Basic Concept on Bioequivalence Evaluation for Adding New Dosage Forms to Ethical Kampo Formulations in Japan

1) What this document is (and when it applies)

Japan’s MHLW issued an Administrative Notice titled “Basic Concept on Bioequivalence Evaluation for Addition of Formulations with Different Dosage Forms in Ethical Kampo Formulations” dated July 19, 2021 (English is a provisional translation). It provides the basic logic for what tests are required when a company adds a different dosage form to an already-approved ethical Kampo formulation, on the condition that the new dosage form uses the same Kampo extract as the approved product. Reference: PMDA PDF.

2) Why Kampo BE needs special thinking

Kampo formulations are multicomponent and contain many chemical compounds. Even though Kampo extracts listed in the Japanese Pharmacopoeia (JP) typically have marker compounds for quality specifications, those “assay markers” are not always suitable as BE indices—because they may be heavily influenced by biological processes (e.g., intestinal bacterial metabolism, GI absorption, post-absorption metabolism) or be present in food. Therefore, the concept emphasizes selecting marker compounds (or metabolites) that are suitable for BE evaluation and then performing a series of tests to assess equivalence.

3) Overall evaluation strategy (the required sequence)

This basic concept presents a two-step logic:

1. Conduct bioequivalence studies between the reference (old dosage form) and the test (new dosage form) following the Guideline for Bioequivalence Studies of Generic Products (“Generic Product Guideline”).
2. Before the in vivo BE study, confirm similarity of dissolution profiles and verify equivalence of chromatographic elution patterns (“Chromatographic Patterns”) obtained by chromatography.

It also states that sponsors should consult the regulatory authority in advance, as appropriate, when adding a dosage form under this concept.

4) Formulations used for BE evaluation (reference vs test)

Key conditions for the “additional dosage form”

• The proposed additional dosage form should use the same Kampo extract as the approved formulation.
• Indications should be the same, and dosage/administration should remain within the approved scope.

Reference formulation (old dosage form)

• Select a reference lot showing intermediate characteristics among three lots in a dissolution test.
• If dissolution can’t appropriately select a reference lot due to the compound characteristics, use an alternative physicochemical test to pick the intermediate lot.

Test formulation (new dosage form)

• The test formulation should be manufactured using the same manufacturing lot of Kampo extract used for the reference formulation.
• A commercial-scale lot is desirable, but a lot manufactured at ≥ 1/10 of commercial scale is acceptable.
• The manufacturing method should be the same between the commercial-scale lot and the BE-study lot, and the quality should be equivalent.

5) Choosing marker compounds for BE

In principle, select one marker compound from:

• the assay marker compounds specified in the JP or marketing approval document, or
• their major metabolites. If those markers are unsuitable for BE evaluation, another marker compound may be selected.

6) Pre-BE in vitro work: dissolution similarity + chromatographic pattern equivalence

Dissolution similarity

Before the BE study, perform dissolution tests on the reference and test formulations to evaluate similarity of dissolution profiles for multiple assay marker compounds. The concept refers to the dissolution-test method and similarity judgement described in the Generic Product Guideline, and allows changing test conditions if dissolution evaluation is difficult due to coning of disintegrated products at the vessel bottom.

Chromatographic Patterns (HPLC) equivalence

After dissolution testing, compare chromatograms of the dissolution test solutions to confirm that Chromatographic Patterns are practically equivalent. The concept describes comparing peaks between reference and test chromatograms by:

• comparing retention times, and
• evaluating peak intensity by an appropriate method.

7) In vivo BE study execution

Only after confirming dissolution similarity and chromatographic-pattern equivalence, conduct the BE study following the Generic Product Guideline, using the selected marker compound (or relevant parent compound when a metabolite is evaluated) as the indicator.

Practical takeaway for sponsors

When planning a new dosage form for an existing ethical Kampo product in Japan, build your package around:

• a defensible marker compound strategy,
• a documented reference/test lot selection approach,
• dissolution + chromatographic pattern evidence before humans,
• and a BE study aligned with the generic BE framework, with early PMDA consultation when needed.

Reference: PMDA PDF.