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When evaluating a drug’s risk assessment for elemental impurities, one must consider all aspects of its lifecycle.
The safety of a drug product is as important as its effectiveness. Testing a drug for potential impurities that may impact the lives of the patients who use these medicines before and after the drug hits the market is integral in the development and manufacture of these products.
Pharmaceutical Technology® spoke with Magdalena Pringgoadimuljo, department manager, Metals at Element, and Sarayu Rao, PhD, supervisor, Trace Metals at Element, to find out how drug manufacturers can best go about testing their products for elemental impurities.
PharmTech: How are drugs tested for elemental impurities? Is there a difference between testing of dosage forms?
Pringgoadimuljo and Rao (Element): Advanced spectroscopy techniques are used to test for elemental impurities in drugs. Some of these techniques are commonly used, such as inductively coupled plasma mass spectrometry (ICP–MS), inductively coupled plasma optical emission spectrometry (ICP–OES), and atomic absorption spectrometry (AAS). The choice of technique depends primarily on the sample matrix and permitted daily exposure (PDE) limits of the elemental impurities of interest.
USP [United States Pharmacopeia] General Chapter <233> recommends the use of ICP–MS or ICP–OES to measure elemental impurities concentrations in pharmaceutical products (1). While both techniques can measure multiple elements simultaneously, ICP–MS has lower detection limits than ICP–OES for most elements. AAS can measure only one element at a time and is commonly used for assay tests, limit tests, and identification tests following individual monographs (e.g., USP, Ph.Eur. [European Pharmacopoeia], ACS [American Chemical Society]).
The potential toxicity of the elemental impurities varies depending on the route of administration. Three main dosage forms for which PDE limits are enumerated by ICH [International Council for Harmonisation] Q3D(R2) (2) and USP <232>/<233>, parenteral, inhalation, and oral. Since the limits are different for each dosage form, the sample preparation and analysis technique may vary accordingly.
PharmTech: Are there best approaches for testing for elemental impurities?
Pringgoadimuljo and Rao (Element): There are a variety of approaches for testing elemental impurities, depending on goals and resources. However, the entire drug product lifecycle should be factored in—including manufacturing equipment, container closure system, drug substance, excipients, and the water used for processing.
A proper risk assessment is key to ensuring the safety of a drug product while avoiding performing unnecessary extra work. For instance, identifying which elements need to be tested for a product can result in testing only seven elements instead of 24. Risk assessments can be based on a variety of factors, including findings from published literature, data from similar processes, supplier data, data from tests of components and/or drug product, and prior knowledge.
PharmTech: At what stage of development/manufacturing should testing be performed?
Pringgoadimuljo and Rao (Element): There are multiple potential sources of elemental impurities during the development and manufacturing of a drug product. All potential sources of elemental impurities should be considered in the product risk assessment, including elements intentionally added (e.g., catalysts, inorganic reagents); elements not intentionally added but could be present in the API, excipient, raw material, or water used in the preparation of the drug product; elemental impurities that could be potentially introduced from the manufacturing equipment used in the production of the drug product; and elemental impurities that may be introduced from container closure systems (for liquid and semi-solid dosage forms).
Manufacturers should assess each elemental impurity expected to be present in the drug product by determining the observed or predicted level and compare it with the established PDE for that specific dosage form. If the risk assessment data demonstrates [that] results can be expected to be less than 30% of the PDE, no additional controls are necessary, provided the manufacturer has properly assessed the data and demonstrated that adequate controls have been applied.
PharmTech: Are there any innovations in testing equipment or procedures that the industry should be implementing but are not currently for the detection of elemental impurities?
