A special thanks to Matt Webberley, Associate Director Analytical Research and Development at our sister company, SK biotek Ireland Limited, for his assistance with the profiles of AAS, ICP-OES, ICP-MS, and XRD.
A Definition of These Newsmakers
Elemental impurities in food have been in the news recently, with reports of everything from lead being found in baby food to arsenic, cadmium, and assorted heavy metals in dark chocolate and other foods.1-8 Of course, the FDA and Congress are taking notice.3 The US Pharmacopeia definition of elemental impurities states they “include catalysts and environmental contaminants that may be present in drug substances, excipients, or drug products. These impurities may occur naturally, be added intentionally, or be introduced inadvertently (e.g., by interactions with processing equipment and the container closure system).”9 As recent news reports show, the concern can be expanded beyond drugs and APIs (active pharmaceutical ingredients) to include food and beverages.
Classifying Elemental Impurities
In addition to the recalls and resources, there are a variety of impurity classification levels, too. In the following table, the FDA and EMA sort them by elements.12,13 They are classified into three categories based on their toxicity and also based on occurrence in the drug product (note: this is usually assumed to be the same as for the drug substance but not always).
|Class 1: The elements, As, Cd, Hg, and Pb are human toxicants that have limited or no use in the manufacture of pharmaceuticals. Their presence in drug products typically comes from commonly used materials (e.g., mined excipients). Because of their unique nature, these four elements require evaluation during the risk assessment across all potential sources of elemental impurities and routes of administration. The outcome of the risk assessment will determine those components that may require additional controls, which may, in some cases, include testing for Class 1 elements. It is not expected that all components will require testing for Class 1 elemental impurities; testing should only be applied when the risk assessment identifies it as the appropriate control to ensure that the PDE will be met.
|Class 2: Elements in this class are generally considered as route-dependent human toxicants. Class 2 elements are further divided into sub-classes 2A and 2B based on their relative likelihood of occurrence in the drug product.
|• Class 2A elements have [a] relatively high probability of occurrence in the drug product and thus require risk assessment across all potential sources of elemental impurities and routes of administration (as indicated). The class 2A elements are: Co, Ni, and V.
|• Class 2B elements have a reduced probability of occurrence in the drug product related to their low abundance and low potential to be co-isolated with other materials. As a result, they may be excluded from the risk assessment unless they are intentionally added during the manufacture of drug substances, excipients, or other components of the drug product. The elemental impurities in class 2B include: Ag, Au, Ir, Os, Pd, Pt, Rh, Ru, Se, and Tl.
|Class 3: The elements in this class have relatively low toxicities by the oral route of administration (high PDEs, generally > 500 μg/day) but may require consideration in the risk assessment for inhalation and parenteral routes. For oral routes of administration, unless these elements are intentionally added, they do not need to be considered during the risk assessment. For parenteral and inhalation products, the potential for inclusion of these elemental impurities should be evaluated during the risk assessment unless the route-specific PDE is above 500 μg/day. The elements in this class include: Ba, Cr, Cu, Li, Mo, Sb, and Sn.
|Other elements: Some elemental impurities for which PDEs have not been established due to their low inherent toxicity and/or differences in regional regulations are not addressed in this guidance. If these elemental impurities are present or included in the drug product, they are addressed by other guidance and/or regional regulations and practices that may be applicable for particular elements (e.g., Al for compromised renal function; Mn and Zn for patients with compromised hepatic function), or quality considerations (e.g., presence of W impurities in therapeutic proteins) for the final drug product. Some of the elements considered include: Al, B, Ca, Fe, K, Mg, Mn, Na, W, and Zn.
|Ag, Silver; Al, Aluminum; As, Arsenic; Au, Gold; B, Boron; Ba, Barium; Ca, Calcium;
Cd, Cadmium; Co, Cobalt; Cr, Chromium;
Cu, Copper; Hg, Mercury; Fe, Iron;
|Ir, Iridium; K, Potassium; Li, Lithium;
Mg, Magnesium; Mn, Manganese;
Mo, Molybdenum; Na, Sodium; Ni, Nickel;
|Pb, Lead; Pd, Palladium; Pt, Platinum;
Rh, Rhodium; Ru, Ruthenium; Sb, Antimony; Se, Selenium; Sn Tin; Tl, Thallium; V, Vanadium;
W, Tungsten; Zn, Zinc
Tools for Testing Elemental Impurities
Beyond the FDA, EMA, and the USP, other assets are available to industries, including testing for and mitigating these elemental impurities. Detection by testing plays a crucial role in ensuring the quality and safety of food, beverages, and medical products. In a very relevant article in Pharmaceutical Technology, published two years ago, Felicity Thomas states, “The most commonly used techniques to analyze elemental impurities are inductively coupled plasma–mass spectrometry (ICP–MS) or inductively coupled plasma–optical emission spectroscopy (ICP–OES).” Both systems utilize high-energy plasma charges that ionize any elements present in the sample preparation and detect them using elemental masses or emission bands. The authors quote Paul Kippax, Pharmaceutical Sector director at Malvern Panalytical, who says, “The advantage of using ICP is that it can detect a wide range of elemental impurities at very low concentrations. This [capability] enables the product safety requirements for the main product types (oral solid dose, inhaled, and injectable products) to be assessed.”14 However, elemental impurity testing is not limited to ICP-MS or ICP-OES. Other techniques available include material characterization (including particle size and thermal analysis), chromatography, x‐ray diffraction and foreign matter identification, and NMR (nuclear magnetic resonance) spectroscopy, each with specific advantages or limitations depending on factors such as time, budget, material or impurities and levels being tested. Here is each profile:
Atomic Absorption Spectroscopy (AAS)
Atomic absorption spectrometry (AAS) detects elements in either liquid or solid samples through the application of characteristic wavelengths of electromagnetic radiation from a light source. Individual elements will absorb wavelengths differently, and these absorbances are measured against standards. In effect, AAS takes advantage of the different radiation wavelengths that are absorbed by different atoms. In AAS, analytes are atomized by an Air/Acetylene or Nitrous oxide/Acetylene flame so that their characteristic wavelengths are emitted and recorded. When a hollow cathode lamp is passed into the cloud of atoms, the selected metals to monitor absorb the light from the lamp, and the concentration is measured by a detector. Most of the elements reach excitation temperature using this source, which has a maximum temperature of 2,600 °C. For a few elements, such as V, Zr, Mo, and B, the source temperature is not sufficient to atomize the molecules, and as a result, sensitivity is reduced. Moderate detection limits and not all elements can be determined by AAS are some of the limitations of atomic absorption spectroscopy.
