Sarah Thompson

The principles of quality by design (QbD) and life cycle management, as outlined in International Council for Harmonisation (ICH) Q8–Q12, can equally be applied to the development, validation, and ongoing verification of analytical procedures. The first publicly available drafts of ICH Q14 (1) and Q2(R2) (2) issued in March 2022 cover the lifecycle management of analytical procedures and provide guidance on the development and validation stages of the lifecycle. There is little mention, however, of the ongoing procedure performance verification stage. 

’s) general chapter <1220>, entitled “Analytical Procedure Life Cycle” (3), which became official in May 2022, holistically pulls together the design, qualification, and ongoing performance verification of analytical procedures in a single document via a three-stage approach similar to FDA’s lifecycle-based process validation guidance (4).

 <1220> is to ensure that the analytical procedure is fit for purpose across the entirety of the analytical procedure’s life cycle. The requirements that the analytical procedure have to meet can be defined using the analytical target profile (ATP) (a concept explained in both 

 <1220> and ICH Q14 as well as in the literature [5–8]). The ATP is a prospective description of the desired purpose and performance of an analytical procedure that is used to measure a quality attribute and defines the required quality of the reportable value produced by the procedure (3). In Stage 3 of 

 <1220>, the ATP can also be used to determine the acceptance criteria needed to verify the performance of the analytical procedure during routine use (e.g., through a system suitability test [SST] or verification criteria applicable to procedure changes and transfers) and to ensure that the procedure continues to be fit for purpose. Performance verification can still take place even if an ATP hasn’t previously been defined. The verification acceptance criteria in these situations can be derived from validation or system suitability criteria. The principles in Stage 3 of 

 <1220> can therefore equally be applied to procedures that have been formally designed/developed (where an ATP exists) via an enhanced approach as well as procedures where a minimal approach was taken. For high-risk analytical procedures (see later section for how risk is determined), control-chart monitoring of selected performance data, generated during routine use of the procedure, can provide early warning of changes in performance. These data could be direct measures of accuracy and precision (e.g., through the analysis of a quality control sample) or indirect measures (e.g., chromatographic resolution between peaks, signal to noise response, peak tailing factor, etc.). Where the risk is low, performance verification may simply involve monitoring of atypical results and/or system suitability failures.

In addition to ensuring that the analytical procedure is fit for purpose during routine use, ongoing verification can also be used to evaluate the impact of any changes (9) to the procedure across the lifecycle and ensures that the performance of the procedure is maintained at an acceptable level over the procedure lifetime. Ongoing verification can also act as a preventive measure by providing an early indication of potential performance issues or adverse trends and aids in identifying required changes for the analytical procedure.

Determining performance monitoring via risk assessment

The performance of all analytical procedures used in the product control strategy should be assessed across the lifecycle of the product to ensure they remain fit for their intended purpose. This assessment should include routine monitoring (for prioritized procedures) as well as the evaluation of changes made to procedures. The extent of the routine monitoring required can be defined using a risk-based approach (10). It is important to consider which measures of analytical procedure performance or risk are readily available as inputs to a risk assessment. Two risk assessment approaches are described below.

 This approach may focus only on the type and complexity of the analytical procedure and its intended use. This approach would enable the establishment of a platform risk assessment per analytical procedure (technique) type. A complexity factor can be used to ensure that any unusually complex procedures are not underestimated. Analytical procedures that do not form a critical part of the control strategy can be treated as low risk by default.

 This approach may include an assessment of the current performance of the manufacturing process (which includes variability from the product and the analytical procedure) through an assessment of process performance (Ppk [11]) if enough representative batches of the manufacturing process (and analytical procedure) are available. A more involved risk assessment approach may include an assessment of the capability (precision) of the specific analytical procedure relative to the product specification or ATP. Precision to tolerance ratio (P/TOL [12]) and Z-score (13) are metrics that can be calculated to aid such an assessment. Conformity and validity rates and/or procedure robustness and reproducibility can also be used. Where procedures have been shown to be sensitive to changes (e.g., analyst, equipment, environment, reagent lots, or small changes in procedure parameters), this sensitivity presents a higher risk. 

 depicts sources of variability associated with Ppk and procedure capability metrics (such as P/TOL and Z-score). 

ALL FIGURES ARE COURTESY OF THE AUTHORS. 

 Product and analytical procedure sources of variability. P/TOL is precision to tolerance ratio.

Manufacturing process performance assessment through Ppk.

 Ppk (11) is a process performance index and can be used as a worst-case surrogate measure for analytical procedure precision. It represents a combination of manufacturing process and analytical procedure variability over the long term. If a drug product has a good overall process capability (Ppk) for a particular quality attribute (i.e., if the test results show little variation versus the specification), then it can be assumed that the analytical procedure precision is good (see 

where USL is the upper specification limit, LSL is the lower specification limit, 

overall is the combined process and analytical procedure standard deviation.

Analytical procedure performance assessment through P/TOL or Z-Score.

 P/TOLis described by Chatfield and Borman (12), and it is defined as shown in 

a is the analytical procedure standard deviation. Low P/TOL values are desirable.

