Laura Rutter is a SM manager, analytical services at GlaxoSmithKline

Laura Rutter

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," 

Articles

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

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 

, it is recommended to focus primarily on the manufacturing steps that occur after the formation of the final intermediate. Washes, crystallizations, phase separations, chromatography, distillations, and processing aids/scavengers aid in purging of elemental impurities and, therefore, reduce the risk of carryover into the finished drug substance from stages earlier in the upstream process. Areas for further consideration include manufacturing equipment, processing aids/inorganic reagents, solvents, water, and packaging. 

 In general, GMPs, including equipment compatibility assessment and qualification, are sufficient to ensure that significant levels of elemental impurities are not leached from manufacturing equipment into the drug substance. Hastelloy, stainless steel, and glass are the most commonly used materials of construction for drug substance manufacturing equipment, due to their superior chemical resistance. Nickel, cobalt, vanadium, molybdenum, chromium, and copper are key elements in some Hastelloy and stainless-steel alloys. Under extreme/corrosive reaction conditions, such as high temperature and low/high pH, these elements could have the potential to leach from manufacturing equipment. In such cases, it may be necessary to supplement standard GMP equipment compatibility assessments with specific studies to assess the elemental impurity-leaching propensity from manufacturing equipment due to corrosive reaction conditions. 

	Other potential sources include high-energy processes such as milling/micronization equipment. These are also generally considered to be low risk, but should be addressed via appropriate GMP including cleaning records and visual inspection. Particle size reduction is discussed in the Drug Product Manufacture section.

 Processing aids such as charcoal, silica, celite, and darco, and inorganic reagents such as sodium chloride, magnesium sulfate, and sodium sulfate, are often used in drug-substance manufacturing processes and may be used in significant quantities. Depending on their specific composition, inorganic reagents should be considered within the risk assessment, especially when ICH Q3D elements are integral to the formula. The levels used should also be considered as some reagents may be employed in higher relative amounts (i.e., in stoichometric amounts). In such instances not only the elements (intentionally) present in the reagents, but also reagent purity (or lack thereof) need to be taken into account. 

	In general, the use of such reagents presents a low risk. In studies conducted within the organizations associated with this article, there is little evidence to support such materials being a significant risk. Therefore, the risk assessment should primarily focus on processing aids and inorganic reagents used late in the drug substance manufacturing process, and/or where aggressive reaction conditions exist (e.g., extreme pH/high temperatures for prolonged times).

 Most solvents used in the manufacture of drug substances, particularly those listed in ICH Q3C, Impurities: Guideline for Residual Solvents (2) Class 3, are unlikely to contribute elemental impurities to the finished drug substance. The majority of solvents are purified by distillation and few involve the direct use of metal catalysts in their manufacture; hence they are considered a low risk source of elemental impurities. In the event that solvents have not been purified by distillation, especially if a catalyst in used in their manufacture, further evaluation in the risk assessment should be considered.

 Refer to the environmental factors discussion is the Drug Product Manufacture section.

 Packaging is discussed in the section Container-closure Systems (CSS) as a Potential Source of Elemental Impurities in Finished Drug Product. 

 It must be recognized that, from a compliance perspective, the limits for elemental impurities in ICH Q3D apply only to the drug product. To ensure effective control of the level of elemental impurities in the drug substance a number of options are available:

		The ICH Q3D option 1 concentration limits assume a maximum daily drug product intake of 10 g/day. Drug substances that meet option 1 concentration limits can be used at any dose in the drug product.

		ICH Q3D option 2 concentration limits are calculated specifically based on the actual daily drug product intake (and composition) and may provide higher concentration limits than option 1 (if the maximum daily intake of drug product is <10g).

	The acceptable level of elemental impurities in a drug substance may be defined and agreed upon in a suitable quality agreement between the drug substance manufacturer and the drug product manufacturer.


	While drug substance manufacturing often involves a complex series of processes, some simple scientific principles can be applied to ensure that elemental impurity levels in the final drug substance are controlled to appropriate levels. The application of a risk-based control strategy, involving an understanding of the manufacturing process and key sources of elemental impurities, appropriate equipment selection/qualification, adoption of suitable GMP processes/procedures, and the selection and application of appropriate control options will typically result in the manufacture of drug substances with elemental impurity levels well below ICH Q3D option 1/option 2 concentration limits. This overall low risk status is supported by the emerging dataset from ICP-optical emission spectrometry (OES) and ICP-mass spectrometry (MS) screening of a wide range of drug substances plus the significant body of historical heavy-metals test data. 


	One of the greatest challenges to performing an elemental impurity risk assessment for a drug product is to understand the potential contribution of elemental impurities from excipients. 

	Elemental impurities of concern for excipients would typically be:

		Class 1 and Class 2a elements potentially present at trace levels in the excipient based on environmental factors

		Intentionally added catalysts or reagents for synthetic excipients

		Class 3 elements from excipients that are targeted for a specific route of administration (e.g., inhaled).

