Search

The purpose of this publication is to show how an elemental impurities excipient database can be used in assisting the execution of a drug product elemental impurities risk assessment as required by the ICH Q3D guidelines. As a result of this exercise, we have demonstrated that the database, used in conjugation with other sources of information, is a credible source of elemental impurity levels in excipients therefore, a valuable source of information in completion of drug product risk assessments. This useful collection of data helps to reduce the burden of analytical testing for elemental impurities in excipients.

Rubber stoppered glass vial systems are widely used as primary containers for storing and delivering therapeutic protein products to patients. Addressing concerns and regulatory expectations related to the risk to biologic drug product quality and patient safety from rubber stoppered glass vial systems requires implementation of an extractable and leachable evaluation program based on material understanding, risk assessment, literature review, and a comprehensive scientifically sound analytical testing methodology. The extractable and leachable study design consisted of twelve drug products filled in twelve different size glass vials capped with laminated and nonlaminated rubber stoppers made from three different rubber formulations. Design of the model solvents was successful as they had little to no analytical interference and mimicked the formulation conditions and generated representative extractables capable of predicting leachables. The extraction conditions of time and temperature were appropriate as not to degrade the test materials or the extractable compounds, and yet generated significant quantities for identification of the extractable compounds with confidence. The extractables testing results were capable of predicting the leachable profiles of the twelve drug products. In each case, the leachable profile was a subset of the extractable profile. The organic and elemental impurities of the leachable profiles of drug products were the end-to-end verification of the quality of the glass vials, rubber stoppers and drug product lifecycles. Overall, the holistic approach was fully successful in the qualification of different vial systems as primary containers and delivery systems for different biotherapeutic products to ensure product quality and patient safety.

Control of elemental impurities in the drug products evolved from the generic visual testing of heavy metals as their sulfides to specific elements of toxicological concern in the final drug products by instrumental analysis. The International Council for Harmonisation (ICH) Q3D (R1) guideline for elemental impurities describes a risk-based approach to identify, assess, and control the potential elemental impurities in drug products within the established permitted daily exposures (PDE). Challenges to this approach include how to assess the risks associated with contributing sources such as utilities, manufacturing equipment, container-closure systems, and excipients. Defining at what stage of development that such assessment should be performed to identify the risk levels can be equally challenging. In this article, we report an approach to control elemental impurities of toxicological concern, compliant to the Q3D (R1) guideline, and a summary of results obtained on multiple protein therapeutic products. This approach follows the elements of Process Validation, i.e., Design, Qualification, and Continuous Verification. The design includes the selection of excipients and their suppliers that meet the Option 1 requirement of Q3D (R1). It also comprises the selection of manufacturing equipment, container-closure systems, and utilities. The qualification includes the testing of the potential sources of elemental impurities, i.e., excipients, utilities, and leachables/extractables from the manufacturing equipment and container-closure systems. The Continuous Verification comes from the testing of representative batches at the initiation of stability studies of clinical or commercial drug product batches and at the end of shelf-life expiry of the drug product, and when changes are made to the manufacturing equipment, sources of excipients and container closure systems, and any formulation changes. Our experience shows that the risk associated with the impurity levels of the ten elements of toxicological concern in the therapeutic protein drug products, parenterally administered, is well below the control threshold (30% PDE) in the drug product recommended by the ICH Guideline. Although our focus is on the injectable therapeutic proteins, this approach can be applied to the products administered via other routes as well.

The novel laser ablation inductively coupled plasma mass spectrometry methodology for the rapid screening of elemental impurities in solid pharmaceutical samples with the daily dose less than 2.0 g has been developed in accordance with requirements of established USP chapters and ICH-Q3D guideline. The LA-ICP-MS methodology covering the determination of Cd, Pb, As, Hg, Co, V, Ni, Tl, Au, Pd, Ir, Os, Rh, Ru, Se, Ag, Pt was successfully validated in terms of linearity, limit of quantification, accuracy, precision, intermediate precision, specificity and range. Moreover, the presented ‘in-house’ matrix-matched standards preparation methodology helps to overcome crucial analytical problem connected with unavailability of commercial certified matrix-matched reference material suitable for the direct elemental impurities analysis in various kinds of solid pharmaceutical products. A two step homogeneity study of prepared matrix-matched calibration standards is also reported to investigate the homogeneity of distribution of elemental impurities and internal standards across the pressed pellet. The validated LA-ICP-MS method was applied on analysis of several types of solid pharmaceutical samples (active pharmaceutical ingredients, excipients, placebo and final drug products). The proposed method allowed the accurate, precise and fast screening of elemental impurities without necessity of time and labour consuming solutions preparation and thus it can be used in routine practice as an alternative to conventional ICP-MS or ICP-OES for the rapid quality control of different stages of pharmaceutical production.

