www.pharmtech.com90 Pharmaceutical Technology OCTOBER 2004

USP General Notices andGeneral Test ChaptersInterpretations and MisinterpretationsSusan J. Schniepp,* Rafik H. Bishara, and Martin G. VanTrieste

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he United States Pharmacopeial Convention, Inc. (USPC)is an independent organization that sets the standardsfor determining the quality of pharmaceutical productsmarketed in the United States of America. The USPC is

responsible for publishing the United States Pharmacopeia(USP), a legally recognized compendium used by the pharma-ceutical industry. Established in 1820 as a collection of recipesfor pharmacists, the USP has evolved into a collection of testmethodologies and associated specifications used primarily byproprietary and generic pharmaceutical manufacturers. Thesestandards govern the quality, strength, purity, and potency ofexcipients, active pharmaceutical ingredients (APIs), pharma-ceutical dosage forms, and many of the reagents, solutions, andindicators used to test these materials. Because of the exten-sive industry applicability of USP methods, any pharmaceuti-cal testing laboratory must be capable of using the technolo-gies and performing the procedures described in thisworld-recognized compendium.

The Federal Food, Drug, and Cosmetic Act (FD&C Act) andthe Code of Federal Regulations refer to the standards in the USPand mandate the recognition of those standards by the Foodand Drug Administration (1–4). FDA does not offer any guid-ance, however, on how to interpret the compendium. This ar-ticle clarifies some of the requirements contained in the “Gen-eral Notices and Requirements” section and offers possibleinterpretations of the information contained in general testchapters, where little interpretive guidance is offered. The au-thors dispel common misinterpretations made when review-ing the USP.

The USP consists of various sections. The bulk of the bookcomprises monographs for excipients, APIs, and final products.In addition to those monographs, the compendium includes a“Guide to General Chapters,” which contains information aboutbasic test procedures (“General Tests and Assays”), and broad-scope guidance advice (“General Information”). With few ex-ceptions, general test chapters define the criteria for frequentlyused methods such as loss on drying or pH, which are inde-pendent of the material being tested. General Information chap-ters, numbered 1000 and above, describe the USPC’s philoso-phies about broad-scope issues such as the recommendedrequirements for validating compendial methods.

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Susan J. Schniepp is a quality manager at Hospira,Inc., 13520 Evening Creek Dr., Suite 200, San Diego, CA92128, tel. 858.391.1118, fax 858.391.1186, schnisj@hospira.com. Rafik H. Bishara is the director ofquality knowledge management and technical support atEli Lilly and Company, Indianapolis, IN. Martin G.VanTrieste is the president of VanTrieste andAssociates, Grayslake, IL.

*To whom all correspondence should be addressed.

The authors dispel common misinterpretationsof the United States Pharmacopeia.

www.pharmtech.com92 Pharmaceutical Technology OCTOBER 2004

The “General Notices and Requirements” section at the be-ginning of the USP provides the overall guiding principles forusing the monographs and General Chapters. The first para-graph of this section states, “The General Notices and Require-ments … provide in summary form the basic guidelines for in-terpretation and application of the standards, tests, assays, andother specifications of the United States Pharmacopeia …” It isby referring to this section that common misinterpretations re-garding information contained in the USP can be clarified forthe reader. The following examples aim to clarify some of themost common misunderstandings attributed to the USP. Allpage numbers refer to USP 27–NF 22 (5).

Misinterpretation: The word “about” in the USP alwaysmeans 610%.Clarification. This statement is true when referring to weights,volumes, and apparatus dimensions but does not apply to tem-peratures, times, or product specifications. The relevant state-ment in the “General Notices” section reads, “In stating the ap-propriate quantities to be taken for assays and tests, the use ofthe word ‘about’ indicates a quantity within 10% of the speci-fied weight or volume. However, the weight or volume taken isaccurately determined and the calculated result is based on theexact amount taken. The same tolerance applies to specified di-mensions.” When a method specifies a time or temperature atwhich the analysis is to be performed, the tolerance range is

generally provided in the monograph or the applicable generaltest chapter. (See “General Notices and Requirements, Tests andAssays, Procedures,” p. 7.)

