March 07, 2025

The Biopharmaceutical Classification System (BCS) categorizes drugs based on solubility and permeability properties, guiding regulatory decisions on waivers for in vivo bioequivalence (BE) studies. For BCS Class III drugs—characterized by high solubility and low permeability—the current FDA guidance stipulates that a biowaiver (waiver of in vivo BE studies) may be granted only if:

  • The test product is qualitatively (Q1) the same and quantitatively (Q2) very similar to the reference listed drug (RLD) in terms of excipients.
  • The drug product meets the “very rapidly dissolving” criteria, defined as ≥85% drug release within 15 minutes.

Despite these criteria, minimal regulatory precedence exists for granting biowaivers for BCS Class III drugs. This raises significant questions regarding formulation similarity, dissolution behaviour, and broader implications for regulatory policies. Additionally, there is ambiguity around “BCS Class III-like” drugs, which may exhibit characteristics bordering Class III but do not fit perfectly within the classification framework.

Methodology

A total of nine BCS Class III- “like” drugs were selected from approximately 70 Abbreviated New Drug Applications (ANDAs). The assessment focused on:

  • Formulation composition of test and RLD products.
  • Dissolution profiles of these drug products.
  • Bioequivalence (BE) outcomes based on excipient differences.

Key Findings

The study produced significant findings, challenging the assumption that strict Q1/Q2 similarity is required for bioequivalence in BCS Class III drugs:

  • Bioequivalence was demonstrated even when key excipients differed between the test and RLD products.
  • Critical excipients such as croscarmellose sodium, magnesium stearate, povidone, corn starch, and lactose were not always Q1/Q2 the same between test and RLD formulations.
  • Despite these differences, the test products met bioequivalence criteria.
  • Most BCS Class III- “like” drug products met the “very rapidly dissolving” threshold, with ≥85% drug release within 15 minutes.

Implications and Regulatory Challenges

1. Rethinking the Q1/Q2 Similarity Criteria

The study’s results suggest that strict Q1/Q2 excipient similarity may not be necessary for demonstrating bioequivalence in BCS Class III drugs, if dissolution occurs very rapidly. This raises the question of whether the FDA should:

  • Reconsider its current guidance to allow for greater flexibility in excipient selection.
  • Develop a risk-based approach that assesses excipient impact on absorption rather than requiring rigid Q1/Q2 alignment.

2. Need for Additional Regulatory Precedence

  • There is limited regulatory precedence for biowaivers in this category, making it challenging for ANDA applicants to predict FDA decisions.
  • More real-world case studies are needed to provide clarity on acceptable formulation variations.
  • A comparison with EMA guidelines, which may have slightly different criteria, could provide insights into alternative regulatory pathways.

3. Establishing Clearer Criteria for BCS Class III Biowaivers

  • The FDA’s biowaiver framework for BCS Class III drugs is less established than for Class I drugs (high solubility, high permeability).
  • Additional scientific evaluation and regulatory discussions are needed to refine the criteria for granting biowaivers in this category.
  • Incorporating modeling and simulation approaches could support alternative biowaiver justifications.

How Maven Can Support Biowaiver Applications

Maven provides end-to-end Toxicological Risk Assessment (TRA) and regulatory consulting services, which are critical in navigating the complex regulatory landscape surrounding BCS Class III biowaivers. Our expertise can support pharmaceutical companies in the following ways:

Regulatory Strategy & Compliance

  • Assisting in the preparation of biowaiver applications in compliance with FDA, EMA, and other regulatory guidelines.
  • Providing guidance on Q1/Q2 excipient assessments and their regulatory acceptability.
  • Conducting gap analysis to assess formulation risks concerning biowaiver eligibility.

Toxicological Risk Assessments (TRA)

  • Evaluating excipients and their potential impact on absorption and systemic exposure.
  • Conducting in silico and in vitro studies to support bioequivalence without in vivo testing.
  • Providing risk assessments for excipients with limited safety data to justify formulation differences.

Dissolution & Bioequivalence Studies

  • Supporting dissolution profile assessments to meet the “very rapidly dissolving” criteria.
  • Conducting in vitro–in vivo correlation (IVIVC) studies to predict BE outcomes.
  • Offering biostatistical analysis and simulation models to strengthen biowaiver justifications.

Regulatory Submission Support

  • Preparing comprehensive dossiers for ANDA applications, including justification for biowaiver requests.
  • Developing robust responses to regulatory agency queries regarding excipient selection and bioequivalence.
  • Interfacing with regulatory authorities to ensure smooth approval processes.

Conclusion

The findings of this study indicate that bioequivalence can still be achieved despite excipient variations, provided the drug exhibits very rapid dissolution. This presents an opportunity for the FDA to revisit and potentially update its biowaiver criteria for BCS Class III drugs. Future investigations should focus on:

  • The role of excipients in drug absorption beyond simple Q1/Q2 matching.
  • Developing a more flexible yet scientifically robust biowaiver framework.
  • Expanding regulatory precedence and case studies to provide a clearer pathway for ANDA applicants seeking biowaivers for BCS Class III drugs.

Future Directions

  • Industry stakeholders should collaborate with regulatory agencies to refine alternative biowaiver approaches.
  • Regulatory agencies should consider integrating new modelling and simulation techniques to predict the impact of excipient variations.
  • Ongoing research should explore how dissolution and permeability interact in BCS Class III drugs to inform next-generation regulatory policies.

With Maven’s expertise in toxicological risk assessment, regulatory compliance, and scientific support for bioequivalence studies, pharmaceutical companies can confidently navigate the evolving landscape of BCS Class III biowaivers. Our comprehensive solutions ensure efficient drug development, reduce unnecessary in vivo studies, and maintain high standards of drug safety and efficacy.