The Z-score (13) is similar to P/TOL as it is defined as the number of analytical procedure standard deviations between the process mean and the nearest specification limit (see 

where SL is the nearest specification limit to the process mean (

A data-driven risk assessment that considers both process and analytical procedure capability is shown in 

 Data-driven risk assessment for identification of high-risk analytical procedures. P/TOL is precision to tolerance ratio.

When performing a risk assessment, it is possible that a low-risk procedure could become a high-risk procedure during a subsequent periodic risk assessment due to changes in the manufacturing process that impact the process mean, or changes to specification limits, despite the analytical procedure precision (

a) remaining constant. In such cases it may not be possible/practical to improve the procedure performance to reduce the risk of out-of-specification data, but it may be appropriate to consider manufacturing process improvements or review of the specification limit(s).

Development of risk-based performance-monitoring plans

Three types of procedure performance indicators categorized by Ermer 

Conformity: the number of out-of-specification results with analytical procedure root cause in a given time period. The number and types of analytical procedure errors will provide information on the reliability of the analytical procedure.

Validity: the number of invalid test results due to failures of system suitability criteria (established during Stage 1 of the lifecycle approach) in a given time period

Measurements collected during each analytical procedure test occasion monitored using control charts: these measurements could be critical analytical procedure attributes or parameters specified in the analytical procedure with well-defined acceptance criteria or ranges, respectively, or attributes or parameters selected due to a potential link with procedure performance.

“Conformity” monitoring is usually sufficient for low-risk analytical procedures, whereas for high-risk procedures “validity” monitoring and monitoring of informative analytical procedure attributes and/or parameters can provide early warning of potential changes in procedure performance.

A useful mechanism to identify the most value-adding performance attributes or parameters to monitor for high-risk procedures is to perform a procedure performance cause-and-effect review (PPC&ER). This review provides the analytical team with an understanding of likely root causes of any high risks identified from the risk assessment. Potential improvement ideas and tailored procedure performance indicators can then be documented for further consideration (and potentially taken forward for inclusion in the monitoring plan).

 <1220> and ICH Q14 describe the use of Ishikawa or fishbone diagrams (11) for risk identification. These are highly useful tools for collectively brainstorming potential sources of variability associated with a procedure. Gembas (11) (or “procedure walk-throughs” used in the implementation of lean principles) are also very important for this activity, and the analysts that are most familiar with the procedures should be included. It can also be useful to include independent experienced analytical scientists who are not familiar with the particular procedure under assessment and/or technique subject matter experts. Augmented reality technology can be a useful way to orientate all meeting participants with the procedure under assessment and to demonstrate any particularly problematic steps. Once sufficient analytical procedure platform knowledge has been acquired, creation of generic Ishikawa diagrams and process maps can prove useful starting points and serve to significantly accelerate this step. As it is not practical to monitor all potential sources of variability, it is important to prioritize the most value-adding procedure performance indicators for the monitoring plan.

A PPC&ER can be performed for new high-risk procedures that have been developed following the guidance in Stage 1 of 

 <1220> or ICH Q14 (as part of procedure development) and a monitoring plan developed at the same time as design of the analytical procedure control strategy. For established analytical procedures where 

’s Stage 1 was not followed/documented, then a new PPC&ER can be a good first step towards the design of a monitoring plan. Once the procedure performance indicators for routine monitoring have been selected, a decision on the most appropriate method of monitoring can be taken. The use of control charting in a similar fashion to statistical process control (SPC) should be considered to facilitate the identification of any drifts in performance of high-risk analytical procedures over time. The authors recommend the adaptation of SPC (14) tools and have termed this “Statistical Analytical Procedure Performance Control (SAPPC).” Well established SPC control chart types such as Shewhart (14), cumulative sum (Cusum) (14), and exponentially weighted moving average (EWMA [14]) can be applied to analytical procedures. Performance data compiled over time allows for the calculation of average parameters, for example repeatability from replicate sample preparations or intermediate precision from control sample analysis. Such average parameters are very reliable estimates of the long-term performance (10) and facilitate the identification of atypical results.

Analytical procedure performance monitoring will enable opportunities for proactive improvement of procedure performance to be identified over time. Improvements could be relatively small, such as updating training plans or changing wording in method documentation to improve clarity and consistency of procedure operation. Improvements could relate to instrument or reference standard management, or sometimes more fundamental procedure changes that require regulatory pre-approval action (e.g., changes to critical analytical procedure parameters or analytical technology).

Opportunities for improvement can be considered as a part of periodic review (e.g., reviews may occur during scheduled revisits of the analytical procedure risk assessment and PPC&ER or in response to a procedure performance trend alert during routine performance monitoring).

Case study 1: quantification of API polymorphic purity

 (15) describe how ongoing verification of a solid-state nuclear magnetic resonance (ssNMR) procedure used to quantify polymorphic purity of an API enabled an unusual effect relating to a standard used in the procedure to be identified and remediated promptly through a detailed PPC&ER. The level of an unwanted Form (Form 3) in the standard was observed to gradually increase over time. Following a thorough PPC&ER, corrective actions were implemented that resulted in the variability of the procedure due to the standard being significantly reduced with an acceptable range of ±1%. Following implementation of remedial actions, it was agreed to routinely monitor the amount of Form 3 as part of the routine procedure performance monitoring plan to ensure the integrity of the standard was maintained.

