What a biowaiver is
To show that a generic medicine is equivalent to the original, a bioequivalence study in volunteers is normally carried out. The EAEU Rules also provide grounds on which a study in people (in vivo) can be replaced by a laboratory study (in vitro) — they are named directly among the subjects of the Rules (clause 1). Such a replacement is called a biowaiver. One kind is described in Annex 4 to the Rules: a biowaiver under the Biopharmaceutics Classification System (BCS), as amended by EEC Council Decision No. 30 of 12 April 2024.
What it is based on
For a substance to enter the blood, it must first dissolve and then pass through the intestinal wall. The BCS divides active substances into four classes by these two properties:
| Class | Solubility | Permeability |
|---|---|---|
| I | high | high |
| II | low | high |
| III | high | low |
| IV | low | low |
If a substance dissolves well and passes the intestinal wall well, and the product releases it quickly, the speed of dissolution is the main thing that can differ between two products. A laboratory dissolution comparison can then replace a study in people. Annex 4 of the EAEU Rules allows such a biowaiver for active substances of BCS class I (high solubility, high permeability) and class III (high solubility, low permeability), but only for solid oral dosage forms and suspensions with immediate release; it is not allowed for drugs with a narrow therapeutic range (clauses 5–6). Dissolution profiles are compared in media at pH 1.2, 4.5 and 6.8; class III requires very rapid dissolution (at least 85 % in 15 minutes) in all media, while for class I rapid dissolution (at least 85 % in 30 minutes) is enough if the profiles are similar (clauses 39–45). The excipients are also restricted (clauses 33–35).
What it looks like in practice
- Classifying the substance. Solubility and permeability of the active substance are determined from published data or own studies.
- Checking the product. The dosage form (immediate release), the speed of dissolution and the composition are reviewed: excipients must not change absorption.
- Comparing dissolution. The dissolution profiles of the generic and the reference product are compared in several media of different acidity.
- Justification in the dossier. The results and the justification go into the registration dossier in place of a bioequivalence study report.
When a study in people is needed
A biowaiver does not suit a product if:
- the substance is in BCS class II or IV, or the product has a narrow therapeutic range;
- the product does not release the substance quickly, or differs from the reference in composition in a way that may change absorption;
- the dissolution profiles do not match.
In those cases a bioequivalence study is needed. It works like this: volunteers receive both products in different periods, and the blood concentration of the substance is compared by Cmax and AUC — see “What is bioequivalence”. The size of the group can be estimated in the calculator.
What next
If you doubt that your product needs a study in people, first take the question to a regulatory specialist: the decision affects both registration and the budget. If a study is needed, send the protocol or synopsis: we will assess feasibility and prepare a proposal for the bioequivalence study.
Sources
- EAEU Bioequivalence Rules — EEC Council Decision No. 85 of 3 November 2016: clause 1 (grounds for replacing in vivo studies with in vitro studies), Annex 4.
- EEC Council Decision No. 30 of 12 April 2024 — Annex 4 “biowaiver under the BCS” in its new version.
Questions and answers
What is a biowaiver in plain words?
It is permission not to run a bioequivalence study in volunteers: instead, a laboratory compares how the generic and the reference product dissolve. Dissolution in a medium resembling the contents of the stomach and intestine is the first step towards absorption, so for some products comparing it is enough.
Does a biowaiver suit every medicine?
No. It is possible for products that meet set conditions: the properties of the active substance, the form and speed of dissolution, the composition. The conditions are set by the EAEU Rules (Annex 4 as amended by Decision No. 30 of 2024). If they are not met, a bioequivalence study is needed.
This material is for information only and is not legal advice. The rules are cited as of the date of the last update; check the current versions of the documents before making decisions.
See also
Bioequivalence and therapeutic equivalence: what is the difference
Bioequivalence compares how a generic and an original medicine reach the bloodstream, usually in healthy volunteers. Therapeutic equivalence compares their clinical effect in patients. The law allows both kinds of study for generic medicines.
Learn more
EAEU rules for bioequivalence studies: a short guide
The EAEU Rules for Conducting Bioequivalence Studies (EEC Council Decision No. 85 of 3 November 2016) set the study design, the number and selection of volunteers, data analysis and the content of the report. The standard is a two-sequence crossover study, with at least 12 subjects in the analysis.
Learn moreBioequivalence studies in Moscow
A bioequivalence study shows that a generic medicine reaches the bloodstream in the same way as the reference medicine. Bessalar Clinic conducts such studies in healthy volunteers in its in-patient unit and processes samples on site.
Learn more