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First Draft of Roadmap for Addressing Element-Specific Chapters and Tests in Excipient Monographs

Type of Posting: General Announcement
Posting Date: 05–Aug–2020
Expert Committees: Excipient Monographs 1 and Excipient Monographs 2 Expert Committees 


The Excipient Monographs 1 and Excipient Monographs 2 Expert Committees (Excipient ECs) are announcing the release of a draft Roadmap for addressing tests for elemental impurities (EIs) in USP–NF excipient monographs. The purposes of this announcement are: (1) to obtain feedback from excipient stakeholders on a proposed approach for addressing EIs in excipient monographs; (2) to encourage excipient stakeholders to assist USP with identifying excipients for which EI tests are necessary because of their impact on an excipient’s quality; and (3) to obtain scientific information on typical levels of EIs and methodologies used. The Excipient ECs will consider stakeholder feedback and scientific information/data when updating excipient monographs.


USP welcomes your feedback on the draft Roadmap and encourages you to submit your supporting data within 90 days from the post of this announcement through mail, email or an online response option described below.


For further information, please contact Galina Holloway Ph.D., USP, Science Division, Excipients, 12601 Twinbrook Parkway, Rockville, MD 20852–1790, USA; tel. +1-301-816-8133;


    The General Chapters-Chemical Analysis Expert Committee (GC-CA EC) has been evaluating the impact of removing references to element-specific chapters and standalone element-specific tests (tests for which procedures are described in a monograph) from USP–NF monographs, including excipient monographs, because of the implementation of USP General Chapters <232> Elemental Impurities—Limits and <233> Elemental Impurities—Procedures. Although, per <232>, “The limits presented [in <232>] do not apply to excipients and drug substances, except where specified in an individual monograph.”

    In the Stimuli article titled “Future of Element-Specific Chapters in the USP–NF,” published in Pharmacopeial Forum (PF) 42(4) [Jul–Aug 2016], the GC-CA EC stated that “Unless there is a known quality- or safety-related reason to maintain the specific elemental impurity limit(s) currently in place for selected components (drug substances or excipients), implementation of <232> renders the specific element chapters and limit tests in monographs as unnecessary.” However, GC-CA EC also advised that the “removal of element-specific chapters and any element-specific limit tests in monographs is a big step and requires thoughtful discussions.”

    In response to the GC-CA EC’s effort to determine the future of element-specific chapters in USP–NF, the Excipient ECs have developed a path forward (draft Roadmap) to address the use of procedures described in the element-specific chapters and standalone element-specific tests for EIs in excipient monographs. The Excipient ECs considered the European Pharmacopoeia (Ph. Eur.) Commission’s policy on EIs as a possible basis for developing the draft Roadmap. The Ph. Eur. Commission’s decisions and recommendations were published in a 2017 press release, which indicated that they would do the following:

    1. retain the published element-specific tests for monographs of substances of natural origin only;

    2. recommended retention of the element-specific tests for elements that do not have established limits for Permitted Daily Exposure in individual monographs (for USP–NF monographs, these tests are for aluminum, zinc and iron); and

    3. remove specific tests for EIs that originate from the production process from monographs of excipients of synthetic origin, unless otherwise justified.


    The Excipient ECs and USP staff used the following multistep approach to create a draft Roadmap that addresses element-specific tests in excipient monographs:

    1. Identify USP–NF excipient monographs that have tests for EIs

    2. Group these monographs based on the following criteria:
      1. Specific elements
      2. References to an element-specific chapter
      3. Techniques: instrumental or wet chemistry for standalone EI tests

    3. Prioritize monographs as:
      1. Immediate impact/immediate priority – monographs with references to the element-specific chapters
      2. High priority – monographs with standalone wet-chemistry tests that require modernization
      3. Low priority – monographs with instrumental standalone tests that may remain until a better test is provided

    4. Characterize monographs as follows:
      1. Monographs in which the Excipients ECs propose deleting the element-specific tests. These are typically monographs for excipients of synthetic origin that are not derived from starting materials sourced from plants, animals or inorganic minerals and excipients that are not products of fermentation.
      2. Monographs in which the Excipient ECs propose revising the element-specific tests to include updated limits and/or procedures. These are typically monographs for excipients of natural origin that are derived from starting materials sourced from plants, animals or minerals or excipients that are products of fermentation.

    1. USP identified about 133 monographs that contain about 193 tests for EIs. This list of monographs includes monographs that contain standalone tests and monographs that have references to element-specific general chapters. Some monographs have multiple tests, including the combination of a reference to an element-specific general chapter and a standalone EI test.

