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.