Modernization of the Standards for Elemental Impurities - Pharmaceutical Technology

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Modernization of the Standards for Elemental Impurities
Recent activity in standards-setting organizations has raised interest in the impact of testing for impurities that may enter the product before it is mined or harvested or even due to intentional use of some reagents.


Pharmaceutical Technology
Volume 37, Issue 2

The blind spot and proactive change

Concerns about increasing separation of suppliers from manufacturers have resulted in an increased need for and greater reliance on testing standards. Ambiguous testing standards have resulted in poor quality products that have repeatedly resulted in harm to patients. Consider that glycerin was used in manufacture of oral liquid preparations for decades while the standard was not capable of distinguishing the safe glycerin from the deadly diethylene glycol (DEG). Multiple incidents throughout the world resulted in scores of deaths until a more precise standard was implemented. These incidents led to an improvement of the standard to provide a test procedure to assess the DEG level in glycerin and demonstrate its absence. Consider also that the standard for heparin was not capable of distinguishing heparin from a contaminant, over-sulfated condroiton sulfate. The poor quality product was unrecognized until a contamination disaster resulted in deaths to multiple patients. Based on these tragedies, the standard was revised to monitor for this adulterant in the product. Considering the weaknesses of the current standard procedures for elemental impurities and potential disasters demonstrated by these examples, it is easy to conclude that there is a blind spot in the heavy metals standard that needs to be addressed to ensure that the obligation of regulators and manufacturers to protect public health is met. The test procedures in the current standard are not capable of demonstrating dangerous levels of contamination. There is wide agreement from industry, government, trade associations, and standards-setting organizations that a lack of proper tests can no longer be tolerated. The ever-increasing complexity of the supply chain makes it imperative that we revise these standards.

Inductively coupled plasma

Technologies capable of quantifying the amounts of a wide range of elements from a single sample preparation at concentrations near the extinction of toxicological effects have existed in environmental and academic laboratories for more than 30 years. These technologies could be prohibitively expensive, with variable results, and require very specific analyst skill sets, thus leading to uses best suited for a research environment. The capabilities of the technologies have expanded over the years, however, and the costs associated with the technologies have been reduced to the point that these technologies are now revolutionizing the way that we think about the risks associated with elemental impurities. For more than a decade, it has been feasible to consider the risks associated with contamination levels that are commensurate with the levels where toxicological effects emerge. The need to tolerate the weaknesses present in the sulfide test has ended (2, 4-5).

The most effective technology for the screening of materials for low levels of contamination from a wide range of elements is inductively coupled plasma (ICP). This technology has been adopted globally for metals testing across most industries that are concerned with metal content. The elements in the plasma produced by this technology are typically detected and quantified by either optical emission spectroscopy (OES) or mass spectrometry (MS). Multiple organizations in the world, including pharmaceutical manufacturers and excipient producers, have moved to ICP as the preferred analytical procedure for measurement and subsequent control of elemental impurities.

History of the emerging European standards

Taking advantage of the new ICP ability to unequivocally measure metal-specific contamination, the European Medicines Agency (EMA) Committee on Medicines for Human Use (CHMP) released its first draft of the Guideline on the Specification Limits for Residues of Metal Catalysis or Metal Reagents in 2001 (6). After several years of consultation, the final document was adopted by EMA in January 2008, with an effective date of September 2008. It applies to new and existing marketed drug products, with a five-year transition period for implementation of the guideline for existing drug products. The EMA guideline will apply to all drug products marketed in Europe in September 2013.

During the 142nd session of the European Pharmacopoeia Commission (EP) (Apr. 3-4, 2012, Strasbourg, France), the EP adopted the general chapters on metal catalysts or metal reagents residues (5.20) and one method for the determination of metal catalysts or metal reagent residues (2.4.20). Chapter 5.20 is a reproduction of the EMA guideline on the specification limits for residues of metal catalysts or metal reagents. The methodology described in general method 2.4.20 describes the general approach for the determination of metal catalysts or metal reagent residues in substances for pharmaceutical use and is to be applied wherever possible. The general chapters will be published in Supplement 7.7 of the European Pharmacopoeia and implemented on April 1 2013.


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