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USP applies metrological principles to the dissolution procedure alone and in collaborative studies to understand and minimize potential sources of variability.
According to the International Vocabulary of Basic and General Terms in Metrology (VIM), metrology is the science of measurement that "includes all aspects both theoretical and practical with reference to measurements, whatever their uncertainty, and in whatever fields of science or technology they occur" (1). Quality in the measurement process depends on method validation, uncertainty, and the traceability of the result. The role of reference materials is to help enable quality measurements. This article examines the background and evolution of the USP dissolution procedure and steps that USP is taking to apply metrological principles to better characterize the procedure and minimize variables associated with dissolution testing.
For pharmaceutical tablets and capsules (solid oral dosage forms), quality can be represented by human in vivo bioavailability. The Federal Food, Drug, and Cosmetic Act of 1938 states that:
"a drug or device shall be deemed to be adulterated...if it purports to be or is represented as a drug the name of which is recognized in an official compendium, and its strength differs from, or its quality or purity falls below, the standard set forth in such compendium. Such determination as to strength, quality, or purity shall be made in accordance with the tests or methods of assay set forth in such compendium (2)."
In the 1970s, the Pharmaceutical Manufacturers Association (now known as the Pharmaceutical Research and Manufacturers of America, PhRMA) moderated a dissolution collaborative study involving industry, USP, and the US Food and Drug Administration (FDA) showing that in certain cases dissolution is predictive of bioavailability (3).
In 1976, USP adopted a policy that favored dissolution requirements for every tablet and capsule (i.e., every solid oral dosage form). In the Preface to USP XIX (1976), USP expressed the view that both dissolution and bioavailability were important quality characteristics and that dissolution testing should be considered in terms of both bioavailability and quality control:
"The attributes of a drug product that make possible full and consistent utilization of its active ingredient are dependent upon the product's formulation and an exercise of production control—and, in turn, such attributes determine what is now commonly termed bioavailability... The term bio-equivalence has come to the fore quite recently. Two or more different specimens of what purport to be the same strengths of the same type of dosage form of a given drug substance are said to be bio-equivalent when their bioavailabilities are similar. It is the ultimate objective of the Pharmacopeia to provide standards ensuring that all specimens of a given dosage form are bioequivalent (4). "
The polite, if somewhat stiff, language at the conclusion of this passage glosses over an often acrimonious public debate. During the 1970s and early 1980s, government entities and other payers were eager to lower the costs of pharmaceuticals, but some parts of the innovator industry, among others, were opposed to the introduction of generic drugs because of purported bioequivalence and safety issues. FDA took bioequivalence to be its purview and frequently insisted that USP restrict its interests to the quality-control aspects of dissolution testing, much to the displeasure of USP's Board of Trustees, volunteer scientific Council of Revision (now known as the Council of Experts), and staff. The Drug Price Competition and Patent Term Restoration Act (commonly known as the Hatch–Waxman Act, 1984) provided some relief by formalizing the mechanism by which manufacturers of generic drugs could file abbreviated new drug applications (5).
Since USP XIX, when the Dissolution general chapter featured only Apparatus 1 and was half a page long, USP has studied bioavailability data while revising, expanding, and updating USP General Chapter ‹711› Dissolution. Whenever bioavailability studies have been available, they have been the basis for dissolution standards. USP Expert Committees also have established dissolution requirements in the absence of a bioavailability study, basing those requirements on known pharmaceutics. Since the publication of USP XIX, USP has amassed a portfolio of more than 2000 reference standards for use with individual monographs, and USP uses collaborative tests involving FDA, industry, and USP laboratories to qualify different lots of USP reference standard tablets that are distributed to 130 countries around the world.
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.
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).
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.
Figure 1: The variables that affect precision.
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).
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, firstname.lastname@example.org
*To whom all correspondence should be addressed.
1. ISO, Guide 99: International Vocabulary of Basic and General Terms in Metrology (VIM), (Geneva, Switzerland, ISO, 2004).
