Meeting Report: AAPS/USP/CRS Workshop on Dissolution; New Technologies and Regulatory Initiatives

Abstract

Day One On March 29-31,2004,AAPS,CRS and USP cosponsored an interesting and exciting Workshop on Dissolution/ New Technologies and Regulatory Initiatives, in Bethesda,MD. Approximately 198 people attended the meeting from diverse disciplines and cultures. The attendees included engineers,pharmacists,chemists,regulators, and researchers. The presentations provided a wide variety of opinions and insight into dissolution testing and addressed performance testing of dosage forms other than solid orals. Vivian Gray opened the meeting with an outline of the information to be provided on vessel design,apparatus, fiber optics,BCS extensions,comparator studies,and USP initiatives. FDA followed with information on the current test requirements, identifying some areas for future growth. Academic researchers provided state of the art evaluations of the hydrodynamics of the vessel and were followed by presentations on the introduction of fiber optics as a method of detection. The presentations on day two focused on new technologies and new apparatus designs. The last day of the workshop was highlighted by a presentation on USP initiatives and actual case studies for comparator product testing. Vinod Shah, of the FDA, provided a regulatory opinion of the current status of dissolution testing and insight into agency perspective. “Where are we now and where will we be in the future?”The purpose and role of dissolution testing was discussed. Dr. Shah emphasized that the amount of testing should be based upon the ability to characterize the performance of the product. In all cases, atypical test conditions should be justified. The in vitro release profile should incorporate sufficient data points for characterization of the performance of a particular product; more for modified release, and transdermals; however, he cautioned about the use of overly discriminatory methods. Dr. Shah also discussed the use of a minimal amount of surfactant in dissolution fluids, sodium lauryl sulfate being the most common. The need to add surfactant to the test medium should be correlated with the drug performance. The Biopharmaceutic classification of the drug helps in the determination of the amount of testing and the qualification for biowaivers. A review of the standards for meeting these classes was provided. The need to standardize the deaeration process and sinkers was indicated. Alternate products such as transdermals were discussed. Future developmental standards were presented with a goal towards assuring product sameness. The remaining presentations on Tuesday morning focused on the hydrodynamics of the dissolution vessel. Fernando Muzzio, of Rutgers University, presented a computational fluid dynamics (CFD) understanding of the dissolution process including both low and high shear models. He provided a demonstration of potential problems at low speeds and under laminar flow. He stated that the USP tablet dissolution test is an analytical tool used for the verification of drug release processes and formulation selection within the pharmaceutical industry. Although engineers do not typically perform this analysis, a failed test can strongly impact the work of engineers in the industry. Variability in test results often leads to delays and alterations in formulation research and development. Given the impact of this test, he found it surprising that operating conditions and testing devices have been selected by trial and error rather than through analysis. In fact, he contended that the flow phenomena in the USP test has received little, if any, attention in the past. An examination of the hydrodynamics in the USP Apparatus 2 by his research group showed that the device is highly vulnerable to mixing problems that can affect testing performance and consistency. Experimental and computational techniques revealed that the flow field within the device is not uniform, and dissolution results can vary dramatically with the position of the tablet within the vessel. Specifically, computations predict sharp variations in the shear along the bottom of the vessel where the tablet is most likely to settle. He described how geometric modifications to the USP paddle are evaluated, focusing on how these modifications influence the hydrodynamics and tablet dissolution rates. Specifically, vessel shape, agitator type, and impeller position were explored. He concluded that the peak vessel reduced the shear rate variability, but the high shear rate may result in the inability to distinguish differences in tablets. The other modifications of differing the impeller height and shape did not resolve the hydrodynamic variability. He told the audience that Rutgers would create a consortium of interested parties that will have its first meeting on 5/9/04 to develop dissolution testing technology where test variability is minimized by systematic application of scientific design methods. Email: jeanne.taborsky@sciregs.com