Roger L. Williams, MD, is executive vice-president and chief executive officer, USP

Roger L. Williams

The United States Pharmacopeial Convention (USPC) asked the Institute of Medicine (IOM) of the National Academy of Sciences to convene a workshop at which stakeholders, including pharmaceutical manufacturers, could discuss ways to update 

General Chapter <231> "Heavy Metals" (1). IOM responded positively and formed a planning committee composed of national and international experts in metal measurement and toxicity.  

The workshop took place at IOM Aug. 26–27, 2008. In an effort to promote harmonization and at USP's request, IOM invited compendial experts from Europe and Japan to attend. Because 

 <231> is relevant to food ingredients (standards are provided in USP's 

) and dietary supplements (standards are provided in 

's dietary supplement section), IOM also invited stakeholders from those sectors. 

 <231> relies on classical (i.e., wet) chemistry procedures that have been in the compendium for more than 90 years. The test suffers from a lack of instrumental output and is a nonspecific, subjective test based on the precipitation of metal sulfides from a solution with visual comparison to the color of a standard solution (2). Several groups have shown that the method routinely underestimates the levels of the few metals it was designed to detect (2, 3). Certain toxic metals thus may appear in drug products and their ingredients because of their use as catalysts or starting materials. Other metals such as arsenic, cadmium, lead, and mercury are highly toxic and ubiquitous in the environment. Not surprisingly, many of these metals also have been detected during market surveillance of dietary supplements and food ingredients (4). 

Workshop deliberations resulted in a consensus that the current classical chemistry procedure in 

 <231> is no longer suitable. Participants agreed that the current procedure should be replaced by specific and sensitive instrumental procedures that detect and quantify the broad range of metals and elements of interest in pharmaceuticals, dietary supplements, and food ingredients. 

Modern instrumental methods can identify and quantify at low levels many metals that currently are not detected by 

 <231>. Because many metals may not pose a public health risk when consumed for a brief time or at low levels, the challenge for participants was to identify metals of interest, and levels that should be monitored, especially considering the broad range of exposures posed by articles such as food ingredients. 

For certain metals (e.g., arsenic, cadmium, lead, and mercury) analysis was relatively straightforward. These substances have known toxic effects and are potential contaminants. Thus, analytical methods should be validated to detect arsenic, cadmium, lead, and mercury. The methods should detect the metals at toxicologically relevant concentrations; and pharmacopeial monographs for these metals should be revised. 

Workshop participants grappled with the questions of which metals should be monitored and to what level of detection. The European Medicines Agency (EMEA) has released a 

Guideline on the Specification Limits for Residues of Metal Catalysts

 (5). Because the metals specified in the guideline are sometimes used as catalysts or processing agents and can appear as contaminants in drug substances and drug products, EMEA recommends that pharmaceutical manufacturers test for them at levels commensurate with their toxicity.  

Workshop participants identified various reagents that may require monitoring and contain elements such as aluminum, beryllium, boron, chromium, cobalt, copper, gallium, germanium, gold, indium, iron, lithium, magnesium, manganese, nickel, silicon, silver, tin, thallium, titanium, and zinc. 

Speciation (i.e.,  valence state of the metal or its existence as an organic complex) can play an important role in toxicity. The cases of arsenic and mercury are instructive: Inorganic arsenic compounds are typically highly toxic. Dietary supplements that contain kelp or certain other nontoxic materials also contain high concentrations of essentially nontoxic organoarsenic compounds. Similarly, metallic mercury is relatively nontoxic, but inhaled mercury metal, methyl mercury, and similar organomercury compounds that can be concentrated in foods such as fish are highly toxic. Thus, workshop attendees concluded that tests for arsenic or mercury  by themselves may not yield suitable data on which to base specifications. Further, reports of total arsenic or total mercury content may unnecessarily confuse consumers about the safety of the products they consume, leading the public to question the efficacy of regulatory standards. 

 Participants agreed that several related factors must be considered when evaluating the acceptable rate and extent of exposure in vulnerable populations. Humans may experience degrees of environmental exposure to metals.  

Another consideration is the duration of exposure. Long-term exposure to lead is associated with decreased intelligence quotient, and long-term exposure to organic mercury causes neuropathic effects. Concurrent exposure to both metals has not been well studied, but risk-assessment models suggest incremental risk.  

 If analysts do not separate metal forms (i.e., perform speciation) before undertaking metal analysis, the results will report the total of all forms detected (e.g., the method will report both inorganic and organic arsenic). Workshop participants did not reach a consensus about the level of detection required for each metal. A reasonable approach might involve the development of pharmacopeial specifications for the total amount of an individual metal at some limit (worst case), and requiring manufacturers to use speciation to justify a higher limit. 

