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SEPARATIONS AND PURIFICATIONS
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Enhancing Efficiency of Trace Metals Analysis using a Validated Generic
ICP-OES Method
Ila Patel, C.J. Venkatramani, Colin D. Medley, Kavita Mistry, Larry Wigman, and Nik Chetwyn
Genentech, Inc. Small Molecule Pharmaceutical Sciences Small Molecule Analytical Chemistry and Quality Control
Abstract
Catalysts are commonly used in the pharmaceutical industry for the synthesis of active pharmaceutical ingredient (APIs).
Effective
removal of catalysts and trace metals is critical in ensuring patient safety. Regulatory agencies around the world mandate that the pharmaceutical industry must monitor and limit the levels of trace metals in pharmaceutical products. Trace metals are often analyzed using spectroscopic techniques such as inductively coupled plasma (ICP) spectroscopy. Developing and validating analytical methods for APIs is often time-consuming. While outsourcing is an option, it is expensive and requires the oversight of contract labs to ensure data quality.
The objective of this study is to enhance the efficiency of
trace metal analysis by developing a platform technology to address multiple project needs. Universal methods reduce the time and cost associated with method development and validation specifically for every individual project. This paper outlines the validation strategies on aqueous matrices. A generic ICP method was successfully developed and validated for 9 elements commonly used in API synthesis: nickel, copper, zinc, iron, magnesium, tin, palladium, platinum, and ruthenium. This study has significant bearing on other industries as well as the pharmaceutical industry.
Introduction
Submitted: 12/12/2014 Accepted for Publication: 02/10/2015
Patel I, Venkatramani CJ, Medley CD, Mistry K, Wigman L, Chetwyn N. Enhancing Efficiency of Trace Metals Analysis using a Validated Generic ICP-OES Method. Am Pharm Rev. 2015;18(1):36-43.
The presence of residual metallic impurities is an issue of increasing importance and concern to regulatory agencies around the word to ensure patients’ safety. Several common metals such as cadmium, lead, mercury, and arsenic are known to impact human health negatively, and agencies have set strict exposure limits to minimize exposure to humans.1,2
In addition, toxicological data have also led regulatory
agencies to limit the exposure levels of other metallic impurities used in active pharmaceutical ingredient (API) manufacturing. Metal- catalyzed reactions are standard practice in the modern-day API manufacturing industry. Metals are extensively used in cross-coupling reactions including palladium-catalyzed Suzuki reactions and copper- catalyzed azide-alkyne cycloadditions to enable C–C bond formation under mild conditions. Metallic impurities could originate from multiple sources including catalysts; raw materials; glassware; reactors; and equipment used in the storage and handling of starting materials, intermediates, and reagents at different stages of API synthesis.
The detection of residual metals in APIs has evolved considerably in the past century since USP <231> was first issued.
The USP
colorimetric method for heavy metals is sensitive for few metals of concern. However, this method lacks sensitivity and specificity for
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