Challenges and Opportunities in Developing Up-to-Date USP-NF Excipients

• United States Pharmacopeial Convention

Abstract

The United States Pharmacopeial Convention (U.S. Pharmacopeia or USP) is a global, scientific nonprofit organization that sets standards for the identity, strength, quality, and purity of medicines, food ingredients, and dietary supplements manufactured, distributed, and consumed worldwide. USP’s monographs for drugs, including their ingredients such as excipients, contain official methods and acceptance criteria that provide the Food and Drug Administration (FDA) with a set of standards that are enforceable in the United States. USP standards are also used in more than 140 countries. USP is committed to bringing its compendia, the United States Pharmacopeia–National Formulary (USP–NF), up to date. The objective of this initiative is to ensure that all monographs and general chapters in the USP–NF—including those for drug products, drug substances, excipients, biologics, and dietary supplements— are current, relevant, and suitable for their intended use.

Increasing concerns about the effect of globalization on the integrity and transparency of the excipient supply chain, and hence quality and safety, led FDA to form a Monograph Modernization Task Group (MMTG) to lend support to the USP initiative. The MMTG is comprised of members from the Center for Drug Evaluation and Research (CDER) and the Office of Regulatory Affairs (ORA). A list of 19 excipient monographs was subsequently identified as high priority for update in three letters from FDA to USP. The list included several very commonly used excipients. FDA pointed to the risk that adulteration might not be detectable without increased specificity and sensitivity of tests as an important reason for assigning priority. In response to FDA’s request, the USP Excipient Expert Committees are making significant efforts to establish up-to-date quality standards by adding or revising specific Identification, Assay, and Impurity tests for excipient monographs.

This article describes USP’s comprehensive approaches for updating several high-priority excipient monographs and discusses the challenges encountered and progress made by USP in implementing the initiative to develop up-to-date USP–NF excipient monographs.

Introduction

The objective of the USP initiative is to develop standards that reflect state-of-the-industry techniques for sufficiently monitoring drug quality, purity, and strength. USP has made steady progress in updating outdated methodologies in the USP–NF through collaborative efforts with FDA and its stakeholders. USP currently employs several approaches that include the traditional donor model (externally sourced from a sponsor), USP laboratories (internally sourced), USP Expert Panels to leverage industry expertise and gain early stakeholder input as well as harmonization initiatives through the Pharmacopeial Discussion Group (PDG) in partnership with the European Pharmacopoeia (EP) and Japanese Pharmacopeia (JP). In providing a list of excipients for modernization, FDA focused efforts on revising monographs with outdated and nonspecific identification and assay test methods that could render the excipient vulnerable to intentional adulteration. Under FDA’s regulations for CGMP [c.f.21 CFR § 211.84(d)(1) in Control of Components (Subpart E)], pharmaceutical drug manufacturers must perform at least one test to verify the identity of each component used in the manufacture of a drug product; specific identity tests, if they exist, are expected to be used¹. Excipients are often derived from plant or animal tissue and many are polymers. This gives rise to excipient compositions which can be quite complex and variable, making development of specific identification (ID) and assay tests with appropriate ranges for excipient composition quite challenging. As a result, qualification of excipients for pharmaceutical use is challenging for both the excipient manufacturer and the pharmaceutical user in terms of analytical testing necessary to determine whether the excipient is fit for its intended pharmaceutical use.

In this article, the first in a series of three articles, several highpriority excipient monographs–Guar Gum, Shellac, and Butylated Hydroxytoluene (BHT)–are discussed to highlight the challenges encountered and progress made by USP in implementing the excipient monograph modernization initiative. USP has made significant efforts to establish up-to-date excipient quality standards by adding or revising specific identification, assay, and/or related substances tests for excipients including those identified as high priority for modernization, listed in Table 1. This, combined with USP’s investment in extensive lab testing facilities for procedure development, has resulted in the revision of 62 excipient monograph identification tests, 30 assays, and 11 impurity tests, as well as development of the general chapters Good Distribution Practices for Bulk Pharmaceutical Excipients <1197>, Identification of Fixed Oils by Thin-Layer Chromatography <202>, and Ethylene Glycol, Diethylene Glycol, and Triethylene Glycol in Ethoxylated Substances <469>. These new and updated monograph quality specifications and general chapters help improve testing controls and provide tools to use in qualifying an excipient for its intended use.

