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Changing regulations are impacting the identification and monitoring of variable materials in excipients.
For approximately 100 years, a wet chemical method with visual evaluation of the results has been the standard test for determining the total quantity of heavy metals in APIs and excipients. Both the United States Pharmacopeia (USP) and the International Conference on Harmonization (ICH) have updated, or are in the process of updating, analytical requirements for controlling elemental impurities. The new risk-based approach will result in significant changes, including new proposed limits, all of which are challenging pharmaceutical companies, contract manufacturers, contract laboratories, and suppliers to the industry. As a consequence, USP extended the deadline for compliance with USPGeneral Chapters <232> Elemental—Impurities Limits and <233> Elemental Impurities—Procedures to December 1, 2015. The ICH Q3D guidelines are not yet finalized, but there presently remain some differences in the limits required by the two standards.
Need for change
Revisions to USP’s standards for elemental impurities (heavy metals) were proposed in the interest of better protecting public health, according to Kahkashan Zaidi, USP principal scientific liaison. Elemental impurities include environmental contaminants such as arsenic, cadmium, lead, and mercury, and other elements that appear in drug products for various reasons. Some are present in naturally-derived APIs and excipients, such as those that are mined or extracted from plants. Others, such as catalysts, are intentionally added during the synthesis, while some are introduced unintentionally through interactions with processing equipment and/or container closure systems.
The method in USP General Chapter <231> Heavy Metals has several limitations. Most importantly, it is a qualitative method that involves the reaction of metallic impurities with sulfide ions to generate a colored precipitate. A visual comparison of the precipitate is made to a standard to determine if the sample exceeds specified limits. For insoluble materials, aggressive digestion is required that may lead to evaporation of the target metal species and thus lead to underestimation of the impurity content. In addition, the method is only effective for metals that react with sulfide ions, and therefore, other contaminants are not detected.
“Better understanding of the limitations of the current methods in USP General Chapter <231> Heavy Metals made it very clear that a revision was needed,” states Zaidi. Significant advances in testing methods and our understanding of the toxicity of various elements often found in excipients and APIs has occurred since the traditional method was developed, according to Janeen Skutnik-Wilkinson, vice-president of NSF Health Sciences’ Pharma/Biotech division. “Comprehensive, globally harmonized guidelines for all elemental impurities are essential given the global sourcing that occurs today in the pharmaceutical industry,” she adds.
USP began the standards-setting process in 2008. Several public meetings and USP Pharmacopeial Education courses were held to gather and share user input. The proposed standards were developed by an advisory USP Expert Panel, which considered comments from all stakeholders including industry (e.g., manufacturers of APIs, excipients, and drug products), FDA, and other relevant analysts and toxicologists.
Pharmaceutical manufacturers and laboratories have been concerned about the substantial changes that accompany implementation of the new USP standard for elemental impurities and appealed to the organization for extension of the initial deadline for compliance. Because the new analytical method requires advanced instrumentation, many laboratories have needed time to acquire and qualify the necessary equipment and train staff on the digestion process.“USP’s standards revision process involves international collaboration among USP experts, industry, regulators, and other stakeholders. We wanted to allow ample time for careful deliberation and scientific dialog in order to reach conclusions that are supported by a maximum number of interested stakeholders,” says Zaidi. In addition, she notes that because the new elemental impurities standards represent a significant change from existing standards, it was important to provide sufficient time for manufacturers to incorporate the changes necessary to implement the new standards into their processes. As a consequence, USP responded to industry concerns, with the deadline for implementation extended more than once.
The changes in the new USP chapters include limits for 15 specific elemental impurities (rather than determining a total amount) and analytical procedures based on modern analytical technology. The limits for acceptable levels of elemental impurities in drug products are included in General Chapter <232> Elemental Impurities--Limits. Manufacturers must demonstrate that the levels of lead, mercury, arsenic, and cadmium are below the limits. The remaining 11 elements, which are derived from common catalysts, must be considered if their presence can be expected based on catalyst use. Notably, according to Zaidi, unlike the previous General Chapter <231>, which applied to drug substances and excipients, the limits in <232> will apply only to drug products that are subject to a USP drug product monograph. “This requirement is a major change, because previously testing for elemental impurities only applied to APIs and excipients,” she says.
The limits for each elemental impurity in drug products are expressed as permissible daily exposure (PDE) values, which are determined after evaluation of toxicity data. For most drug products, the product itself can be analyzed. Manufacturers also do have the option of analyzing all ingredients in a formulation rather than the formulated product, but must be able to provide assurance that additional contaminants cannot be unintentionally added from product manufacturing processes or container closure systems for the product, for example. For large-volume parenterals (daily dose > 100 mL), however, each ingredient must be evaluated to determine if it meets the specified limits.
New detection methods
The procedures in General Chapter <233> for the evaluation of elemental impurities in drug products use inductively coupled plasma-atomic (optical) emission spectroscopy (ICP-A(O)ES) or inductively coupled plasma-mass spectrometry (ICP-MS), depending on the instrument and sample used, according to Zaidi. Alternative procedures may be used as long as they meet the validation criteria in chapter <233>.
Sample preparation is crucial for these analytical techniques. Some samples may be analyzed directly, but many will require dissolution in water or an organic solvent prior to analysis. Others that are not soluble in either water or organic solvents will require digestion using acids, which USP recommends be performed in a closed-vessel digestion apparatus.
