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Introduction: Kratom is commonly used by consumers, and the elemental impurity exposure that consumers would have at different kratom ingestion doses has been determined. Methods: This assessment used original data from independent third-party laboratory testing of kratom products to identify the percentage of products that exceeded permissible daily exposure limits for lead (5 µg/day), nickel (200 µg/day), arsenic (15 µg/day), and cadmium (5 µg/day), the interim reference level for lead in adults (12.5 µg/day), and the tolerable upper intake level for manganese (11 mg/day) and nickel (1 mg/day). We assessed all products regardless of type and then evaluated non-extract products, extract products, and a soda preparation separately for elemental impurities. Results: Three assessments of elemental impurities in kratom products have been published, totaling 68 products. Assessing all products and assuming a 3 g daily dose of kratom, 7.4% would exceed the permissible daily exposure limits for lead, 0% for nickel, 3.1% for arsenic, and 0% for cadmium. At a kratom dose of 25 g daily, 70.6% would exceed the permissible daily exposure limits for lead, 20.6% for nickel, 9.4% for arsenic, and 0% for cadmium. The interim reference level for lead would be exceeded by 1.5% of products at a kratom daily dose of 3 g and 33.8% of products at 25 g. The tolerable upper intake level for manganese would be exceeded by 12.5% of products at a kratom daily dose of 3 g and 41.7% of products at 25 g. Non-extract products generally contain greater concentrations of elemental impurities than extract products or the soda preparation. Discussion: Apart from their concentrations in a gram of product, assessing the amount of exposure to elemental impurities at different kratom ingestion doses is also important. Elemental impurities exceeding regulatory permissible concentrations for many products, especially with greater daily kratom ingestion doses, may impact human health. Conclusions: Some kratom products contain excessive concentrations of elemental impurities of toxicological concern, such as lead and arsenic. Non-extract products (powders, capsules, tablets) generally contain greater concentrations of elemental impurities than extract products or the soda preparation. Daily use of these products can result in exposures exceeding regulatory thresholds and adverse health effects. [ABSTRACT FROM AUTHOR]

INTRODUCTION. This work continues the authors’ earlier study on gelatine capsule contamination with elemental impurities, which resulted in proposing a list of elements for standardisation. To ensure the safe use of medicinal products in this dosage form, it is necessary to develop criteria for the quantitative assessment of potential human health risks associated with elemental impurities in gelatine capsule shells.AIM. This study aimed to determine the permitted daily concentration (PDC) limits for elemental impurities in gelatine capsules from a risk-based pharmaceutical quality control perspective.MATERIALS AND METHODS. The authors analysed their previous experimental data, the relevant Russian State Standard (GOST), the requirements of the State Pharmacopoeia of the Russian Federation and leading world pharmacopoeias (USA, UK, EU, China, Japan, and India), and the scientific literature published from 1980 to 2023 on the content of elemental impurities (Al, As, Cd, Cu, Cr, Cr, Fe, Hg, Mn, Pb, and Zn) in gelatine capsule shells and medical gelatine.RESULTS. When standardising the content of elemental impurities in gelatine capsule shells, it is necessary to consider not only the toxicity of impurities but also their potential to compromise the quality of gelatine. Complexing elements (Cd, Cu, Hg, Cr, and Zn) can affect the quality of gelatine at subtoxic concentrations. For Cd, Cu, and Hg, the authors recommended using the PDC limits specified in GOST 23058-89 Gelatine. Raw materials for the medical industry. Specifications. For Cr and Zn, the authors recommended adhering to the PDC limits specified in the State Pharmacopoeia of the Russian Federation, edition XIV, Monograph 2.1.0099.18 Gelatine. Lead affects the quality of gelatine at concentrations above the toxicity threshold, and arsenic does not cause clustering of gelatine molecules. For Pb and As, the authors recommended using the PDC limits specified in the State Pharmacopoeia of the Russian Federation, edition XV, General Monograph 1.1.0040 Elemental impurities. The authors proposed a conversion factor to account for the complexing potential of Al when limiting its content in gelatine capsule shells. The authors recommended assessing the risks to human health associated with Mn intake with gelatine capsule shells indirectly by listing total heavy metals as a quality attribute to be controlled at the level of medical gelatine. The content of Fe should also be standardised at the raw material level.CONCLUSIONS. The content of elemental impurities in gelatine capsule shells should not exceed the following limits: 45 µg/g for Al, 1.5 µg/g for As, 0.03 µg/g for Cd, 10 µg/g for Cr, 15 µg/g for Cu, 0.05 µg/g for Hg, 0.5 µg/g for Pb, and 30 µg/g for Zn. The standardisation of these elements in gelatine capsule shells will prevent negative effects on the human body and shell quality.

