Modernization of the Standards for Elemental Impurities

Heavy metals have been a concern to society for more than a century. The term "heavy metals" has been useful to describe contamination from a number of different sources. These impurities may be part of the surrounding environment or may be introduced during the processing and delivery of liquids, food, medicines, or even the air. Heavy metals exposure can cause wide-ranging health effects, and standards should be available to prevent these effects. Testing of the environment and consumables has become a routine way to estimate these risks (1). The magnitude of acceptable risks from being exposed to impurities, in general, has become smaller over time as the serious impacts of the toxic effects are more accurately measured. For example, 100 years ago, the capability of a simple colorimetric (sulfide precipitation) test was considered to be an adequate way to estimate the risk associated with the most toxic and common sources of heavy metals. In fact the term, heavy metals, is more closely associated with the name of the test than it is an indicator of the contamination itself. Because the spectrum of contaminants that can be indicated by the test is greater than just the "heavy metals" and greater even than "metals," the term is really about how much color is produced and not so much about what is causing the positive indication.

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The heavy-metals analysis test enables testing for gross contamination of any consumable sample that can be prepared, so that the contaminants that react with the sulfide source create a black precipitate. The intensity of the precipitate can be compared to a Lead standard to provide a general idea of how contaminated the sample may be. The chemistry of this method proved reliable enough to support testing standards used throughout the world for many decades. This procedure was successful in spite of two weaknesses: the chemistry behind these standards cannot identify the metal causing the color change and toxic levels of many elements can remain undetected by the method. The visual comparison nature of the sulfide method makes it, at best, a semi-quantitative method for lead determination and, at worst, unable to detect potentially toxic levels of some elements.

In spite of these inherent weaknesses, efforts to improve the sulfide test were ignored for many decades. As evidence of the health effects of low levels of some metal contaminants increased, efforts to better understand the level of contamination were requested. One such call was voiced in 1995 (2), leading to a concerted effort to improve this test. Ten years later, the methods were revised to include standardized "monitor solutions" designed to provide assurance that the sulfide test was working (i.e., assuring the test was revealing actual metal contamination) (3). Further attempts at improvement of the sulfide procedure were abandoned to focus efforts on newer, more capable technologies.

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 142^nd 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.

History of the emerging USP standard

The United States Pharmacopeial Convention (USP) published two chapters in the Second Supplement to USP 35-NF 30 that are proposed to apply to USP articles in May 2014. The need for an upgrade of the USP Heavy Metals General Chapter <231> was first brought forward in 1995 in a stimulus article in USP's Pharmacopeial Forum (2), and again in 2000 with a stimulus article arguing for industry use of ICP-MS technology for this purpose (4). In its 2005-2010 cycle, USP decided to replace General Chapter <231> with a general chapter that actually did what General Chapter <231> purports to do but is incapable of doing adequately (i.e., identify and quantify elemental impurities in articles of commerce at levels that could be used to assess the safety of the elements observed).

The process began in earnest with a broadly advertised workshop organized by the Institute of Medicine (IOM) at USP's request. IOM staff brought together toxicology and analytical experts and key stakeholders including pharmaceutical manufacturers and excipient producers from around the world to discuss elements to be measured and to discuss the process for establishing permissible daily exposures (PDE). The key output from this meeting was the conclusion that the possibility of contamination from four environmental contaminants (mercury, lead, cadmium, and arsenic) needed to be evaluated for all drug products.

USP built on the IOM workshop by establishing an Expert Panel reporting to the General Chapters Expert Committee to develop general chapters that established a list of toxic elements, their permissible daily exposures (PDE) associated with the appropriate dosage form, and procedures capable of quantifying each element in the matrix of interest (excipient, drug substance or drug product). The IOM workshop, USP Heavy Metals Testing Methodologies held Aug. 26–27, 2008, was a closed discussion limited to invited attendees. Those attendees were chosen by the IOM for the ability to provide credible, expert information. A summary can be found at www.usp.org/usp-nf/key-issues/elemental-impurities.

