Bioequivalence & biowaivers

For dosage forms such as tablets, capsules and oral suspensions, bioequivalence studies are required unless a biowaiver is applicable (see Appendix III). SFDA BE v3.1 · Appendix II – Oral immediate release dosage forms with systemic action

It also sets the relevant criteria under which bioavailability studies need not be required (either waiver for additional strength, see section 3.1.6, a specific type of formulation, see Appendix II or BCS based biowaiver, see Appendix III). SFDA BE v3.1 · 2. Scope

Bioequivalence studies are generally not required if the test product is to be administered as an aqueous intravenous solution containing the same active substance as the currently approved product. SFDA BE v3.1 · Appendix II – Parenteral solutions

For dosage forms such as tablets, capsules and oral suspensions, bioequivalence studies are required unless a biowaiver is applicable (see APPENDIX III). EMA BE guideline · Appendix II

It also sets the relevant criteria under which bioavailability studies need not be required (either waiver for additional strength, see section 4.1.6, a specific type of formulation, see Appendix II or BCS based Biowaiver, see Appendix III). EMA BE guideline · 2

The Biopharmaceutics Classification System (BCS)-based biowaiver may be used to waive in vivo BE studies for certain orally administered IR solid dosage forms as delineated in ICH M9, Biopharmaceutics Classification System-Based Biowaivers. ICH M13A · 1.2.1

Any person submitting an abbreviated new drug application to FDA shall include in the application either: (1) Evidence demonstrating that the drug product that is the subject of the abbreviated new drug application is bioequivalent to the reference listed drug (defined in § 314.3(b) of this chapter ). 21 CFR 320 · § 320.21(b)(1)

Except as provided in paragraph (f) of this section, FDA shall waive the requirement for the submission of evidence of in vivo bioavailability or bioequivalence if the drug product meets any of the provisions of paragraphs (b), (c), (d), or (e) of this section. 21 CFR 320 · § 320.22(a)

For example, an in vivo BE data requirement can be waived for an oral solution if the formulation has the same active ingredient in the same concentration and dosage form as the RLD and does not contain any excipient that significantly affects drug absorption or availability. FDA ANDA BE 2026 · IV.A

In vivo documentation of equivalence is necessary when there is a risk that possible differences in bioavailability may result in therapeutic inequivalence (2). WHO TRS 1052 Annex 8 · 5.1

(a) oral, immediate-release pharmaceutical products with systemic action, except for the conditions outlined in section 10; WHO TRS 1052 Annex 8 · 5.1 (a)

In the following circumstances, multisource pharmaceutical products are considered to be equivalent without the need for further documentation. (a) When the pharmaceutical product is to be administered parenterally (for example, intravenously, subcutaneously or intramuscularly) as an aqueous solution containing the same API in the same molar concentration as the comparator product and the same or similar excipients in comparable concentrations to those in the comparator product. WHO TRS 1052 Annex 8 · 4 (a)

If two formulations are compared, a randomized, two-period, two-sequence single dose crossover design is recommended. SFDA BE v3.1 · 3.1.1 Study design – Standard design

The treatment periods should be separated by a wash out period sufficient to ensure that drug concentrations are below the lower limit of bioanalytical quantification in all subjects at the beginning of the second period. Normally at least 5 elimination longest half-lives are necessary to achieve this. SFDA BE v3.1 · 3.1.1 Study design – Standard design

In order to reduce variability not related to differences between products, the studies should normally be performed in healthy volunteers unless the drug carries safety concerns that make this unethical. SFDA BE v3.1 · 3.1.3 Subjects – Selection of subjects

A randomised, single-dose, crossover study design is recommended when comparing test and comparator formulations, as single-dose studies provide the most sensitive conditions to detect differences in the rate and extent of absorption. Treatment periods should be separated by a sufficiently long washout period, e.g., at least 5 elimination half-lives (see Section 2.2.3.3). ICH M13A · 2.1.2

For drugs with long elimination half-lives, a randomised parallel design may be employed when a crossover design is impractical due to the need for a prolonged washout period. ICH M13A · 2.1.2

A multiple-dose study may be conducted in patients if a single-dose study cannot be conducted in either healthy subjects for safety and/or tolerability reasons or in patients for ethical reasons. ICH M13A · 2.1.2