2. 21 USC 351 Â§501(a)(2)(B).
3. R. Hanson and V. Gray, Handbook of Dissolution Testing, 3rd ed. (Dissolution Technologies, Hockessin, DE, 2004).
4. US Pharmacopeial Convention, United States Pharmacopeia XIX (USP, Rockville, MD, 1975), xv–xvi.
5. Public Law 98–417 (1984).
6. G.L. Amidon et al., "A Theoretical Basis for a Biopharmaceutics Drug Classification: The Correlation of In Vitro Drug Product Dissolution and In Vivo Bioavailability," Pharm. Res. 12 (3), 413–420 (1995).
7. L. Bhattacharyya et al., "The Value of USP Public Standards for Therapeutic Products," Pharm. Res. 21 (10), 1725–1731.
8. L. Buhse, "Dissolution Measurement Systems: Current State and Opportunities for Improvement," presented at FDA Advisory Committee for Pharmaceutical Science meeting, Rockville, MD, 3–4 May 2005.
9. FDA, Guidance for Industry: Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System (2000) accessed at www.fda.gov/cder/guidance/3618fnl.pdf on Mar. 22, 2007.
10. WHO, Multisource (Generic) Pharmaceutical Products: Guidelines on Registration Requirements to Establish Interchangeability (2005) accessed at www.who.int/medicines/services/expertcommittees/pharmprep/QAS04_093Rev4_final.pdf on Mar. 22, 2007.
11. National Institute of Standards and Technology, "Guidance on Federal Conformity Assessment Activities," Fed. Regist. 65, 48894–48902 (2000).
12. FDA, Guidance for Industry: Text on Validation of Analytical Procedures (1995) accessed at www.fda.gov/cder/guidance/ichq2a.pdf on 26 March 2007.
13. J. Dressman and J. Kramer, Pharmaceutical Dissolution Testing (Boca Raton, FL, Taylor & Francis, 2005).
14. USP, USP 30–NF 25: Dissolution ‹711› (US Pharmacopeial Convention, Inc., Rockville, MD, 2007), 277–284.
15. ISO, Guide 5725: Accuracy (Trueness and Precision) of Measurement Methods and Results. Parts 1–6 (Geneva, Switzerland, ISO, 1994).
16. USP, "The USP Performance Test: Mechanical Calibration vs. a Periodic Performance Verification Test with Reference Standard Tablets (Calibrators)" [and links therein]. Web page, 2006, accessed at www.usp.org/USPNF/notices/calibratorsPublicStatement.html on Mar. 26 2007.
17. P. Nithyanandan et al., "Evaluation of the Sensitivity of USP Prednisone Tablets to Dissolved Gas in the Dissolution Medium Using USP Apparatus 2," Dissolution Technol. 13 (3), 15–18 (2006).
18. J. Eaton et al., "Perturbation Study of Dissolution Apparatus Variables—A Design of Experiment Approach," Dissolution Technol. 14 (1), 20–26 (2007).
19. M.R. Liddell et al., "Evaluation of Glass Dissolution Vessel Dimensions and Irregularities," Dissolution Technol. 14 (1) 28–33 (2007).
20. ISO, Guide 43: Proficiency Testing by Interlaboratory Comparisons. Parts 1–2. 2nd ed. (Geneva, Switzerland, ISO, 1997).
21. FDA, "Mechanical Qualification of Dissolution Apparatus 1 and 2" (2006) accessed at http://www.fda.gov/cder/Offices/OTR/dissolution.pdf on Mar. 27 2007.
22. ASTM Committee E55 on Pharmaceutical Application of Process Analytical Technology and Subcommittee E55.03 on General Pharmaceutical Standards, Standard Practice for Qualification of Basket and Paddle Dissolution Apparatus, (Work Item Number WK9936) (ASTM, West Conshohocken, PA, 2006).