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The US Pharmacopeia's revised General Chapters on elemental impurity limits and testing procedures are set to take effect in December 2012.
An industry coalition has emerged in response to the new USP requirements. The authors are a subgroup of the Coalition for the Rational Implementation of the USP Elemental Impurities Requirements, and herein, state their position on USP’s new chapters and the pending harmonization of heavy metal limits and procedures across the bio/pharmaceutical industry.
Background: Compendial and regulatory changes affecting elemental impurity limits in pharmaceuticals
As has been reported previously in Pharmaceutical Technology, the United States Pharmacopeial Convention (USP) has published changes to control the levels of elemental impurities in bio/pharmaceutical drugs, scheduled to become official on Dec. 1, 2012, with an implementation date of May 1, 2014 (1). Specifically, these changes are included in two new USP General Chapters: <232> Elemental Impurities—Limits, and <233> Elemental Impurities—Procedures (2, 3). These chapters will replace USP General Chapter <231> Heavy Metals (4). Because USP requirements apply to all products in the marketplace through USP–National Formulary (NF) monographs, the changes will have a significant impact on pharmaceutical manufacturers, ingredient suppliers, and others involved in the supply chain. Determining exactly how to implement these requirements, through a combination of analytical testing and risk assessment, is already consuming a good deal of effort and resources in the industry.
In addition to USP's activities, the International Conference on Harmonization (ICH) is working on a new guideline on metal impurities, ICH Q3D, to complement existing harmonized guidelines on organic impurities (ICH Q3A and Q3B) and residual solvents (ICH Q3C) (5). There is broad industry support for development of this guideline—indeed, the initial proposal to establish the ICH Q3D working party was made by industry (specifically the Pharmaceutical Research and Manufacturers Association of America [PhRMA] and the European Federation of Pharmaceutical Industries and Associations [EFPIA]).
The ICH effort is especially valuable because it will ensure that consistent requirements will be applied by regulatory agencies throughout the affected regions: Europe, Japan, and the United States. However, the ICH metal impurities guideline is in an early stage of development and the working group is still gathering feedback from affected parties. An initial draft of the ICH Q3D pre-step 2 document has been circulated for comments. The approved guideline will not be available before 2014.
Of note, the European Medicines Agency (EMA) also has a guideline pending, Specification Limits for Residues of Metal Catalysts or Metal Reagents, which becomes effective for all pharmaceutical ingredients in September 2013. The EMA guideline, focused on metals deliberately used in manufacturing, has strongly influenced related USP and ICH efforts.
Meanwhile, USP has maintained its intention to make its requirements for the new General Chapters effective May 1, 2014. USP originally planned to make implementation effective September 2013, but based on feedback from the industry, the organization delayed it until May 2014 (6). This delay does not impact the real issue, which is the disconnect between USP and ICH. There is a real concern among many in the industry that USP requirements will differ significantly from those that will eventually be applied with the finalization of ICH Q3D.
The International Pharmaceutical Excipients Council of the Americas (IPEC–Americas) is leading an industry coalition* to address these issues (see section on "Coalition Activities" below).
USP staff has stated in industry forums that it will make every effort to ensure that USP's requirements align with those of ICH, and it has already updated acceptance criteria for various metals to agree with the initial draft from ICH (6). However, until the final ICH guideline is approved, it is the authors' view that USP cannot accurately predict its contents.
As a result, manufacturers will have to implement USP's elemental impurities requirements, which call for new analytical procedures, specifications and specification limits, and then later revise practices to meet the later, finalized ICH upon acceptance and publication by FDA, EMA and other regulatory agencies. The potential impact that this will have on the industry is described in detail later in this article.
It is important to note that it is not the intent of either the coalition or the authors to express any concerns with the ICH or EMA implementation strategies or timelines, but rather to voice concerns for both the strategy and implementation timelines communicated by USP. The primary objective of this article is to present a case for harmonization of requirements in USP with those in the upcoming ICH guideline, and to encourage USP to act responsibly in its implementation plans to ensure the safety of patients without causing unnecessary expense, confusion, and potential drug shortages.
