Nancy Lewen is research fellow, CSD Analytical chemistry, Bristol-Myers Squibb.

Nancy Lewen

A version of this article was published in 

APIs, Excipients, and Manufacturing 2019 Supplement

The current interest in nanotechnology and its application to the medical field has historical precedent. Initial products employed general physical chemistry of colloids to produce stable drug suspensions and improve bioavailability. The later introduction of liposomes began the evolution to today’s more sophisticated, and potentially revolutionary, new technologies accompanying the rapid growth in biotechnology product opportunities, notably including targeted drug delivery products.

	The term ‘nanomaterials’ describes materials that have features or structures that exist on the nanoscale in any of the three spatial dimensions. The large numbers of formulations containing nanomaterials that are currently under development, under review, or have already received approval from the US FDA emphasizes the need to identify important properties of these formulations and methods of measurement of their properties to ensure quality and performance. FDA has offered guidance to nanomaterials (1). The document emphasizes the need to evaluate materials with any dimension in the nanoscale (1–100 nm) as well as products showing size-dependent properties with dimensions up to 1000 nm.

	Nanomaterials may be added to the dosage form to confer a desired physicochemical or mechanical properties; for example, colloidal silicon dioxide (i.e., fumed silica), which acts as a glidant in tablet manufacture. Despite achieving the desirable properties, undesirable effects of excipients should also be considered. A guidance for industry from FDA addresses the needs of this class of nanomaterials (2).

	When considering the composition of specific nanomaterial formulations a variety of structures can be considered including: carbon nanotubes (3,4); dendrimers (5); drug (6) and inorganic (7) nanoparticles; liposomes (8), micelles (9,10), nanobubbles (11); nanoemulsions (12), nanofibers (13–15), polymeric (16,17) (natural and synthetic); and solid-lipid nanoparticles (18). Characterization of nanomaterial is presented below.

	Products may initially contain nanomaterials, or this state of matter might result from post-market changes to existing products through processes to create nanostructures. Over a period of 10 years, spanning the turn of the Millennium, products for cancer (doxorubicin and paclitaxel), anemia (sodium ferric gluconate complex), macular degeneration (pegaptanib sodium), tear production (cyclosporine), aspergillosis (amphotericin B), acromegaly (lanreotide acetate), and hypercholesterolaemia (fenofibrate) as liposomes, inorganic, and polymeric (natural and synthetic, nanotubes, nanocrystal emulsions, and micelles (19) were prepared. Many of the aforementioned formulations have yet to be translated to commercialized products. However, it should be anticipated that many will find their way onto the market.

	Nanotechnology can be employed to modify the biopharmaceutical disposition, bioavailability, and biodistribution, of a drug substance. Desired characteristics such as solubility and the route of administration of the drug substance dictate how critical the size and structure of nanomaterials are to their function. 

	Rapidly degrading/dissolving nanoparticles exhibit near instantaneous loss of morphology and release drug substance for absorption and distribution, whereas nanoparticles that remain intact for extended time periods may play a role in the pharmacological effect of the drug in the central compartment due to their size and/or structure. Following oral administration, a rapidly dissolving, readily bioavailable nanocrystal drug substance/formulation is known to exhibit different pharmacokinetics compared to that exhibited by a formulation containing the drug substance of larger particle size. Similarly, differences in integrity of nanoparticles, rapid or slow dissolution, will influence systems administered by the parenteral route. Hydrophobic systems are routinely used for intravenous injection and inhalation. Synthetic and natural polymeric nanoparticles forming rigid structures have been used primarily for intramuscular depot delivery. Nanocrystals have been delivered in oral solid dosage forms for gastro-intestinal (GI) absorption. 

	Generalizing critical quality attributes from one product to the next to accommodate the needs of quality by design is difficult (19). Nevertheless, key variables should be identified, and their impact characterized and controlled to support quality metrics. Considerations with respect to products containing nanomaterials have been reviewed (20) and risk has been characterized (21). 

	General texts on the safety of nanomaterials exist (22). Specific considerations for drug products containing nanomaterials relate to the kinetics of dissolution and disposition following administration and the fate of components of the materials. Safety considerations for pharmaceutical nanomaterials in a regulatory context have been described (13,16,20,22). 

