This general chapter specifies limits for the amounts of elemental impurities in drug products. Elemental impurities include catalysts and environmental contaminants that may be present in drug substances, excipients, or drug products. These impurities may occur naturally, be added intentionally, or be introduced inadvertently (e.g., by interactions with processing equipment and the container closure system).2S (USP38) When elemental impurities are known to be present, have been added, or have the potential for introduction, assurance of compliance to the specified levels is required. A risk-based control strategy may be appropriate when analysts determine how to assure compliance with this standard. Due to the ubiquitous nature of arsenic, cadmium, lead, and mercury, they (at the minimum) must be considered in the risk assessment.2S (USP38) Regardless of the approach used, compliance with the limits specified is required for all drug products unless otherwise specified in an individual monograph or excluded in paragraph three of this introduction.

This chapter does not apply to radiopharmaceuticals, vaccines, cell metabolites, DNA products, allergenic extracts, cells, whole blood, cellular blood components or blood derivatives including plasma and plasma derivatives, dialysate solutions not intended for systemic circulation, and elements that are intentionally included in the drug product for therapeutic benefit. This chapter does not apply to products based on genes (gene therapy), cells (cell therapy), and tissue (tissue engineering).2S (USP38)

The limits presented in this chapter do not apply to excipients and drug substances, except where specified in this chapter or in the individual monograph. However, elemental impurity levels present in drug substances and excipients must be known, documented, and made available upon request.

This chapter does not apply to2S (USP38) articles intended only for veterinary use. Requirements listed in this chapter also do not apply to total parenteral nutritions (TPNs) and dialysates.2S (USP38) Dietary supplements and their ingredients are addressed in Elemental Contaminants in Dietary Supplements 2232.

The determination of the oxidation state, organic complex, or combination is termed speciation. Each of the elemental impurities has the potential to be present in differing oxidation or complexation states. However, arsenic and mercury are of particular concern because of the differing toxicities of their inorganic and complexed organic forms.

The arsenic limits are based on the inorganic (most toxic) form. Arsenic can be measured using a total-arsenic procedure under the assumption that all arsenic contained in the material under test is in the inorganic form. Where the limit is exceeded using a total-arsenic procedure, it may be possible to show via a procedure that quantifies the different forms that the inorganic form meets the specification.

The mercury limits are based upon the inorganic (2+) oxidation state. The methyl mercury form (most toxic) is rarely an issue for pharmaceuticals. Thus, the limit was established assuming the most common (mercuric) inorganic form. Limits for articles that have the potential to contain methyl mercury (e.g., materials derived from fish) are to be provided in the monograph.

The toxicity of an elemental impurity is related to its extent of exposure (bioavailability). The extent of exposure has been determined for each of the elemental impurities of interest for three routes of administration: oral, parenteral, and inhalational. These limits are based on chronic exposure. Consider the oral permissible daily exposures (PDEs) in Table 1, as a starting point in developing specific PDEs for other routes of administration except where otherwise stated in the individual monograph.2S (USP38) [Note—The routes of administration of drug products are defined in Pharmaceutical Dosage Forms 1151. ]

The limits described in the second through fourth columns of Table 1 are the base daily dose PDEs of the elemental impurities of interest for a drug product taken by a2S (USP38) patient according to indicated routes of administration. 2S (USP38)

The concentration2S (USP38) of elemental impurities in drug substances and excipients must be controlled and, where present, documented.2S (USP38) The acceptable levels for these impurities depend on the material's ultimate use. Therefore, drug product manufacturers must determine the acceptable level of elemental impurities in the drug substances and excipients used to produce their products.

The values provided in Table 2 are example2S (USP38) concentration limits for components (drug substances and excipients) of drug products dosed at a maximum daily dose of 2S (USP38) 10 g/day. These values serve as default concentration limits to aid discussions between drug product manufacturers and the suppliers of the components of their drug products. [Note—Individual components may need to be limited at levels different from those in the table depending on monograph-specific mitigating factors. ]

If, by process monitoring and supply-chain control, manufacturers can demonstrate compliance,2S (USP38) then further testing may2S (USP38) not be needed. When testing is done to demonstrate compliance, proceed as directed in Elemental Impurities—Procedures 233 and minimally include arsenic, cadmium, lead, and mercury in the Target Elements evaluation.