When can additional strengths be waived from bioequivalence testing?

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SFDA: “If bioequivalence has been demonstrated at the strength(s) that are most sensitive to detect a potential difference between products, in vivo bioequivalence studies for the other strength(s) can be waived.” (SFDA BE v3.1 · 3.1.6 Strength to be investigated) “The following general requirements must be met where a waiver for additional strength(s) is claimed: a) the pharmaceutical products are manufactured by the same manufacturing process, b) the qualitative composition of the different strengths is the same, c) the composition of the strengths are quantitatively proportional, i.e. the ratio between the amount of each excipient to the amount of active substance(s) is the same for all strengths …” (SFDA BE v3.1 · 3.1.6 Strength to be investigated – General biowaiver criteria) “… appropriate in vitro dissolution data should confirm the adequacy of waiving additional in vivo bioequivalence testing (see section 3.2). Comparative dissolution testing should be conducted on 12 dosage units each of all strengths of the test with biobatch.” (SFDA BE v3.1 · 3.1.6 Strength to be investigated – General biowaiver criteria (d)) EU: “In general, PK can be considered dose proportional if the difference in dose-adjusted mean Cmax and AUC is no more than 25% when comparing the range of strengths proposed. For the purpose of an additional strength waiver, AUC and Cmax are evaluated to demonstrate proportionality, however, should the available data establish dose proportional PK for AUC but the available data for Cmax are insufficient, e.g., due to variability, to make a conclusion, the PK can be treated as dose proportional.” (ICH M13A · 2.1.6) “The following general requirements must be met where a waiver for additional strength(s) is claimed: a) the pharmaceutical products are manufactured by the same manufacturing process, b) the qualitative composition of the different strengths is the same, c) the composition of the strengths are quantitatively proportional, i.e. the ratio between the amount of each excipient to the amount of active substance(s) is the same for all strengths (for immediate release products coating components, capsule shell, colour agents and flavours are not required to follow this rule)” (EMA BE guideline · 4.1.6) “… d) appropriate in vitro dissolution data should confirm the adequacy of waiving additional in vivo bioequivalence testing (see section 4.2).” (EMA BE guideline · 4.1.6) US FDA: “An in vivo BE requirement for one or more strength(s) can be waived based on (1) acceptable BE study or studies on the designated strength, (2) acceptable in vitro dissolution testing of all the strengths, and (3) proportional similarity of the formulations across all strengths.” (FDA ANDA BE 2026 · IV.B.2) “All active and inactive ingredients are in similar proportion between different strengths (e.g., a tablet of 50-milligram (mg) strength has for the active and inactive ingredients almost half that of a tablet of 100-mg strength, and almost twice that of a tablet of 25-mg strength).” (FDA ANDA BE 2026 · IV.B.2) “Under any of the above scenarios, FDA recommends that in vivo BE studies be accompanied by in vitro dissolution profiles on all strengths of each product in the selected quality control method.  See section V.F, In Vitro Dissolution Testing for more information.  FDA recommends that the similarity factor (f2) test or other appropriate statistical approach (e.g., multivariate model-independent approach or a model-dependent approach) be used to compare dissolution profiles.” (FDA ANDA BE 2026 · IV.B.2) WHO: “Under certain conditions, approval of different strengths of a multisource product can be considered on the basis of dissolution profiles if the formulations have proportionally similar compositions.” (WHO TRS 1052 Annex 8 · 10.3) “… the dissolution profiles for the different strengths are similar at pH 1.2, 4.5, 6.8 and for the quality control media, unless justified by the absence of sink conditions.” (WHO TRS 1052

When can additional strengths be waived from bioequivalence testing?

SFDA Saudi Food and Drug Authority

EU European Union

US FDA US Food and Drug Administration

WHO World Health Organization

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