Andrew Teasdale, PhD, is a Principle Scientist at AstraZeneca.

Andrew Teasdale

The removal of the general testing text in the 

) 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elemental impurities to be well-controlled without addition of more quantitative modern assay techniques, these outdated compendial tests are in most cases still being performed to remain compliant to marketing licenses in markets where an annual reporting mechanism to implement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paper, a collaborative cross-pharmaceutical industry effort, presents evidence further supporting the retiring of these outdated assays and a proposal for a means of updating related specifications with minimal regulatory burden.

2.4.8 heavy metals tests are outdated qualitative methods relying on an analyst’s visual comparison to a standard solution resulting in both high variability and unreliability of reported results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.

<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. 

<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 

<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. 

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 

<233> and the scientifically based quantitative limits for a much broader set of elemental impurities, 

<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 

chapters, data collection towards compilation of the risk assessments prescribed by the ICH Q3D guideline and 

	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 

<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.

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, 

Guideline on the Specification Limits for Residues of Metal Catalysts or Metal 

(London, UK, 2008).
	6. USP, General Chapter <233> “Elemental Impurities-Procedures,” pp.1-5, 

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,” 

Articles

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.

Retirement for Obsolete Heavy Metals Tests

: This article appears in the September 2018 issue of 


	Vol. 30, No. 9
	September 2018
	Pages: 48, 50–51

	When referring to this article, please cite it as E. Corbett, A. Teasdale, S. Shabrang, L. Wong, N. Lewen, “Pharma Collaboration Proposes Retirement of Obsolete Heavy Metals Tests," 

The authors support the retiring of Ph. Eur. and USP heavy metal assays and propose a means of updating related specifications with minimal regulatory burden.

Pharma Collaboration Proposes Retirement of Obsolete Heavy Metals Tests

An industry workgroup comprised of toxicologists and manufacturing equipment cleaning subject matter experts was formed to examine the European Medicines Agency (EMA) shared facilities guideline, specifically the provision for alternative approaches to establishing limits and how to practically implement any proposed alternatives (1). This paper describes the outcomes of these evaluations, including alternatives for estimating health-based exposure limits using available assessments and a strategy to prioritize existing commercial products for health-based exposure limit evaluation. It provides a screening tool to identify products that require calculation of a health-based cleaning limit, and those where cleaning to existing cleaning limits (e.g., based on 1/1000th the minimum therapeutic dose) may continue. The presumption is that all newly introduced products will have formally documented health-based exposure limits. EMA was consulted during development of this paper, which is intended to support implementation of the European Union GMP Chapter 3 and 5 revisions for prevention of cross-contamination (2).

	EMA published a guideline on setting healthbased exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities in November 2014 (1). The European Commission (EC) also revised related General GMP Chapters 3 and 5 in January 2015 by updating sections on prevention of cross-contamination; these revisions became effective on 1 March 2015 (2).

	The EMA guide effective date was 1 June 2015 for new products and 1 December 2015 for existing products. These timelines represent a significant challenge for the industry.  The EMA guide implementation timelines are aggressive considering the current number of existing products. The implications of the EMA guide are that current cleaning limits would need re-evaluation in relation to newly derived health-based cleaning limits. If revisions are necessary, then cleaning validation activities may need to be re-started for impacted manufacturing equipment. Cleaning sampling and analytical test method detection levels may need to be re-evaluated, and potentially lower detection limits established/validated. Because re-evaluation  may consume significant resources, efforts need to be prioritized according to impact on patient safety.

	The EMA guide uses permitted daily exposure (PDE) values as a basis for establishing appropriate limits but states that PDE values are considered synonymous with the acceptable daily exposure (ADE) values. Both represent a dose that is not expected to cause an adverse effect in an individual, even with a lifetime of exposure. The EMA guide also states that “the use of other approaches to determine health-based exposure limits could be considered acceptable if adequately and scientifically justified.”

	This paper describes the potential to adopt scientifically justified and health-protective options for estimating ADE values from available assessments. It also provides examples on how to prioritize existing products and evaluate currently used cleaning limits to identify those products that require calculation of an ADE- or PDE-based cleaning limit, and those where cleaning to existing cleaning limits (e.g., 1/1000th the minimum therapeutic dose) already provides sufficient patient protection. The presumption is that all newly introduced products will have documented health-based exposure limits.

