Insights into Elemental Impurities

Elemental impurities in drug products are impurities that either are or contain certain chemical elements – most notably those elements identified as metals and transition metals. The ICH Harmonized Guideline Q3D, Guideline for Elemental Impurities (1), notes in its introduction that “because elemental impurities do not provide any therapeutic benefit to the patient, their levels in the drug product should be controlled within acceptable limits”. This is a logical observation, and the guideline (which applies to both new finished drug products and new drug products containing existing drug substances) presents a process for assessing and controlling elemental impurities. A related document, United States Pharmacopeia (USP) Monograph <232> Elemental Impurities – Limits (2), also specifies limits for the amounts of elemental impurities in drug products. Both have been aligned to provide a consistent position on safety requirements for elemental impurities.

Q3D and USP <232> represent an evolutionary – rather than revolutionary – advance in drug product impurity profiling. It has been a long-standing requirement that drug products be characterized for metallic impurities via the so called heavy metals test, so Q3D and USP <232> are not noteworthy in the sense that they introduce, for the first time, the concept of elemental impurity profiling. However, Q3D and USP <232> are noteworthy in that they establish more rigorous and quantitative test methods for drug product characterization, notably:

• Increased breadth (Q3D/USP <232> target a greater number of elemental impurities).
• Increased sensitivity (the Q3D /USP <232> methods are several orders of magnitude more sensitive).
• Improved focus (Q3D/USP <232> emphasize a “customized” focus on individual elemental impurities as opposed to total heavy metals).

It seems clear that implementation of Q3D and USP <232> will provide a more rigorous assessment of the safety of future drug products. However, a ‘great unknown’ in the implementation of these procedures is currently how the test results obtained by applying these evolutionary tests (and specifications) to existing drug products will correlate with compliance obtained via heavy metals testing. Indeed, until such products are tested via the new, evolutionary methods and held to the new specifications, the precise impact of the implementation of Q3D and USP <232> remains to be established.

Packaging systems are in intimate contact with the drug product, raising the possibility that packaging material components may leach out and become foreign impurities. Both ICH Q3D and USP <232> establish a drug product’s packaging system as a potential source of elemental impurities and both documents note that “the potential contributions from (container-closure systems) should be considered to determine the overall contribution of elemental impurities to the drug product”. However, neither document provides a specific or detailed means of determining and assessing a packaging system’s contributions to a drug product’s elemental impurity profile.

On the other hand, guidance on how to establish the presence of potential elemental impurities in packaging is provided by the USP in the form of various relevant monographs; in particular, USP <661> Plastic Packaging Systems and their Materials of Construction (3).

Looking into USP <661>

USP Monograph <661> notes that contact between plastic packaging systems and the packaged drug products “may result in an interaction between the therapeutic products and the packaging systems and its materials or components of construction” and further states that “these interactions must be such that the suitability for use (including safety and efficacy) of the therapeutic products and the packaging systems is not adversely affected by the interaction.” The monograph establishes the tests and specifications that are needed to make sure that packaging systems are suitable for use – and accomplishes this via two associated Monographs, Plastic Materials of Construction <661.1> (4) and Plastic Packaging Systems for Pharmaceutical Use <661.2> (5).

While the two monographs – <661.1> and <661.2> – are logically connected and together support the development and use of packaging systems that are suited for their intended use, they address different aspects of plastic packaging systems characterization and/or qualification. <661.1> seeks to ensure that packaging systems are suited for their intended use by focusing on selection of appropriate construction materials. The concept is to avoid using candidate materials that could adversely affect the quality and safety of pharmaceutical products. By contrast, <661.2> considers the entire packaging system from a more holistic perspective. Correctly applied, each may produce data significant to a competent safety assessment.

Proper material selection

Focusing on materials of construction, <661.1> is based on the premise that “to ensure that a packaging system is suited for its intended use, it is important to select materials of construction which are suited for use in packaging systems.” It adds: “intentional selection of well-characterized materials minimizes the risk that a system made from those materials will be unsuitable.”

The overall objective of <661.1> is to “establish, with a degree of confidence, whether potential material candidates could adversely affect the quality and safety of pharmaceutical products.” While <661.1> characterization establishes the composition or characteristics of the material and thus aids decision making about whether the material is an appropriate candidate for use in a packaging system, there is no guarantee that plastic systems constructed from materials meeting <661.1> specifications will be suitable for their intended use. As the monograph points out, “the actual qualification of the material occurs when the entire system is qualified for use in a particular application via <661.2> testing.”