	The risk associated with the drug alone exposure is a baseline consideration for a nanoparticle formulation. It can be assumed that rapidly dissolving nanoparticles carry the same risk as molecular drug presentation, because the existence of the nanomaterial is transient. Long residence-time nanoparticles potentially modulate the risk. Limiting the release rate of the drug may reduce the risk of adverse effects. In contrast, the risk may be elevated beyond that of the drug and components alone if accumulation or concentration in specific physiological compartments occurs. Parenterally administered inorganic particles (e.g., gold and silver), micelles, and liposomes are among the drug nanomaterial combinations that might present an elevated risk. Oral administration of nanoparticles may affect the residence time of nanoparticles in the GI tract as a desirable drug delivery function but may also raise the potential for elevated risk.

	Every drug product requires the assessment of quality parameters to grant safety and efficacy to be released for human and veterinary use. Yet, nanomaterials add an additional layer of complexity to the formulation steps. For example, the processes of mixing/blending, filling (solid and liquid), compression, and lypophilization require consideration of the nanomaterial state and its preservation throughout manufacturing. Performance quality tests follow the dosage form characterization and route of administration considerations set forth in the 

) and regulatory guidance. If the nanomaterial is essential to the function of the dosage form, additional specific tests may be requested.

	A comprehensive approach to the measurement of physicochemical characteristics includes the following: 

		Aerodynamic particle size distribution using 

<601> for micro-aggregated nanoparticles and <1601> nebulized particles or low-pressure impactor for nanoparticle aerosols (23) 

		Composition and structure using atomic absorption spectroscopy and photon-correlation spectroscopy 

release using microdialysis (24), fiber optic probe (25), infrared (26) and Raman (27) spectroscopy 

		Particle size using scanning and transmission electron microscopy (SEM and TEM) and atomic force microscopy (AFM)

		Particle distribution using photon correlation spectroscopy, small angle X-ray and neutron scattering (SAXS and SANS); 

		Purity, shape using SEM, TEM, AFM, SAXS and SANS, and solubility 

		Surface area using gas adsorption, surface properties using X-ray photoelectron spectroscopy, secondary ion mass spectroscopy, zeta potential, and freeze fracture SEM

Critical quality attributes (CQA) and regulatory considerations. 

It should be noted that FDA and the European Medicines Agency (EMA) do not formally use the term ‘nanomedicines’ and EMA has only recently acknowledged it.

	Nanomedicines in combination products are subject to the overarching FDA guidance and then assessed on a case-by-case basis. There are no combinations in the EMA lexicon so it is important to meet with the regulatory agency early to address requirements.

	FDA has guidance that is overarching, class-specific, and product-specific. The International Pharmaceutical Regulators Forum is developing a map of relevant guidance and regulations.

Methods and specific product considerations. 

An example of specific consideration is the use of an oral formulation with and without nanomaterial. In this case, FDA would conduct a risk assessment and track this information over time as it would for products not containing nanomaterials. Each product would be managed on a case-by-case basis, and the complete package would be evaluated regarding the materials and their physicochemical properties, and how they impact quality. This approach ensures that methods are appropriate to the way the product is characterized. This approach necessitates that CQAs are defined and have adequate characterization methods, stability testing, and a risk management plan.

	As bioequivalence implies drug bioavailability from the drug product, the extent to which the unique contribution of nanomaterials as a subcomponent should be evaluated depends on the dosage form. For example, drug release information from drug products containing nanomaterials may be required by FDA. Consequently, dissolution testing may be a tool that can be used for evaluation. The analysis of dimers (or other polymers) may require a different method and gel electrophoresis has been considered.

	There may be subtle differences in the way in which dynamic light scattering (DLS) measures particles based on their material properties, hard versus soft, for example. FDA is also working with the International Organization for Standardization (ISO), American Society for Testing and Materials (ASTM) International, and USP to develop and disseminate DLS standards. It is important to recognize which materials DLS would appropriately characterize. Complementary methods to DLS seem to focus on microscopy.

An informatics strategy for the collection and collation of data is required to characterize CQAs of the nanomaterial in the product. It is difficult to identify biological endpoints attributable to the nanomaterial. Measures of efficacy and safety should be derived from the studies of the drug product. 

	The most prominent drug formulations comprising nanoparticles are liposomes, drug nanocrystals, and iron colloids as illustrated by the earlier mentioned extensive description. The most frequently measured characteristic-particle size distribution-and the DLS and high-resolution imaging techniques employed will be the initial focus of the USP in preparing general chapters to address these topics. 

	A strategy will then be adopted to continue to introduce general chapters as new delivery systems come to market and to increase the compendium of important physicochemical properties measured. In this regard zeta-potential measurement has been identified as an important method for which a general chapter should be developed. In addition, the expert committee with the most relevant expertise to prepare these chapters will be alerted to the need and tasked with generating the document (e.g., physical analysis, dosage forms or excipients).

