Criteria and Requirements for Biowaiver based on Biopharmaceutics Classification System

INTRODUCTION

A biowaiver permits the waiver of in vivo bioequivalence studies for certain drug products, offering significant savings in time and cost during regulatory approval. However, before such a waiver is granted, comprehensive studies based on the Biopharmaceutics Classification System (BCS) must be submitted to satisfy regulatory authorities in regions such as the United States, Europe, and many developing markets.

Only pharmaceutical products that fulfill specific regulatory criteria for solubility, dissolution, and permeability are eligible for a biowaiver. Due to their high solubility and favorable permeability profiles, BCS Class I and Class III drugs are most commonly accepted for biowaiver consideration by global regulatory agencies.

A biowaiver allows for the exemption of in vivo bioavailability and/or bioequivalence studies, which are typically required for product approval. Instead, a dissolution test can serve as a surrogate to determine if two pharmaceutical products are equivalent, avoiding costly and time-intensive in vivo studies. 

Even with comprehensive clinical studies, the risk of therapeutic inequivalence between two immediate-release products cannot be entirely eliminated. Decisions from comparative clinical studies, in vivo bioequivalence studies, in vitro equivalence tests, and biowaivers rely on statistical and scientific data presumed to represent the products in question.

Biowaiver guidance seeks to minimize the risk of bioinequivalence to an acceptable level. Pharmaceutical development focuses on reducing the likelihood of producing inequivalent formulations by addressing critical product aspects. The absorption phase is considered the key process influencing the equivalence of pharmacokinetic profiles and, consequently, the therapeutic equivalence between the test and reference products.

This article concentrates on BCS-based biowaivers, though other types of biowaivers are also addressed in regulations.

BIOPHARMACEUTICS CLASSIFICATION SYSTEM (BCS)

BCS categorizes APIs into four classes:

CRITERIA FOR BCS-BASED BIOWAIVER

To qualify for a biowaiver based on the Biopharmaceutics Classification System (BCS), certain criteria established by regulatory bodies such as the FDA and WHO must be met. The drug substance must be classified as having high solubility and high permeability under BCS guidelines.

The key requirements for a BCS-based biowaiver include:

• Dissolution Testing: Conducted in three different dissolution media (900 mL, at 37°C), including:

1. Buffer at pH 1.2, simulated gastric fluid without enzymes, or 0.1N HCl
2. Buffer at pH 4.5
3. Buffer at pH 6.8 or simulated intestinal fluid without enzymes

• Sample Quantity and Apparatus: Testing must be carried out using 12 dosage units in each medium, employing either:

1. A paddle apparatus rotating at 50 rpm, or
2. A basket apparatus rotating at 100 rpm

• Sampling Time Points: Samples should be collected at the following time intervals: 10, 15, 20, 30, 45, and 60 minutes.
• Comparative Dissolution Profiles: The test and reference products must exhibit similar dissolution profiles across all three media.
• Criteria for Similarity: The dissolution profiles are considered similar if the similarity factor (f2) is ≥ 50, and both formulations demonstrate at least 85% drug release within 15 minutes.

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DATA REQUIREMENTS TO SUPPORT BCS-BASED BIOWAIVER REQUEST

To support a request for a biowaiver, the drug substance must meet the criteria of high solubility and high permeability as defined by the Biopharmaceutics Classification System (BCS).

High Solubility:

A drug substance is classified as highly soluble if the highest dose strength dissolves in less than 250 mL of water across a pH range of 1.0 to 7.5.

High Permeability:

A drug substance is considered highly permeable when more than 90% of the administered dose is absorbed in humans. This can be determined through mass balance studies or by comparing the extent of absorption to that of an intravenous reference dose.

Rapid Dissolution:

An immediate-release (IR) drug product is deemed rapidly dissolving if not less than 85% of the labeled drug amount dissolves within 30 minutes. The dissolution should be performed using USP Apparatus I (100 rpm) or Apparatus II (50 rpm) in a medium volume of 900 mL or less, using one of the following media:

1. 0.1 N HCl or Simulated Gastric Fluid USP without enzymes
2. pH 4.5 buffer
3. pH 6.8 buffer or Simulated Intestinal Fluid USP without enzymes

Applicants must provide comprehensive data to justify a biowaiver request. When submitting a BCS-based biowaiver application, the sponsor should include all relevant supporting documentation for regulatory review.

A. Data Supporting High Solubility

The application must provide detailed evidence demonstrating the high solubility of the drug substance. The following information should be included:

• Description of Test Methods: Detailed procedures of the solubility tests, including the analytical method used and the composition of buffer solutions.
• Physicochemical Properties of the Drug Substance: Information such as chemical structure, molecular weight, the nature of the drug (e.g., acidic, basic, amphoteric, or neutral), and its dissociation constant (pKa).
• Solubility Test Results: A tabulated summary showing:

1. Solution pH values
2. Solubility of the drug (e.g., mg/mL)
3. Volume of dissolution medium required to dissolve the highest marketed dose
4. Mean, standard deviation (SD), and coefficient of variation (CV) of the measurements

• Graphical Representation: A plotted pH-solubility profile showing the mean solubility across the pH range.