A randomized, single-dose, crossover study design is recommended when comparing test and comparator formulations, as single-dose studies provide the most sensitive conditions to detect differences in the rate and extent of absorption. Treatment periods should be separated by a sufficiently long washout period, e.g., at least 5 elimination half-lives (see section 2.2.3.3). FDA M13A · 2.1.2

For most dosage forms that release a drug intended to be systemically available, FDA recommends that applicants perform a single-dose, crossover study using either healthy subjects or other populations, as appropriate. In this design, each subject should receive each treatment (the test product and the reference standard) in a random order. FDA ANDA BE 2026 · III.A.4

FDA recommends that applicants use (1) a single-dose, nonreplicate crossover study design, (2) a single-dose, parallel study design, or (3) a single-dose, replicate crossover study design for BE studies. FDA ANDA BE 2026 · III.A.4

In general, for a bioequivalence study involving a multisource product and a comparator product, a randomized, two-period, two-sequence, single-dose, crossover study conducted with healthy volunteers is the preferred study design. In this design each subject is given the multisource product and the comparator product in randomized order. An adequate washout period should follow the administration of each product. WHO TRS 1052 Annex 8 · 7.1

The washout period should be the same for all subjects and should normally be more than five times the median terminal half-life of the API. WHO TRS 1052 Annex 8 · 7.4.5

The minimum washout period should be at least seven days unless a shorter period is justified by a short half-life. WHO TRS 1052 Annex 8 · 7.4.5

In general, a number of 24 normal healthy subjects, preferably non smoking, between 18 years of age or older and within 15% of ideal body weight, height and body build (Metropolitan Life Insurance Company Statistical Bulletin, 1983) to be enrolled in a crossover bioequivalence study. SFDA BE v3.1 · 3.1.3 Subjects – Number of subjects

A number of subjects of less than 24 may be accepted (with a minimum of 18 subjects) when statistically justifiable. However, in some cases (e.g., for highly variable drugs) more than 24 subjects are required for acceptable bioequivalence study. SFDA BE v3.1 · 3.1.3 Subjects – Number of subjects

Subjects should be 18 years of age or older and have a Body Mass Index between 18.5 and 30 kg/Sq.m. SFDA BE v3.1 · 3.1.3 Subjects – Selection of subjects

The number of subjects with evaluable data for primary statistical analysis in a pivotal BE study should not be less than 12 for a crossover design or less than 12 per treatment group for a parallel design. ICH M13A · 2.1.3

To reduce variability not related to differences between drug products, the studies should normally be performed in healthy subjects unless the drug carries safety concerns that make this approach unethical. ICH M13A · 2.1.1

If the investigated active substance is known to have adverse effects and the pharmacological effects or risks are considered unacceptable for healthy subjects, the study may instead be conducted in a targeted patient population under suitable precautions and supervision. ICH M13A · 2.1.1

The number of evaluable subjects in a PK BE study should not be less than 12. For highly variable drug products, a minimum of 24 subjects are recommended for BE assessment (Davit and Conner 2010). FDA Statistical Approaches 2026 · II.A.3

The number of subjects with evaluable data for primary statistical analysis in a pivotal BE study should not be less than 12 for a crossover design or less than 12 per treatment group for a parallel design. FDA M13A · 2.1.3

Subjects recruited for in vivo BE studies should be 18 years of age or older and preferably have a body mass index between 18.5 and 30.0 kg/m2. FDA ANDA BE 2026 · III.A.5

A minimum of 12 subjects is required. WHO TRS 1052 Annex 8 · 7.2.1

Bioequivalence studies should generally be performed with healthy volunteers. Clear criteria for inclusion and exclusion should be stated in the study protocol. If the pharmaceutical product is intended for use in both sexes, the sponsor should include both males and females in the study. WHO TRS 1052 Annex 8 · 7.2.4

Generally, subjects should be aged between 18 and 55 years and their weight should be within the normal range, with a body mass index between 8 and 30 kilograms per square metre (kg/m²). WHO TRS 1052 Annex 8 · 7.2.4

Note: [sic] — the published WHO text reads “8”.

