Key Issue: Elemental Impurities
Original Posting: 20–Jul–2010; Last Update: 28–Jan–2013
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January 28, 2013: Revision Bulletin re-establishing the official dates for general chapters <232> and <233> to February 1, 2013, following adjudication by the Council of Experts Executive Committee of the combined appeals filed by three appellants.
It is important to note that although general chapters <232> and <233> will become official on February 1, 2013, there will be no requirement for an article covered by an applicable USP–NF monograph to comply with their provisions on this date. USP’s position is that until a general chapter is referenced in a monograph or in General Notices, it is not applicable to any article named in USP–NF. Typically, a standard becomes official six months after publication in a book or supplement, and implementation is required as of that official date. In this case, however, the official date is separate from the implementation date, as implementation cannot occur until the general chapters are referenced in a monograph or in General Notices.
November 15, 2012/Updated November 21, 2012: Notice of Postponement (Accelerated Revision History)
April 27, 2012/Revised November 21, 2012: The USP Expert Panel on Elemental Impurities has revised General Chapters <232> Elemental Impurities—Limits and <233> Elemental Impurities—Procedures to address the comments received, and has forwarded the revised General Chapters to the General Chapters—Chemical Analysis Expert Committee for approval. The Expert Committee approved these General Chapters for publication in Second Supplement to USP 35–NF 30 (official Dec 1, 2012). USP intends to implement these General Chapters through a proposed provision in the General Notices that would make the chapters applicable to all articles in the compendia, as was done with General Chapter <467> Residual Solvents in Section 5.60.20 of the General Notices. This provision will be proposed in PF 39(1) [Jan–Feb 2013] for public comment. If, after review of the comments received, the Council of Experts Executive Committee (which is responsible for the General Notices) approves this General Notices provision, it will be published in USP 37–NF 32 with an official date of May 1, 2014. If this occurs, conformance with these chapters will be required as of May 1, 2014, when the General Notices provision becomes official.
Further, the implementation approach for general chapters <232> and <233> will include removal of all references to USP General Chapter <231> Heavy Metals from monographs in the compendia. This also is being proposed in PF 39(1) for public comment, and if after review of the comments received, and the Executive Committee of the Council of Experts approves this revision, it will be published in USP 37–NF 32 with an official date of May 1, 2014, simultaneously with the proposed implementation of general chapters <232> and <233> through the new General Notices provision. Read More
USP indicated previously that it would be moving these general chapters forward to official status after the Expert Panel and Expert Committee considered the final set of public comments and after the ICH Q3D Expert Working Group developed an initial set of elements and limits for consideration. With the exception of mercury, the limits in the revised General Chapter <232> are consistent with those in the ICH-Q3D, pre-stage 2 draft. At a future date, the Expert Panel intends to revisit General Chapter <232> relative to the Step 4 outcome of ICH Q3D deliberations. At that time the Expert Panel may add additional elements and limits to General Chapter <232> based on ICH Q3D or may develop an informational chapter to incorporate elements of low toxicity. The revised General Chapter <2232> Elemental Contaminants in Dietary Supplements has appeared in PF 38(3) for comment, and an update related to this general chapter will be posted separately on the Elemental Impurities Hot Topics page on the USP Web site.
Revisions, Commentary, and Notice:
- Notice of Postponement
- Intent to Revise Notice
- Final approved General Chapter <232> Elemental Impurities–Limits as it will appear in the Second Supplement to USP 35–NF 30
- Commentary for General Chapter <232> Elemental Impurities–Limits
- Final approved General Chapter <233> Elemental Impurities–Procedures as it will appear in the Second Supplement to USP 35–NF 30
- Commentary for General Chapter <233> Elemental Impurities–Procedures
- Notice of Intent to Revise describing the proposed new General Notices provision
The USP Expert Panel on Elemental Impurities has revised the general chapters concerning elemental impurity limits and procedures (<232> and <233>) and the revised proposals appeared in Pharmacopeial Forum (PF) 37(3) (May-June 2011). The Expert Panel is proposing changes in both chapters to address the comments received. These chapters are presented in the PF for an additional comment period to assure that the chapter requirements are clear to all users and to obtain any final input.
