Checklist for Common Inquiry Cases to Be Noted When Submitting Approval Applications for New Active Ingredient Containing Pharmaceuticals (Chemical Products) — PMDA Early Consideration Summary

In Plain Language

This checklist brings together questions that PMDA says have often arisen in quality assessments of new drug applications handled by the Office of New Drug I–V. It helps applicants review the application form and the supporting quality information before submission, from manufacturing descriptions to stability and test methods. For each item, it gives a point to check and a reason or explanation, so applicants can see what information may need clarification. The document says that it is not necessary to fulfil every item: applicants can use the checklist as appropriate to the characteristics and circumstances of their product. Its purpose is to support more efficient submission and assessment by making common points easier to identify and explain.

What This Guidance Covers

The document is a checklist for approval applications for new active ingredient containing pharmaceuticals (chemical products). It is based on frequently raised inquiries during quality assessment of new drug applications conducted by PMDA’s Office of New Drug I–V. It is intended as a reference for applicants to check the contents of their application forms and related quality information, including the Common Technical Document (CTD).

The checklist is organised around application-form matters, CTD Module 2 quality sections, and other considerations. It addresses drug substances and drug products, manufacturing and process controls, specifications and test methods, reference standards, stability, excipients, container-closure systems, adventitious-agent safety evaluation, and matters such as Master File use and Good Manufacturing Practice inspection arrangements. It does not present itself as an exhaustive set of conditions that every application must satisfy: the document explicitly says that applicants need not fulfil all listed items and may refer to them in light of each product’s characteristics and circumstances.

Why It Matters

The stated basis for the checklist is the pattern of inquiries raised during quality assessments. Such points can concern whether the application form describes an aspect of manufacturing or testing clearly, whether the CTD supplies a scientific rationale, or whether information is consistent across documents. The checklist makes those recurring topics visible before an application is submitted and explains why they may draw attention during assessment.

The document also notes a practical timing risk: if an error in a manufacturing site’s licensing or accredited classification is identified during review and an additional classification is needed, the approval timeline may be delayed. More broadly, the checklist links clear descriptions and appropriate supporting information with an aim of facilitating more efficient submissions and assessments. It is reference information based on scientific knowledge and findings as of January 2025, and PMDA says it may change as new knowledge and scientific progress develop.

Key Recommendations

The checklist poses review questions rather than giving a single universal pathway. The points below follow its main sequence and preserve its distinctions between items described as necessary, generally appropriate, or matters to explain or discuss.

