Are You Ready for the USP <231> Heavy Metals Transition?

Last fall the United States Pharmacopeia (USP) published a stimuli article in the Pharmacopeial Forum proposing a new USP General Chapter for the control of inorganic impurities in drugs and dietary supplements. The intent of this article was to initiate a dialogue between the USP, FDA and industry experts, resulting in a scientifically valid and practical method to replace the current USP <231> Heavy Metals method. This stimuli article included a table identifying 21 individual metals and their associated Permissible Daily Exposure (PDE) limits, which are to be used in the newly proposed method.

As expected, the sweeping changes addressed in the article have created quite a stir in the pharmaceutical and dietary supplement industries. Through USP meetings, trade association committees, and online research, we have been following the progress of the proposed changes to USP <231>, and will maintain doing so as they continue to unfold. Here are some of the key points of the proposed new method as they currently stand.

Reason for the Revision:
The current USP <231> Heavy Metals method is over 100 years old and lacks the ability to identify and quantitate individual elements to the new limits of detection deemed necessary by recent toxicologically-based health safety data. Rigorous investigation of the current method indicates that it often fails to detect volatile elements (especially mercury) and may greatly underestimate the amount of other heavy metals in common matrices.

Current PDE values are identified in the stimuli article as amounts as low as 0.02 ug/day for parenteral administration of certain elements (methyl mercury). Several current technology options can now detect such elements with high amounts of accuracy and precision. Some of these technologies were included a few years ago in USP General Chapter <730> titled Plasma Spectroscopy. This chapter, however, did not replace <231> and did not contain the detailed quality control criteria currently proposed for inclusion in the new method.

Who is affected:
The areas intended to be covered by the proposed General Chapter include Drug Articles (drug substances and products including those from natural sources and rDNA), Dietary Supplements, and Ingredients/Excipients for these materials. The article explicitly excludes Foods and Food Ingredients from the initial intended coverage.

Which elements are included:
The article, as it currently stands, lists 21 individual elements as shown in Table 1: USP Proposed Heavy Metal Toxicity Limits. This table includes the oral PDEs for the elements, which are based on a certain amount of each element (ug amounts) consumed daily by a person of average weight (50 kg). Since the PDE is based on a daily consumption amount, the detection limits required for testing each element will vary based upon the serving size of the individual product being tested. A product with a serving size of 1 gram would require that the detection limit (expressed in ppm) be equal to the PDE. A product with a 10 gram serving size would require that the detection limit (expressed in ppm) be 1/10 of the PDE.

While it is not certain what
the next draft of this method will contain, it is clear that there is substantial consensus that an abbreviated list of proposed elements is desired by many experts who have been providing loud feedback to the USP technical committee. Based on the feedback it is expected that the “Big Four” (As, Cd, Hg, Pb) will be included for general testing of most, if not all substances and it is likely that chromium would be the next metal to be added to the ‘hit list’. Other metals may also be included in the order of their toxicological importance and likelihood of being found in commonly covered substances.

Also worth noting is the fact that several elements (As, Cr, Hg) have different PDE limits based upon the various valence states in which they are found. For these particular elements, the toxicology varies greatly based upon the available form of the element. In the proposed method, the ‘speciation’ of these elements is likely to be encouraged only after an initial testing is completed to find the total amount of each element in a given product. If the total amount of arsenic, for instance, is found to be below the PDE for inorganic arsenic, no additional testing would be needed to further identify the source of the arsenic.

As you can see, there are many issues that are likely to be changing with regard to heavy metals testing on dietary products. We at Chemical Solutions are currently testing the full list of elements included in the proposed method and will continue to provide the services necessary to meet the ongoing changes that will almost certainly occur in the method. Our ICP-MS instrumentation includes the most up-to-date features to assure the lowest detection limits with the highest accuracy available. Our Dynamic Reaction Cell technology included in our ICP-MS instrument allows us to eliminate interferences common to other technologies. Please give us a call to see how we can assist you to prepare for and comply with the new USP methods or cGMPs.