Biowaiver for BCS Class 1 Drugs

A biowaiver allows a generic drug to be approved without an in vivo (BE) study based on in vitro dissolution data. This is particularly applicable BCS Class 1 drugs, which have high solubility and high permeability.

Biowaiver Justification for BCS Class 1 Drugs

To obtain a biowaiver for a BCS Class 1 drug, the following scientific justifications and data must be provided:

A. Solubility Data

Methodology:

• Solubility studies must be conducted at 37°C ± 1°C in aqueous media of pH 1.2, 4.5, and 6.8.
• Use a validated shake-flask or equilibrium solubility method.
• Data should confirm that the drug dissolves completely within the required volume (≤ 250 mL).

Regulatory Requirement:

• USFDA, EMA, and WHO require solubility studies at different pH levels covering the gastrointestinal tract.
• Justification if the solubility is pH-dependent.

B. Permeability Data

Methodology:

• Human mass balance studies showing ≥ 85% absorption.
• In vitro Caco-2 cell permeability studies or intestinal perfusion studies as supportive data.

Regulatory Requirement:

• If human mass balance data is unavailable, permeability studies in validated models (Caco-2, rat intestinal perfusion, etc.) can be used.
• EMA and WHO require evidence from at least two independent permeability studies.

C. Comparative Dissolution Testing

To support a biowaiver, comparative in vitro dissolution testing must demonstrate similarity between the test (generic) product and the (RLD).

Dissolution Media:

• pH 1.2 (acidic)
• pH 4.5 (acetate buffer)
• pH 6.8 (phosphate buffer)

Acceptance Criteria:

• ≥ 85% dissolution within 30 minutes.
• Use of f₂ similarity factor to compare dissolution profiles:
• f₂ ≥ 50 indicates similarity.
• f₂ < 50 requires further justification.

D. Excipients Justification

• The formulation should contain excipients in the same qualitative composition as the RLD.
• Excipient effects on permeability and solubility must be justified.
• Surfactants, solubilizers, and complexing agents may require additional justification.

Regulatory Agencies and Biowaiver Approval

A. USFDA

• Accepts BCS Class 1 biowaivers for immediate-release (IR) oral solid dosage forms.
• Comparative dissolution and excipient justification are required.

B. EMA

• Accepts BCS Class 1 and some Class 3 drugs for biowaivers.
• Requires additional permeability studies if mass balance data is unavailable.

C. WHO

• Requires multimedia dissolution data in three different batches.
• May require additional evidence for global regulatory acceptance.

Common Reasons for Biowaiver Rejection

• Dissolution profile difference between the generic and RLD.
• Formulation differences affecting drug absorption.
• Excipient differences impacting permeability or solubility.

Conclusion

For BCS Class 1 drugs, a biowaiver submission can replace costly in vivo bioequivalence studies, reducing time and expenses. However, strict compliance with regulatory requirements is necessary.

Read also:

• Factors Affecting Bioequivalence (BE) Results
• BCS Classification of Drugs and Its Significance

Resource Person: Moinuddin syed. Ph.D, PMP®