Alternative approaches for setting health-based exposure limits: Estimation of ADE values for small molecules


	The goal of applying alternative approaches should be to demonstrate whether or not current cleaning practices provide a sufficient margin of safety for patient health. The approach proposed in this document provides a rationale for estimation of ADE values using existing potency and toxicological evaluations performed for worker safety purposes, followed by an evaluation of facility attributes and product mix. For example, many pharmaceutical organizations establish occupational exposure limits (OELs) for their compounds or use a control banding approach (occupational exposure bands [OEBs]) to categorize compounds of increasing severity based on their inherent pharmacological and toxicological properties and/or limited dataset. ADE values can be estimated using OELs or OEBs, and if an adequate margin of safety is identified between cleaning limits based on the estimated ADE value and maximum possible carryover based on existing cleaning limits, a formal comprehensive ADE value monograph may not be required. Adequate documentation could initially include a brief summary or spreadsheet reflecting the scientific rationale, and formal ADE values would only be needed for a subset of compounds where facility attributes and product mix do not afford an adequate margin of safety. The evaluation approach should be documented for each site and included in plans available for review by regulatory inspectors.

 Prior to issuance of the EMA guideline on setting healthbased limits, categories of drugs were identified that have the greatest concern (e.g., “certain hormones, certain cytotoxics,” etc.); however, specific criteria were never provided. The International Society for Pharmaceutical Engineering (ISPE) Risk-MaPP baseline guide outlines example characteristics of compounds of traditional concern that could benefit from further review (3):

		Genotoxic (specifically mutagenic) compounds that are known to be, or highly likely to be, carcinogenic to humans.

		Compounds that can produce reproductive and/or developmental effects at low dosages.*

		Compounds that can produce serious target organ toxicity, anaphylaxis, or other significant adverse effects at low dosages.* * e.g., clinical doses <1–10 mg/ day or dosages in animal studies <0.1–1 mg/kg/day

	The threshold of toxicological concern (TTC) concept may also be useful to estimate ADE values and applies to products containing mutagenic active ingredients (ADE=1 μg/day), those that are potent or toxic (ADE=10 μg/day), or those that have no prior evidence of these properties (ADE=100 μg/day) (4). In principle, each of these approaches can be used to identify hazardous drugs for risk assessments and, if scientifically justified, can be used for the derivation of healthbased cleaning limits. Identification of a compound as a hazardous drug should not automatically lead to strict control solutions, because it addresses only hazard. A risk assessment should be completed before conclusions can be made about risk and the need to modify controls.

: If I have an OEL. ADE or PDE value derivation and OEL derivation share the same scientific basis (e.g., the same method to define the point-of-departure [PoD]), with some differences in the respective adjustment factors related to the different exposure scenarios or regulatory context. By comparing the respective standard adjustment factors, it is possible to define the systematic difference between the two calculations. If this systematic difference is adequately evaluated and the OEL derivation is scientifically justified, estimation of the ADE from the available OEL could meet expectations to derive health-based cleaning limits, at least on an interim basis to support prioritization and assessment of existing cleaning limits.

	The EMA guide acknowledges that “good quality human clinical trial data is highly relevant” to the assessment for ensuring patient safety. Following the publication by Fourman and Mullen in 1993, many firms have used a minimum therapeutic dose approach (e.g., 1/1000th of the minimum therapeutic dose) to calculate cleaning limits (5). The existing OEL monograph, if available, can be used as a screening tool to determine if this approach is health-protective. OEL monographs typically include a potency and toxicological evaluation of relevant nonclinical and clinical data. In the workplace, compoundrelated effects (including intended pharmacology and unwanted toxicity) are considered adverse. Many products have a favourable therapeutic index, which means that the pharmacological activity is the most sensitive effect. However, EMA doesn’t address derivation of an ADE from clinical data. Because the OEL is frequently derived from the minimum therapeutic dose, it is reasonable to deduce that the ADE value based on 1/1000th the minimum therapeutic dose is sufficiently conservative for most compounds. ISPE Risk-MaPP outlines science-based adjustment factors that support this assumption. For example, a lower composite adjustment factor (i.e., 10 to account for intra-species differences and 3 to extrapolate to a no-effect level) can be scientifically justified if using the minimum therapeutic dose as the PoD for a product with a reasonably robust dataset (e.g., late- to commercial-stage compound). Therefore, when the human dose information is used as the PoD for OEL derivation, the minimum therapeutic dose cleaning limit approach may be considered health-protective, and no additional value would be derived by proceeding to a formal ADE derivation.

	The exception would be compounds (e.g., classical oncology compounds) with an unfavourable therapeutic index that may cause unwanted or even serious adverse health effects at exposures near or below the indicated minimum therapeutic dose. A mutagenic carcinogen administered at a dose of 750 mg/day, for example, would result in a limit of 750 μg/day using the 1/1000th approach, which is almost three orders of magnitude higher than the TTC level of 1 μg/day using Dolan et al. (or 1.5 μg/day under ICH M7) (4, 6). In these cases, a review by a toxicologist is recommended. When the OEL is calculated using a nonclinical PoD (e.g., repeat-dose toxicity or reproductive toxicity in animals), or involves route-to-route extrapolation, then further review by a toxicologist is also recommended to determine an appropriate ADE value.  

Example of an estimated ADE value calculation using data from the OEL monograph for Compound A.

