Category: Clinical Pharmacology
Purpose: For oral solution products, according to 21 CFR 320.22, the in-vivo bioequivalence study may be waived if the generic (i) contains the same active drug ingredient in the same concentration and dosage form as the reference listed drug (RLD); and (ii) contains no inactive ingredient or other change in formulation from the RLD that may significantly affect absorption of the active drug ingredient or active moiety for products that are systemically absorbed. Most generic versions of oral solution products are approved based on biowaiver if the above conditions are met. This study aims to 1) systematically compare different regulatory agencies’ requirements regarding bioequivalence demonstration of oral solution products (e.g., when a biowaiver may be granted), and 2) evaluate the approval basis of U.S. generic oral solution products, especially the ones which contain poorly soluble active pharmaceutical ingredients (API).
Methods: We reviewed U.S. Food and Drug Administration (FDA) and seven other regulatory agencies’ guidance and practice regarding bioequivalence demonstration of oral solution products. For all U.S. approved generic oral solution products, we compared the formulation composition of the generic product to that of the RLD and evaluated conditions that biowaiver were granted or denied for these approved generic drug products.
Results: Regulatory agencies including the U.S. FDA, Therapeutic Goods Administration (Australia), South African Development Community, Health Sciences Authority (Singapore), and Pharmaceuticals and Medical Devices Agency (Japan) grant in-vivo bioequivalence waivers for generic oral solution products containing the same active ingredients in the same concentration as the RLD, with no inactive ingredient known to significantly affect absorption. Health Canada (HC), the European Medicines Agency (EMA), and New Zealand guidelines specify more defined requirements, which limit the waiver of in-vivo BE study only to aqueous oral solutions when the generic contains the same active ingredients in the same concentration as the RLD. There are over 200 RLDs and over 600 generic oral solution products approved by U.S. FDA. About 66% of oral solution products contain highly water-soluble APIs. For poorly water-soluble drugs, solubilization approaches employed in approved oral solution drug products include pH adjustments, use of co-solvents, complexation approach, and oil-based formulations. Overall, most ANDAs have formulation compositions similar to those of the RLDs, thus a low risk of therapeutic inequivalence. For some ANDAs with different formulations from that of the RLD, requests for waivers of in-vivo bioequivalence studies were denied due to certain excipients exceeding the maximum allowed quantity or threshold difference between ANDA and NDA formulations. These ANDAs were either reformulated or in-vivo bioequivalence studies were added. There are FDA internal guidelines to justify different excipient use in oral solution products, but limited to sorbitol, co-solvents, and flavoring agents.
Conclusion: Our evaluation indicates that there is minimal therapeutic inequivalence risk of U.S. approved generic oral solution products based on biowaiver, as their formulations are very similar to the RLD. When formulation differences were noted between generics and RLDs, they were carefully evaluated to determine whether the differences were significant enough for reformulation or a request of an in-vivo bioequivalence study. This study provides a summary about the approval basis of U.S. generic oral solution products and identifies potential areas for specific guideline development and global harmonization regarding the waiver of oral solution products.