    2. In this draft Roadmap, the Excipient ECs will focus only on monographs that reference element-specific chapters and/or have corresponding standalone EI tests.

      There are 7 element-specific chapters in USP–NF:

      • <206> Aluminum (not part of <232>)
      • <211> Arsenic
      • <241> Iron (not part of <232>)
      • <251> Lead
      • <261> Mercury
      • <291> Selenium
      • <591> Zinc Determination (not part of <232>)

      The total number of tests—including references to element-specific chapters and standalone EI tests in a monograph—for the 7 elements is presented in Table 1 below.

      There are 110 monographs that contain 146 tests for the 7 elements. Out of these 110 monographs:

      • 74 monographs contain 90 references to at least one of the element-specific chapters. This group is considered immediate impact /immediate priority.
      • 44 monographs contain 56 standalone tests (including wet chemistry). From these,
        • 11 monographs contain 12 wet-chemistry tests. These are considered high priority – modernization.
        • 35 monographs contain 44 standalone instrumental tests (Atomic Absorption (AA), fluorescence, Induced Coupled Plasma (ICP) and Graphite Furnace (GF)). These are considered low priority – the EI tests may remain in the excipient monographs until a better test is provided.

    3. Characterization of monographs: Proposals to delete or revise EI tests in excipient monographs will be based on excipient origin and whether an EI test addresses a safety or quality concern. The list of excipient monographs with EI tests was shared with IPEC-Americas for confirmation of excipient origin and was subsequently reviewed by the Excipient ECs.

      Out of the 7 element-specific chapters, only 4 (<211> Arsenic, <251> Lead, <261> Mercury and <291> Selenium) describe analytical procedures for elements that have limits established in <232>. The remaining three elements—iron, aluminum and zinc—are not included in <232>. The ECs have established that control of these three elements is quality related, and per the ECs’ recommendation, these EI tests should remain in the excipient monographs.

      • A review of excipient monographs for references to <211> Arsenic, <251> Lead, <261> Mercury and <291> Selenium indicated there are 50 excipient monographs, of which:
        • 36 monographs reference <211> Arsenic; the test for arsenic is recommended for deletion in 4 monographs.
        • 26 monographs reference <251> Lead; the test for lead is recommended for deletion in 2 monographs.
        • No excipient monograph references <261> Mercury. No action is recommended for this chapter.
        • Monothioglycerol (synthetic origin) is the only monograph referencing <291> Selenium, and the test for selenium is recommended for deletion.
      • A review of excipient monographs for references to <206> Aluminum, <241> Iron and <591> Zinc Determination indicated the following:
        • No excipient monograph references <206> Aluminum and <591> Zinc Determination. No action is recommended for these chapters.
        • Twenty-seven excipient monographs contain a reference to <241> Iron (see section 3, A, iii below for recommended disposition).
      1. Review Summary for Immediate Impact and Immediate Priority Monographs:
        1. The following is a list of 7 excipient monographs for which deletion of the EI tests is proposed:
          • <211> Arsenic:
            • Colloidal Silicon Dioxide
            • Silicon Dioxide
            • Sulfuric Acid
            • Tribasic Sodium Phosphate
          • <251> Lead:
            • Povidone
            • Sodium Stearyl Fumarate
          • <291> Selenium:
            • Monothioglycerol

        2. Forty-three monographs for excipients of natural origin containing a total of 56 tests for <211> Arsenic and <251> Lead will be updated by the Excipient ECs on a case-by-case basis.

          The Excipient ECs may consider the Ph. Eur. approach for updating EI tests that reference <211> Arsenic and <251> Lead in monographs for excipients of natural origin. Using Carrageenan as an example:

          The Ph. Eur. Carrageenan monograph has the following EI tests and acceptance criteria:

          • Arsenic (2.4.27): maximum 3.0 ppm
          • Cadmium (2.4.27): maximum 2.0 ppm
          • Lead (2.4.27): maximum 5.0 ppm
          • Mercury (2.4.27): maximum 1.0 ppm

          The Ph. Eur. chapter 2.4.27. “Heavy Metals in Herbal Drugs and Herbal Drug Preparations” is not a performance-based chapter as it provides detailed sample preparation information and suggests using AA, ICP-AES and ICP-MS techniques. Providing a similar USP chapter for excipients of natural origin could be beneficial for stakeholders. The Lhasa database1 may be used for making recommendations for setting new acceptance criteria due to implementation of advanced technology. In contrast, the Carrageenan NF monograph has the following EI tests and acceptance criteria:

          • Arsenic <211>: NMT 3.0 ppm
          • Lead <251>: NMT 10 ppm

          We welcome stakeholder feedback on a possible harmonization of the Carrageenan NF monograph with the corresponding Ph. Eur. monograph.

