Review ArticleReview

Materials in Manufacturing and Packaging Systems as Sources of Elemental Impurities in Packaged Drug Products: A Literature Review

Dennis R. Jenke, Cheryl L. M. Stults, Diane M. Paskiet, Douglas J. Ball and Lee M. Nagao
PDA Journal of Pharmaceutical Science and Technology January 2015, 69 (1) 1-48; DOI: https://doi.org/10.5731/pdajpst.2015.01005

Abstract

Elemental impurities in drug products can arise from a number of different sources and via a number of different means, including the active pharmaceutical ingredient, excipients, the vehicle, and leaching of elemental entities that are present in the drug product's manufacturing or packaging systems. Thus, knowledge about the presence, level, and likelihood of leaching of elemental entities in manufacturing and packaging systems is relevant to understanding how these systems contribute to a drug product's total elemental impurity burden. To that end, a joint team from the Extractables and Leachables Safety Information Exchange (ELSIE) Consortium and the International Pharmaceutical Aerosol Consortium on Regulation and Science (IPAC-RS) has conducted a review of the available literature on elemental entities in pharmaceutically relevant polymers and the presence of these elemental entities in material extracts and/or drug products. This review article contains the information compiled from the available body of literature and considers two questions: (1) What elemental entities are present in the relevant polymers and materials and at what levels are they present? (2) To what extent are these elemental entities leached from these materials under conditions relevant to the manufacturing and storage/distribution of solution drug products? Conclusions drawn from the compiled data are as follows: (1) Elemental entities are present in the materials used to construct packaging and manufacturing systems as these materials either contain these elemental entities as additives or are exposed to elemental entities during their production. (2) Unless the elemental entities are parts of the materials themselves (for example, SiO2 in glass) or intentionally added to the materials (for example, metal stearates in polymers), their incidental amounts in the materials are generally low. (3) When elemental entities are present in materials and systems, generally only a very small fraction of the total available amount of the entity can be leached under conditions that are relevant to packaged drug products. Thus, while sources of certain elemental impurities may be ubiquitous in the natural environment, they are not ubiquitous in materials used in pharmaceutical packaging and manufacturing systems and when they are present, they are not extensively leached under relevant conditions. The information summarized here can be utilized to aid the elemental impurity risk assessment process by providing the identities of commonly reported elements and data to support probability estimates of those becoming elemental impurities in the drug product. Furthermore, recommendations are made related to establishing elements of potential product impact for individual materials.

LAY ABSTRACT: Extraneous impurities in drug products provide no therapeutic benefit and thus should be known and controlled. Elemental impurities can arise from a number of sources and by a number of means, including the leaching of elemental entities from drug product packaging and manufacturing systems. To understand the extent to which materials used in packaging systems contain elemental entities and the extent to which those entities leach into drug products to become elemental impurities, the Extractables and Leachables Safety Information Exchange (ELSIE) and International Pharmaceutical Aerosol Consortium on Regulation and Science (IPAC-RS) Consortia have jointly performed a literature review on this subject. Using the compiled information, it was concluded that while packaging materials may contain elemental entities, unless those entities are intentional parts of the materials, the amounts of those elemental entities are generally low. Furthermore, generally only a very small fraction of the total available amount of the entity can be leached under conditions that are relevant to packaged drug products. Thus, risk assessment of sources of elemental impurities in drug products that may be related to materials used in pharmaceutical packaging and manufacturing systems can utilize the information and recommendations presented here.

Introduction

An impurity in a drug product is an extraneous entity that is “not the drug product substance or an excipient in the drug product” (1). Because impurities do not provide a therapeutic benefit to the user of the drug product and could adversely impact the safety and/or efficacy of the drug product, they are expected to be known and rigorously managed. One set of impurities that present a potentially high risk in terms of reactivity and safety impact are those impurities, organic or inorganic, whose chemical formula include elements from the following series in the periodic table: transition metals, metalloids, other metals, and lanthanides and actinides. Impurities that contain such elements have been termed elemental impurities. Other elements can be extracted from materials (e.g., alkali metals, alkaline earth metals, halogens) but are not considered to be within the scope of elemental impurities. As is the case with all impurities, elemental impurities should be managed so that their levels in drug products are known and low. To this end, standards-setting organizations such as ICH and the USP have developed, or are developing, guidelines and recommendations that address the management of elemental impurities in drug products (2⇓⇓⇓–6).

Elemental impurities in drug products can arise from a number of different sources and via a number of different means. One potential source of elemental impurities is the materials that are used in the drug product's manufacturing or packaging systems. Of specific concern to this paper are polymers used in these systems, although data on other materials of construction (such as glass and stainless steel) is also contained herein. Elemental entities that are present in these polymers may leach into the drug products during the time that the drug product (or its precursors) is in contact with the polymers, and these leached elemental entities become elemental impurities in the drug product. In fact, the product quality impact of the leaching of elemental entities from packaging systems is well documented (for example, 7⇓⇓⇓–11). Thus, knowledge about the presence, level, and “leachability” of elemental entities in polymers used in manufacturing and packaging systems is relevant to understanding how manufacturing and packaging systems contribute to a drug product's total elemental impurity burden. Such an understanding may be instrumental in terms of evaluating the relative risk associated with element entities in polymeric materials and packaging systems and the establishment of appropriate controls and specifications.

Since polymers have been used in packaging and manufacturing systems for decades, there is an extensive, albeit disjointed, body of literature on the subjects of the elemental entity content of polymeric materials and the “leachability” of these elemental entities. Compiling and evaluating this body of literature could facilitate the processes of risk assessment and control. To this end, a joint team from the Extractables and Leachables Safety Information Exchange (ELSIE) Consortium and the International Pharmaceutical Aerosol Consortium on Regulation and Science (IPAC-RS) has conducted a review of the available literature on elemental entities in pharmaceutically relevant polymers and the “leachability” of these elemental entities into extracting solvents and/or drug products. This article contains the information compiled from the available body of literature and considers how such information might be used to set relevant specifications around elemental entities in polymers. While such a compiled body of information could be used to address a number of issues and topics, the following questions are the primary focus of this review article:

  1. What elemental entities are present in the relevant polymers and materials and at what levels are they present?

  2. To what extent are elemental entities present in relevant polymers and materials leached from these materials under conditions relevant to the manufacturing and storage/distribution of solution drug products?