Table 1. Excipient List of FDA Priority Monographs

Three expert panels were formed to address FDA’s request to modernize the excipient monographs for Glycerin, Talc, and the family of Povidones (Povidone, Crospovidone, and Copovidone). These monographs are part of the PDG² excipient work plan. Significant progress has been made through the efforts of these expert panels and will be discussed later in this series of articles.

Gum Monographs: Guar Gum

The Guar Gum monograph was identified by the FDA MMTG as having an elevated risk of adulteration due to lack of specificity in the identification test. FDA has emphasized that the compendial tests for identification must be specific and rigorous because under the cGMP regulations, manufacturers of finished pharmaceuticals must perform at least one test to verify the identity of all component ingredients, and, where available, the compendial identity test is often used. In USP 36–NF 31 (2013), the Guar Gum monograph had two identification tests, which partially characterized guar gum, but did not define the material effectively and did not provide adequate specificity.

Methods Investigated for Use as Suitable Identity Tests

USP’s laboratory performed microscopic tests according to the JECFA (Joint FAO/WHO Expert Committee on Food Additives) procedure³ on several gum products. The laboratory results demonstrated that Guar Gum showed differences from Locust Bean Gum and Tamarind Gum, however, Guar Gum showed similarity to Tara Gum. Thus, microscopic testing could not be incorporated as an identity test at this time. USP’s laboratory results indicated that incorporating infrared (IR) as an identification test for Guar Gum is quite challenging without the use of multivariate statistical analysis (chemometrics).

Figure 1. Chemical Structure of Guar Galactomannans

The 2010–2015 Excipient Expert Committee (EXC EC) found that one of the identification tests in the JECFA and EP Guar monographs^3,4 contained a chromatographic identity test for constituting monosaccharides by using thin-layer chromatography (TLC). The EXC EC also received a TLC procedure from a sponsor. The advantage of the sponsor’s TLC procedure is that it separates effectively and identifies galactose, mannose, glucose, and xylose in one TLC plate, however, the most important drawback is that the procedure runs too long–more than 9 hours. Based on discussions with the EP experts, the EXC EC proposed improvements to the current EP procedure. USP’s laboratory successfully verified the updated version of the TLC procedure. The monosaccharide constituent identity test profiles guar gum (Figure 1) from the perspective of its chemical composition, and therefore TLC can be introduced in the monograph as one of the identification tests.

Among the major changes to the official Guar Gum monograph are:

A. Chemical Structure Addition

B. Improved Identification Tests

1. Combine current identification tests A and B into a single test to be called “Indication for a Polymeric Compound and Distinction from Locust Bean Gum”
2. Add an additional identification test B that identifies mannose and galactose by hydrolyzing guar gum and running the hydrolysate on a TLC plate, and comparing with USP Mannose Reference Standard (RS) and USP Galactose RS. The monosaccharide profile will differentiate guar gum from any other gums such as xanthan gum, gellan gum, karaya gum, etc.

In summary, by following the modernization of fixed oil excipient monographs⁵, the EXC EC formulated a strategic analytical testing plan that balances modernization with ease of adoption, method specificity, and simplicity. Modernization introduces more specific chemical compositional methods that can identify and quantify the analyte(s) of interest. A combination of simple orthogonal methods introduced in the identification differentiates guar gum from other gum products and improves ease of adoption.