New guidelines for the limits of elemental impurities in drug products were introduced by the International Council for Harmonization in 2014. While the guidelines define a limit for each element, the complete quantification of the 24 elements included is, in fact, unnecessary. An accurate "pass/fail" test to determine whether the threshold was exceeded or not could be valuable in this context. In this study, a screening procedure using the features of high-resolution continuum source graphite furnace atomic absorption spectrometry for the evaluation of 12 elements in three different drugs was developed. The three-dimensional absorbance spectrum including time and wavelength in the vicinity of the main line of the element allows for a pass/fail decision related to the presence or absence of the element in the sample. Additionally, the bi-dimensional absorbance-wavelength spectrum defines the elements captured in the window when additional peaks are seen in the spectrum. The analysis of the selected drugs included sample digestion, the definition of pyrolysis and atomization temperatures, determination of the limit of detection and other validation parameters for each element. The evaluation of the spectra, both three- and bi-dimensional, revealed that only three elements, Cr, Ni, and Cu, were present in the samples in amounts above the LOD and therefore "fail" in the test. Nevertheless, they were quantified, and the analysis revealed that their levels were below the permitted daily exposure, which are at least 6 times higher than the LOD of the selected elements. Operating in a routine mode, the proposed method is a good option for the evaluation of elemental impurities in drug active ingredients or drug final products.

Advances in biotechnology and the chemical synthesis of peptides have made biopharmaceuticals and synthetic peptide drugs viable pharmaceutical compounds today and an important source for tomorrow's drugs and therapies. Unfortunately, also falsifications and counterfeit versions of these powerful and promising drugs are offered illegally via the internet. Since these falsified preparations are produced outside the legally required quality systems, end-users have no guarantee regarding the efficacy and safety of these products. Although falsified samples of biotherapeutics were already analysed, looking at a specific aspect of their quality or identity, no systematic studies have been performed regarding the presence of different impurities or possible contaminations. Therefore, in order to obtain a better understanding of the potential health risks related to the usage of falsified polypeptide drugs we performed a systematic screening of the ten most frequently encountered falsified peptide drugs on the Belgian market acquired from three different suspected illegal internet pharmacies. The screening incorporated the analysis of the active pharmaceutical ingredient (API), API-related impurities, small molecule contaminants (defined as organic small molecules not belonging to the other categories), elemental impurities and residual solvents. This comprehensive study showed that these type of falsified drugs not only have a high variation in amount of drugs per unit and a low purity (ranging between 5% and 75% for cysteine containing peptides), but also contained the known toxic class one elemental impurities arsenic (As) and lead (Pb). One sample was contaminated with Pb while multiple samples were found with concentrations up to ten times the ICH toxicity limit for parenteral drugs. Subsequent speciation of As confirmed the elevated concentrations for As and demonstrated that all As was present in the more toxic inorganic form. Together with the (sometimes) high amount of peptide impurities and the inherent dangers associated with the use of unauthorized peptide drugs (such as doping peptides or preclinical drugs) this study confirms the reported potential health risks patients/users take when resorting to falsified peptide drugs. Moreover, the presence of the carcinogen As and the known accumulation in human tissues of Pb raises questions about potential sub-acute to chronic toxicity due to the long term administration of these falsified peptide drugs.

To support the practical implementation of the International Council for Harmonisation (ICH) Q3D guideline, which describes a risk-based approach to the control of elemental impurities in drug products, a consortium of pharmaceutical companies has established a database to collate the results of analytical studies of the levels of elemental impurities within pharmaceutical excipients. This database currently includes the results of 26,723 elemental determinations for 201 excipients and represents the largest known, and still rapidly expanding, collection of data of this type. Analysis of the database indicates good coverage of excipients relevant to real-world drug product formulations and tested element profiles consistent with ICH Q3D recommendations. The database includes the results from multiple analytical studies for an excipient and thus incorporates within it an indication of both excipient supplier and batch-to-batch variability as well as any variability associated with the different testing organizations and methods employed. The data confirm the findings of earlier smaller studies that elemental impurity concentrations in excipients are generally low and when used in typical proportions in formulated drug products are unlikely to pose a significant patient safety risk. The database is now in active use as one line of evidence in ICH Q3D risk assessments.