Discussion

Aspects of the Collated Data

The most desirable dataset for addressing the questions raised in the Introduction would be produced by a systematic study of a large numbers of relevant materials via standardized test methods that consider a well-defined and comprehensive list of targeted elemental entities. Such a study has not been documented in the chemical literature and such a dataset is not presented here. Rather, this paper collates relevant information from approximately 50 articles that are available in the chemical literature (12⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓–61). These various studies are characterized by different purposes, different methodologies, different targeted entities, and different levels of relevance. Some studies were performed for the purpose of developing and validating an analytical methodology. Some studies were performed with the intent of characterizing individual materials, while other studies examined the leaching properties of uncharacterized materials. Some studies clearly focused on pharmaceutical applications, while other studies considered somewhat similar applications, such as packaging for foods.

It is beyond the scope of this article to examine the individual studies collated in this paper and distill out the differences so that all the collated information defines a consistent, cohesive, and comparable dataset. Thus, in addition to reporting the study results, this paper collates and reports those experimental conditions that are relevant and necessary to put each individual study into its proper context, thereby producing a useful collation. It is the authors' opinion that when the collected data is taken in aggregate it provides relevant and useful insights into the questions posed in the Introduction, differences between the source documents and source studies notwithstanding.

Analytical Methodologies

In general, this article summarizes studies that established either the total amount of an elemental entity in a test article or the amount of an elemental entity that could be extracted from a test article under defined extraction conditions. Generally, there are two means to characterize a material with respect to its total elemental entity level, direct analysis and destructive testing. As the name implies, direct analysis utilizes an analytical methodology that is capable of characterizing a material in its natural state, such as neutron activation analysis (NAA) and x-ray fluorescence spectrometry. Alternatively, destructive testing involves solubilization of the test sample (generally via digestion, which involves exposure of the sample to concentrated acids under conditions of high temperature and/or pressure) followed by analysis of the resulting liquid by atomic spectrometric methods such as atomic absorption spectrometry (AAS), inductively coupled plasma atomic emission spectroscopy (ICP/AES), or inductively coupled plasma atomic mass spectrometry (ICP/MS). Compositional characterizations of pharmaceutically relevant materials have been reported using both direct and destructive methodologies, and information using both approaches is compiled here.

Each analytical approach has its strengths and weaknesses, and it is beyond the scope of this article to judge the relative merits of these approaches. Nevertheless, most, if not all, of the studies used in this paper included relevant quality control measures (e.g., analysis of spiked samples or certified reference standards) to establish the accuracy of their analyses. For example, Skrzydlewska and Balcerzak tested a certified polyethylene (PE) reference material, BCR-681, via their acid digestion–ICP/MS methodology and reported recoveries ranging from approximately 85% to 110% for Cr, As, Cd, Hg, and Pb (26, 48). The precision of replicate determinations (n = 3) was generally 11% relative standard deviation (RSD) or less. Zucchi et al. reported the use of x-ray fluorescence to test acid digests for elemental entities and document precisions of approximately 24% RSD (47). Considering only the instrumental analysis (and not the digestion), these authors tested certified multi-element standard solutions and generally recovered 80% to 120% of the known elemental entities [As, Ba, Cr, Co, Cu, Mn, Ni, Pb, Se, Zn with a precision % RSD (for n = 3) of 10% or less]. Considering NAA, Thompson, Parry, and Benzing analyzed National Institute of Standards and Technology (NIST) standard reference material No. 1572 (citrus leaves) along with numerous plastic materials (49). While in general the mean of four determinations was near the certified values for elements such as Al, Ca, Cu, I, K, Mg, Mn, Na, and Sr, the precisions were on the order of 7% to 14% RSD. In another NAA study, Baidoo et al. analyzed Standard Reference Materials GBW07106 (rock matrix) and NIST standard reference material No. 10 (glass) and reported results for over 50 elements (57). In general the recoveries were considered adequate and the precision of the methodology was in the range of 10% to 20% RSD.

In addition to accuracy and precision, several teams of investigators report detection limits for their methodologies. Based on the digestion of 250 mg of material to produce a digest of 10 mL, Zucchi et al. report detection limits of 0.1 to 100 mg/kg using x-ray fluorescence (47). Based on the digestion of approximately 200 mg of material to produce a digest of 50 mL, Skrzydlewska and Balcerzak report detection limits between 0.01 to 0.50 ng/g via time-of-flight ICP/MS (26). A second team of investigators who also used acid digestion followed by ICP/MS analysis reported detection limits ranging from 0.2 to 2 mg/kg, based on digesting approximately 500 mg of material to produce a 50 mL digest (24). While limits of detection via direct NAA analysis vary somewhat across different test materials and different elements, Thompson, Parry, and Benzing report detection limits that range from 0.001 to 10 mg/kg (44).

Considering the analysis of extracts for extracted elemental entities, ICP/MS is generally recognized as the method of choice, due to its low detection limits and multiple element capabilities. In their analysis of extracts from syringes, Van Hoecke, Catry, and Vanhaecke report limits of quantitation that vary from 0.0014 ng/mL for Pt to 26 ng/mL for Na (25). Ding and Nash report limits of detection that range from 0.01 to 2.5 ng/mL in water or ethanol extracts of components used in single-use manufacturing systems (18). Representatives of the Product Quality Research Institute (PQRI) and ELSIE organizations report that detection limits on the order of 1 ng/mL are readily obtainable in aqueous and organic extracts of plastic materials (35, 56).

Elemental Entities in Polymeric Materials

Elemental entities in materials used in the construction of manufacturing and packaging systems are present in such materials for one of five reasons:

  1. The elemental entities themselves or sources of the elemental entities are parts of the materials (e.g., SiO2 in glass) or intentional ingredients in the materials (e.g., zinc stearate in various polymers as an acid scavenger).

  2. The elemental entities themselves or sources of the elemental entities are impurities in the intentional ingredients of the materials (e.g., calcium as an impurity in the technical grades of zinc stearate used as noted in item 1).

  3. The elemental entities themselves or sources of the elemental entities are used in manufacturing the materials (e.g., organometallic catalysts).

  4. The elemental entities themselves or sources of the elemental entities are entrained into the materials due to the material's method of construction (e.g., tungsten metal present in glass syringe barrels due to the use of tungsten pins to form the barrel's cavity).

  5. The materials are unintentionally tainted by elemental entities or sources of elemental entities (e.g., storage of a bonding solvent in metallic canisters, resulting in a solvent that contains metal residuals).

If elemental entities or sources of elemental entities are not intentionally present in materials or intentionally used to manufacture materials, then the issue of elemental entities leaching from materials and becoming elemental impurities in drug products would be an issue related to the control of incidental contamination and the topic of material-derived elemental impurities would be of reduced consequence. However, it is well known that elemental entities or sources of elemental entities are necessary and critical ingredients in materials and necessary and critical reagents used in material manufacturing. For example:

  1. In the manufacture of polyethylene terephthalate (PET), antimony trioxide, germanium oxide, or antimony triacetate are used as both an additive and a catalyst at a maximum level of 0.035%. Bromine is added in the manufacturing stages because brominated flame retarding agents protect against the risk of accidental fires. Cobalt compounds such as cobalt acetate are added as catalysts to improve the clarity of the product or to act as an accelerator (21, 28, 30, 51).

