Modernization of the Standards for Elemental Impurities - Pharmaceutical Technology

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Modernization of the Standards for Elemental Impurities
Recent activity in standards-setting organizations has raised interest in the impact of testing for impurities that may enter the product before it is mined or harvested or even due to intentional use of some reagents.

Pharmaceutical Technology
Volume 37, Issue 2

History of the emerging USP standard

The United States Pharmacopeial Convention (USP) published two chapters in the Second Supplement to USP 35-NF 30 that are proposed to apply to USP articles in May 2014. The need for an upgrade of the USP Heavy Metals General Chapter <231> was first brought forward in 1995 in a stimulus article in USP's Pharmacopeial Forum (2), and again in 2000 with a stimulus article arguing for industry use of ICP-MS technology for this purpose (4). In its 2005-2010 cycle, USP decided to replace General Chapter <231> with a general chapter that actually did what General Chapter <231> purports to do but is incapable of doing adequately (i.e., identify and quantify elemental impurities in articles of commerce at levels that could be used to assess the safety of the elements observed).

The process began in earnest with a broadly advertised workshop organized by the Institute of Medicine (IOM) at USP's request. IOM staff brought together toxicology and analytical experts and key stakeholders including pharmaceutical manufacturers and excipient producers from around the world to discuss elements to be measured and to discuss the process for establishing permissible daily exposures (PDE). The key output from this meeting was the conclusion that the possibility of contamination from four environmental contaminants (mercury, lead, cadmium, and arsenic) needed to be evaluated for all drug products.

USP built on the IOM workshop by establishing an Expert Panel reporting to the General Chapters Expert Committee to develop general chapters that established a list of toxic elements, their permissible daily exposures (PDE) associated with the appropriate dosage form, and procedures capable of quantifying each element in the matrix of interest (excipient, drug substance or drug product). The IOM workshop, USP Heavy Metals Testing Methodologies held Aug. 26–27, 2008, was a closed discussion limited to invited attendees. Those attendees were chosen by the IOM for the ability to provide credible, expert information. A summary can be found at

Because USP needed to provide a forum for the US industry to learn about the findings of the IOM, it held a follow-up workshop (Workshop on Metals in Pharmaceuticals and Dietary Supplements, Rockville, MD, Apr. 28-29, 2009), which was open to all interested parties, at the USP headquarters in Rockville, Maryland. This workshop allowed the newly formed expert panel to interact with stakeholders and incorporate their feedback into the developing standard. At the conclusion of the workshop, the panel met to consider all of the feedback and plan draft chapters. USP published two stimuli articles, one describing the rationale behind the elements, limits, and methodologies chosen for inclusion in the chapters and the other describing the issues received, when the initial draft chapters were published, and the rationale for how each was addressed. These chapters were published by USP in January 2010 (7).

To support the proposed standard, USP has organized more than 40 teaching/listening opportunities through the Pharmacopeial Education organization of USP. Organized throughout the US and in 15 different countries, these sessions ranged from one hour to one day, depending upon the needs of the audience and the venue. The sessions were lead by senior staff and volunteers to ensure that all of the feedback led directly to the evolving standard. Of course, the training has evolved to reflect the standard and continues to be available for interested parties.

ICH history

In October 2009, ICH endorsed the development of a new "Elemental Impurities Q3D" guideline to provide clarification of the requirements for metals (8). A harmonized list of metals and limit criteria based on permissible daily exposure is expected to emerge from this negotiation. Q3D intentionally used the EMA guideline, the USP stimulus article, and USP Draft General Chapter <232> as starting points for the development of a global standard with the understanding that existing regional efforts and timelines would proceed. The intent from the beginning was to proceed with regional modernization of the standard followed by harmonization to the eventual ICH limits. The ICH steering committee, understanding the magnitude of this standard, supported the Q3D EWG by allowing the participation of stakeholders, such as the standards setting organizations USP, EP, and Japanese Pharmacopoeia (JP), as well as additional trade organizations, such as the International Pharmaceutical Excipients Council (IPEC). This participation is to assure that any differences in regional implementation and expectations are minimized, thus easing the standards modernization and harmonization processes. Like other ICH guideline documents, Q3D will move through a series of consultation periods and will ultimately move into the regional implementation phase. This final phase involves the official adoption of the guideline into the regulations of the three regions. This regional implementation allows the regulator to adjust the ICH text to fit the legal landscape and other logistics of their home region.

Another point to consider is that all the parties involved in modernization of this standard have pledged not to allow any inconsistencies to persist in the standards. That does not mean an entire absence of any differences because some may result from either regional regulatory requirements or areas left unresolved by the ICH process.


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