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As of January 1, 2018, both generic and branded drug products must meet the industry guidance published by the US Food and Drug Administration (FDA) regarding elemental impurities.

The permitted daily exposure (PDE) limits, along with procedures for the screening and quantification of potentially toxic metal impurities, have been defined in the United States Pharmacopeia (USP) <232> and <233> chapters, as well as in the International Council for Harmonization (ICH) Q3D guidelines for elemental impurities testing in drug products.

Heavy metal impurities present serious risks to the health of patients and furthermore, provide no therapeutic benefits. Time-to-market can be delayed if biopharmaceutical products are non-compliant with regulations, including the requirements set within USP <232> and <233>. In the second installment of this two-part series of articles, the most frequently asked technical questions on the subject of elemental impurities testing are answered.

Does a method need to be developed for elemental impurities, or can a standard method be run for USP <232>/<233> metals testing?

To account for the variations in drug product matrices, analytical method development is needed. Method development activities include the determination of the metal extraction method, concentration for sensitivity, and verification of suitability for target metals and matrices, resulting in an analytical method tailored to the specific drug product, that will produce the most accurate results. ºÚÁϲ»´òìÈ’s scientists can perform “screens” for metals using semi-quantitative methods. To find out more, get in touch with an expert.

Is method validation required for USP <232> and <233>?

Generally, method validation is performed if metals are found to be close enough to the USP/ICH level causing concern. Methods are validated in accordance with USP <232>/<233> for accuracy, precision, specificity, limit of quantitation, range and linearity.

Can multiple metals be analyzed in the same run or by the same method?

Yes. ºÚÁϲ»´òìÈ’s scientists can quantify up to 64 metals in a single run with the correct setup and correction factors. However, we typically analyze anywhere from 7 to 24 metals based on the specific needs of our clients.

What if just sample analysis services are needed, as a method has been previously developed and validated?

By design, ºÚÁϲ»´òìÈ’s process allows for additional samples to be analyzed in the future, using previously validated procedures.

How are acceptable limits determined for each metal in a finished drug product?

The metal limits are calculated based on the maximum daily dosage (MDD) and the permitted daily exposure (PDE) based on the route of administration. Metals levels have been harmonized across USP and ICH organizations. ºÚÁϲ»´òìÈ’s regulatory and scientific experts can assist in establishing and justifying limits for novel, or unestablished, routes of administration.

Which metals are typically found above the USP/ICH limits for elemental impurities?

In the past, we have found both Ni (nickel) and Cu (copper) above the USP/ICH limits. Commonly, contaminants present from either the raw materials or the manufacturing process can severely impact the quality of the finished product. In these instances, ºÚÁϲ»´òìÈ can assist in determining sources of contamination.

If one or more metals exceed limits or fails during USP <232>/<233> testing, how can ºÚÁϲ»´òìÈ help?

ºÚÁϲ»´òìÈ has expertise in other areas of pharmaceutical analysis and Chemistry, Manufacturing, and Controls (CMC) testing. Our consultative teams of knowledgeable scientists can help identify sources of contamination, including with extractables and leachables studies per USP <1663>/<1664>. As part of a standard E&L study, we will look for extractable metals which may be contaminating the drug product resulting from contact with manufacturing line components, as well as the final container-closure system.