Composition of the USP Pharmacists Pharmacopeia (Cont'd)

We will look in detail at selected portions of the Introductory Material, as follows.

INTRODUCTORY MATERIAL

Article's description.

Information about an article's "description and solubility" also is provided in the reference table Description and Relative Solubility of USP and NF Articles. The reference table merely denotes the properties of articles that comply with monograph standards. The reference table is intended primarily for those who use, prepare, and dispense drugs and/or related articles. Although the information provided in monographs and the information in the reference table may indirectly assist in the preliminary evaluation of an article, it is not intended to serve as a standard or test for purity. The approximate solubility of a compendial substance is indicated by one of the following descriptive terms:

Requirements stated in these General Notices apply to all articles recognized in the USP and NF (the "compendia") and to all general chapters, unless specifically stated otherwise.

2.20. Official Articles

An official article is an article that is recognized in USP or NF. An article is deemed to be recognized and included in a compendium when a monograph for the article is published in the compendium and an official date is generally or specifically assigned to the monograph.

The title specified in a monograph is the official title for such article. Other names considered to be synonyms of the official titles may not be used as substitutes for official titles. For a biologic product licensed under the Public Health Service Act, the official title shall be the title specified in the relevant monograph plus any prefix and/or suffix designated by the FDA unless otherwise specified in the applicable monograph (USP 1-Dec-2022). For drug products that incorporate a sensor to detect that the product has been administered, the official title shall be the title specified in the relevant drug product monograph plus the words "with sensor".

Official articles include both official substances and official products. An official substance is a drug substance, excipient, dietary ingredient, other ingredient, or component of a finished device for which the monograph title includes no indication of the nature of the finished form.

An official product is a drug product, dietary supplement, compounded preparation, or finished device for which a monograph is provided.

2.30. Legal Recognition

The USP and NF are recognized in the laws and regulations of many countries throughout the world. Regulatory authorities may enforce the standards presented in the USP and NF, but because recognition of the USP and NF may vary by country, users should understand applicable laws and regulations. In the United States under the Federal Food, Drug, and Cosmetic Act (FDCA), both USP and NF are recognized as official compendia. A drug with a name recognized in USP-NF must comply with compendial identity standards or be deemed adulterated, misbranded, or both. See, for example, FDCA § 501(b) and 502(e)(3)(b); also U.S. Food and Drug Administration (FDA) regulations, 21 CFR § 299.5(a&b). To avoid being deemed adulterated, such drugs must also comply with compendial standards for strength, quality, and purity, unless labeled to show all respects in which the drug differs. See for example, FDCA § 501(b) and 21 CFR § 299.5(c). In addition, to avoid being deemed misbranded, drugs recognized in USP-NF must also be packaged and labeled in compliance with compendial standards. See FDCA § 502(g). Enforcement of USP standards is the responsibility of FDA and other government authorities in the U.S. and elsewhere. USP has no role in enforcement.

3. CONFORMANCE TO STANDARDS

3.10. Applicability of Standards

Where conformance to any specifications represented by Chemical information is critical to establishing identity, purity, potency, or another quality attribute of an official article, the monograph will include such specifications in the text that states requirements.

"Applicable general chapters" means general chapters numbered below 1000 or above 2000 that are made applicable to an article through reference in General Notices, a monograph, or another applicable general chapter numbered below 1000. Where the requirements of a monograph differ from the requirements specified in these General Notices or an applicable general chapter, the monograph requirements apply and supersede the requirements of the General Notices or applicable general chapters, whether or not the monograph explicitly states the difference.

General chapters numbered 1000 to 1999 are for informational purposes only. They contain no mandatory tests, assays, or other requirements applicable to any official article, regardless of citation in a general chapter numbered below 1000, a monograph, or these General Notices. General chapters numbered above 2000 apply only to articles that are intended for use as dietary ingredients and dietary supplements. General chapter citations in NF monographs refer to USP general chapters.