  2. A large number of catalysts within the polymer industry are organometallic or inorganic compounds, for example, the so-called Ziegler-Natta and chromium-based catalysts used for the polymerization of polyolefins and antimony-based catalysts used in the production of PET. For PE and PP, catalysts employed are either Ziegler-Natta (complexes formed by the interaction of alkyls of metals of groups I–III in the periodic table with halides and other derivatives of transition metals in groups IV–VII) or supported metal oxide catalysts (where typical catalyst compositions include oxides of Cr, Mo, Co, and Ni, supported on silica alumina, titanium, zirconia, or activated carbon) (21).

  3. Metals such as Pd, Pt, and Sn are used extensively as catalysts (24).

  4. For other plastics, Cr is extensively used for plating of plastic molding dies and surface finishing of plastic materials (28).

  5. In PP, inorganic compounds are confined to lubricants such a metal stearates. Mg may be derived from processing aids. Polystyrene (PS), polymethylmethacrylate (PMMA), polyvinyl chloride (PVC), and poly(vinylidene chloride) do not use metallic polymerization aids. Metals such as Al, Mg, and Zn can arise as processing aid residues (21).

  6. The main leachable components from stainless steel are iron, chromium, and nickel (55).

  7. Manganese and iron oxide are present in Type 1 amber bottles to act as coloring agents. Typical levels of iron oxide in Type 1 molded amber vials range from 1% to 1.25% in contrast to less than 0.05% in Type 1 molded clear vials. Zinc and barium oxides are also present in Type 1 glass. Levels of manganese oxide in amber vials range from 5% to 7%. Type 1 glass typically contains arsenic oxide at levels less than 0.5%. Antimony trioxide is used as an opacifier in the manufacturing of glass (25, 41, 51, 55, 57).

  8. For a prefilled glass syringe, the silicon in the leachate can either originate from the silicon dioxide structure of the glass material and/or from the silicone oil applied as lubricant. Glass syringes manufactured from Type 1glass contain a variety of oxides, which are prone to leaching by ion exchange (e.g., Al, Na). Extractable tungsten present in glass syringe barrels probably occurred during puncturing of the glass with a tungsten pin to create the cavity holding the needle (25).

  9. A chlorobutyl rubber may contain approximately 30% calcined clay, aluminum silicate, as a reinforcing agent (15). The source of extractable Al in chlorobutyl rubber is its calcined clay filler (42). Sources of extractable Zn in rubber closures include zinc oxide and zinc stearate (15).

  10. Traces of toxic substances in packaging materials can originate from contaminants occurring in various substrates used in the production process, from numerous additives (e.g., catalysts, thermal stabilizers, adhesives, lubricants, antioxidants, pigments, printing inks) assuring the appearance, strength, and attractiveness of final products as well as from process equipment. The level of contaminants in packaging materials can rapidly increase if recycling wastes are used in the production process (26).

Thus, there is every reason to expect that elemental entities may be routinely present in materials used in the construction of packaging and manufacturing systems and that these elemental entities are potential sources of elemental impurities in manufactured and packaged drug products. Therefore, the issue of elemental impurities derived from materials of construction in manufacturing and packaging systems cannot be readily dismissed as unlikely, infrequent, or inconsequential based on an unsubstantiated claim that the use of elemental entities in such materials is rare and largely unknown. However, although the possibility of elemental impurities arising from elemental entities in materials of construction cannot be dismissed, it may still be the case that the likelihood of such an occurrence is small.

Elemental Entities Present in Materials Used in Manufacturing and Packaging Systems

Testing a material for its total levels of elemental entities is relevant to the consideration of the material's contribution to elemental impurities in drug substances for the simple reasons that (a) elemental impurities in drug products due to packaging or manufacturing systems can only be derived from elemental entities that are actually present in systems' materials of construction (if it isn't in the material to begin with then it can't leach into the drug product) and (b) the amounts of elemental impurities contributed by the materials cannot exceed the total amount of elemental entities that are present in the material (you can't leach out more than what is in the material in the first place). Although elemental entities can be introduced to the system during fabrication and assembly from its materials of construction, testing of materials of construction for elemental entities provides an estimate of the maximal levels of the system-derived elemental impurities.

Tables I (A) through I (C) summarize the collated data for the total pool of elemental entities in materials commonly used in packaging and/or manufacturing systems. The tables collate information for general classes of materials (e.g., PE, PP, PET, etc.) for 30 elements, including those that are routinely reported to be present in these types of materials and those in the higher risk ICH Q3D elemental impurity classes (specifically Class 1, 2A, and 2B). When information beyond these 30 elements is available from the source documents, that information is summarized in footnotes to these tables. Tables I (A) through I (C) contains the same materials but report different sets of elements.

View this table:
TABLE I (A)

Total Amounts of Elemental Impurities in Materials (Digestion or Total Pool)

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TABLE I (B)

Total Amounts of Elemental Impurities in Materials (Digestion or Total Pool)

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TABLE I (C)

Total Amounts of Elemental Impurities in Materials (Digestion or Total Pool)

As noted previously, drawing conclusions from the data contained in Tables I (A) through I (C) is complicated by the fact that (a) a sufficient number of samples of a given type were not always tested and (b) the testing did not always include all the elements of interest. Nevertheless, the following observations for the tested materials are offered:

  1. Acrylonitrile-butadiene-styrene (ABS) copolymer: An insufficient number of studies were reported, and the studies performed did not target a sufficient number of elements to allow generalizations to be drawn. Nevertheless, the elements that were reported at levels of approximately 1 mg/kg or higher were Mg, Zn, and Pb. Al, Co, Cr, Ge, Mn, Sb, and Zr were not reported at levels above 1 mg/kg.

  2. Cardboard and paper: Cd, Cr, and Pb were reported to be present in these materials at measurable levels. Hg was not reported at levels above 1 mg/kg.

  3. Glass: An insufficient number of studies were reported, and the studies performed did not target a sufficient number of elements to allow generalizations to be drawn. Nevertheless, elements associated with the major components of glass (e.g., Al, B, Ca, Na, K, Mg, Fe, Si) were reported in all studies. Ag, Co, Cr, Mn, Mo, Pb, Pd, Sb, Se, Ti, V, and Zr were present in one or more of the tested materials at levels greater than 1 mg/kg. As, Au, Cd, Cu, Ge, Hg, Ir, Ni, Pt, Ti, and Zn were not present in any of the tested materials at levels greater than 1 mg/kg.