In efforts to control the potential presence of heavy metals in pharmaceuticals, the United States Pharmacopeia (USP) and International Conference on Harmonization (ICH) have put forth new requirements and guidelines for their control. The new requirements and guidelines establish specific daily exposures (PDE) for 24 heavy metals/elemental impurities (EI) based upon their toxicological properties. USP General Chapter 〈233〉 provides a general reference procedure for preparing pharmaceutical samples for analysis employing microwave assisted digestion (MWAD). It also provides two Compendial Procedures, Procedure 1 employing ICP-AES, and Procedure 2 employing ICP-MS. Given the extremely low detection limits afforded by ICP-MS, much work has been done in developing and evaluating analytical methods to support the analysis of elemental impurities in finished pharmaceutical products, active pharmaceutical ingredients, and excipients by this analytical technique. In this study, we have evaluated the use of axial ICP-AES. This employs ultrasonic nebulization (UN) for the determination of Class 1 and 2 EI, instead of traditional pneumatic nebulization. The study also employed closed vessel MWAD to prepare samples for analysis. Limits of quantitation were element specific and significantly lower than the PDEs for oral drugs. Spike recoveries for the elements studied ranged between 89.3% and 109.25%, except for Os, which was subject to OsO4 formation during MWAD. The use of axial ICP-AES UN provides an alternative to ICP-MS in the analysis of EI requiring low detection limits.

Spectrochemical elemental analysis of pharmaceuticals and raw materials used for their production will be in the nearest future an obligatory part of quality and safety control for compliance with new standards announced by the International Council for Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH Q3D). The present paper surveys R&D articles and scientific papers devoted to determination of the elemental impurities by inductively coupled plasma optical emission spectrometry and mass spectrometry (ICP-OES and ICP-MS) in different pharmaceuticals products that have been published since 2000. In reference to recent changes described in the United States Pharmacopoeia (USP) general chapters and , different aspects of such measurements are presented, including appropriate sample preparation procedures, possible interferences and means of their avoidance, suitable calibration strategies and validation parameters that have to be assessed to prove reliability of the analytical results on the elemental impurities in pharmaceutical products.

Reactive impurities in excipients can cause drug product degradation or protein modification even at trace levels, and thus impact drug stability and quality. It is critical to understand the potential impact of these impurities during development in order to ensure a robust clinical and commercial product. In this article, we review reactive impurities in pharmaceutical and biopharmaceutical excipients for both small molecule and large molecule drugs. The common reactive impurities in excipients, including peroxides, aldehydes, organic acids, reducing sugars and elemental impurities are reviewed. Sources of these impurities, reactions and impact, analytical methods, and control and risk mitigation strategies are also discussed.

Thorough knowledge and control of impurities is an expectation for the registration of pharmaceuticals. Actual and potential impurity investigations are phased during drug development to acquire the appropriate information necessary to ensure drug safety from the standpoint of patient exposure to impurities. Regulatory expectations and common practices for the timing of impurity investigations during development are discussed. Investigations for synthetic drug substances include process-related impurities such as intermediates, by-products, mutagenic impurities, residual solvents, and elemental impurities. Stress or forced degradation studies are used to investigate degradation impurities for both drug substances and products. The goals of stress studies conducted at different phases of development are discussed. Protein products have related considerations for impurity investigations, but the nature of impurities and technologies used for determining them can be quite different compared to classical synthetic molecules. Considerations for protein product impurities are discussed with an emphasis on process impurities in monoclonal antibodies.