Early adoption of revised standards in advance of the official date is allowed by USP unless specified otherwise at the time of publication. Where revised standards for an existing article have been published as final approved "official text" (as approved in section 2.10 Official Text) but have not yet reached the official date (6 months after publication, unless otherwise specified; see "official date", section 2.20 Official Articles), compliance with the revised standard shall not preclude a finding or indication of conformance with compendial standards, unless USP specifies otherwise by prohibiting early adoption in a particular standard.

The standards in the relevant monograph, general chapter(s), and General Notices apply at all times in the life of the article from production to expiration. 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. Every compendial article in commerce shall be so constituted that when examined in accordance with these assays and test procedures, it meets all applicable pharmacopeial requirements (General Notices, monographs, and general chapters). Thus, any official article is expected to meet the compendial standards if tested, and any official article actually tested as directed in the relevant monograph must meet such standards to demonstrate compliance.

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. These procedures should not be confused with statistical sampling plans. The similarity to statistical procedures may seem to suggest an intent to make inference to some larger group of units, but in all cases, statements about whether the compendial standard is met apply only to the units tested. 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 proscribed 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 compliance testing, and other users of USP-NF, including manufacturers, buyers, or regulatory authorities.

Official products are prepared according to recognized principles of good manufacturing practice and from ingredients that meet USP or NF standards, where standards for such ingredients exist (for dietary supplements, see section 3.10.20 Applicability of Standards to Medical Devices, Dietary Supplements, and Their Components and Ingredients).

Official substances are prepared according to recognized principles of good manufacturing practice and from ingredients complying with specifications designed to ensure that the resultant substances meet the requirements of the compendial monographs.

3.10.10. Applicability of Standards to Drug Products, Drug Substances, and Excipients

The applicable USP or NF standard applies to any article marketed in the United States that (1) is recognized in the compendium and (2) is intended or labeled for use as a drug or as an ingredient in a drug. Such articles (drug products, drug substances, and excipients) include both human drugs (whether dispensed by prescription, "over the counter", or otherwise), as well as animal drugs. The applicable standard applies to such articles whether or not the added designation "USP" or "NF" is used. The standards apply equally to articles bearing the official titles or names derived by transposition of the definitive words of official titles or transposition in the order of the names of two or more drug substances in official titles, or where there is use of synonyms with the intent or effect of suggesting a significant degree of identity with the official title or name.

3.10.20. Applicability of Standards to Medical Devices, Dietary Supplements, and Their Components and Ingredients

An article recognized in USP or NF shall comply with the compendial standards if the article is a medical device, component intended for a medical device, dietary supplement, dietary ingredient, or other ingredient that is intended for incorporation into a dietary supplement, and is labeled as conforming to the USP or NF.

Generally, dietary supplements are prepared from ingredients that meet USP, NF, or Food Chemicals Codex standards. Where such standards do not exist, substances may be used in dietary supplements if they have been shown to be of acceptable food grade quality using other suitable procedures.

3.10.30. Applicability of Standards to the Practice of Compounding

USP compounding practice standards, Pharmaceutical Compounding-Nonsterile Preparations 〈795〉 and Pharmaceutical Compounding-Sterile Preparations 〈797〉, as appropriate, apply to compounding practice or activity regardless of whether a monograph exists for the compounded preparation or these chapters are referenced in such a monograph. In the United States, 〈795〉 and 〈797〉 are not applicable to drugs compounded by entities registered with FDA as outsourcing facilities as defined by FDCA § 503B, because such facilities are required to comply with FDA's current good manufacturing practice requirements. Compounded preparations, including drug products compounded by outsourcing facilities, may also be subject to applicable monographs; see section 2.20 Official Articles and section 4.10 Monographs.

3.20. Indicating Conformance

A drug product, drug substance, or excipient may use the designation "USP" or "NF" in conjunction with its official title or elsewhere on the label only when (1) a monograph is provided in the specified compendium and (2) the article complies with the identity prescribed in the specified compendium.

When a drug product, drug substance, compounded preparation, or excipient differs from the relevant USP or NF standard of strength, quality, or purity, as determined by the application of the tests, procedures, and acceptance criteria set forth in the relevant compendium, its difference shall be plainly stated on its label.

