ABSTRACT
OVERVIEW In the early 1990s, research collaborations established between academic scientists and the U.S. Department of Health and Human Services Food and Drug Administration (FDA) focused on the development of new regulatory standards for bioequivalence (BE), to reduce regulatory burden without compromising the quality of drug products. One of the major developments of this effort was the Biopharmaceutics Classification System (BCS) in 1995, which lays the scientific foundation for classifying drugs into four groups on the basis of drug solubility and permeability (Table 1). In BCS, the criteria for high solubility of the drug substance is met when the highest dose can be dissolved in 250 mL of aqueous media or less over the pH range 1 to 7.5 or 1 to 8 at 378C, as currently stipulated by the FDA and European Medicines Evaluation Agency (EMEA), respectively (2,3). High permeability is defined as 90% or more of absorption based on mass balance or compared to an intravenous reference dose (FDA), or as “linear and complete absorption” (EMEA) (3). To obtain a biowaiver from FDA, dissolution of the test and reference drug products must be 85% or more of the labeled amount of drug substance within 15 minutes, or alternatively within 30 minutes passing an f2 test, using U.S. Pharmacopeia apparatus I at 100 rpm or apparatus II at 50 rpm in a volume of 900 mL or less of the following media:
-Acidic medium (e.g., 0.1 N HCl or simulated gastric fluid USP without enzymes) -A pH 4.5 buffer -A pH 6.8 buffer or simulated intestinal fluid USP without enzymes
During the past decade, the rationale of BCS has been extensively discussed in the scientific community, effectively implemented by regulatory agencies, and widely practiced by the pharmaceutical industry. These efforts led to regulatory relief including an improved Scale-Up and Post-Approval Changes-immediate release (SUPAC-IR) guidance in 1995 (4), a guidance on dissolution testing of IR solid oral dosage forms in 1997 (5), and a draft of 1999 and subsequently the final version of the guidance for waiver of in vivo bioavailability (BA) and BE based on BCS in 2000 (2).
