USP’s new standards related to elemental impurities will present some new challenges to drug manufacturers and raw material suppliers. The standards include newly established limits for selected elemental impurities and new test procedures based on modern instrumentation that undoubtedly will require a shift in industry practices for compliance. With the advance notice that has accompanied the standard development process and a required compliance date of May 1, 2014, manufacturers, suppliers and contract organizations have time to prepare for implementation and will need to plan accordingly for these requirements.
Elemental impurities include substances such as arsenic, cadmium, lead and mercury, which can appear in a drug product through various routes. They can occur naturally as a result of their presence in the ground from which materials are sourced, be added intentionally as part of a product’s synthesis (e.g., use of a catalyst), or be introduced inadvertently (e.g., interactions with processing equipment during manufacturing).
Throughout the course of the new standards’ development, deliberations about them have triggered debates among stakeholders about how far-reaching the standards should be and what could reasonably be expected of manufacturers regarding new requirements. Some in manufacturing and quality management circles demanded that the outdated method in USP’s existing standard for detecting and testing elemental impurities be modernized to better reflect current practices. Others have questioned the need for more stringent—and more costly—testing when no known adverse health effects resulting from elemental impurities have been reported using the legacy test method.
Published June 1, 2012 in the Second Supplement of United States Pharmacopeia (35) and National Formulary (30) (USP 35–NF 30), USP’s new standards will become official on December 1, 2012. However, the new standards will not be applicable to articles recognized in USP-NF until a new General Notices provision addressing and specifically applying these General Chapters becomes official on May 1, 2014. This approach for applying the new General Chapters is intended to (1) provide clarity on the broad range of compendial articles to which the new elemental impurities standards are intended to apply, (2) utilize General Notices as a means of avoiding the need to revise each and every USP-NF monograph in order to apply the two chapters, and (3) also provide manufacturers and their suppliers with ample time to develop suitable strategies and schedules for addressing the testing needs of the new standards. General Chapters <232> and <233> will replace existing standards related to elemental impurities found in General Chapter <231> Heavy Metals.
This implementation concludes this phase of an extended standards-setting process that began in 2008 and involved several public meetings, including one conducted by the Institute of Medicine. In 2009, USP held a workshop on the topic of elemental impurities. Since 2008, USP also has hosted several stakeholder forums and pharmacopeial education courses to gather and share user input on the topic. In addition to a 2008 stimuli article published in Pharmacopeial Forum (PF)—USP’s public notice and comment journal—the general chapters were published twice (in 2010 and 2011) in PF for additional stakeholder feedback. The standards were developed by an advisory USP Expert Panel reporting to the appropriate decisional USP Expert Committee, and involved input from analysts and toxicologists from industry, academia, government laboratories, the U.S. Food and Drug Administration (FDA) and international regulatory bodies.
USP’s new standards apply to drug products, which is a major change for manufacturers. Previously, testing for elemental impurities only applied to active pharmaceutical ingredients (APIs) and excipients. With the new standards, drug product manufacturers will have to ensure that all their products adhere to the new requirements, and they must also be certain of the quality of product components provided by their suppliers.
General Chapters <232> and <233> include procedures based on modern instrumentation techniques for evaluating elemental impurities. Used primarily in pharmaceutical research and development, these procedures involve instruments and expertise not commonly applied in post-market quality testing. However, the new methodologies and techniques do allow for better and more comprehensive evaluations of elemental impurities including the ability to screen for multiple elements in one analysis. In addition, these standards allow manufacturers to use other procedures as alternatives to those in the chapter, provided that these alternate procedures undergo proper validation.
The new standards also will require manufacturers to test for the presence of selected individual impurities, rather than test for the cumulative amount of impurities in a product (which was the minimum requirement of USP’s existing standard). The new requirements also specify limits for each of these impurities based on levels known to be toxic.
As some manufacturers begin to incorporate the in-house expertise and capabilities needed to deal with the new standards, others are turning to contract laboratories to support their compliance efforts. And still some others—particularly suppliers of raw or component materials for drug products—must assess the broader impact that these new standards will have on their ability to deliver the materials needed to their customers.
