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.
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.