FDA official: Biowaiver framework needed for modified release generics
ROCKVILLE, MD – There is a need for the scientific community to explore the use of additional strength biowaivers for modified release (MR) drugs given the increasing market demand for these “patient centric” products, said Robert Lionberger, director of the US Food and Drug Administration’s (FDA) Office of Research and Standards in the Office of Generic Drugs.Lionberger made these remarks at the 18 April FDA/PQRI workshop on challenges and opportunities for modified release oral drug product development.
He said this work should be conducted as part of efforts to establish a global harmonized framework for bioequivalence (BE) testing for MR products.
“We are close to wrapping up the M13 harmonization for immediate-release (IR) products so logically the thing that come after immediate release is modified release,” Lionberger said.
He added that “it is important to not just to look at a global framework but a more scientifically sound framework.” Earlier in the week, FDA officials announced that ICH M13A guideline, which sets a harmonized framework for assessing BE for IR drugs, is set to be adopted this summer. (RELATED: ICH M13A BE testing guideline expected to be adopted this summer, Regulatory Focus 17 April 2024)
Currently, FDA does not waive BE studies for additional strengths of MR products. Rather, FDA makes a determination about BE for each MR strength based on in vitro data. Generic drugmakers can file suitability petitions if there is a market need for different strengths of a MR product. Biowaivers can also be granted if sponsors can establish an In Vivo/In Vitro Correlation (IVIVC) between the test and reference drug.
FDA’s revised guidance on BE testing issued in August 2021 sets out limited conditions for which it will make a determination of BE for each MR strength based on in vitro data.
One of these conditions state that “the test product includes the same excipients for different strengths and the ratios of drug and excipients among different strengths of the test product is justified and appropriate for the drug release mechanism of the test product (e.g., drug and excipients of different strengths can be either proportional or not proportional in quantity).”
Lionberger said that there is a need to “build a foundation for better guidance” in this area.” He added that “today we begin a deep dive into justified and appropriate for the drug release mechanism” and added that addressing this question “is the scientific foundations for the strength biowaiver.”
He notes that the 2021 guidance was an improvement over the previous version issued in 2002, which said that BE testing can be waived if MR products are “compositionally proportional across strengths.”
He said the concept of proportionality is fine for immediate release, which are simpler formulations, yet this principle does not hold up to MR products where the dosage form controls the release, and there are many different mechanisms for release, including osmotic pumps, matrix tablets coated tablets, and coated beads.
“The reason we made this change is that the older language really told generic applicants that the way to get less questions from the agency was to make a proportional formulation. And that is not always the most appropriate thing to do.”
PQRI workshop
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