No Clinical Study Required — How the EAEU Biowaiver Works for BCS Class I and III Generics
An in vivo bioequivalence (BE) study is expensive. A full-scale study on healthy volunteers in the Russian Federation starts at several million rubles, excluding the costs of the clinical site, analytical work, and monitoring. Add six to nine months from protocol development to the final report, and the registration of a generic drug product becomes a separate project with its own distinct budget.
For some drug products, however, such a study is simply not necessary. If the active substance dissolves well and is well absorbed in the intestine, the tablet behaves in the body the same way as the originator product, regardless of the manufacturer—provided that it has been manufactured correctly and dissolves appropriately under the right conditions. The biowaiver procedure was built around this logic: replace the clinical study with a laboratory dissolution test.
In the Eurasian Economic Union (EAEU), the biowaiver operates under the Decision of the Council of the Eurasian Economic Commission (EEC) dated November 3, 2016, No. 85 (as amended April 12, 2024), specifically Annex 4. Under the simplified registration pathway pursuant to Russian Federation Government Decree No. 593, the procedure is explicitly permitted for generic solid oral dosage forms with immediate release. On the surface, it is straightforward: if your drug product and the reference product dissolve equally rapidly in three standard media, they are recognized as bioequivalent. No volunteers—only the laboratory and a correctly compiled dossier.
In practice, each component of this formula requires dedicated work.
What Is the BCS and Why Do Its Principles Hold
The Biopharmaceutics Classification System (BCS) categorizes active substances based on two parameters: aqueous solubility and intestinal permeability. These are precisely the factors that determine what happens to a tablet after it is swallowed. Everything else is secondary.
This gives us four classes.
Class I: High solubility, high permeability. The sole rate-limiting step is gastric emptying time. If the tablet has dissolved while still in the stomach, its pharmacokinetics will match those of the originator. The best candidates for a biowaiver. Metoprolol, verapamil, and fluoxetine are commonly assigned to this class (based on published clinical data; Decision No. 85 does not provide a normative list of substances).
Class II: Low solubility, high permeability. The substance is absorbed well, but must first dissolve—a slow process that depends on the formulation. Two different formulations will produce different pharmacokinetic profiles. A biowaiver is not possible. Itraconazole, carvedilol, and phenytoin are commonly assigned to this class.
Class III: High solubility, low permeability. The substance dissolves readily but penetrates the intestinal barrier with difficulty. Excipient composition can influence absorption through intestinal motility or the activity of transport proteins. A biowaiver is possible, but requirements are significantly stricter. Acyclovir, metformin, and cimetidine are commonly assigned to this class.
Class IV: Low solubility, low permeability. Absorption is unpredictable; a biowaiver is excluded.
| Class | Solubility | Permeability | Biowaiver | Dissolution Requirement |
|---|---|---|---|---|
| I | High | High | Permitted | 85% in ≤30 min (rapid) or ≤15 min (very rapid) |
| II | Low | High | Not permitted | — |
| III | High | Low | Permitted | 85% strictly within 15 min |
| IV | Low | Low | Not permitted | — |
BCS classification is a scientific conclusion that must be demonstrated experimentally. Citing a reference book and writing «Class I substance» will not be accepted. The expert assessor will request the applicant’s own laboratory data.
How to Demonstrate Solubility and Permeability
Solubility
Under EAEU rules (paragraph 8 of Annex 4 to Decision No. 85), an active substance is considered «highly soluble» if the maximum single therapeutic dose dissolves completely in 250 mL of aqueous medium at 37 ± 1°C across a pH range of 1.2–6.8. The 250 mL volume is derived from clinical practice, as this is the amount of water administered in pharmacokinetic studies.
Testing must be conducted in at least three media:
- 0.1 M hydrochloric acid solution, pH 1.2 (gastric medium);
- Acetate buffer, pH 4.5 (intermediate medium);
- Phosphate buffer, pH 6.8 (primary absorption zone).
If the substance has a pKa value within the 1.2–6.8 range, solubility must also be studied at the pH of minimum solubility. A minimum of three replicate determinations is required for each pH value. The standard shake-flask method or potentiometric titration are used, provided the latter is validated.
Two limitations are frequently overlooked. First, the EEC expert review does not accept data from published literature—applicant-generated laboratory data are required for the specific maximum dose strength. Second, if the active substance degrades by more than 10% during the test, it is impossible to correctly determine solubility and BCS class under those conditions (paragraph 15 of Annex 4).
Permeability
Permeability is classified as high when the substance is absorbed at ≥85%. Under EAEU rules (paragraph 16 of Annex 4), the assessment should preferably be based on human pharmacokinetic data.
Priority sources of evidence:
- Absolute bioavailability from intravenous administration (most robust);
- Mass balance studies, provided the cumulative excretion of the parent compound and its Phase I (oxidized) and Phase II (conjugated) metabolites in urine and bile (feces) exceeds 85% (paragraph 17 of Annex 4);
- Published clinical pharmacokinetic data.