 The following example illustrates the calculation of an OEL for Compound A using the minimum therapeutic dose of 2.5 mg/day as the PoD. All relevant nonclinical, clinical, and post-marketing data were evaluated. The details are provided to show the similarity to ADE derivation while highlighting that assessment factors used might differ.

	The OEL incorporates a composite adjustment factor (AF) of 30, derived as follows (see 

- UF is uncertainty factor; LOAEL is lowest observed adverse effect level; NOAEL is no observed adverse effect level).

	For the calculation of the OEL, a bioavailability correction factor of 0.3 is included in the numerator to account for oral bioavailability in humans (30%). Therefore, an ADE estimated from the OEL is conservative (i.e., approximately three-fold lower than needed) if the oral route of exposure is applicable for the cross-contamination scenario (see 

	By comparison, 1/1000th the minimum therapeutic dose is 2.5 μg/day (2.5 mg/day/1000), which is 10 times lower than the estimated ADE value. Therefore, the existing cleaning limit is acceptable, and development of a formal ADE value is not a high priority at this time.

Alternative approach 2: What if I don’t have an OEL but I do have an OEB?

 Many companies assign new compounds to an OEB, or equivalent designation by airborne concentration ranges, to provide guidance on safe handling before sufficient data are available to establish a numerical OEL. The OEB is assigned based on the compounds’ inherent pharmacological and toxicological characteristics, including the intended use, mechanism-of action dose-response, and safety pharmacology studies. One option is to use the OEBs to estimate ADEs for the most hazardous subset of compounds (i.e., those with the most restrictive OEBs).

	Example OEB assignment criteria are provided in 

 corresponding to ADE values of 10 and 1 μg/day corresponding to respective OEBs of ≥ 1 <10 μg/m3 and <1 μg/m3 because it is assumed that 10 m3 are breathed during the workday. These are the same values that would be derived using the TTC concept outlined in Dolan et al. (4). Application of these default values presumes that sufficient compound-specific data are not available to estimate an ADE (5). The examples focus on “potent” or “high containment” compounds, but in practice, the principle would still hold across less restrictive bands. As with application of the OEL, a bioavailability correction could be considered if the compound is anticipated to have extremely low bioavailablity via a relevant route.

How can consistent screening to evaluate the effectiveness of existing cleaning limits using the OEL/OEB be implemented? 

 provides an example decision process for systematic determination of whether traditional cleaning limit calculations are adequate using the OEL and OEB. The decision tree shows that use of OEL and application of 1/1000th the minimum therapeutic dose approach could be acceptable under the following conditions:

		For existing commercial products where existing cleaning limits are based on the 1/1000th approach 

		If an OEL monograph including toxicological evaluation of relevant nonclinical and clinical data is available

		If the pharmacological activity is the most sensitive (critical) effect.


	The EMA guide states that “determination of health-based exposure limits using PDE limits of the active and intact product may not be required” for macromolecules (proteins and peptides) (1). When macromolecules are exposed to pH extremes and/or heat, they rapidly degrade and denature and are considered pharmacologically inactive. Only breakdown products such as smaller peptide fragments or amino-acid derivatives formed due to protein hydrolysis would be present after cleaning under conditions that are shown to effectively degrade and inactivate protein-based products.

	In these scenarios, health-based exposure limits of the active products are no longer relevant. An experimental approach and analytical methods for assessing degradation and inactivation of the API during cleaning, and an approach for setting safety-based acceptance limits for inactivated product and process residuals are described in separate industry publications (7, 8). However, if effective protein degradation and inactivation could not be demonstrated in the cleaning studies, cleaning limit should be based on PDE.


	The proposed screening tool and methods for estimating ADE values are appropriate for implementation of the EMA guide with the goal of ensuring health-protective cleaning limits. It is valuable to note that compound-specific hazard is not the only concern as the hazard of all compounds in the matrix must be considered in order to calculate the worst-case cleaning limit for all Product A-to-Product B changeover permutations. Hence, implementation of worst-case permutations affords an additional level of safety for many limits. Further assurance is provided on completion of the cleaning; when the equipment is dry, a visual inspection is typically performed for those surfaces that can be visually inspected.

Guideline on Setting Health-Based Exposure Limits for Use in Risk Identification in the Manufacture of Different Medicinal Products in Shared Facilities 

EudraLex-Volume 4 Good Manufacturing Practice (GMP) Guidelines

(Production), Revisions (January 2015).
	3. ISPE, 

Volume 7: ISPE Baseline Guide: Risk-Based Manufacture of Pharmaceutical Products 

(Risk-MaPP) (ISPE, September 2010).
	4. D.G. Dolan et al. 

