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

The evolution of dissolution testing

Laboratory scientists have gained more than 30 years of experience with dissolution testing, and General Chapter ‹711› Dissolution has grown to more than seven pages that include four apparatuses. In 1995, the development of the Biopharmaceutics Classification Scheme (BCS) refined the use of dissolution (6). Dissolution is considered the best surrogate for bioperformance if an in vitro–in vivo correlation (IVIVC) can be established. To receive BCS consideration, a dosage form should dissolve rapidly and release no less than 85% of its label claim within 30 min using either USP Apparatus 1 at 100 rpm or USP Apparatus 2 at 50 rpm across the same pH range. In the absence of an IVIVC, the dissolution procedure is primarily a quality-control tool for a specified solid oral dosage form. That is, absent an IVIVC, the dissolution procedure assesses the performance component of quality. Procedures and general acceptance criteria for dissolution are described in ‹711›.

When adapted to a specific solid oral dosage form, the procedure with acceptance criteria becomes part of either a private dosage-form specification or the public specification in the USP dosage-form monograph (7). Dissolution signals acceptable bioavailability (BA) and bioequivalence (BE) if the appropriate scientific links are established and maintained with these developmental characterization studies (7, 8). When a dissolution method is correlated to in vivo performance by an IVIVC or can be relied on in the application of the BCS to allow waiver of an in vivo study, dissolution is used increasingly in regulatory and World Health Organization (WHO) guidelines as a means of documenting BA and BE (9, 10).

Metrology and performance verification testing

The dissolution procedure is not as simple as one might believe. The procedure relies on a test assembly by which an analyst prepares samples to measure percent released from a dosage form as the latter dissolves over time. Test assemblies (assemblies hereafter) with different types of vessels, stirrers, temperature controls, and media have advanced technologically in recent years and have improved substantially in capability. Metrologic science, which relies on reference materials, also has advanced during this time as a result of harmonizing efforts in national metrology organizations such as the National Institutes of Standards and Technology and nongovernmental bodies such as the International Organization for Standardization (ISO) and the International Bureau of Weights and Measures. Both types of advances merit careful consideration regarding the dissolution procedure, given the latter's wide and increasing application (e.g., in IVIVC). The dissolution procedure is not an easy one—it requires not only a modern apparatus but also carefully trained personnel, a well-validated analytical procedure for collected samples, and close attention to detail.

Many elements are involved in ensuring the integrity of the dissolution procedure, and pharmaceutical technologists will be among the first to focus on the assembly itself, including installation qualification (IQ) and operational qualification (OQ). OQ is performed by mechanical calibration, usually at six-month intervals. Performance qualification (PQ) is performed through conduct of an Apparatus Suitability Test as described in ‹711›, again usually at six-month intervals.

USP provides official USP reference standard tablets for PQ. When supplied with a technical data sheet and troubleshooting guide, USP's reference standard tablets can be used by first parties (manufacturers), second parties (purchasers), and third parties (independent or governmental laboratories) to determine whether results within their laboratories are similar to the results from the USP collaborative study (11, 12). Beyond PQ, USP RS Tablets are used in proficiency testing, in which a single laboratory assesses its capability relative to the laboratories in the USP collaborative study. As a general matter, proficiency testing is not a calibration process, and USP's reference standard tablets are not used in assembly calibration. For this reason, the term calibrator tablets is a misnomer. Similarly, the Apparatus Suitability Test in ‹711› is poorly titled. In response to these observations, the USP Biopharmaceutics Expert Committee has renamed the Apparatus Suitability Test in ‹711› in favor of the more accurate descriptor, Performance Verification Test (PVT). Going forward, USP will cease using the term calibrator as a descriptor for its reference standard tablets.


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