Background on USP’s Standards for Elemental Impurities
In USP parlance, documentary standards are conveyed in monographs, applicable general chapters and General Notices published in USP–NF. Monographs include tests related to the identity, strength, quality and purity of individual drug substances, drug products and excipients. General chapters apply to multiple monographs (by being named for application in individual monographs, or as here in General Notices). Those designated as above-1000 are considered interpretive and informational. General chapters designated as below-1000—such as <232> and <233>—contain tests that can be made to apply to items recognized in USP–NF. When General Chapters apply to a particular monograph, they become a component of the overall compendial standard, generally one of the specified tests or methods required to demonstrate conformance to an article’s compendial specifications. Under Federal law in the United States, a drug with a name recognized in USP-NF must comply with compendial standards or risk being deemed adulterated and/or misbranded. Enforcement of USP standards is the responsibility of FDA and other government authorities in the U.S. and elsewhere; USP has no role in enforcement.
General Chapters<232> and <233> will be implemented through a provision in the General Notices, making them applicable to all articles in USP–NF, as was recently done for another type of impurity testing in General Chapter <467> Residual Solvents. Implementation of <232> and <233> will include removal of all references to General Chapter <231> from monographs in USP–NF.
It is important to note that USP has made an attempt to harmonize many of its standards with those of other pharmacopoeial organizations and bodies. In the 1990s, the International Conference on Harmonisation (ICH) initiated a process for establishing guidelines on different types of pharmaceutical product impurities. These efforts have generated ICH guidelines related to organic impurities (ICH Q3A and ICH Q3B) as well as residual solvents (ICH Q3C). ICH currently is developing ICH Q3D, which is intended to provide guidance on elemental impurities. As USP moves forward with the implementation of General Chapters <232> and <233>, it will continue to monitor the results of the ICH Q3D deliberations. Based on these deliberations, USP may add additional elements and limits to General Chapter <232> and and may develop an informational chapter on elements of low toxicity.
Limits in USP’s New Standards
The test procedure in outgoing General Chapter <231> (visual comparison to a lead sulfide precipitate) applies a more than100-year-old method for detecting elemental impurities. It relies upon a visual comparison of the test sample color against that of a standard, making an assessment highly subjective. Additionally, many acknowledge that the legacy method is not sensitive enough to detect some impurities at levels known to be toxic, some at very low levels.
During the development of these new standards, USP has taken a risk-based approach for identifying limits and appropriate methods for detecting and measuring elemental impurities. As mentioned, the minimum requirement of General Chapter <231> was testing for the cumulative total of elemental impurities in a product. In General Chapter <232>, fifteen elements have been identified as key impurities for testing, with limits specified for each. For the “Big Four”—arsenic, cadmium, lead and mercury—which are considered to be the most ubiquitous of elemental impurities, compliance with the limits specified in General Chapter <232> will be required for all drug products. The remaining eleven elements on the list of target impurities are used as catalysts in manufacturing processes. These catalysts must be considered if their presence is expected based on an assessment of a product’s formulation and manufacturing process.
In General Chapter <232>, limits for the impurities are expressed as permissible daily exposure (PDE) values, given that the toxicity of an elemental impurity is tied to its extent of exposure. Depending on the type of pharmaceutical product being tested and whether its route of administration is oral, parenteral or inhalational, General Chapter <232> lists a specific PDE limit, the value of which is determined from chronic exposure data. For the purpose of this standard, mucosal and topical routes of administration are deemed to be the same as oral. Additionally, General Chapter <232> addresses large-volume parenterals (LVP), in which the daily dose of an injected product is greater than 100 mL. The amount of elemental impurities present in an LVP drug product must be controlled through the individual components used to make that product.
General Chapter <232> also provides two options for users to demonstrate compliance. The first is based on a measurement of each impurity in a typical dosage unit of a drug product. The second is based on a summation of the amount of each impurity present in each component in a drug product. If a manufacturer uses the summation option, it will be necessary to assure that additional elemental impurities cannot inadvertently be added through the manufacturing process.