Some inorganic impurities are toxic to human health even when present at low concentrations and therefore must be carefully monitored in products as continuous use drugs. This work aimed the development of a simple microwave-assisted digestion procedure for different types of drugs and excipients and the analytical determination of elemental impurities according to the new regulations of the United States Pharmacopeia (USP) 232 and 233 using inductively coupled plasma optical emission spectrometry (ICP-OES) or inductively coupled plasma mass spectrometry (ICP-MS). Eight drugs samples and two excipients of different brands were microwave-assisted digested with inverse aqua regia. Addition and recovery experiments were performed according to J values, once permissible daily exposure value is specific for each element and estimated according to the maximum daily dose of drug indicated by the label. Samples were spiked with values of 1.5 J in order to check accuracies for As, Cd, Hg, and Pb. Recoveries obtained by ICP-OES ranged from 75 to 148% and for ICP-MS ranged from 74 to 120%. The limits of detection for ICP-OES ranged from 0.4 to 17 mg kg − 1 and for ICP-MS from 7.4 to 41.6 μg kg − 1 . Both analytical methods were adequate in terms of accuracies and sensitivities. Considering the maximum daily dose, all drugs samples and excipients contained As, Cd, Hg and Pb below the maximum limits stipulated by USP since all of them presented contents below respective limits of detection.

A simple, fast, sensitive and green pretreatment method for determination of Cd, Co, Hg, Ni, Pb and V in oral and parenteral drug samples using inductively coupled plasma optical emission spectrometry (ICP OES) has been developed. According to United States Pharmacopoeia (USP), those metals must be reported in all pharmaceutical products for quality control evaluation (i.e., elemental impurities from classes 1 and 2A of USP Chapter 232). To improve the analytical capabilities of ICP OES, a dispersive liquid-liquid microextraction (DLLME) has performed using a safe, cheap and biodegradable deep eutectic solvent (DES) as extractant solvent (a mixture of 2:1 molar ratio of DL-menthol and decanoic acid). Seven parameters affecting the microextraction efficiency have carefully optimized by multivariate analysis. Under optimized conditions, the DES-based DLLME-ICP OES procedure improved limit of quantitation (LOQ) values on range from 12 to 85-fold and afforded an enrichment factor on average 60-times higher than those obtained to direct ICP OES analysis. Consequently, LOQ values for Cd, Co, Hg, Ni, Pb and V have been on average 10-times lower than target limits recommended for drugs from parenteral route of administration. Trueness has evaluated by addition and recovery experiments following USP recommendations for three oral drug samples in liquid dosage form and three parenteral drugs. Recovery and RSD values have been within the range of 90-109% and 1-6%, respectively. All analytes were below the repectives LOQ values, hence, lower than the limits proposed by USP Chapter 232. The authors are grateful to the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, grants no. 141634/2017-0, 202722/2019-8, 305201/2018-2 and 428558/2018-6), the Ministry of Economy and Competitiveness of Spain (PGC2018-096616-B-I00) the Regional Government of Valencia (Spain) (PROMETEO/2018/087, ACIF/2020/186), and University of Alicante (VIGROB-316FI) for the financial support, Agilent Technologies Inc. for the loan of the ICP OES spectrometer, and Ingeniatrics for the OneNeb® Series 2 provided. This study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - Brasil (CAPES) - Finance Code 001. The authors extend their appreciation to Ministry of Science, Innovation and Universities for granting the Spanish Network of Excellence in Sample Preparation (RED2018-102522-T). This article is based upon work from the Sample Preparation Study Group and Network, supported by the Division of Analytical Chemistry of the European Chemical Society.

Elemental impurities (EIs) profiling in final pharmaceutical products is often not adequately treated, however it is crucial problem in pharmaceutical analysis by reason of the various regulatory authorities (like ICH Q3D guideline). EIs in pharmaceuticals may arise from numerous sources of which the herbal ingredients are not a frequent subject of pharmaceutical analyses. However, based on number of traditional use registrations per year for herbal medicinal products (HMPs) in the EU, it can be stated that monocomponent HMPs are still very popular for use. Due to the high frequency of use, exposure to EIs from HMPs may be high during long-term use. The aim of our article was Ni and Cr impurities profiling of Valeriana officinalis L., radix (Valerian root) as an example of the HMP available in Polish pharmacies for the relief of mild nervous tension and sleep disorders. The choice of metals was justified by: (1) a single dose of Ni administered via oral route can induce dermatitis in nickel-sensitised individuals; (2) Cr is a very problematic element from toxicological point of view. Our results indicate that the standards of the ICH Q3D guideline are met for all EIs.

