Hot Topics: Elemental Impurities

Original Posting: 20–Jul–2010; Last Update: 26–May–2011

Contacts

  • Scientific Liaison: Kahkashan Zaidi (kxz@usp.org or 301-816-8269)
  • Reference Standards Technical Support: RS Technical Service (rstech@usp.org or 301-816-8129)
  • Reference Standards Ordering: USP Customer Service (custsvc@usp.org or 800-227-8772)
  • Media: Laura Provan (lnp@usp.org or 301-816-8268)

Updates

(May 26, 2011): 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):

Past Updates

October 6, 2010

The proposed new general chapters concerning elemental impurity limits and procedures (<232> and <233>), initially published in Pharmacopeial Forum (PF) 36(1), have received a number of comments that have been individually reviewed and considered by the USP Expert Panel on Elemental Impurities. Based on these comments, the Expert Panel is recommending revisions to the chapters including numerous changes in wording intended to improve the clarity of the presentation. While these changes do not change the scientific content of the chapters, the presentation has changed sufficiently that the Expert Panel is recommending presenting the chapters for an additional comment period in PF to assure that the chapter requirements are clear to all users and obtain any final input.

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.

July 20, 2010

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.

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

Related Events

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)

Background Documents

Reference Standards

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.