In general, a bioequivalence study should be conducted under fasting conditions as this is considered to be the most sensitive condition to detect a potential difference between formulations. SFDA BE v3.1 · 3.1.4 Study conduct – Fasting or fed conditions

For products where the SPC recommends intake of the reference medicinal product on an empty stomach or irrespective of food intake, the bioequivalence study should hence be conducted under fasting conditions. For products where the SPC recommends intake of the reference medicinal product only in fed state, the bioequivalence study should generally be conducted under fed conditions. SFDA BE v3.1 · 3.1.4 Study conduct – Fasting or fed conditions

However, for products with specific formulation characteristics (e.g. microemulsions, solid dispersions), bioequivalence studies performed under both fasted and fed conditions are required unless the product must be taken only in the fasted state or only in the fed state. For modified release product, bioequivalence studies performed under both fasted and fed conditions are required. SFDA BE v3.1 · 3.1.4 Study conduct – Fasting or fed conditions

For a drug product that is labelled to be taken only under fasting conditions or can be taken under fasting or fed conditions, i.e., without regard to food, a single BE study conducted under fasting conditions is recommended to demonstrate BE. ICH M13A · 2.1.5

For a drug product that is labelled to be taken only with food due to PK reasons, i.e., enhancing absorption or reducing variability, a single BE study conducted under fed conditions is recommended to demonstrate BE. ICH M13A · 2.1.5

For these high-risk products, BE studies should be conducted under both fasting and fed conditions, irrespective of the drug product labelling with regard to food intake, if safety permits. ICH M13A · 2.1.5

For immediate-release drug products with a high risk of bioinequivalence due to food effect, FDA generally recommends that applicants conduct the following studies: (1) a single-dose, fasting BE study comparing the highest strength of the test product and reference standard; and (2) a single-dose, fed BE study comparing the highest strength of the test product and reference standard. FDA ANDA BE 2026 · IV.B.1

For a drug product that is labeled to be taken only with food due to PK reasons, i.e., enhancing absorption or reducing variability, a single BE study conducted under fed conditions is recommended to demonstrate BE. FDA M13A · 2.1.5

For all orally administered modified-release drug products, FDA recommends that applicants conduct BE studies under both fasting and fed conditions, irrespective of the RLD labeling regarding food intake. FDA ANDA BE 2026 · III.A.10

Fasted-state studies are generally preferred. However, when the product is known to cause gastrointestinal disturbances if given to subjects in the fasted state, or if the labelling of the comparator product restricts administration to subjects in the fed state, then a fed-state study becomes the preferred approach. WHO TRS 1052 Annex 8 · 7.4.4 — Immediate-release formulations

For products with specific formulation characteristics (such as microemulsions or solid dispersions), bioequivalence studies performed under both fasted and fed conditions are required, unless the product is only taken in a fasted or fed state. WHO TRS 1052 Annex 8 · 7.4.4 — Immediate-release formulations

Therefore, bioequivalence studies conducted under both fasted and fed conditions are required for orally administered, modified-release pharmaceutical products. WHO TRS 1052 Annex 8 · 7.1.4

Reference Products must be the original brand-name (i.e. manufactured in the country of origin of the original brand name); if this is not available in the local market then the brand-name regarding the same company but different country of origin is used, marketed in GCC region, ICH region, or in any stringent regulatory authority. SFDA BE v3.1 · 3.1.2 Reference and test product – Selection of reference drug

If the original brand-name is not available in the market or no longer produced, then the product which is the local market leader may be used as a reference product. SFDA BE v3.1 · 3.1.2 Reference and test product – Selection of reference drug

The study report should include the reference product name, strength, pharmaceutical form, batch number, manufacturer, expiry date and country of purchase. SFDA BE v3.1 · 3.3.1 Bioequivalence study report

For Article 10(1) and 10(3) marketing authorisation applications reference must be made to the dossier of a reference medicinal product for which a marketing authorisation is or has been granted in the Union on the basis of a complete dossier in accordance with Articles 8(3), 10a, 10b or 10c of Directive 2001/83/EC, as amended. EMA BE guideline · 4.1.2

Bioequivalence studies comparing the product applied for with non-EU reference products should not be submitted and do not need to be included in the list of studies. EMA BE guideline · 4.1