1. Review the application form and its links to the CTD. Check manufacturing-site licensing or accredited classifications and codes, and consult the relevant office as early as possible if classification is uncertain. The checklist warns that discovering a classification error during review may delay the approval timeline. It says drug-substance specifications are generally open-part information and should appropriately be included in the application form; if there is a special reason the Master File (MF) holder does not disclose information, consult PMDA early. Check that target values or set values, standard batch size and related brackets are used appropriately, and do not designate process control values as target or set values. The document refers to the applicable description guideline for establishing target and set values.
2. Explain manufacturing controls and change categories. Where impurity control depends on manufacturing process capability, describe the critical elements needed to ensure that capability in the application form under the appropriate change category. For process parameters affecting quality, the rationale for settings, including supporting data, should be documented in CTD Module 2. The checklist identifies situations that may be discussed, including describing proven acceptable range (PAR) limits as minor change notifications, omitting details of endpoint control, or not including the amount of seed crystal added. It says the justification data, or rationale for considering a description unnecessary, should also be explained in CTD Module 2.
3. Make testing, release and application appendices clear. Identify where release testing takes place and where the final release decision is made, including when the decision in Japan relies on overseas test results under a Mutual Recognition Agreement or Memorandum of Understanding (MRA/MOU). Include the required list of target or set values and other parameters in CTD Module 1.13; the document describes this list as including minor-change-notification parameters (excluding charge quantities) and relevant product-quality-affecting process parameters not described in the application form. For an MF-based drug substance, it says the list should be submitted with the CTD Module 2 document. Generally specify the column name used for testing, include container descriptions in storage-condition and shelf-life sections, and fully describe pharmacopoeial methods from overseas unless deemed interchangeable under the ICH Q4B guideline and annexes. Explain specific situations intended by phrases such as “if necessary,” and refer to appendix tables and figures in the application-form main text.
4. Support the drug-substance quality sections. Check that potential mutagenic impurities are comprehensively listed, that the results of two types of QSAR analyses are presented, and that the rationale for the estimated purge factor is clearly stated. In CTD Module 2, provide an abbreviation list when abbreviations are used. Explain the justification for starting-material selection in accordance with ICH Q11 and demonstrate appropriate control elements and acceptance criteria. The checklist says critical quality attributes (CQAs) should include, at a minimum, all items in specifications and test methods; determining CQAs is not based solely on quality-risk-management results. Demonstrate that batches used for design-space (DS) or PAR evaluation reflect commercial production. Explain whether recovered solvents are used, how they are controlled and recovered, how they are reused, and whether distillation purification is performed; take measures according to impurity-profile risk. Explain impurity fate, providing a fate map or purge-study results if necessary. For reprocessing, provide information allowing assessment of its appropriateness, including rationale, history and validation results.
5. Justify drug-substance specifications and analytical controls. Set acceptance criteria using batch and stability data; the checklist says criteria excessively broader than batch data are not appropriate. Explain the basis if early-development batch data are used. Provide basic batch information linking drug-product batch, site, date, scale classification, intended use and the drug-substance batch. Broader specifications for Japan-only drug substance are generally considered inappropriate; if needed, explain the rationale in detail. Analytical procedure validation should comply with ICH Q2. System suitability test (SST) acceptance criteria should be based on validation results, supported by data, and consistent with the Japanese Pharmacopoeia. If liquid-chromatography system-reproducibility injections are fewer than six, stricter acceptance criteria should be established in accordance with the Japanese Pharmacopoeia. Describe operating procedures in the CTD when the application uses a rationalized description, and provide validation results for test methods outside Japanese or internationally harmonised official compendia. Follow Japanese Pharmacopoeia format conventions and establish two or more identification tests based on different principles where one test is not specific; for salts, counterion tests are required.
6. Describe reference materials and stability evidence. In principle, establish acceptance criteria and test methods for reference standards rather than relying on foreign pharmacopoeias; consult PMDA in advance if establishing them is challenging. Avoid self-referential identification wording, and specify comparison with an attached reference spectrum or define specific peaks. For stability, check primary-batch status under ICH Q1A, explain photostability wrapping’s sufficient UV transmission where wrapping is used, discuss differences between specification and stability test methods, and address possible crystal-form changes during storage. The stability-study packaging should match the application; if not, give a scientific rationale for using the data. Where retest period or shelf-life extrapolation is based on ICH Q1E, state this and explain its appropriateness in accordance with that guideline.
7. Address formulation development and manufacture of the drug product. Ensure the application does not imply that formulation changes batch by batch: one formulation should correspond to one prescription. Demonstrate that DS/PAR evaluations apply to commercial production. If the clinical-trial formulation differs from the intended commercial formulation, appropriately confirm bioequivalence (BE); the commercial formulation should be the one whose efficacy and safety were confirmed in clinical trials or one shown bioequivalent to it. For products prepared at use, evaluate compatibility with intended containers, devices and equipment under simulated-use conditions, including adsorption and stability, and explain the evaluation in the relevant CTD section. Describe development history, linking CQAs to the target product quality profile (QTPP), recording risk assessments and design of experiments (DoE), and explaining the control strategy and selection of critical processes, parameters and intermediates. Explain the need for tablet score lines and provide split-tablet quality data, such as content uniformity, dissolution and stability, if a score line is needed. For manufacture, address sterility-assurance parameters in the change category specified by the checklist, explain change-category rationale and omitted parameters, and document solvent reuse, impurity fate and reprocessing where applicable.
8. Cover excipient and drug-product controls. For premixed excipients, establish at least description, identification and assay methods for the main components. Except where identical to those in already approved products, provide lot-analysis, analytical-validation and stability data to support specifications, test methods, storage conditions and shelf life. Set functionality-characterising specifications for functional excipients, and in principle use excipients that meet the applicable Japanese official-compendia standards. For drug products, set acceptance criteria taking actual measured values into account; criteria deviating excessively from them are not appropriate. Broader Japan-only product specifications are generally considered inappropriate unless justified in detail. Follow ICH Q2 for validation, establish and support SST criteria, and provide validation for non-compendial methods. Explain control of elemental and DNA-reactive (mutagenic) impurities in accordance with ICH Q3D and ICH M7, respectively, providing batch analysis results if available. If proposing to omit release tests in Japan, the records should be from an appropriate importing country, such as one subject to an MRA or MOU. Explain the dissolution test and its specification values, including discriminative ability: it should identify products unsuitable in quality or showing significant biological inequivalence.
9. Explain the container, stability and other submission matters. Describe applicable rubber-stopper halogenation or coating, primary-container sterilisation, and relevant residual specifications or radiation-dose upper limits. Specify silicone oil or similar substances used in syringes in the CTD and application form. Address extractables and leachables and risk assessments for manufacturing plastics such as filters; explain special container features such as child-resistant mechanisms. When needed, include package-insert precautions for products that become unstable after opening, taking possible pharmacy repackaging into account. For stability, consider actual-use conditions, especially for multi-dose products; select relevant parameters, including Ostwald ripening for suspensions and active-ingredient precipitation for transdermal patches. Evaluate solutions in horizontal or inverted positions as well as upright storage. Conduct photostability testing under direct exposure in accordance with ICH Q1B and present fully exposed product results. Explain differing batch trends, different test methods or sites, and packaging differences. For biological raw materials, explain compliance with Japan’s Standards for Biological Raw Materials. Include disclosed MF information in the Marketing Authorization Holder’s CTD as a general rule, explain any basis for omitted Good Manufacturing Practice (GMP) inspection and submit the stated documents, and communicate a prefectural inspection schedule to the PMDA reviewer once determined. Finally, check transcription and consistency across the application form, CTD Modules 2 and 3, and current standard operating procedures (SOPs); identify critical processes and intermediates in the specified places and ensure draft package-insert storage conditions do not conflict with the application form.