Inductively Coupled Plasma-Optical Emission Spectroscopy (ICP-OES or ICP-AES)
The source in ICP-OES is plasma at temperatures as high as 10,000 °C, where all elements, including refractory elements, atomize with higher efficiencies than in AAS. As a result, elements can be determined more precisely, and lower limits of detection levels are possible. There are two variants in ICP-OES, radial and axial. Axial viewing increases the path length and reduces the plasma background signal [over radial viewing], resulting in lower detection limits. ICP-OES is a multi-element technique. Under the source of plasma, the sample dissociates into its atoms and ions. At their excitation level, they emit light at characteristic wavelengths. The concentration of a particular element in the sample can be measured from the intensity of the emitted light with a detector. However, the detection limits in ICP-OES are moderate to low.
Inductively Coupled Plasma-Mass Spectrometry ICP-MS (ICP-MS)
The same source as in ICP-OES is used to dissociate a sample into atoms and ions. It is also a multi-element technique. The basic difference between ICP-OES and ICP-MS is that ions are directly detected by an MS detector rather than by emission of light, as in the case of ICP-OES. The ions are separated by a Quadrupole based on the mass-to-charge ratio. The best detection limits are available for most of the elements in ICP-MS as the number of ions produced is high, and although some spectral interference is seen, these are defined and limited.
X-ray fluorescence (XRF)
X-ray fluorescence (XRF) is a non-destructive analytical technique used to determine the elemental composition of materials. Analyzers determine the chemistry of a sample by measuring the fluorescent (or secondary) X-rays emitted from a sample when it is excited by a primary X-ray source. Each element in a sample produces a set of characteristic fluorescent X-rays (“a fingerprint”) unique for that specific element, which is why XRF spectroscopy is an excellent technology for qualitative and quantitative analysis of material composition. The ICP-OES technique has better sensitivity and lower detection limits compared to XRF. Therefore, using XRF for determining lower levels has higher errors, and the correlation with ICP-OES is weaker.
Recalls and Resources
The FDA’s actions on contamination from elemental impurities range from issuing guidance to product recalls. There are three class recall levels (I-III) and two related activities: a market withdrawal and a medical device safety alert.10 The former of these are voluntary, while the latter can be considered, in some cases, a recall.
Additionally, the FDA has a range of resources available for both consumers and manufacturers. For consumers, these include:
- Identifying Recalled Products
- Major Product Recalls
- FDA Recall Information on Twitter
- Your Guide to Reporting Problems to FDA
For industry resources, the offerings consist of the following:
- Industry Guidance: Information on Recalls of FDA-Regulated Products
- Enforcement Reports
- Public Availability of Lists of Retail Consignees to Effectuate Certain Human and Animal Food Recalls
- Public Warning and Notification of Recalls Under 21 CFR Part 7, Subpart C Guidance for Industry and FDA Staff
- Guidance for Industry: Product Recalls, Including Removals and Corrections
- Industry Notices and Guidance Documents10
The European Medicines Agency also provides numerous guides and requirements on their site, including the International Council for Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use’s ICH Q3D Elemental impurities – Scientific Guideline.11
Final Thoughts on Elemental Impurities
Whether it is in food and beverages or drug products, there is increased scrutiny by regulatory agencies and consumers on the presence of elemental impurities. Industries hoping to avoid costly product withdrawals, recalls, and possible litigation is advised to safeguard the quality and safety of food, beverages, and medical products by testing for elemental impurities. AMPAC Analytical has decades of experience and the full array of equipment and methods to ensure our products avoid these worst-case scenarios. Furthermore, these analytical services are accompanied by a devoted customer focus, with communication and guidance at each step to assist with all regulatory and filling requirements.
Resources, Related Topics, and Further Reading