Is My Medicine Toxic?

Elemental Impurities in Pharmaceutical Products and New Analytical Methods

In today's world where industry plays an indispensable role in our lives and continues to develop every day, product purity is a critically important issue in pharmaceutical manufacturing just as it is in every other sector. The presence of certain contaminant substances in a manufactured drug is a risky situation in many respects. In such a situation, the manufacturer may face serious problems such as the health of those using the drug being negatively affected, the product quality being poor, or the product shelf life being shortened. What these contaminant substances may be and the maximum quantities in which they can be present in a product are regulated by authorized regulatory bodies. Among the major pharmacopeias and guidelines followed by the pharmaceutical sector—USP, EP and ICH—certain changes have been made to protect consumer health regarding this issue. One of these changes concerns the elements that may be present in the product, their permissible maximum levels, and analytical methods.

Need for Change

The analytical method called "Heavy Metal Limit Test" in USP 231 was nearly a century old, lacked sufficient sensitivity and specificity, and was prone to deviations in analytical results. There was a need to use more specific and robust analytical techniques. Building on this, changes were made to place human health ahead of the method's capacity for pharmaceutical products analysis, determining elements and their limits based on toxicological risks and adapting these limits according to the route of administration of the drug. Following these changes, details regarding elemental impurities are set out in EMA/CHMP/ICH/353369/2013 for Europe, USP 232 and 233 (limits and procedures) for the United States, and ICH Q3D sections as international guidance. In these new sections, the number of elements has been increased and elements have been classified according to their toxicological risks. Additionally, daily exposure limits have been determined based on the route of administration of the drug.

Table 1. Permitted daily exposure (PDE) values for elements

Risk Assessment

Pharmaceutical manufacturers must conduct a risk assessment regarding elemental impurities for products placed on the market. To conduct this assessment, information generated by the applicant, information provided by active pharmaceutical ingredient, raw material or excipient suppliers, or published literature information can be used. The risk assessment process can be performed in three steps: • Identifying potential and known sources of elements likely to transfer to the pharmaceutical product. • Evaluating the presence of a specific element in the pharmaceutical product by comparing the estimated level of the element with PDE values; here, 30% of PDE values is defined as the control threshold. • Summarizing and documenting; determining whether the controls performed are sufficient and whether additional controls are needed. If, following the assessment, the elemental impurity level that could come from all possible sources is predicted not to exceed 30% of the PDE value, no additional controls will be required.

Sources of Contamination

The medicines we use go through many stages before reaching their final form. If certain elements in the final product are found above limits, anything from raw material purity to packaging material, from active ingredients to solvents, from containers to equipment used in processes—in short, all substances added to the product and everything they contact can be a potential source of contamination.

Sample Preparation for Analysis

Various techniques and instruments can be used to specifically and quantitatively analyze the elements contained in a pharmaceutical product or raw material. However, before deciding on the instrument to be used, certain matters must be carefully evaluated. The form of the product, its chemical composition, solubility, available sample quantity, the route of administration of the product, and the limit values of the elements to be analyzed play an important role in sample preparation method and instrument selection.

The main sample preparation methods mentioned in USP 233 following the changes made to the guidelines are as follows:

• If the sample is a liquid that can be analyzed directly with an instrument without further processing, it can be analyzed directly with the appropriate instrument. • If the sample is water-soluble, it can be dissolved and diluted with a specific amount of water. • If the sample is not water-soluble, it can be dissolved with an appropriate organic solvent and analyzed. • Insoluble or difficultly soluble samples can be prepared using a closed-vessel microwave digestion method. In the microwave digestion method, a specific amount of sample is taken, placed in closed vessels, heated with a strong acid or acid mixture in a laboratory-type microwave oven system. The sample digestion is performed by applying a specific temperature program under high pressure. The benefit of this method is that since the heating is performed in closed vessels under pressure, some volatile elements in the sample (Sb, Hg, Sn, As, Ag, etc.) are kept in solution. After the sample is digested, the elements in the solution are analyzed with an appropriate instrument. Selection of the Appropriate Instrument At this point, pharmaceutical manufacturers are deciding whether to conduct elemental impurity analyses through a qualified external laboratory or in their own facility laboratory. If the manufacturer plans to conduct these analyses in their own laboratory, the correct approach for selecting the appropriate instrument is only possible by correctly determining the laboratory's analytical needs. When determining this need, the manufacturer's product portfolio, the routes of administration of the drugs, which elements need to be analyzed in which products, the education level of laboratory personnel, and of course the budget allocated for the instrument are factors considered in instrument selection. Additionally, comparing the performance capacity of the instrument planned to be invested in with method requirements is one of the most important factors in making the right decision. One of the most important parameters of performance capacity is the lowest levels that instruments can measure. The instrument to be used for risk assessment of the product must be capable of meeting the PDE values in the guidelines. For samples that must undergo a pre-treatment such as dilution or digestion, the maximum levels corresponding to PDE values in the prepared solution must be calculated. In this calculation, the daily dose of the drug should also be taken into account and the following formula can be used for this calculation.