	Unlike drug substances, there may be less information available from excipient vendors with respect to the manufacturing equipment and processes used (e.g., any high energy steps, corrosive reagents, or added catalysts), which may potentially introduce elemental impurities. While many vendors will supply, on request, a compliance statement with the European Medicines Agency (EMA) metal catalyst guideline (3), the elemental impurity testing reported on the certificate of analysis is typically based on a non-specific, wet chemistry heavy-metals limit test with the result reported as less than the specification value in parts per million. When considering the risk of elemental impurities potentially being introduced into the drug product via excipients at levels greater than the PDE, the following points should be considered:

		Source of the excipient (mined, plant, animal, synthetic, etc.)

		Excipient level in the formulation (wt. %) (4)

 The origin of an excipient can have a significant impact on the degree of risk associated with elemental impurities. 

:  Potential sources of elemental impurities in excipients.

	Mined excipients may exhibit a natural variation depending on the location of the mine and the natural geology. The potential levels of elemental impurities from mined excipients may be more variable and therefore pose a higher risk than synthetic excipients manufactured using metal reagents and/or catalyst where the levels are less variable as a result of well-defined manufacturing processes and controls. 

	Excipients harvested from plants also pose a potential risk as a result of their uptake of metals from their environment. Synthetic excipients that are manufactured without the use of metal catalysts and/or reagents present the lowest risk of introducing elemental impurities to the drug product. 

 An essential consideration in determining the risk contribution for elemental impurities from an excipient is the proportion of the excipient used in the formulation. The risk contribution from a mined excipient used as a filler or diluent (typically >20 wt% of the blend), for example, will be greater than the risk contribution of a mined excipient used in a tablet film coat (typically <5 wt%).  

	Generally, low-weight percentage components that are not mined are regarded as low risk; however, the daily product dosing and route of administration also need to be considered. 

 Dose and dosing regimens should also be considered. A low, orally administered, daily dose clearly presents a lower risk than an inhaled product as shown by the lower PDE limits for inhalation vs. oral found in Table A.2.1 of the ICH Q3D guideline (1). 


	The above principles can be used as part of an excipient risk assessment and are a useful guide in the absence of data. In addition, manufacturers should consider the principles for controlling elemental impurity generation from manufacturing equipment, as described in the Manufacturing equipment section for Drug substances.

 (USP) <231> from the United States Pharmacopeial Convention, however, uncertainty exists as to whether excipient manufacturers and vendors will test for elemental impurity concentrations and, if so, for what elements, to what levels, and using what procedures/equipment.

	It must be recognized that, from a compliance perspective, the limits for elemental impurities in ICH Q3D only apply to the drug product. Excipient manufacturers may, however, be requested to assist in assuring compliance through awareness of the level of elemental impurities within the excipient itself. In addition, the same general principles of evaluation options for drug substances described previously apply to excipients.

	In some instances, it may be appropriate to define and agree on the acceptable level of elemental impurities in an excipient through a suitable quality agreement between the excipient manufacturer and the drug product manufacturer.

	Ultimately, it is the responsibility of pharmaceutical manufacturers to demonstrate, via risk assessment and/or data, that the drug product is compliant with ICH Q3D. To this end, the development of a common database for excipient elemental impurity profiles will be a useful activity to support risk assessments. The International Pharmaceutical Excipients Council of the Americas (IPEC-Americas) and FDA have performed an exercise examining elemental impurity levels from multiple excipients, which is planned for publication. This information indicates that the vast majority of excipients (analyzed by ICP-MS) contain elemental impurities at levels unlikely to cause concerns at typical usage levels in oral solid dosage forms. 


	The drug-product risk assessment needs to consider the potential elemental impurity contribution from the drug product manufacturing equipment/process. Manufacturing for solid products encompasses a large variety of processes, such as solid mixing (blending), granulation, tableting (compression), coating, and particle size reduction. For liquid product manufacture, dissolution or suspension of solid excipients and drug substance is often carried out in metallic equipment. In contemporary cGMP facilities, the likelihood of additional contribution of elemental impurities is negligible. However, there is a theoretical risk associated with Class 2A metals such as vanadium, nickel, etc., because these elements are commonly found in manufacturing equipment; for example, 316L stainless steel contains approximately 10% w/w nickel. Therefore, understanding the drug product equipment in terms of materials of construction will be a key factor in completing the risk assessment. The risk assessment should focus on any steps involving high kinetic energy (solids) or corrosive liquids that may facilitate the transfer of elements from the equipment into the product.

	A consideration of typical drug product manufacturing steps and conditions is provided in 

 Processing a liquid product containing a drug substance, excipients, and solvent (typically water-based buffer) in metallic vessels can potentially facilitate the transfer of elements into the liquid drug product, particularly at high/low pH. An assessment of material compatibility should be completed, taking into account factors such as ionic content, pH, temperature, hyrdophilicity/hydrophobicity, terminal sterilization conditions, and contact time. Testing should only be required if this assessment identifies a substantive risk.


