3.2.S.4.4 — Batch Analyses

Results of batch analyses for drug substance batches used in development and clinical trials

Requirements by Phase

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

Content (NCE/Small Molecule)

• Description of batches used in nonclinical, clinical, and scale-up studies
• Results of batch analyses for all batches
• Impurity levels per batch

Content (Biotech)

• Description and batch analysis results for all representative batches
• Comparison of batch results across development

Expected Deliverables

• Batch analysis table
• Batch certificates of analysis

ICH Guidelines: Q3A, Q3C, Q6A, Q6B

Regulatory Requirements (FDA IND PHASE 1)

• [Phase 1] Submission of a copy of the certificate of analysis of the clinical batch is suggested.

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)

• [Development] Stability testing should be carried out on a single batch of the drug substance.
• [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] The long term testing for drug substance should cover a minimum of 12 months' duration on at least three primary batches at the time of submission.
• [Pre-approval] In the absence of an accelerated storage condition for drug substances intended to be stored in a freezer, testing on a single batch at an elevated temperature (e.g., 5°C ± 3°C or 25°C ± 2°C) for an appropriate time period should be conducted to address the effect of short term excursions outside the proposed label storage condition.
• [Post-approval] When available long term stability data on primary batches do not cover the proposed re-test period granted at the time of approval, a commitment should be made to continue the stability studies post approval.
• [Post-approval] If the submission includes long term stability data on three production batches covering the proposed re-test period, a post approval commitment is considered unnecessary.
• [Post-approval] If the submission includes data from stability studies on at least three production batches, a commitment should be made to continue these studies through the proposed re-test period.
• [Post-approval] If the submission includes data from stability studies on fewer than three production batches, a commitment should be made to continue these studies through the proposed re-test period and to place additional production batches, to a total of at least three, on long term stability studies through the proposed re-test period.
• [Post-approval] If the submission does not include stability data on production batches, a commitment should be made to place the first three production batches on long term stability studies through the proposed re-test period.
• [Post-approval] The stability protocol used for long term studies for the stability commitment should be the same as that for the primary batches.
• [Pre-approval] The purpose of the stability study is to establish, based on testing a minimum of three batches of the drug substance and evaluating the stability information, a re-test period applicable to all future batches.
• [Pre-approval] If batch-to-batch variability for drug substance is small, combine data into one overall estimate.
• [Pre-approval] If it is inappropriate to combine data from several drug substance batches, the overall re-test period should be based on the minimum time a batch can be expected to remain within acceptance criteria.

Regulatory Requirements (ICH Q1B)

• [Registration] Photostability testing is normally carried out on a single batch of material selected as described under Selection of Batches in the Parent Guideline.
• [Development] Normally, only one batch of drug substance is tested during the development phase.
• [Registration] The photostability characteristics should be confirmed on a single batch selected as described in the Parent Guideline if the drug is clearly photostable or photolabile.
• [Development] Normally, only one batch of drug product is tested during the development phase.
• [Registration] The photostability characteristics should be confirmed on a single batch selected as described in the Parent Guideline if the product is clearly photostable or photolabile.

Regulatory Requirements (ICH Q3AR2)

• [Development, Commercial] The applicant should summarise laboratory studies conducted to detect impurities, including test results from development and proposed commercial batches, and stress testing results.
• [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] Analytical results should be provided for all batches used for clinical, safety, stability testing, and representative commercial batches.
• [Registration] The applicant should ensure complete impurity profiles (e.g., chromatograms) of individual batches are available, if requested.
• [Registration] A tabulation linking each new drug substance batch to each safety and clinical study should be provided.
• [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] Selection of impurities in the specification should be based on impurities found in batches manufactured by the proposed commercial process.
• [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 Q5C)

• [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.
• [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 (Initial Submission)] Data from pilot-plant scale batches of drug product 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.
• [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.
• [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.

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