Example of Documents on Assessment and Control of DNA Reactive (Mutagenic) Impurities attached to Clinical Trial Notification — PMDA Early Consideration Summary

In Plain Language

This document offers examples of how information about DNA-reactive (mutagenic) impurities can be organised for attachment to a clinical trial notification. It groups the examples by development stage and, in Phase 1, by whether dosing is up to 14 days or longer than 14 days. The examples show how a sponsor might describe likely impurities, hazard assessment, proposed controls and supporting test or manufacturing information. They also include checklists to help identify whether important information has been addressed, and examples of circumstances in which attachments may be omitted. The purpose is to make notification assessments more efficient and clinical trials run smoothly by improving the completeness and clarity of submitted information; the document says it does not introduce new regulations or explain how to evaluate and control impurities.

What This Guidance Covers

The document is an example set for materials concerning the assessment and control approach for DNA-reactive (mutagenic) impurities attached to clinical trial notifications. It concerns impurities that may arise during the manufacture or storage of the drug substance or drug product. The document divides its examples into these situations:

• Phase 1 clinical trials for dosing up to 14 days: examples for cases where none of the Class 1 or Class 2 impurities, or impurities in the cohort of concern, are present; and cases where at least one is present.
• Phase 1 clinical trials greater than 14 days and Phase 2a clinical trials: examples for cases with none of the Class 1, Class 2 or Class 3 impurities, or impurities in the cohort of concern, and cases where at least one is present.
• Phase 2b and Phase 3 clinical trials: examples for cases with none of the Class 1, Class 2 or Class 3 impurities, or impurities in the cohort of concern, and cases where at least one is present.
• Cases where attachments can be omitted: examples involving certain subsequent notifications and use of an approved product as an investigational product.

For each situation, the document supplies sample descriptions, tables or checklists rather than a single form that all submissions must follow. It says that documents prepared in different styles or formats may be submitted if the information is sufficient. It does not set out a new method for evaluating or controlling mutagenic impurities, and it does not guarantee that a control approach in an example will be accepted for a particular product or in a marketing authorization application.

Why It Matters

The document explains that assessment and control of DNA-reactive (mutagenic) impurities are required on the basis of the ICH M7 guideline and a revision to questions and answers about clinical trial notifications and implementation of clinical trials for drugs. The contents of the assessment and control approach are required to be submitted as attachments to clinical trial notifications. In PMDA’s investigation of notifications, impurity evaluation and control were assessed, but some investigations took longer because data or descriptions were insufficient.

PMDA compiled typical examples based on operational experience with the ICH M7 guideline to help make investigations more efficient and clinical trials proceed smoothly. The practical gap the document addresses is therefore how to present the relevant assessment and control information clearly in a notification, rather than how to establish a new scientific framework for impurity assessment.

Key Recommendations

The document describes these as typical examples and states that adequate information can be presented in a different style or format. The points below summarise what its sample materials show and ask submitters to check.

1. Choose the example structure that matches the trial. Identify the development stage and, for Phase 1, whether dosing is up to 14 days or greater than 14 days. The examples focus on different sets of impurity classes at those stages: Class 1, Class 2 and impurities in the cohort of concern for dosing up to 14 days; Class 1, Class 2, Class 3 and impurities in the cohort of concern for longer Phase 1 dosing and Phase 2a; and actual or potential Class 1, Class 2 and Class 3 impurities, as well as impurities in the cohort of concern, for Phase 2b and Phase 3.
2. Describe the impurity assessment for the drug substance and drug product. The examples consider impurities that may arise from raw materials, reagents, intermediates and the manufacturing process, as well as degradation products that may form during storage. They show searches of databases and literature for toxicity information and assessment using the information obtained. Where stability studies are discussed, the examples refer to studies on material made by the same manufacturing process as the investigational drug substance or product.
3. When relevant impurities are identified, present them and their proposed controls clearly. The sample tables include impurity name and structure, origin, ICH M7 class and control approach. The examples also show that a control may be described for the drug substance or for a starting material, and that the rationale may refer to an acceptable limit, process purge information or a risk assessment. The sample values and approaches are examples; the document does not present them as universal limits for other products.
4. For Phase 2b and Phase 3 examples, provide more detailed supporting information. The examples include process-flow diagrams for the drug substance and drug product, a list of impurities assessed by two (Q)SAR methodologies, information about the in silico systems used, and a justification where a result is inconclusive or the two methods differ. They also show how bacterial mutagenicity test results and, where used, in vivo test results can appear in the assessment.
5. Explain the proposed control and its evidence. In the later-stage examples, the submission may describe acceptable limits and acceptance criteria, analytical results for relevant batches, and the basis for a control strategy. The document’s checklists prompt the submitter to consider whether the acceptable daily intakes are appropriate to the clinical-trial duration and whether control plans are described.
6. Address nitrosamine risk assessment. The checklists for the development-stage examples ask whether risk assessment and control of nitrosamines have been conducted based on the relevant notifications. The later-stage examples illustrate describing assessment of the drug-substance synthesis and, for the drug product, the drug substance, excipients, manufacturing process and packaging materials.
7. Use the attachment-omission examples only in the described circumstances. The document gives examples for certain second or subsequent notifications where the manufacturing method has not changed and dose, administration and duration do not exceed those in the conducted trial, with an exception for transition from early to late development. It also gives an example for an approved product used as an investigational product, subject to the qualifications described below.

Practical Implications

Interpretation: Sponsors can use the document as a planning aid for assembling notification materials. Its stage-based structure can help teams decide which example is most relevant before drafting, while the checklists can be used to review whether the proposed submission explains the assessment, identified impurities and control approach. They do not replace product-specific assessment or determine whether a particular approach is acceptable.

