Standards for Biological Raw Materials: Operational Guideline (Japan)

Document overview

Japan’s MHLW issued “Standards for Biological Raw Materials, Operational Guideline” (Provisional English translation as of May 2024) under PFSB/ELD Notification No. 1002-1 and PFSB/MDRMPE Notification No. 1002-5, dated October 2, 2014. It specifies how to operate the revised Standards for Biological Raw Materials after the 2014 partial amendments (MHLW Notification No. 375, 2014), reflecting updates related to the regulatory framework for regenerative medical products. Reference: PMDA PDF.

Effective date and regulatory housekeeping

The notification states it applies from November 25, 2014 and withdraws several earlier notices/administrative communications related to partial change approvals, virus confirmation for changes, administrative procedures after the 2003 enforcement-regulation revision, handling of raw materials specified in the standards, and certain Brazil-origin bovine materials self-inspection notices/Q&As (as listed in the guideline). Reference: PMDA PDF.

What this “Operational Guideline” is for

Think of this document as an implementation manual for the Standards for Biological Raw Materials:

• It clarifies definitions and interpretations used in audits, applications, and inspections.
• It explains what evidence is expected, and when exceptions are possible (with scientific and regulatory justification).
• It connects practical operational controls (collection sites, consent, testing timing, records) to the high-level standard clauses. Reference: PMDA PDF.

Key operational clarifications by section

I. General Notices: what “source materials” means (and what it does not)

The guideline defines “source materials” as tissues/body fluids collected from humans or animals (including tissue extracts or pooled materials) that become raw/ancillary materials used as starting materials in manufacturing “drugs, etc.” (drugs, medical devices, regenerative medical products). It also gives examples of materials that do not fall under “source materials” in the standards (e.g., certain materials used only to construct cell banks or create selection media, under specific conditions), helping sponsors avoid misclassification. It further explains how to interpret General Notice 10 (e.g., if a product allowed as a nonconforming raw material is used as a raw material for another product, a new risk–benefit evaluation for that use is needed).

II. Blood products: when “blood rules” apply versus “human-derived raw material” rules

When human blood components are used as excipients/media in manufacturing processes of drugs, etc. (excluding blood products), the guideline states that the Standards for Human-Derived Raw Materials should be applied (rather than treating it as a blood product case).

III. Human-derived raw materials: practical expectations for cell/tissue materials and donor controls

Human cell/tissue-based raw materials, etc. are defined as human-derived cells/tissues constituting the product, including cells/tissues before processing (e.g., iPS(-like) derived cells) if the materials undergo processing such as differentiation or genetic manipulation. For autologous materials, the guideline clarifies the meaning of “if necessary”: autologous materials may not require the same approach in principle, but if there is concern about viral proliferation during culture, confirming viral infection at an appropriate time (e.g., collection) is necessary for safety. Where pathogens cannot be inactivated/removed by the manufacturing process, the guideline indicates the sponsor should confirm sterility testing, viral infection risk verification, and other required tests, in addition to donor eligibility determination. It also provides practical interpretations on retesting (e.g., umbilical cord blood retesting not always necessary when supply conforms to specific national standards), defines “important diseases” (with an explicit list), and elaborates operational points for consent (including proxy consent conditions), ethics review documentation, and anonymization that is preferably linkable for traceability.

Human-derived raw materials (non-cell/tissue): what must be tested and when

Human-derived raw materials include cell-derived extracts (proteins, hormones, nucleic acids, etc.) and may include human blood as an origin of certain components; the guideline also notes examples not covered when purification is considered sufficiently severe (e.g., amino acids made from human hair). For virus testing, the guideline states that at least nucleic acid amplification tests for HBV, HCV, and HIV must be performed, and when a human blood-derived raw material is used, serological + NAT testing at least for those viruses is required with reference to the blood-product rules. It clarifies that the “appropriate stage” for testing can include unprocessed/unpurified bulk or cell-bank stages, with flexibility when later-stage testing improves detection accuracy. It further emphasizes that pathogen inactivation/removal processes are, as a rule, feasible for many non-cell/tissue human-derived materials and should be implemented in principle (while allowing scientifically justified exceptions where applicable).

IV. Animal-derived raw materials: viral safety, heating exceptions, and ruminant/prion risk thinking

For animal cell/tissue-based materials, the guideline references other public-health guidance (e.g., xenotransplantation infectious disease guidance) and points to Attachment 1 examples for verifying viral infection risk. It notes that if virus-inactivating heating is performed under illustrated or more stringent conditions (depending on material properties and timing), a separate risk assessment may not be required. For broader animal-derived materials, it clarifies what may be “known publicly in the scientific field” (including highly purified/semisynthetic materials and those listed in Attachment 2), while cautioning that prion transmission risk may not be eliminated by chemical processing alone—so ruminant-derived standards still apply where relevant. It also discusses how to interpret “healthy” animals and provides operational notes for wild-animal materials (referencing Codex hygienic practice for game as an example expectation).

Practical implementation checklist for QA/RA teams

• Classify correctly: decide whether a material is “source material,” “raw material/ancillary material,” or outside scope, using the guideline’s examples.
• Define testing points: document the “appropriate stage” for virus testing (cell bank, collection, bulk), and justify any deviation.
• Strengthen traceability: design records so donor/animal eligibility, consent, ethics review, anonymization approach, and test results remain auditable and (where appropriate) linkable.
• Plan for residual risk: when inactivation/removal is not feasible (notably for certain cell/tissue materials), ensure sterility testing + viral risk verification are built into the control strategy.

Reference: PMDA PDF.