History of elemental impurities
The starting point for USP's new elemental impurities chapters were challenges to the accuracy and recovery of the existing pharmacopeial methods for heavy metals. USP General Chapter <231> Heavy Metals provides three methods, all based on the precipitation of metal ions by a sulfide reagent (4). In 1995, a report was published in the USP Pharmacopeial Forum showing very poor recovery from Method 2, which uses an ignition technique for sample preparation in some excipients (7). Follow-up articles in the literature investigating these tests concluded that the methods were poorly suited for effective quantification of the level of metal impurities, due to lack of specificity as well as poor recovery (8).
Over several years, USP made efforts to improve the existing sulfide precipitation methods. USP 28–NF 23 Supplement 1, effective April 1, 2005, for example, added monitor solutions to check the recovery and require rejection of results if the standard was not met. These approaches did not work well and were withdrawn in USP 30–NF 25, effective May 1, 2007.
The European Pharmacopoeia (Ph.Eur.) also made attempts to improve the existing methods, but with greater success. Using a technique of standard addition, the performance of the method was confirmed with greater confidence. In addition, Ph. Eur. developed several new methods, including methods F–H in EP 7.5, Chapter 2.4.8 Heavy Metals using organic solvents to dissolve samples, and detection using filter papers to concentrate precipitate for better visualization (9). Current Ph.Eur. policy is not to accept new monograph submissions using the ignition method because there are concerns over the robustness of the test.
When USP reached its final conclusions on replacements for the heavy metals tests, the sulfide precipitation test was abandoned in favor of modern techniques, most specifically inductively coupled plasma (ICP), which are now included in the new USP General Chapter <233>.
This change further complicated the new limits to be adopted, because it is virtually impossible to correlate the current limits based on sulfide precipitation of several metals with limits for specific metals detected by newer technology, such as ICP. The USP expert panel working on the chapter revisions resolved this disconnect between the current limits and the new methodology by developing new limits for the specific metal impurities based on toxicology considerations.
It is important to realize that the USP's terminology switch from "Heavy Metals" to "Elemental Impurities" was prompted by analytical issues (10, 11) as described above. Although the new methodology proposed in USP represents a significant advance from an analytical standpoint, the driver is not, and has never been, a clearly identified risk to patients in current pharmaceutical products.
Implementation plans and timelines
The plan being pursued by USP to update its elemental impurities limits and procedures represents years of consideration and discussion. Although the industry in general supports the goals of improving test methodology and providing an extra measure of assurance of product safety, as seen in the USP "Commentary–Second Supplement to USP 35–NF 30" (12) for proposed General Chapter <232> where of the 39 comments submitted, USP chose to only incorporate five of them, there is widespread concern that USP has not adequately considered the impact of its implementation plan. USP stakeholders have been vocal in citing the potential that currently approved, and safe, drug products may be pushed out of compliance or forced to reformulate, and that drug shortages may result. There is also concern that a substantial increase in routine testing, without a commensurate increase in product quality or safety, will result unless manufacturers and suppliers are provided with adequate options for using risk assessment. (Risk assessment is expected to be a major topic in the ICH Q3D guideline.)
Although the current test requirements in USP General Chapter <231> Heavy Metals require improvement, industry believes that an effective public standard should focus more on improving control rather than simply adding routine tests. Testing may be used to confirm appropriate controls, but knowledge of material sources, supply chains, and processes—while applying the tool of risk assessment—should be the basis of control to ensure patient safety.
Because of the wide use of the heavy metals test by sulfide precipitation, for example, simple replacement with ICP for multiple metals would represent a huge increase in test load and expense. From the beginning of USP's project, many members of the industry have anticipated that much of the existing, unnecessary testing of heavy metals could be eliminated. The use of quality by design (QbD) and risk-based analysis should allow manufacturers to qualify materials and the supply chain in order to remove testing which does not add value.
The primary driver for USP's implementation timelines of the new chapters seems to be to replace older methods with more modern methodology; however, this methodological problem is not believed by the coalition to reflect a deeper issue of unsafe products reaching consumers. A recent paper by FDA representatives surveyed 45 pharmaceutical products to determine lead concentrations by ICP and found lead concentrations far below currently acceptable levels (13).
