Fixed-Oil Excipient Monographs: Development of USP Fixed-Oil Reference Standards - Pharmaceutical Technology

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Fixed-Oil Excipient Monographs: Development of USP Fixed-Oil Reference Standards
This article summarizes the development and modernization of the United States Pharmacopeia-National Formulary (USP-NF) fixed-oil excipient monographs. This article contains bonus online-exclusive material.


Pharmaceutical Technology
Volume 37, Issue 4, pp. 102-108


Table II: Specification for Almond Oil NF in USP 28−NF 23 (2005) (Ref. 3).
Status of fixed-oil monographs before modernization. The Preface of USP−NF indicates that a USP−NF monograph for an official substance or preparation includes the article’s definition; packaging, storage, and other requirements; and a specification (1). The specification consists of a series of universal tests (description, identity/identification, impurities, and assay) and specific tests, one or more analytical procedures for each test, and acceptance criteria. Following the format defined in the Preface (similar to the current USP−NF monograph redesigned format), the Almond Oil NF specification in USP 28−NF 23 (2005) is shown in Table II.

Specifications for fixed-oil monographs that were developed several decades ago and included in USP 28−NF 23 (2005) were substantially similar to those of Almond Oil NF. Table III presents the Olive Oil NF specification in USP 32−NF 27 (2009) (6) by following the format defined in the Preface. EM2 EC proposed a revision to Olive Oil NF in 2009. The modernized Olive Oil NF monograph became official in USP 33−NF 28 Reissue (2010) (7). Like almond oil, olive oil is one of the most frequently adulterated fixed oils.

Monograph test deficiencies before modernization. An evaluation of the fixed-oil monographs in 2005 indicated that previous USP−NF monograph content had been developed using characterization methods that were available at that time, before global supply chains became the norm, and in some instances, with incomplete understanding of the fixed oils. Substances derived from natural sources historically were characterized mostly from a safety perspective using generally applicable but nonspecific tests to detect elemental impurities, residual process impurities, and pesticides. Because of the deficiencies in these fixed-oil excipient monographs (Table I), users were unable to relate the material’s chemical composition to its physical and chemical properties or to anticipate any potential degradation or decomposition during storage. A majority of the oil monographs, including petrochemical oil and essential oil monographs in USP 28–NF 23 (2005) did not contain identification tests. As a result, the existing compendial specifications in USP 28−NF 23 would conform with difficulty to cGMPs for finished pharmaceuticals, specifically Subpart E—Testing and Approval or Rejection of Components and Drug Product Containers and Closures, 21 CFR 211.84(d)(1) and (2) (8).


Table III: Specification for Olive Oil NF in USP 32−NF 27 (2009) (Ref. 6).
Table II and Table III provide examples of the types of test procedures from NF 23 and NF 27, respectively, used to detect heavy metals and several fixed-oil substitutes (either contaminants or adulterants) in the Impurities sections of the monographs for Almond and Olive Oils. As shown in Tables II and III, no test procedure existed for the Identification and Assay. For Almond Oil shown in Table II, in the Specific Tests section, a few of the tests such as Specific gravity, Solidification range of fatty acids, Free fatty acids, Iodine value, and Saponification value were used as a rough measure of purity and quality. In fixed-oil excipient monographs before modernization, most procedures for testing fixed oil substitutes were wet chemistry–based methods with undefined or poor sensitivity and specificity (e.g., color reactions caused by the presence of particular nonfat ingredients). However, because these specific nonfat ingredients could be removed from oils by refining, refined oils would not test positive (9). Therefore, it was desirable to replace these wet chemistry tests with tests that could detect specific adulterants or contaminants. Incorporating such tests in USP−NF fixed-oil monographs could help ensure the authenticity of the fixed oils. However, most importantly, monograph modernization should introduce tests to determine fixed oil chemical composition specifications.

EM2 EC evaluated the fixed-oil substances with regard to their basic chemical composition, structure and properties, and manufacturing processes and investigated potential applications of current scientific knowledge to modernize and improve the compendial specification. New advances in analytical methodology allow scientists to profile the entire chemical composition of a substance derived from natural sources. Based on this evaluation and improved understanding, USP reference standards then could be developed for these complex mixtures.

Monograph modernization—a key initiative for the 2010–2015 USP revision cycle. Excipient monograph modernization is one of the key initiatives for the current 2010–2015 USP revision cycle. USP staff and the EXC EC collaborate with stakeholders in the USP public standards-setting processes (10). Unlike drug substances, so-called inactive ingredients (excipients) are sourced from several different industries, their production processes are different from pharmaceutical drug manufacturing, and usually they are less costly than drug substances. In general, sophisticated or technically advanced and costly analytical methods are reserved for research and development laboratories and are not routinely employed in quality control laboratories for excipient testing and release. EXC EC values input from stakeholders, especially from excipient producers, and recognizes the importance of advanced, highly reproducible, specific, and cost-effective analytical methods for characterizing excipients.


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