Materials that have been tested by <661.1> methods and which meet the specifications therein are said to be “well characterized”. The implication is that decisions concerning the use of the material in a specific packaging situation can be made and justified on the basis of the characterization data.

However, the data do not specifically or universally qualify the material for use in packaging systems, as the conditions of use can vary depending on the packaging application. It is the developer or user’s responsibility to expertly review the <661.1> test results, as well as additional information as necessary, to decide if the characterized material is appropriate for its intended use. In other words, the intent of <661.1> is to provide information that enables decision-making, but not to make decisions!

The quest for elemental knowledge

Monograph <661.1> addresses elemental impurities by focusing on extractable elements (not total element content) because elements from plastics become elemental impurities in drug products only if they leach (or extract) from the plastic packaging component or system. Thus, while knowledge of the presence and amount of an element in a plastic is useful information, the more relevant information from the perspective of elemental impurities is knowledge of the element’s leaching characteristics and potential.

To support the generation of this knowledge, <661.1> advises on:

• The means of generating and testing an extract.
• The “relevant” elements that must be targeted.
• The reporting thresholds (with regard to the outcome of the testing).
• The limits for specific metals consistent with specifications that exist in other pharmacopeia (typically non-safety).

The recommended methodology for extracting elements is the “standard extraction” – heating the sample in the presence of strong acid (0.1N hydrochloric acid). An acid extraction is justified by the generalization that elements, specifically metals, are extracted in their highest quantities in acidic media. The exact means of generating the extract (amount of material per volume of acid, means of heating) is customized somewhat for individual plastic materials. Overall, the <661.1> methodology is designed to generate a ‘worst-case’ profile of extracted elements as few drug products will have a pH as low as that of the extraction solvent.

An element is deemed to be relevant (i.e., targeted for quantitation) in any of the following circumstances:

• If the element or substances containing the element are intentionally added to the plastic material.
• If the plastic material is contacted by the element or a source of the element during its production and it is possible that the element could be entrained in the material as a result of this contact.
• If the element is targeted in other pharmacopeia.
• If the element has been established in the elemental impurity guidelines as being an elemental impurity that is applicable to all drug product dosage forms, regardless of whether the element is intentionally added to the dosage form or not.

Note that although the driving force for assessment in the USP guidelines is safety, the principal driver in other pharmacopeias may be some other attribute.

For those elements that <661.1> targets for safety reasons, the monograph proposes a reporting threshold that is tied to a concentration of 0.01 mg/L in the extract; this level was chosen on the basis of a survey of laboratories well-versed in trace metal analysis. Since the extraction stoichiometry varies somewhat from material to material, material-based reporting thresholds (in µg/g) would be a less meaningful measure. For those elements that <661.1> targets because they are stipulated in other pharmacopeia, the limits specified in those pharmacopeia are reproduced in <661.1>.

The use of reporting thresholds by <661.1> assists in material selection. Thresholds, as opposed to limits, are particularly appropriate given the difficulties in aligning impurity limits for packaging with impurity limits for packaged products – difficulties which are exacerbated when one moves from packaging to materials of construction, as materials of construction are at least one step further removed from the packaged drug product.

Relevant or Irrelevant?

There is an interesting discontinuity between the capabilities of the screening test procedures for elemental impurities and the concept of “relevant elements”.  Elemental impurities that are present in packaging systems, which can leach from such systems and which could adversely affect patient safety, are clearly “relevant” elemental impurities.  Elemental impurities that are not present in packaging systems, which cannot leach from packaging systems or are generally recognized as safe, are clearly “irrelevant” elemental impurities.  Screening test procedures for elemental impurities quantify both “relevant” and “irrelevant” elemental impurities, so routine analysis of extracts could produce information on elemental impurities that are not strictly reportable per guidelines such as <661.1>.  This opens the question of “what to do with the data for “irrelevant” elemental impurities?”  As it is clear that information on “irrelevant” elements might be useful in making decisions concerning packaging for quality attributes other than safety, and that collecting data is a primary means for establishing what elemental impurities are irrelevant, users of guidelines such as <661.1> must recognize that it is not the guideline’s intent to exclude “irrelevant” metals when data on such metals is readily available; rather, the guideline’s aim is to ensure that proper focus is applied to the relevant metals.