Two Master Craftsmen of Element Analysis: ICP-MS and ICP-OES

Techniques such as AAS can be used in elemental impurity analysis provided that the method is validated. However, the instruments recommended for these analyses in USP 233 are ICP-MS or ICP-OES instruments. For many years, these instruments have been used in laboratories of many sectors—food, environment, textiles, consumer products, academic, clinical, forensic—for element analysis. However, they have not yet found their deserved place in the pharmaceutical sector. Nevertheless, especially following these innovations in guidelines and pharmacopeias, these two instruments are candidates for ranking among the most commonly used instruments in the pharmaceutical sector. But what are the differences between these two instruments? Which instrument fully meets the needs of pharmaceutical manufacturers? Of course, this is a question that each pharmaceutical manufacturer can answer by evaluating it specially within their own organization, but it is possible to compare the capabilities of both instruments in general terms and form an opinion. Although both instruments use plasma technology and are quite similar in hardware, they are different spectroscopic techniques based on different measurement principles.

Figure 1. ICP (Inductively Coupled Plasma)

ICP-OES (Inductively Coupled Plasma-Optical Emission Spectrometer)

The ICP-OES instrument is a system equipped with optics based on the principle of element atoms emitting radiation at specific wavelengths. Its ability to measure all elements simultaneously results in very high analysis speed. Although many different models exist in the market, some instruments can handle hundreds of samples daily. Being an instrument with wide matrix tolerance, it is very suitable for analyzing sample solutions with high total solids content (~20-30% TDS). Also, being an easy-to-use system, it can be put into operation for new laboratories and standard users with brief training. ICP-OES instruments generally have sensitivity down to the ng/g level. For this reason, they are more suitable for pharmaceutical manufacturers working on products used orally. Of course, depending on the usage doses, if measurement limits are favorable, it may also be appropriate for use with other products. Although it is a multi-element technique, ICP-OES requires hydride generation reaction to measure certain elements such as mercury and arsenic at low levels. A unit or apparatus specially manufactured for this technique is combined with ICP-OES to perform these measurements.

ICP-MS (Inductively Coupled Plasma-Mass Spectrometer)

The ICP-MS instrument, on the other hand, is based on the principle of separating elements by mass in a vacuum environment and counting them at a detector. All elements can be measured simultaneously. Although the analysis speed is not as high as ICP-OES, there is no major difference between them. In terms of matrix tolerance, sample solutions containing total solids around 2-3% TDS can be used. Being a somewhat more high-tech technique compared to other instruments, full learning for new users may take longer. However, it should be noted at this point that all these instruments are operated with software and software becomes increasingly user-friendly every day. The ICP-MS instrument has a higher measurement speed compared to other techniques in element analysis and is the only instrument capable of reaching the lowest levels. In terms of sensitivity, it can measure concentrations of pg/g and lower. For this reason, it is an ideal solution for pharmaceutical manufacturers to measure all products regardless of their route of administration. Additionally, the ICP-MS instrument does not require units such as hydride generation that may be needed for certain elements in other techniques. Speciation analysis; the ICP-MS instrument has another capability that is not possible with other techniques. The toxic nature of some elements such as arsenic, mercury, and chromium can vary depending on the form in which the element is present. By coupling with a chromatographic system such as HPLC or IC, it is possible to have more detailed information about the form of elements in the sample using ICP-MS.

Stricter Control, Healthier Generations

The pharmaceutical sector, unlike other sectors, places products with relatively high importance on consumer use. For this reason, it is of great importance that products placed on shelves pose no health risk. Thanks to the new regulations introduced by authorized bodies, the new controls and inspections that manufacturers must implement will not only contribute to protecting consumers' health but will also help prevent major losses the manufacturer might face due to adverse situations. Ultimately, it will ensure that medicines distributed for human consumption are placed on shelves in a more secure manner. Be well. Veysel Boz Product Specialist SEM Laboratuvar Cihazları