  4. PET: Sb is almost always present on PET materials at levels of 50 mg/kg or higher. Al, Ba, Ca, Co, Cr, Fe, Mg, Mn, Pb, Si, and Zn may be present in PET materials at levels of 1 mg/kg and above. Other elemental entities are either infrequently or never reported in PET materials at levels above 1 mg/kg.

  5. PE: There is great disparity in the levels of elemental entities in PE materials, with the levels of several elements varying from essentially undetected to values above 10 mg/kg. There is no single element that is reported in all the PEs at levels greater than 1 mg/kg; however, Al and Cr are present in many of the PEs tested in levels greater than 1 mg/kg. Elements such as Pb and Ti are present in several PEs at levels greater than 1 mg/kg, and elements such as Ba, Ca, Cu, Mg, Ni, Sb, Si, and Zn are present in one or more of the tested materials at levels greater than 1 mg/kg. Ag, As, Au, Cu, Fe, Ge, Hg, Ir, Mn, Mo, Os, Pd, Pt, Se, Tl, and V were not present in any of the tested materials at levels greater than 1 mg/kg.

  6. PP: Al was present in all of the PPs tested for this element in levels greater than 1 mg/kg. Ti was present in several PPs at levels greater than 1 mg/kg, and elements such as Ca, Cr, Mg, Pb, and Ti are present in one or more of the tested materials at levels greater than 1 mg/kg. As, Cd, Co, Cr, Ge, Mn, Sb, V, and Zn were not present in any of the tested materials at levels greater than 1 mg/kg. Although other elements were measured in at least one sample, and the measured level was less than 0.1 mg/kg, there is insufficient data to make a generalization for such elements (including Ag, Au, Ba, Ca, Cu, Fe, Hg, Ir, Mo, Ni, Os, Pd, Pt, Se, Tl, and Zr).

  7. PS: Zn was present in all of the PS materials tested for this element in levels greater than 1 mg/kg. Al and Ti were present in several PS materials at levels greater than 1 mg/kg, and Cr, Cu, and Mg were present in one or more of the tested materials at levels greater than 1 mg/kg. Cd, Co, Mn, Pb, and Sb were not present in any of the tested materials at levels greater than 1 mg/kg. Although other elements were measured in at least one sample, and the measured level was less than 0.1 mg/kg, there is insufficient data to make a generalization for such elements (including Ag, Au, As, Ba, Ca, Fe, Hg, Ir, Mo, Ni, Os, Pd, Pt, Se, Tl, and Zr).

  8. PMMA: Mg was present in all the PMMA materials tested at levels that could be higher than 1 mg/kg. Zn was present in several of the PMMA materials tested at levels less than 1 mg/kg. Although other elements were measured in at least one sample, and the measured level was less than 0.1 mg/kg, there is insufficient data to make a generalization for such elements (including Al, Co, Cr, Ge, Mn, Pb, Sb, and Zr). Numerous elements were not targeted in any of the studies performed on this class of material.

  9. Polytetrafluoroethylene (PTFE): Al, Ca, and Fe were present in all the PTFE materials tested at levels that are higher than 1 mg/kg. Cu, Mg, and Ni were present in all the PTFE materials tested at levels between 0.1 and 1 mg/kg. Ag, Cd, Co, and Cr were not present in any of the tested materials at levels greater than 0.1 mg/kg. Numerous elements were not targeted in any of the studies performed on this class of material.

  10. Rubber: Al was present at levels much higher than 1 mg/kg in all the rubber materials tested. Elements that were not targeted in all the studies but which were present in quantities greater than 1 mg/kg when they were tested included As, Ba, Ca, Cr, Cu, Fe, Mg, Mn, Ni, Pb, Si, Ti, and Zn. Elements that were not targeted in all the studies but which were present in quantities less than 1 mg/kg when they were tested included Ag, Au, Cd, Co, Ge, Ir, Mo, Pd, Pt, Sb, Se, Tl, V, and Zr. Several elements were not targeted in any of the studies performed on this class of material.

  11. Layered polyolefin: Cr and Pb were present in all the polyolefin materials tested at levels that could be higher than 1 mg/kg. While Sb was not targeted in all the studies, it was present in quantities greater than 1 mg/kg when it was targeted. While Cd and Hg were not targeted in all the studies, they were present in quantities less than 1 mg/kg when they were targeted. Numerous elements were not targeted in any of the studies performed on this class of material.

  12. Materials for which there is insufficient data to make generalizations: Polycarbonate, polyester, PVC.

Elemental Entities Extracted from Materials Used in Manufacturing and Packaging Systems

Although testing of materials for total elemental entities establishes the maximum exposure of the drug product to material-derived elemental impurities, it does not establish the actual degree to which the material and the drug product interact because the elemental entity must be leached from the material in order to become an elemental impurity. There are a number of thermodynamic and kinetic reasons why it is reasonable to suspect that the amount of elemental entities that are actually leached to become elemental impurities is a small portion of the total pool of the elemental entity.

Tables II through XV summarize the collated data from extraction or leaching studies performed on materials commonly used in packaging and/or manufacturing systems and under conditions that could be reasonable simulations of manufacturing and clinical applications. The tables collate information by general class of materials (e.g., PE, PP, PET, etc.) for those elements that are reported in the literature.

View this table:
Table II

Extracted Elemental Impurities Reported for Acrylonitrile-Butadiene-Styrene (ABS) Copolymer

As was noted previously, drawing conclusions from the data contained in Tables II through XV is complicated by the fact that (a) an insufficient number of samples of a given type may have been tested and (b) the testing did not always include all the elements of interest. Nevertheless, the following observations for the tested materials are offered:

  1. ABS copolymer (Table II): Studies reported for ABS materials included a relatively large number of elements and multiple individual test articles, extracted with three solvents: low pH (≈3), high pH (≈9), and an ethanol/water mixture. Elements that were not extracted in reportable levels (generally 0.01 mg/kg or higher) included Ag, As, Ba, Be, Bi, Cd, Co, Ge, Li, Mo, Ni, Pb, Sb, Se, Sn, Sr, Ti, V, Zn, and Zr. The reported extracted levels of Al, B, Ca, and Fe were less than 1 mg/kg. Elements such as Cr, Mg, Na, P, S, and Si were extracted at levels greater than 1 mg/kg under certain extraction conditions.