43, 1–9 (2005).
	5. G.L. Fourman and M.V. Mullen, 

M7 Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceutical to Limit Potential Carcinogenic Risk 

(ICH M7), Step 4 version (ICH, 23 June 2014, Adopted by EMA September 2014).
	7. A. Mott et al., 


	Andrew Teasdale is a principal scientist at AstraZeneca, andrew. teasdale@astrazeneca.com; Bruce D. Naumann is executive director, Toxicology, Merck & Co.; Gretchen Allison is a senior director in Global Quality Operations at Pfizer Inc.; Wendy Luo is an associate director, Drug Safety Evaluation, Bristol-Myers Squibb; Courtney M. Callis is research scientist, Health/ Safety/Environmental, Lilly Research Laboratories; Bryan K. Shipp is director, Risk Management, Pfizer Inc.; Laura Rutter is SM manager, Analytical Services, GlaxoSmithKline; and Christopher Seaman is senior manager, Occupational Toxicology, GlaxoSmithKline. 

:
	When referring to this article, please cite it as A. Teasdale, "EMA Guideline on Setting Health-Based Exposure Limits," 

The results of an industry workgroup’s examination of EMA’s guide on shared facilities are presented.

EMA Guideline on Setting Health-Based Exposure Limits

	
	Peer reviewed:
	Submitted: Feb. 11, 2015. Accepted: April 7, 2015.

Applications for a drug product that is administered dermally must define acceptable limits for elemental impurities in the product. Current guidelines for exposure limits, however, are based on oral, parenteral, or inhalation exposure and do not adequately address other routes, such as dermal exposure. This article reviews the information available about dermal exposure to metals and considers how it differs from oral or parenteral exposure.

	The International Conference on Harmonization’s (ICH’s) 

 establishes acceptable exposure limits and defines these limits based on route of administration, but does not specifically address dermal limits (1). Thus, developers of dermally delivered drugs are challenged to establish and define those limits. Is it appropriate, for example, to transpose limits based on other routes of administration (i.e., to apply oral or even parenteral limits)? This article seeks to examine the available data relating to dermal exposure to metals and evaluate appropriate approaches to ensure that the limits established will adequately address actual risk.

	The skin is made up of several layers including 

, viable epidermis, and dermis (2). The largest organ in the body, the skin provides a formidable barrier to exogenous materials. Within the skin, the outer layer (the 

) provides the most significant barrier and is rate limiting for any substance applied to the skin, whether intentional, in the form of a deliberately applied ointment, or a contaminant to which the skin is inadvertently exposed (e.g., a metal impurity present in a dermal product). The 

is highly lipophilic and contains very little water. As a result, penetration of hydrophilic or charged molecules is particularly difficult, and such species are effectively unable to partition into the lipid layer and hence pass through the skin at significant levels.


	The skin provides a formidable barrier to any drug. Even when a formulation has been deliberately designed to facilitate transport across the dermal barrier, exposure levels are typically a fraction of those obtained when the drug is delivered by injection. Consider lidocane, for example. Using topical formulations containing lidocaine, the systemic levels that are reached are as follows (3):

		5 µg/mL, after the application of 2 g ointment to the endotracheal tube

		1.3 µg/mL, after the application of 10 g ointment to the oral mucosa for 30 minutes

		0.6 µg/mL, after an oral (ingested) dose of 10 g ointment (bioavailability 35%)

		2.5 µg/mL, after a rectal dose of 10 g ointment (bioavailability 60-70%)

		0.3 µg/mL, after the application of 10 g ointment to a partial thickness burn

		0.1 µg/mL after the application of 10 g ointment to intact skin.

	Systemic levels of lidocaine of 0.1 µg/mL were observed following the application of 10 g dermally (to intact skin). For the same dose administered orally, the level is 6 times higher.  Even when applied to burnt skin, the level (0.3 µg/mL) is still 50% lower than the level achieved through oral administration. When compared to endotracheal application, where there is no effective barrier, the level adjusted for dose is significantly below 5% of the systemic concentration level. These data clearly demonstrate the significant barrier the skin provides and indicate significant concerns for the simplistic approach of applying oral-based limits for elemental impurities.

	Similar data have been generated for polydimethylsiloxane and linear and cyclic siloxanes.

 Dimethicone, a polysiloxane polymer, is widely used in a range of cosmetics. 

human dermal absorption/penetration studies in which neat material was applied to abdominal skin showed that 0.2% and 0.1% of the applied dose of PDMS (10 cST fluid) or PDMS (350 cSt fluid), respectively, remained at the dosing site and could be considered absorbed. The percentage of applied dose that penetrated through the skin to the receptor fluid was ~0.0002% for the 10 cSt fluid and ~0.0003% for the 350 cSt fluid. Studies of its dermal absorption showed no evidence that it had penetrated the dermal barrier (4).

