Can My Drug Use a BCS Biowaiver Instead of an EAEU Bioequivalence Study?

A BCS-based biowaiver can remove an in-vivo bioequivalence study from an EAEU generic-drug development programme. For the right product, that can save months of development time, eliminate clinical-site and bioanalytical work and reduce exposure of healthy volunteers to a study that adds little scientific value.

But a biowaiver is not granted because an active substance appears on an internet list, because the formulation dissolves quickly, or because another regulator accepted a biowaiver for a similar product.

Under the Eurasian Economic Union rules, eligibility is determined by a chain of evidence:

correct reference product → eligible dosage form → BCS Class I or III active substance → acceptable excipient relationship → comparative dissolution meeting the EAEU criteria → complete, auditable supporting package.

If one link fails, an in-vivo bioequivalence study may still be required.

The practical question is therefore:

Can this specific formulation, at this specific strength, against this specific EAEU reference product, satisfy the current Decision No. 85 biowaiver criteria?

That is the question Pharegis answers before a manufacturer commits to a bioequivalence study.

The current EAEU biowaiver rules changed materially in 2024

BCS-based biowaivers in the EAEU are governed by Appendix No. 4 to EEC Council Decision No. 85.

EEC Council Decision No. 30 of 12 April 2024 substantially revised that appendix. The revised rules entered into force on 13 June 2024 and aligned the Union approach more closely with modern international practice, including ICH and WHO concepts.

The amendment matters commercially because it expanded the range of products for which a biowaiver can be considered.

Among the important changes:

• BCS-based biowaivers are expressly available for Class I and Class III active substances;
• prodrugs can be considered where they are absorbed in the prodrug form and meet the applicable criteria;
• Class III products no longer require the previous case-by-case Expert Committee approval merely because they are Class III;
• the rules now contain much more explicit criteria for excipient similarity, dissolution and supporting documentation;
• the hierarchy for selecting a reference medicinal product was also updated.

This means an internal company SOP written around the pre-2024 EAEU rules may now be too restrictive.

What BCS Class I and Class III actually mean

The Biopharmaceutics Classification System classifies active substances by two properties: solubility and intestinal permeability/extent of absorption.

The four classes are:

• Class I — high solubility, high permeability;
• Class II — low solubility, high permeability;
• Class III — high solubility, low permeability;
• Class IV — low solubility, low permeability.

For an EAEU BCS-based biowaiver, the active substance generally has to fall into Class I or Class III.

Class II and Class IV substances are not eligible for this ordinary BCS-based waiver because dissolution/solubility can become a major determinant of in-vivo exposure.

A literature statement that an API is “BCS I” is useful screening information, but it is not by itself the regulatory proof required in the dossier.

WHO and ICH lists are valuable screening tools—not automatic EAEU approvals

The international evidence base has become much more useful for early feasibility work.

ICH maintains M9: Biopharmaceutics Classification System-based Biowaivers, which establishes a harmonized scientific framework for Class I and Class III biowaivers.

WHO also publishes a Biowaiver List for immediate-release solid oral dosage forms on the WHO Model List of Essential Medicines. The latest WHO list, published in June 2026, identifies APIs for which waiver of in-vivo bioequivalence can be considered and provides API-specific scientific conclusions. WHO expressly recognizes BCS-based biowaivers for Class I and III APIs using comparative dissolution as surrogate evidence where the relevant conditions are met.

These documents are extremely useful for a preliminary screen.

However:

a WHO or ICH classification does not replace the EAEU dossier requirements.

Decision No. 85 remains the binding regulatory framework for an EAEU registration. The applicant still has to establish the relevant BCS properties, formulation acceptability and comparative dissolution in a package that satisfies the Union rules.

Pharegis therefore uses WHO/ICH evidence as a starting point and supporting scientific source—not as a substitute for the EAEU assessment.

Step 1: confirm that the dosage form is eligible

Under the revised Appendix No. 4, BCS-based biowaivers apply to medicinal products that are:

• oral dosage forms;
• immediate-release;
• intended to deliver the active substance to the systemic circulation;
• the same dosage form and strength as the reference product for the comparison being made.

The rules also allow the approach to be applied to suspensions in the circumstances covered by the current wording.

BCS biowaiver is not appropriate for products with a narrow therapeutic index.

Products relying on buccal or sublingual absorption are not eligible for the ordinary BCS waiver. If an orally disintegrating product can be taken without water, an in-vivo study under the no-water administration condition can still be required.

This eligibility screen should happen before any dissolution programme is designed.

Step 2: select the correct EAEU reference medicinal product

Reference-product selection is one of the most underestimated risks in generic development.

The 2024 revision of Decision No. 85 establishes a hierarchy.