	There is a need for clarity on CQAs, their measurement and impact on product quality, safety, and efficacy.

	1. FDA, Guidance for Industry Considering Whether an FDA-Regulated Product Involves the Application of Nanotechnology (Rockville, MD, June 2014).
	2. FDA, Guidance for Industry, Non-Clinical Studies for the Safety Evaluation Of Pharmaceutical Excipients (Rockville, MD, May 2005).
	3. A. Bianco, N. Kostarelos, and M. Prato, 

, 9 (6) 674–679 (2005).
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, 47 (4) 366–374 (2016).
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, 38 (3) 185–196 (2009).
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., 115 (19) 10938–10966 (2015).
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., 12 (36) 4669–4684 (2006).
	10. C.J.H. Porter, N.L. Trevaskis, and W.N. Charman, 

., 6 (3) 231–248 (2007).
	11. J. Ma, et al., 

., 12 (3) 4022–4028 (2015).
	12. M. Jaiswal, R. Duhde and P.K. Sharma, 

, 5 (2) 123–127 (2015).
	13. D.H. Reneker, et al., 

., 87 (9) 4531–4546 (2000).
	14. S Thakkar and M. Misra, 

., 107 148–167 (2017).
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., 30 (5) 472–489 (2015).
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, 75 (1) 1–18 (2010).
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., 6 877–895 (2011).
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., 50 (1) 161–177 (2000).
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., 7 (5) 640–654 (2015). 
	20. R.H. Müller, K. Mäder, and S. Kohla, 

., 50 (1) 161–177 (2000).
	21. A.S. Narang, R.K. Chang, and M.A. Hussain, 

., 102 (11) 3867–3882 (2013).
	22. U. Vogel, et al., 

Handbook of Nanosafety: Measurement, Exposure and Toxicology 

(Elsevier-Academic Press, 2014).
	23. M. Marjamäki, et al., 

., 31 (2) 249–261 (2000).
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., 3 (5) 409–415 (2013).
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., 28 (7) 1643–1652 (2011).
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., 83 (10) 3943–3949 (2011).
	27. R.L. McCreery, M. Fleischmann, and P. Hendra, 


	Supplement: APIs, Excipients, and Manufacturing
	October 2019
	Pages: s12–s15

	When referring to this article, please cite it as A. Hickey, et al., "Perspectives on Quality Attributes of Drug Profucts Containing Nanomaterials," 

Pharmaceutical Technology APIs, Excipients, and Manufacturing

Articles

In this article, the contents of a stimulus article produced by the joint subcommittee of the USP Expert Committees on Dosage Forms, Physical Analysis, and Excipients and relevant comments from a workshop session are summarized.


Perspectives on Quality Attributes of Drug Products Containing Nanomaterials

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,” 

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

The determination of elemental impurities is one of the standard tests performed as part of leachable and extractable studies for a final container-closure system (CCS). The Code of Federal Regulations(21 CFR 211.94) (1) states “drug product containers and closures shall not be reactive, additive, or absorptive as to alter the safety, identity, strength, quality, or purity of the drug beyond the official or established requirements.” To ensure that the CCS does not alter the performance of the product, nor that anything is being introduced into the final drug product, extractable and leachable testing is performed. FDA’s Guidance for Industry on Container Closure Systems for Packaging Human Drugs and Biologics (2) recommends that extraction studies be conducted for the critical components of the packaging system. 


An extractable study is initiated with all the components of the CCS that will be in direct contact (i.e., the primary component) with the drug product. For example, in a vial/stopper system, the vial and stopper are examined, but not the metal seal that secures the stopper to the vial. For a ready-to-use syringe, the syringe barrel, needle, needle shield, and stoppers are tested, but not the plunger. Oral products have blister packs, plastic bottles, or heat seals as contact surfaces. These primary components are examined individually and are subjected to a variety of conditions, such as extremes of temperature, pH, organic solvents, and placebo. The exact conditions are based upon the drug-product formulation and storage conditions. The extractable study is designed to provide a worst-case scenario to determine what impurities, if any, can be extracted from the components of the CCS. Studies are designed to minimize any degradation of the extracted compounds that might occur to provide an accurate profile of the extraction products.

