ICH M13B Guideline: Additional Strengths Biowaiver for Immediate-Release Solid Oral Dosage Forms

9 hours ago

4 min read

ICH M13B Guideline: Additional Strengths Biowaiver for Immediate-Release Solid Oral Dosage Forms

The European Medicines Agency (EMA) has adopted the ICH M13B Guideline on Bioequivalence for Immediate-Release Solid Oral Dosage Forms – Additional Strengths Biowaiver, together with a related Questions and Answers (Q&A) document. The guideline provides recommendations for obtaining a biowaiver for one or more additional strengths when in vivo pharmacokinetic bioequivalence or efficacy/safety has already been demonstrated for at least one strength. The guideline is scheduled to come into effect on 17 March 2027.

Part 1: EMA – ICH M13B Guideline – Additional Strengths Biowaiver

The main ICH M13B guideline establishes the scientific and technical considerations for demonstrating bioequivalence of additional strengths of an immediate-release solid oral dosage form. It applies to products such as tablets, capsules and granules or powders for oral suspension intended to deliver drugs to the systemic circulation.

Selection of the Biobatch Strength

The biobatch strength is selected based on the pharmacokinetic dose proportionality of the drug. Once bioequivalence has been demonstrated for the relevant strength, additional strengths may potentially qualify for a biowaiver based on their relationship with the biobatch strength.

Formulation and Manufacturing

The additional strengths should generally have the same qualitative composition as the biobatch strength, with the core formulation being quantitatively proportional.

The guideline allows certain deviations from direct proportionality when appropriately justified. The manufacturing process for the additional strengths should also be representative of the biobatch manufacturing process, including the type and operating principle of the equipment.

Comparative Dissolution

Comparative in vitro dissolution is a key element of the additional-strength biowaiver approach.

Testing should generally use three standardised dissolution media covering approximately pH 1.2, 4.5 and 6.8. At least 12 replicates of the additional strength and biobatch strength should generally be evaluated.

Where both strengths demonstrate very rapid dissolution, no further mathematical evaluation may be required. Where mathematical comparison is necessary, an f₂ value of ≥50 can support dissolution similarity when the specified variability conditions are met.

When In Vivo BE May Be Required

An additional-strength biowaiver may not be appropriate when there is dissolution dissimilarity, significant deviation from direct formulation proportionality or certain situations involving non-dose-proportional pharmacokinetics.

The guideline also describes a bracketing approach, where the highest and lowest strengths may be selected for in vivo BE assessment to support a waiver for intermediate strengths when the relevant conditions are met.

Documentation

The biowaiver submission should include the scientific rationale for the strategy and biobatch selection, formulation information, dissolution methodology, batch details, sampling information, dissolution results, similarity assessment and conclusions.

Part 2: ICH M13B Q&A – EMA – Practical Clarifications

The ICH M13B Q&A was developed following questions received during the M13B public consultation. It provides additional clarification on several concepts to support consistent and harmonised application of the guideline.

M13B and ICH M9

The Q&A clarifies the distinction between ICH M13B and ICH M9.

ICH M9 addresses BCS-based biowaivers and focuses on the relationship between a test product and a comparator product. ICH M13B, in contrast, focuses on the relationship between different strengths within the same product line.

M13B uses previously established in vivo BE data together with formulation and in vitro dissolution information and is not limited to a particular BCS class.

Deviations from Formulation Proportionality

The Q&A explains that deviations from direct proportionality are intended primarily for situations where small quantitative excipient adjustments are needed for practical manufacturing reasons.

Such deviations should remain within the ranges described in the guideline and should be scientifically justified. Deviations beyond the specified ranges require additional information to support bioequivalence.

When the Biobatch Is Unavailable

The same batch used in the BE study should generally be used for comparative dissolution testing.

If the original biobatch is unavailable, representative batches may be considered in appropriate circumstances. These batches should represent the formulation and manufacturing process of the biobatch, with appropriate scientific justification.

Dissolution Testing Clarifications

The Q&A provides additional clarification for dissolution studies involving solubility limitations, multiple units, filtration and methodological issues.

Where equivalent doses cannot be achieved using one unit of each strength, combinations of units may be considered. Two to three units are generally considered acceptable, while using more units requires consideration and justification of potential effects on dissolution vessel hydrodynamics.

Dissolution Media and pH

The Q&A clarifies that minor deviations of approximately ±0.05 pH units from the specified dissolution media pH values may generally be acceptable when the pH is controlled, documented and consistent across the strengths being compared.

Significant deviations or alternative pH selections should be scientifically justified and documented.

Sampling and f₂ Assessment

Sampling should adequately characterise the dissolution profile through completion of dissolution or a plateau.

The Q&A provides examples of sampling schedules depending on whether dissolution is rapid, moderately rapid or slow.

For f₂ calculations, the guideline recommends no more than six sampling time points in principle, unless additional time points are scientifically justified.