Bioequivalence studies: Biowaivers

In vitro dissolution tests can replace in vivo bioequivalence studies when a strong correlation exists between a drug's dissolution and bioavailability. Additionally, the FDA permits waiving bioequivalence studies for products where bioequivalence is self-evident, such as solutions for parenteral, oral, or local use, provided they have identical ratios of active and inactive ingredients as reference products.

Bioequivalence testing for lower-strength products can be waived when the drug maintains proportional similarity in active and inactive ingredients across all strengths, provided the highest strength passes both dissolution and in vivo bioequivalence tests. If lower-dose-strength products demonstrate substantial similarity in composition, comparative in vitro dissolution may suffice instead of full bioequivalence studies.

Most immediate-release tablets and capsules lack a strong correlation between dissolution and bioavailability, making in vitro dissolution tests inadequate to establish bioequivalence. Therefore, in vivo bioequivalence studies are necessary to demonstrate that these drug products achieve comparable systemic exposure and therapeutic effects as reference formulations.

For oral solid dosage forms, at least one dose strength, typically the highest strength, must be supported by an acceptable in vivo bioequivalence study. Once the highest strength demonstrates bioequivalence, lower-strength variants may qualify for biowaivers if they meet proportional similarity and acceptable in vitro dissolution criteria.

No, generic modified-release products are generally ineligible for biowaivers. These formulations require full bioequivalence studies because their complex release mechanisms and absorption profiles cannot be reliably predicted from in vitro dissolution data alone, necessitating in vivo evaluation to ensure therapeutic equivalence.

To grant biowaivers to non-biostudy strengths of generic immediate-release solid oral dosage forms, the FDA requires conducting an acceptable bioequivalence study on at least one strength, demonstrating proportional similarity in active and inactive ingredients, and providing acceptable in vitro dissolution data for the strength seeking the biowaiver.

When a drug product maintains the same ratio of active and inactive ingredients across all strengths, proportional similarity is established. This similarity is a key criterion for biowaiver eligibility, allowing lower strengths to avoid full bioequivalence testing if the highest strength passes required dissolution and in vivo studies.