The sequence starts with:

1. an original medicinal product whose quality, safety and efficacy were established in the EAEU or under member-state legislation;
2. if that is not feasible, an original medicinal product registered in an ICH-region country; under the conditions specified by Decision No. 85, a generic or hybrid medicinal product registered in an EAEU state and shown bioequivalent to the original may also be considered, with the required Expert Committee involvement;
3. a medicinal product specifically accepted by the EAEU Expert Committee;
4. in defined circumstances, a product with at least 20 years of use in an EAEU member state and accepted by the Expert Committee;
5. specific routes for fixed-combination reference products.

This hierarchy is important because global companies often start from the comparator used for EU, US, Chinese or WHO-prequalification development. That comparator may be scientifically useful yet not automatically be the correct regulatory comparator for the EAEU programme.

For Russia, the GRLS/interchangeability information maintained with the involvement of the Russian expert institution can also help identify the nationally recognized reference/interchangeability history of marketed products. The Russian expert institution states that its interchangeability lists are updated regularly in the State Register.

But the EAEU bioequivalence comparator decision is still made under Decision No. 85.

Pharegis therefore documents comparator selection before comparator procurement and before comparative dissolution batches are committed.

Step 3: prove high solubility under the EAEU definition

An active substance is considered highly soluble when the maximum single therapeutic dose is completely soluble in 250 ml or less of aqueous buffer across the required physiological pH range.

The current EAEU rules require experimental evaluation across pH 1.2–6.8 at 37 ± 1°C, including at least pH 1.2, 4.5 and 6.8 and an additional pH where the substance shows its lowest solubility if that point falls inside the range.

The lowest measured solubility across the pH range is used for classification.

At least three replicate determinations are required for each condition/pH, using an appropriate validated analytical method and pharmacopoeial buffer systems.

Stability in the test media also matters. If the API degrades materially during the solubility experiment, the resulting value may not support a reliable BCS classification.

A database classification is therefore not enough where the EAEU dossier needs an experimentally defensible solubility package.

Step 4: establish permeability—or accept Class III conservatively

For Class I status, high permeability has to be demonstrated.

Decision No. 85 prefers evidence based on the extent of human absorption, such as absolute bioavailability or human mass-balance data.

The current threshold is at least 85% absorbed for a conclusion of high permeability under the specified criteria.

Published human data can be used where their quality and relevance can be assessed.

The EAEU rules also allow validated Caco-2 methodology in defined circumstances, particularly where passive diffusion can be demonstrated and the cellular method itself has been appropriately validated against model compounds with known human absorption.

If high permeability cannot be established, an otherwise highly soluble API is classified conservatively as Class III.

That does not automatically disqualify the product from a biowaiver—but it makes formulation similarity much more important.

Class I gives more formulation flexibility than Class III

The scientific logic is different for the two eligible classes.

Class I

A Class I substance is highly soluble and highly permeable. Because absorption is not strongly limited by either factor, the formulation can tolerate more excipient variation—provided those differences do not affect absorption.

Under the current EAEU rules, qualitative and quantitative differences in ordinary excipients can be acceptable.

However, excipients capable of affecting absorption should be qualitatively the same and quantitatively similar. The current EAEU rule uses a 10% difference limit for individual absorption-affecting excipients and a 10% cumulative difference for that group.

Potentially relevant excipients include, for example, sugar alcohols such as mannitol or sorbitol and surfactants such as sodium lauryl/dodecyl sulfate, depending on dose and mechanism.

Class III

For Class III substances, permeability is the limiting factor. An excipient that changes gastrointestinal transit, membrane transport or local solubilization can therefore change systemic exposure more easily.

The rules are correspondingly stricter.

For Class III products, the test and reference formulations should be qualitatively the same and quantitatively similar, apart from specified allowances such as certain coating/capsule-shell components and minor color/flavor differences.

Decision No. 85 provides explicit quantitative similarity parameters for fillers, disintegrants, binders, lubricants, glidants and excipients capable of affecting absorption.

This means a formulation can fail the biowaiver even where the API is unquestionably BCS Class III and the dissolution profiles look excellent.

Step 5: demonstrate the correct comparative dissolution behaviour

Comparative dissolution is the central product-level experiment in the BCS waiver.

Decision No. 85 requires comparison of the test and reference product using at least 12 dosage units of each product and pharmacopoeial dissolution conditions.

The standard comparison uses:

• pH 1.2;
• pH 4.5;
• pH 6.8;
• an additional medium at the pH of minimum solubility where relevant;
• 37 ± 1°C;
• Paddle Apparatus at 50 rpm or Basket Apparatus at 100 rpm under the stated conditions;
• no organic solvents or surfactants added to the dissolution medium for the ordinary BCS comparison.

