Bioequivalence

Bioequivalence refers to the absence of a significant difference in the rate and extent of absorption of the active substance from two drug products when administered at the same molar dose under similar conditions. It is generally assessed by comparing the pharmacokinetic parameters of a test product and a reference product against predefined acceptance limits.

Definitions

US FDA

Under 21 CFR 314.3 bioequivalence is defined as:

Bioequivalence is the absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study. Where there is an intentional difference in rate (e.g., in certain extended-release dosage forms), certain pharmaceutical equivalents or alternatives may be considered bioequivalent if there is no significant difference in the extent to which the active ingredient or moiety from each product becomes available at the site of drug action. This applies only if the difference in the rate at which the active ingredient or moiety becomes available at the site of drug action is intentional and is reflected in the proposed labeling, is not essential to the attainment of effective body drug concentrations on chronic use, and is considered medically insignificant for the drug. For drug products that are not intended to be absorbed into the bloodstream, bioequivalence may be assessed by scientifically valid measurements intended to reflect the rate and extent to which the active ingredient or active moiety becomes available at the site of drug action 1.

EMA

The European Medicines Agency defines bioequivalence as:

Two medicinal products containing the same active substance are considered bioequivalent if they are pharmaceutically equivalent or pharmaceutical alternatives and their bioavailabilities (rate and extent) after administration in the same molar dose lie within acceptable predefined limits. These limits are set to ensure comparable in vivo performance, i.e. similarity in terms of safety and efficacy 2.

ICH

Under the International Council for Harmonisation bioequivalence is:

Two drug products containing the same drug(s) are considered bioequivalent if their relative bioavailability (BA) (rate and extent of drug absorption) after administration in the same molar dose lies within acceptable predefined limits. These limits are set to ensure comparable in vivo performance, i.e., similarity in terms of safety and efficacy 3.

Assessment of Bioequivalence

Bioequivalence is commonly assessed when comparing a generic medicinal product with its reference product. The products may differ in excipients, manufacturing processes, or other formulation characteristics while containing the same active substance. Demonstration of bioequivalence, together with satisfaction of other applicable requirements, may support a determination of therapeutic equivalence under the relevant regulatory framework.

The principal pharmacokinetic parameters evaluated are:

  • Area under the concentration-time curve (AUC). A measure of the extent of systemic exposure to the active substance.
  • Maximum plasma concentration (Cmax). The highest measured plasma concentration, reflecting peak systemic exposure.
  • Time to maximum plasma concentration (Tmax). The time at which Cmax is reached, providing information about the rate of absorption.

For many conventional bioequivalence assessments, the 90% confidence intervals for the test-to-reference ratios of AUC and Cmax must fall within predefined acceptance limits, commonly 80.00%-125.00%. The applicable parameters and acceptance criteria depend on the product and relevant regulatory requirements.

Bioequivalence does not require identical concentration-time profiles or identical formulations. It requires the comparative pharmacokinetic results to satisfy the applicable acceptance criteria.

Scope and Limitations

Bioequivalence demonstrates comparability in the rate and extent of systemic exposure to an active substance under specified study conditions. It does not establish that two products have identical formulations, identical pharmacokinetic profiles, or identical clinical effects in every patient.

Bioequivalence alone does not establish:

  • Pharmaceutical identity. Products may differ in excipients, manufacturing processes, and other formulation characteristics.
  • Identical clinical outcomes. Bioequivalence does not demonstrate identical efficacy or safety outcomes in every patient or clinical setting.
  • Absence of all safety risks. It does not exclude adverse reactions associated with excipients, product quality, or individual patient characteristics.
  • Overall product quality. It does not replace applicable requirements for pharmaceutical quality, manufacturing, stability, or regulatory approval.

Related Terminology

References

  1. U.S. Food and Drug Administration. 21 CFR § 314.3 – Definitions. Electronic Code of Federal Regulations. Available at: https://www.ecfr.gov/current/title-21/chapter-I/subchapter-D/part-314/subpart-A/section-314.3 ↩︎
  2. European Medicines Agency. 2010. Guideline on the Investigation of Bioequivalence (Rev. 1). Reference No. CPMP/EWP/QWP/1401/98 Rev. 1. Available at: https://www.ema.europa.eu/en/scientific-guidelines/investigation-bioequivalence ↩︎
  3. International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). 2024. M13A: Bioequivalence for Immediate-Release Solid Oral Dosage Forms. Final version, adopted 23 July 2024. Available at: https://www.ich.org/page/multidisciplinary-guidelines ↩︎