	Oral-dosage absorption is also challenged. In studies where an oral dose of 350-cSt 14C-PDMS was administered to rats at 1000 mg/kg body weight, more than 99% of the recovered dose was excreted by the animals (4). PDMS by the dermal or oral route is minimally absorbed.

 human dermal absorption data for cyclic siloxanes (octamethylcyclotetrasiloxane, D4; decamethylcyclopentasiloxane, D5; and dodecamethylcyclohexasiloxane, D6) again showed extremely low levels of absorption following dermal application (5,6). As the molecular weight and lipophilicity of the cyclic siloxane increased (from D4 through D5 and D6), the percutaneous absorption decreased. The percentages of applied dose absorbed following a neat application was 0.5%, 0.05%, and 0% for D4, D5, and D6, respectively. Penetration into the receptor fluid was 0.01%, 0.002%, and 0.003% for D4, D5, and D6, respectively.

	Absorption data are available in rats following a single oral administration to rats of D4 (300 mg/kg), D5 (1000 mg/kg), and D6 (1000 mg/kg). These mass balance studies indicate that 52%, 20%, and 12% of the orally administered dose was absorbed (7-9). In the case of cyclic siloxanes, a greater percentage of the administered dose was absorbed orally than dermally.


	There are several comprehensive reviews covering exposure to metals. These reviews are predominantly focused on environmental exposure from sources such as soils. In 1993, Hostynek et al. (10) sought to summarize data relevant to the qualitative and, where possible, quantitative evaluation of metal permeation through skin. They looked at assessments for 31 elements, although coverage of ICH Q3D Class 1 metals (mercury, arsenic, cadmium, and lead) is incomplete, as there is no assessment of mercury or lead.

	They concluded that dermal absorption of metals is a complex process affected by multiple factors including size, charge, and oxidation state. They did not, however, draw any definitive overall conclusions regarding generic estimates of absorption, nor does it seek to generically compare rates to other routes of administration.

	A review by the National Environmental Policy Institute, 

Assessing the Bioavailability of Metals in Soil for Use in Human Health Risk Assessments

 (11), sought to specifically examine bioavailability. This review provides a thorough assessment of the available toxicological data for soil samples containing six metals: arsenic, cadmium, chromium, lead, mercury, and nickel. This review focuses on evaluations performed using soluble salt forms of the metals and assesses main routes of administration, including dermal limits. The overriding conclusions are that there are little data available to allow for the specific calculation of dermal exposure; however, the data that are presented support the view that even when present in an aqueous soluble form, metals are poorly absorbed through the skin.

	The most comprehensive and most recent review of dermal exposure to metals is the HERAG 1 factsheet, 

Health Risk Assessment Guidance for Metals--Assessment of Occupational Dermal Exposure and Dermal Absorption for Metals and Inorganic Metal Compounds 

(12). This review, sponsored by the International Council on Mining and Metals and Eurometaux, critically examines existing models used to estimate levels of dermal exposure, and determines their value in assessing the absorption of inorganic metals. One of the most prevalent models used is the EASE (Estimation and Assessment of Substance Exposure) model, developed by the United Kingdom’s Health and Safety Executive. This model defines default dermal absorption rates of 100% or 10% depending on the properties of the substance in question.

	Without relevant experimental data, 10% dermal absorption is used when the molecular weight (MW) of the substance is > 500 and the log P

 [partition coefficient for the compound in question between octanol (o) and water (w)] is smaller than -1 or higher than 4, otherwise 100% dermal absorption is used. The major issue with such an approach is that it was developed for organic chemical compounds; this is not considered relevant for metals, for the following reasons:

 is a parameter that has no bearing whatsoever in the prediction of the properties of a metal or of an inorganic salt of a metal. Inorganic metal species do not permeate the skin by passive diffusion. Instead, the uptake of metals largely depends on the presence of specific transport systems that provide biological gateways for the metal to cross the membrane.

		The dissolution of an inorganic metal compound or the metal itself on the skin surface will intrinsically require dissociation and ultimately liberation of free metal cations. Thus, molecular weight, the second criterion for assigning a dermal absorption rate, is irrelevant for metals. Under no circumstances could any metal cation exceed the cut-off value of 500.

	The review repeatedly makes the point that such general approaches are not only scientifically flawed, but also grossly overestimate the actual levels of exposure.

	Crucially, the review cites recent studies that fundamentally challenge the EASE model, with data derived from studies performed on soluble and insoluble zinc compounds. These data show that penetration of the dermis by soluble zinc sulfate is low and that dermal penetration of insoluble zinc oxide is even lower. The review concludes that dissolution kinetics are the rate-limiting factor. The results from these and other studies are summarized in 

	The article concluded, based on these experimental data, that recent studies conducted to Organization for Economic Cooperation and Development (OECD) standards indicate dermal absorption rates to be at or below 0.3% (12). There is no clear correlation between absorption and such factors as speciation, valency, and/or water solubility. Crucially, the HERAG guidance document concluded that it should be feasible to establish default absorption factors, concluding that a default absorption rate of 1% was reasonable and adequately conservative when the skin is exposed to metals in wet or liquid media. For “dry” exposure to dusts, it proposes a default dermal absorption factor of 0.1% (12).