The leachable study is designed to provide an estimation of the extent that any of the extractable impurities actually leach into the drug product during normal shelf life and storage conditions. To design the leachable study, a toxicological assessment of the compounds identified in the extraction study is performed to determine the safe level of exposure based upon the route of administration. Based on this toxicological assessment, target limits are established for the extractable compounds, methods are developed and validated for quantitation, and the leachable study is initiated. The leachable study is performed with the actual drug product (or placebo) in the CCS that is to be the final commercial presentation using materials obtained from the targeted commercial suppliers. The leachable studies are generally performed using the long-term stability study supplies. 

Requirements for elemental impurity analysis


The extractable studies will include any elemental impurities that may be extracted from the CCS components. The results of these studies identify which elements will be monitored in subsequent leachable studies. Recently, the United States Pharmacopeial Convention (USP) issued in the

(3), which provides a listing of the elemental impurities of potential toxicological concern as well as acceptable limits for those elements. USP General Chapter <232> applies to drug products.

The European Medicines Agency (EMA) also issued its 

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

 (4), which addressed elements of interest and maximum daily exposure limits for patients. In establishing its listing of elements and their corresponding limits, EMA evaluated existing toxicological information and based the final listing of elements and limits on patient safety. In 2012, the European Directorate for the Quality of Medicines & HealthCare (EDQM) in the

(Ph. Eur. ) adopted the EMA guideline as a new chapter, 5.2.0 

 (5), publishing it verbatim and thereby adopting both the EMA’s listing of analytes of interest and their corresponding limits.  

While the EMA guideline and the new USP General Chapter <232> are not completely harmonized, there is nonetheless, a considerable amount of harmonization between the two documents. For both EMA and USP, patient safety was the foremost reason for an element’s inclusion on the list of analytes of interest. These assessments are based on an assumed maximum daily dose of 10 g/day (of drug product) and have factors built into them to assure that the limits are well within the safety limits for each elemental impurity.  

Historically, any elemental impurities that are seen in extractable studies are further evaluated and followed during subsequent leachable studies. This testing is often done, regardless of whether there is any toxicological data that would indicate a potential for impact on patient safety or the contrary. As a result, costly and often unnecessary testing has been performed. Because the EMA and USP toxicological assessments have conservatively established limits based on patient safety, it is appropriate to use those limits to make any decisions regarding the need (or lack thereof) to monitor elemental impurities during leachable studies.

Risk-based approach for elemental impurity analysis in leachable studies


With the publication of the EMA guideline, 

 5.20, and USP General Chapter <232>, the analytical community has been provided with a complete listing of the limits for all elements that have the possibility to negatively impact patient safety should they find their way into pharmaceutical products. Because the listing of elements and limits have been thoroughly vetted by a cadre of toxicologists from around the world, this information can be used to establish a risk-based approach for assessing elemental impurities in the context of leachables studies.

Risk-based approaches are permitted by the EMA guideline, the

., and the USP and take into account the entire process, requiring good control on all aspects of manufacture, including the supply chain of both raw materials and packaging components. Using this approach, it is possible to assess whether or not a specific test, or--in the case of elemental impurities--a specific element must be tested.   

Given the acceptability of a risk-based approach, and the acceptable safety limits provided by the EMA guideline, the 

, it is now possible to identify target limits for elements of interest in leachable studies based on the context of those documents. Table I provides a listing of the 

 elements of interest and limits. Although the permitted daily exposures (PDEs) provided in 

 assume a 10 g/day maximum daily dose, it is possible to calculate the appropriate daily concentration limit (µg/g) for a product with a different daily dose using the following equation:
  
  Concentration limit (µg/g) =              PDE (µg/day) 
                                             Maximum daily dose (g/day)	(Eq.1)
  
Once the appropriate concentration limits are calculated, it is possible to use the listing of elemental concentration limits to determine whether or not to include a given elemental impurity in a leachable study. The example in 

 illustrates how this risk-based approach would be used for an oral dosage form. The same approach may be used for other routes of administration, such as parenteral. Use

 to calculate the appropriate concentration limits for the analytes observed in the extractable study--silicon (Si), sulfur (S), boron (B), pallidum (Pd), iron (Fe), lead (Pb), chromium (Cr), arsenic (As), sodium (Na), potassium (K), and mercury (Hg)--for an oral drug product with a maximum daily dose of 200 mg. Where the 

 limits differ, use the lower of the two limits. For example, for iron, the

 guidelines list the concentration limit as not applicable (N/A) and 13,000 µg/g, respectively, in

. Using Equation 1, the appropriate concentration limit would be (13,000 µg/day)/(0.2 g/day) = 65,000 µg/g. 

Large-volume parenteral component limit (µg/g)

The authors discuss a strategy for developing a risk-based approach for testing of elemental impurities in leachable studies.