Because USP needed to provide a forum for the US industry to learn about the findings of the IOM, it held a follow-up workshop (Workshop on Metals in Pharmaceuticals and Dietary Supplements, Rockville, MD, Apr. 28-29, 2009), which was open to all interested parties, at the USP headquarters in Rockville, Maryland. This workshop allowed the newly formed expert panel to interact with stakeholders and incorporate their feedback into the developing standard. At the conclusion of the workshop, the panel met to consider all of the feedback and plan draft chapters. USP published two stimuli articles, one describing the rationale behind the elements, limits, and methodologies chosen for inclusion in the chapters and the other describing the issues received, when the initial draft chapters were published, and the rationale for how each was addressed. These chapters were published by USP in January 2010 (7).

To support the proposed standard, USP has organized more than 40 teaching/listening opportunities through the Pharmacopeial Education organization of USP. Organized throughout the US and in 15 different countries, these sessions ranged from one hour to one day, depending upon the needs of the audience and the venue. The sessions were lead by senior staff and volunteers to ensure that all of the feedback led directly to the evolving standard. Of course, the training has evolved to reflect the standard and continues to be available for interested parties.

ICH history

In October 2009, ICH endorsed the development of a new "Elemental Impurities Q3D" guideline to provide clarification of the requirements for metals (8). A harmonized list of metals and limit criteria based on permissible daily exposure is expected to emerge from this negotiation. Q3D intentionally used the EMA guideline, the USP stimulus article, and USP Draft General Chapter <232> as starting points for the development of a global standard with the understanding that existing regional efforts and timelines would proceed. The intent from the beginning was to proceed with regional modernization of the standard followed by harmonization to the eventual ICH limits. The ICH steering committee, understanding the magnitude of this standard, supported the Q3D EWG by allowing the participation of stakeholders, such as the standards setting organizations USP, EP, and Japanese Pharmacopoeia (JP), as well as additional trade organizations, such as the International Pharmaceutical Excipients Council (IPEC). This participation is to assure that any differences in regional implementation and expectations are minimized, thus easing the standards modernization and harmonization processes. Like other ICH guideline documents, Q3D will move through a series of consultation periods and will ultimately move into the regional implementation phase. This final phase involves the official adoption of the guideline into the regulations of the three regions. This regional implementation allows the regulator to adjust the ICH text to fit the legal landscape and other logistics of their home region.

Another point to consider is that all the parties involved in modernization of this standard have pledged not to allow any inconsistencies to persist in the standards. That does not mean an entire absence of any differences because some may result from either regional regulatory requirements or areas left unresolved by the ICH process.

Detailed situations

The ultimate goal of this standard procedure modernization is the protection of the consumer from potentially harmful levels of toxic, elemental impurities in drug products. The manufacturers are the most responsible parties for drug-product quality, and only by working with them on implementation of new test procedures can patient safety be assured. Part of that work is to discuss various concerns and how they might be alleviated.

The improved capabilities of the new ICP–MS standard have created some anxiety in parts of the industry. There is a growing sense that where there were previously no functional controls, there may now be numerous standards, each requiring a different compliance standard. First, the pledge to harmonize the elemental impurities standards and their limits where and when conflicts are identified should provide some comfort. While it may appear that all these efforts are independent, in fact, they are all relying on the same safety data to derive their limits. All parties involved are in the same room in the harmonization discussion. Differences in scope are mostly due to the regulatory structures in various regions. Second, efforts to survey the industry through laboratory testing has revealed nothing alarming, either in excipients or in the range of drug products tested to date (9). These preliminary studies indicate that the tested products will meet the new standard. This survey goes on as time and resources allow. In spite of this, it is understandable that a change of this magnitude causes consternation amongst those who must implement the change. All parties involved are working together in concert to address not only harmonization but implementation as well.

Some concerns persist that this new standard will somehow create a drug shortage when there is no actual risk from elemental impurity exposure. For example, some component may have a contamination level that is above the criteria and yet is used in low levels or in low frequencies so that the risk is minimal compared to the benefit of the product. Consider that all the regulatory agencies involved in modernizing this standard are capable of risk-benefit balancing and part of that is the survey of products and components previously mentioned. In addition, if there is a known situation, the supplier should be in contact with the product manufacturer. The product manufacturer then works with the regulatory authority to develop considerations that might be made to assure continued drug supply. Unless there is a risk to the patient, the drug will remain available through whatever provision is most pragmatic at the time. There are procedures in place to keep standards revisions from needlessly making a product out of compliance that was previously compliant. Industry, the regulators, and pharmacopoeias understand the serious implications of drug shortages, especially those created by activity such as standards modernization and not related to a change in product quality (10). Consideration for a product can also be made at the level of the standards organization. In the USP-NF, a special consideration for a product is generally made within the monograph itself. The USP is structured such that the monograph standard for a particular material or article supersedes that of the general chapter where the metals limits appear. It is in these monographs where the materials that need special handling are considered. If needed, the regulatory authorities should be asked to provide timely risk-assessment guidance for industry that can help alleviate industry anxiety.

