintain an appropriate control of temperature to minimize the effect of localized temperature changes or include a dark control in the same environment unless otherwise justified.
• [Registration] For both options 1 and 2, a pharmaceutical manufacturer/applicant may rely on the spectral distribution specification of the light source manufacturer.
• [Registration] Any light source that is designed to produce an output similar to the D65/ID65 emission standard such as an artificial daylight fluorescent lamp combining visible and ultraviolet (UV) outputs, xenon, or metal halide lamp may be used.
• [Registration] For a light source emitting significant radiation below 320 nm, an appropriate filter(s) may be fitted to eliminate such radiation.
• [Registration] For option 2 the same sample should be exposed to both the cool white fluorescent and near ultraviolet lamp.
• [Registration] A cool white fluorescent lamp designed to produce an output similar to that specified in ISO 10977(1993) should be used.
• [Registration] A near UV fluorescent lamp having a spectral distribution from 320 nm to 400 nm with a maximum energy emission between 350 nm and 370 nm; a significant proportion of UV should be in both bands of 320 to 360 nm and 360 to 400 nm should be used.
• [Registration] For confirmatory studies, samples should be exposed to light providing an overall illumination of not less than 1.2 million lux hours.
• [Registration] For confirmatory studies, samples should be exposed to light providing an integrated near ultraviolet energy of not less than 200 watt hours/square meter.

Regulatory Requirements (ICH Q3AR2)

• [Stability] Any degradation product observed in stability studies at recommended storage conditions at a level > identification threshold should be identified.
• [Development, Commercial] Analytical results should be provided for all batches used for clinical, safety, stability testing, and representative commercial batches.
• [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] The cell line history and production of the cell banks should be described in detail, including methods and reagents used during culture, in vitro cell age, and storage conditions.

Regulatory Requirements (ICH Q5C)

• [Pivotal Stability Studies] Assays for biological activity, where applicable, should be part of the pivotal stability studies.
• [Stability Program] Appropriate physicochemical, biochemical and immunochemical methods for the analysis of the molecular entity and the quantitative detection of degradation products should also be part of the stability program whenever purity and molecular characteristics of the product permit use of these methodologies.
• [Marketing Application] Primary data to support a requested storage period for either drug substance or drug product should be based on long-term, real-time, real-condition stability studies.
• [Marketing Application] Stability data should be provided on at least 3 batches for which manufacture and storage are representative of the manufacturing scale of production.
• [Marketing Application (Initial Submission)] Data from pilot-plant scale batches of drug substance produced at a reduced scale of fermentation and purification may be provided at the time the dossier is submitted to the regulatory agencies with a commitment to place the first 3 manufacturing scale batches into the long-term stability program after approval.
• [Stability Program] The quality of the batches of drug substance placed into the stability program should be representative of the quality of the material used in preclinical and clinical studies and of the quality of the material to be made at manufacturing scale.
• [Pilot-Plant Scale Production] The drug substance (bulk material) made at pilot-plant scale should be produced by a process and stored under conditions representative of that used for the manufacturing scale.
• [Stability Program] The drug substance entered into the stability program should be stored in containers which properly represent the actual holding containers used during manufacture.
• [Manufacturing Process Development] The manufacturer should identify intermediates and generate in-house data and process limits that assure their stability within the bounds of the developed process.
• [Manufacturing Process Development] While the use of pilot-plant scale data is permissible, the manufacturer should establish the suitability of such data using the manufacturing scale process.
• [Marketing Application] Stability information should be provided on at least 3 batches of final container product representative of that which will be used at manufacturing scale.
• [Stability Testing] Where possible, batches of final container product included in stability testing should be derived from different batches of bulk material.
• [Marketing Application] Product expiration dating will be based upon the actual data submitted in support of the application.
• [Regulatory Review] Continuing updates of initial stability data should occur during the review and evaluation process.
• [Stability Studies] The quality of the final container product placed on stability studies should be representative of the quality of the material used in the preclinical and clinical studies.

Regulatory Requirements (ICH Q6A)

• [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] The concept of different acceptance criteria for release vs. shelf-life specifications applies to drug products only, allowing for more restrictive criteria at release.
• [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.
• [Marketing Approval] Justification for each procedure and acceptance criterion should refer to relevant development data, pharmacopoeial standards, toxicology/clinical study data, and stability study results, considering expected analytical and manufacturing variability.
• [Marketing Approval] Test results from stability and scale-up/validation batches, especially primary stability batches, should be considered in setting and justifying specifications.
• [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.
• [Marketing Approval] Particle size testing for particle size distribution should be carried out using an appropriate procedure with acceptance criteria for new drug substances intended for use in solid or suspension drug products where particle size significantly affects dissolution rates, bioavailability, and/or stability.
• [Marketing Approval] If different crystalline forms (polymorphism, solvation/hydration products, amorphous forms) of a new drug substance exist and affect drug product performance, bioavailability, or stability, the appropriate solid state should be specified.
• [Marketing Approval] Antimicrobial preservative content: For oral liquids needing an antimicrobial preservative, acceptance criteria for preservative content should be established based on levels necessary to maintain microbiological quality throughout usage and shelf-life.
• [Marketing Approval] Extractables: Elimination of this test can normally be accepted if development and stability data show extractables from container/closure systems are consistently below acceptable and safe levels.
• [Marketing Approval] Antimicrobial preservative content: For parenteral products needing an antimicrobial preservative, acceptance criteria for preservative content should be established based on levels necessary to maintain microbiological quality throughout usage and shelf-life.

Regulatory Requirements (ICH Q6B)

• [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] Documentation of the characterization, storage conditions and formulation supportive of reference material(s) stability should also be provided.
• [All] The concept of release limits vs. shelf-life limits may be applied where justified.
• [Submission] The manufacturer should propose a stability-indicating profile.
• [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.

Regulatory Requirements (ICH S9)

• [Nonclinical] Stability of the conjugate in the test species and human plasma should be provided.

Note: P1: ≥2 months. P2: ≥6 months. P3: ≥12 months. NDA: full ICH Q1A

Source: ICH Q1A(R2); ICH Q1E