Mechanical Calibration of Dissolution Apparatus—Stefan

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Dissolution testing was developed by pharmaceutical scientists to ensure that oral solid dosage forms do in fact dissolve and that one batch of tablets or capsules dissolves at the same rate as previous, approved batches. Dissolution testing helps ensure that tablets and capsules do not pass through the gastrointestinal (GI) tract intact without releasing the drug, and it also helps show that the dosage form is equivalent from batch to batch.

The 2 most common dissolution testers consist of temperature-controlled U-shaped glass vessels that are filled with liquid (usually purified water brought to acidity similar to that of the human stomach). In Apparatus 1 tablets or capsules are placed inside a rotating mesh basket that is lowered into the vessel. In Apparatus 2, a paddle is lowered into the fluid and the dosage is placed into the vessel, where the paddle rotates above it. The turning of the basket or the paddle inside the acidic liquid mimics the conditions in the stomach and GI tract.

At specified intervals analysts withdraw samples of the liquid and measure the amount of drug released from the tablets or capsules. Each drug has a specific drug-release profile, and by measuring this release and comparing it with established profiles analysts can measure dissolution profiles. In the US dissolution testing is performed according to the specifications in US Pharmacopeia (USP) General Chapter Dissolution <711> (http://www.usp.org/pdf/EN/USPNF/chapter711.pdf accessed 04 February 2010).

Studies have shown that dissolution profiles can be affected by several factors, including the temperature in the U-shaped vessel, vibration, irregularities in the interior walls of the vessels, variations in the alignment or speed of the basket or paddle rotation, and many others. These variables can significantly alter dissolution profiles and have sparked a debate about the relative values of mechanical calibration vs use of reference standards Basically, the question is: Can physical measurements of the dissolution apparatus ensure consistent results, or do analysts need to use certified reference standards (USP Prednisone Reference Standard Tablets) to determine if their equipment meets standards?

To address these questions the Food and Drug Administration (FDA) released its Guidance for industry: the use of mechanical calibration of dissolution apparatus 1 and 2—current good manufacturing practice (CGMP) in January 2010 (available at: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM198649.pdf accessed 04 February 2010). This guidance will help analysts, regulatory affairs professionals, and compendial scientists to conduct dissolution testing accurately and consistently.

FDA’s cGMP regulations for dissolution testing [21 CFR 211.160(b)(4) and 211.68] are satisfied by demonstrated compliance with <711>. At issue in FDA’s recent guidance is whether mechanical calibration is sufficient or whether analysts must compare the results of their equipment with USP Reference Standard tablets. The guidance recognizes the utility of both approaches and concludes “Either the Apparatus Suitability procedure in <711> [involving USP Reference Standard tablets] or an appropriately enhanced [mechanical calibration] method executed according to a written procedure will satisfy the CGMP requirement for calibration ...”

The guidance reviews recent publications about the relative merits of USP Reference Standards and calibration, citing several articles that draw attention to both the use of Reference Standards and some limitations of mechanical calibration. The guidance notes that an industry group advises manufacturers to use “enhanced mechanical calibration.” The final guidance avoids either extreme of mechanical calibration without use of Reference Standards or exclusive reliance on the latter without mechanical calibration. FDA also notes that neither approach is “as comprehensive or as stringent as those in the enhanced [mechanical calibration] procedure recommended in this guidance (for detailed specifications about enhanced mechanical calibration, see http://www.fda.gov/downloads/AboutFDA/CentersOffices/CDER/UCM142492.pdf accessed 04 February 2010). Finally, the guidance recommends that manufacturers pay particular attention to 3 aspects of mechanical calibration during dissolution testing: dissolved gases (which can cause bubbles to form on tablet or capsule surfaces) in the dissolution liquid, vibration, and vessel dimensions.

Overall, the guidance will give industry additional tools and increased confidence that the results of dissolution testing are accurate and reliable.

Stefan Schuber