USFDA’s Draft Guidance: Bioequivalence Biowaivers for Additional Strengths of Immediate-Release Oral Drugs

Developing drug products across multiple strengths is a common strategy in pharmaceutical formulation, allowing dose flexibility and individualized therapy. Traditionally, each strength would require a separate in vivo bioequivalence (BE) study to confirm therapeutic equivalence, but this is not always necessary.

The newly released draft ICH M13B Guideline "Bioequivalence for Immediate-Release Solid Oral Dosage Forms: Additional Strengths Biowaiver", endorsed by the FDA in February 2025, provides a detailed scientific and regulatory framework for when biowaivers for additional strengths of immediate-release (IR) solid oral dosage forms may be justified.

The M13B draft guidance provides scientific and technical recommendations for demonstrating bioequivalence (BE) for additional strengths of immediate-release (IR) solid oral dosage forms, such as tablets, capsules, and oral granules/powders, without the need for in vivo studies for every strength. Instead, it lays out criteria for when a biowaiver can be granted based on data from one strength and supporting in vitro evidence.

This guidance applies to:

• Immediate-release solid oral dosage forms (tablets, capsules, granules/powders for suspension)

• Additional strengths of a drug product for which in vivo BE has been demonstrated for at least one strength, using principles from the prior M13A guidance

Biowaivers reduce the need for duplicative clinical testing and support efficient regulatory review. Waivers are based on dose proportionality, formulation similarity, and dissolution profile comparison.

Scientific Criteria for Biowaivers

To qualify for a biowaiver, certain scientific conditions must be met. The pharmacokinetics of the drug must demonstrate dose proportionality, meaning that the pharmacokinetic parameters (such as Cmax and AUC) change proportionally with the dose. This helps ensure that the additional strength behaves similarly in the body to the strength used in the original bioequivalence study.

In terms of formulation, the additional strengths must be both qualitatively the same (i.e., contain the same inactive ingredients) and quantitatively proportional to the tested strength. For high-potency drugs, where the active pharmaceutical ingredient (API) comprises less than 5% of the tablet’s weight, minor variations in the amount of filler or diluent are permitted, but the composition must remain functionally consistent.

Moreover, all strengths must be manufactured using the same process, ensuring that changes in strength do not introduce variability in product performance.

Dissolution Testing and In Vitro Similarity

A central element of the biowaiver process is dissolution testing, which serves as a surrogate for bioavailability when performed under stringent conditions. The guidance requires dissolution testing in three different pH media (1.2, 4.5, and 6.8) using either paddle or basket apparatus with not more than 900 mL of medium at 37°C.

At least 12 dosage units per strength must be tested, and the results compared to the reference (biobatch) strength. If all formulations dissolve more than 85% of their API within 15 minutes, no further similarity analysis is necessary. However, if this threshold is not met, similarity must be demonstrated using the f2 similarity factor or bootstrap statistical methods, particularly when variability exceeds 8%.

Applicants must submit a biowaiver report with:

• Rationale and selection of biobatch

• Comparative formulations and excipient % w/w

• Prospective dissolution test plans

• Individual and mean dissolution data

• Similarity analyses and conclusions

This guidance, once finalized, will be vital for global harmonization, reducing duplicative studies and accelerating access to medicines. Want to learn more or submit your comments?

• Read the full FDA guidance here.

• See the FDA’s official guidance page.