The new guidelines of the United States pharmacopeia (USP), European pharmacopeia (EP) and international conference on harmonization (ICH) regulating elemental impurities limits in pharmaceuticals signify the end of unspecific analysis of metals as outlined in USP 〈231〉. The new guidelines specify both daily doses and concentration/limits of elemental impurities in pharmaceutical final products, active pharmaceutical ingredients (API) and excipients. In chapter USP 〈233〉 method implementation, validation and quality control during the analytical process are described. We herein report the use of a stabilising matrix that overcomes low spike recovery problem encountered with Os and allows the determination of all USP required elemental impurities (As, Cd, Hg, Pb, V, Cr, Ni, Mo, Cu, Pt, Pd, Ru, Rh, Os and Ir) in a single analysis. The matrix was used in the validation of a method to determine elemental impurities in TP-6076 active pharmaceutical ingredient (API) by ICP-MS according to the procedures defined in USP〈233〉 and to GMP requirements. This validation will support the regulatory submission of TP-6076 which is a novel tetracycline analogue effective against the most urgent multidrug-resistant gram-negative bacteria. Evaluation of TP-6076 in IND-enabling toxicology studies has led to the initiation of a phase 1 clinical trial.

Control of elemental impurities in pharmaceutical materials is currently undergoing a transition from control based on concentrations in components of drug products to control based on permitted daily exposures in drug products. Within the pharmaceutical community, there is uncertainty regarding the impact of these changes on manufactures of drug products. This uncertainty is fueled in part by a lack of publically available information on elemental impurity levels in common pharmaceutical excipients. This paper summarizes a recent survey of elemental impurity levels in common pharmaceutical excipients as well as some drug substances. A widely applicable analytical procedure was developed and was shown to be suitable for analysis of elements that are subject to United States Pharmacopoeia Chapter and International Conference on Harmonization’s Q3D Guideline on Elemental Impurities. The procedure utilizes microwave-assisted digestion of pharmaceutical materials and inductively coupled plasma mass spectrometry for quantitative analysis of these elements. The procedure was applied to 190 samples from 31 different excipients and 15 samples from eight drug substances provided through the International Pharmaceutical Excipient Council of the Americas. The results of the survey indicate that, for the materials included in the study, relatively low levels of elemental impurities are present.

Inorganic impurity analysis of pharmaceutical drug products is of paramount importance at trace levels due to the availability of toxic metals. The existing techniques require extensive development and chemical treatment to evaluate the presence of class I (Pb, Cd, Hg and As) and class II (Co, V and Ni) heavy metal elements which are harmful to the environment. To overcome these issues, a cost and time effective wavelength dispersive X-ray fluorescence spectrometry (XRF) was introduced to determine the concentration of trace elements in one of the angiotensin receptor blocker (ARB) (tablet sample 300 mg) according to guidelines addressed in ICH Q3D and USP. The validation study focused on class I and class II elements are also in accordance with regulatory guidelines. Overall it includes the comprehensive characterization of analytical method which is compliant with the requirement of USP. The novelty of this work includes the application of EDXRF in routine analysis of trace elements (especially volatile Hg) present in the pharmaceutical product beyond the previously published studies for the limited number of the non-pharmaceutical regime. Apart from this it also requires minimal sample preparation and method development and is able to quantify toxic impurities which are present in the sample in less than 20 ppm concentration, with the lowest level of detection up to 0.1 ppm.

Presented here is a look at different inductively coupled plasma (ICP) platforms including sector field, triple quadrupole mass spectrometric configurations, and optical emission spectroscopy. The goal of this manuscript was to convey the feasibility of trace elemental analysis of a uranium ore concentrate with varying ICP-based platforms. It was predicted that low mass elements would be better determined through optical means, or the mass collision/reaction technology of the triple quadrupole mass spectrometer, in comparison to high resolution measurements of magnetic sector-based configurations. Ultimately, it is difficult to achieve an “optimal” analysis of 20+ elements, for numerous samples, on a single platform, especially when time, measurement reproducibility, sensitivity, and robustness should be considered. The work presented here highlights the advantages and disadvantages of the respective trace elemental analysis platforms.