When a drug product, drug substance, compounded preparation, or excipient fails to comply with the identity prescribed in USP or NF or contains an added substance that interferes with the prescribed tests and procedures, the article shall be designated by a name that is clearly distinguishing and differentiating from any name recognized in USP or NF.

A medical device, dietary supplement, or ingredient or component of a medical device or dietary supplement may use the designation "USP" or "NF" in conjunction with its official title or elsewhere on the label only when (1) a monograph is provided in the specified compendium and (2) the article complies with the monograph standards and other applicable standards in that compendium.

The designation "USP" or "NF" on the label may not and does not constitute an endorsement by USP and does not represent assurance by USP that the article is known to comply with the relevant standards. USP may seek legal redress if an article purports to be or is represented as an official article in one of USP's compendia and such claim is determined by USP not to be made in good faith.

The designation "USP-NF" may be used on the label of an article provided that the label also bears a statement such as "Meets NF standards as published by USP", indicating the particular compendium to which the article purports to apply.

When the letters "USP", "NF", or "USP-NF" are used on the label of an article to indicate compliance with compendial standards, the letters shall appear in conjunction with the official title of the article. The letters are not to be enclosed in any symbol such as a circle, square, etc., and shall appear in capital letters.

If a dietary supplement does not comply with all applicable compendial requirements but contains one or more dietary ingredients or other ingredients that are recognized in USP or NF, the individual ingredient(s) may be designated as complying with USP or NF standards or being of USP or NF quality provided that the designation is limited to the individual ingredient(s) and does not suggest that the dietary supplement complies with USP standards.

4. MONOGRAPHS AND GENERAL CHAPTERS

4.10. Monographs

Monographs set forth the article's name, definition, specification, and other requirements related to packaging, storage, and labeling. The specification consists of tests, procedures, and acceptance criteria that help ensure the identity, strength, quality, and purity of the article. For general requirements relating to specific monograph sections, see section 5. Monograph Components.

Because monographs may not provide standards for all relevant characteristics, some official substances may conform to the USP or NF standard but differ with regard to nonstandardized properties that are relevant to their use in specific preparations. To assure substitutability in such instances, users may wish to ascertain functional equivalence or determine such characteristics before use.

4.10.10. Applicability of Test Procedures

A single monograph may include more than one test, procedure, and/or acceptance criterion for the same attribute. Unless otherwise specified in the monograph, all tests are requirements. In some cases, monograph instructions allow the selection of tests that reflect attributes of different manufacturers' articles, such as different polymorphic forms, impurities, hydrates, and dissolution. Monograph instructions indicate the tests, procedures, and/or acceptance criteria to be used and the required labeling.

The order in which the tests are listed in the monograph is based on the order in which they are approved by the relevant Expert Committee for inclusion in the monograph. Test 1 is not necessarily the test for the innovator or for the reference product. Depending on monograph instructions, a labeling statement is not typically required if Test 1 is used.

4.10.20. Acceptance Criteria

The existence of compendial acceptance criteria does not constitute a basis for a claim that an official substance that more nearly approaches 100% purity "exceeds" compendial quality. Similarly, the fact that an article has been prepared to tighter criteria than those specified in the monograph does not constitute a basis for a claim that the article "exceeds" the compendial requirements.

An official product shall be formulated with the intent to provide 100% of the quantity of each ingredient declared on the label. Where the minimum amount of a substance present in a dietary supplement is required by law to be higher than the lower acceptance criterion allowed for in the monograph, the upper acceptance criterion contained in the monograph may be increased by a corresponding amount.

The acceptance criteria specified in individual monographs and in the general chapters for compounded preparations are based on such attributes of quality as might be expected to characterize an article compounded from suitable bulk drug substances and ingredients, using the procedures provided or recognized principles of good compounding practice, as described in these compendia.

4.20. General Chapters

Each general chapter is assigned a number that appears in angle brackets adjacent to the chapter name (e.g., Chromatography 〈621〉). General chapters may contain the following:

• Descriptions of tests and procedures for application through individual monographs,
• Descriptions and specifications of conditions and practices for pharmaceutical compounding,
• General information for the interpretation of the compendial requirements,
• Descriptions of general pharmaceutical storage, dispensing, and packaging practices, or
• General guidance to manufacturers of official substances or official products.