  2. Acrylic copolymer (Table III): Studies reported for acrylic copolymer materials included a relatively large number of elements and two individual test articles, extracted with three solvents: low pH (≈3), high pH (≈9), and an ethanol/water mixture. Elements that were not extracted in reportable levels (generally 0.1 mg/kg or less) included Ag, As, Be, Bi, Cd, Co, Cr, Fe, Ge, Li, Mg, Mn, Mo, Ni, Pb, Se, Sn, Sr, Ti, V, and Zr. Extracted levels for elements such as Al, B, Ba, Ca, Cu, Na, Sb, Si, and Zn were quite different for the two materials tested; in one material the levels were either not reportable or less than 1 mg/kg, while in the other material the levels exceeded 10 mg/kg under certain extraction conditions. The reason for this difference in behavior was not indicated in the source article.

  3. Glass (Table IV): Extraction of elemental entities from glass has been extensively reported. Not surprisingly, elemental entities associated with glass's major components (e.g., oxides of Al, Si, B, Na, Ca, Mg) can be extracted from glass in relatively high amounts (greater than 1 mg/kg) under certain extraction conditions. This is especially true for Si, whose extracted levels at high pH can exceed 10 mg/kg. Generally speaking, those elements that are present at low levels (<1%) in the composition of glass, such as As, Cr, Fe, Mn, Pb, Sb, W, Zn, and Zr, are extracted from glass in quantities much less than their total amounts, generally less than 1 mg/kg or 1 mg/L in the extract.

  4. Polycarbonate (Table V): Elements that were not extracted in reportable levels included Ag, Ba, As, Be, Bi, Cd, Co, Cu, Ge, K, Li, Mn, Mo, Ni, Pb, Sb, Se, Sn, Sr, Ti, V, and Zr. Elements that were extracted at levels less than 1 mg/kg (or 1 mg/L if reported in that manner) under all the reported conditions included Al, B, Cr, Fe, Mg, Na, S, and Zn. The levels of extracted Br, Ca, and Si varied greatly between materials; in certain materials and under certain conditions, extracted levels of Br, Ca, and Si exceeded 1 mg/kg, while for other materials and other conditions the levels were not reportable, generally less than 0.01 mg/kg.

  5. PE (Table VI): Extraction of elemental entities from PE has been extensively reported. The levels of elemental entities extracted from individual PEs was variable across all the PEs tested, and it is clear that PEs are not all compositionally similar as a class. In general, certain elements, such as Ag, Al, As, Ba, Be, Bi, Br, Cd, Cr, Fe, Ge, Li, Mg, Mn, Ni, P, Pb, Se, Sb, Sn, Sr, Ti, and Zr, were not extracted from any material under any condition at levels exceeding 1 mg/kg and in fact the reported levels were much lower than this value. The extracted levels of other elements, such as B, Ca, Cu, Na, S, and Zn, were material-dependent and varied from not reportable levels to levels above 1 mg/kg.

  6. Polyethersulfone (PES) (Table VII): Studies reported for PES materials included a relatively large number of elements and three individual test articles, extracted with three solvents: low pH (≈3), high pH (≈9), and an ethanol/water mixture. Elements that were not extracted in reportable levels, generally less than 0.01 mg/kg, included Ag, Al, As, Ba, Be, Bi, Cd, Co, Cr, Cu, Fe, Ge, Li, Mn, Mo, Ni, Pb, Sb, Se, Sn, Sr, Ti, V, and Zr. Extraction of the other elements reported varied from material to material but were less than 1 mg/kg for B, Mg, and Si. Elements including Ca, Na, P, S, and Zn were extracted in amounts ranging from not reportable (generally less than 0.01 mg/kg) to amounts greater than 1 mg/kg.

  7. PVC (Table VIII): Extraction of elemental entities from PVC has been extensively reported. Elements that were not extracted in reportable levels, generally less than 0.01 mg/kg, included Ag, Ba, Be, Bi, Cd, Co, Cr, Ge, Hg, Ir, Pd, Pt, Os, Rh, Ru, and Zr, although it is noted that not all the reported studies targeted all these elements. Elements that were not extracted in quantities greater than 1 mg/kg from any sample under any conditions included As, Fe, Mo, Mn, Na, Ni, Sb, Se, Sr, Ti, and V. The extracted amounts of other elements, such as Al, B, Cu, Mg, Pb, S, and Si, varied among the materials tested and the test conditions, ranging from not reportable levels to levels above 1 mg/kg. Elements that are associated with typical additives in PVC, such as Ca and Zn (metal stearates as acid scavengers), were typically extracted from all materials at levels greater than 1 mg/kg under most extraction conditions.

  8. PMMA (Table IX): Studies reported for PMMA materials included a relatively large number of elements and two individual test articles, extracted with three solvents: low pH (≈3), high pH (≈9), and an ethanol/water mixture. Elements that were not extracted in reportable levels included Ag, As, Ba, Be, Bi, Cd, Co, Cr, Cu, Fe, Ge, Li, Mg, Mn, Mo, Ni, Pb, Sb, Se, Sn, Sr, Ti, V, Zn, and Zr. The extracted amounts of other elements, such as Al, B, Ca, Na, P, and S, varied among the materials tested and the test conditions, ranging from not reportable levels to levels above 1 mg/kg. Silicon was extracted in measureable quantities from both materials tested but in different amounts, approximately 1 mg/kg from one material and approximately 10 mg/kg in the second material.

  9. PP (Table X): Extraction of elemental entities from PP has been extensively reported. The levels of elemental entities extracted from individual PPs was variable across all the PPs tested, and it is clear that PPs are not all compositionally similar as a class. In general, certain elements, such as Ag, As, Be, Bi, Cd, Co, Cu, Ge, Li, Mo, Mn, Ni, P, Pb, Se, Sb, Sn, Ti, and V, were not extracted from any material under any condition at reportable levels, generally 0.01 mg/kg or less. Other elements including Cr, Fe, Mg, P, Sr, and Zr were not extracted from any material at levels exceeding 1 mg/kg. The extracted amounts of other elements, such as Al, B, Ba, Ca, Na, S, Si, and Zn, varied among the materials tested and the test conditions, ranging from not reportable levels to levels above 1 mg/kg.

  10. Rubber elastomers (REs) (Table XI): Extraction of elemental entities from REs has been extensively reported. The levels of elemental entities extracted from individual REs was variable across all the REs tested, and it is clear that REs are not all compositionally similar as a class. In general, certain elements, such as Ag, As, Be, Bi, Cd, Co, Cu, Ge, Li, Mo, Ni, Pb, Se, Sb, Sr, and Ti, were not extracted from any material under any condition at reportable levels, generally 0.01 mg/kg or less. Other elements including Cr, Fe, Mn, Ni, Sr, Ti, V, and Zr were not extracted from any material at levels exceeding 1 mg/kg. The extracted amounts of other elements, such as Al, B, Ba, Br, Ca, K, Mg, Na, P, S, Si, and Zn varied among the materials tested and the test conditions, ranging from not reportable levels to levels well above 1 mg/kg.

