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Table I Similarities and Differences in Criteria for an Acceptable BCS-Based Biowaiver for the US-FDA, EMA, and WHO

From: BCS Biowaivers: Similarities and Differences Among EMA, FDA, and WHO Requirements

Attribute/criteria Parameter US-FDA EMA WHO Common positions
Type of BCS biowaiver considered by agency I and III I and III I and III I and III
Formulation comparison to reference or to risk Type - IR solid oral dosage forms;
- Applicable to pharmaceutical equivalents;
- May be applicable to pharmaceutical alternatives with justification
- IR solid oral dosage forms;
- Applicable to pharmaceutical equivalents or alternatives
- IR solid oral dosage forms;
- Applicable to pharmaceutical equivalents or alternatives
- IR solid oral dosage forms;
- Pharmaceutical equivalents or alternatives
Excluded - Any product designed to be absorbed in oral cavity (e.g., buccal or sublingual tablets);
- Narrow therapeutic index drugs
- Buccal, sublingual, and orodispersable formulations with absorption in oral cavity;
- Narrow therapeutic index drugs
- Orodispersible tablets are eligible if there is no sublingual or buccal absorption;
- Narrow therapeutic index drugs
- Any product designed to be absorbed in oral cavity;
- Narrow therapeutic index drugs
Acceptable excipients Class I: Usual excipients with quantity consistent with the intended function (e.g., lubricant); does not contain any excipients (e.g., surfactants and alcohol sugars like mannitol and sorbitol) that will affect the rate or extent of absorption of the drug;
Class III: Qualitatively the same and quantitatively very similar
Class I: Well-established excipients in usual amount; qualitatively and quantitatively the same for critical excipients (e.g., surfactants, mannitol, and sorbitol) that affect bioavailability;
Class III: Qualitatively the same and quantitatively very similar
Class I: well-known excipients in usual amounts; critical excipients (e.g., surfactants, mannitol, and sorbitol) should not differ qualitatively or quantitatively
Class III: Qualitatively the same and quantitatively very similar
Class I: Well-established excipients in usual amount; qualitatively and quantitatively the same for excipients that affect bioavailability
Class III: Composition must be qualitatively the same and quantitatively very similar
API Pharmaceutical alternatives not acceptable for ANDA;
For prodrug, site of conversion will determine whether permeability of prodrug or active drug should be determined
Not eligible if different ester, ether, isomer, mixture of isomer, complex, or derivative Not discussed Not accepted if different ester, ether, isomer, mixture of isomer, complex, or derivative;
site of conversion for prodrug must be discussed
Solubility/high solubility conditions pH Within 1 to 6.8. Base number of pH conditions on ionization characteristics of test drug substance to include pH = pKa; pH = pKa + 1; pH = pKa − 1, and at pH = 1 and 6.8 Within 1 to 6.8 (preferably at pH 1.2, 4.5, and 6.8 plus pKa if within 1– 6.8) Over the range of 1.2 to 6.8 Within 1 to 6.8; pH = pKa, pH = pKa + 1 and pKa − 1, and at pH 1 or 1.2, 4.5, and 6.8
Method Shake-flask or other justified method Shake-flask or other justified method Shake-flask or other justified method Shake-flask or other justified method
Volume Soluble in 250 mL or less Soluble in 250 mL Soluble in 250 mL or less Soluble in 250 mL or less
temperature 37°C ± 1 37°C ± 1 37°C ± 1 37°C ± 1
unit studied Highest strength Highest single therapeutic dose Highest single therapeutic dose Highest strength and highest single therapeutic dose
timing of pH measure After addition of the drug Before and after addition of the drug Not specified Before and after addition of the drug
Origin of data Sponsor Sponsor Not specified Sponsor
How to assess intestinal permeability First choice - High permeability if human Fa ≥ 85%;
- Human Fa data based on absolute BA or mass balance studies;
- In vivo intestinal perfusion studies in humans;
- In vivo or in situ intestinal perfusion studies in animals;
- In vitro methods with epithelial monolayer cultures such as Caco-2 are acceptable only for passively absorbed drugs;
- Must show absence of dose dependency on Caco-2;
- Limit the use of animal or in vitro permeability test methods for drug substances that are transported by passive mechanisms;