When a general chapter is referenced in a monograph, acceptance criteria may be presented after a colon.

Some chapters may serve as introductory overviews of a test or of analytical techniques. They may reference other general chapters that contain techniques, details of the procedures, and, at times, acceptance criteria.

5. MONOGRAPH COMPONENTS

5.10. Molecular Formula

The use of the molecular formula for the official substance(s) named in defining the required strength of a compendial article is intended to designate the chemical entity or entities, as given in the complete chemical name of the article, having absolute (100%) purity.

5.20. Added Substances

Added substances are presumed to be unsuitable for inclusion in an official article and therefore prohibited, if their presence impairs the bioavailability, therapeutic efficacy, or safety of the official article; or they interfere with the assays and tests prescribed for determining compliance with the compendial standards (see section 3.20 Indicating Conformance).

The air in a container of an official article may, where appropriate, be evacuated or be replaced by carbon dioxide, helium, argon, or nitrogen, or by a mixture of these gases. The use of such gas need not be declared in the labeling.

5.20.10. Added Substances in Official Substances

Official substances may contain only the specific added substances that are permitted by the individual monograph. Such added substances shall not exceed the quantity required for providing their intended effect. Where such addition is permitted, the label shall indicate the name(s) and amount(s) of any added substance(s).

5.20.20. Added Substances (Excipients and Ingredients) in Official Products

Suitable substances and excipients such as antimicrobial agents, pharmaceutical bases, carriers, coatings, flavors, preservatives, stabilizers, and vehicles may be added to an official product to enhance its stability, usefulness, or elegance, or to facilitate its preparation, unless otherwise specified in the individual monograph.

Added substances and excipients employed solely to impart color may be incorporated into official products other than those intended for parenteral or ophthalmic use, in accordance with the regulations pertaining to the use of colors issued by the FDA, provided such added substances or excipients are otherwise appropriate in all respects. (See also Injections and Implanted Drugs Products 〈1〉, Product Quality Tests Common to Parenteral Dosage Forms, Specific Tests, Vehicles and added substances, Added substances.)

The proportions of the substances constituting the base in ointment and suppository products and preparations may be varied to maintain a suitable consistency under different climatic conditions, provided that the concentrations of drug substances are not varied and provided that the bioavailability, therapeutic efficacy, and safety of the preparation are not impaired.

5.20.20.1. In Compounded Preparations

Compounded preparations for which a complete composition is given shall contain only the ingredients named in the formulas unless specifically exempted herein or in the individual monograph. Deviation from the specified processes or methods of compounding, although not from the ingredients or proportions thereof, may occur provided that the finished preparation conforms to the relevant standards and to preparations produced by following the specified process.

Where a monograph for a compounded preparation calls for an ingredient in an amount expressed on the dried basis, the ingredient need not be dried before use if due allowance is made for the water or other volatile substances present in the quantity taken.

Specially denatured alcohol formulas are available for use in accordance with federal statutes and regulations of the Internal Revenue Service. A suitable formula of specially denatured alcohol may be substituted for Alcohol in the manufacture of official preparations intended for internal or topical use, provided that the denaturant is volatile and does not remain in the finished product. A preparation that is intended for topical application to the skin may contain specially denatured alcohol, provided that the denaturant is either a usual ingredient in the preparation or a permissible added substance; in either case the denaturant shall be identified on the label of the topical preparation. Where a process is given in the individual monograph, any preparation compounded using denatured alcohol shall be identical to that prepared by the monograph process.

5.20.20.2. In Dietary Supplements

Additional ingredients may be added to dietary supplement products provided that the additional ingredients (1) comply with applicable regulatory requirements, and (2) do not interfere with the assays and tests prescribed for determining compliance with compendial standards.

Loyd V. Allen, Jr., PhD, RPh
Editor-in-Chief
International Journal of Pharmaceutical Compounding
Remington: The Science and Practice of Pharmacy Twenty-second edition

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