	The following summarizes literature references with specific data relating to ICH Class 1 metals.

 A white paper specifically focused on arsenic was developed by the New Jersey Department of Environmental Protection (13). The paper provides a useful summary of several studies pertaining to the dermal absorption of arsenic. The data presented show that significant levels of arsenic were found to penetrate the skin of mice; however, this contrasted markedly with the results obtained for human skin, for which levels were within the range of 2-6% of the dose applied. The differences were attributed to the significant intra-species variation in skin thickness, that of a human being substantively greater.

	The National Research Council (1999) (14) evaluated the available information on this subject and stated that “these results indicate a low degree of systemic absorption of arsenic via the skin.” The Agency for Toxic Substances and Disease Registry (15) concluded that “it is usually considered that dermal uptake of Arsenates and Arsenites is sufficiently low that this route is unlikely to be of health concern …, but studies to test the validity of this assumption would be valuable.” Arsenic does not act as a sensitizer upon casual skin contact due to poor skin-penetrating ability of its naturally occurring compounds.

	Further studies were reported by Wester et al. (16). These studies reported a low permeability coefficient of 2.71 x 10

 following topical application of water containing radio-active arsenic.

 Absorption of cadmium through the skin is reported to be extremely low (0.5%) (17). Specific 

 experiments reported by Hostynek et al. (10) were conducted using human skin; these involved exposure for 16 hours to 116 ppb cadmium chloride applied as 2.5 and 5 ul/cm

 solution. Only 0.1 to 0.6% was found in the receptor solution.

	The HERAG factsheet (12) cites the relative absorption rate for cadmium metal and cadmium oxide, concluding that percutaneous absorption is likely to be significantly less than 1%.

The US Occupational Safety and Health Organization (OSHA) (18) concluded that lead can be absorbed by inhalation (breathing) and ingestion (eating) lead (except for certain organic lead compounds not covered by the standard, such as tetraethyl lead). It was also concluded, however, that lead is not readily absorbed through skin, concluding that cutaneous absorption of lead is limited. The amount absorbed through the skin depends on the physical characteristics of the lead (i.e., organic vs. inorganic) and the integrity of the skin.

	The HERAG paper (12) presented data from a variety of studies concluding that dermal absorption rates greater than 0.01% were unfeasible.

 The Hostynek paper (10) concludes that mercury can penetrate the skin in all forms including its elemental form, outlining both intra and intercellular pathways. Data relating to studies performed using guinea-pig skin and limited data relating to human skin are described. The data are complex, showing an apparent non-linear dose response, which was thought to be related to significant skin retention caused by reaction with skin proteins. There are no specific conclusions as to the actual level (%) absorbed.


	The following summarizes literature references with specific data relating to ICH Class 2 metals.

 No specific studies were located regarding absorption in humans or animals after dermal exposure to vanadium, although absorption by this route is generally considered to be very low, according to the World Health Organization (19). Absorption through the skin is thought to be quite minimal due to its low lipid/water solubility.

 The dermal absorption of molybdenum (as the molybdate ion) is low to negligible at approximately 0.2% of the applied dose. These results were shown in an in-vitro percutaneous study by Roper of the absorption of sodium molybdate dehydrate, a highly soluble substance, in human skin (20).

 While the HERAG report (12) raises concerns over the methodology employed in the studies described, it reports that even in the highest example (one where data for level absorbed was combined with the level retained in the 

) the absorption of a soluble salt form was reported to be only 2%.

 There is some evidence of absorption of cobalt metal through skin. Scansetti et al. (21) found that an experimental study with four volunteers, whose skin was exposed to freshly mixed or waste powder containing 5-15% cobalt, measured a ten-fold increase of cobalt in urine. Results confirmed that absorption through skin is a potential route of entry. Later studies by Filon et al. (22) concluded that cobalt can pass through the skin only when it is oxidized to ionic cobalt (Co

 The US Environmental Protection Agency (EPA) has not developed actual toxicity values for metals based on dermal administration. Instead, the EPA has devised a process for making route-to-route (oral-to-dermal) extrapolations for systemic effects. The EPA developed 

Risk Assessment Guidance for Superfund: Volume I Human Health Evaluation Manual (Part E, Supplemental Guidance for Dermal Risk Assessment)

 (23) to address human health risk related to dermal exposures. Part E uses a consistent methodology for assessing the exposures from the dermal pathway for Superfund human health risk assessments.

