Registering a Modified-Release Generic in the EAEU Requires Two Bioequivalence Studies. Here Is Why
A 500 mg immediate-release metformin tablet and a 500 mg metformin XR tablet look almost identical on a pharmacy shelf. For the regulator, however, they are fundamentally different objects. Proving the bioequivalence (BE) of the latter is several times more demanding: two clinical studies instead of one, an analysis of partial areas under the pharmacokinetic curve, and dissolution testing in three pH media including an ethanol-containing medium. If these requirements were overlooked during development planning, the problems will surface at the expert review stage.
Below, we examine exactly what the EAEU requires for MR forms (modified release, hereafter MR), and where the most common difficulties arise when preparing a dossier.
Why an MR Form Cannot Be Registered as an Ordinary Generic
A standard immediate-release generic is registered through a fasting BE study. For most products, this is sufficient. The logic is straightforward: the form dissolves rapidly, absorption follows much the same pattern as the originator, and two parameters are enough to compare — AUC (area under the plasma concentration-time curve) and Cmax (maximum plasma concentration).
This approach does not work for MR forms. Here, the dosage form mechanism itself controls substance release: a polymer matrix, a functional coating, or an osmotic system. The manufacturer must reproduce the release profile. Identical composition alone does not guarantee this: both products must behave identically throughout the dosing interval in the gastrointestinal (GI) tract, whether that interval is 12 or 24 hours.
Total AUC may match while the shape of the curve does not. If a generic releases the substance faster in the early hours and more slowly toward the end of the interval, the patient will experience a sharper concentration peak and a trough before the next dose. This is exactly what the EAEU aims to prevent.
Types of MR Forms
The MR designation covers several fundamentally different technologies.
Prolonged release (PR) — the substance is released slowly over several hours. The goal is to reduce dosing frequency and smooth out «peak-to-trough» concentration fluctuations. Common examples: metformin XR, metoprolol ER, verapamil SR.
Delayed release (DR) — release does not begin immediately after administration. Most often these are enteric-coated forms: the coating protects the substance from the acidic gastric environment, or conversely protects the gastric mucosa from the drug’s irritating effect. Dissolution begins at the appropriate pH in the intestine.
Pulsatile release — the substance is released in discrete portions at set intervals. Less common; used where chronobiological rhythms need to be mimicked.
Multiphasic forms — combine components with different release rates. Part of the dose is released immediately for a rapid onset of action; the remainder is released in a prolonged fashion to maintain the effect.
The type of modification directly influences the BE study design. A single protocol cannot be applied to all MR forms, and Recommendation No. 2 of the EEC Collegium, dated January 16, 2018 (hereinafter Recommendation No. 2), reflects this.
What Recommendation No. 2 Requires for Systemic MR Forms
Two Studies Instead of One
The key difference from a standard generic: most oral MR forms of systemic action require two BE studies — fasting and fed. For an ordinary generic, the fed study is often unnecessary.
Why does food matter so much for MR forms? A high-fat meal slows gastric emptying, alters pH across different GI segments, and prolongs drug-mucosa contact time. If the polymer matrix is sensitive to these conditions, the release profile will change. Recommendation No. 2 specifies a standard fed-study protocol: a high-calorie, high-fat breakfast (approximately 800-1000 kcal, with about half the calories from fat). This is a stress test for the dosage form. The Bioequivalence Rules (EEC Council Decision No. 85 of November 3, 2016, as amended by Decision No. 22 of February 15, 2023) further specified the protocol: unless the reference product’s summary of product characteristics (SmPC) provides other instructions, subjects must begin eating 30 minutes before taking the drug and finish within that same 30-minute window.
Enteric-coated DR forms undergo both studies even though the coating isolates the substance from gastric acid. In practice, delayed gastric emptying after a meal affects the onset of dissolution — and this matters when comparing with the reference.
Partial AUC Instead of Total AUC
Another requirement without which an MR BE program is incomplete: analysis of partial areas under the curve (partial AUC, pAUC). For a standard generic, total AUC from time zero to the last measured timepoint and from zero to infinity is compared. For MR forms, this is not sufficient.
Total AUC will confirm that both products delivered the same overall amount of drug. It will not reveal how absorption was distributed over time. Two products with identical total AUC can have completely different profiles: one produces a peak in the first three hours; the other delivers drug uniformly across the entire interval.
pAUC divides the curve into time segments. Typically, both an early interval (up to the Tmax of the reference product) and a late interval are assessed. If the early pAUC diverges, the absorption rates in the initial phase differ; if the late pAUC diverges, the product fails to maintain concentration toward the end of the dosing interval. Both deviations are clinically significant.
| Parameter | Standard Generic | MR Form |
|---|---|---|
| AUC (0-t) | Required | Required |
| AUC (0-∞) | Required | Required |
| Cmax | Required | Required |
| pAUC (early) | Not required | Required |
| pAUC (late) | Not required | Required |
| Fed study | Often not required | Required for most forms |
Statistical evaluation uses the 90% confidence interval (CI) of the geometric mean ratio. Standard acceptance limits are 80-125%. For narrow therapeutic index (NTI) drugs, these limits are tightened, because even small deviations in concentration can lead to toxicity or loss of effect.
