This article discusses the retiring of Ph. Eur. and USP heavy metal assays as well as a means of updating related specifications with minimal regulatory burden.
The removal of the general testing text in the European Pharmacopoeia (Ph. Eur.) 2.4.8 and the deletion of the United States Pharmacopeia (USP) Chapter <231> have extensive regulatory impact for drug product marketing license holders, as the historical practice for registered specifications for many non-compendial materials, drug substances, and drug products has been consistent inclusion of these tests. Although the data collected industry-wide towards compilation of International Council for Harmonization (ICH) Q3D prescribed risk assessments convincingly demonstrates elemental impurities to be well-controlled without addition of more quantitative modern assay techniques, these outdated compendial tests are in most cases still being performed to remain compliant to marketing licenses in markets where an annual reporting mechanism to implement stop-testing without approval doesn’t exist. In such markets, it remains unclear how industry should approach the regulatory updates of these non-compendial specifications in order to discontinue the procedure without creating enormous industry regulatory and agency reviewer burden. This paper, a collaborative cross-pharmaceutical industry effort, presents evidence further supporting the retiring of these outdated assays and a proposal for a means of updating related specifications with minimal regulatory burden.
The deleted USP <231> and Ph. Eur. 2.4.8 heavy metals tests are outdated qualitative methods relying on an analyst’s visual comparison to a standard solution resulting in both high variability and unreliability of reported results (1,2). Additionally, the tests do not provide information regarding which elements may or may not be responding to the procedure.
With no means of differentiating the method response, identification and quantitation of the specific metals being measured is not possible. This lack of specificity generates concern that other potential elemental impurity contaminants introduced through the manufacturing process, equipment, and materials cannot and were not being assessed with these methods, and that the metals that were present were not identified and quantified appropriately.
When the US Pharmacopeial Convention (USP), and subsequently ICH, began to look into ways to improve upon heavy metals testing, it became clear that it was important to assess elemental impurities in the context of toxicity and patient safety.
Both USP <232> (3) and ICH Q3D (4), which are largely harmonized, address the potential impact of elemental impurities from all aspects of the drug product manufacturing process, unlike the previous heavy metals tests. USP <232> and ICH Q3D include all metals of concern, including most of the metal catalysts or metal reagent residues listed in EMEA/CHMP/SWP/4446/2000 (5).
The prescribed limits for metals of concern set forth in USP <232> and ICH Q3D are based on observed toxicity levels. Although ICH Q3D does not provide an analytical procedure, it directs analysts to compendial methods. USP <233> (6) Elemental Impurities–Procedures provides methods for performing elemental impurities testing. The analytical techniques given therein (inductively coupled plasma-mass spectroscopy [ICP-MS] and inductively coupled plasma-atomic emission spectroscopy or optical emission spectroscopy [ICP–AES/OES]) are far superior in both detection and quantitation of elemental impurities.
In addition to the superior analytical techniques provided in USP <233> and the scientifically based quantitative limits for a much broader set of elemental impurities, USP <232> and ICH Q3D provide a risk-assessment approach towards assessing all potential contributing factors to the total elemental impurities in the final drug product.
These risk assessments are to be data driven and used by the drug product manufacturer to determine whether additional controls may be needed to ensure that no metals of concern are approaching the toxicologically determined permitted daily exposure (PDE) in the final product.
With impending removal of the general testing procedure described in the Ph. Eur. and USP chapters, data collection towards compilation of the risk assessments prescribed by the ICH Q3D guideline and USP <232> was conducted industry-wide.
The two most likely key contributing factors to total elemental impurities shown in the guideline’s Ishikawa diagram were anticipated to be drug substance and excipients. Of particular concern was the potential for contaminants to be present in mined excipients.
In 2015, the US Food and Drug Administration (FDA) and the International Pharmaceutical Excipient Council (IPEC) jointly published the outcome of a focused study on 200 excipient samples covering a range of excipients (7).
This initial study concluded that the overall risk associated with excipients was relatively low, especially when typical proportions in formulated drug products were considered.
With the express aim of building upon this initial study, a consortium of pharmaceutical companies established a database to collate the results of analytical studies of the levels of elemental impurities within pharmaceutical excipients.
This database (coordinated by Lhasa, a not-for-profit organization that facilitates data sharing in the pharmaceutical and related industries) currently includes the results of more than 25,000 elemental determinations for over 200 different excipients and represents the largest known, and still rapidly expanding, collection of data of this type.
An analysis of the database (8) examined a series of aspects, including both data coverage as well as impurity levels and variability (across supplier/grade etc.). The database includes results from multiple analytical studies for many of the excipients and thus is able to give a clear indication of both excipient supplier and batch-to-batch variability (although batch and supplier
information is not included in the database) as well as any variability associated with the different testing organizations and methods employed.
The results are telling. Critically, the data confirm the findings of previous smaller FDA–IPEC studies re-iterating the finding that elemental impurity concentrations in excipients, including mined excipients, are generally low and when used in typical proportions in formulated drug products are unlikely to pose a significant patient safety risk.