Including comparator products from different regions in one trial is acceptable to streamline the BE demonstration by conducting one single higher-order crossover BE study with multiple comparator products. ICH M13A · 2.2.5.1

To receive approval for an ANDA, an applicant generally must demonstrate, among other things, that its proposed drug product is bioequivalent to the reference listed drug (RLD). FDA ANDA BE 2026 · II

During such BE studies, an applicant compares the systemic exposure profile of a test drug product to that of the reference standard designated in FDA’s Approved Drug Products with Therapeutic Evaluations (the Orange Book). FDA ANDA BE 2026 · II

As discussed further below, a comparator product used in conducting an in vivo BE study to support an ANDA in the United States is the reference standard (21 CFR 314.3(b)). FDA ANDA BE 2026 · II, footnote 7

The comparator product is a pharmaceutical product with which the multisource product is intended to be interchangeable in clinical practice. The comparator product will normally be the innovator product for which efficacy, safety and quality have been established. WHO TRS 1052 Annex 8 · 2. Glossary — comparator product

Preferably this will mean employing the innovator product available on the market when studying multisource products for national and regional approval. There will be situations, however, where this is not feasible. Detailed guidance for the selection of comparator products for use in national and regional applications is provided in the comparator guidance (8). WHO TRS 1052 Annex 8 · 7.3.2

Content of the API of the comparator product should be close to the label claim and the difference between two products being compared should not be more than ± 5%. WHO TRS 1052 Annex 8 · 7.3.2

The bioequivalence study should in general be conducted at the highest strength. For products with linear pharmacokinetics and where the drug substance is highly soluble (see Appendix III), selection of a lower strength than the highest is also acceptable. SFDA BE v3.1 · 3.1.6 Strength to be investigated – Linear pharmacokinetics

Selection of a lower strength may also be justified if the highest strength cannot be administered to healthy volunteers for safety/tolerability reasons. SFDA BE v3.1 · 3.1.6 Strength to be investigated – Linear pharmacokinetics

For drugs with a less than proportional increase in AUC with increasing dose over the therapeutic dose range, bioequivalence should in most cases be established both at the highest strength and at the lowest strength (or a strength in the linear range), i.e. in this situation two bioequivalence studies are needed. SFDA BE v3.1 · 3.1.6 Strength to be investigated – Non-linear pharmacokinetics

In general, the highest to-be-marketed strength should be used in a BE study (see Section 2.1.6). ICH M13A · 2.1.2

In cases of documented less than proportional increases in AUC and/or Cmax with increasing dose over the range of strengths proposed, BE should be established with the lowest strength if this is due to saturation of absorption. ICH M13A · 2.1.6

If data are not available to establish dose proportionality, then BE studies should be conducted with the lowest and highest strengths of the proposed series of strengths. ICH M13A · 2.1.6

In general, BE studies should be conducted in healthy subjects (see section III.A.5, Study Population) and should be conducted on the highest to-be-marketed strength. FDA ANDA BE 2026 · III.A.4

If an applicant does not intend to submit an ANDA for the highest strength of the RLD, then FDA generally recommends using the highest to-be-marketed strength for BE studies. FDA ANDA BE 2026 · IV.B.1

In cases of documented less than proportional increases in AUC and/or Cmax with increasing dose over the range of strengths proposed, BE should be established with the lowest strength if this is due to saturation of absorption. If the less than proportional increase in AUC and/or Cmax with increasing dose is due to limited drug solubility, BE studies should be conducted with both the lowest and highest strengths. FDA M13A · 2.1.6

In bioequivalence studies, the molar equivalent dose of multisource and comparator product must be used. For a series of strengths that can be considered proportionally formulated (see subsection 10.3), the strength with the greatest sensitivity for bioequivalence assessment should be administered as a single unit. This will usually be the highest marketed strength. WHO TRS 1052 Annex 8 · 7.4.1

In certain cases, a study performed with a lower strength can be considered acceptable if this lower strength is chosen for reasons of safety or if the API is highly soluble and its pharmacokinetics are linear over the therapeutic range. WHO TRS 1052 Annex 8 · 7.4.1

