ICH M13B: Why a Waiver Can't Rest on Another Waiver

ICH reached Step 4 on M13B on August 4, 2026 — the second guideline in the M13 bioequivalence series, this one governing when a sponsor can biowaive additional strengths of an immediate-release solid oral dosage form rather than repeating a bioequivalence study on every strength in the line. EMA has since adopted it at Step 5, with the guideline entering into force on March 17, 2027. The scope question teams get right almost immediately: does my product line qualify? The one they get wrong more often: can the strength I want to use as the anchor actually support the waiver at all?

What M13B actually waives

The guideline's scope is narrow and specific: once a sponsor has shown bioequivalence for one strength of an immediate-release solid oral product under M13A, M13B sets the conditions under which additional strengths of that same product can skip a repeat BE study. The test has three parts — dose proportionality in the pharmacokinetics across strengths, proportionality of the additional strength's formulation (drug substance and excipients) relative to the strength that was actually studied, and similarity in dissolution behavior under the conditions the guideline specifies. ICH's accompanying Q&A is direct about scope: this approach is not restricted to BCS Class I or Class III drug substances. That single line is what separates M13B from the biowaiver sponsors already know.

Why this isn't M9 with a new number

M9 and M13B solve adjacent but different problems, and conflating them is the first mistake teams make. M9's biowaiver operates at the initial bioequivalence stage: it lets a sponsor skip an in vivo BE study altogether, based on the drug substance's solubility and permeability classification under the Biopharmaceutics Classification System — and, as the site has covered before, even a clean BCS Class I classification does not guarantee the waiver holds once formulation and excipient conditions are checked. M13B starts from a different premise entirely: bioequivalence has already been demonstrated, by an actual study, for at least one strength. The question is whether the other strengths in the line need their own study too. BCS class does not enter into that test at all.

• Dose proportionality. The pharmacokinetics across the strength range need to scale with dose in the way the guideline expects before a waiver is available.
• Formulation proportionality. The additional strength's qualitative and quantitative composition is compared against the biobatch strength that was actually studied; deviations are permitted only under the guideline's own stated terms.
• Dissolution similarity. Comparative dissolution testing runs under conditions M13B specifies — and ICH's Q&A separately warns that changing excipients purely to manufacture dissolution similarity between strengths is not an acceptable workaround.
• No BCS gate. Unlike M9, the M13B test applies the same way regardless of the drug substance's BCS classification — a non-BCS-I or III molecule is not excluded from the additional-strength route the way it would be from an M9 biowaiver.

M9 asks whether you need a study at all. M13B asks whether the study you already ran covers the strengths you haven't tested yet. Answering the wrong question with the right-sounding guideline is how submissions stall at the biowaiver stage. Why the two guidelines get confused

The trap: a waiver can't rest on another waiver

The restriction most likely to catch a multi-strength program off guard is the one ICH's Q&A states most plainly: a "waiver on a waiver" is not acceptable where the strength serving as the M13B basis was itself approved solely on an M9 BCS-based biowaiver, rather than on an actual bioequivalence study. It is an intuitive-looking shortcut — the basis strength was cleared without a study, so why not waive the next strength from it too — and it is explicitly foreclosed. The practical consequence runs upstream into program design: if a sponsor is counting on biowaiving every strength past the first, at least one strength in the line needs real BE data behind it, and that strength is the one every other waiver in the family traces back to. Get that sequencing wrong and the biowaiver strategy for the whole line collapses at the strength the program assumed was already settled.

For sponsors building out a multi-strength line on a single pivotal BE study, M13B is genuinely useful — it is a narrower, more defensible route than arguing a case-by-case biowaiver with each reviewer. But it rewards sequencing the program correctly from the first strength forward, not reverse-engineering a waiver chain after the fact. Our CMC regulatory strategy work runs the dose-proportionality, formulation, and dissolution test against a client's actual strength ladder before a 505(b)(2) or multi-strength generic submission goes in, so the waiver a program is counting on is one that will actually hold.