Addressing safety – <661.2>

Of course, compliance with <661.1> tests does not guarantee that plastic packaging systems will be suitable for their intended use; it only enables a decision as to whether a given material is an appropriate candidate for use in a packaging system. Definitively establishing the suitability of a given material in a given application requires that the complete package system be tested in that application according to <661.2> guidance. Indeed, “the intent of <661.2> is to define and delineate the testing needed to produce the data required for establishing the packaging system’s safety”(5).

Monograph <661.2> establishes that the chemical safety assessment required for a packaging system must address the relevant elements established in the elemental impurities guidelines, and should also consider the relevant permissible daily exposure (PDE) values contained in those guidelines. However, it is not necessary – and is largely inappropriate – for <661.2> to interpret the drug product PDEs in relation to allowable levels of impurities (or impurity generating entities) in packaging systems because of the great diversity of packaging systems, as well as storage and distribution conditions. Establishing limits that would be applicable in every circumstance would be impractical.

Moreover, the “proper contribution” that a packaging system can make to a packaged drug product’s elemental impurity profile varies case by case. In one extreme, where other contributors to a product’s elemental impurity “use up” a product’s entire PDE, it is clear that the elemental impurity limits for the packaging system would need to be a very small portion of the product PDE. At the other end of the spectrum, where other contributors to a product’s elemental impurity use up only a very small portion of the entire PDE, then elemental impurity limits for the packaging system could be a very large portion of the product PDE. Each particular drug product will sit in the continuum between these two extremes and its place on the continuum cannot be established by solely testing the packaging system, as this does not address the other contributors to the packaged drug product’s impurity profile. Therefore, any attempt to establish a fixed portion of the PDE that is allowable for, or assigned to, the packaging system in all cases would be an arbitrary exercise.

By not specifying limits for extractable elemental impurities for packaging systems, <661.2> embraces the spirit of the elemental impurity guidelines: though PDEs are an appropriate tool to use in the safety risk assessment of elemental impurities, comparison of exposure levels to PDEs does not necessarily represent the only means to comprehensively assess safety in all cases. Circumstances associated with individual situations may dictate how PDEs are used in a risk-based process of safety assessment.

Strictly necessary?

It may be legitimate to ask if elemental impurity guidelines are actually necessary for plastic packaging. Guidelines to establish and limit the presence of extractable elemental impurities in plastic packaging systems are necessary only if (a) plastic packaging systems contain sources of elemental impurities and (b) the elemental impurities are leached from the packaging at high enough levels that they could adversely affect the safety of patients who receive the packaged drug product. A recent review of published information concerning the levels and extractability of elemental entities from plastic materials commonly used in pharmaceutical packaging systems (6) concluded that:

• Sources of elemental impurities are not typically intentionally added to plastics used in pharma packaging.  
• Sources of elemental impurities are rarely accidentally or unintentionally present in plastics used in pharma packaging.
• Only a small fraction of the total amount of elemental entities present in plastics used in pharma packaging is leached into the packaged drug product under the conditions of production, storage, distribution and clinical use.

If these conclusions are valid over a wide range of materials and situations, then elemental impurity profiling of plastic packaging materials, components and systems by screening (meaning looking for elements which may or may not be present) may not provide a greater assurance of drug product quality or safety – which in turn could indicate that scouting might not be required by pharmacopeia or regulatory guidelines. Alternatively, targeting intentionally added or otherwise known elemental impurities and their sources could provide a greater assurance of drug product quality and safety – which in turn could indicate that targeting should be required by pharmacopeia or regulatory guidelines.

Although the existing information is compelling, it is not currently definitive enough to justify the reduction in or the elimination of elemental impurity profiling of plastic packaging materials, components or systems. But will this change in the future? Testing materials, components and systems using the methods and specifications contained in <661.1> and <661.2> will produce an extensive body of information and it may be that the preponderance of evidence that this information represents will support the reduction or elimination such testing. We will just have to do the testing and evaluate the results to establish the proper path moving forward.

Dennis Jenke is Distinguished Scientist at Baxter Healthcare Corporation, USA.