Dissolution Testing Session Focuses on Basics

In the spirit that a good review of the fundamentals is always beneficial, the American Association of Pharmaceutical Scientists' Annual Meeting and Exposition featured an early morning discussion about the basic aspects of dissolution testing, including common sources of errors and deviations.

The well-attended session proved that dissolution testing remains a topic of interest, especially as the industry continues to extend its application to media other than solid dosage forms, most notably soft gels.

A feature article in the Oct. 27

Pharmaceutical Technology

electronic newsletter (

http://www.pharmtech.com/pharmtech/article/articleDetail.jsp?id=190230

) reported that 15.5% of recalls in 2005 have been attributed to failed USP dissolution test requirements. During his overview of dissolution apparatus, media, and the overall testing methodology, Bryan Crist of Varian Inc. (Palo Alto, CA,

www.varianic.com

) emphasized that the overall goal of dissolution testing is to understand the behavior of drugs

in vivo

. To gain this understanding, analysts must identify all sources of possible variance. As Crist observed, this is especially important because in the future the industry could see a tightening of parameters. For example, in the near term, the industry could see the need to include a vibrational measurement. According to Crist, deviations can occur as a result of improper use and maintenance of equipment. For example, a wobble gauge may be inappropriately placed. (Although no measure of wobble is documented in USP, typical measures are approximately 0.5 mm). Analysts can minimize errors stemming from equipment use, for example, by maintaining the dimensions of the paddle, taking particular care to note that any degradation of the paddle coating changes the paddle's dimensions. Rotating paddle speed must also be maintained, typically about 25-75 rpm. Any variance from normal operating parameters, says Crist, must be supported. Tracking failure data is also vital. Crist also noted that the only allowable modification to equipment is the "sinker," which can have a wide range in type. Other common sources of variation might be in how the equipment performs. To reduce this variation, analysts should maintain the equipment clean, says Crist. Proper attention to the handling and loading of the media can also reduce variation, including maintaining volumetric accuracy, media temperature, media integrity, and (if applicable) measuring the weight of the media. Crist also emphasized the importance of documentation and ensuring proper calibration of timing devices. "This is a source of numerous 483s," he said. Media must be allowed to sink to the bottom of a nonrotating system before the test begins and samples must be withdrawn at the proper time (typically +/- 2%) to maintain precision. Focusing on the regulatory aspects of dissolution testing, Vivian Gray discussed FDA's role in dissolution. As she observed some of the common mistakes leading to 483s included failure to investigate out-of-specification (OOS) results, failure to follow standard operating procedures (SOPs), lack of process validation, not having a proper SOP for OOS results, and, increasingly, the lack of validation of robotic systems. Gray also emphasized that although much can be gained from analytical data, physical observation provides a good understanding of the process as well. Information about particle size (snowflake or fine particles), whether the dosage form is on- or off-center, whether floating chunks of media or bubbles are present, and whether there are coning, sticking, or clogging effects can all be determined by observation. The remainder of the discussion focused on regulatory issues such the eventual combining of USP chapters and and the new General Chapter , which aims to provide guidance on method development. Participants in the symposium were

Moderator: Margareth R. Marques, PhD, US Pharmacopeia

Performing the Dissolution TestBryan Crist, Varian Inc.

Basics of Dissolution Testing RequirementsVivian A. Gray, VA Gray Consulting, Inc.