Elemental impurities contained in drug product create a risk for patients and potential toxic elemental impurities defined and classified in Guideline for Elemental Impurities Q3D(R1). Among the finished product dosage forms, parenteral products could be critical for elemental impurities because elemental impurities are given directly to systemic circulation. For determination of elemental impurities, one of the most frequently used methods is inductively coupled plasma–mass spectrometry (ICP–MS). In this study we aimed to develop and validate an ICP-MS method for determination of 24 elemental impurities in micafungin powder for concentrate for solution for infusion manufactured in our own facility. Results showed that correlation coefficients of calibration curves were found higher than 0.99 for all elements in determined ranges and all validation parameters were achieved successfully. With this method, all 24 elemental impurities can be tracked throughout the shelf life of the product.

Elemental impurities are generated in pharmaceuticals at various stages of the manufacturing process and storage. The presence of elemental impurities in pharmaceuticals may lead to severe health complications. In this work, the presence of elemental impurities was determined in doxycycline hyclate tablets using microwave-assisted sample preparation. Concentrated nitric acid (70%) and hydrofluoric acid (47–51%) were used for the preparation of sample solution. Spike recovery experiments were performed using a matrix to detect class 1 (As, Cd, Hg, and Pb) and class 2A (Co, V and Ni) elements in a single analysis. The developed ICP-MS method was validated using different analytical parameters, i.e. specificity, linearity, precision (system precision and method precision), accuracy, limit of detection (LOD) and limit of quantitation (LOQ). All the experimental results demonstrated that the developed ICP-MS method is suitable for the simple and sensitive analysis of trace elements in doxycycline hyclate tablets. [ABSTRACT FROM AUTHOR]

Elemental impurities contained in a drug product create a risk for patients. Potential toxic elemental impurities are defined and classified in the Guideline for Elemental Impurities Q3D(R1). Among the finished product dosage forms, parenteral products could be critical for elemental impurities because elemental impurities go directly into systemic circulation. One of the most frequently used methods to determine elemental impurities is inductively coupled plasma–mass spectrometry (ICP–MS). In this study we aimed to develop and validate an ICP-MS method for the determination of 24 elemental impurities in micafungin powder for infusion manufactured in our own facility. Results showed that correlation coefficients of calibration curves were found higher than 0.99 for all elements in the determined ranges and all validation parameters were achieved successfully. With this method, all 24 elemental impurities can be tracked throughout the shelf life of the product. [ABSTRACT FROM AUTHOR]

Gallium ［68Ga］ is an important positron-emitting radionuclide in PET imaging radiopharmaceuticals. In order to ensure that the quality of gallium ［68Ga］ solution, a key raw material of gallium ［68Ga］ radiopharmaceuticals, meets the requirements of high labeling efficiency and safety, a detailed study on impurities in gallium ［68Ga］ solution from the generator was carried out, analytical method for impurity detection was developed and the validation of the methodology was completed. To control radiochemical impurities, radioactive thin-layer chromatography (Radio-TLC) method was used. The effects of key variables such as mobile phase, pH of the mobile phase, and system suitability solution on the test results were studied. After method optimization, iTLC-SG was determined to be the stationary phase, methanol-1 mol/L ammonium acetate (1∶1, V/V, ammonium acetate pH=2.8±0.2) as the mobile phase. In order to control elemental impurities, twelve elements including Fe, Ni, Zn, Sb, Pb, Li, V, Co, Cu, As, Cd, and Hg were determined by inductively coupled plasma mass spectrometry (ICP-MS) method. The radionuclide purity was determined by high-purity germanium (HPGe) γ spectroscopy, and the γ nuclide impurities such as 68Ge were controlled. Combined with the properties of the samples and the characteristics of each analytical method, the established analytical methods were validated. The validation included system suitability and resolution, linearity, limit of detection (LOD), limit of quantification (LOQ), accuracy, precision, durability, etc. These validated methods were used to determine impurities in gallium-［68Ga］ chloride solutions. The impurity test results of gallium-［68Ga］ chloride solution show that the Rf of 68Ga3+ is ≤0.2, and its radiochemical purity is 99.04%±0.35% (n=3). Its iron content is ≤0.5 μg/GBq, zinc content is ≤0.1 μg/GBq, and other elements do not exceed 30% of the PDE limits. Gallium ［68Ga］ radionuclide purity is more than 99.9%, other γ nuclide impurities are not detected at the first detection. 24 hours later, germanium ［68Ge］ breakthrough and other γ nuclide impurity content is 0.000 19%±0.000 05% (n=3). The results show that the established analytical methods can accurately determine the impurity of gallium-［68Ga］ chloride solution and effectively control its quality. The impurity content is lower than the limit required by European Pharmacopoeia (EP10.0). The successfully established detection method for impurities of gallium-［68Ga］ chloride solution provides a reference for the impurity control of medical radionuclides and the establishment of quality standards.