According to General Chapter <232>, the presence of elemental impurities in drug substances and excipients must be controlled and, where present, reported. Acceptable levels for these impurities depend on the material’s ultimate use. Therefore, the drug product manufacturer must determine the acceptable level of elemental impurities in the drug substances and excipients used to make its products. Close collaboration between suppliers and their customers will be important as manufacturers establish that their supply chain is in good control. To help facilitate discussions between drug product makers and their suppliers, the general chapter includes a table of values of default concentration limits for elements in drug substances and excipients. These concentration limits are for components (drug substances and excipients) of drug products dosed at a maximum daily dose of 10 grams/day.
Procedures in USP’s New Standards
Transitioning from the chemical approach of General Chapter <231> to the instrument-based methodology included in General Chapter <233> does introduce some significant considerations for drug product manufacturers. The procedures in General Chapter <233> for the evaluation of elemental impurities in drug products use inductively coupled plasma–atomic (optical) emission spectroscopy (ICP-AES) or industry coupled plasma–mass spectroscopy (ICP-MS). General Chapter <233> also provides criteria for acceptable procedures that may be used as alternatives to the ICP procedures specified in the chapter.
Whether a manufacturer uses ICP or acceptable alternative procedures, it is important that the correct sample preparation approach be applied to the test material at hand. Some pharmaceutical samples can be analyzed directly (unsolvated samples). Others require aqueous or organic solvents before being tested. For drug products, APIs, excipients and other raw materials that cannot be dissolved using aqueous or organic solvents, General Chapter <233> recommends a sample preparation procedure that uses digestion acids in a closed-vessel digestion apparatus.
Many drug products are differentiated based on properties that make them unique compared to competitor’s products. This uniqueness can come from a combination of APIs, excipients and other components in a formulation designed to affect the drug product’s performance. To address this uniqueness resulting from different matrices that make up a wide range of drug products, closed-vessel microwave digestion is recommended.
While some drug product makers have started to use or bring microwaves in-house, sample preparations must be specific to every product in a manufacturer’s complete portfolio. Among the key considerations for the manufacturer is whether or not it has the necessary expertise to conduct the sample preparation needed with instrumentation use, and, if not, how much time would be needed to develop such expertise. Sample preparation includes honing techniques for working with different types of product matrices and being able to work through matrix interference, and for the manufacturer with many drug products, compliance by the May 1, 2014 deadline may pose some timing challenges.
If a drug product manufacturer decides to outsource its analytical and validation work to a contract laboratory in order to meet the requirements of the new standards, it must allow enough time to work strategically with its partner contract organization. In addition to developing the necessary sample preparation techniques for multiple products, the contract laboratory must also conduct feasibility testing, draft protocols and establish a good balance for meeting the QA requirements of the manufacturer as well as its own—not to mention completion of the validation work itself.
Manufacturers of raw materials will have the challenge of needing to test and validate large amounts of materials. Since raw materials are produced as bulk products and often in continuous processes, suppliers will need to know the levels of elemental impurities on an on-going basis. Raw materials also are prone to interferences. Thus, having the correct expertise for sample preparation techniques and instrumentation requirements—whether in-house or through a contract laboratory—will be critical for raw material manufacturers to be able to supply their customers with elemental impurity levels.
In the criteria described in General Chapter <233> for alternative procedures, the level of validation necessary to ensure that an alternative procedure is acceptable depends on whether a limit test or a quantitative determine is needed. The requirements for validation of an elemental impurities procedure for either type of determination are described in General Chapter <233>.
Meeting USP’s New Standards for Elemental Impurities
Given that the new standards for elemental impurities will apply to all monographs in USP–NF, drug manufacturers, particularly those that produce a large number of pharmaceutical products, will need to determine how best to handle large volumes of materials. In addition, drug manufacturers must be certain that if impurities are detected in drug substances and excipients used in their final products, the level of those impurities must be known relative to the limits specified in the new standards. By laying the foundation for these new general chapters in 2008 and providing for an implementation date of May 1, 2014, USP has provided manufacturers and their suppliers with the time needed to determine how best to address their compliance needs in an effort to better protect drug supplies from unwanted and intended elemental impurities. Contract laboratories should be prepared to work with their customers on developing strategies and timelines that help to meet compliance requirements.
For more detailed information about General Chapters <232> and <233>, go to: http://www.usp.org/usp-nf/hot-topics/elemental-impurities.