For APIs with non-linear pharmacokinetics within the range of strengths due to saturable absorption and resulting in less than proportional increases in AUC with increasing dose, the bioequivalence study should be conducted on at least the lowest strength (or a strength in the linear range). WHO TRS 1052 Annex 8 · 7.4.2

In principle, evaluation of bioequivalence should be based upon measured concentrations of the parent compound. The reason for this is that Cmax of a parent compound is usually more sensitive to detect differences between formulations in absorption rate than Cmax of a metabolite. SFDA BE v3.1 · 3.1.5 Characteristics to be investigated – Parent compound or metabolites

Hence, the use of a metabolite as a surrogate for active parent compound is expected to be accepted only in exceptional cases. SFDA BE v3.1 · 3.1.5 Characteristics to be investigated – Use of metabolite data as surrogate for active parent compound

The use of achiral bioanalytical methods is generally acceptable. However, the individual enantiomers should be measured when all the following conditions are met: 1) the enantiomers exhibit different pharmacokinetics 2) the enantiomers exhibit pronounced difference in pharmacodynamics 3) the exposure (AUC) ratio of enantiomers is modified by a difference in the rate of absorption. SFDA BE v3.1 · 3.1.5 Characteristics to be investigated – Enantiomers

Demonstration of BE should be based on the analysis of the parent drug … ICH M13A · 2.1.7.1

However, some prodrugs are rapidly eliminated resulting in difficulties in demonstrating BE based on parent drug data, as the parent drug levels are too low to allow reliable bioanalytical measurement. In this situation, it is acceptable to demonstrate BE based on a primary metabolite, i.e., a first-step metabolite of the parent drug, without measurement of the parent compound. ICH M13A · 2.1.7.1

The use of an achiral bioanalytical assay to measure the racemate is generally acceptable. However, a stereoselective assay measuring individual enantiomers in BE studies should be employed when it is known that all of the following conditions have been met: a) the enantiomers exhibit different pharmacodynamic properties, b) the enantiomers exhibit different PK properties, and c) the exposure (AUC) ratio of enantiomers is modified by a difference in the rate of absorption. ICH M13A · 2.1.7.2

FDA generally recommends that applicants measure only the parent drug, rather than metabolites, because the concentration-time profile of the parent drug is usually considered more sensitive to changes in formulation performance than a metabolite, which is more reflective of metabolite formation, distribution, and elimination. FDA ANDA BE 2026 · V.A.1

Primary active metabolite(s) should be measured if they (1) are formed substantially through presystemic metabolism (i.e., gut wall or gut lumen metabolism) and (2) contribute significantly to the safety and/or efficacy of the product. FDA ANDA BE 2026 · V.A.1

For BE studies, FDA recommends using an achiral bioanalytical assay to measure the racemate. FDA recommends measuring individual enantiomers in BE studies only when all the following conditions have been met: (1) the enantiomers exhibit different PD characteristics, (2) the enantiomers exhibit different PK characteristics, and (3) the exposure (AUC) ratio of enantiomers is modified by a difference in the rate of absorption. FDA ANDA BE 2026 · V.A.2

The concentration–time profile of the API is more sensitive to changes in formulation performance than a metabolite, which is more reflective of metabolite formation, distribution and elimination. WHO TRS 1052 Annex 8 · 7.4.9

In rare cases it may be necessary to measure concentrations of a primary active metabolite rather than those of the API if concentrations of the API are too low to allow reliable analytical measurement in blood, plasma or serum for an adequate length of time, or when the parent compound is unstable in the biological matrix. WHO TRS 1052 Annex 8 · 7.4.9

A non-stereoselective assay is acceptable for most bioequivalence studies. A stereospecific assay measuring the individual enantiomers should be employed when the enantiomers exhibit different pharmacokinetic properties or different pharmacodynamic properties, and the exposure of the enantiomers, as estimated by their AUC ratio or Cmax ratio, changes when there is a change in the rate of absorption. WHO TRS 1052 Annex 8 · 7.4.10

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

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

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)

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

In specific cases of products with a narrow therapeutic index, the acceptance interval for AUC should be tightened to 90.00-111.11%. Where Cmax is of particular importance for safety, efficacy or drug level monitoring the 90.00-111.11% acceptance interval should also be applied for this parameter. SFDA BE v3.1 · 3.1.9 Narrow therapeutic index drugs