Abstract Background These days, the presence of simple impurities in pharmaceuticals is a major cause for worry. This is because some contaminants are dangerous on their own, and even small impurities can make a drug less stable and shorten its shelf life. The goal of this study was to see if creams with ximenynic acid could be tested with inductively coupled plasma-mass spectrometry to find out how much arsenic, mercury, lead, cadmium, vanadium, cobalt, and nickel were in them. The best way to do things would be one that was quick, accurate, sensitive, and very productive (ICP-MS). The method included both inductively coupled plasma mass spectrometry (ICP-MS) and microwave digestion. Results Seven of the seven linearity correlation coefficient (‘R’) value were more than 0.99. LOD values were calculated using 33% of the 0.25 J threshold. Six LOQ responses (0.25 J level) were taken after considerable discussion. Calculated and reported %RSD for six LOQ copies. All elemental impurities Vanadium (V), Cobalt (Co), Nickel (Ni), Arsenic (As), Cadmium (Cd), Mercury (Hg), and Lead (Pb) were recovered between 83.33% and 115.97%, within acceptability limits. RSD% for procedure precision and intermediate precision data never exceeded 5%. The available evidence shows that the ICP-MS technique is a good way to measure these components. Conclusion The statistical analysis showed that the developed ICP-MS method for measuring elements in Topical Cream with Ximenynic Acid is selective and accurate. Since this ICPMS method is good at estimating several elements simultaneously, it could be used to check for elemental contaminants in the formulation.

The main objective of the study is the estimation of elemental impurities in selected packaged commercial fruit juices and fresh fruit juices available in Ahmedabad, Gujarat. Estimation of seventeen samples (9 commercial fruit juices and 8 fresh fruit juices) was carried out for elemental impurities which include lead, cadmium, arsenic, mercury, methyl mercury, nickel, chromium, tin, copper, and zinc. Inductively coupled plasma-mass spectroscopy (ICP-MS) with microwave-assisted sample digestion was used to determine the element content of samples. The ICP-MS method was confirmed for accuracy by performing validation with validation parameters such as linearity, precision, and accuracy. The method’s trueness was confirmed with single-element standards. The results were compared with Food Safety and Standards Authority of India (FSSAI) standards. Arsenic, mercury, methyl mercury, tin, and copper were within permissible limits in all samples of fruit juices. The concentration of lead was found to exceed limits in 5 samples of commercial fruit juices which were 0.07, 0.13, 0.18, 0.21, and 0.38 mg/kg, respectively. The concentration of nickel was found to be above permissible limits in 5 samples (1.26, 1.72, 1.95, 3.24, and 4.07 mg/kg) of commercial fruit juices and 6 samples of fresh fruit juices (0.19. 0.21, 0.21, 0.42, 0.66, and 2.42 mg/kg). The concentration of chromium was found to be above permissible limits in 5 samples (3.13, 3.51, 4.29, 5.91, and 6.02 mg/kg) of commercial fruit juices and 6 samples of fresh fruit juices (0.80. 0.88, 0.98, 0.99, 1.16, and 8.95 mg/kg). Health risk assessment was performed for elemental impurities. Target hazard quotient and health risk index for elemental impurities were found to be less than 1 which is considered safe for consumers. Hazard index for elemental impurities was found to be more than 1 in two samples which can cause serious non-carcinogenic risk to consumers. Target carcinogenic risk was found within acceptable levels for all elemental impurities in all samples of fruit juices. Essential elements like copper and zinc are required by the human body for various body functions but heavy metals like lead, arsenic, and cadmium are highly toxic to human beings due to their adverse effects and it needs to be controlled. Lead poses a significant health risk to human health. It is essential to further monitor the levels of elemental impurities on a regular basis in commercial and fresh fruit juices. [ABSTRACT FROM AUTHOR]