        3. The Excipient ECs propose keeping specifications for iron in the excipient monographs until <241> Iron is revised to address excipients specifically.

      2. Review Summary for High Priority – Modernization Monographs:
        1. Out of 11 monographs containing 12 standalone wet-chemistry tests, only one monograph, Polyisobutylene, was identified for deletion of a test for lead.
        2. Ten monographs for excipients containing a total of 11 standalone wet-chemistry tests will be updated by the Excipient ECs on a case-by-case basis.

      3. Review Summary for Low Priority Monographs:
        1. Out of 35 monographs containing 44 standalone instrumental tests, 5 monographs were identified for deletion of the following EI tests:
          • Calcium Propionate: Lead
          • Calcium Silicate: Lead
          • Ferrosoferric Oxide: Arsenic, lead, mercury
          • Inositol: Lead
          • Neotame: Lead

        2. Thirty-seven standalone EI instrumental tests is 30 monographs for excipients of natural origin may remain until a better test is provided.


    The following decision tree represents the draft Roadmap described above.


    Excipient origin is an important criterion in developing the draft Roadmap. However, for some excipients, this information is still missing. The default approach for developing the draft Roadmap was to consider these excipients of natural origin. Upon receiving confirmation of an excipient origin from stakeholders, the draft Roadmap will be updated and the number of monographs in which the EI tests are proposed for deletion or revision will be corrected.

    A list of excipient monographs containing EI tests is available in the hyperlinked Excel table. While the draft Roadmap only covers 7 elements, the Excel table lists all of the excipient monographs that have EI tests. The table contains the following columns:

    • Monograph title
    • Proposed excipient origin
    • Element
    • Element-specific chapter or test
    • Prioritization
    • Proposed path forward

    Additionally, there are two columns for stakeholder feedback: updated excipient origin (column C) and stakeholder comments (column H). The prioritization levels listed in column F are based on whether a monograph contains a reference to an element-specific chapter (immediate priority) or has a standalone wet-chemistry test (high priority) or standalone instrumental test (low priority). Some EI tests have no prioritization level identified because they are scheduled for future consideration. Those tests are for elements outside the scope of the draft Roadmap. In summary, the proposed path forward was derived from 1) the origin of the excipient, 2) the specific element and 3) whether the monograph references an element-specific chapter or includes a standalone EI test.

    The Excipient ECs kindly ask USP stakeholders to answer the following questions and provide the requested information:

    1. Is the draft Roadmap approach for addressing the EI tests in excipients appropriate? If not, please provide recommendations for changes.
    2. Verify the source, natural or synthetic, of the excipient. Please see the definitions of natural and synthetic excipients in subsection 4 of the Proposed Approach for a Path Forward.
    3. If an excipient is identified as synthetic but you recommend keeping the EI test in the monograph because the presence of this EI impacts the quality of the excipient, please indicate this and provide your justification.
    4. Are there any excipient monographs that do not have tests for EIs but would benefit from adding an EI test? Please identify those excipient monographs and EIs.
    5. Please indicate if you are willing to sponsor a revision to update an EI test in any of the excipient monographs and provide your contact information.


    On the basis of the recommendations from the Elemental Impurities Joint Subcommittee, the Excipient Monographs 1 EC revised a Limit of Nickel test in the following monographs:

    • Sorbitol
    • Sorbitol Solution
    • Noncrystallizing Sorbitol Solution
    • Maltitol
    • Maltitol Solution
    • Sorbitol Sorbitan Solution

    These revisions were published in PF 45(6) [Nov–Dec 2019].

    The GC-CA EC is working on the revisions to the element-specific chapters listed in section 2 of the Draft Roadmap with exception of <591> Zinc Determination. These revisions are planned to appear in PF 46(6) [Nov.–Dec. 2020].

    Please choose one of the submission options below.

    Hardcopy Submissions

    Please click here to open the Excel table. Follow the directions at the top of the table for answering questions and providing your input. Print the updated copy of the Excel table and mail to 12601 Twinbrook Parkway, Rockville, MD 20852–1790, USA, Attention to Galina Holloway.

    Email Submissions

    Please click here to open the Excel table. Follow the directions at the top of the table for answering questions and providing your input. Email the updated copy of the Excel table to Galina Holloway at

    Online Submissions

    Please submit comments online at, or scan this code using your mobile device to go directly to the online submission.