In his Feb. 2005 viewpoint article, "In Defense of Singlet Testing," Torbeck (1) draws an important philosophical distinction
between "standards" and "specifications." He argues that specifications are criteria selected by manufacturers for statistical
control of their products, whereas compendial standards are absolute requirements. This distinction is entirely compatible
with modern concepts of statistical process control. US Pharmacopeia (USP) standards provide solid benchmarks for industry
and assurance of quality product for patients. We agree that USP standards should (and in many cases do) encourage the design
of manufacturing and measuring systems so that the risk that any one lot will fail to meet the standard is acceptably small.
Torbeck also raises other interesting points which merit further discussion. We explain these points and propose an alternative
David LeBlond, Tim Schofield And Stan Altan
Philosophical position on singlet testing
Under the concept of singlet testing (1), every lot of a pharmaceutical product—with possibly millions of dosage units per lot—must be made by processes that
guarantee that every dosage unit tested by the filed analytical method at any time before expiry conforms with the stated
USP standard. To take the specific example quoted (1), the USP standard for aspirin tablets (2) of not less than 90% and not
more than 110% should apply to every USP-grade aspirin tablet.
It is necessary to point out that this view is contradictory to the USP "uniformity of dosage units" standard for aspirin,
which allows at least one tablet in a lot to be outside the 85–115% label claim. This contradiction in requirements questions
the viewpoint that every dosage unit must meet the 90–110% USP standard. We believe, instead, that this latter standard is
intended to apply to the result of the compendial aspirin tablet assay that takes, as a sample, a composite of at least 20
aspirin tablets. Although the USP wording may be open to debate, we agree with the British and European pharmacopeias, whose
description of the application of their standard to the result of the assay is quite clear (3, 4):
"Limits of content: Where limits of content are prescribed, they are those determined by the methods described under Assay.
Pharmacopoeia offers similar wording.
The result taken from a physically blended composite effectively averages out contributions from individual tablets. Thus,
we are led to the view that the result of the compendial aspirin tablet assay is meant to provide an estimate of the batch
mean and that the stated standard was intended to control the batch mean potency, not the content uniformity of individual
dosage units." (5)
We suggest that a "singlet testing" view, in which the stated compendial standard applies to every individual dosage unit,
is an unattainable requirement for a manufacturer and is a testing disincentive. It may discourage a full scientific understanding
of a manufacturing process and interfere with the objective of providing quality product to the patient. Recognizing the central
value estimate (e.g., a mean or median) from a representative sample as a statistic of interest encourages companies to make better decisions that
serve the interests of both the customer and the manufacturer.
Standards and specifications
The special concept of a "standard" is useful (1), but we are not sure that a broad dichotomy between standards and specifications
is justified. Although standards and specifications may differ in their immediate purpose (e.g., compliance versus process control) and in the rationale for setting the limit (e.g., therapeutic versus statistical), they do not differ in application. In both cases, one compares a statistic with a limit and makes a fixed decision
(e.g., lot release or internal action). In both cases, decision gray zones are handled by incorporating staged-testing into the
application process. Extending an artificial dichotomy into the area of application does not seem helpful and may inhibit
a clear understanding of the operational characteristics of standards.