ICH M9 Biowaivers: Why Solubility and Permeability Alone Aren't Enough

ICH M9 reached Step 4 adoption by the ICH Assembly on November 16, 2019, and FDA adopted it the same way, via a May 12, 2021 Federal Register notice. Since then, sponsors have quietly compressed the guideline into a single sentence: BCS Class I means the biowaiver is available. It doesn't. Classification tells FDA the drug substance behaves like Class I or Class III — nothing about whether this specific formulation dissolves fast enough, or whether this specific excipient list is safe to waive a bioequivalence study around. Both are separate, formulation-level tests, and either one can fail a drug substance with an otherwise clean solubility and permeability profile.

What BCS classification actually establishes

Biopharmaceutics Classification System status is a property of the drug substance, established independent of any particular formulation. High solubility means the highest single therapeutic dose fully dissolves in 250 mL or less of aqueous media across pH 1.2 to 6.8 at 37 ± 1°C. High permeability is established through an accepted method — a Caco-2 monolayer study is the most common, though human mass-balance or absolute-bioavailability data can also support it. Get a Class I or Class III result, and the drug substance is eligible to be considered for a waiver. That determination sits upstream of, and is entirely separate from, the formulation-specific work in a CMC regulatory strategy that actually earns the waiver.

The dissolution gate classification doesn't settle

A biowaiver additionally requires the test and reference products to demonstrate comparable, fast dissolution — a formulation-specific outcome, not a drug-substance property. ICH M9 defines this in tiers: “rapid” dissolution is at least 85% of label claim dissolved within 30 minutes, and “very rapid” is the same threshold within 15 minutes, each tested in all three compendial media. For BCS Class I, both products generally need to show similar rapid (or very rapid) dissolution profiles. Class III is held to the stricter very-rapid standard, reflecting the guideline's lower tolerance for formulation variability once permeability — not solubility — is the limiting factor for absorption.

• Both products, all three media. The dissolution comparison runs across pH 1.2, 4.5, and 6.8, not a single condition chosen because it happens to pass.
• Similarity, not just speed. Where dissolution isn't very rapid for both products, a similarity comparison (an f2 or equivalent statistical test) has to hold across the profiles, not just the endpoint values.
• Class III has less room. A Class III drug substance's lower permeability means the guideline leans harder on dissolution and excipient control to justify skipping an in vivo study.

A BCS classification answers one question: does the drug substance behave like Class I or Class III. It says nothing about whether this specific formulation dissolves fast enough, or whether this specific excipient list is safe to waive around. Why the classification isn't the waiver

Excipients are the gate teams underestimate

The formulation's excipients are the second gate, and the one most often assumed away. FDA's 2017 BCS guidance told sponsors that excipients used at normal levels in an already-approved immediate-release product would not meaningfully affect absorption of a highly soluble, highly permeable drug — a working assumption many CMC teams still carry into new programs. ICH M9 does not repeat it. Surfactants, sugar alcohols and other agents that can affect gastrointestinal transit time or membrane permeability now require a case-by-case risk assessment against the specific drug substance, whether or not the excipient has appeared in other approved products. That risk assessment applies with less tolerance to Class III formulations, where the drug substance's own lower permeability leaves less margin for an excipient to push absorption in the wrong direction. A generic or 505(b)(2) pathway program that reuses a formulation approach validated under the older FDA framework, without re-running that risk assessment under M9's tighter standard, is the most common way a biowaiver case falls apart late in development.

None of this makes the pathway less valuable — a defensible ICH M9 biowaiver still removes an in vivo bioequivalence study from a program's timeline and budget, which is exactly why it belongs in small-molecule development planning from the earliest formulation decisions rather than as a late-stage argument to a reviewer. The teams that keep the waiver are the ones who treat BCS classification as the entry ticket, not the case itself, and build the dissolution and excipient-risk record before anyone asks for it.