5. MONOGRAPH COMPONENTS
5.10. Molecular Formula
The use of the molecular formula for the active ingredient(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 percent) purity.
5.20. Added Substances, Excipients, and Ingredients
Substances are regarded as unsuitable for inclusion in an official article and therefore prohibited unless: (1) they do not exceed the minimum quantity required for providing their intended effect; (2) their presence does not impair the bioavailability, therapeutic efficacy, or safety of the official article; and (3) they do not interfere with the assays and tests prescribed for determining compliance with the compendial standards.
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, Excipients, and Ingredients in Official Substances
Official substances may contain only the specific added substances that are permitted by the individual monograph. 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 U.S. Food and Drug Administration (FDA), provided such added substances or excipients are otherwise appropriate in all respects. (See also Added Substances under Injections 1.)
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 active ingredients are not varied and provided that the bioavailability, therapeutic efficacy, and safety of the preparation are not impaired.
126.96.36.199. 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.
188.8.131.52. 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.
5.30. Description and Solubility
Only where a quantitative solubility test is given in a monograph and is designated as such is it a test for purity.
A monograph may include information regarding the 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:
5.40. Identification Test
The compendial test titled Identification is provided as an aid in verifying the identity of articles as they are purported to be, e.g., those taken from labeled containers. Tests presented in the Identification section shall be used to assist in establishing the identity of the substance but are not necessarily sufficient to establish proof of identity. Other tests and specifications in the monograph often are necessary to establish or confirm the identity of an article. Failure of an article to meet the requirements of a prescribed Identification test may indicate that the article is mislabeled.
Assay tests for compounded preparations are not intended for evaluating a compounded preparation before dispensing, but instead are intended to serve as the official test in the event of a question or dispute regarding the preparation's conformance to official standards.
5.50.10. Units of Potency (Biological)
For substances that cannot be completely characterized by chemical and physical means, it may be necessary to express quantities of activity in biological units of potency, each defined by an authoritative, designated reference standard.
Units of biological potency defined by the World Health Organization (WHO) for International Biological Standards and International Biological Reference Preparations are termed International Units (IU). Monographs refer to the units defined by USP Reference Standards as USP Units. For biological products, units of potency are defined by the corresponding U.S. Standard established by FDA, whether or not International Units or USP Units have been defined (see Biologics 1041).
5.60. Impurities and Foreign Substances
Tests for the presence of impurities and foreign substances are provided to limit such substances to amounts that are unobjectionable under conditions in which the article is customarily employed (see also Impurities in Official Articles 1086).
Nonmonograph tests and acceptance criteria suitable for detecting and controlling impurities that may result from a change in the processing methods or that may be introduced from external sources should be employed in addition to the tests provided in the individual monograph, where the presence of the impurity is inconsistent with applicable good manufacturing practices or good pharmaceutical practice.
5.60.10. Other Impurities in USP and NF Articles
If a USP or NF monograph includes an assay or organic impurity test based on chromatography, other than a test for residual solvents, and that monograph procedure does not detect an impurity present in the substance, the amount and identity of the impurity, where both are known, shall be stated in the labeling (certificate of analysis) of the official substance, under the heading Other Impurity(ies).
The presence of any unlabeled other impurity in an official substance is a variance from the standard if the content is 0.1% or greater. The sum of all Other Impurities combined with the monograph-detected impurities may not exceed 2.0% (see Ordinary Impurities 466), unless otherwise stated in the monograph.
The following categories of drug substances are excluded from Other Impurities requirements:
Any substance known to be toxic shall not be listed under Other Impurities.
5.60.20. Residual Solvents in USP and NF Articles
All USP and NF articles are subject to relevant control of residual solvents, even when no test is specified in the individual monograph. If solvents are used during production, they must be of suitable quality. In addition, the toxicity and residual level of each solvent shall be taken into consideration, and the solvents limited according to the principles defined and the requirements specified in Residual Solvents 467, using the general methods presented therein or other suitable methods.
5.70. Performance Tests
Where content uniformity determinations have been made using the same analytical methodology specified in the Assay, with appropriate allowances made for differences in sample preparation, the average of all of the individual content uniformity determinations may be used as the Assay value.
5.80. USP Reference Standards
USP Reference Standards are authentic specimens that have been approved by the USP Reference Standards Expert Committee as suitable for use as comparison standards in USP or NF tests and assays. (See USP Reference Standards 11.) Current official lots of USP Reference Standards are published in the USP Reference Standards Catalog. Where a procedure calls for the use of a compendial article rather than for a USP Reference Standard as a material standard of reference, a substance meeting all of the compendial monograph requirements for that article shall be used. No new USP or NF standard or procedure requiring the use of a new USP Reference Standard shall be official until the specified USP Reference Standard is available.
Unless a reference standard label bears a specific potency or content, assume the reference standard is 100.0% pure in the official application. Unless otherwise directed in the procedure in the individual monograph or in a general chapter, USP Reference Standards are to be used in accordance with the instructions on the label of the Reference Standard.