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Executive Summary

Drug dissolution tests in vitro cannot replace in vivo bioavailability studies in determining bioequivalence, a panel of three expert consultants concluded at FDA's bioequivalence hearing Sept. 29. William Barr, PharmD/Phd, Virginia Commonwealth University, stated that dissolution "promotes good bioavailability, but it doesn't absolutely assure it." Barr said that "in some cases you can have good correlation between dissolution rates and in vivo bioavailability, particularly for a specific formulation." He added, however, that "the degree to which you can change that formulation and still continue to have that correlation will remain to be a mystery because it will be dependent upon the formulation." He said dissolution "is an excellent quality control standard." FDA Bioequivalence Division Director Shrikant Dighe, PhD, co-chairperson of the session on in vitro testing for bioequivalence, commented that "nobody is ready to make a quantum jump" to replace in vivo studies with in vitro dissolution studies "at this point." He noted that "sometime in the future" FDA may look at dissolution at different pH levels, "different gradients, perhaps is different buffer solutions, and a battery of tests for dissolution of a particular product." Dighe explained that FDA's aim "is to collect, in general, as much data as possible for dissolution of products that have undergone in vivo bioequivalent study and tie these in vitro and in vivo data together so that we will have assurance of bioequivalence from batch to batch." Upjohn Director of Biopharmaceutics & Bioanalytical Research Kenneth Albert, PhD, asserted Upjohn's opinion that "meaningful in vitro/in vivo relationships are possible only when dissolution rate dominates membrane transport and transit rate, thus limiting rate and/or extent of absorption." He said it has been Upjohn's experience that "any in vitro/in vivo relationships that are established are formulation specific and manufacturing process specific." Albert presented data to demonstrate that ibuprofen is an example of a drug "in which dissolution is not predictive of in vivo bioavailability." He said that while Upjohn was developing a new dry blend formulation of ibuprofen, the company conducted a bioavailability study with 24 healthy volunteers to determine which of three formulations was bioequivalent to a currently marketed tablet. Albert said the three formulations were "slightly more slowly absorbed" than the marketed tablet, with one on the borderline of significance and one deemed bioequivalent. The company then attempted "to develop a discriminating dissolution test predictive of bioavailability," Albert said. The in vitro system found to correlate with bioavailability was the 50 RPM basket using pH 7.2 phosphate buffer. Albert stated that the dissolution profile suggested that "the dry blend formulation should be absorbed significantly more rapidly than the currently marketed wet blend formulation tablet because its dissolution is so much more rapid." However, he said an in vivo bioavailability study found that the dry blend formulation was absorbed significantly more slowly. Arnold Beckett, King's College London, University of London, asserted that in vitro and in vivo data cannot be correlated using one point. He said all the work presented at the hearing was possibly done "on a single batch of material, with the characteristics of that particular material in terms of its release." Beckett asked whether an agreement could be made to use a smaller number of subjects in a crossover design to study various batches, "provided we can truely correlate between our dissolution data and our in vivo response."

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