  11. Silicones (Table XII): Clearly the major extracted element associated with this class of materials was Si, which was routinely extracted at levels of approximately 10 mg/kg or greater. Elements that were not extracted in reportable levels, generally less than 0.01 mg/kg, included Ba, Be, Bi, Cd, Co, Ge, Pb, Se, Sr, V, and Zn. Other elements including Ag, Al, As, Cr, Cu, Fe, Li, Mg, Mn, Mo, Ni, P, Pt, Sb, Sn, Ti, and Zr were not extracted from any material at levels exceeding 1 mg/kg. The extracted amounts of other elements, such as B, Ca, Na, and S, varied among the materials tested and the test conditions, ranging from not reportable levels to levels above 1 mg/kg.

  12. Thermoplastic elastomers (TEs) (Table XIII): Studies reported for TE materials included a relatively large number of elements and six individual test articles, extracted with three solvents: low pH (≈3), high pH (≈9), and an ethanol/water mixture. Elements that were not extracted in reportable levels included Ag, Al, As, Ba, Be, Bi, Cd, Co, Cr, Cu, Fe, Ge, Li, Mg, Mn, Mo, Ni, Pb, Sb, Se, Sn, Sr, Ti, V, Zn, and Zr. In general, certain elements, such as B and Ca, were not extracted from any material at levels exceeding 1 mg/kg. The extracted amounts of other elements, such as Na, P, S, and Si, varied among the materials tested and the test conditions, ranging from not reportable levels to levels well above 1 mg/kg.

  13. PS (Table XIV): PS extraction was reported in only one study, which considered Al, Co, Cu, Mg, and Zn. Under the extraction conditions of this study, the levels of these extracted elements did not exceed 0.005 mg/kg.

  14. PET (Table XIV): As PET bottles are commonly used for beverages, there is a fair body of information on these types of products. Because Sb is a known process chemical in PET production, its extraction from PET bottles is well documented. In general, Sb was extracted from PET containers at levels less than 1 mg/L. While additional elements have been reported in extracts of PET at low levels (e.g., Al, Ca, Mg, and Pb), other elements were not present in PET extracts in reportable quantities (including Ag, As, Br, Cd, Cr, Cu, Fe, Mo, Ni, Se, Si, Sn, Sr, Sn, Ti, and V).

  15. Ethylene vinyl acetate (EVA) (Table XIV): Elemental entities extracted from EVA were reported in aqueous extracting media: low pH (≈3), high pH (≈9), and an ethanol/water mixture. Elements that were not extracted in reportable levels included Ag, As, Ba, Be, Bi, Cd, Co, Cr, Cu, Fe, Ge, Li, Mg, Mn, Mo, Ni, Pb, Sb, Se, Sn, Sr, Ti, V, Zn, and Zr. Other elements, such as Al, B, Ca, Na, S, and Si, were extracted from EVA at levels above 1 mg/kg.

  16. Cyclic olefin copolymer (COC) (Table XIV): Several studies addressed the extraction of elemental entities from COC materials. Al, Ba, Br, Fe, Mg, Na, Sr, Zn, and Zr were all reported to be extracted from COC at levels that did not exceed 1 mg/kg. Under certain extraction conditions, individual COC materials had levels of extracted B and Ca that were greater than 1 mg/kg. Elemental entities that were not extracted in reportable quantities, generally 0.01 mg/kg or less, included Ag, As, Be, Bi, Cd, Co, Cr, Cu, Ge, Li, Mn, Mo, Ni, P, Pb, S, Sb, Se, Si, Sn, Ti, and V.

  17. Components consisting of multiple materials (Table XV): The extraction of individual or small groups of elements from components or systems consisting of multiple materials has been reported. In most cases, the amount of extracted metals is small, unless there is a specific source in the component. For example, Al is extracted in measurable quantities from components that include glass parts.

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Table III

Extracted Elemental Impurities Reported for Acrylic Copolymer

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Table IV

Extracted Elemental Impurities Reported for Glass

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Table V

Extracted Elemental Impurities Reported for Polycarbonate (PC)

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Table VI

Extracted Elemental Impurities Reported for Polyethylene (PE)

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Table VII

Extracted Elemental Impurities Reported for Polyethersulfone (PES)

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Table VIII

Extracted Elemental Impurities Reported for Plasticized Polyvinyl Chloride (PVC)

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Table IX

Extracted Elemental Impurities Reported for Polymethylmethacrylate (PMMA)

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Table X

Extracted Elemental Impurities Reported for Polypropylene (PP)

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Table XI

Extracted Elemental Impurities Reported for Rubber Elastomers (RE)

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Table XII

Extracted Elemental Impurities Reported for Silicones (SI)

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Table XIII

Extracted Elemental Impurities Reported for Thermoplastic Elastomers (TEs)

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Table XIV

Extracted Elemental Impurities Reported for Miscellaneous Plastics

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Table XV

Extracted Elemental Impurities Reported for Multi-material Systems

Elemental Impurities in Drug Products

Table XVI contains information related to the levels of elemental impurities measured in packaged drug products and levels of elemental entities extracted from materials when drug products (or their very close simulants) are used as extracting media. Studies in which the levels of elemental impurities are measured in packaged drug products are not directly relevant to the topic of such impurities derived from the packaging because such studies frequently specify the amounts of the impurities and not their source. Thus such studies establish the maximum amount of an elemental impurity that could have been derived from packaging if one ascribes the total amount measured in the drug product to the packaging. This situation is alleviated somewhat if the levels of elemental impurities in the drug product components (e.g., active pharmaceutical ingredient, excipients, diluents, etc.) are known and the elemental impurity contribution of the packaging can be estimated by difference. Nevertheless, measuring elemental impurities at low levels in packaged products implies that the levels of elemental entities leached from the packaging are equally low. Considering this point, it is noted that generally the reported accumulation of certain elemental impurities is relatively low, less than 100 ng/mL (ppb), including Cd, Co, Cr, Cu, Mn, Ni, and V. It is noted that Al was found in varying levels in many of the tested drug products.