	Primarily, Part E accounts for the fact that most oral reference doses (RfDs) and slope factors are expressed as the amount of substance administered per unit time and body weight, whereas exposure estimates for the dermal pathway are expressed as absorbed dose. The process uses the dose-response relationship obtained from oral administration studies and makes an adjustment for absorption efficiency to represent the toxicity factor in terms of absorbed dose. Crucially, this does not advocate direct correlation between oral and dermal exposures, which would be crude and simplistic, nor does it advocate the simple direct application of oral limits to dermal application.

European Union (EU) risk assessments, occupational dermal exposure.

 EU assessments have historically been based on the EASE model, which proposes a default absorption of 10%. This is now largely discredited (see HERAG review [12]).

Michigan Department of Environmental Quality (MDEQ)

. The review by the National Environmental Policy Institute (NEPI) (11) reports that MDEQ has had a 1% value in place as the default dermal absorption value for all inorganic compounds since 1995.

West Virginia Department of Environmental Protection (WVDEP).

 In addition, the NEPI report (11) indicates that WVDEP relies heavily on EPA in providing guidance for considering bioavailability in assessing dermal exposures. Default assumptions provided for dermal absorption of metals from soil are 3% for arsenic and 1% for cadmium and other metals.


	Although fragmentary in nature, existing data do nevertheless show that dermal exposure to metals is limited, often well below 10% of that observed when the same materials are administered orally. This conclusion is entirely consistent with the fundamental nature of the dermis and the obvious barrier it presents to charged materials in particular, such as metal ions. Reflecting on the variable approaches taken by regulatory bodies, it is clear than even the most conservative and largely discredited (in the context of applicability to charged metal species) EASE model differs substantially from assumed parity with parenteral or even oral exposure. Certainly the assumptions prescribed by MDEQ and WVDEP of exposure levels equivalent to <5% absorption correlate well with data available, even though it is limited.

	With respect to ICH Q3D and the establishment of dermal exposure limits, the available evidence and data challenge any attempt to correlate dermal limits directly with oral data.  The available evidence and data strongly support the need for a case-by-case approach that takes into consideration such factors as metal form and relevant specific data to establish scientifically justifiable limits. Ultimately, the overriding evidence to date supports the view that dermal exposure to low-level elemental impurities is unlikely to represent a substantive toxicological concern.

		R. Mehta, “Topical and Transdermal Drug Delivery: What a Pharmacist Needs to Know,” 

		Astra Zeneca internal report, “Clinical Documentation on Xylocaine Ointment 5% (50mg/mL),” 2003.	

Technical Report No. 55. Linear Polydimethylsiloxanes 

		Hostynek et al., Critical Reviews in Toxicology  23 (2) 171-235 (1993).	

		National Environmental Policy Institute, 

Assessing the Bioavailability of Metals in Soil for Use in Human Health Risk Assessments. Bioavailability Policy Project Phase II Metals Task Force Report

Health Risk Assessment Guidance For Metals--Assessment Of Occupational Dermal Exposure And Dermal Absorption For Metals And Inorganic Metal Compound

Environmental Assessment and Risk Analysis Element

 (National Academy Press, Washington, 1999).	

		US Dept. of Health and Human Services, Agency for Toxic Substances and Disease Registry, “

Toxicological Profile for Arsenic (Aug. 2007)

Vanadium. Environmental Health Criteria 8

		C. Roper, “Disodium Molybdate Dihydrate: The In Vitro Percutaneous Absorption Of Molybdenum Through Human Skin,” Unpublished study report by International Molybdenum Association (2009).	

Risk Assessment Guidance for Superfund (RAGS), Volume I: Human Health Evaluation Manual (Part E, Supplemental Guidance for Dermal Risk Assessment)


	Andrew Teasdale, PhD* is principal scientist, chair of AstraZeneca‘s Impurities Advisory Group, Hurdsfield Road, Macclesfield, Cheshire, England, SK10 2NX, andrew.teasdale@astrazeneca.com; Katherine Ulman is global regulatory compliance healthcare manager, and Jean Domoradzki is an EHS specialist, both at Dow Corning Corporation, Auburn, MI; and Phyllis Walsh is associate director, compendial affairs at Merck, Rahway, NJ.

	*To whom all correspondence should be addressed.

 When referring to this article, please cite it as A. Teasdale et al., “Establishing Limits for Dermal Absorption of Elemental Impurities,” 

Current guidance for absorption of elemental impurities does not address dermal exposure, resulting in a simplistic approach to limit setting.

Establishing Limits for Dermal Absorption of Elemental Impurities

New guidelines relating to elemental impurities from the International Conference on Harmonization (ICH), Q3D 

 (1) have presented the pharmaceutical industry with new challenges. These challenges include the complexity of introducing new analytical technology-specifically inductively coupled plasma (ICP)-based techniques replacing the wet chemical “heavy metals” limit test-along with new and specific limits for individual elements. Perhaps the most significant challenges, however, are related to the practical implementation of the guideline. 