For quality and process teams, the examples indicate the kinds of manufacturing information that may help explain impurity origin and control: process descriptions, starting materials, process steps, stability findings and, in some examples, evidence about removal during manufacture. For toxicology and analytical teams, the examples illustrate connecting hazard-assessment results with a proposed control plan and reporting measurements or detection limits where relevant. For regulatory teams and clinical operations, the omission examples make it important to document the applicable conditions rather than simply state that an attachment is not being provided.

The document expressly notes that the appropriateness of control depends on the status of the individual product and that additional data may be requested during notification assessment. It says PMDA consultation should be considered if there is uncertainty about the control approach or the contents of the risk assessment. It also cautions that the examples reflect standard descriptions at the clinical-trial-notification stage and do not guarantee the acceptability of a control approach in a marketing authorization application.

Technical Details

The document uses the impurity classes and control-option labels of the ICH M7 guideline but does not define those classes or options in this example collection. In the tables, an option is paired with a sample explanation of how an impurity is controlled. For instance, one example describes Option 1 as control at or below an acceptable limit in the drug substance; other entries place control in a starting material or describe evidence from a purge study or estimated purge factor. These are examples of presentation, not a complete account of the options.

Early Phase 1 examples. For trials with dosing up to 14 days, the examples focus on Class 1, Class 2 and impurities in the cohort of concern. For longer Phase 1 trials and Phase 2a, they also include Class 3 impurities. Where none of the listed categories is identified, the example describes searches for toxicity information and assessment of manufacturing- and storage-related impurities, then reports that none in the relevant categories were identified. Where relevant impurities are present, the example provides a table with their identity, origin, class and control approach, followed by a conclusion and checklist. For the longer Phase 1 and Phase 2a examples, the document states that no comprehensive (Q)SAR is expected at this early development stage.

Phase 2b and Phase 3 examples. These examples present a fuller account, including process-flow diagrams and a list of actual or potential impurities assessed using two (Q)SAR systems. Here, (Q)SAR refers to computer-based methods used in the examples to predict the outcome of bacterial mutagenicity tests. The sample table records each system’s result, bacterial mutagenicity test results where applicable, the resulting ICH M7 class and the control approach. The checklist asks for the systems and their relevant information and a justification for results such as “inconclusive” or disagreement between the two systems.

The later-stage example that includes identified impurities illustrates calculations of an acceptable limit using the acceptable intake (AI) and maximum daily dose (MDD). Its stated relationship is:

In the example for Impurity A, the planned MDD is 1000 mg/day, or 1.0 g/day, and the AI is 117 μg/day. The example therefore reports an acceptable limit of 117 ppm and describes measurement results below that limit. For Impurities C and D, the example uses an AI of 10 μg/day for Less-Than-Lifetime (LTL) exposures, based on the Threshold of Toxicological Concern (TTC), for a stated treatment duration of >1-10 years. With the same MDD of 1.0 g/day, it reports an acceptable limit of 10 ppm for individual impurities. These figures belong to the specific sample scenario and should not be read as limits for a different trial or impurity.

The document also illustrates a process-based risk assessment for Impurity F. It shows estimated purge factors across manufacturing steps and compares the estimated purge factor with the factor required to reduce the impurity to the acceptable limit. The example reports a purge factor ratio of \(2.3 \times 10^3\) and concludes that the impurity will not remain in the drug substance in that scenario. The tables and accompanying footnotes explain the example’s assigned removal factors by reference to reactivity, solubility, volatility and other process effects.

Omitting attachments. For a second or subsequent notification, the example describes omission when the manufacturing method has not changed since the previous notification and the dosage, administration and duration have not exceeded those in the conducted trial. It excludes transition from the early development examples to the late development example. Its checklist also asks whether no new impurities have been detected in stability studies, among other points. For an approved product used as an investigational product, the example depends on identity with a product approved in Japan and on conditions relating to dosage and administration, manufacturing process and duration; if the investigational product’s duration of administration exceeds the approved product’s standard duration, the acceptable intake must not be reduced based on the Less-Than-Lifetime (LTL) concept. The document cautions that the data cannot be omitted in the stated situation where the approved drug is not subject to the ICH M7 guideline and the assessment has not previously been conducted. It further notes that a different salt or solvate is considered a different manufacturing process for this purpose, and documents are necessary in principle.

Who Should Read It

This document is relevant to sponsors preparing clinical trial notifications for drug products where assessment and control of DNA-reactive (mutagenic) impurities are being documented. It may also be useful to regulatory affairs staff, toxicologists, pharmaceutical scientists, analytical and process chemists, quality teams and clinical operations staff who contribute to or review those materials. The examples are especially pertinent when planning the contents of a notification attachment, checking whether its evidence and rationale are described, or considering whether one of the document’s specific omission examples applies.

Official PMDA Source

• Official title: Example of Documents on Assessment and Control of DNA Reactive (Mutagenic) Impurities attached to Clinical Trial Notification (Early Consideration)
• Issuing body: Pharmaceuticals and Medical Devices Agency, Center for Product Evaluation
• Date on the cover: January 16, 2025
• PMDA PDF: Official PMDA document (PDF)
• PMDA list page: PMDA Early Consideration documents

Source: Pharmaceuticals and Medical Devices Agency (PMDA) website, PMDA Early Consideration documents. This page was created by editing and summarising the PMDA document.

Please consult the official document; this summary does not replace it. PMDA provides the English version for reference, and the Japanese original prevails if the two differ. PMDA describes Early Consideration documents as reference information reflecting the Agency’s views at the time of publication; they may change as scientific knowledge develops.

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