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Table XVI

Elemental Impurities Reported in Packaged Drug Products, Pharmaceutical Materials, or in Extracts Generated with Drug Products or Their Simulants

Focus on Elemental Impurities of High Concern with Respect to Potential Safety Impacts

Relevant standards concerned with elemental impurities in finished products include ICH Q3D (2), USP <232> (3), and the European Medicines Agency guideline on residuals from metal catalysts or metal reagents (62). The documents group elemental impurities in classes, based on their perceived safety risk. For example, ICH Q3D proposes the Class 1 elemental impurities (As, Cd, Hg, and Pb) as being significantly toxic that they require consideration across all their potential sources. Class 2 elemental impurities are generally less toxic, depending on their route of administration. Within this class, Class 2A elemental impurities (V, Mo, Se, and Co) require assessment across all potential sources and routes of administration due to their relatively high abundance. Furthermore, USP <232> highlights the ICH Q3D Class 1 elements, noting that “due to the ubiquitous nature of As, Cd, Pb and Hg they (at a minimum) must be considered in the risk-based control strategy” (3).

Addressing these high-risk elemental impurities specifically, Tables XVII and XVIII consider the ICH Q3D Class 1 elemental impurities, where Table XVII summarizes the reported total composition levels of the Class 1 elemental entities in materials and Table XVIII summarizes the reported levels of Class 1 elemental impurities extracted from materials. In general, a number of materials have been tested for their total level of ICH Q3D Class 1 elemental impurities, and such impurities have been measured in numerous materials at generally low levels, less than 1 mg/kg (Table XVII). Nevertheless, individual materials have been reported to contain higher levels of the Class 1 elemental impurities, including As in PET bottles (1–4 mg/kg) and a bromobutyl rubber (3 mg/kg), Cd in a cardboard/PE composite (25 mg/kg), a high-density PE (113 mg/kg) and in PVC materials (65–112 mg/kg), as well as Pb in PET bottles (2–9 mg/kg), in high-PE materials (4.1, 1222 mg/kg), a PP material (5.5 mg/kg), a PP/PE blend (160 mg/kg), and PVC materials (112–157 mg/kg).

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Table XVII

Summary of the Total Amount of Elemental Impurities in Materials; ICH Q3D Class 1 Elements (As, Cd, Hg, Pb)

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Table XVIII

Summary of Reported Occurrences for the ICH Q3D Class 1 Metals (As, Cd, Hg, Pb) in Material Extracts

As shown in Table XVIII, the ICH Class 1 elemental impurities are rarely reported as being extracted from materials at levels that exceed 0.1 mg/kg or 50 ng/mL in the extract. In fact, Cd and Hg were not extracted in reportable levels from any of the materials and under any of the extraction conditions examined in the studies cited in this review article. The element arsenic (As) was rarely reported to be extracted from materials in reportable quantities and when extracted its reported levels are low, less than 40 ng/mL or 0.01 mg/kg. Although extracted quantities of Pb are more frequently reported, the extracted levels are also typically less than 80 ng/mL or 0.01 mg/kg; exceptions to this generalization included specific glass samples (less than 1 mg/kg) and a plasticized PVC resin (1.4 mg/L).

Similarly, Tables XIX and XX summarize data for the ICH Class 2A elemental impurities. Considering total pool, the element Co is rarely present in relevant materials at levels greater than 0.2 mg/kg, with the exception of PET; reported total Co levels in PET ranged from 0.5 to 59 mg/kg. Mo was present in some materials, generally at levels less than 0.5 mg/kg, although a single Type 1 glass sample had 4.8 mg/kg and a single PP/PE blend contained 2.1 mg/kg. The element Se was not present at levels greater than 0.3 mg/kg in any material tested for this elemental entity, and V was present in only one material, a bromobutyl rubber sample, at levels greater than 1 mg/kg (1.3 mg/kg).

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Table XIX

Summary of the Total Amount of Elemental Impurities in Materials; ICH Q3D Class 2A Elements (Co, Mo, Se, V)

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Table XX

Summary of Reported Occurrences for the “Second Tier” ICH Q3D Class 2A Metals (Co, Mo, Se, V) in Material Extracts

As was the case for the Class 1 elemental impurities, the Class 2A elemental impurities were rarely extracted from relevant materials at reportable levels (Table XX). When amounts of the Class 2A elemental impurities were reported as being extracted, the extracted levels were low, typically 0.01 mg/kg, or 100 ng/mL, or less. One exception, Se in a plasticized PVC at a level of 1 mg/kg, is noted.

The Relationship between the Total Amount of an Elemental Entity Present in a Material and the Amount That Can Be Extracted

As seen from the results presented above, it is clear that there is a marked difference between the total composition amount of an elemental entity in a material of construction and the level of the extracted elemental entity. This is an important consideration for elemental impurities that might be found in the drug product. Although an element may be extracted under defined laboratory conditions (extractable), in order for an element present in material of construction to accumulate in the drug product as an elemental impurity it would have to be leached from the material under normal storage or use conditions (leachable). Thus it is reasonable to consider extractables to be potential leachables and thus to note that whether an extractable is a risk to patient safety depends on the extent to which it leaches into the drug product. It is possible that a packaging system could contain a relatively large quantity of an elemental extractable and still be deemed to be safe in a particular application if, under the conditions of that application, the elemental entity leaches out of the packaging and produces levels of an elemental impurity in drug products that are below a quality-driven threshold.

Studies that include both the determination of the total pool of elemental entities and the level to which those elemental entities can be leached are relatively uncommon; nevertheless, Table XXI summarizes the results of several studies where total pools were compared to extracted levels. These results are consistent with the following generalization: The amount of an elemental entity than can be extracted from materials commonly used in packaging or manufacturing is a small portion of the total amount of the elemental entity that is present in the material.

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Table XXI

Comparison of Total Available Elemental Impurities Versus Amount Extracted

In fact, Table XXI establishes that in most situations the amount of an elemental entity that can be extracted from materials under pharmaceutically relevant conditions is less than 0.1% of the total amount of that elemental entity present in the materials. However, the absolute difference between the total pool and extracted amount of the elemental entity depends on three key circumstances, including

  1. The chemical form of the elemental entity

  2. The chemical nature of the extracting medium

  3. The extraction conditions

Thus there can be very specific situations where the proportion extracted versus the total pool is greater than 1 to 1000. For example, very low-pH extractions of materials containing metals salts as additives (for example, zinc and calcium stearate) may result in the extraction of more than 0.1% of the pool of these metals as ion exchange occurs between the acidic proton and the metal in the salt.

Conclusions

Global guidelines addressing the levels of elemental impurities in finished drug products are in the final stages of their development and implementation. Such guidelines suggest that packaging and manufacturing systems for such products may be sources of these elemental impurities; however, the guidelines do not provide specifications regarding elemental entities in such systems and/or their materials of construction. Knowledge about elemental entities present in materials of construction for packaging and manufacturing systems used in pharmaceutical applications and the leaching characteristics of these entities may facilitate setting meaningful, actionable, and appropriate specifications on the composition and properties of such materials and systems. This article contains the information compiled from the available body of literature and considers how such information might be used to set relevant specifications for elemental entities in primarily polymers. While such a compiled body of information could be used to address a number of issues and topics, the following questions are the primary focus of this work:

  1. What elemental entities are present in the relevant polymers and materials and at what levels are they present?

  2. To what extent are elemental entities present in relevant polymers and materials leached from these materials under conditions relevant to the manufacturing and storage/distribution of solution drug products?