Caco-2 cell data are accepted subject to strict system validation (Annex 1 to the Requirements of Annex 4). The laboratory must demonstrate system performance using a sufficient number of model compounds across zero, poor, moderate, and high permeability categories. A fundamental limitation: Caco-2 cells are appropriate only for demonstrating passive diffusion. For substances that are substrates of efflux transporters (e.g., P-glycoprotein), in vitro data may be falsely optimistic, making in vivo data mandatory.
Comparative Dissolution Testing
Comparative dissolution testing (CDT) is the central experiment of a biowaiver. Its purpose: to demonstrate that the test product dissolves as rapidly as the reference product under controlled in vitro conditions.
Parameters under EAEU rules (paragraph 39 of Annex 4):
- No fewer than 12 units of each product (test and reference);
- Apparatus 2 (paddle) at 50 rpm, or Apparatus 1 (basket) at 100 rpm;
- Medium temperature: 37.0 ± 1.0°C;
- Medium volume: ≤900 mL;
- Three buffer media: pH 1.2, 4.5, and 6.8;
- No surfactants are added to the medium.
If coning is observed with the paddle apparatus at 50 rpm, switching to the basket or using sinkers is permitted. All such decisions must be documented in the protocol. Time points must generate a complete dissolution profile; for rapidly dissolving dosage forms, sampling every 5–10 minutes is recommended. All individual values for each unit must be retained and included in the dossier—not only means.
Pathway 1 — Very Rapid Dissolution
If both products release ≥85% of the active substance within 15 minutes across all three media, the profiles are considered similar without further calculation (paragraph 43 of Annex 4). For Class III, this result is mandatory.
Pathway 2 — Similarity Factor f2
If dissolution takes 15–30 minutes (applicable to Class I only), profile similarity is assessed using the similarity factor f2. A value of 50–100 indicates similar profiles.
Conditions for a valid f2 calculation (paragraph 42 of Annex 4):
- Assessment at a minimum of three time points (excluding zero);
- Identical sampling time points for both products;
- No more than one time point included after the mean dissolution of both products exceeds 85%;
- The coefficient of variation (CV) must not exceed 20% at early time points (≤10 minutes) and 10% at all remaining points.
Special case: if one product shows «rapid dissolution» (85% in 30 minutes) while the other shows «very rapid» dissolution (85% in 15 minutes), similarity must still be confirmed by calculating f2 (paragraph 44 of Annex 4).
If CV exceeds these thresholds, the f2 calculation is considered invalid and a conclusion on profile similarity cannot be drawn from it (paragraph 43). In such cases, alternative statistically sound methods are applied with appropriate justification—for example, the difference factor f1, the Weibull function, or pairwise comparison of dissolution levels (Annex 5 to Decision No. 85, paragraph 11).
| Situation | Requirement | Applicability |
|---|---|---|
| Both products: 85% in ≤15 min | f2 not required | Class I and III |
| Both or one: 85% in 15–30 min | f2 ≥ 50 | Class I only |
| CV above threshold | Alternative statistical methods | With justification |
| Dissolution >30 min | Biowaiver not possible | — |
Excipient Composition
Excipient composition is the second most frequent source of issues during regulatory assessment, after BCS classification.
For Class I (paragraph 33 of Annex 4), qualitative and quantitative differences in composition are permitted, except for excipients capable of affecting absorption. Such excipients must be qualitatively identical and differ quantitatively by no more than ±10% relative to the reference product. The cumulative difference across all «absorption-affecting» excipients must also not exceed ±10%.
For Class III (paragraph 34 of Annex 4, with accompanying table), requirements are considerably stricter. All excipients must be qualitatively identical. Quantitative deviations are strictly limited:
| Excipient Type | Tolerance |
|---|---|
| Absorption-affecting substances (each) | ±10% of the content in the reference product |
| All absorption-affecting substances (cumulative) | ±10% |
| Diluent/filler | ±10% of core mass |
| Disintegrant (starch) | ±6% of core mass |
| Disintegrant (other) | ±2% of core mass |
| Binder | ±1% of core mass |
| Lubricant (stearates) | ±0.5% of core mass |
| Lubricant (other) | ±2% of core mass |
| Glidant (talc) | ±2% of core mass |
| Glidant (other) | ±0.2% of core mass |
| All excipients (cumulative) | ±10% of core mass |
Among absorption-affecting excipients, sugar alcohols (mannitol, sorbitol) and surfactants (sodium lauryl sulfate) warrant particular attention. If an excipient is introduced that is absent from the reference product, its lack of pharmacokinetic influence must be justified in writing. Without such a justification, the expert typically requests an in vivo study.
Reference Product Selection
EAEU rules establish a clear hierarchy for reference product selection (paragraph 18 of the Rules to Decision No. 85). The first choice is the originator product whose safety and efficacy were confirmed upon registration within the Union. If it is not in circulation, the originator from International Council for Harmonisation (ICH) member countries is selected. Next are products approved by the Expert Committee on Medicinal Products, followed by products with a clinical history of at least 20 years in one of the member states.
When the reference product is sourced from the US or EU markets, the applicant must confirm it is the same product as the one marketed in the EAEU. Good practice before procurement: review the Certificate of Analysis (CoA) and compare specifications against those described in the EAEU registration dossier. If identity is in doubt, conduct an independent comparative batch analysis.