	In general, the risk for elemental impurity contribution due to processing of solid drug product components in cGMP facilities is low, as stated explicitly in ICH Q3D. Although much equipment used to process drug product is metallic (e.g., stainless steel vessel), the majority of the processes used in drug product manufacture can be discounted as a source of risk. Even areas highlighted as needing consideration (

) are expected to only result in controls outside routine cGMP in extreme cases.

 As part of the holistic risk assessment of elemental impurities described in ICH Q3D, there is a need to consider the potential contribution resulting from environmental factors such as water and air. 

 Water used in the manufacture of both drug substances and formulated drug products is a potential source of elemental impurities. The level of risk, however, may be strongly related to the quality of water. This risk was examined in detail in a USP stimuli article on water for pharmaceutical use (5). The following position was articulated:

		The source water used in drug product manufacturing must meet the World Health Organization (WHO) standard for drinking water. When this source water is further purified in a contemporary plant to generate purified water (PW) and/or water-for-injection (WFI), the elemental impurity levels should be below acceptable concentrations allowed for drug roducts using option 1 control strategy defined in ICH Q3D.

		As part of standard GMP, water quality should be routinely monitored and the purification system and storage of the water should not re-introduce elemental impurities.

	Based on this position, the risk of elevated elemental impurity levels within aqueous-based formulations-even large-volume parenterals-is considered negligible. The risk associated with the use of water in the manufacture of the drug substance can also be effectively eliminated through the appropriate use of WHO-standard potable water combined with the use of USP purified water for the final stage in the manufacture of the drug substance, including its isolation. 

 Air is not likely to present a substantive risk; furthermore, air quality can also be managed through proper GMPs via use of HEPA filtered air, etc. No specific assessment is therefore generally required.

Container-closure systems as a potential source of elemental impurities in finished drug product


	One of the potential sources of elemental impurities is product packaging, often referred to as container-closure system (CCS). In determining the risk posed by the CCS, there are a number of factors that need to be taken into consideration including:

		Nature of formulation--mechanism for contamination

		Nature of risk: safety vs. quality risk

	In terms of the type of formulation, it is inconceivable that substantive or even trace-level contamination would occur where physical contact is limited to solid-to-solid contact. This is entirely consistent with the FDA Guidance for Industry, Container Closure Systems for Packaging Human Drugs & Biologics (6), which in relation to extractables and leachables considers solid-to-solid contact of low risk. It is therefore reasonable to conclude that any assessment of risk associated with CCSs should be limited to those associated with either liquid or semi-solid formulations.

	The second aspect of any risk assessment of the CCS involves an understanding of the potential levels of metals present within the material concerned. A major review of materials in manufacturing and packaging systems as sources of elemental impurities in packaged drug products was published in 2013 (7). The publication summarized literature data for a number of common packaging materials, including levels of elemental impurities within the component material (determined by digestion), as well as elemental impurities extracted from the component materials. The data, while fragmentary, are nevertheless comprehensive, and several key conclusions were drawn. While certain materials were found to contain elemental impurities, the presence of the elemental impurity was predominantly associated with deliberate use of metal catalysts, for example the use of antimony in the manufacture of polyethylene terephthalate (PET). In the case of PET, levels of antimony of approximately 50 ppm are typical (full digestion). Focusing particularly on those elements of high concern (Class 1 and Class 2), only fragmentary data exist to suggest even trace levels present within the component material, for example cadmium and lead levels up to 100 ppm were reported in polyvinyl chloride. Even when low levels of elemental impurities are present in the material itself, the effective “availability” of the elemental impurity needs to be considered. What is consistently clear from the extraction data presented is that extracted elemental impurity levels (under relevant conditions) are a minute fraction of the total elemental impurity levels present in the component materials, typically <0.1% of that observed following digestion. Therefore, even when trace levels of certain elements are found in the component material, the available elemental impurity concentration may represent an extremely low safety risk (

:  Illustration of risk factors associated with packaging.

	There may, however, be potential quality-related risks. Such risk may result from potential metal-catalyzed degradation of the product in question. While the interaction between packaging material and solid dosage forms is negligible (ICH Q3D), this may not always be the case for non-solid drug products. Reported examples include iron (8), nickel (9), and tungsten oxide. In the case of tungsten, this related to leaching from the syringe barrel, causing protein aggregation (10). As a consequence, many biopharmaceuticals include ethylenediaminetetraacetic acid to “mop up” metals. Assessments of such risks should be addressed on a case-by-case basis.

	Evaluations should thus focus on liquid and semi-solid formulations. Detailed leachable studies should only be required where there is a lack of elemental impurity extractives data for the packaging components in question.

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