USP Requirements for Elemental Impurities: Current Status
The United States Pharmacopoeia (USP) continually updates General Chapters and product monographs to reflect modern analytical methods, add new products, and/or address public health concerns. Recent proposed changes by USP to General Chapter <231> Heavy Metals though, are proving to be controversial. Although these changes will update analytical technology and add limits for many metals, there is currently no proven risk to public health posed by heavy metals in pharmaceutical products. USP’s timeline for the implementation of these changes is imposing a significant burden on industry because it is not harmonized with associated international agencies. Rx-360 is providing the following information to raise awareness of the current status of the USP effort to modernize the requirements for heavy metals (now renamed elemental impurities).
A Brief History of Handling Heavy Metals in Pharmaceutical Products
Metals in pharmaceutical products are typically the result of use of metal catalysts or reagents, contaminants present in processing equipment, raw materials, bulk packaging, cleaning solvents, and/or the environment. These metal residues do not have any therapeutic effect, but limits provide assurance of acceptable product quality.
The process of modernizing and updating USP General Chapter <231> Heavy Metals has been progressing for a number of years:
2004: A more concerted effort was initiated when a subcommittee of the Pharmaceutical Analysis 6 Expert Committee was formed. One of the issues at the time was to evaluate the possibility of introducing advanced sample preparation and analytical techniques.
2005: The work was assumed by the General Chapters Expert Committee, which formed a Heavy Metals Advisory Panel. This Panel included representatives from the European Medicines Agency (EMA) and the US FDA. Panel members initiated work in their own laboratories and concluded that Inductively Coupled Plasma-Atomic (Optical) Emission Spectroscopy (ICP-AES) was the method of choice for measurement of heavy metals.
2010: The Chemical Analysis Expert Committee assumed responsibility, with input from the Elemental Impurities Expert Panel. During this period several proposals were published in the Pharmacopoeial Forum (PF), starting with planned revisions of <231>, and evolving into the creation of <232> Elemental Impurities - Limits and <233> Elemental Impurities - Procedures.
May 1, 2011:The final drafts of both proposed new chapters were published in PF 37(3).
June 1, 2012:General Chapters <232> and <233> were published in USP 35 / NF 30 Supplement 2 (official as of December 1, 2012) to modernize the standards and analytical methodologies stated in <231>.
Nov 1, 2013: General Chapter <231> is scheduled to be deleted in USP 37 / NF 32 (official as of May 1, 2014). As part of this process, all monographs which currently reference <231> will be revised to reference <232> and <233>.
In addition to the modernization work by USP, the International Committee on Harmonization (ICH) formed an Expert Working Group (EWG) in October 2009 to address heavy metal impurities following the publication of a USP Stimuli article and the drafts of the proposed new chapters. The proposed ICH Q3D guideline is currently at pre-step 2 status. Step 2 is targeted for June 2013, and the step 4 document is targeted for publication in June 2014, after which regional implementation will occur. USP staff have observer status at ICH deliberations. USP had also indicated that it plans on harmonizing their General Chapters with the ICH Q3D guideline after it is finalized.
Impact of Proposed USP Changes
There is general agreement in the chemical suppliers and pharmaceutical industries on the need to modernize analytical methods for metal detection. Over the last several months, however, various industry associations have expressed concern about the USP implementation timeline, the nature of the sample preparation procedure, and the acceptable limits for various elemental impurities. Because the change in the analytical method is substantial, from a semi-quantitative visual estimation technique to the fully quantitative ICP-AES, industry laboratories will need time to obtain and qualify the required equipment and train laboratory staff. In addition, the new sample digestion process requires the use of concentrated acid, which may require upgrading the laboratories to ensure operator safety.
In the case of limits established for elemental impurities in General Chapter <232>, significant differences exist between USP and the ICH Q3D draft. Although several limits are the same for parenteral daily dosages (e.g., Palladium and Lead), in many cases the USP limits are substantially tighter than ICH (e.g., Arsenic, Mercury, Nickel, Platinum). While the ICH draft limits may change in the final guideline, regional implementation of ICH Q3D will occur months and possibly several years after the USP General Chapters are official. Industry is concerned that companies will have to work on a tight schedule to meet the USP requirements only to have to perform additional work after the final ICH Q3D guideline is published, since the guideline will be used to update regulatory requirements in many parts of the world.
Appeals to USP
Because of these concerns, PhRMA, EFPIA, and the Coalition for the Rational Implementation of the USP Elemental Impurities Requirements submitted appeals to USP in November 2012. The Coalition mentioned above includes members from GPhA, IPEC Americas and Europe, PDA, and CHPA. As a result, USP postponed the December 1, 2012 official date for <232> and <233>, pending the outcome of the appeals. The USP Executive Committee of the Council of Experts met on January 7, 2013 to consider these appeals. The Committee voted to uphold the general chapters. The Committee concluded that ICH’s actions “are not pertinent to USP’s actions.” Also, “the new chapters are needed now because current elemental impurities standards cannot differentiate between safe and unsafe products.”
A number of observers noted that this statement was actually in contrast to the existing data. Despite testing dozens of products by the new method at FDA laboratories during the second half of 2012, no “unsafe” products were identified.
After the Committee vote on January 7, 2013, the official date for the chapters was changed to February 1, 2013. USP acknowledged that there may be issues relating to the application of <232> and <233> to specific articles and requests that those affected work with USP and its relevant Expert Committees to resolve the issues prior to the planned May 1, 2014 official date for specific monographs (which may be further revised if needed). The appellants were informed of the Executive Committee decision in a January 25, 2013 letter from Roger Williams, Chair, Council of Experts (also CEO). The USP website was updated on January 28, 2013 to provide a summary of the appeal, the Executive Committee decision, and the re-establishment of the official date (to read the notice, see: http://www.usp.org/usp-nf/official-text/revision-bulletins/elemental-impurities-limits-and-elemental-impurities-procedures-0 )
On January 28, 2013, the law firm representing R.T. Vanderbilt, a supplier of minerals and chemicals to various industries, including pharmaceuticals, filed an appeal to the USP Board of Trustees regarding the USP Executive Committee decision. Vanderbilt claims that the decision will have a high impact on industry, and that USP did not follow its own Rules and Procedures (section 7.03) by not providing the affected parties the courtesy and the right to a public hearing. This appeal also states that the implementation timeframe is “unnecessarily short.”
As of the time of this publication, USP has not responded to this latest appeal. Regardless, modernization of the current analytical techniques in detecting and quantifying elemental impurities will occur, utilizing the latest technology; limits will reflect this technological capability and patient safety considerations. Global harmonization will occur at some point in the future, providing clarity and direction for industry and safety assurance to patients.
Future updates will be provided as this situation evolves.