In addition to the evidence that excipients present little concern, contributors to this paper, representing several large pharmaceutical manufacturers, were polled regarding the conclusions drawn from the full risk assessment exercises conducted across their product portfolio. Industry representatives were asked to provide information on the outcome of the collated data generated in these exercises, represented as a number of the company’s marketed product portfolio, wherein the data gathered to support a risk assessment revealed a need to implement a new assay and specification as a quality control. Two large pharma companies conveyed that in a total of 68 assessments compiled at Company A and 126 compiled at Company B, not one concluded a need for an additional specification to be implemented for control of elemental impurities. At a third, Company C, more than 1000 assessments had been conducted in total across a vast portfolio only to identify two instances where an additional specification would be needed.
As demonstrated in this sample of industry information and based on additional discussions with both manufacturers and third-party testing labs, the results of testing collected towards the drug-product risk assessments have established that elemental impurities are well controlled without additional specification setting.
These outcomes support removal of the former Ph. Eur. 2.4.8 and/or USP <231> tests, while also demonstrating that there is not a need for those general tests to be replaced with new and specific ICP-MS assays. Existing regulatory specifications for non-compendial materials that currently carry the former compendial heavy metals tests, therefore, should be updated to remove references to the obsolete compendial chapters and replacement of these with ICP-MS assays can be justified as unnecessary.
In markets such as the United States and Canada where annual reporting is in place, agency communication of expectation was to utilize the annual report as a means to update specifications to eliminate these tests while allowing for testing with the now obsolete compendial wet chemistry tests to stop without a formal agency approval. In addition to the annual report’s replacement of specifications, agencies conveyed that future on-site inspections may be used as a vehicle to review full risk assessment reports.
What is not clear is how the removal of specifications’ reference to the former compendial heavy metals assays should be categorized and submitted to a local health authority when an annual reporting mechanism doesn’t exist. Deletion of an assay from specifications without replacement with an equivalent or better assay often has a categorization requiring prior approval to do so. Thus, in lieu of making numerous submissions to remove the general tests at this time, most manufacturing license holders have chosen to generate internal general method versions of the former compendial text in order for analysts to continue to perform the assays as listed in the existing registered specifications.
This continued wet chemistry testing is being implemented solely as a means of ensuring compliance to the registrational information in the dossier despite the evidence, not only of the lack of utility of the now obsolete assays, but of the risk assessments’ demonstration of adequate elemental impurities control. However, in the long term, these outdated tests should be retired from specifications.
The submissions needed to make these updates present significant regulatory burden if categorized according to regulations in place in most global markets. However, the reporting categories prescribed for reporting specification changes (deletion of an assay) in such regulations do not seem to correctly apply to the unique position that the new ICH Q3D guidance and consequential compendial changes have presented.
The compendia have been updated to remove these assays because they are antiquated and lend no reliable quality-indicating information. Continuing to perform the assay to ensure compliance with the text in the license causes a misdirection of resources towards generation of ineffective information.
Without a clear regulatory reporting mechanism to stop testing without risking non-compliance, manufacturers must either continue to test or prepare portfolio-wide submissions that will then pose both burdensome use of regulatory resources internally and at the respective agencies.
For these reasons, the authors propose that the industry regionally engage with these global health agencies to request retirement of performing these assays without requiring numerous standalone submissions to remove from regulatory specifications. Instead, the authors recommend requesting agreement from the local agency to cease testing using this obsolete procedure, though it may linger in the filed license for a period until a variation with other regulatory changes is necessitated. The formal specification revision to remove the obsolete tests from the license would be provided via an unrelated upcoming variation for the product but with an understanding that the testing would not continue in this interim pending the eventual formal licensure update.
Industry would ask that the regulatory agencies consider this unique approach as a logical exception in order to circumvent continued performance of methods obsoleted due to their futility and to avoid expenditure of reviewer and regulatory resources towards a massive volume of undue industry-wide submissions.
This solution allows industry and regulators to partner in the commitment to ensuring patient safety and access to quality therapeutic agents with the acknowledgement that performance of these obsolete methods does not contribute to these shared objectives.
1. K. Blake, Pharm. Forum 21 (6), 1632-1637 (1995).
2. Lewen, et al., Journal of Pharmaceutical and Biomedical Analysis 35 (1) 739–752 (2004).
3. USP, General Chapter <232>, “Elemental Impurities- Limits,” pp.1-3, USP 39 (USP, November 2016).
4. ICH, Q3D Guideline for Elemental Impurities, Step 4 version (ICH, 2014).
5. EMEA, Guideline on the Specification Limits for Residues of Metal Catalysts or Metal Reagents (London, UK, 2008).
6. USP, General Chapter <233> “Elemental Impurities-Procedures,” pp.1-5, USP 40.(USP, June 2017).
7. Li, et al., J. Pharm. Sci 104 (1), 4197-4206 (2015).
8. C. Marchant et al., “An Elemental Impurities Excipient Database: A Viable Tool for ICH Q3D Drug Product Risk Assessment,” J. Pharm. Sci. online, September 2018.