As noted, in addition to USP's changes, both ICH and EMA are drafting plans for the bio/pharmaceutical industry to develop methods and establish compliance limits to meet defined metal impurity specification limits for drug products and drug product components. It is the industry's hope that these various organizations would work to harmonize with the ICH Q3D guidelines; however, there currently appears to be significant differences in what and when materials will be required to comply. It should also be noted that until the Ph. Eur. and Japanese Pharmacopeia are updated to reflect the new ICH Q3D guideline, the older tests for heavy metals within those pharmacopeias will still be required. Any benefits of test reduction will not be gained until the ICH Q3D guideline is fully implemented and the compendia are harmonized.
Affected products. As shown in Table I, USP implementation plans have been defined differently in the new USP chapter <232> Elemental Impurities—Limits than those found in the preliminary pre-step ICH Q3D guideline. The differences in scope between USP and ICH create serious implementation difficulties for industry. The new USP chapters <232> and <233> encompass all products, new and existing, which presents industry with an impractical compliance task by the May 2014 date. The greater number of elements in the ICH scope forebodes either a doubling of implementation efforts to achieve compliance by the USP timeline for all 27 elements, or the prospect of duplicating implementation efforts to include elements not covered by USP once the ICH guideline is completed.
Table I: Comparison of USP and ICH implementation plans for elemental impurities.
Implementation timelines. As noted, the ICH Q3D working group is at the pre-step 2 (of 5) stage of development for its guideline on metal impurities and plans to finalize the document by mid-2014. USP has already published its two new elemental impurities chapters in the second supplement to USP 35–NF 30, which becomes official Dec. 1, 2012. In addition, USP is planning to implement the new tests and specifications contained in the new General Chapters through General Notices, with a planned implementation date of May 1, 2014. Finally, all references to USP General Chapter <231> Heavy Metals are scheduled to be removed from the monographs in USP 37–NF 32.
Full implementation of the new USP chapters would therefore be required before the ICH Q3D guideline is complete, which as noted is likely to result in duplicative efforts among the industry.
Test adoption. The use of tools such as that illustrated in Figure 1 have highlighted just how difficult it is to estimate the resources and time needed to change elemental impurities limits in final product, regardless of whether one is considering USP or ICH methods. This complexity is a consequence of the large number of unknowns that require consideration. Pharmaceutical excipients and APIs have never been routinely tested for the specific metals proposed by USP and ICH Q3D. The nonspecific limit test has been the standard for many years. It is the coalition's view that it will take industry a long time to compile enough data to understand the levels of these specific metals actually present and then implement appropriate testing and/or controls.
Figure 1: USP implementation limits for elemental impurities, based on USP . Adjusted duration is in weeks.
A key factor in the USP implementation timeline is that some suppliers may not be aware of these pending requirements, and many do not have sufficient information or data on levels of metal impurities in their products. IPEC–Americas has developed an Information Exchange Request Form (available online at http://ipecamericas.org/content/ich-q3d-information-exchange-request) designed to initiate an exchange of information between drug product manufacturers and suppliers of the ingredients used in those formulations to bring awareness to the proposed ICH Q3D guideline and to gain a better understanding of the potential metal impurities, and their normal variation in the ingredients used in those drug formulations.
Whereas a few companies may already have well-established laboratories fully equipped with appropriate analytical instruments (e.g., ICP–mass spectrometry [MS]) and procedures developed for sample preparation and analysis, many excipient manufacturers and some drug companies currently do not. As a result, some companies may require more than 18 months to fully implement testing for a few drug products, and the time required would be much greater if they have a large number of products involved.
Additional concerns. As companies begin to work through the process of completing their impact assessments, installing and validating equipment, developing, validating and transferring methods, generating and assessing data, and documenting results/establishing limits, it is expected that there are other potential issues which may arise. For example:
The role of GMPs, QbD, and risk analysis in metals testing
FDA regulations state that pharmaceutical manufacturers are ultimately responsible for the quality of the products they produce and sell and the level of quality achieved by these manufacturers is based on implementation of GMPs. According to the USP 31 General Notices,
"While one of the primary objectives of the Pharmacopeia is to assure the user of official articles of their identity, strength, quality, and purity, it is manifestly impossible to include in each monograph a test for every impurity, contaminant, or adulterant that might be present, including microbial contamination. These may arise from a change in the source of material or from a change in the processing, or may be introduced from extraneous sources. Tests suitable for detecting such occurrences, the presence of which is inconsistent with applicable good manufacturing practice or good pharmaceutical practice, should be employed in addition to the tests provided in the individual monograph" (14).