Copyright of Chinese Journal of Bioprocess Engineering is the property of Chinese Journal of Bioprocess Engineering Editorial Office and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Elemental impurities are the traces of metals that can be found in finished drug products which may enter through various sources like excipients, and active pharmaceutical ingredients etc., their toxicity is to be estimated as they may pose serious toxicological effects to patients. The aim of this work is to estimate Class-I elements (Cd, Pb, As, Hg) simultaneously in Propofol 10 mg/mL Emulsion for Injection or Infusion using modern technique Inductively coupled plasma mass spectrometry, employing microwave-assisted digestion of sample. The developed method was validated for various parameters according to ICHQ2(R1) to prove that the developed method is fit for the required purpose and can be adaptable regularly. Validation results showed that the method was linear over the range of LOQ to 250%, with a good linearity correlation factor of R=0.99, the method was found to be robust against the deliberate changes in sample preparation and uptake speed. [ABSTRACT FROM AUTHOR]

Copyright of Atomic Energy Science & Technology is the property of Editorial Board of Atomic Energy Science & Technology and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Aim: The objective of this study was to determine the amount of twenty-three elemental impurities in Azithromycin API. A rapid, selective, precise, accurate and sensitive approach for detecting elemental impurities in Azithromycin API was developed and validated using Inductively Coupled Plasma-Mass Spectrometry (ICP-MS). Background: Conventional analytical methods used in pharmacopoeia's are less sensitive and accurate to detect heavy metal impurities. Concerning this issue, a new inductively coupled plasma mass spectrometry-based method was developed and validated as a different choice to investigate the Elemental impurities in an Azithromycin API sample. Materials and Methods: In the present research work, test samples were prepared with microwave supported acid digestion. Results: After a sequence of trails, the mixture of nitric acid, hydrochloric acid, and hydrogen peroxide (4 mL: 1 mL: 0.5 mL) with the accepted recovery range was chosen for the Azithromycin API's digestion. Conclusion: According to ICH and USP 233 guidelines, the proposed technique was successfully validated using ICP-MS for linearity, precision, accuracy, LOD, LOQ, and ruggedness. [ABSTRACT FROM AUTHOR]

Activated charcoal is an adsorbent material which is consumed as a dietary supplement (100 mg) and as non-specific antidote treatment in acute poisoning at 0.5–1 g kg−1 body weight in infants and 50 g in adults. The ingestion of large quantities of it has aroused our interest in the presence of metals impurities. Therefore, the present study aimed to assess trace elements in activated charcoal products. Multielement analysis were performed using Inductively Coupled Plasma—Mass Spectrometry after digestion. Estimated daily Intake was calculated and compared to references doses for each element. Varying trace elements have been found: chromium (0.3383 ± 0.089 µg g−1), cadmium (0.5991 ± 0.2967 µg g−1), aluminum (0.7033 ± 0.1215 µg g−1), nickel (0.0111 ± 0.003 µg g−1), lead (0.0052 ± 0.0021 µg g−1), zinc (0.0414 ± 0.0076 µg g−1), and manganese (0.0036 ± 0.0006 µg g−1). when 50 g of activated charcoal is consumed by a 70 kg adult, aluminum estimated daily intake is 0.0005 mg/kg bw/day which exceeds the reference dose (0.0004 mg/kg bw/day). In the infants, consumption of 15 g of contaminated activated charcoal exposes to chromium, cadmium and aluminum as their estimated daily intake (0.00034; 0.0006; 0.0007 mg/kg bw/day respectively) exceed their reference doses (0.0003; 0.0005; 0.0004 mg/kg bw/day respectively). These trace elements are not without risk to consumers health. Activated charcoal products could be contaminated with elemental impurities. Pharmaceutical industries should be vigilant to raw materials (plants and wood) used in the preparation, these materials should come from unpolluted areas to avoid contaminations. [ABSTRACT FROM AUTHOR]