Practical Implications

Interpretation: Applicants can use the checklist as a structured quality-document review, matching each relevant question to the application form, CTD explanation and supporting evidence. This does not mean that every item applies to every product: PMDA explicitly leaves use to the applicant’s judgement in light of product characteristics and circumstances. A useful practical approach is to record whether a point applies, where it is addressed, and what rationale or evidence supports the description. This is an interpretation of how the checklist could be used, not a separate PMDA instruction.

For quality and regulatory teams, several items point to the value of checking document consistency before submission, particularly where manufacturing-process descriptions, change categories, batch information or release arrangements appear in more than one place. For analytical and stability teams, the checklist highlights the need to connect methods and acceptance criteria to validation, actual results and stability conditions. For manufacturing and supply-chain colleagues, it draws attention to sites, scale, packaging, recovered solvents, excipients and containers. Where the document specifically advises early consultation with PMDA—such as uncertainty about site classification, non-disclosure of MF open-part information, or difficulty establishing reference-standard specifications—the checklist says to consult with the relevant office or PMDA, as applicable.

Technical Details

The document is a quality checklist, not a statistical methods guideline. Its technical content is organised by application and CTD topic, with a question, a reason or supplementary explanation, and a check column. It contains no calculation formula or single decision algorithm. Instead, it repeatedly asks applicants to connect a proposed description or control to its scientific basis and supporting information.

Other technical themes include identifying CQAs in relation to the QTPP and the control strategy; explaining process parameters and critical intermediates; demonstrating method validation; and justifying test specifications with batch, stability and analytical data. The checklist describes an SST as confirming that a measurement system shown to be appropriate during analytical procedure validation remains in an appropriate state during the period of analysis. It therefore says that SST settings differing from validation results cannot be considered appropriate, and that they should comply with the Japanese Pharmacopoeia’s general tests.

Stability considerations are tied to the actual product and its intended use: packaging configuration, possible crystal-form changes, direct light exposure, storage orientation for solutions, and simulated use for products prepared at the time of use. The checklist also expects explanations where evidence is not directly representative of the intended commercial product—for example, stability batches made at a different manufacturing site or data generated using a different packaging configuration. These points illustrate the document’s consistent emphasis on explaining how submitted data support the product and conditions described in the application.

Who Should Read It

This document is relevant to regulatory affairs professionals preparing new active ingredient chemical-product applications, quality assessors and quality-assurance staff checking submission readiness, and pharmaceutical scientists responsible for manufacturing, analytical procedures, specifications, stability or packaging. It may also be useful to statisticians and data specialists who support batch, validation or stability analyses, and to clinical and operational teams where formulation comparability or product preparation at use is relevant. Its most direct use is during quality-document preparation and cross-functional review before an approval application is submitted.

Official PMDA Source

• Official title: Checklist for Common Inquiry Cases to Be Noted When Submitting Approval Applications for New Active Ingredient Containing Pharmaceuticals (Chemical Products) (Early Consideration)
• Issuing body: Pharmaceuticals and Medical Devices Agency (PMDA), Center for Product Evaluation
• Date on the document: January 16, 2025
• Official PMDA PDF: View the PMDA document (PDF)
• PMDA Early Consideration list page: View PMDA’s list page

Source: Pharmaceuticals and Medical Devices Agency (PMDA) website, PMDA Early Consideration list page. 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 purposes, and the Japanese original prevails if there is any inconsistency between it and the English translation.

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