Misinterpretation: If no USP Reference Standard (RS) is available, then the product does not need to be tested according to the USP monograph requirements.Clarification.This statement only applies to new monograph tests(e.g., an impurities method) that require using the specific RS.Other monograph tests not requiring the use of the RS are stillapplicable to the product being examined. The actual sentencereads, “The requirements for any new USP or NF standards,tests, or assays for which a new USP Reference Standard is spec-ified are not in effect until the specified USP Reference Stan-dard is available.” Should the USP run out of established refer-ence standard material, companies should qualify an internalstandard until the USP standard becomes available. This infor-mation is not stated in the USP, but FDA provided guidance inits September 1996 “GMP Notes” in response to a similar ques-tion regarding the unavailability of the prednisone dissolutioncalibrator tablets. In addition, companies are encouraged tocontact the USPC regarding any concerns related to referencestandards. (See “General Notices and Requirements, USP Ref-erence Standards,” p. 5.)

Misinterpretation: I can use alterna-tive methods to USP methods.Clarification. This statement is true undercertain circumstances. Before you can usean alternative method to an official USPmethod you must validate the alternativemethod and prove it is equivalent to orbetter than the existing official method.In such cases, the company may need toupdate its regulatory filings to state the

test used. In the case of an inconsistencyor dispute, however, only results gener-ated using the official method are consid-ered conclusive. The section addressingthis issue reads, “Automated proceduresemploying the same basic chemistry asthose assay and test procedures given inthe monograph are recognized as beingequivalent in their suitability for deter-mining compliance. Conversely, where an

automated procedure is given in themonograph, manual procedures employ-ing the same basic chemistry are recog-nized as being equivalent in their suitabil-ity for determining compliance.” Thesection adds that “such alternative or au-tomated procedures or methods shall bevalidated.” This section of the USP goeson to state “where a difference appears orin the event of dispute, only the result ob-tained by the procedure given in this Phar-macopeia is conclusive.” (See “General No-tices and Requirements, Tests and Assays,Procedures,” p. 7.)

Misinterpretation: The USP test forcontent uniformity gives 10 results because it uses 10 units.Clarification. This statement is false. Theuser obtains only one result for the testeven though 10 individual units are tested.The clarifying sentence in USP states,“Tests and Assays in this Pharmacopeiaprescribe operation on a single specimen,that is, the singlet determination, whichis the minimum sample on which the at-tributes of a compendial article should bemeasured. Some tests, such as those fordissolution and uniformity of dosageunits, require multiple dosage units inconjunction with a decision scheme. Thesetests, albeit using a number of dosageunits, are in fact the singlet determina-tions of those particular attributes of thespecimen.” (See “General Notices and Re-quirements, Tests and Assays, Test Results,Statistics, and Standards,” p. 8.)

Misinterpretation: If a product is notlabeled “USP,” then USP monograph requirements are not applicable to theproduct.Clarification. This statement is false. Evenif a product is not labeled “USP,” if an of-ficial USP monograph exists for that prod-uct, then the product must meet the spe-cific monograph requirements. Theapplicable statements for this interpreta-tion are provided in section 501(b) of theFD&C Act as well as the USP (“GeneralNotices and Requirements,” p. 3). TheFD&C Act “deems an official drug (i.e., adrug purported to be or represented as adrug, the name of which is recognized inan official compendium) to be adulter-ated if it fails to conform to compendialstandards of quality, strength, or purity.

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Compendial tests or assay methods are used when determin-ing such conformance under 501(b). The standards are statedin individual monographs as well as in portions of the ‘GeneralNotices’ section of the USP–NF. Standards and test methodshave been established for such characteristics as potency, steril-ity, dissolution, weight variation, and content uniformity. If anofficial drug fails to conform to one or more compendial stan-dards of strength, quality, or purity, but the label plainly stateshow it differs from the standard, then the drug is not deemedto be adulterated under Section 501(b)” (1).

Similarly, the USP states that “The designation USP in con-junction with the official title or elsewhere on the label of anarticle means that the article purports to comply with USP stan-dards…” The USP also states that “standards apply equally toarticles bearing the official titles or names derived by transpo-sition of the definitive words of the official titles or transposi-tion in the order of the names of two or more active ingredi-ents in official titles, whether or not the added designation USPis used.” Occasionally an approved pharmaceutical product willhave requirements different from those contained in the mono-graph. The USP covers this scenario by declaring,“Where an ar-ticle differs from the standards of strength, quality, and purity,as determined by the application of the assays and tests set forthfor it in the Pharmacopeia, its difference shall be plainly statedon its label.” (See “General Notices and Requirements, ‘Official’and ‘Official Articles,’” p. 3.)