Assay

In the test for Content of Galactomannans of the Guar Gum monograph in USP 38–NF 33 (2015), the analysis is performed by subtracting from 100.0 the total percentages from the tests for Articles of Botanical Origin, Total Ash, Acid-Insoluble Matter, Protein, and Loss on Drying.

The EXC EC and stakeholders thought that the current test left too much uncertainty about the remaining excipient composition and requested updating the monograph to include a test for the analysis of galactomannans.

In Pharmacopeial Forum (PF) 41(2) [Mar–Apr 2015], it was proposed to replace the current test for Content of Galactomannans with a high-performance liquid chromatography (HPLC) method that was developed and validated by USP. The HPLC procedure not only determines the sum of the constituting mannose and galactose, but also provides the ratio of constituting mannose and galactose in galactomannans. Implementation of the HPLC procedure and addition of the specification for the Ratio of Constituting Mannose and Galactose greatly help to define the guar gum substance and to strengthen the quality of the Guar Gum monograph. Meanwhile, the potential contaminants glucose and xylose can be identified and quantified by using the proposed HPLC method, as the two glucose and xylose standards are included in the system suitability solution. The EXC EC further modernized the Guar Gum monograph by updating the monograph definition and expanding the test title from “Content of Galactomannans” to “Content of Galactomannans and Ratio of Constituting Mannose and Galactose”.

Shellac

The NF Shellac monograph lacks an up-to-date identification test. The complex chemical composition of shellac is not yet completely understood, which poses problems in updating the monograph. Shellac is obtained from an insect secretion after which it is suitably processed to enable it to be used in edible products. Exhibiting complex chemical composition even after purification, shellac is a polyester resin consisting of inter- and intra-esters of polyhydroxyl carboxylic acids formed from certain hydroxyl acids and sesquiterpenic acids. It also contains variable amounts of wax (Figure 2) which can be removed during processing or alternatively remains in the final product. It has a natural color and is often bleached or carbon treated to improve its appearance. Thus there are four types of shellac, which differ based on the nature of the treatment of the crude secretion (seedlac).

Figure 2. Chemical Structure of Shellac

As part of the revision to the shellac identification test, it was proposed in PF 40(4) [July–Aug 2014] to do the following: 1) add the chemical structure and the CAS number; 2) update the monograph definition section; and 3) introduce more specific tests to the identification by changing Identification test A based on a wet chemistry procedure to Infrared Absorption (IR) and introducing two new USP Shellac RS to support the IR procedure. The supporting USP lab study showed that the shellac refinement process impacts the IR spectrum results. The RS introduced will help users differentiate between the types of shellac on the market.

The revision also includes an Identification test B that detects aleuritic acid and shellolic acid (by hydrolyzing shellac, running the hydrolysate on a TLC plate, and comparing with USP Aleuritic Acid RS). In addition, it was proposed to add the tests for Limit of Chloride, Total Ash, and Ethanol-Insoluble Substances to limit process impurities. The test for Acid Value, the Packaging and Storage section, and the Labeling requirements were updated. The revised Shellac monograph will provide users with more specific and rigorous Identification tests that address FDA’s concerns.

The proposed changes to the Shellac monograph provide a good example of how monograph modernization not only introduces new identification tests that use a new technology and USP reference materials providing better specificity but also creates some challenges in setting appropriate requirements for Shellac composition. The EXC EC 2015–2020 will begin to address the challenges that relate to reaching a better understanding of the chemical composition of shellac.