Case study 2: ion chromatography procedure performance monitoring

Ion chromatography instrument failures were observed for the same analytical procedure at two independent quality control laboratories after years of normal operation. These failures resulted in lengthy investigations, system downtime, and wasted resources. A PPC&ER determined the root cause to be an aging component within the ion chromatography system. As the aging of the instrument component led to a slow decline in procedure precision over time, calibration standard injection % RSD and % sample duplicate difference have now been added to the routine procedure performance monitoring plan for this procedure to provide an early detection mechanism. 

 provides examples of how these procedure performance indicators are trended. Drift in performance can be identified and the aging component replaced before batch results are impacted, and before system failure occurs. 

 Drift in precision detected over time for an ion chromatography procedure. RSD is relative standard deviation.

Ongoing analytical procedure performance verification can be used to ensure that procedures continue to be fit for their intended purpose across the lifecycle of their use. It can be equally applied to analytical procedures that have been developed via an enhanced approach (where an ATP has been created) as well as established procedures where 

 <1220> Stage 1 was not followed/documented. The extent of monitoring should be risk-based, and the assessment of both the manufacturing and analytical capability is recommended to determine which analytical procedures carry the greatest risk. A detailed procedure PPC&ER employing tools such as fishbone diagrams and gembas can be used to identify the most value-adding performance attributes or parameters to monitor (control charting is recommended for high-risk procedures). Performance verification can provide an early indication of potential performance issues and highlight opportunities to improve procedures. It can also be used to assess any changes made to analytical procedures over the lifecycle.

 <1220>, Analytical Procedure Lifecycle. 

Guidance for Industry, Process Validation: General Principles and Practices

 (CDER, CBER, 2011).
5. Barnett, K.L.; McGregor, P.L.; Martin, G.P.; et al. Analytical Target Profile: Structure and Application Throughout the Analytical Lifecycle. 

, 42 (5).
6. Jackson, P.; Borman, P.; Campa, C.; et al. Using the Analytical Target Profile to Drive the Analytical Method Lifecycle. 

, 91 (4), 2577–2585.
7. Rignall, A.; Borman, P.; Hanna-Brown, M.; et al. Analytical Procedure Lifecycle Management: Current Status and Opportunities. 

, 42 (12), 18–23.
8. Borman, P.; Campa, C.; Delpierre, G.; et al. Selection of Analytical Technology and Development of Analytical Procedures Using the Analytical Target Profile. 

, 94 (2), 559–570.
9. Chatfield, M.J.; Borman, P.J.; Damjanov, I. Evaluating Change During Pharmaceutical Product Development and Manufacture-Comparability and Equivalence. 

, 27 (5), 629–640.
10. Ermer, J.; Aguiar, D.; Boden, A.; et al. Lifecycle Management in Pharmaceutical Analysis: How to Establish an Efficient and Relevant Continued Performance Monitoring Program. 

, 181, 113051. DOI: 10.1016/j.jpba.2019.113051.
11. Ishikawa, K. 

What is Total Quality Control? The Japanese Way

; Prentice-Hall, Englewood Cliffs, NJ, 1985.
12. Chatfield, M.J.; Borman, P.J. Acceptance Criteria for Method Equivalency Assessments. 

, 81 (24), 9841–9848.
13. Vukovinsky, K.; Watson, T.; Ide, N.; et al. Statistical Tools to Aid in the Assessment of Critical Process Parameters. 

, 40 (3), 34–44.
14. Suman, G.; Prajapati, D. Control Chart Applications in Healthcare: a Literature Review. 

, 9 (5).
15. Barry, S.J.; Pham, T.N.; Borman, P.J.; Edwards, A.J.; Watson, S.A. A Risk-Based Statistical Investigation of the Quantification of Polymorphic Purity of a Pharmaceutical Candidate by Solid-State 19F NMR. 

Phil Borman is vice-chair of the USP Measurement and Data Quality Expert Committee (USP M&DQ EC); Amanda Guiraldelli Mahr is scientific affairs manager, US Pharmacopeia; Jane Weitzel is chair of the USP M&DQ EC; Sarah Thompson is principal scientist—Analytical Project Expert, AstraZeneca; Joachim Ermer, Stephanie Sproule, and Jean-Marc Roussel are members of the USP M&DQ EC; Jaime Marach is member of USP Analytical Procedure Life Cycle Joint Subcommittee; and Horacio Pappa is senior director, US Pharmacopeia.

When referring to this article, please cite it as Borman, P.; Mahr, A.G.; Weitzel, J.; et al. Ongoing Analytical Procedure Performance Verification—Stage 3 of 

Articles

Analytical procedure performance can be continually verified by risk-based monitoring of performance related data.

Ongoing Analytical Procedure Performance Verification—Stage 3 of USP<1220>

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.