USP美国药典 232 元素杂质-限度

á232ñ ELEMENTAL IMPURITIES—LIMITS

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INTRODUCTION

or drug products. These impurities may occur naturally, be added intentionally, or be introduced inadvertently (e.g., by inter-actions with processing equipment and the container–closure system). 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

SPECIATION

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 inor-ganic 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.Change to read:

ROUTES OF EXPOSURE

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.[N OTE —The routes of administration of drug products are defined in Pharmaceutical Dosage Forms á1151ñ

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DRUG PRODUCTS

Table 1 are the base daily dose PDEs of the

Parenteral Products

Parenteral drug products with maximum daily volumes up to 2 L may use the maximum daily volume to calculate permissi-missible concentrations from PDEs.

8066 á232ñ Elemental Impurities—Limits / Chemical Tests

First Supplement to USP 40–NF 35

Recommendations for Elements to be Considered in the Risk Assessment

Table 2 identifies elemental impurities for inclusion in the risk assessment. This table can be applied to all sources of elemen-tal impurities in the drug product.

Options for Demonstrating Compliance

DRUG PRODUCT ANALYSIS OPTION

The results obtained from the analysis of a typical dosage unit, scaled to a maximum daily dose, are compared to the Daily Dose PDE.

Daily Dose PDE³ measured value (m g/g) × maximum daily dose (g/day)The measured amount of each impurity is NMT the Daily Dose PDE, unless otherwise stated in the individual monograph.

SUMMATION OPTION

Separately, add the amounts of each elemental impurity (in m g/g) present in each of the components of the drug product:

Daily Dose PDE³ [S M

1(C

M

× W

M

)] × D

D

M= each ingredient used to manufacture a dosage unit

C M = element concentration in component (drug substance or excipient) (m g/g)

W

M = weight of component in a dosage unit (g/dosage unit)

D D = number of units in the maximum daily dose (unit/day)

The result of the summation of each impurity is NMT the Daily Dose PDE, unless otherwise stated in the individual mono-graph. Before products can be evaluated using this option, the manufacturer must ensure that additional elemental impurities cannot be inadvertently added through the manufacturing process or via the container–closure system over the shelf life of the product.

INDIVIDUAL COMPONENT OPTION

For drug products with a daily dose of NMT 10g, if all drug substances and excipients in a formulation meet the concentra-tion limits shown in Table 3, then these components may be used in any proportion. No further calculation is necessary. While elemental impurities derived from the manufacturing process or the container–closure system are not specifically provided for in the Individual Component Option, it is expected that the drug product manufacturer will ensure that these sources do not contribute significantly to the total content of elemental impurities.

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DRUG SUBSTANCE AND EXCIPIENTS

products dosed at a maximum daily dose of 10g/day. These values serve as default concentration limits to aid discussions be-tween drug product manufacturers and the suppliers of the components of their drug products. [N OTE—Individual compo-nents may need to be limited at levels different from those in the table depending on monograph-specific mitigating factors.]

8068á232ñ Elemental Impurities—Limits / Chemical Tests First Supplement to USP 40–NF 35

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ANALYTICAL TESTING

If, by process monitoring and supply-chain control, manufacturers can demonstrate compliance, then further testing may Elemental Impurities—Procedures á233ñOTHER TESTS AND ASSAYS

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All radioactive determinations required by this method should be made with a suitable counting assembly over a period of time optimal for the particular counting assembly used. All procedures should be performed in replicate to obtain the greatest accuracy.

USP REFERENCE STANDARD á11ñ

USP Cyanocobalamin RS .

CYANOCOBALAMIN TRACER REAGENT

Dilute an accurately measured volume of a solution of radioactive cyanocobalamin* with water to yield a solution having a radioactivity between 500 and 5000 counts per minute per mL. Add 1 drop of cresol per L of solution prepared, and store in a refrigerator.

Standardization

Prepare a solution of a weighed quantity of USP Cyanocobalamin RS in water to contain 20 to 50 m g per mL. Perform the entire assay on a 10.0-mL portion of this solution, proceeding as directed under Assay Preparation , beginning with “Add water to make a measured volume.”

First Supplement to USP 40–NF 35

Chemical Tests / á371ñ Cobalamin Radiotracer Assay 8069