B. Data Supporting High Permeability

To establish that a drug substance is highly permeable, evidence must demonstrate an extent of absorption in humans of ≥90%, with no known gastrointestinal instability. The following data sources are acceptable:

Extent of Absorption in Humans:

• Mass-Balance Pharmacokinetic Studies: Evaluate the total recovery of the administered dose in urine and feces.
• Absolute Bioavailability Studies: Compare plasma drug concentrations after oral and intravenous administration.

Intestinal Permeability Studies (Supportive Evidence):

• In Vivo Human Studies: Intestinal perfusion studies in humans.
• Animal Studies: In vivo or in situ intestinal perfusion experiments.
• In Vitro Tissue Models: Using excised intestinal tissue from humans or animals.
• Cell-Based Models: Permeation experiments across epithelial cell monolayers (e.g., Caco-2 cells).

Note: According to European regulatory guidelines, the term "permeability" has been replaced by "absorbability." For a drug to be considered highly absorbable, human absorption must be ≥85%, as determined by mass balance or absolute bioavailability studies. Non-human data (e.g., from animals or cell cultures) are considered only as supportive evidence.

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ADDITIONAL CONSIDERATIONS FOR BIOWAIVER REQUESTS

A. Excipients

While the BCS classification is based solely on the properties of the active pharmaceutical ingredient (API), it is important to recognize that excipients can influence drug absorption. They may affect the disintegration, solubilization, or stabilization of a specific polymorphic form, ultimately altering the dissolution behavior of the API.

Regulatory guidelines impose strict limitations on excipient-related variations:

1. Qualitative Differences: Formulations containing excipients known to impact bioavailability in a significant way are generally not acceptable.
2. Scientific Justification: Minor qualitative or quantitative differences may be permitted if supported by robust scientific reasoning and safety data.
3. Regulatory Precedent: All excipients included in the formulation must have a history of use in previously approved immediate-release (IR) solid oral dosage forms sanctioned by the FDA.
4. Functional Consistency: The quantity of each excipient must align with its intended functional role in the formulation.

Caution with Certain Excipients: Large amounts of excipients such as surfactants (e.g., sodium lauryl sulfate) or osmotically active substances (e.g., sorbitol) may negatively impact drug absorption and thus are discouraged.

B. Prodrugs

For prodrugs, the site of biotransformation to the active drug must be carefully considered:

• If conversion to the active form occurs before intestinal absorption, the permeability of the active drug should be assessed.
• If conversion occurs after intestinal absorption, the permeability of the prodrug must be evaluated instead.
• These considerations are crucial to ensuring that permeability studies accurately reflect the form of the compound that undergoes intestinal absorption.

EXCEPTIONS TO BIOWAIVER APPLICATIONS

Certain pharmaceutical products are not eligible for biowaivers of comparative bioavailability and bioequivalence studies, primarily due to safety concerns or formulation characteristics. These exceptions include:

Narrow Therapeutic Index (NTI) Drugs: 

• Biowaiver applications are generally not permitted for drugs with a narrow therapeutic index due to the high risk associated with small variations in drug concentration, which can lead to toxicity or therapeutic failure.
• While regulatory guidelines, such as those from the European Medicines Agency (EMA), do not provide a universally accepted definition for NTI drugs, it is acknowledged that such classification should be determined on a case-by-case basis.
• Examples of NTI drugs typically excluded from biowaiver consideration include digoxin and phenytoin, due to their narrow margin between therapeutic and toxic doses.

Products Intended for Absorption in the Oral Cavity

• Drug products that are formulated for local or systemic absorption in the oral cavity, such as buccal tablets, lozenges, or sublingual formulations, are not eligible for biowaivers.
• This exclusion is due to the differing absorption pathways and conditions in the oral cavity, which are not adequately simulated by standard gastrointestinal dissolution testing.

SUMMARY OF CONDITIONS FOR BCS-BASED BIOWAIVERS

An important regulatory application of the Biopharmaceutics Classification System (BCS) is its use in guiding the approval of biowaiver procedures. A critical determinant in the eligibility for a BCS-based biowaiver is the BCS classification of the active pharmaceutical ingredient (API).

The following summarizes current eligibility based on BCS classes and regional regulatory policies:

BCS Class I (High Solubility, High Permeability):

APIs in this class are universally accepted for biowaiver procedures in all regions that permit such applications, including the United States, the European Union, and WHO-member countries.

Note: Japan currently does not allow BCS-based biowaivers.

BCS Class II (Low Solubility, High Permeability):

Generally not eligible for biowaivers due to solubility limitations. However, in countries following WHO guidelines, biowaivers may be granted for weak acids that exhibit high solubility at pH 6.8.

BCS Class III (High Solubility, Low Permeability):

In the United States, products containing Class III APIs are not currently eligible for biowaivers.

In the European Union and countries following WHO criteria, biowaivers may be considered only if the product is very rapidly dissolving (≥85% dissolution within 15 minutes in all three media).

BCS Class IV (Low Solubility, Low Permeability):

APIs in this class are not eligible for BCS-based biowaivers in any regulatory jurisdiction, due to the high variability in absorption.

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