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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