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Christopher Burgess is with Burgess Consultancy, "Rose Rae," The Lendings, Starforth Barnard Castle, Co. Durham, DL12 9AB UK.
Is there a difference between a specification and a standard?
In February 2005, Lynn Torbeck wrote “In Defence of USP Singlet Testing,” in which he discussed the US Pharmacopeial Convention’s (USP) philosophy of singlet testing and the clear differentiation between standards and specifications (1). Later that year, Tim Schofield, David Leblond, and Stan Altan offered comments and an alternative viewpoint (2). Much has changed over the past 12 years, although many people in industry still regard the USP standard as a specification for the release of product to the market. This article reviews these changes based on the latest USP General Notices (3) and provides a view on the meaning of ‘singlet testing’.
Torbeck emphasized the important philosophical difference between a standard and a specification, and he quoted from the United States Pharmacopeia (USP) 28 (2005) General Notices (1), “Compendial standards define what is an acceptable article and give test procedures that demonstrates that the article is in compliance. These standards apply at any time in the life of the article from production to consumption.”
Furthermore, these General Notices defined the testing, which constitutes a singlet determination.
“Thus, when tested from the viewpoint of commercial or regulatory compliance, any specimen tested directed in the monograph for that article shall comply…,” and “Tests and assays in this Pharmacopeia prescribe operations on a single specimen, that is, the singlet determination which is the minimum sample on which the attributes of a compendial article should be measured.”
It is this last sentence that has given rise to much debate and dissention. Schofield et al. took this to mean that “Every lot of a pharmaceutical products with possibly millions of dosage units per lot must be made by processes that guaranteed that every dosage unit tested by the filed analytical method at any time before expiry conforms with the stated USP standard” (2).
Clearly, this guarantee is unattainable from both a statistical and practical viewpoint and appears to contradict the uniformity of dosage requirements, which they point out. However, what is clear is that USP monographs are standards and not specifications. The current version of the USP General Notices and Requirements doesn’t mention the singlet determination and clearly states in 3.10 Applicability of Standards (3): “Standards for an article recognized in the compendia (USP–NF) are expressed in the article’s monograph, applicable general chapters and General Notices.” Hence, there is a strict hierarchy for compliance in the order; monograph, General Chapters and General Notices: “The standards in the relevant monograph, General Chapters and General Notices’ apply at all times in the life of the article from production to expiration” (3). This has not changed from 2005.
“It is also noted that the manufacturer’s specifications and manufacturing practices (e.g., quality by design, process analytical technology, and real-time release testing initiatives), generally are followed to ensure that the article will comply with compendial standards until its expiration date, when stored as directed” (3). This is a significant change from 2005. This quotation addresses the valid concern of Scofield et al. in 2005 that a singlet determination may discourage a full scientific understanding of a manufacturing process and interfere with the objective of providing quality product to patient.
USP standards are legal benchmarks of acceptable quality or performance and must be met with some acceptable degree of confidence (probability). In testing of a sample, there is no such thing as an exact value. There is only an estimate of the true value with an associated confidence or tolerance interval.
Specifications, on the other hand, apply to reportable results and are decision limits. They must be met or failure occurs. There is no probability level associated with specifications.
What is not disputed is that all acceptance criteria in any monograph must be met to achieve compliance (3). However, the basis for the acceptance criteria often is disputed. USP 4.10.20 in the General Notices says, “The acceptance criteria allow for analytical error, for unavoidable variations in manufacturing and compounding, and for deterioration to an extent considered acceptable under practical conditions …” and requires in addition that, “An official product shall be formulated with the intent to provide 100% of the quantity of each ingredient declared on the label” (3).
The purpose of compliance testing is to demonstrate that the sample taken from the lot meets the acceptance criteria for the specific monograph. General Notices 3.10 states, “… in all cases, statements about whether the compendial standard is met apply only to the units tested” (3).
This statement leaves no doubt that compliance with the monograph relates only to the sample tested and not to the batch or lot. Therefore, it is scientifically unsound to use the acceptance criteria of the standard as the release specification for a lot. The General Notices go on to state, “Repeats, replicates, statistical rejection of outliers, or extrapolations of results to larger populations, as well as the necessity and appropriate frequency of batch testing, are neither specified nor prescribed by the compendia; such decisions are based on the objectives of the testing. Frequency of testing and sampling are left to the preferences or direction of those performing the compliance testing …” (3).
In 7.10, Interpretation of Requirements, the reportable value is defined as: “The reportable value, which often is a summary value for several individual determinations, is compared with the acceptance criteria. The reportable value is the end result of a completed measurement procedure, as documented” (3).
In addition, regarding multiple dosage unit testing, USP states, “Some tests, such as those for Dissolution and Uniformity of Dosage units, require multiple dosage units in conjunction with a decision scheme. These tests, albeit using a number of dosage units, are in fact one determination” (3).
The statement regarding the singlet determination was removed from the General Notices in Pharmacopeia 32 in 2011.
The USP requirements for sampling remains very weak. The only mention is in 6.60 Units necessary to complete a test, “Unless otherwise specified, a sufficient number of units to ensure a suitable analytical result shall be taken” (3).
This review of changes to the meaning of singlet testing raises the following points:
1. L.D. Torbeck, Pharm. Tech. 28 (2) 105-106 (2005).
2. T. Schofield, D. Leblond, and S. Altan, Pharm. Tech., 29 (6) (2005).
3. USP, USP 40-NF 35, First Supplement, General Notices (USP, 2017) (valid from Aug. 1, 2017).
4. USP, USP 40-NF 35, First Supplement, General Chapter <1010>, Analytical Data--Interpretation And Treatment, (USP, 2017) (valid from Aug. 1, 2017).
5. C. Burgess, Pharm. Tech. 36 (7) 3 (2013).
6. C. Burgess, Pharm. Tech. 37 (10) 3 (2014).
Vol. 41, No. 10
Pages: 82–83, 92
When referring to this article, please cite it as C. Burgess, "Singlet Determination Revisited," Pharmaceutical Technology 41 (10) 2017.