What are the bioequivalence acceptance limits for AUC and Cmax (90% confidence interval)?

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Accepted Answer

SFDA: “In studies to determine bioequivalence after a single dose, the parameters to be analyzed are AUC(0-t), or, when relevant, AUC(0-72h), and Cmax. For these parameters the 90% confidence interval for the ratio of the test and reference products should be contained within the acceptance interval of 80.00-125.00%.” (SFDA BE v3.1 · 3.1.8 Evaluation – Parameters to be analyzed and acceptance limits) “To be inside the acceptance interval the lower bound should be ≥ 80.00% when rounded to two decimal places and the upper bound should be ≤ 125.00% when rounded to two decimal places.” (SFDA BE v3.1 · 3.1.8 Evaluation – Parameters to be analyzed and acceptance limits) “For studies to determine bioequivalence of immediate release formulations at steady state, AUC(0-τ) and Cmax,ss should be analyzed using the same acceptance interval as stated above.” (SFDA BE v3.1 · 3.1.8 Evaluation – Parameters to be analyzed and acceptance limits) EU: “The 90% confidence interval for the geometric mean ratio of these PK parameters used to establish BE should lie within a range of 80.00 - 125.00%.” (ICH M13A · 2.2.4) “The assessment of BE is based on 90% confidence intervals for the geometric mean ratios (test/comparator) for the primary PK parameters under consideration.” (ICH M13A · 2.2.3.1) “To be inside the acceptance interval the lower bound should be ≥ 80.00% when rounded to two decimal places and the upper bound should be ≤ 125.00% when rounded to two decimal places.” (EMA BE guideline · 4.1.8) US FDA: “The assessment of BE is based on 90% confidence intervals for the geometric mean ratios (test/comparator) for the primary PK parameters under consideration.” (FDA M13A · 2.2.3.1) “For a broad range of drugs, a BE limit of 80.00 percent to 125.00 percent for the ratio of the product averages has been adopted for use of an average BE criterion.” (FDA Statistical Approaches 2026 · I.B, footnote 6) “For unscaled average BE analyses, to pass a confidence interval limit of 80 to 125 percent, the rounded confidence interval value should be at least 80.00 percent and not more than 125.00.” (FDA ANDA BE 2026 · Appendix (Confidence interval values for unscaled average BE analyses)) WHO: “The 90% confidence interval for this measure of relative bioavailability should lie within a bioequivalence range of 80.00–125.00%.” (WHO TRS 1052 Annex 8 · 7.7 — AUC0–t ratio) “For maximal concentration data, the acceptance limit of 80.00–125.00% should be applied to the 90% confidence interval for the mean Cmax ratio.” (WHO TRS 1052 Annex 8 · 7.7 — Cmax ratio) “The same criterion applies to the parameter AUCτ in multiple-dose studies and for partial AUCs if they are necessary for comparative testing of a modified-release product.” (WHO TRS 1052 Annex 8 · 7.7 — AUC0–t ratio)

What are the bioequivalence acceptance limits for AUC and Cmax (90% confidence interval)?

SFDA Saudi Food and Drug Authority

EU European Union

US FDA US Food and Drug Administration

WHO World Health Organization

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