Control is clearly needed when a metal catalyst is used in manufacturing. The manufacturer determines which metal is used as a catalyst, designs a process to control it, and performs testing to confirm control. However, the proposed applications of elemental metals testing in the new USP chapter <232> includes the concern for unexpected contamination, where there is no particular metal suspected of being present. Because contamination is often erratic and may vary within the batch, merely testing a sample does not assure control. Through the application of GMPs, especially the control of supply chains and supplier assessment/audits, along with appropriate process knowledge and controls, a manufacturer can determine that the risk of contamination is insignificant and that testing is unnecessary.
Frequent references to instances of contamination need to be looked at more critically. One example of significant metals contamination, attributed to lack of supply chain controls in China, involved chromium contamination in gelatin capsules.
Risk assessment. One challenge likely to arise with respect to ICH Q3D and USP General Chapters <232> and <233> is defining the scope of any product risk assessment. As it presently stands, <232> offers little in the way of guidance, simply stating that such an assessment should address elemental impurities including catalysts and environmental contaminants. Chapter <232> does place a specific emphasis on arsenic, cadmium, lead, and mercury due to their apparent ubiquitous nature (2). As to whether this is a valid concern is contestable; it is certainly somewhat at odds with the principles of a truly risk-based approach.
For a drug product, there are a number of potential sources of metals. These include raw materials used in synthesis of the drug substance (e.g., starting materials, catalysts, reagents, and/or or intermediates); the drug substance itself; excipients; manufacturing equipment (e.g., vessels and utilities used during production of the drug substance and drug product); and environmental sources (e.g., water, air; and the primary packaging/container–closure system). Extensive and untargeted screening of all potential sources is neither scientific nor a viable solution. What is required is an appropriate risk-based approach, one that is aligned with the principles outlined in ICH Q9. Such an approach needs first to define a sensible framework in terms of the scope of such an assessment. How such a framework can be established is described below, consistent with the initial draft of ICH Q3D.
Raw materials used in synthesis of the drug substance. The first question for manufacturers to address is, "How far back in the synthesis should a risk-assessment begin?' Most synthetic processes involve multiple steps between the registered starting material and the final drug substance. Each step, especially those employing an aqueous solution, either for the reaction itself or in the form of washes, have the potential to remove metal residues. Hence, a sensible approach would be to start the assessment from the registered starting materials. Such an assessment would also include reagents and catalysts used in the synthesis of the active substance.
This scope raises a further question in terms of what, if any, testing should be required for a starting material or reagent used in the process. The answer is relatively straightforward where the manufacturing route is known for a starting material; hence, testing can be focused on any metal deliberately used in the manufacturing process. It should be recognized that assessing materials of commerce, such as simple reagents, is more difficult as the route of manufacture may not be apparent. Nevertheless, any testing relating to input materials into the synthesis of the drug substance should be focused on known risk as opposed to being subject to untargeted screening.
Drug substance. It is easy to assume that the removal of the apparent "catch-all" heavy metals limit test, <231>, should be replaced by a similar general screen, that is, one involving tests for multiple elements. The new USP General Chapter <232> might appear to advocate such an approach, which at a minimum might involve a screen for arsenic, cadmium, lead, and mercury. However, provided a robust risk assessment of the process has been conducted, considerations for other key process factors (e.g., water, reagents) should not be necessary. Instead, a true risk-based assessment should focus on identified risk factors, such as catalyst residues.
Water. Water is a significant potential source of environmental contaminants, including arsenic, cadmium, lead, and mercury. However, precisely because of this and other concerns relating to water quality, there are strict standards in place that define the minimum quality of water, such as those defined in ICH Q7 (15). Q7 stipulates that unless otherwise justified, process water should, at a minimum, meet World Health Organization (WHO) guidelines for drinking (potable) water quality. Such a standard, augmented in many cases by the use of purified water for API final step, precludes the need to routinely screen the resultant API for metals potentially arising from water. Furthermore, water quality is routinely monitored (through resistivity/conductivity measurement) as a part of current GMP.