Challenging examplesIn some cases, the USP does not offer clear interpretations. Forthese situations, the user must review applicable informationto draw a conclusion that is based on the data presented in theUSP. The following two scenarios demonstrate how one mightundertake the responsibility of supporting such a position. Thereader should be warned that the following interpretations arenot viewed as official positions by any standard or regulatoryauthority and are merely the opinion of the authors.

Example 1: The USP specifies an incubation time of 48 hoursand the laboratory method specifies an incubation time of 2days. Is the laboratory method in compliance with USP?

Interpretation. The answer depends on how the laboratoryrecords incubation start and stop times. In general, the USPtypically indicates incubation times in terms of hours for testscompleted in 3 days and in terms of days for tests requiring 5days or more incubation time. Therefore, the authors concludethat 2 days is not necessarily compliant with a 48-hour incuba-tion time. We believe the USP requires 48 hours of incubationfrom the start of incubation time. However, recording 14 cal-endar days would be sufficient for a 14-day incubation periodfor a sterility test. This conclusion was determined by review-ing microbiological test incubation times in the USP. The in-formation was tabulated and evaluated before the aforemen-tioned general conclusion was made. Refer to the following USPGeneral Tests and Assays chapters:

,51. “Antimicrobial Effectiveness Testing”,55. “Biological Indicators–Resistance Performance Tests”,61. “Microbial Limits Tests”,71. “Sterility Tests.”

Example 2: The second Supplement to USP 24–NF 19 removedreference to using control standard endotoxins in the text ofGeneral Test Chapter ,85., “Bacterial Endotoxins Test” (BET).Does this mean only reference-standard endotoxins can be usedwhen performing BET testing?

Interpretation. Control standard endotoxins may be used whenperforming BET testing. The information needed to make thisdetermination incorporates information contained in the Phar-macopeial Forum (the USPC’s journal of standards develop-ment and compendium revision), in addition to official infor-mation contained in the USP. The Pharmacopeial Forum briefingsupporting this interpretation states,“The use of in-house stan-dards shown to be equivalent to USP Reference Standards ispermitted under the requirements for alternative methods inthe ‘General Notices.’ The control standard endotoxin (CSE)has thus been deleted because in-house standards have to beshown to be equivalent to the USP Endotoxin RS” (6). The state-ment in the “General Notices” to which the briefing refers iscontained in the same paragraph used in the third misinterpre-tation above: “Compliance may be determined also by use ofalternative methods chosen for advantages in accuracy, sensi-tivity, precision, selectivity, or adaptability to automation orcomputerized data reduction or in other special circumstances.Such alternative or automated procedures or methods shall bevalidated.” In this case, the authors are considering the use ofCSEs as a special case.

ConclusionMost misinterpretation of the USP can be clarified by readingthe “General Notices and Requirements” section in its entirety.Other appropriate information contained in the text of the USPshould be considered, if applicable. To determine a suitable in-terpretation when no clear statement is made, users should in-vestigate the issue by referring to appropriate PharmacopeialForum proposals and related USP chapters. In addition, one canalso contact USPC to ask questions (www.usp.org).

References1. Federal Food, Drug, and Cosmetic Act (1938), section 501(b).2. Code of Federal Regulations, Title 21, Food and Drugs (General Services

Administration, Washington, DC, 1 April 1973), Part 20205.50(c).3. Code of Federal Regulations, Title 21, Food and Drugs (General Services

Administration, Washington, DC, 1 April 1973), Part 299.4(c), (d),and (f).

4. Code of Federal Regulations, Title 21, Food and Drugs (General ServicesAdministration, Washington, DC, 1 April 1973), Part 11.194(a)(2).

5. United States Pharmacopeia 27–National Formulary 22 (United StatesPharmacopeial Convention, Rockville, MD, 2003).

6. Pharmacopeial Forum, 26 (1), 2000.PT

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