- For permeability that is based on mass balance studies using total radioactivity, stability in GIT must be determined in vitro and discussed in relation with presystemic degradation
- High permeability if human Fa ≥ 85%;
- Human Fa data based on absolute BA or mass balance studies;
- Lack of degradation and metabolism in GIT must be ensured if BA data is derived from radiolabeled mass-balance studies
- Human Fa ≥ 85%;
- Human Fa data based on absolute BA or mass balance studies;
- In vivo intestinal perfusion in humans is acceptable
- For high permeability, human Fa ≥ 85%
- Human data preferred based on absolute BA or mass balance studies
- Stability in GIT must be discussed for using mass balance studies
  Supportive In vivo or in vitro permeability studies published in the scientific literature - In vitro permeability investigations;
- Similar F between various formulations within the same route
- In vivo or in situ perfusion in animal models;
- In vitro permeation against a monolayer of intestinal cells
- In vivo or in situ perfusion in animal models;
- In vitro permeation against a monolayer of intestinal cells;
- Similar F between various formulations within the same route
Origin of data Sponsor or in the labeling of the reference product; literature may be considered but always only in a supportive role Sponsor or reliable source Not specified Sponsor or in the labeling of the reference product; literature may be considered but always only in a supportive role
Linearity of in vivo PK profile Linear Linear Linear Linear
Dissolution
- Criteria for fast and complete dissolution;
- Dissolution profile comparison
Rate of dissolution Similarly rapid/very rapid Similarly rapid/very rapid Similarly rapid/very rapid Similarly rapid/very rapid
Extent dissolved
Maximum time
Class I: ≥85% 30 min
Class III: ≥85% 15 min
Class I: ≥85% 30 min
Class III: ≥85% 15 min
Class I: ≥85% 30 min
Class III: ≥85% 15 min
- If ≥85% in 15 min, will support both Class I/III;
- ≥ 85% in30 min, will support Class I only
Apparatus Basket (USP Apparatus I) at 100 rpm or paddles (USP Apparatus II) at 50 rpm or at 75 rpm when appropriately justified Usually basket at 100 rpm or usually paddles at 50 rpm Basket at 100 rpm or paddles at 75 rpm Basket at 100 rpm. Paddles at 50 rpm
Volume 500 mL 900 mL or less 900 mL or less 500 mL
Media 3 pH (0.1 N HCl or Simulated Gastric Fluid without enzyme, 4.5, 6.8)
Surfactant discouraged
No organic solvent
3 pH (0.1 N HCl or Simulated Gastric Fluid without enzyme, 4.5, 6.8)
No surfactant
No organic solvent
3 pH (1.2, 4.5, 6.8)
No surfactant
3 pH (1.2, 4.5, 6.8)
No surfactant
No organic solvent
Enzyme Yes in case of gelatin capsule shell Yes in case of gelatin capsule shell Yes in case of gelatin capsule shell Yes in case of gelatin capsule shell
Unit tested Strength (1 dosage unit) for which BCS biowaiver is requested Strength (1 dosage unit) for which BCS biowaiver is requested Strength (1 dosage unit) for which BCS biowaiver is requested Strength (1 dosage unit) for which BCS biowaiver is requested
No. of units 12 12 12 12
Sampling times Recommend 5, 10, 15, 20, 30 min Recommend 10, 15, 20, 30, 45 min Recommend 10, 15, 20, 30, 45 min 5, 10, 15, 20, 30, 45 min
If ≥85% in 15 min No statistical test needed No statistical test needed No statistical test needed No statistical test needed
If ≥85% dissolved in less than 30 min but longer than 15 min F2 or other statistical test F2 or other suitable test if conditions not fulfilled F2 or equivalent statistical criterion F2 or other suitable test if conditions not fulfilled
Number of batches Not specified Advise more than 1 of test and reference Not specified More than 1 of test and reference
Fixed dose combinations (FDC) Both API’s must comply Both API’s must comply Waiver for only 1 component of a FDC is possible Both API’s must comply
Biowaivers of other strengths if 1 strength meets BCS biowaiver criteria Not discussed BCS-based biowaivers must be requested for all strengths Not discussed BCS-based biowaivers must be requested for all strengths
  1. US-FDA US Food and Drug Administration, EMA European Medicines Agency, WHO World Health Organization, ANDA Abbreviated New Drug Application, API active pharmaceutical ingredient, BCS Biopharmaceutics Classification System, IR immediate-release, BA bioavailability, GIT gastrointestinal tract