Biowaivers for topical drug products: Regulatory approaches, criteria and requirements

Posted June 20, 2016

During the period in which the licence of a reference listed drug (RLD) expires, a generic drug company rushes to develop copies of RLD. However, in order get the product on the market, a generic drug must demonstrate bioequivalence (BE) to the RLD as per draft FDA guidance1, including Hatch-Waxman Amendments, Act, 19842.

A generic drug is considered bioequivalent to the RLD if there are no significant differences in rate and extent of drug absorption, as well as other ingredients being absorbed into the body. In such cases, it is assumed that the generic drugs have the same safety and efficacy as the RLD.  Consequently, no further clinical trials for generic drugs are required as the already existing safety and efficacy data of the RLD can be used during generic drug submissions.

Bioavailability (BA) is the amount of an active ingredient that becomes available to the body and that reaches the target organ or absorbs into the circulatory system through oral ingestion, inhalation, or other topical absorption sites.

Both BA and BE encompass two phases: release of the drug substance from its dosage form and absorption into the body.

Determining BE of topical dermatologic products is a challenge for both the regulatory and pharmaceutical industry.

FDA guidelines explain how BE studies should be designed, in which cases biowaivers can be requested. Although BE is mainly performed for generic products, the FDA may request BE testing for innovator’s drugs in some cases. For instance, if changes in excipients of a formulation occurs once the drug has already been approved, the FDA will request to demonstrate BE of pre- and post-changed formulations.

Current approaches and guidelines for BE of topical drug products in the US and Canada are identified in FDA, 21 CFR 320.243:

  1. Pharmacokinetic (PK)
  2. Pharmacodynamics (PD)
  3. Comparative clinical trials (endpoint-BE) 
  4. In vitro release rate tests

Clinical trials to prove BE often lack sensitivity and require large and costly trials. It is not cost effective for generic manufacturers to conduct large clinical trials. Several surrogate methods have been proposed to address this issue as summarized in our IVRT/IVPT e-book

Biowaivers are the waivers of clinical BE studies. In some instances, a request for a biowaiver may be granted with supporting data qualitative (Q1) and quantitative (Q2) equivalence to the RLD. Additionally, the FDA will request data to demonstrate acceptable comparative physicochemical characteristics (particle size, viscosity, morphic form, molecular weight distribution, etc.) and equivalent in vitro release profile (Q3) to the RLD.

For each new generic topical drug product submission, the FDA determines the optimal BE approach on a case-by-case basis. In determining the optimal BE approach for each product, FDA considers:

  • Drug mechanism of action, site of action
  •  Complexity of RLD formulation
  • Feasibility, sensitivity of an approach
  •  Whether a biowaiver is appropriate

European Medicines Agency (EMA) 4 and the FDA permits the waiver when in vivo studies are not feasible and topical pharmaceutical products meet specified criteria. Thus, the costly and time consuming in vivo studies may be replaced by fast and low cost in vitro tests.

In Vitro Release Testing (IVRT) for semisolid preparations using modified Franz diffusion cells has been recognized by the FDA’s SUPAC-SS guidance as a test for product performance and to demonstrate sameness after certain manufacturing related changes. Recently, USP General Chapter <1724> IVRT has also been accepted as a reasonable and useful test to be considered as a product performance, release and stability test.

In order to meet regulatory requirements, an in vitro release methodology should be appropriately developed and validated. Having an appropriate validated IVRT method is mandatory for semisolid product development and FDA approval.

A development/validation approach should include the selection of an appropriate synthetic membrane and receptor solution, and demonstrate the reproducibility, selectivity and sensitivity of the IVRT method. It should also evaluate the IVRT method’s ability to discriminate rates of release of drug from formulations with altered concentrations of drug and composition of excipients or altered process parameter(s). The validation of sample assay method typically uses HPLC-UV in compliance with ICH guideline Q2 (R1) for analytical method validation. It is highly recommended that IVRT method established during product development phase and validate for at least one final formulation.

For more information about biowaivers for topical drugs, contact Neil Holman at DiTEBA today (

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