	ICH Q3D advocates the use of a risk-based approach to assessing the potential presence of elemental impurities in drug products. While such assessments are common within other aspects of pharmaceutical development, application to elemental impurity assessment presents new challenges. Specific challenges include determining how to assess or quantify the risks associated with factors such as water, container-closure systems, and excipients. Defining where in the assessment process data may be required and identifying where risks can be determined to be negligible through a thorough scientific theoretical risk assessment also present significant questions. This article seeks to review these questions by looking at the various risk factors and, where possible, weighting the risk factors based on appropriate and relevant considerations to establish an effective framework for the systematic assessment of risk and final control strategy. 


	 The introduction of ICH Q3D (1) is one of the most complex changes in regulations pertaining to impurities seen by the pharmaceutical industry. While the guideline is ultimately intended to focus on final drug product quality, the actual risk assessment will touch all facets of the manufacture of a drug product. The guideline introduces toxicologically relevant permitted daily exposure (PDE) limits to individual elements replacing non-specific 19th century wet chemical “heavy metal” limit tests. ICH Q3D advocates the use of a risk-based approach to assessing the potential for presence of elemental impurities in drug products. The process of executing and documenting the risk assessment is a major challenge, primarily as a result of a limited global understanding about how to assess or quantify the risk associated with factors such as water, container-closure systems, and excipients.

	Defining where in the assessment process data may be required and identifying where risks can be determined to be negligible through a thorough scientific theoretical risk assessment also present a significant challenge. Where the risk assessment identifies the need for testing, the level of the PDEs for the element(s) of concern may also require the broader introduction of new, more sensitive, and specific analytical technology, adding still further to the complexity.

	This article specifically seeks to examine relevant risk factors and, where possible, the weighting of these risks based on appropriate and relevant considerations. It also seeks to specifically define where in the assessment process data may be required as well as seeking to identify where risks can be determined to be negligible simply through a thorough scientific theoretical risk assessment.

	The general principles outlined in this article are believed to address most scenarios or product types; however, ultimately any drug-product manufacturer needs to consider potential sources of elemental impurities appropriate for their specific product. 


	The evaluation of the potential risk posed by elemental impurities within a formulated drug product requires a holistic approach taking into account all potential sources of elemental impurities. 

 illustrates potential sources that should be considered in such an evaluation. 

: Sources of elemental impurities in finished drug products.

, the drug substance is a key component that can contribute elemental impurities to the finished drug product. The risk of inclusion of elemental impurities from a drug substance, therefore, needs to be considered when conducting a drug product risk assessment. Control of the elemental impurity content of a drug substance can be assured through a thorough understanding of the manufacturing process including equipment selection, equipment qualification, GMP processes, packaging components, and the selection and application of appropriate control strategies.

	A principal responsibility for any drug-substance manufacturer is to develop a strategy to ensure effective control of the levels of elemental impurities in the finished drug substance. An approach based on assessing and controlling potential sources of elemental impurities, coupled with focused, limited testing, is preferable to exhaustive testing on the finished drug substance. A scientific, risk-based approach combined with knowledge and control of the key sources of elemental impurities in the drug-substance manufacturing process such as catalysts, provides an efficient and comprehensive elemental impurity control strategy for finished drug substances. 

 shows potential sources of elemental impurities in the drug substance manufacturing process. Of the sources highlighted, the greatest risk comes from intentionally added metals (e.g., metal catalysts used in the process). Manufacturing equipment, processing aids, inorganic reagents, water, solvents, and other organic materials are less likely to serve as major contributors of elemental impurities in the finished drug substance, but do require consideration.

: Primary sources of elemental impurities in drug substances (DS).

 Metal catalysts such as palladium and platinum are often used in the drug-substance manufacturing process and can therefore be present at low levels in the finished drug substance. The synthetic route should be reviewed for intentionally added metals, and data from purging studies, including any supportive testing of appropriate isolated intermediates, should be used in the design of an appropriate control strategy.
	 The ability to remove the catalyst (purge capacity) will be influenced by catalyst loading and the nature of the catalyst used in the process (i.e., homogeneous vs. heterogeneous catalysts). Heterogeneous catalysts, such as palladium on carbon, are often easily removed from reaction mixtures by filtration, and therefore, the risk of carryover of elemental impurities into the drug substance is typically low. Even in cases where metal catalysts are used in the final stages of the process, good historical data and/or understanding of carry-over may permit reduced testing schemes. 

	Biotech products do not normally rely on the use of catalysts. As ICH Q3D points out, typical purification schemes in biotech drug substance manufacturing are well capable of clearing any elements introduced either intentionally or inadvertently “to negligible levels.” The principles outlined previously may nonetheless be relevant in some specific cases (e.g., chemically modified biotech drug substances).

	When considering the other potential sources highlighted in 

Assessing risk factors is key to implementing the new ICH Q3D guidelines for elemental impurities.