Butylated Hydroxytoluene

The Butylated Hydroxytoluene (BHT) monograph that appeared in USP 38–NF 33 does not have an Assay test. The content of BHT is determined indirectly based on the results of the Congealing Temperature test. The monograph contains a TLC test for Organic Impurities, however there are no impurities listed and the acceptance criteria are defined as “Any spot from the Sample solution, apart from the principal spot, is not more intense than the spot from the Standard solution (NMT 0.5%)”. In addition, the BHT monograph was identified by the FDA MMTG to be at an elevated risk of adulteration because of a lack of specificity of the Identification test. In order to address all of these issues, a stability-indicating HPLC method separating 13 potential impurities was developed by USP. The new method is capable of detecting all the impurities down to a level of 0.02%. This allowed USP to set a new limit for any individual impurity not to exceed 0.1% to comply with section 5.60.10 of the General Notices and Requirements, Other Impurities in USP and NF Articles. Although it was not easy to develop such a specific and sensitive method, setting appropriate acceptance criteria for impurities and the Assay was even more challenging because:

1. Introduction of a new methodology reveals the presence of impurities that were not originally specified in a monograph, and there is no defined process for translating old, mostly general requirements to new, more specific ones.
2. Evaluation of a limited number of samples of an excipient that is sold on the U.S. market may not provide sufficient justification for keeping old acceptance criteria or establishing new ones. Input from manufacturers on the levels of impurities typically present in their material is critical for setting reasonable standards.

The Butylated Hydroxytoluene monograph is a good example of how monograph modernization not only introduces a new technology with better specificity and sensitivity but also creates some challenges in setting appropriate requirements for impurities and Assay values, particularly when the impurities have never been specified and the content of BHT has been determined indirectly.

Conclusion

USP continues to work with FDA and other stakeholders to update USP− NF standards for excipients focusing mainly on improving specificity of Identification tests and assays, and to some extent on impurities. USP Expert Committees also rely on stakeholders’ and sponsors’ comments to keep monographs current. The expansion of USP’s laboratories has facilitated USP’s modernization efforts in situations where it becomes difficult to obtain stakeholders’ input. Updated monograph quality specifications help improve testing controls and provide tools to use in qualifying an excipient for its intended use. In combination with other suitable controls on excipient quality, compendial testing plays a very important role in assuring the quality of pharmaceutical products.

USP is holding its 2nd Excipient Workshop: Focus on Excipient Quality, Compendial Testing, and Regulatory Impact, November 17–18, 2015, at USP Headquarters, Rockville, Maryland. This workshop will offer participants an opportunity to discuss and collaborate on excipient monograph modernization and harmonization initiatives as well as identify the challenges faced in developing updated monographs that are fit for their intended pharmaceutical and biopharmaceutical purposes. For registration, workshop objectives, and exhibitor opportunities, please visit the USP website at http://www.usp.org/meetings-courses/workshops/2nd-excipient-workshop-focusexcipient-quality-compendial-testing-and-regulatory-impact

References

1. FDA 21CFR211.84 http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=211.84 Accessed August 8, 2015
2. Pharmacopeial Discussion Group http://www.usp.org/usp-nf/harmonization Accessed August 8, 2015
3. JECFA Guar Gum monograph, http://www.fao.org/ag/agn/jecfa-additives/specs/monograph5/additive-218-m5.pdf Accessed August 8, 2015
4. EP, Ph Eur. 8th ed. Strasbourg, France: European Directorate for the Quality of Medicines and Health Care (2013).
5. H. Wang, C. Sheehan, L. H. Block, R. C. Moreton, R. H. Wendt, S. P. Apte, E. J. Munson, Fixed Oil Excipient Monographs—Development of USP Fixed Oil Reference Standards, Pharmaceutical Technology April 2013 page 102 (online version: http://www.pharmtech.com/USPfixedoil)
6. USP Key Issues: Monograph Modernization: Talc/Povidones: http://www.usp.org/sites/default/files/usp_pdf/EN/USPNF/key-issues/modernizationlistouderkirkseo.pdf
7. FDA High Priority excipient list List of 13: http://www.usp.org/sites/default/files/usp_pdf/EN/USPNF/key-issues/2012-07-02_fda_letter-monograph_modernization_listexcipients.pdf
8. Gelatin: http://www.usp.org/sites/default/files/usp_pdf/EN/USPNF/key-issues/2013-12-02_fda_mmtg_letter.pdf