Checklist for Quality-Related Documents for Biotechnology Products Derived from Cell Lines of Human or Animal Origin at the Time of Initial Clinical Trial Notification — PMDA Early Consideration Summary

In Plain Language

Before a clinical trial begins, PMDA’s quality reviewer considers information about the investigational product that relates to participant safety. This checklist focuses on quality-related documents submitted with an initial clinical trial notification (CTN), particularly notifications subject to the 30-day CTN review for biotechnology products made using human or animal cell lines. It highlights information to describe about biological materials used in making the product, evidence addressing viral safety, and provisional specifications for selected impurities and safety tests. Its examples show ways results and information may be presented, while sponsors are expected to refer to the document when preparing CTN attachments. The purpose is to help make relevant quality information available for review, including points that the document says have frequently prompted inquiries.

What This Guidance Covers

The document is an Early Consideration checklist for quality-related documents submitted at the time of an initial CTN. Its stated focus is biotechnology products derived from cell lines of human or animal origin, especially CTNs subject to the 30-day CTN review. The document explains that quality reviewers use test data and other relevant information to consider issues related to ensuring the safety of clinical trial participants.

The checklist addresses descriptions of human- or animal-derived raw materials, including materials used in establishing or preparing cell banks and materials used in manufacturing the drug substance and drug product. It also addresses viral safety, including viral clearance studies, and provisional specifications for selected impurity-control and safety-related tests. The annex provides illustrative tables of results for a master cell bank, unprocessed or unpurified bulk, and viral clearance studies.

The introduction says that the checklist is based on Q&A No. 27 of a named administrative notice and a checklist for inquiries during 30-day CTN review in the biopharmaceutical quality area, and that it adds key points and examples reflecting inquiries frequently raised in recent years. It also says the document provides specific examples of descriptions to include in informed consent documents and related materials. The material set out here does not provide those example wordings, so no particular consent-document language is summarised on this page.

Why It Matters

A quality review at the initial notification stage depends on the information submitted about the product and its manufacturing process. The document identifies omissions in descriptions of human- or animal-derived raw materials used during cell-bank preparation as a point needing particular attention. It also calls for information that lets the reviewer assess viral safety and understand the proposed limits for selected impurities and safety-related tests.

The document’s stated context is that certain inquiries have been raised frequently in recent years during review of initial CTNs. It aims to make those areas more visible to sponsors preparing their documents. In particular, it connects test results and proposed specifications with references named in the document, and includes example tables to illustrate how some results may be reported. These examples provide context for the checklist; they do not, by themselves, describe the specifications or complete testing strategy for every product.

Key Recommendations

1. Use the checklist when preparing initial CTN attachments. The document says sponsors are expected to refer to it when preparing documents attached to CTNs. Its focus is quality-related information for relevant biotechnology products, especially those subject to the 30-day CTN review.
2. Describe human- or animal-derived materials and where they are used. Materials used in cell-bank establishment or preparation, and in manufacturing the drug substance and drug product, should be described. If such materials are used, identify the process step where each is used and explain its compliance with the Standards for Biological Raw Materials. If they are not used, state that explicitly. The document calls particular attention to possible omissions of raw materials used when establishing or preparing cell banks.
3. Present evidence addressing viral safety. The document calls for results of viral clearance studies for manufacturing steps associated with viral inactivation and/or removal, with reference to the ICH Q5A(R2) Guideline. Describe the viral inactivation and/or removal capacity of the manufacturing process. Select multiple virus species to reflect differences in viral characteristics, including envelope status, size and genome type.
4. Establish provisional specifications for relevant impurity and safety tests. The document identifies tests included in drug-substance and drug-product specifications, giving product-related impurities, process-related impurities, sterility, foreign insoluble matter, insoluble particulate matter and endotoxins as examples. It then provides specific considerations for host-cell-derived DNA, host-cell-derived proteins, endotoxin and insoluble particulate matter.
5. Use the cited references and stated guides when setting the listed limits. For host-cell-derived DNA, the specification limit should be established with reference to the named World Health Organization recommendations, using 10 ng/dose or less as a guide. If the host-cell-derived protein specification limit exceeds 100 ng/mg, present the actual measured value and justify the appropriateness of the limit. Establish the endotoxin specification limit with reference to the Japanese Pharmacopoeia’s “Decision of Limit for Bacterial Endotoxins.” For insoluble particulate matter, refer to the specified Japanese Pharmacopoeia general tests and use the particle-count values described below as a guide.