It is not possible to define a set of criteria to categorize drugs as narrow therapeutic index drugs (NTIDs) and it must be decided case by case if an active substance is an NTID based on clinical considerations. SFDA BE v3.1 · 3.1.9 Narrow therapeutic index drugs

In specific cases of products with a narrow therapeutic index, the acceptance interval for AUC should be tightened to 90.00-111.11%. Where Cmax is of particular importance for safety, efficacy or drug level monitoring the 90.00-111.11% acceptance interval should also be applied for this parameter. EMA BE guideline · 4.1.9

It is not possible to define a set of criteria to categorise drugs as narrow therapeutic index drugs (NTIDs) and it must be decided case by case if an active substance is an NTID based on clinical considerations. EMA BE guideline · 4.1.9

It is, therefore, highlighted that the requirements of both ICH M13A and the existing EMA Guideline read in conjunction may be applicable to e.g., • BE studies with highly variable drugs (replicate design) • drugs with narrow therapeutic index, and • complex BE study designs and data analysis e.g., • adaptive design. EMA M13A implementation · Implementation

NTI drugs are those drugs where small differences in dose or blood concentration may lead to serious therapeutic failures and/or adverse drug reactions that are life-threatening or result in persistent or significant disability or incapacity. For NTI drugs, a fully replicate crossover design should be used. The statistical analysis should be carried out using both the average BE and the reference-scaled average BE tests for both AUC and Cmax. FDA Statistical Approaches 2026 · III.B

NTI BE studies should pass both the reference-scaled average BE criteria and the unscaled average BE limits of 80.00 percent to 125.00 percent. FDA Statistical Approaches 2026 · III.B

In addition, the test/reference ratio of the within-subject standard deviation should be evaluated. The within-subject variability comparison of T and R is carried out by a one-sided F test. FDA Statistical Approaches 2026 · III.B

If the API is determined to possess a narrow therapeutic index, the bioequivalence acceptance range should be restricted to 90.00–111.11%. WHO TRS 1052 Annex 8 · 7.7 — AUC0–t ratio

If the API is determined to possess a narrow therapeutic index, the bioequivalence acceptance range may need to be restricted to 90.00–111.11%, if appropriate. WHO TRS 1052 Annex 8 · 7.7 — Cmax ratio

Highly variable drug products (HVDP) are those whose intra-subject variability for a parameter is larger than 30%. If an applicant suspects that a drug product can be considered as highly variable in its rate and/or extent of absorption, a replicate cross-over design study can be carried out. SFDA BE v3.1 · 3.1.10 Highly variable drugs or drug products

Those HVDP for which a wider difference in Cmax is considered clinically irrelevant based on a sound clinical justification can be assessed with a widened acceptance range. If this is the case the acceptance criteria for Cmax can be widened to a maximum of 69.84 – 143.19%. For the acceptance interval to be widened the bioequivalence study must be of a replicate design where it has been demonstrated that the within-subject variability for Cmax of the reference compound in the study is >30%. SFDA BE v3.1 · 3.1.10 Highly variable drugs or drug products

The geometric mean ratio (GMR) should lie within the conventional acceptance range 80.00-125.00%. The possibility to widen the acceptance criteria based on high intra-subject variability does not apply to AUC where the acceptance range should remain at 80.00 – 125.00% regardless of variability. SFDA BE v3.1 · 3.1.10 Highly variable drugs or drug products

Those HVDP for which a wider difference in Cmax is considered clinically irrelevant based on a sound clinical justification can be assessed with a widened acceptance range. If this is the case the acceptance criteria for Cmax can be widened to a maximum of 69.84 – 143.19%. For the acceptance interval to be widened the bioequivalence study must be of a replicate design where it has been demonstrated that the within-subject variability for Cmax of the reference compound in the study is >30%. EMA BE guideline · 4.1.10

The geometric mean ratio (GMR) should lie within the conventional acceptance range 80.00-125.00%. The possibility to widen the acceptance criteria based on high intra-subject variability does not apply to AUC where the acceptance range should remain at 80.00 – 125.00% regardless of variability. EMA BE guideline · 4.1.10