The Expert Panel intends to incorporate the elements and limits described by the International Congress on Harmonization (ICH) Q3D, employing both general chapter <232> and an informational chapter as appropriate, as these become available. However, the Expert Panel does not intend to tie the implementation of general chapter <232> to the ICH implementation time frame. Instead, the Expert Panel intends to move forward with general chapter <232> using limits consistent with the latest available ICH Q3D recommendations and revisit general chapter <232> relative to the final outcome of ICH Q3D deliberations at a future date. The Expert Panel will recommend an appropriate official date for <232> and <233>, balancing input from FDA, industry and other stakeholders to assure timely, yet orderly, implementation of this standard. Recommendations of the Expert Panel will be presented to the Chemical Analysis Expert Committee, and be voted on by the Expert Committee in its August ballot.
Revised general chapters proposed in PF 37(3):
In the spirit of transparency, the Expert Panel is presenting its revised general chapters on the USP website with the expectation that the Expert Committee will consider them for presentation in a future PF. These general chapters are only the preliminary recommendations from the Expert Panel to the Chemical Analysis Expert Committee and do not represent a proposed standard. In addition, the Expert Panel intends to incorporate the elements and limits described by the International Congress on Harmonization (ICH) Q3D, therefore the Expert Panel will await the outcome of the November meeting before making its final recommendation on general chapter <232> to the Chemical Analysis Expert Committee. Finally, because the scientific content of the standard is not significantly different than the initial presentation, the Expert Panel recommends no change to the proposed implementation date of September 2013.
The revised chapters presented herein are:
The Chemical Analysis Expert Committee is currently reviewing these recommendations and will review and consider any further recommendations from the Expert Panel regarding <232> prior to republication of the chapters in PF.
USP proposed three new General Chapters on Elemental Impurities Limits, Methods, and Dietary Supplements Metals Limits in the January–February issue of Pharmacopeial Forum [PF 36(1)].
Other related information also appeared in PF 36(1), including a draft General Notices statement about the applicability of the standard to all monographs and two Stimuli articles outlining the rationale for the revisions and the comments received from an original Stimuli article and Workshop.
- <232> Elemental Impurities—Limits
- <233> Elemental Impurities—Procedures
- <2232> Elemental Contaminants in Dietary Supplements
- Stimuli article Elemental Impurities—Information
- Stimuli article Elemental Impurities—Comments and Responses
These revisions focus on two areas of work:
- Updating the methodology used to test for elemental impurities in drugs and dietary supplements to include procedures that rely on modern analytical technology; and
- Setting limits for acceptable levels of metal impurities (including, but not limited to, lead, mercury, arsenic, and cadmium) in drugs and dietary supplements.
The USP Metal Impurities Expert Panel, which will report to the USP Chemical Analyses Expert Committee in the new USP cycle, worked with USP staff and stakeholders to assess methodologies and limits that provide greater patient/consumer protection and can reasonably be deployed across industry laboratories. The limits for exposure are toxicologically based and developed by an expert consensus process to provide quality standards that reflect consensus views about potential health/toxicity concerns.
These new approaches are intended to replace the existing methods in General Chapter <231> Heavy Metals. Deadline to submit comments to USP ended on April 15, 2010. The USP Metal Impurities Expert Panel is currently reviewing comments and will propose a revision to these chapters in the next available PF. Although the official comment period has ended interested parties are encouraged to submit data at any time to Kahkashan Zaidi, Ph.D., Senior Scientific Liaison, General Chapters, Division of Standards Development (email@example.com).
Frequently Asked Questions
Workshop on Metals in Pharmaceuticals and Dietary Supplements (April 28–29, 2009)
Note: The content of these presentations reflects the ideas and suggestions of the participants at the workshop. These deliberations are advisory and are not binding in any way to the Council of Experts, its Expert Committees and Advisory Panels, or USP staff.
USP Heavy Metals Testing Methodologies Workshop (April 26–27, 2008)
- The Digest of Comments Received on the Stimuli Article “General Chapter on Inorganic Impurities: Heavy Metals” Published in Pharmacopeial Forum 34(5)
- The USP Advisory Panel on Metal Impurities “Draft Metals and Limits Table”
USP intends to develop official USP Reference Standards in support of the revisions for the General Chapter on Metal Impurities. These new USP Reference Standards will provide high quality reference materials designed to help demonstrate compliance with the new chapter on metal impurities.
As the General Chapter evolves through the revision process, the type and number of USP Reference Standards will also need to be developed in USP's Analytical Research and Development laboratory. If you would like to receive email notifications when these new, first time Reference Standards become available, sign up for USP's Reference Standards Release Notification Program. Since there currently is no official USP Reference Standard name in the “Name of Reference Standard(s)” field please type “Metal Impurities.”
USP Compendial Updates
Stay informed about any Revision Bulletin to General Chapter <231> Heavy Metals through USP’s free Compendial Updates email service.