Workshop participants decided that the following tests are probably suitable for compendial metal analysis: electrothermal atomic absorption spectrometry, inductively coupled plasma–optical emission spectrometry, inductively coupled plasma–mass spectrometry, and any other methods with similar specificity and sensitivity. 

 <231> will rely on reference materials to demonstrate recovery (i.e., precision and accuracy) during sample preparation and analysis. Reference materials also are needed to establish systems suitability and quantitation or detection limits, particularly when several technologies may be used to produce acceptable results. 

Workshop participants advocated the revision of 

 <231>. Further consideration of limits for various metals will be required. Arsenic, cadmium, lead, and mercury were singled out by participants for particular attention. Other metals used in manufacture or present in starting materials will be considered using a risk-based approach. USP will continue to work with stakeholders to update General Chapter <231> using harmonized approaches and a public process of review and comment. 

 is executive vice-president and chief executive officer, 

 is chief science officer, all at the United States Pharmacopeial Convention, 12601 Twinbrook Parkway, Rockville, MD 20852-1790, tel. 301.816.8184, 

. *To whom all correspondence should be addressed. 

 26 General Chapter <231>, "Heavy Metals," pp. 133–134. 

 2.  T. Wang et al., "An Atomic Spectroscopic Method as an Alternative to Both 

 3.  USP Ad Hoc Advisory Panel on Inorganic Impurities and Heavy Metals, "General Chapter on Inorganic Impurities: Heavy Metals," 

 4.  D.R. Abernethy et al., "Adulteration of Drugs and Foods: Compendial Approaches to Lowering Risk," 

Guideline on the Specification Limits for Residues of Metal Catalysts 

Articles

Attendees at a recent workshop endorsed new methods to detect metals in drugs, dietary supplements, and food ingredients.

Inside USP: USP Metals Testing: A Workshop Report

In early 2007, the United States Pharmacopeia (USP) produced 

which allows the organization to create web-based monographs with available official USP reference standards in advance of a US Food and Drug Administration approval of a manufacturer's product for which the monographs are applicable. In response to comments, USP recently revised the guideline and has made it available as version 2.1. This article describes the purpose of the guideline and notes the revisions.

 allows development and online publication of monographs for certain drug products and their drug substances that have been or will be submitted to FDA for approval to market in the United States. It is intended to be useful particularly for generics manufacturers and drug-master-file (DMF) holders, because at times an existing USP monograph is not suitable at the time of FDA approval. Without a suitable monograph, the generics manufacturer and referenced DMF holder may experience marketing delays. In some ways, the pending monograph approach is similar to FDA's tentative approval, which has been applied recently to drug combinations used to treat HIV/AIDS (1). After posting on USP's website, the pending monograph is authorized rather than official (i.e., it is text authorized by USP, but it is not legally enforceable by FDA), and the manufacturer may not use USP on certificates of analysis or on container labeling. If the manufacturer receives marketing approval from FDA, a pending monograph and associated reference standards may move to official status in 

USP has revised the guideline to take into account several comments:  					

Clarification of what constitutes intent to file with FDA.

A requirement that the sponsor promptly inform USP of any changes to methods or specifications that arise during the regulatory review and approval process. This will ensure consistency between the proposed monograph and the private specification approved by FDA. 

Use of USP's Revision Bulletin process to move a pending monograph to official status upon product approval, which will allow monographs to become official more quickly than under the Interim Revision Announcement process formerly used. 

A requirement that USP must receive the bulk material necessary to develop any USP reference standard(s) before the proposed monograph is posted on USP's website. This will help manufacturers meet the requirement that the USP reference standard(s) must be available, as feasible, when the product is approved and the monograph becomes official.

Patients and consumers have a right to good quality drugs. These are available in the US thanks to many requirements, including testing to ensure quality. USP's primary public health purpose is to create and maintain sound public monographs with reference materials to allow this testing. The general idea is articulated clearly in the US Federal Food, Drug, and Cosmetic Act and ties FDA to USP in a historic public–private partnership that has benefited practitioners and patients for many years. The partnership is critically important in an era when adulterated and counterfeit drugs are on the rise.

The guideline is intended to assist all manufacturers seeking FDA approval to enter the US market quickly, with a solid public monograph available as well as associated reference standards at the time of approval. Pending the time to market in the US, the policy also gives the opportunity to manufacturers, regulators, and anyone in other countries to use an authorized pending monograph and official USP reference materials to check the quality of medicines.

 is director of small molecules and monograph acquisition, and 

* is executive vice-president and chief executive officer, both at the US Pharmacopeia, 12601 Twinbrook Parkway, Rockville, MD 20852-1790, tel. 301.816.8300, 

*To whom all correspondence should be addressed.

Guidance for Industry: Fixed Dose Combination and Co-Packaged Drug Products for Treatment of HIV 

USP's guideline for pending monographs can speed up publication of monograhs and time to market.