It is, therefore, highlighted that the requirements of both ICH M13A and the existing EMA Guideline read in conjunction may be applicable to e.g., • BE studies with highly variable drugs (replicate design) • drugs with narrow therapeutic index, and • complex BE study designs and data analysis e.g., • adaptive design. EMA M13A implementation · Implementation

Highly variable drugs are drugs for which within subject variability (%CV) in BE measures 30 percent or greater and that are not considered NTI drugs. In order to use the reference-scaled average BE approach for highly variable drugs, a partial or fully replicate crossover design should be used. The statistical analysis should be carried out using the mixed scaling approach below for both AUC and Cmax. FDA Statistical Approaches 2026 · III.C

If the estimated within-subject standard deviation of the reference is < 0.294, the average BE two one-sided test procedure should be used to determine BE for the individual PK parameter. Otherwise, the reference-scaled average BE procedure should be used to determine BE for the individual PK parameter together with a point estimate constraint for the estimated test/reference geometric mean ratio, which should be bounded by 80.00 percent to 125.00 percent. FDA Statistical Approaches 2026 · III.C

A replicate design is advantageous over a nonreplicate design for non-narrow therapeutic index (NTI) drugs with a high intrasubject variability. Either a partial or fully replicate design may be used, but a reference-scaled BE analysis approach should only be applied to specific PK metrics that exhibit a high within-subject variability for the reference standard in the pivotal BE study. FDA ANDA BE 2026 · III.A.4

A “highly variable API” has been defined as an API with an intrasubject variability of > 30% in terms of the ANOVA coefficient of variation (CV) (14). WHO TRS 1052 Annex 8 · 7.9.3

For highly variable FPPs it is recommended that a three-way partial replicate (where the comparator product is administered twice) or a four-way fully replicated crossover bioequivalence study be conducted and reference-scaled average bioequivalence be employed to widen the acceptance interval for the Cmax parameter, if the intrasubject variability for Cmax following replicate administrations of the comparator product is > 30%. If this is the case, the acceptance criteria for Cmax can be widened to a maximum of 69.84–143.19%. WHO TRS 1052 Annex 8 · 7.9.3

The geometric mean ratio for Cmax should lie within the conventional acceptance range of 80.00–125.00%. The standard bioequivalence acceptance criterion for AUC should be maintained without scaling. WHO TRS 1052 Annex 8 · 7.9.3

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)

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

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

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 Annex 8 · 10.3.2 — Immediate-release tablets

For extended-release tablets, when there is a series of strengths of a multisource product that are proportionally similar in their active and inactive ingredients and have the same API release mechanism, in vivo bioequivalence studies should be conducted with the highest proposed strength. Subsequently, lower strengths in the series can be granted a biowaiver if they exhibit similar dissolution profiles to the highest strength, f2 ≥ 50, in three different pH buffers (between pH 1.2 and 7.5) and the quality control media by the recommended test method. WHO TRS 1052 Annex 8 · 10.3.2 — Extended-release tablets and capsules

Applying for a BCS-based biowaiver is restricted to highly soluble drug substances with known human absorption and considered not to have a narrow therapeutic index (see section 3.1.9). The concept is applicable to immediate release, solid pharmaceutical products for oral administration and systemic action having the same pharmaceutical form. SFDA BE v3.1 · Appendix III – I. Introduction

BCS-based biowaiver are applicable for an immediate release drug product if • the drug substance has been proven to exhibit high solubility and complete absorption (BCS-class I; for details see section III) and • either very rapid (> 85 % within 15 min) or similarly rapid (85 % within 30 min ) in vitro dissolution characteristics of the test and reference product has been demonstrated considering specific requirements (see section IV.1) and • excipients that might affect bioavailability are qualitatively and quantitatively the same. SFDA BE v3.1 · Appendix III – II. Summary Requirements

The drug substance is considered highly soluble if the highest single dose administered as immediate release formulation(s) is completely dissolved in 250 ml of buffers within the range of pH 1 – 6.8 at 37±1°C. SFDA BE v3.1 · Appendix III – III.1 Solubility

BCS-based biowaivers are applicable to drug products where the drug substance(s) exhibit high solubility and, either high permeability (BCS Class I) or low permeability (BCS Class III). ICH M9 · 2

