Frequently Asked Questions: USP's Proposed Standards for Elemental Impurities
Q. Why is USP revising its standards for elemental impurities?
A. USP is revising its standards for elemental impurities in the interest of better protecting public health. The revisions focus on two areas of work:
- Updating the methodology used to test for elemental impurities in drugs and dietary supplements to include procedures that rely on modern analytical technology; and
- Establishing limits for acceptable levels of elemental impurities (including, but not limited to, lead, mercury, arsenic, and cadmium) in drugs and dietary supplements.
Q. Why is any level of elemental impurities considered "acceptable?" Shouldn't the level always be zero?
A.The human body requires trace elements of many substances to function properly. For example, iron is an element that would be harmful or toxic beyond certain levels, but is frequently taken as a dietary supplement to help ensure healthy blood. The human body is also well suited to eliminate a small amount of most toxins. For most toxic elemental impurities, toxicologists have indicated that daily ingestion of low part-per-million levels constitutes a very low risk even in chronic applications.
Additionally, the definition of "zero" or "absence" is very easy in a general sense (i.e. there are zero apples in a basket) but much more difficult from a measurement perspective. Requiring that "zero" molecules of an impurity may be present bases the standard on the technical ability to make the measurement rather than making it health based. Basing the standard on the best available detection technology may be prohibitively difficult for users to implement and not best serve public health.
Q. What is wrong or deficient about the current test methodology?
A. The test methodology currently described in the USP–NF, was first introduced more than 100 years ago. The test can be difficult to conduct, and can fail to detect some important elementals such as mercury at toxicologically-relevant levels.
Q. Why has USP waited until now to revise standards for elemental impurities? Was there a specific event that prompted the revision?
A. USP undergoes regular re–evaluation and revision of all its standards to update their scientific and public health relevance. There was no specific event that triggered the revision of elemental impurities standards, but our scientific experts felt that the elemental impurity standards should be updated to incorporate modern methods and health information. As we have gained a better understanding of the limitations of the current methods, it has become clear that a revision is called for.
Q. How is USP approaching the revision?
A. USP is taking a risk–based approach that focuses on the likelihood of a given impurity being found in a drug or dietary supplement and on a consensus-based evaluation of the health implications of the impurity at levels that may be found. We have included toxicologists as well as chemists in the group of experts revising the standards to obtain the best available input on both health and methodology issues.
Q. What is the timing of the new standard?
A. USP's standards–revision process involves international collaboration among USP experts, industry, regulators, and the general public. When there is no specific medical emergency, as is the case with elemental impurities, it is beneficial to allow careful deliberation and scientific dialog to reach conclusions that are supported by a maximum number of interested stakeholders. In addition, where the new standards represent a significant change from existing standards, as is also the case with elemental impurities, it is important to provide sufficient time for manufacturers to incorporate the changes in their processes necessary to implement the new standards. The new elemental impurities standards, which are intended to replace the existing methods in General Chapter <231> Heavy Metals, are expected to be finalized sometime in 2010 and become official at a later date which has not yet been determined.
Q. Some in the pharmaceutical industry believe that USP is creating unrealistic, unworkable requirements for testing, which could lead to non–compliance and shortages of key medicines. For example, the article published in USP's Pharmacopeial Forum (PF) (2008, 34(5), page 1345) includes a list of 31 substances to be tested. And the proposed limits for each individual element may be unworkable across the many quality assurance labs that would be affected.
A. USP does not intend to burden industry with unwieldy and unnecessary testing requirements. The list in the PF article was intended as a proposal for discussion. As the revision moved forward, that list has been shortened. USP will not mandate the methodology that each lab must use. Manufacturers will have the flexibility to choose a test that best fits their processes.
Q. The proposed leeway for manufacturers to choose their own test methods is attractive because of the added flexibility. But doesn't that expose manufacturers to added risk of FDA rejection?
A. Potentially, but USP is going to great lengths to work with both FDA and industry to ensure widespread agreement on interpretation of the revised standard. And the revision will include two referee methods, which manufacturers can choose from if they want to ensure a means of demonstrating unquestioned compliance to the standard.
Q. Have imports posed an increased problem with elemental impurities? How is USP dealing with this?
A. To date, there have been no known incidents involving elemental impurities in pharmaceuticals. However, there are continuing concerns above the quality of imports. Ultimately, manufacturers are responsible for assuring conformance to FDA requirements and USP standards, no matter what the source. As more ingredients are sourced abroad, the presence of modern, scientifically sound quality standards will help protect both manufacturers and patients in the United States.