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

Draft Guidance for Industry: M13B – Bioequivalence for Immediate-Release Solid Oral Dosage Forms: Additional Strengths Biowaiver (May 2025):

Background & Purpose

• Developed under the ICH M13 series to harmonize global requirements for bioequivalence (BE) assessment of immediate-release (IR) solid oral dosage forms (tablets, capsules, granules/powders for suspension).

• Objective: Reduce the need for duplicative in vivo BE studies for multiple strengths of the same drug product by allowing biowaivers when certain scientific criteria are met.

• Builds on ICH M13A (finalized Oct 2024), which covers BE for IR solid oral dosage forms using PK endpoints.

Scope

• Applies during development and post-approval for:

  • IR solid oral dosage forms intended for systemic absorption.

  • Additional strengths of a drug product where in vivo BE has been demonstrated for at least one strength

Key Criteria for Biowaiver

1. Pharmacokinetic (PK) Dose Proportionality

   • PK parameters (Cmax, AUC) should scale proportionally with dose across strengths.

2. Formulation Similarity

   • Qualitative sameness: All strengths must contain the same inactive ingredients.

   • Quantitative proportionality: Excipients should be in the same ratio across strengths.

   • Exceptions:

     • High-potency drugs (API ≤5% of core weight): Minor filler adjustments allowed if functionally equivalent.

     • Coating or capsule shell differences discouraged unless justified.

3. Manufacturing Process

   • All strengths should be manufactured using the same process to ensure consistent performance.

4. Dissolution Testing

   • Conducted in three media (pH 1.2, 4.5, 6.8) at 37°C using USP paddle/basket apparatus.

   • Criteria:

     • ≥85% drug dissolved within 15 min → no further analysis.

     • If not met, demonstrate similarity using f₂ similarity factor or bootstrap methods (especially if variability >8%).

   • Minimum 12 units per strength tested.

Additional Considerations

• Fixed-Dose Combinations (FDCs): Criteria apply to each active component.

• Bracketing: May be used when proportionality criteria are not fully met, with justification.

• Documentation: Biowaiver report must include:

  • Rationale for biobatch selection.

  • Comparative formulations and excipient composition.

  • Dissolution data and similarity analysis.

Impact

• Regulatory Efficiency: Reduces cost and time by avoiding unnecessary in vivo studies.

• Global Harmonization: Aligns BE requirements across ICH regions.

• Supports Faster Access: Facilitates approval of multiple strengths for patient dose flexibility.

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