Dissolution in Multiple pH Media and the Alcohol Test
In parallel with the clinical program, comparative in vitro dissolution tests are conducted. For MR forms, testing is performed in at least three media: pH 1.2 (gastric conditions), 4.5, and 6.8 (different intestinal segments). Timepoints are selected to fully characterise the release profile rather than simply capture an endpoint. For prolonged-release forms, these are typically 1, 2, 4, 6, 8, and 12 hours.
Profile comparison uses the similarity factor f2. A value between 50 and 100 indicates similarity; below 50, profiles are considered dissimilar and an explanation or additional data is required.
A separate requirement that is frequently overlooked at the development planning stage: the alcohol resistance test. Ethanol can dissolve polymer matrices and coatings, causing a sharp, accelerated release of the entire dose — the phenomenon known as dose dumping. For the patient, this means: one tablet taken with a glass of wine, and the full daily dose reaches systemic circulation within an hour. The consequences can be serious for opioid analgesics, antiarrhythmics, or antihypertensive drugs with a narrow therapeutic index.
Dissolution is tested in media supplemented with ethanol at 5%, 20%, and 40%. If the release profile accelerates markedly compared with the ethanol-free medium, this is either grounds for refusing registration or justification for strong warnings in the SmPC.
Prohibition on Splitting and Chewing
One more requirement that must appear in the SmPC and on labelling. Most MR tablets must not be split or chewed unless the design specifically allows this (a functional score line with appropriate justification). Destroying the matrix or coating converts a prolonged-release form into an immediate-release tablet delivering an excessively high single dose. The regulator requires that this restriction be stated clearly on the label.
When the MR Form Acts Locally
Oral MR forms of systemic action and MR forms of local action are governed by different logic. The Bioequivalence Rules, as amended in 2023, were supplemented with three appendices devoted specifically to locally acting forms.
This group includes products for which any systemic exposure is undesirable: anti-inflammatory agents acting in the intestinal lumen (for example, in inflammatory bowel disease treatment), as well as topical MR preparations — creams, ointments, and gels with delayed or sustained substance release.
Special methods are required for these forms: in vitro release testing (IVRT) using diffusion cells, in vitro permeation testing (IVPT), and the tape-stripping (stratum corneum sampling) method. The evidentiary framework is structured differently: pharmaceutical quality data and in vitro results are evaluated first, and only if these are insufficient does the dossier proceed to clinical therapeutic equivalence studies.
The requirements for a modified-release ointment and for a prolonged-release oral tablet are fundamentally different. Confusing them at the development planning stage is an expensive mistake.
When a Biowaiver is Available for MR Forms
A biowaiver exempts a product from in vivo studies if certain conditions are met. For standard generics, it is available when the active substance belongs to Class I or Class III of the Biopharmaceutics Classification System (BCS).
For oral systemic MR forms, this route is closed. The BCS biowaiver works for standard generics because absorption rate is determined by the properties of the active substance itself. For MR forms, absorption rate is controlled by the dosage form. An in vitro dissolution test cannot substitute for a living organism when assessing how a polymer matrix or coating behaves in the dynamic GI environment with its variable pH, motility patterns, and transit time.
One alternative is available: the strength proportionality biowaiver. If a manufacturer’s portfolio includes several strengths of the same MR product with an identical release mechanism and proportional composition, the BE study needs to be conducted only for one strength (usually the highest or most sensitive), while the remaining strengths are supported by comparative dissolution testing. This saves time and cost, but requires rigorous documented justification of proportionality.
What to Do
Registration of an MR product begins long before dossier submission. The critical decisions are made during development planning, and this is precisely where the errors most often detected during expert review originate.
Determine the MR form type and its specific requirements before starting formulation work. Systemic prolonged release, enteric-coated forms, locally acting GI products, topical preparations — each type has its own evidentiary framework.
Plan both BE studies from the outset. A fasting-plus-fed programme requires more subjects and more time. If the budget covers only one study, revision is unavoidable. Better to know this before the programme starts.
Include the alcohol test in the dissolution protocol during formulation development. Testing in 5%, 20%, and 40% ethanol must be part of composition development, not an add-on at dossier preparation. If the matrix does not survive 40% ethanol, it is far better to know that early.
Verify proportionality across all strengths. If multiple strengths are planned, confirm that the composition is genuinely proportional and the release mechanism is identical. This is what enables the strength proportionality biowaiver.
For locally acting MR forms, study Appendices 11-13 of the Bioequivalence Rules (EEC Council Decision No. 85, current version). The study programme for a modified-release ointment is structured differently from that for an oral tablet.
Regulatory basis:
1. Recommendation of the Eurasian Economic Commission Collegium No. 2, dated January 16, 2018, on the Guideline for Bioequivalence Studies of Modified-Release Medicinal Products within the EAEU
2. EEC Council Decision No. 85, dated November 3, 2016, on Approval of the Rules for Conducting Bioequivalence Studies within the EAEU (as amended by EEC Council Decision No. 22 of February 15, 2023)