Air. Air is an extremely unlikely source of metal contaminants and air quality is routinely addressed through GMP control via the use of HEPA filters and heating, ventilation, and air conditioning systems, to achieve the appropriate airborne classification.
Manufacturing equipment. Manufacturing equipment, although a potential source, is unlikely to pose a significant risk of metals. The most common materials are hastelloy and stainless steel. Such materials are resistant to both chemical corrosion and abrasion; this is why they are used in the industry. Furthermore, in terms of their composition, the major components of manufacturing equipment are iron, nickel, chromium, and manganese; none of these are considered highly toxic, according to USP or ICH, based on published data as described in EMA's pending guideline, Specification Limits for Residues of Metal Catalysts or Metal Reagents.
In addition, compatibility tests, combined with routine plant monitoring, both of which form part of routine GMP practices, should preclude the need to routinely monitor for metals associated with equipment.
Excipients. Perhaps the most contentious of all the potential sources of metal contaminants are excipients. Excipients broadly fall into three classes:
Of most concern are those excipients that are mined. These excipients are very likely to be subject to natural variation, both in terms of metals present and levels. In many cases, the metals content in excipients is inherent from their source and cannot "easily" be purified. Excipient manufacturers may not be able to change the metal content of a material. Also of concern is the difference between bioavailable metal and the total level present in such materials. It is almost certainly the case that a total level derived through an aggressive approach such as HF digestion will significantly overestimate the actual level of the metal biologically available upon ingestion of an insoluble mineral based excipient
Another important factor to consider when assessing the risk associated with an excipient is the contribution of the excipient in weight terms to the drug product. Certainly a number of excipients, for example titanium dioxide used as a table coating, are used at very low levels, although they may themselves contain elevated levels of a particular metal the overall contribution to the levels of metals in the drug product is negligible. Taking such factors into consideration is important if the industry is to avoid an over-reaction to the risk associated with individual excipients.
Container–Closure systems. Another potential source of metals is the primary container–closure system (CCS). The scope of any such assessment should be carefully considered. FDA's guideline on CCS (see Table II) provides a useful guide to assist in this process (16).
Table II: Examples of packaging concerns for common classes of drug products. Adapted from FDA containerâclosure guidance (Ref. 16).
In the context of metal leachables, the highest risk is associated with liquid formulations. Solid dose formulations, such as tablets in a foil blister pack, have low risk of leaching.
Even where a CCS is in scope, the risk assessment should focus on known potential risks, for example, antimony levels in polyethylene terephthalate (PET), rather than an unfocused general screening.
By conducting a well-designed focused risk assessment it should be possible to accurately assess and counter the risk of metal contaminants without the need for exhaustive analytical testing.
Of note, although the USP has publically communicated how it plans to implement changes and replace use of <231> Heavy Metals in monographs, at this time, it is not clear how the pharmacopeia plans to update and implement changes in other related General Chapters (e.g., USP <661> Closure Systems or USP <381> Elastomeric Components).
Coalition activities and path forward
As described herein, the industry has major concerns about the direction USP has taken with respect to implementation of new General Chapters <232> and <233> by not aligning with the pending ICH Q3D guideline in terms of targeted metals, limits, and applicability and implementation timeframes. Many members in the industry believe that realistic implementation should involve a phased-in approach due to the current lack of information available about metals in products and the need to collect and evaluate a tremendous amount of data by all stakeholders. The authors believe that coordination of USP's goals with that of ICH Q3D is essential to facilitate this process.
To that end, industry has organized the Coalition for the Rational Implementation of the USP Elemental Impurities Requirements. The coalition's mission is to: "develop risk assessment concepts for evaluating the potential for metal impurities in excipients, APIs and drug products and will evaluate what is a realistic timeframe for implementation of both the USP and the ICH Q3D requirements based on the PDEs and concentration limits in the [ICH Q3D] pre-Step 2 document. ICH is carefully reviewing all metal risk assessments and the pre-step 2 PDE limits are subject to change. At this time the Coalition is not specifically highlighting any concerns with the current ICH implementation strategy or plans, but rather, the seemingly independent strategy being implemented by USP. To this point the coalition plans to meet with high-level FDA officials involved in this issue to discuss this information and determine the type of timeframe that is realistic for implementation. The initial mission of the Coalition is to align USP's implementation timeline with that of ICH for Q3D once the guideline is completed."