Erythritol tetranitrate (ETN) is a homemade explosive with high explosive performance which can easily be synthesized using widely available chemical precursors. Ascertaining the manner in which ETN is synthesized and being able to trace the ETN back to its precursor materials may aid in the forensic identification. As a proof of concept, seven different types of ETN were synthesized with laboratory grade materials as well as commercially available chemicals from the hardware store and grocery store. The seven different types of solid ETN and the reaction quenches were analyzed using high performance liquid chromatography (HPLC). Partial least squares discriminant analysis (PLS-DA) was used to probe the different classes of ETN and reaction quenches. Several PLS-DA models were produced with the seven different types of ETN and quenches having their own classification, ETN and quenches based on their acid source, and ETN and the quenches based on their nitrate source. Regardless of which classification manner was used, there were no differences found between the different types of ETN or their reaction quenches. Moreover, it is demonstrated that there is inherent variability in the synthesis of ETN making HPLC an unreliable method to determine the source of the synthesis materials. Elemental impurities were measured in seven solid ETN samples and their reaction quenches by inductively coupled plasma mass spectrometry (ICP-MS). No differences were found between the solid ETN samples, but there were trace metals found in the reaction quenches which were found to be identifiers of the source material.

The pharmaceuticals may generate impurities at various stages of development, transportation and storage which make them risky to be administered. Thus, it is essential that these impurities must be detected and quantified. However, their presence as impurities in finished products is virtually unavoidable, even under GMP conditions. Control of elemental impurities in pharmaceutical materials is currently undergoing a transition from control based on concentrations in components of drug products to control based on permitted daily exposures in drug products. Within the pharmaceutical community, there is uncertainty regarding the impact of these changes on manufactures of drug products. This uncertainty is fueled due to lack of publicly available information on elemental impurity levels in common pharmaceutical excipients. The present compilation gives an account of updated information about elemental impurities and reviews the regulatory aspects for such impurities in active pharmaceutical ingredients/drug formulations. In addition, the aim of this article is to review and discuss the currently used quantitative analytical method, which is used for quality control of elemental impurities in pharmaceutical products.

Background The European Pharmacopoeia as well as further legal provisions contain rules for the assessment of potential residues and contaminants in herbal substances and preparations used for the production of herbal medicinal products, e.g. for the assessment of pesticide residues, heavy metals and other elemental impurities, mycotoxins and microorganisms. As a potential contamination caused by weeds, the occurrence of pyrrolizidine alkaloids is being discussed for several years which lead to measures of health authorities limiting the PA content in herbal medicinal products and to measures of industry consisting of reducing the probability of PA occurrence in medicinal plants and the respective products. Conclusion In this context and with regard to all kinds of potential residues or contaminants, collection and evaluation of data from daily analytical practice of manufacturers and suppliers is useful for the assessment of the situation and the definition of testing strategies.

Over the last 20 years there has been an increasing interest in the development of robust systems, both analytical and statistical, to enable the linkage of seizures of illicit drug to each other. Much of this work has concentrated on the analysis of synthetic drugs, such as amphetamine and its analogues. In recent years, the analysis of both organic and elemental impurities as well as isotope ratios has advanced the usefulness of the techniques available. The application of specific chemometric methods to the derived analytical data has begun to provide the possibility of robust methods by which the resultant information can be interrogated.

Carbon black has been analysed for elemental contamination using the particle induced X-ray emission (PIXE) technique. A 3 MV Dynamitron accelerator was employed to produce the 2.5 MeV proton beam used for the PIXE measurements. The carbon black particulates were pelletised to form thick targets and also collected on 25 mm diameter cellulose-ester filters for thin target measurements. The targets were placed normally to the incident proton beam in a multisample chamber for analysis. A conventional Si(Li) X-ray detector, placed at 135° to the proton beam was employed to detect the emitted X-rays. The results obtained from the thick and thin target analyses are compared and discussed. Calculations of the maximum Stoke's diameter of the carbon black particles are included.

This paper presents a method for increasing the accuracy in the determination of impurities in metals by spark source mass spectrometry (SSMS). The method is based on the application of a parametric equation to calculate sensitivity coefficients. The parameters of this equation are determined from results obtained by analysis of an appropriate standard material. Concentrations in the sample of elements certified in the standard material are determined using experimental values of sensitivity coefficients, while the concentrations of remaining elements in the test sample are determined using coefficients calculated from the proposed parametric equation.