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Generic Oral Modified Release Drug Products: Establishing Bioequivalence for “Additional Strengths”

The Office of Generic Drugs within the U.S. Food and Drug Administration (FDA) regularly receives controlled correspondences from prospective generic drug applicants inquiring about approaches, studies, or methodologies for establishing bioequivalence (BE) of their proposed generic versions (or “test products”) of brand name products (or “reference products”). For oral modified release (MR) products, in vivo BE studies are generally being conducted with the highest strength (“bio-strength”). If the product has multiple strengths, one commonly asked question has been what alternative methods may be used to demonstrate BE for “additional strengths” of a test product to the corresponding strengths of the reference product in lieu of in vivo BE studies on these strengths.

In general, when the reference product exhibits similar bioavailability for different strengths given at the same dose, the additional strengths of the test product may be demonstrated to be bioequivalent to the corresponding strengths of the reference product without the need for additional in vivo BE studies. In this regard, the following points may be considered to support the demonstration of BE for additional strengths of MR products under 21 CFR 320.24(b)(6):
  • Test product vs. reference product : Is BE demonstrated based on in vivo BE studies for the bio-strength?
  • Test product: Additional strengths vs. Bio-strength
    • Is drug release mechanism the same across strengths of the test product (which can be a different mechanism from that of the reference product)?
    • Are excipients qualitatively the same across strengths of the test product?
    • Are the ratios of drug and excipients among different strengths justified to be appropriate, taking into consideration of the drug release mechanism?
    • Are dissolution profiles similar between the bio-strength and additional strengths based on similarity factor (f 2) test or other appropriate statistical testing in at least three media (e.g., at pH 1.2, 4.5, and 6.8)?

The objective of this webinar is to discuss the above principles using case examples to illustrate various elements considered in regulatory assessment with respect to BE demonstration of additional strengths for which in vivo BE studies are not conducted. Through these examples, we also aim to enhance the understanding that (a) totality of evidence is key in establishing BE for additional strengths and (b) identifying drug release controlling excipients in the formulation is important during formulation development for oral MR products.   

Learning Objectives:
  • Understand principles and data that may be used for BE demonstration for additional strengths of oral MR drug products
  • Discuss critical elements in BE assessment for additional strengths including
    • Drug release mechanism 
    • Release rate controlling and non-release rate controlling excipients
  • Learn the value of exploring the safe space of release controlling excipients during drug development

Who Should Attend:

Generic drug industry scientists seeking to gain an understanding of the principles in BE demonstration of additional strengths of oral MR drug products

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