BRIEFING

The Permissible Daily Exposure (PDE) limits presented in the proposed new general chapter 232 are consistent with the current early deliberations of the International Congress on Harmonization (ICH) Q3D expert working party on metal impurities. Changes by ICH Q3D to the PDE limits for the elements contained in this chapter will be managed as proposed changes to the chapter via existing USP revision processes, with corresponding changes to the implementation times if the limits decrease. The addition of elements to this chapter based on additions made by ICH Q3D will be managed similarly. However, any elements (and their accompanying PDE) included in the final ICH document that are less toxic than those included in chapter 232 will be incorporated in a future informational general chapter rather than in 232.

The previously published PF 36(1) revision to the General Notices and Requirements pertaining to the Elemental Impurities chapters (section 5.60.30) was deferred from USP 34–NF 29. Any change in the implementation date will be reflected in a General Notices revision. This proposal will be included on the official ballot when chapters 232 and 233 are considered for approval by the Expert Committee.

(GCCA: K. Zaidi.)

INTRODUCTION

Class	Assessment
Class 1	Elements should be essentially absent
	Known or strongly suspected human toxicants
	Environmental hazards
Class 2	Elements should be limited
	Elements with less toxicity than Class 1
	Elements deliberately added to an article

LIMITS OF ELEMENTAL IMPURITIES

Class 1 elemental impurities (Table 2), because of their unacceptable toxicities or deleterious environmental effects, should not be present in a drug substance, excipient, or drug product. However, if their presence is unavoidable, their levels should be restricted as shown in Table 2, unless otherwise stated in the individual monograph.

Class 2 elemental impurities (Table 3) should be limited in drug substances, excipients, and drug products because of their inherent toxicities.

OPTIONS FOR DESCRIBING LIMITS OF ELEMENTAL IMPURITIES

This option is generally applicable. The results obtained from the analysis of a typical dosage unit, scaled to a maximum daily dose, are compared to the Daily Dose PDE, as shown in Table 2 and Table 3.

Daily Dose PDE measured value x (maximum daily dose)

For drug products with a maximum daily dose of NMT 10 g, the product meets the requirements when each drug substance and excipient meets the limits provided in the Component Limit column (Table 2 and Table 3). If all drug substances and excipients in a formulation meet the limits shown in the Component Limit, these components may be used in any proportion. No further calculation is necessary.

This option can be used for drug products that are administered in doses other than 10 g/day or products in which any component of a product exceeds the applicable Component Limit. The Daily Dose PDE, as shown in Table 2 and Table 3, can be used to calculate the concentration of elemental impurities allowed in a drug product. Apply this option by separately adding the amounts of each elemental impurity (in µg/day) present in each of the components of the drug product, using the following equation:

Result = S1m(CM × WM)

The sum of the quantities of each element/day should be less than that shown by the Daily Dose PDE in Table 2 and Table 3 for that element.

Consider an example of the application of the Individual Component Option and the Summation Option to the arsenic concentration in a drug product. The Daily Dose PDE is 15 µg/day, and the Component Limit is 1.5 µg/g (ppm). The maximum administered daily weight of a drug product is 5.0 g, and the drug product contains two excipients. The composition of the drug product and the calculated maximum content of arsenic are shown in Table 4.
Excipient 2 and the drug substance do not meet the Component Limit, but Excipient 1 does. Thus, the Individual Component Option cannot be used. However, under the Summation Option, the drug product meets the Daily Dose PDE limit of 15 µg/day and thus conforms to the acceptance criteria in this chapter.
Consider another example where the maximum administered daily weight of a drug product is 5.0 g, and the drug product contains two excipients. The composition of the drug product and the calculated maximum content of arsenic are shown in Table 5.
In this example, the drug product exceeds the limits in Table 2, using both the Individual Component Option and the Summation Option. The manufacturer can test the drug product by using the Drug Product Analysis Option. If the level of arsenic in the formulation exceeds the Daily Dose PDE, the product fails to meet the impurity limits as described in this chapter.

Because of the presumption of 100% bioavailability of the elemental impurity during parenteral administration, versus the presumed 10% bioavailability via the oral route, the Parenteral Component Limit and the Parenteral Daily Dose PDE (Table 2 and Table 3) are 10% of those for the oral route of introduction. To evaluate the limits for elemental impurities, one can apply the three options described above, using the Parenteral Component Limit instead of the Component Limit, and using the Parenteral Daily Dose PDE instead of the Oral Daily Dose PDE.

ANALYTICAL PROCEDURES

Introduction

Speciation

Routes of Exposure

DRUG PRODUCTS

DRUG SUBSTANCE AND EXCIPIENTS

ANALYTICAL TESTING