The goal of all parties involved is to ensure the safety of patients and the quality of our products. However, there is no overriding issue of patient safety involved in the USP changes. USP has pursued its current path in a proactive way to prevent possible safety issues, but there have been no demonstrated cases of metal impurities in drugs at levels of toxicological concern. Instead, the USP initiative seems to have been prompted by issues with the analytical techniques. These issues need to be resolved, but there is no urgency that requires USP to adopt requirements independent of ICH. The primary objective of the coalition is to encourage USP and other parties to follow the same path, with compatible timelines, so that industry will be able to meet a harmonized standard.
*The Coalition is comprised of members from the following trade and professional associations: IPEC (International Pharmaceutical Excipients Council) Americas, IPEC Europe, Pharmaceutical Research and Manufacturers Association of America (PhRMA), European Federation of Pharmaceutical Industries and Associations (EFPIA), NJ Pharmaceutical Quality Control Association (NJPQCA), Consumer Health Products Association (CHPA), Generic Pharmaceutical Association (GPhA), and the Society of Chemical Manufacturers and Affiliates–Bulk Pharmaceutical Task Force (SOCMA–BPTF).
Katherine Ulman is a Global Regulatory Compliance Manager at Dow Corning; Neil Schwarzwalder is Quality Consultant, Compendial Affairs, at Eli Lilly and Company; Andrew Teasdale, PhD, is a Principle Scientist at AstraZeneca; David Schoneker is Director of Global Regulatory Affairs at Colorcon and Chair of the Coalition for the Rational Implementation of the USP Elemental Impurities Requirements; and Priscilla Zawislak* is a Global Regulatory Affairs Manager at Ashland Inc.
*All corresopondence should go to firstname.lastname@example.org.
Note: The authors are a subgroup of an industry coalition called the Coalition for the Rational Implementation of the USP Elemental Impurities Requirements.
1. A. Cross, Pharm. Technol. 36 (8), 62–64 (2012).
2. USP 35–NF 30 General Chapter <232>, "Elemental Impurities—Limits."
3. USP 35–NF 30 General Chapter <232>, "Elemental Impurities—Procedures."
4. USP 28–NF 23 General Chapter <231>, "Heavy Metals."
5. ICH, Q3D, Metal Impurities, Step 1 Concept Paper (2009).
6. A. DeStefano, "USP's Elemental Impurities Initiative —Current Status," presentation at the 2010–2015 Prescription/Non-Prescription Stakeholder Forum—Meeting #1 (Nov. 2009).
7. K.B. Blake, "Harmonization of the USP, EP, and JP Heavy Metals Testing Procedures," USP Pharmacopeial Forum 21 (6) 1632 (1995).
8. Basel Working Group on Determination of Metal Traces, Basel Excipients Working Group, "Determination of Metal Traces—A Critical Review of the Pharmacopeial Heavy Metals Test," USP Pharmacopeial Forum, 21 (6) (Nov.–Dec. 1995).
9. A. Lodi, "The Evolution of the Pharmacopoeial Test for Heavy Metals," Pharmeuropa Scientific Notes, 2007–1, p. 33.
10. E. Silverman, "Heavy Metals In Your Drugs? USP's Zaidi Explains," Pharmalot Blog, July 24, 2012, www.pharmalot.com/2012/07/heavy-metals-in-your-drugs-usps-zaidi-explains/.
11. USP, "New Quality Standards Limiting Elemental Impurities in Medicines Announced," USP Press Release, May 23, 2012.
12. USP Commentary—Second supplement to USP 35–NF 30,
13. J.F. Kauffman, Reg. Toxicol. and Pharmacol. 48 (2) 28–134 (2007).
14. USP General Notices, "Test and Assays, Foreign Substances and Impurities," USP 31, p. 7 (2008). (Note: This exact text was removed when the General Notices were restructured in USP 32. This is still a valid view of the role of a pharmacopoeia.)
15. ICH, Q7 Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients (Nov. 2000).
16. FDA, Guidance for Industry: Container Closure Systems for Packaging Human Drugs and Biologics (Rockville, MD, 1999).