Key Issue: Elemental Impurities

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

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):

• <232> Elemental Impurities–Limits 
• <233> Elemental Impurities–Procedures 

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:

• <232> Elemental Impurities—Limits
• <233> Elemental Impurities—Procedures

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 (kxz@usp.org).

Frequently Asked Questions

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