Getting the Truth out of Dissolution Testing

Industry, equipment vendors, and regulators are busy refining the precision and reliability of dissolution testing.
Oct 02, 2009
Volume 33, Issue 10

Solid dosage formulators rely on dissolution testing to mechanically model the biological conditions of drug release in the body. For quality control, analysts use dissolution studies to ensure product and process consistency. Although the objectives of these two groups are different, both are developing means to improve testing methodologies and ensure results are reliable.

For the most part, the industry is not in disagreement with the usefulness of current dissolution testers. Roy Hanson, CEO of Hanson Research (Chatsworth, CA), estimates over 80% of dissolution work is conducted using either US Pharmacopeia (USP) Apparatus 1 (basket) or Apparatus 2 (paddle), with the paddle method perhaps being more popular because of its ease in set up. (Apparatus 3 involves the use of biodisks to study extended-release dosage forms designed to release the active pharmaceutical ingredient according to pH; and Appartus 4 is a flow-through cell unit that some analysts believe is more representative of the gastrointestinal tract because it provides a constant flow.)

Evolution of dissolution equipment
Nor is there much disagreement regarding the general regulatory guidance of dissolution testing. According to Lucinda Buhse, PhD, Director, Division of Pharmaceutical Analysis, at FDA's Center for Drug Evaluation and Research (CDER), the Pharmacopeia Discussion Group (comprising USP, European Pharmacopeia, and Japanese Pharmacopeia) has harmonized the USP dissolution test general chapter ‹711› (1). Instead, much of the current discussions among regulators, manufacturers, and equipment vendors are centering on making dissolution testing more clinically relevant, implementing the US Food and Drug Administration's quality by design (QbD) principles, and reaching an agreement on equipment calibration and qualification.

QbD and biorelevance

To bring QbD principles to dissolution testing, FDA and industry are focusing on the development of biorelevant specifications, which requires that dissolution tests also be clinically relevant. "I've seen clinical studies where they have shown differences in drug release due to age, gender, diet, race, whether a patient is in a fed or fasted state, and many other factors that come into play for how a specific individual may assimilate a medicine at a given point in time," says Hanson.

Figure 1: Rigorous mechanical calibration has been proposed as a replacement for the need to conduct performance-verification testing. IMAGE COURTESY OF HANSON RESEARCH.
Developing a design space of critical attributes that are related to the dissolution test methodology and linking this space to the level of product quality has become a formidable task (2). Christine M.V. Moore, PhD, acting deputy office director of CDER's Office of New Drug Quality Assessment points out that in the past year, there were several workshops and conference sessions on QbD in biopharmaceutics. "We expect continued dialogue on this subject. Already we are seeing some companies apply QbD approaches to better understand the link between product characteristics and its performance. Additionally, we are seeing some companies use modeling approaches to relate product quality attributes and process parameters with dissolution as a way to facilitate real-time release testing."

Some scientists are focusing on the characteristics and properties of the particular dissolution media (3, 4). Media containing biosalts, for example, that can imitate the fed and fasted state or of the gastric juices or intestinal fluid are making a lot of progress, according to Vivian Gray, owner of V.A. Gray Consulting (Hokkesin, DE). "Media is a very critical component. There's a good stream of communication and learning going on right now about media and the composition of media," says Gray. FDA recently collaborated with the University of Wisconsin on a workshop that focused on applying QbD in dissolution, including the rationale for choosing dissolution media.

Figure 2: A bathless unit incorporates heating jackets for each vessel and a control system that communicates the temperature of each unit. IMAGE IS COURTESY OF DISTEK
Other work has focused on modifying the dissolution equipment (5). According to Hanson, some university laboratories have developed complex prototypes of equipment that more closely mimic biochemical and biomechanical actions, subjecting the drug through acid pH stage, a peristaltic action, a different pH, and a peristaltic flow that's more like the intestinal tract. "However, it may take a while for a very complex system to give results that are reproducible and not extremely variable," says Hanson. "Honestly, probably what we have right now [in equipment], with some work on the media and the agitation rate and so forth, we can come up with the appropriate relevant test."

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