The BCS-based biowaiver is only applicable to immediate release, solid orally administered dosage forms or suspensions designed to deliver drug to the systemic circulation. Drug products having a narrow therapeutic index are excluded from consideration for a BCS-based biowaiver in this guidance. ICH M9 · 1.2

A drug substance is classified as highly soluble if the highest single therapeutic dose is completely soluble in 250 ml or less of aqueous media over the pH range of 1.2–6.8 at 37±1°C. ICH M9 · 2.1

A drug product is eligible for a BCS-based biowaiver provided that the drug substance or substances satisfy the criteria regarding solubility and permeability (BCS Class I and III), the drug product is an immediate-release oral dosage form with systemic action, and the drug product is the same dosage form and strength as the reference product. FDA M9 · 3

A drug substance is classified as highly soluble if the highest single therapeutic dose is completely soluble in 250 milliliter (mL) or less of aqueous media over the pH range of 1.2– 6.8 at 37±1°C. FDA M9 · 2.1

The BCS-based biowaiver is only applicable to immediate release, solid orally administered dosage forms or suspensions designed to deliver drug to the systemic circulation. Drug products having a narrow therapeutic index are excluded from consideration for a BCS-based biowaiver in this guidance. FDA M9 · 1.2

Following the publication of the WHO guideline on Biopharmaceutics Classification System-based biowaivers, the relevant sections from this guideline have been removed, including the appendix Equilibrium solubility experiments for the purpose of classification of active pharmaceutical ingredients according to the Biopharmaceutics Classification System. WHO TRS 1052 Annex 8 · Background

Guidance providing recommendations to support the biopharmaceutics classification of APIs and the BCS-based biowaiver of bioequivalence studies for FPPs can be found in the WHO guideline on Biopharmaceutics Classification System-based biowaivers. WHO TRS 1052 Annex 8 · 10.2

The results of in vitro dissolution tests at three different buffers (normally pH 1.2, 4.5 and 6.8) and the media intended for drug product release (QC media), obtained with the batches of test and reference products that were used in the bioequivalence study should be reported. SFDA BE v3.1 · 3.2.1 In vitro dissolution tests complementary to bioequivalence studies

Where more than 85% of the drug is dissolved within 15 minutes, dissolution profiles may be accepted as similar without further mathematical evaluation. SFDA BE v3.1 · Appendix I – 2. Similarity of dissolution profiles

An f2 value between 50 and 100 suggests that the two dissolution profiles are similar. SFDA BE v3.1 · Appendix I – 2. Similarity of dissolution profiles

An f2 value between 50 and 100 suggests that the two dissolution profiles are similar. EMA BE guideline · Appendix I, 2

Where more than 85% of the drug is dissolved within 15 minutes, dissolution profiles may be accepted as similar without further mathematical evaluation. EMA BE guideline · Appendix I, 2

The results of in vitro dissolution tests at three different buffers (normally pH 1.2, 4.5 and 6.8) and the media intended for drug product release (QC media), obtained with the batches of test and reference products that were used in the bioequivalence study should be reported. EMA BE guideline · 4.2.1

Two dissolution profiles are considered similar when the f2 value is ≥50. When both test and reference products demonstrate that ≥85% of the labeled amount of the drug is dissolved in 15 minutes, comparison with an f2 test is unnecessary, and the dissolution profiles are considered similar. FDA M9 · 3.2

Three buffers: pH 1.2, pH 4.5, and pH 6.8. Pharmacopoeial buffers should be employed. Additional investigation may be required at the pH of minimum solubility (if different from the buffers above). FDA M9 · 3.2

To allow the use of mean data, the coefficient of variation should not be more than 20% at early time-points (up to 10 minutes) and should not be more than 10% at other time points. FDA M9 · 3.2

Studies should be performed in at least three media covering the physiological range, including pH 1.2 hydrochloric acid, pH 4.5 buffer and pH 6.8 buffer. WHO TRS 1052 Annex 8 · Appendix 1

If both the test and reference (comparator) products show more than 85% dissolution in 15 minutes, the profiles are considered similar (no calculations required). WHO TRS 1052 Annex 8 · Appendix 1

An f2 value between 50 and 100 suggests that the two dissolution profiles are similar. WHO TRS 1052 Annex 8 · Appendix 1