2010 Pharmaceutical Sciences World Congress Provides Dissolution Programming with an International Flavor

In November, the FIP 2010 Pharmaceutical Sciences World Congress was held in New Orleans in association with the American Association of Pharmaceutical Scientists Annual Meeting and Exposition. Some of the latest thinking on dissolution was presented with a distinctly international flavor, since many of the speakers and participants were from outside the United States. In a Roundtable on Analytical Instrument Qualification: Towards Globalization, Horacio Pappa from the United States Pharmacopeia highlighted the USP Dissolution Toolkit to be used in conjunction with PVTs. Recently, USP introduced several changes with respect to dissolution instrument qualification to reduce testing and make it more robust. Cindy Busche from FDA stated that AIQ is the foundation of quality data. She discussed recent Warning Letters and 483s, and indicated that dissolution made the Top 10 list. She also pointed out the importance of a written program for performance qualification and instrument calibration. Robert McDowall, McDowall Consulting, discussed the relationship between USP Chapter <1058> and GAMP 5 for computerized instruments. He pointed out the need for an integrated guidance that brings both of these together. Relevance of Dissolution Testing in a QbD Approach to Drug Release was discussed in a Roundtable. Patrick Marroum from FDA said that a goal of QbD is that all batches within the design space should be considered bioequivalent. This may be demonstrated by relating pK or plasma data to in vitro data. Of course, this requires a meaningful in vitro test, one that is discriminating and sensitive to changes in manufacturing parameters. Ideally, sponsors would vary the formulation (perhaps using Design of Experiments) and then generate meaningful in vitro and corresponding bioavailability data. If in vivo data are available, they can be used to evaluate the appropriateness of the design space; alternatively, the f2 test can be used to compare dissolution profiles. Ruben Lozano from BMS pointed out that there may be an opportunity to replace dissolution with a surrogate. It is possible that other tests may be more meaningful; upstream control of critical quality attributes could make dissolution testing redundant. He pointed out that sometimes there is no correlation between dissolution results and bioequivalence (BE) or bioavailability (BA). Surrogate tests might include disintegration, control of API particle size, granule size, blending process, or tablet hardness. Nonetheless, it may be necessary to perform dissolution testing on stability, even if it is avoided as a release test. An EMA perspective on dissolution and QbD was presented by Evdokia Korakianiti from EMA. She pointed out that dissolution testing, media recommendations, and specifications rely on the Pharm Europa chapter on Dissolution and ICH Guidances Q8 (Pharmaceutical Development) and Q6 (Specifications). She also indicated that key documents are under revision, pointing to EMA/CHMP/QWP/202350/10 (1), which attempts to address issues such as in vitro tests that are not biorelevant, and CPMP/EWP/QWP/1401/98 (2), which will provide updated guidance on such as topics appropriate study designs, analytes to be measured, and dissolution test conditions. She also questioned whether dissolution is overdiscriminating in the case of immediate-release products that are BCS Class I and III. With a QbD approach, it is appropriate to examine product performance based on CQAs and to recognize that consistency comes from design and control of the manufacturing processes. The dissolution test should be developed to mimic in vivo performance and may be replaced by a surrogate procedure when appropriate. In the roundtable discussion that followed the presentations, topics included the FDA stance on alcohol dose-dumping (particularly if in vitro results are different from those observed in vivo), the number of subjects necessary to develop an IVIVC, appropriate situations for use biorelevant methods, and the acceptability of noncompendial dissolution apparatus. When asked how many QbD applications had been received, Marroum indicated FDA had over 30 while Korakianiti said that two or three had used full QbD. On the subject of using biorelevant media to predict food effects, Marroum indicated that in vivo data is required. When asked if surfactants in the media are okay if they are justified, he responded that the method must still be discriminating and the concentration *Corresponding author.