The test batch should normally be at least 1/10 of commercial batch size or 100,000 dosage units, whichever is greater, unless another batch size is properly justified.

Class I dissolution criterion

For Class I, test and reference products should show either:

• very rapid dissolution: at least 85% dissolved within 15 minutes; or
• rapid dissolution: at least 85% within 30 minutes, with similar dissolution profiles across all media.

Where one product is very rapidly dissolving and the other is only rapidly dissolving, similarity should be demonstrated, normally using the f2 approach where applicable.

Class III dissolution criterion

For Class III, the requirement is stricter:

• both test and reference products should show very rapid dissolution — at least 85% within 15 minutes — and comparable behaviour across the required media.

This difference is one of the most important preformulation considerations for a Class III biowaiver.

f2 is not always required

Where both test and reference products dissolve at least 85% of the claimed amount within 15 minutes, Decision No. 85 treats the profiles as similar without requiring calculation of the similarity factor f2.

Where f2 is used, the ordinary methodological conditions for appropriate time points and variability have to be satisfied.

A common mistake is to force an f2 calculation onto highly variable data or to use sampling points that do not meet the rule assumptions.

Pharegis reviews the dissolution design before the study starts so that the resulting data are capable of supporting the intended regulatory conclusion.

A positive WHO “Biowaiver List” entry should trigger a feasibility assessment—not an automatic filing

WHO’s 2026 Biowaiver List is particularly useful for portfolio screening.

For manufacturers with dozens of immediate-release oral generics, it can identify APIs for which an in-vivo study may be avoidable and therefore help prioritize development resources.

The right operational use is:

WHO/ICH screen → EAEU Decision 85 eligibility review → formulation comparison → evidence-gap assessment → confirm biowaiver strategy.

The wrong use is:

API appears on WHO list → no BE study required.

The WHO list evaluates API-level suitability and model formulations within its own framework. The EAEU authority evaluates the actual test product, actual reference product, actual excipients, actual dissolution data and actual dossier.

Prodrugs can now qualify—but not every prodrug does

The 2024 amendments expressly allow BCS-based biowaiver for a prodrug where the substance is absorbed in the prodrug form and otherwise satisfies the relevant criteria.

If conversion occurs before intestinal absorption or the absorption mechanism cannot be adequately characterized under the BCS framework, the scientific basis becomes more complex.

A company should therefore not classify a prodrug solely on the properties of its active metabolite.

The relevant absorption entity must be established.

Different salts are only eligible in a narrow scenario

Decision No. 85 permits use of different simple salts of the same active moiety between test and reference products only where both salts qualify as BCS Class I, subject to the applicable requirements.

The waiver is not available simply because the different salt forms eventually generate the same pharmacologically active species.

Different esters, ethers, isomers, complexes or other derivatives are generally outside this simplified route because they can produce bioavailability differences that BCS experiments cannot reliably exclude.

This is a classic area where a proposed “generic” can become a hybrid-type regulatory problem.

Fixed-dose combinations require every component to qualify

A BCS biowaiver can be applied to a fixed-dose combination only where all active substances meet the applicable BCS requirements.

If the combination contains only Class I APIs, the formulation/excipient assessment follows the Class I logic.

If any active substance is Class III, the stricter Class III excipient logic applies to the combination.

Dissolution similarity must be demonstrated for each active substance under the applicable Class I or Class III criteria.

One ineligible component can therefore eliminate the BCS-waiver route for the whole fixed combination.

Every strength needs its own product-level assessment

BCS-based biowaiver and additional-strength waiver are related but different concepts.

Decision No. 85 states that the BCS-biowaiver approach is applied to each strength, including comparative dissolution against the corresponding reference strength.

A separate “additional strength” waiver can sometimes reduce the number of in-vivo studies in a conventional BE programme, but that does not mean one successful BCS assessment automatically covers every strength in a portfolio.

Pharegis therefore maps strength-by-strength:

API dose → high-solubility criterion → formulation proportionality → reference strength → excipient similarity → dissolution result.

What has to be submitted in the dossier

The BCS waiver is an evidence package, not a one-page justification.

Decision No. 85 expects documentation that can include:

• critical quality characteristics of the API and drug product;
• information on polymorphic form and stereochemical purity where relevant;
• known bioavailability/bioequivalence issues;
• API solubility study protocol and report;
• permeability/absorption evidence;
• Caco-2 validation and study data where used;
• complete qualitative and quantitative excipient comparison;
• risk assessment for excipients capable of affecting absorption;
• comparative dissolution protocols and reports;
• analytical-method validation;
• batch numbers, manufacture dates, batch size and expiry information;
• individual and mean dissolution results and graphical data;
• comparator identification and regulatory justification.

