Guideline for Ensuring Quality, Safety, and Efficacy of Biosimilars in Japan

Document status and intent

Japan’s Ministry of Health, Labour and Welfare (MHLW) issued PSEHD/PED Notification No.0204-1 dated February 4, 2020, attaching the Guideline for Ensuring Quality, Safety, and Efficacy of Biosimilars. The notice explains that the guideline summarizes current scientific concepts and does not mandate strict adherence if an alternative approach is scientifically justified. Reference: PMDA PDF.

What the guideline means by “biosimilar” and “comparability”

A biosimilar is defined as a product developed by a different marketing authorization holder that is comparable in quality, safety, and efficacy to a biotechnology-derived product already approved in Japan as a new active ingredient (the original biopharmaceutical). In this guideline, comparability means the biosimilar’s quality attributes are highly similar to the reference, and any differences can be scientifically justified as having no adverse impact on clinical safety or efficacy based on nonclinical studies and clinical trials (with certain acceptable differences described in the glossary). Reference: PMDA PDF.

Scope: products covered (and not covered)

Covered

The guideline covers recombinant proteins (including simple proteins and glycoproteins), recombinant peptides, derivatives, and products where these are components (examples in the text include PEG-conjugated proteins and antibody-drug conjugates). It may also apply to some other highly purified, well-characterized proteins/peptides case-by-case, with consultation encouraged. Reference: PMDA PDF.

Not covered

The guideline explicitly does not cover, for example, antibiotics, synthetic peptides, polysaccharides, vitamins, cell metabolites, nucleic acid products, allergen extracts, conventional vaccines based on attenuated/inactivated pathogens, cells, whole blood, and blood cell components. Reference: PMDA PDF.

Core development principle: stepwise “totality of evidence”

Because biologics are inherently heterogeneous (e.g., post-translational modifications), biosimilars cannot be developed using the same approach as small-molecule generics. Sponsors should demonstrate comparability through a stepwise package of:

1. Quality (analytical) comparability
2. Nonclinical comparisons (as needed, informed by analytical results)
3. Clinical comparisons (as needed, informed by residual uncertainty) The guideline states that the extent and necessity of nonclinical and clinical data depend on how strongly similarity is demonstrated in comparative analytical studies. Reference: PMDA PDF.

Selecting the reference product

In principle, the reference (original) biopharmaceutical for quality, nonclinical, and clinical comparisons must be a product approved in Japan. If an overseas-approved product is used as the reference in some testing, sponsors should justify that the Japan-approved and overseas-approved products can be regarded as identical based on comparative analytical studies. Reference: PMDA PDF.

Quality: manufacturing and analytical comparability expectations

Manufacturing process and control strategy

Sponsors typically cannot access the originator’s manufacturing know-how, so they must build an independent process that ensures consistency and robustness, and evaluate comparability in light of process differences. The guideline encourages incorporation of up-to-date safety measures where they do not adversely affect efficacy. Reference: PMDA PDF.

Key considerations highlighted

• Host cells and glycosylation: Using the same host cell is desirable when disclosed, but different host cells may be justified; glycosylation similarity deserves particular attention, and potential impacts should be evaluated through nonclinical/clinical work when relevant.
• Formulation: Route of administration should be the same as the originator; some dosage-form differences may be acceptable if justified (e.g., liquid vs lyophilized) and without adverse safety/efficacy impact.
• Specifications: Specifications need not match the originator’s exactly; they should be set to control key quality attributes and risks.
• Stability: Long-term stability studies under real-time/real-condition are expected; at least six months of stability data should be submitted at application. Shelf life/storage conditions do not need to be identical, but extremely shorter shelf life may cause confusion in practice. Reference: PMDA PDF.

Comparative quality attributes (what to compare)

The guideline frames comparative analytical assessment as central, including:

• Structure / physicochemical properties
• Biological properties
• Impurities
• Quality attributes related to immunogenicity Reference: PMDA PDF.

Nonclinical studies: tailored to residual uncertainty

Nonclinical studies should be designed rationally after thorough product characterization and in light of analytical similarities/differences, with pharmacology and safety components as appropriate. Reference: PMDA PDF.

Clinical trials: PK/PD first, then efficacy/safety as needed

The guideline describes clinical development elements including:

• Comparative PK/PD studies
• Comparative clinical efficacy (when needed and designed to be sensitive)
• Clinical safety confirmation, including immunogenicity assessment at an appropriate development stage using appropriately validated assays for anti-drug antibodies Reference: PMDA PDF.

Grant of indications and extrapolation

If high similarity is established and comparability is demonstrated (quality and nonclinical), and efficacy/safety are shown comparable in certain indications, those indications can be granted. For originators with multiple indications, the guideline allows extrapolation to indications not directly studied only when similar pharmacological action can be expected and there are no safety concerns. If mechanism of action differs by indication or is unclear, additional indications may not be granted without further clinical data. The guideline also limits extrapolation to the indications of the reference originator product (and does not broadly extend to other products with similar indications). Reference: PMDA PDF.

Post-marketing risk management (RMP and pharmacovigilance)

The guideline emphasizes that pre-approval data are limited and that biosimilars have characteristics different from small-molecule generics (including immunogenicity), so post-marketing risk management and information provision are important. It expects:

• A post-marketing Risk Management Plan (RMP) draft at application, to be discussed during review
• Pharmacovigilance planning that considers product quality attributes, clinical-trial limitations, patient population, and overseas post-marketing knowledge
• Selection of efficient methods (e.g., use-results surveys, database surveys, post-marketing clinical trials including multi-regional trials, and other methods referenced in ICH E2E), and potentially disease registries in certain settings
• Reporting progress/results to regulators per the RMP timeline and considering appropriate public communication of results Reference: PMDA PDF.

Practical checklist for sponsors (early planning)

• Confirm whether your product type is within scope; consult PMDA when borderline.
• Define the reference product strategy (Japan-approved reference; justify any overseas reference bridging analytically).
• Build the comparability plan around analytical similarity first; let residual uncertainty drive nonclinical/clinical scope.
• Plan immunogenicity evaluation (assays, sampling schedule, interpretation) early.
• Prepare an RMP approach aligned to the remaining uncertainties and real-world use in Japan. Reference: PMDA PDF.