Last updated: 3-March-2021
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.
- Standards for elemental impurities are continuously updated and revised as necessary and as always in alignment with USP Procedures for setting and revision of written Standards.
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.
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.
USP took 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.
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.
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.
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 at the time of publication of the article (2008). As the revision moved forward, that list was shortened. The current effective list of elements is given in the -now effective- chapter <232>. 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.
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.
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.
Detectability:
The intent of the chapter is not to require analysts to determine the absolute limit of detection or limit of quantitation. Demonstrating that the method is capable of reliably detecting 0.5J is sufficient. The rationale for this is because the drug product must meet the requirements of chapter <232> with regard to the PDE. Demonstrating that the method reliably can “see” 50% of the PDE adequately demonstrates that the method is suitable for its intended use. There is no need to demonstrate orders of magnitude lower than the PDE may be reliably quantitated, since compliance with regard to the PDE is the chapter requirement.