There are differences between the standards and how they are implemented around the world. These differences go beyond harmonization at ICH and into the framework of regional regulations. For example, there are differences between the European and USP compendial standards implementation. The European standards tend to be tests and limits that are applied directly to the components of a drug product; however, the USP standard is applied to the drug product itself and not directly to the components. Although USP provides the option for the product manufacturer to demonstrate compliance through testing and summing up the components, the limit criteria apply directly to the drug product. The USP requirement for components is to know the elemental content and be able to report it. In order to limit or even eliminate the potential for redundant retesting, there will be a need for communication between the component manufacturers and the product manufacturers. IPEC has developed a standardized form that may help create a predictable format for communicating this information to the product manufacturers (11).

Some raw material suppliers and drug product manufacturers have expressed concern that obtaining equipment and expertise for testing every batch of material is excessively expensive. It may help to explain that testing every batch according to the standard procedures is not a requirement. This subtle point regarding USP standards is often lost in these discussions (i.e., the USP is a compliance standard and not a testing requirement). USP states that the material (article) must comply with the standard when tested, and that is up to the individual purporting that it complies to come up with a plan for how that is done. Consider also that USP relies on FDA to enforce its standards. While FDA has yet to produce any specific statement regarding these chapters, it is common for FDA to allow alternative testing procedures for routine batch-by-batch testing. There is no need for acquiring enough equipment and expertise for testing every batch by the standard procedure. It should be enough to have staff and instruments only for the validation and occasional verification that the alternate procedure is working.

Summary

Modernization of the heavy-metals standard has been a long time in development and involves experts from all over the world. The improvements include being able to identify the contaminant and being able to measure it at levels where toxic impacts occur. The new term for this standard has changed from "Heavy Metals" to "Elemental Impurities" to reflect these improvements.

Harmonization efforts are proceeding through normal channels at ICH and the parties are agreed to standardize limit criteria whenever the same metals are involved. The normal process of harmonizing existing regional standards is being used.

Jon E. Clark is the Associate Director for Program Policy in the FDA Office of Pharmaceutical Science. He is a founding member of the ICH Expert Working Group on Elemental Impurities (Q3D) and has been a member of multiple ICH working groups, Jon.Clark@fda.hhs.gov. John S. Punzi, PhD, is Director, Quality Assurance & Technical Affairs at CHPA.

References

1. D. Abernathey et al., Pharm. Research, 27 (5) 750-755 (May 2010).

2. K. Blake, Pharmacopeial Forum 21 (6) 1632-1637 (Nov.-Dec. 1995).

3. USP, USP-NF 1S to USP 28 (2005).

4. Wang et al., Pharmacopeial Forum 29 (4) 1328-1336 (July-August 2003).

5. N. Lewen et al., J. Pharm and Biomed Analysis 35 739-752 (2004).

6. EMA, Guideline On The Specification Limits For Residues Of Metal Catalysts Or Metal Reagents (London, Feb. 21 2008), www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003586.pdf, accessed Jan. 16, 2013.

7. USP, Pharmacopeial Forum 36 (1).

8. ICH, Quality Guidelines, www.ich.org/products/guidelines/quality/article/quality-guidelines.html, accessed Jan. 16, 2013.

9. J.F. Kauffman, Reg. Toxicol. and Pharmacol. 48 (2) 28–134 (2007).

10. FDA, Drug Shortages, www.fda.gov/Drugs/DrugSafety/DrugShortages/default.htm, accessed Jan. 9, 2013.

11. IPEC, ICH Q3D Information Exchange Request, http://ipecamericas.org/content/ich-q3d-information-exchange-request, accessed Jan. 9, 2013.