A spirited discussion ensued during the Hot Topic session on dissolution testing at the recent AAPS Annual Meeting and Exposition in San Antonio, Texas. In one corner was Mario Gonzalez from PKinetics International, Inc. and a member of the USP Biopharm Expert Committee. In the other was Ajaz Hussain, vice president of drug development for Sandoz, and the former Deputy Director, Office of Pharmaceutical Science, at the FDA's Center for Drug Evaluation and Research (CDER). The debate centered on whether a known testing tablet could establish the stability of solid dosage forms.
Gonzales is a firm believer in dissolution testing using referenced testing tablets, identifying them as "the only indicator" of dosage form consistency from batch to batch over time. He also cited their increased use to document bioequivalence. He emphasized how the dissolution procedure should align with cGMPs and with principles of sound science. These cGMPs stress instrumental qualification (IQ), operational qualification (OQ) and performance qualification (PQ). For the dissolution procedure, OQ is performed using mechanical calibration and PQ is conducted through a USP Performance Verification Test (PVT). These tablets are used as reference standards for a PVT.
He described the USP approach as a "proficiency test" that assesses a laboratorys ability to conduct a procedure competently. It tries to ensure that measurements made at different times, by different analysts or different methods can be compared adequately. Gonzalez did acknowledge variances in tests run by different labs but insisted that USPs reference tablets were not to blame. He cited problems with vessels, dissolved gas and even environmental noise as contributing factors to differences in dissolution rates.
USP supports mechanical calibration as way to enhance experimental results through OQ. However, USP experts believe that mechanical calibration alone is not adequate to assess performance across laboratories.
Although an acknowledged expert on the issue, Hussain is no longer involved in dissolution testing at his current position, a fact that he emphasized numerous times during his presentation. However, he stressed the concept that dissolution tests are not sufficient to assure bioequivalence between products.
Hussain argued that the intrinsic performance from tablet to tablet within a production lot of reference tablets adds an underlying source of variability to the results. He also reasoned that a dissolution test may not be a sensitive enough indicator for dosage forms such as highly soluble and highly permeable drugs. He suggests, instead, using an internal calibrator tablet developed from a clinical batch in ones own system. He explained, this internal reference developed from a clinical or biobatch may be more applicable to the product than dissolution calibrators.
The key to dissolution testing, according to Hussain, is precise relevant control and an effective corrective/preventive action (CAPA) system. There are many sources of variability; knowing and minimizing them will help with uncertainty. Hussain said that experts at FDA expect dissolution to function less as a quality control test in the future, but to play a more important role in Quality by Design during drug development, by providing clinical linkage.