Practical Implications

Interpretation: Teams preparing an initial CTN can use the checklist as a prompt to connect each quality statement with evidence or an explanation. For raw materials, that means recording not only whether a material is used, but also the process step in which it appears and the explanation of compliance requested by the document. Explicitly stating that such materials are not used also avoids leaving that point unclear.

For viral safety, the submission should allow a reviewer to follow the evidence from individual study results to the described inactivation and/or removal capacity of the process. The document’s instruction to select several viruses with different characteristics means the rationale for selection should reflect the listed differences: envelope status, size and genome type. The example table can help readers recognise the type of information shown, but it is presented as an example, not as a universal set of study outcomes.

For specifications, teams may need to coordinate proposed limits with analytical results and the cited references. The document specifically asks for actual measured host-cell-derived protein values and a justification when the proposed limit is above 100 ng/mg. It also distinguishes between a value used “as a guide” and a general requirement: its wording for the DNA and particulate-matter values is guide language, which should not be strengthened into a universal mandate.

The document also mentions an e-learning video on PMDA’s approach to quality review of biopharmaceuticals. This page does not add expectations beyond the checklist or infer that a particular example result is suitable for a different product.

Technical Details

The numerical values and table entries below are reported in the document. Terms such as “master cell bank” and “unprocessed/unpurified bulk” identify the materials for which the annex presents example test results; the tables are examples, not stated universal panels or acceptance criteria.

• Host-cell-derived DNA: Establish the specification limit with reference to the WHO recommendations named in the document, using 10 ng/dose or less as a guide.
• Host-cell-derived proteins: If the specification limit exceeds 100 ng/mg, present the actual measured value and justify why the limit is appropriate.
• Endotoxins: Establish the specification limit with reference to the Japanese Pharmacopoeia general information titled “Decision of Limit for Bacterial Endotoxins.”
• Insoluble particulate matter: Refer to the Japanese Pharmacopoeia’s “Insoluble Particulate Matter Test for Injections <6.07>” or “Insoluble Particulate Matter Test for Therapeutic Protein Injections <6.17>.” As a guide, the document gives not more than 6,000 particles per container for particles ≥10 μm and not more than 600 particles per container for particles ≥25 μm.

The annex illustrates the types of test results that may be reported. For the master cell bank, its example includes sterility, microbial-limit, mycoplasma and adventitious-virus tests, among others. The table gives results such as “No growth observed” for the sterility test and “Not detected” for several listed assays; it also reports microbial counts as less than 10 CFU/mL. For unprocessed or unpurified bulk, the example includes microbial-limit and mycoplasma tests, an in vitro adventitious-virus assay, a minute virus of mice test by polymerase chain reaction (PCR), and transmission electron microscopy (TEM). The reported outcomes in that example include “Not detected.”

For viral clearance, the annex gives an example table for xenotropic murine leukemia virus (X-MuLV) and minute virus of mice (MVM). It reports log₁₀ reduction factors by manufacturing step: Protein A affinity chromatography, low pH viral inactivation, anion exchange chromatography and virus filtration. Some example entries are “Not performed,” and several values are given as lower bounds, such as ≥5.88. The example’s overall viral clearance factors are ≥18.03 for X-MuLV and ≥13.36 for MVM. These are example results in the annex, not universal targets stated for every product.

Who Should Read It

This document is relevant to sponsors and sponsor-investigators preparing initial CTN attachments for biotechnology products derived from human or animal cell lines, particularly where the notification is subject to 30-day CTN review. It may also be useful to quality and manufacturing specialists compiling cell-bank and process information, analytical teams preparing test results and proposed specifications, and regulatory affairs staff coordinating the submission.

Clinical operations and investigators involved in preparing trial documentation may be interested because the introduction mentions specific examples for informed consent documents and related materials. The checklist is also relevant to overseas startups, venture companies and other developers considering these products, a group the document identifies in describing the context for its publication.

Official PMDA Source

• Official title: Checklist for Quality-Related Documents for Biotechnology Products Derived from Cell Lines of Human or Animal Origin at the Time of Initial Clinical Trial Notification (Early Consideration)
• Issuing body and offices: Pharmaceuticals and Medical Devices Agency; Office of Cellular and Tissue-based Products; Office of Vaccines and Blood Products
• Date on the cover: July 3, 2026
• 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.

Consult the official document for its full content; this summary does not replace it. PMDA provides the English version as reference information, and if it differs from the Japanese original, the Japanese original prevails.

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