Dissolution Testing and Metrological Measurement of Quality for Solid Oral Dosage Forms - Pharmaceutical Technology

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Dissolution Testing and Metrological Measurement of Quality for Solid Oral Dosage Forms
USP applies metrological principles to the dissolution procedure alone and in collaborative studies to understand and minimize potential sources of variability.


Pharmaceutical Technology


In contrast to well-established conventional analytical techniques such as high-performance liquid chromatography, it has long been recognized that dissolution testing is associated with issues of repeatability and reproducibility (3, 13). USP prednisone reference standard tablets were first introduced to industry in 1981 as a collaborative effort of pharmaceutical manufacturers and USP to address the reliability issue, especially the interlaboratory variability. The current general chapter ‹711› Dissolution requires dissolution testers with USP Apparatus 1 and 2 to pass the PVT with nondisintegrating salicylic acid reference standard tablets and disintegrating prednisone reference standard tablets (14).


Figure 1: The variables that affect precision.
USP periodically receives comments that dissolution testing is specific to a particular manufactured article or that a manufacturer may develop its own physical standard for a PVT. Metrologic aspects of proficiency testing are based on interlaboratory comparisons and generally refute this approach (see ISO Guide 5725-1, Accuracy (Trueness and Precision) of Measurement Methods and Results, at 3.18) (15). In a similar manner, USP also at times sees claims that only mechanical calibration is needed without a PVT. This claim seems to be based on the erroneous assumption that USP's tablets are responsible for much of the observed interlaboratory variance. USP rejects this claim, which, if accepted, would bypass the valuable opportunity to gain data by means of interlaboratory comparisons (16). Figure 1 succinctly shows that ISO 5725 identifies five variables that affect precision: operator, equipment, calibration, environment, and time between measurements. Calibration alone is sufficient to define neither precision nor accuracy. If testing takes place in one laboratory and the five variables are held constant (intralaboratory variability), one is measuring the lower limit of precision, or repeatability. If testing takes place in different laboratories and the five variables are not held constant (interlaboratory variability), then one is measuring the upper limit of precision, or reproducibility.

USP collaborative studies typically involve at least three laboratories representing industry, FDA, and USP. Experiments at USP have shown that USP prednisone reference standard tablets are highly sensitive to dissolved gas in the dissolution medium using Apparatus 2; that in a design-of-experiment study eight of nine variables studied—alone and in combination—produced statistically significant variation; and that dissolution vessels differed markedly both among vessels from various vendors and from the same source, to the extent that differences in hemisphere radius could result in as much as an 18% change in the volume of dissolution media surrounding the paddle in Apparatus 2 (17–19).

Conclusions

Clearly, dissolution testing with USP prednisone lot P reference standard tablets is a sensitive procedure that is subject to perturbations both from the apparatus and operator expertise. Results of recent studies suggest that metrology-based PVT can help industry practitioners better understand both the performance of dissolution testers and the conduct of interlaboratory collaborative dissolution testing. As ISO 43, Proficiency Testing by Interlaboratory Comparisons, succinctly states, "One of the main uses of proficiency testing schemes is to assess laboratories' ability to perform tests competently" (20).

USP supports mechanical calibration as a means of enhancing experimental results by OQ (21, 22). Mechanical calibration alone, however, is not adequate to assess performance among laboratories. More precisely, in terms of ISO 5725, mechanical calibration by itself cannot detect trueness and precision, which are the two components of accuracy (see Figure 1) (15). Similarly, USP's reference standard tablets are not a substitute for mechanical calibration; instead, both USP reference standard tablets and mechanical calibration belong together in a well-designed overall program of IQ, OQ, and PQ, the latter now understood as PVT. Numerous studies during the past decades tackled the issues of repeatability and reproducibility associated with dissolution testing (Figure 1). The sources of variability were not well understood, however. Recent studies clearly demonstrate the very different performance characteristics of dissolution apparatuses, although more work remains to be done to refine our understanding of the dissolution process and variables that can affect dissolution data.

Ronald G. Manning, PhD,* is vice-president, Scientific Outreach; Samir Z. Wahab, PhD, is director, Research and Development Laboratory, William E. Brown is senior scientist, Department of Standards Development, Walter W. Hauck, PhD, is senior scientific fellow, Department of Standards Development, Stefan Schuber, PhD, is director, Corporate Planning, Development, and Communications, and Roger L. Williams, MD, is executive vice-president and chief executive officer, all at the US Pharmacopeia, 12601 Twinbrook Parkway, Rockville, MD 20851-1790, tel. 301.816.8562,

*To whom all correspondence should be addressed.


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