Considering the topic of elemental entities in general and these two questions specifically, the following observations are made and the following conclusions are drawn.

  1. Pharmaceutical packaging and manufacturing systems and their materials of construction contain elemental entities as such entities are either

    1. Known and intentionally utilized as materials of construction

    2. Known and intentionally included as additives in the materials of construction

    3. Known or logically inferred impurities in the materials of construction and/or their additives

    4. Known or logically inferred residuals arising from the manufacturing of the systems and/or their materials of construction. The inferred presence of elemental entities in systems and/or their materials of construction have been confirmed by laboratory testing of said materials and systems.

  2. The sources of these elemental entities can be grouped into four classes:

    1. Elemental entities that are actual materials of construction (for example, metal oxides in glass, stainless steel)

    2. Elemental entities that are intentionally present in the materials of construction because they are important and necessary components in the materials (e.g., metal stearates as acid scavengers)

    3. Elemental entities that may be unintentionally present in the materials of construction because they are used in the generation of the materials and may not be completely removed by the generation process (e.g., residual organometallic catalysts)

    4. Elemental entities that are unintentionally, coincidentally, and unpredictably present in the materials of construction because they are ubiquitous contaminants that cannot be avoided.

  3. Because elemental entities in classes (a) through (c) above are either intentionally present or expected to be present, their ability to be leached from the materials must be established, especially for products that are at risk for leaching (such as liquid formulations). However, because these elemental entities are known, such leachables testing involves quantifying known and targeted entities and not screening for unanticipated entities.

  4. Because elemental entities in class (d) above cannot be anticipated, they can only be evaluated by screening. Nevertheless, available data suggests that such unforeseen and unpredictable elemental entities are rarely encountered and when they are encountered their levels in materials and systems are low. Furthermore, when such elemental entities are present in materials and systems, only a small fraction of the total available amount of the entity can be leached under conditions that are relevant to packaged drug products. Thus while sources of certain elemental impurities may be ubiquitous in the natural environment, they are not ubiquitous in materials used in pharmaceutical packaging and manufacturing systems and when they are present they are not extensively leached under relevant conditions. Therefore, there are a number of elemental impurities that may be relevant for packaged drug products that are much less relevant as elemental entities in packaging and manufacturing systems. The value of including such elemental entities in tests that are performed on packaging and manufacturing systems (and their materials of construction) for the purpose of establishing or controlling the levels of elemental impurities in drug products is low because the risk that such elemental entities would accumulate as elemental impurities at levels sufficiently high to produce an adverse effect is low.

  5. The information contained in this paper may be sufficient to establish certain elemental entities as being relevant targets for assessing the impact of packaging and manufacturing systems on the safety of the packaged drug product. Furthermore, this same information may be sufficient to establish that certain elemental entities are not relevant targets for this purpose. Lastly, this information could be used to support the development of acceptance criteria for elemental entities in systems and their materials of construction.

Based on the previous conclusions, the following recommendations are made:

  1. Specifications should be established for elemental entities that are both of toxicological concern and known or likely to be present in the material of construction. Based on the review of the literature and the guidance provided in ICH Q3D and USP <232>, Table XXII lists such elements of potential safety impact for a given material.

  2. A risk assessment for elemental impurities related to the materials of construction used in the packaging or manufacturing systems should be performed for each pharmaceutical product. To this end, ICH Q9 establishes that that the assessment process can be accomplished in four steps: identification, analysis, evaluation, and control (5). This concept is mirrored in section 5.1 of the Step 2b ICH Q3D document. Regarding the identification step, which can interpreted as a requirement to “identify known and potential sources of elemental impurities that may find their way into the drug product” (2), those elements that can be present in materials in quantities greater than 10 mg/kg are listed in Table XXII. This table, alongside supplier information, should be considered when establishing possible sources of elemental impurities. Although some of the elements to be considered may not be toxic, they could affect the quality, efficacy, or stability of the drug product and thus they should be considered as part of a rigorous quality impact assessment. Regarding the analysis step, which can be interpreted as a requirement to “determine the observed or predicted level of the impurity” (2), Tables XVII through XXI can be used for this purpose. Especially in cases where there is a high likelihood for leaching, it is recommended that establishing the levels of packaging-related elemental impurities in a drug product is most readily accomplished by testing the materials of construction, the fabricated component, or the finished packaging system for extractable elemental entities and/or performing leachables studies on the drug product. Such studies should include analysis for elemental impurities that are known or likely to be present in the materials of construction that may be toxic or react with the drug formulation (see Table XXII). It is important that such testing for elements of potential concern be carefully designed to avoid elemental contributions from extraction solvents, handling, or the test environment so that elemental impurities in the drug product that arise from packaging and manufacturing systems are correctly quantified. Completion of the risk assessment involves the comparison of the observed or predicted levels of an elemental impurity with an established permitted daily exposure (PDE) (2).

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Table XXII

Recommendations on Elements That May Be Considered in the Risk Assessment Process for Specific Materials Used in Pharmaceutical Packaging or Manufacturing Systems

This broad and comprehensive survey of the literature illustrates that in most cases levels of extracted elemental entities and leached elemental impurities in the materials assessed are low and are unlikely to significantly contribute to the elemental impurity profile of a final drug product. Nevertheless, a comprehensive risk management process for drug product safety and quality should consider the potential for elemental impurities from drug product packaging and manufacturing systems.

Conflict of Interest Declaration

The author(s) declare that they have no competing interests.

Footnotes

  • Extractables and Leachables Safety Information Exchange (ELSIE), Washington, DC.

  • International Pharmaceutical Aerosol Consortium on Regulation and Science (IPAC-RS), Washington, DC.

  • Observations made, opinions expressed and conclusions drawn in this article reflect the views of the authors acting in their role as participants in ELSIE and IPAC-RS and should not be construed to represent the views or policies of their affiliated organizations.

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Materials in Manufacturing and Packaging Systems as Sources of Elemental Impurities in Packaged Drug Products: A Literature Review
Dennis R. Jenke, Cheryl L. M. Stults, Diane M. Paskiet, Douglas J. Ball, Lee M. Nagao
PDA Journal of Pharmaceutical Science and Technology Jan 2015, 69 (1) 1-48; DOI: 10.5731/pdajpst.2015.01005
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