When Can Dissolution Data Reduce the Need for In-Vivo BE Studies?

In-vivo bioequivalence (BE) studies are commonly used to compare the rate and extent of drug absorption between a proposed generic product and the relevant reference product.

However, an in-vivo study may not be required in every development scenario.

Under defined regulatory conditions, dissolution data—together with evidence relating to the drug substance, formulation, dosage form, and applicable regulatory framework—may support a request to waive certain in-vivo BE studies. This is generally referred to as a biowaiver.

A biowaiver does not mean that similar dissolution profiles automatically establish bioequivalence. It means that, where accepted scientific and regulatory criteria are met, in-vitro evidence may be used instead of a specific in-vivo study.

Understanding this distinction helps development teams determine when dissolution data may serve as supportive evidence and when an in-vivo comparison remains necessary.

What Is a Biowaiver?

A biowaiver is a regulatory waiver of an in-vivo bioequivalence study.

Instead of generating comparative pharmacokinetic data in human subjects, the applicant may submit in-vitro and supporting scientific evidence to justify why the in-vivo study is not required.

Biowaivers may be considered in situations such as:

• Eligible immediate-release products under the Biopharmaceutics Classification System
• Additional strengths of a product after BE has been demonstrated on one strength
• Certain product-specific circumstances identified in regulatory guidance

The availability of a biowaiver depends on the product, dosage form, drug-substance characteristics, formulation, and applicable regulatory expectations.

Dissolution data therefore support a biowaiver request. They do not independently create an entitlement to a waiver.

BCS-Based Biowaivers

The Biopharmaceutics Classification System, or BCS, categorizes drug substances according to their aqueous solubility and intestinal permeability.

For certain immediate-release solid oral dosage forms, a BCS-based biowaiver may allow in-vitro evidence to be used instead of an in-vivo BE study.

The assessment generally considers:

• Drug-substance solubility
• Drug-substance permeability
• Dosage-form characteristics
• Dissolution performance
• Formulation composition
• Potential effects of excipients
• Therapeutic and absorption-related risks

The test and reference products are usually compared across defined dissolution conditions. However, dissolution similarity is only one part of the assessment—the drug substance and formulation must also satisfy the criteria of the applicable BCS framework.

For this reason, a product cannot be considered eligible for a BCS-based biowaiver solely because it dissolves rapidly or shows an acceptable comparative dissolution profile.

Role of Comparative Dissolution Data

Comparative dissolution testing evaluates how the test and reference products release the active ingredient under controlled in-vitro conditions.

The comparison may consider:

• Dissolution media
• Apparatus and agitation speed
• Sampling time points
• Number of units tested
• Variability within the results
• Similarity between the two profiles

As discussed in our previous article on Comparative Dissolution Profiles and bioequivalence, the similarity factor f2 may be used, where appropriate, to compare dissolution profiles. An acceptable f2 result may support the conclusion that the profiles are similar under the tested conditions.

However, similar dissolution profiles do not establish equivalent absorption in the body. Dissolution testing does not fully reproduce physiological factors such as:

• Gastric emptying
• Intestinal transit
• Permeability
• Food effects
• Metabolism
• Transporter activity

Comparative dissolution data should therefore be interpreted within the relevant regulatory and scientific context.

Biowaivers for Additional Strengths

Dissolution data may also reduce the need to conduct a separate in-vivo BE study for every strength of a product.

In a multiple-strength product line, an in-vivo study may be conducted using one selected strength. A waiver may then be requested for the remaining strengths where applicable criteria are met.

Supporting considerations may include:

• The strengths are manufactured using the same process
• The formulations are proportionally similar or otherwise meet applicable compositional requirements
• The products use the same release mechanism
• The pharmacokinetics are appropriately understood
• Comparative dissolution supports consistent performance across strengths
• In-vivo BE has been demonstrated for the selected strength

In this context, dissolution data function as bridging evidence—they help demonstrate that the additional strengths perform consistently with the strength evaluated in vivo.

The strength selected for the BE study may depend on factors such as safety, dose proportionality, solubility, analytical sensitivity, and product-specific recommendations.

When Dissolution Data May Not Be Sufficient

Dissolution data may not adequately predict in-vivo performance for every drug product.

Additional in-vivo evidence may still be required where the product presents characteristics such as:

• Modified-release behavior
• Narrow therapeutic index
• Low or variable permeability
• Site-specific absorption
• Complex formulation characteristics
• Excipients that may influence absorption
• Significant food effects
• Product-specific regulatory concerns

In such situations, similar dissolution profiles may not provide sufficient assurance that the test and reference products will behave similarly in the body. This is why the acceptability of a biowaiver depends on more than the dissolution result alone.

Product-Specific Guidance and Regulatory Expectations

General guidance provides a scientific framework for bioequivalence and biowaivers. However, individual drug products may be subject to product-specific recommendations.

These recommendations may address:

• Whether an in-vivo study is required
• The appropriate strength for testing
• Fasting or fed conditions
• Additional-strength waiver criteria
• Recommended dissolution methods
• Alternative in-vitro approaches
• Special characteristics of the drug or dosage form

Development teams should therefore assess both general guidance and current product-specific recommendations before finalizing the BE strategy. Where the proposed approach differs from the published recommendation, regulatory consultation may be appropriate.

As covered in our article on whether a Comparative Dissolution Profile is required in an ANDA, the role and extent of dissolution data in a submission can vary depending on the product and regulatory pathway.

Implications for Reference Product Selection

Where dissolution data will support a biowaiver request, correct reference product selection remains important.

Development teams typically consider:

• Confirmation of the applicable reference product
• Alignment with the target submission market
• Correct strength and dosage form
• Batch and expiry traceability
• Storage according to labeled conditions
• Sufficient quantity for testing
• Consistency between the sourced product and submission documentation

A poorly documented, incorrectly identified, or improperly stored reference product may affect the reliability of comparative dissolution data. Reference product sourcing therefore remains part of the evidence chain supporting a biowaiver strategy.

Key Takeaways

• In-vivo BE studies remain a primary method of comparing test and reference drug products.
• Under defined regulatory conditions, dissolution data may support a waiver of certain in-vivo BE studies.
• BCS-based biowaivers apply only to eligible drug substances and qualifying dosage forms.
• Dissolution data may support waivers for additional strengths after BE has been demonstrated on one strength.
• Similar dissolution profiles do not independently establish bioequivalence.
• Product-specific guidance may determine whether an in-vitro or in-vivo approach is appropriate.
• Correct reference product identification, traceability, storage, and documentation remain important.
• Acceptance of a biowaiver depends on the totality of evidence submitted.

Dissolution data can reduce the need for in-vivo BE testing when they are used within an accepted scientific and regulatory framework. The objective is not to replace in-vivo studies wherever possible, but to apply the appropriate evidence to the product, pathway, and development question being evaluated.