Japan adopts ICH M13A for immediate-release oral solids

MHLW's Pharmaceutical Evaluation Division issued the ICH M13A guideline "Bioequivalence for Immediate-Release Solid Oral Dosage Forms" on November 12, 2026, as a division director notification (Notification No. 1112-5), with two administrative notices of the same date. One carries the Q&As agreed at ICH. The other sets out how Japan handles M13A in marketing approval applications. The guideline applies to new marketing approval applications and partial change applications made on or after that date. The annex to the notification is the Japanese text of M13A, and the clause numbers below follow it.

BE studies and reference product selection now follow M13A

If your product is an immediate-release solid oral dosage form, the design of its bioequivalence (BE) study moves to ICH M13A for applications made on or after November 12. For oral products, therapeutic equivalence is usually confirmed by a BE study, a pharmacodynamic study or a clinical study, as Chapter 1 of Japan's generic BE guideline describes. That guideline is Annex 1 to Notification No. 0319-1 of March 19, 2020. Where a BE study is run on an immediate-release solid oral product, it now follows M13A.

The same holds for the BE studies that Japan's own guidelines already require, among them differences in strength, formulation changes, added dosage forms, fixed-dose combinations, and the BCS-based biowaiver guideline (ICH M9). For those, both the selection of the reference product and the BE study follow M13A.

The scope is immediate-release oral solids designed to deliver the drug to the systemic circulation: tablets, capsules, granules or powders for oral suspension and the like. The recommendations cover BE studies both in development and after approval.

Prolonged-release, enteric-coated and narrow therapeutic index products stay outside

Oral products outside M13A keep referring to the generic BE guideline as before. The handling notice names prolonged-release oral products, enteric-coated oral products, and products containing a drug with a narrow therapeutic index, among others. Where therapeutic equivalence is shown by a pharmacodynamic study or a clinical study rather than a BE study, the generic BE guideline also continues to apply. If the scope is unclear for a given product, the notice says to consult PMDA as needed.

The generic BE guideline is still available, but the two cannot be mixed

As a transitional measure, referring to the generic BE guideline for the BE study of an immediate-release solid oral product remains acceptable for the time being. The two guidelines operate independently, so the notice requires that one guideline be chosen and then followed on its own terms.

The handling notice deals with dissolution testing separately. A dissolution study is not required as part of the data package for a BE evaluation under M13A. For prescription generics, however, the notice says to keep running the dissolution testing set out in Chapter 3, A.V. of the generic BE guideline, for quality control across the lifecycle.

What to check before the next filing

The first question is whether the product meets all four parts of the scope: immediate release, oral, solid, and designed to reach the systemic circulation. The second is which guideline the BE study will reference, decided at the planning stage.

Three numbers in M13A are worth reading against your own protocol. For tablets and capsules, the test product batch should usually come from a batch of at least one tenth of production scale or 100,000 units, whichever is larger, unless otherwise justified (2.1.4 a). Where production scale is under 100,000 units, a production-scale batch is required, and the ICH Q&As put other dosage forms at 10% or more of production scale. The content of that batch should not differ from the reference product batch by more than 5%, again unless justified (2.1.4 b). For most drugs the PK parameters are Cmax and AUC(0-t) in a single-dose study, and the 90% confidence interval of the geometric mean ratio has to fall within 80.00% to 125.00% (2.2.4).

One further condition catches products whose absorption depends on gastric pH. M13A in principle requires a BE study with an acid-reducing agent where three things hold together (3.4 a to c). The drug substance shows pH-dependent solubility across pH 1.2 to 6.8. The product is expected to be taken with an acid-reducing agent such as a proton pump inhibitor, or used in a specific population such as achlorhydric patients. And the two products differ in the type or amount of a pH-adjusting excipient, in a significant manufacturing difference that could affect absorption when gastric pH differs, or in a salt or polymorph with pH-dependent solubility. An applicant may instead justify that the assessment is unnecessary.

For a product already approved, a partial change application filed on or after November 12 is in scope, so the application category and the guideline the BE study follows are worth settling together. On dosage forms, PMDA posted a pharmacopoeia committee's view on minitablets and granular tablets as Japanese Pharmacopoeia technical information on November 5. The Japanese texts of the notification and the two notices are the operative ones; the English titles here are ours.