Pringgoadimuljo and Rao (Element): ICP–MS and ICP–OES are the most used instrumental techniques for the determination of elemental impurities in pharmaceutical products due to their low detection limit capabilities (sub-ppt and ppb levels) and wide linear dynamic range. Depending on the sample matrix, the sample may require simple dilution with a solvent or acid digestion. For difficult-to-digest samples, one modern tool that pharmaceutical labs should have at their disposal is a microwave capable of performing high-pressure/high-temperature closed-vessel digestion. Furthermore, for difficult organic matrices, ICP–MS systems can be configured to withstand direct analysis of organic solvents.
Though ICP–MS is a highly specific technique, polyatomic interferences can become an issue unless effectively addressed. Many polyatomic interferences can be effectively mitigated by using a reaction/collision cell on the ICP–MS. Common examples include ArCl+ interference on arsenic (75As), ArAr+ interference on selenium (78Se), and ArNa+ interference on copper (63Cu). Another common issue is the response enhancement that can be observed with certain elements (e.g., arsenic, selenium, and phosphorus) in the presence of a highly organic matrix, which may cause a high bias on the response for these elements. This effect can be mitigated by [having the] matrix match the nebulizer stream with organic material.
The latest technology in interference removal is the triple quadrupole ICP–MS (ICP–MS/MS), which can resolve spectral interferences for the analysis of complex matrices and can also provide lower detection limits for challenging analytes (e.g., selenium, chromium, sulfur, phosphorus, and silicon) by reducing background interferences with the use of its MS/MS operation. Lower detection limits offer more flexibility with sample preparation techniques, enabling measurements at lower target concentrations.
Finally, for matrices where the limits of arsenic or mercury are exceeded, USP <232> provides speciation analysis as an option for evaluating the compliance of the materials to specifications. This is due to the differing toxicities of mercury and arsenic in their inorganic and complexed organic forms. Using ICP–MS in conjunction with liquid chromatography (LC), the hyphenated technique LC–ICP–MS can provide an alternate approach for demonstrating a material is safe.
PharmTech: Which elemental impurities are most common in solid-dosage drugs?
Pringgoadimuljo and Rao (Element): Class 1 elements (arsenic [As], cadmium [Cd], mercury [Hg], and lead [Pb]) and class 2A elements (vanadium [V], cobalt [Co], and nickel [Ni]) are highly toxic and have a high probability of occurrence in drug products. These elements should be included in risk assessments for all routes of administration, whether it is intentionally added during the
PharmTech: What are the acceptable limits for such impurities?
Pringgoadimuljo and Rao (Element): ICH Q3D has established PDE values for elemental impurities based on safety data and individual safety assessments (information recorded in monographs found in Appendix 3 of ICH Q3D [R2]). The elements of concern are classified into three classes based on their toxicity—Class 1, Class 2A, 2B, and Class 3. Based on the dosage form, and individual safety assessments, different PDE limits have been established for different routes of administration. For example, oral and parenteral routes have the same PDE (15 µg/day) for arsenic, however, a lower PDE limit for inhalation (2 µg/day).
Regulating impurity testing
PharmTech: How have updated regulatory guidelines (e.g., ICH Q3D) impacted analysis for elemental impurities?
Pringgoadimuljo and Rao (Element): Previously, the guideline for elemental impurities was based on a colorimetric ‘heavy metals limit’ test. This test was limited to 10 elements (lead, mercury, bismuth, arsenic, antimony, tin, cadmium, silver, copper, and
molybdenum), provided no information about the individual concentrations of each element, and could not be used for many other potential elemental impurities (e.g., platinum group elements). Therefore, the guideline was not specific or sensitive.
ICH Q3D replaced the flawed 100-year-old colorimetric test with modern instrumentation such as ICP–MS and ICP–OES techniques. The ICH Q3D guideline identifies and provides PDE limits for the highest risk elements across different dosage forms and provides a framework for the risk assessment and control of elemental impurities across a product lifecycle. USP <233> illustrates analytical procedures that possess characteristics, such as accuracy, precision, and specificity, that help manufacturers be certain measurements are reliable.
Susan Haigney is managing editor for Pharmaceutical Technology.