The dossier should allow the assessor to reproduce the reasoning from raw evidence to the final conclusion.

Where biowaiver projects most often fail

The recurring failure modes are predictable:

• relying on a published BCS class without demonstrating that the evidence is suitable for the EAEU dossier;
• using the wrong reference medicinal product;
• assuming a WHO Biowaiver List entry is automatically accepted in the EAEU;
• using maximum strength instead of the current EAEU maximum-single-therapeutic-dose concept without checking the exception logic;
• failing to study the pH of minimum solubility;
• classifying permeability from weak literature data;
• overlooking narrow therapeutic index exclusion;
• treating Class III excipients as if the more permissive Class I rules applied;
• using a test formulation that differs materially from the reference in absorption-sensitive excipients;
• manufacturing a pilot batch too small to meet the Decision No. 85 expectation without justification;
• performing comparative dissolution under non-compliant media, apparatus or sampling conditions;
• filing f2 calculations that are invalid because variability criteria are not met;
• attempting to bridge different salts, derivatives or strengths without a valid regulatory basis;
• deciding on a biowaiver only after the pivotal formulation has already been locked.

The best time to evaluate a biowaiver is during formulation strategy—not after the clinical-development budget is approved.

How Pharegis determines whether a product is suitable

Pharegis can perform a staged BCS-biowaiver feasibility assessment before the manufacturer commits to a BE study.

Typical work products include:

• reference-product selection memo under the current Decision No. 85 hierarchy;
• review of Russian GRLS/reference-product history where relevant;
• WHO 2026 Biowaiver List and ICH M9 screening;
• BCS classification evidence review for the API;
• assessment of whether new experimental solubility or permeability work is needed;
• maximum-single-therapeutic-dose/high-solubility assessment;
• excipient Q1/Q2 comparison and absorption-risk analysis;
• Class I vs Class III formulation suitability assessment;
• comparative-dissolution protocol review;
• batch-size and batch-representativeness assessment;
• f2/statistical review where required;
• multi-strength and fixed-combination strategy;
• regulatory justification and Module 2/5 dossier integration;
• expert-query support if the biowaiver is challenged during assessment.

Where laboratory work is required, Pharegis can coordinate the necessary solubility, comparative dissolution or related analytical studies with suitable laboratories and review the resulting reports before they enter the registration dossier.

A practical go/no-go screen

A product is a strong candidate for a BCS biowaiver when the answers to the following questions are all favorable:

1. Is it an immediate-release oral systemic product eligible under Appendix No. 4?
2. Is the therapeutic index sufficiently wide for the BCS route?
3. Is the correct EAEU reference product identified and obtainable?
4. Is the API demonstrably BCS Class I or Class III under the current EAEU criteria?
5. Does the test formulation satisfy the relevant Class I/Class III excipient rules?
6. Can the test and reference products meet the required comparative dissolution criteria?
7. Is the test batch representative and of acceptable scale?
8. Can the complete scientific evidence be documented in the dossier?

If one answer is uncertain, that point should be investigated before an in-vivo BE study is cancelled.

Discuss a biowaiver feasibility assessment

For an initial review, prepare:

• active substance and salt/form;
• dosage form and strengths;
• proposed EAEU reference product;
• maximum single therapeutic dose;
• test and reference qualitative/quantitative formulations where available;
• existing BCS classification or solubility/permeability data;
• dissolution data;
• pilot/commercial batch size;
• intended manufacturing process;
• any existing WHO, ICH, EMA, FDA or other regulatory biowaiver assessment;
• target EAEU filing date.

Pharegis can then determine whether the product is a realistic BCS-biowaiver candidate, identify the missing evidence and compare the cost and regulatory risk of the waiver route against a conventional in-vivo bioequivalence study.

The objective is not to avoid a clinical study at any cost. It is to avoid an in-vivo study when the EAEU rules already allow the same bioequivalence conclusion to be demonstrated scientifically in vitro.

Regulatory and scientific basis

• EEC Council Decision No. 85 of 3 November 2016 — Rules for Conducting Bioequivalence Studies of Medicinal Products in the EAEU.
• EEC Council Decision No. 30 of 12 April 2024 — current major revision of reference-product selection and Appendix No. 4 BCS-based biowaiver requirements.
• ICH M9 — Biopharmaceutics Classification System-based Biowaivers.
• WHO TRS 1067, Annex 7 (2026) — current WHO Biowaiver List for immediate-release solid oral dosage forms on the Model List of Essential Medicines.
• WHO List of International Comparator Products, updated January 2026 — international comparator information useful for equivalence-development planning.
• Russian State Register / NCESMP interchangeability information — national reference/interchangeability context for medicinal products registered in Russia.

Regulatory status reviewed: August 2026.