Pharmaceutical toxicity: AAS and other techniques measure pharma heavy metal

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  • Published: May 15, 2011
  • Author: David Bradley
  • Channels: Atomic
thumbnail image: Pharmaceutical toxicity: AAS and other techniques measure pharma heavy metal

Metallic assessment

Metals and metalloid impurities are an increasing focus for pharmaceutical regulators anticipating high standards of QC/QA for pharmaceuticals with regard to efficacy and patient safety. A review by a team at Bristol-Myers Squibb assesses the various techniques available to the industry. The report offers insights into how these various applications can be used and ultimately how they might address concerns about metal toxicity in raw materials, intermediates, active pharmaceutical ingredients and final drug products.

Writing in the Journal of Pharmaceutical and Biomedical Analysis, Nancy Lewen of Bristol-Myers Squibb Co., in New Brunswick, New Jersey, USA, explains how metal and metalloid analysis has become of increasing importance during the last ten to fifteen years in the pharmaceutical industry. Part of the driving force underlying this increased interest is simply that techniques have come online for quality analysis and regulatory testing that provide "element-specific, accurate and meaningful information related to pharmaceutical products".

However, the authorities armed with these techniques and data from toxicological research, are investigating starting materials and products with the issue of metal contaminants now relatively high on the agenda. Manufacturers of active pharmaceutical ingredients (APIs), raw materials and intermediates have the whole periodic table on which to call in their synthetic procedures, indeed, some APIs contain metals and metalloids by design. These include antimicrobials containing iron, silver and gold, imaging agents using barium, gadolinium, iron, manganese and sodium, lithium drugs for psychotic illness, and platinum-based chemotherapy agents. Moreover, any product or raw materials can come into contact with a wide range of materials during manufacture and processing.


Employing techniques

As such, "analysts have begun to employ the techniques of atomic spectroscopy, such as flame- and graphite-furnace atomic absorption spectroscopy (FAAS, Flame AA or FAA and GFAAS), inductively coupled plasma-atomic emission spectroscopy (ICP-AES) and inductively coupled plasma-mass spectrometry (ICP-MS), to meet their analytical needs," explains Lewen. "Newer techniques, such as laser-induced breakdown spectroscopy (LIBS) and Laser Ablation ICP-MS (LAICP?MS) are also beginning to see wider applications in the analysis of elements in the pharmaceutical industry."

The toxicity of several metallic elements, lead and mercury, have achieved a high degree of infamy and legislation exists in most parts of the world to limit exposure and environmental release. Health limits and tolerable exposures are continuously revised as new evidence emerges regarding the potentially detrimental effects on health of these two elements and others including antimony, arsenic, cadmium, copper, iron, zinc and other metals and metalloids. Other elements have been added to the standard lists of metals of concern and bismuth, boron, germanium, silicon, tellurium, polonium and others are now seen as analytical targets for regulatory assessment of products.

Lewen points out that while the term "heavy metals" has been used colloquially for many years, it has no precise meaning and if the pharmaceutical industry is to agree on what does and what does not constitute an element of concern, a definitive list and analytical tools to test for the members of that list needs to be agreed upon. AAS techniques are particularly powerful and so well suited to elemental analysis. Moreover, given the rapid advances in these and closely related techniques that have pushed down detection limits considerably and increased specificity, there is little excuse on either side now for there not to be a definitive compendium.


Safe limits for heavy metal

It is likely the safe limits on extraneous metals and metalloids in pharmaceutical products will continue to be reduced as new evidence emerges about safe and tolerable levels of a wide range of elements. Atomic spectroscopy techniques that can detect parts per billion levels of such elements will therefore be needed and the demands on their precision and specificity will continue to rise. "The versatility of the various techniques available to the analyst makes it possible to meet the challenges of difficult sample matrices and low limits of detection to address both product safety and product quality issues," concludes Lewen.

 

Metals and metalloid impurities are an increasing focus for pharmaceutical regulators anticipating high standards of QC/QA for pharmaceuticals with regard to efficacy and patient safety. A review by a team at Bristol-Myers Squibb assesses the various techniques available to the industry. The report offers insights into how these various applications can be used and ultimately how they might address concerns about metal toxicity in raw materials, intermediates, active pharmaceutical ingredients and final drug products.

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