One further requirement: the active substance content in the test batch must not differ from that of the reference product batch by more than 5% (paragraph 20). The applicant must justify the batch selection through CDT and quantitative assay data.
When a Biowaiver Is Not Possible
Several categories of drug products are entirely excluded from the procedure (paragraph 5 of Annex 4).
Narrow Therapeutic Index (NTI) products. Digoxin, warfarin, cyclosporine, phenytoin, lithium, theophylline. For these products, small fluctuations in bioavailability lead to toxicity or loss of efficacy. Bioequivalence must be confirmed in vivo using a tightened acceptance criterion of 90.00–111.11% for AUC (area under the plasma concentration–time curve) and Cmax (maximum plasma concentration) (paragraph 104 of the Rules). A biowaiver is not applicable even if the substance formally belongs to BCS Class I or III.
Fixed-dose combinations (FDCs). If any component belongs to Class II or IV, the biowaiver is unavailable for the entire product. When all components are Class I or III, CDT is conducted separately for each active substance, and excipient requirements are governed by the stricter Class III criteria if that class is present in the combination (paragraph 36 of Annex 4).
Products with buccal or sublingual absorption. The BCS-based biowaiver applies only to oral administration with water. If the product may also be taken without water (e.g., orally disintegrating tablets), a separate BE study under water-free administration conditions is required (paragraph 24 of Annex 4).
Modified-release dosage forms. Annex 4 applies only to immediate-release solid dosage forms and suspensions.
Different chemical derivatives of the active substance. If the test and reference products contain different salts of the same substance, a biowaiver is permissible provided both salts are BCS Class I (paragraph 7). Other derivatives—esters, isomers, complexes—are excluded from the procedure.
What to Do
Classify the active substance before developing the formulation. Commission your own solubility study in three media at 37 ± 1°C. If the substance has a pKa in the 1.2–6.8 range, add a measurement point near that value. In parallel, gather clinical absorption data: published literature, the active pharmaceutical ingredient (API) manufacturer’s technical documentation (CoA, specification data). If no data are available, plan a Caco-2 study with full validation across three permeability levels.
Screen for exclusions before any other work begins. Confirm the substance is not on the NTI list. Verify the dosage form is immediate release and that the product is not intended for administration without water. If the formulation contains multiple active substances, screen each one against the BCS criteria. This step takes a few hours and can save months.
Design the formulation with Class III requirements in mind. Even for a Class I substance, minimize the quantities of surfactants and sugar alcohols. This reduces risk during regulatory assessment and provides a buffer for any future composition changes.
Conduct CDT strictly per protocol. Three media, minimum 12 units, temperature 37.0 ± 1.0°C, no surfactants. Include early time points no less frequently than every 5–10 minutes. Retain all individual values for each unit. Pre-check filters for active substance adsorption. If CV exceeds 20% at early time points, identify the cause before calculating f2.
Assess profile similarity. If both products released ≥85% within 15 minutes across all media, no further calculation is needed. If one product shows «rapid» and the other «very rapid» dissolution, calculate f2. When CV is too high, f2 is invalid—alternative methods with statistical justification are required.
Write the biowaiver justification. Under EAEU rules (Decree No. 593, paragraph 6), the dossier must include a written justification for the biowaiver and a CDT analytical report with individual data. A strong justification covers the BCS classification conclusion with supporting experimental data, a comparative excipient table against the reference product, and an assessment of each excipient. In practice, the quality of this document determines whether the expert’s questions arise before an official request or only after it.
A biowaiver does not reduce the overall workload—it moves that work from the clinic to the laboratory. What it does eliminate is the most expensive and time-consuming component of a generic registration project. For most generic products with a BCS Class I or III active substance, the procedure is entirely feasible when each step is executed per the rules and properly documented. Questions regarding the application of the rules may be submitted to the Expert Committee on Medicinal Products; this right is explicitly provided under paragraph 10 of the Rules to Decision No. 85.
Regulatory Framework
1. Decision of the Council of the Eurasian Economic Commission dated November 3, 2016, No. 85 «On Approval of the Rules for Conducting Bioequivalence Studies of Medicinal Products within the Eurasian Economic Union» (as amended by EEC Council Decisions dated September 4, 2020, No. 67; February 15, 2023, No. 22; and April 12, 2024, No. 30). Annex 4—BCS-based biowaiver requirements. Annex 5—comparative dissolution testing requirements.
2. Decree of the Government of the Russian Federation dated April 5, 2022, No. 593 «On Specific Features of the Circulation of Medicines…» (current version), paragraph 6—permissibility of a biowaiver for the simplified registration of generic medicinal products.
3. Federal Law of the Russian Federation dated April 12, 2010, No. 61-FZ «On the Circulation of Medicines» (current version), Article 2—definitions of bioequivalence and generic medicinal product.
4. ICH M9 «Biopharmaceutics Classification System-Based Biowaivers» (2019)—an international guideline whose principles are compatible with EAEU requirements.