Consequences for industry
The new requirements for elemental impurities will greatly affect both pharmaceutical manufacturers and their suppliers. “The changes will be significant, because the traditional wet chemistry test will no longer be acceptable unless it has been validated for each analyte element. While switching to an instrumental technique will be easier and enable companies to run more samples in a shorter amount of time, companies may need to purchase analytical instrumentation that they don’t already have, or find a contract laboratory that has the instrumentation necessary to perform the analyses,” says Nancy Lewen, a senior principal scientist in pharmaceutical development for Bristol-Myers Squibb (BMS). She does, however, also appreciate the emphasis on using a risk-based approach rather than a sweeping requirement for analyses for every single sample. “Once companies perform their initial product assessments, then the workload should drop off quite a bit, unless there are changes in the way their products are made,” Lewen observes.
While the new requirements do represent a significant change for the industry, the use of the risk-based approach for determination of elemental impurities will allow companies to prepare, according to Terry L. Harper, supervisor of pre-formulations at AAIPharma Services. “The key to success is for companies to conduct their risk assessments in a logical manner and to plan and design an efficient process. If that can be achieved, it should be a relatively straightforward process to meet the requirements,” adds Joseph Bordas-Nagy, director of structural chemistry with AAIPharma.
Contract laboratory Exova has observed that some pharmaceutical companies are looking to outsource elemental impurities analysis, while others are investing in new ICP-MS or ICP-OES instruments for in-house testing, according to metals group leader Samina Hussain. On a positive note, she comments that the majority of final drug products the company has tested for elemental impurities are below the specifications set in USP <232>. She does note, though, the process of validating for elemental impurities by ICP-MS or ICP-OES is a relatively new concept for pharmaceutical companies, and understanding this process is a crucial step in assuring pharmaceutical products are compliant by December 2015. “The process should involve: method development, drafting of a method validation protocol for review, and the actual execution of the validation,” according to Hussain. “Pharmaceutical companies need to be aware that this will take time for a contract lab to successfully develop. While we have the base capability to carry out this level of testing, it will take time to develop these methodologies to meet specific industry needs,” she notes.
The need to evaluate raw materials for the various elemental impurities will also require supply-chain resources, according to Patty Benson, director of quality assurance at SAFC. “Products such as those derived from plant sources or those that are mined will pose the greatest challenge in that they may vary from batch to batch or year to year,” she notes. Engaging in discussion with suppliers is very important; they don’t need to comply with the guidelines, but manufacturers of finished products must be able to obtain raw materials that meet certain specifications to ensure that they can comply with the requirements for elemental impurities, according to Skutnik-Wilkinson. “It is best to view suppliers as partners, particularly for suppliers, such as excipient manufacturers, for whom the pharmaceutical industry is an insignificant portion of the business. Such a situation presents special challenges and requires a bit of diplomacy,” she says.
BMS has had considerable experience using ICP-OES and ICP-MS, so is already ahead of the curve in that regard, according to Lewen. BMS has also followed the updates and proposed updates and tried to modify its analytical methods to meet the requirements that are announced through publicly-available venues. In some cases, that has meant back-tracking and changing a method procedure, particularly when limits have decreased or an element has been added. “Our goal is to perform an assessment on each of our products to be prepared for compliance, whatever the requirements end up being,” she says.
Exova also has extensive experience with ICP-MS technology and currently has seven ICP-MS instruments and one ICP-OES at its US site, and additional ICP-MS instruments in Canada and Scotland to serve the global market, according to Hussain. “Testing for elemental impurities is not new to us, and we have successfully validated many diverse matrices. The challenge will be to offer timely turnaround on method validations if most companies choose to continue waiting,” she observes.
AAIPharma has two ICP-MS instruments to provide redundant capabilities and has developed conditions for effective solubilization and methods for quantitative screening analyses that are designed to generate data for risk assessment. The quantitative screening method is effective for providing quantitation of elements of interest without prior knowledge of the sample matrix. Quantitation is based on calibration curves established for each element. The method includes assessment of method performance based on spiked recovery at two levels. “We have had good success with 26-27 elemental impurities in a number of drug products and excipients to date and are enthusiastic about applying this method to a wider number of substances and assisting clients in their efforts to comply with the changing standards,” notes Bordas-Nagy. “The key,” says Harper, “is to get as much data as possible as quickly as possible in order to determine a specification is not needed or that a validated method is required.”
To prepare for compliance with new elemental impurities standards, SAFC has developed a draft procedure and checklist to evaluate its raw materials, process water, equipment, and container closure systems with respect to the identification of potential sources of elemental impurities in its regulated products. The company is also working with its biopharmaceutical customers to develop a process to evaluate raw materials that pose the greatest risk to their cell-based processes. “We will follow the regulations with regard to thresholds and have begun to use ICP-MS to systematically monitor many of our raw materials—specifically to develop a good baseline understanding of the trace elements and the levels that we are likely to see in various raw materials. Salts (mined raw materials) have been shown to be more variable in terms of trace metals, and we have been continuing to develop this type of baseline data,” says Benson. She adds that working closely with vendors to determine how much control the company can exercise over this measured variance has been important.
USP recently posted proposed revisions to General Chapters <232> for public comment in Pharmacopeial Forum 40(2) with a comment deadline of May 31, 2014. The revisions to <232> convey USP’s review of and subsequent partial alignment with the ICH Q3D Step 2b limits. “USP’s proposed limits reflect a review of published toxicological data and studies, as well as expert review by toxicologists serving on USP’s Elemental Impurities Expert Panel. In some cases, USP’s proposed limits diverge from the Q3D Step 2b limits, and USP has notified ICH of these divergences via a comment letter on the Q3D Step 2b document,” Zaidi notes.
“Our approach to the lack of full harmonization is to take the most conservative approach and select the lowest limits in all of the existing and proposed standards,” comments Bordas-Nagy. “With such a strategy, we ensure that both our own products and those of our clients are in compliance,” he concludes.