In the framework of the European Commission Support Programme to the International Atomic Energy Agency (EC SP task A1753) 20 samples were obtained from the Dolní Rožínka (DIAMO, Czech Republic) uranium milling facility. The sampling procedure followed stepwise the uranium production and purification from the U ore to uranium ore concentrate (yellow cake) end-product. Elemental concentrations, rare-earth elemental pattern, anion concentrations, morphology and isotope abundance ratios of S, Sr, Pb and U were measured at each sampling stage. The purpose of the measurements was to investigate the applicability of various material characteristics for authentication, propagation and variation of these parameters, and to identify the relevant signatures for nuclear forensics and safeguards during the uranium production. [ABSTRACT FROM AUTHOR]

Elemental impurities are substances present in drug products, excipients, or drug formulations. They may be formed by the presence of catalysts and environmental contaminants. Elemental impurities can be detected by a sophisticated method such as Inductively Coupled Plasma Mass Spectrometry (ICP–MS). ICP-MS is an advanced method to detect elemental impurities in drug substances. In this study Propafenone hydrochloride drug was used, Propafenone Hydrochloride is an antiarrhythmic medication belonging to class 1C used to prevent supraventricular and ventricular arrhythmias. The present study was aimed to develop and validate inductively coupled plasma mass spectroscopic (ICP–MS) method for detection of elemental contaminants, i.e., Class 1, Cd, Pb, As, Class 2A, Hg, Co, V, and Class 2B impurities such as Ni, T1, Se, Ag, Au, Pd, Ir, Os, Rh, Ru, and Pt. Total 17 elemental impurities were detected in Propafenone Hydrochloride and this method was employed for the regular sample analysis of 17 elemental impurities in Propafenone Hydrochloride for pharmaceutical use. The instrument conditions were set using RF power of 1550 W, auxiliary gas of 0.5 L/min, and nebulizer flow of 1.01 L/min nebulizer pump pressure was 0.10 rps, spray chamber temperature was 2°C, and mode used was He, He flow rate was 4.3 mL/min and the energy discrimination rate was 3.0 V. The technique is sensitive and may identify desirable elemental impurities within permissible regulatory limits when additional elements are present. The proposed ICPMS approach has been found to be accurate, precise, linear, rugged, robust, and convenient for the quality control of the drug substance propafenone hydrochloride. The linearity results for each impurity were 0.9990. The methods were validated according to USP requirements and International Council for Harmonization ICH guidelines. The suggested approach is an excellent quality control tool for the concurrent quantitative assessment and detection of elemental contaminants at low levels in the drug substance propafenone hydrochloride. [ABSTRACT FROM AUTHOR]

It is well documented that elemental impurities (EIs) are critical in the field of pharmaceutical development since they could affect the quality, efficacy and safety of the finished dosage form (FDF). The responsibility of pharmaceutical manufacturers is to demonstrate via assessment approach, risk-based control strategy and/or required data analysis that the FDFs are compliant with ICH Q3D (R2). The aim of this research is to conduct a comprehensive comparative EIs risk assessment study of three different Montelukast dosage forms produced as chewable tablets (4 mg and 5 mg) and film-coated tablets 10 mg. The inductively coupled plasma-mass spectrometry (ICP-MS) system was used for the determination of EIs in samples of Montelukast sodium as the active pharmaceutical ingredient (API), placebos for all FDFs, and FDFs. Moreover, the analyses were also conducted on three batches from all three studied FDFs. Based on ICH Q3D (R2) guidelines, the tested products for EIs Class 1 and Class 2A showed that EIs levels in the API and placebos are well below the ICH Option 1 oral and parenteral limits. For the examined batches of each FDF strength (total of 9), none of the EI exceeds their concentration limits.

Arnicas Solidago microglossa DC. and Arnica montana L. are easily-accessible plants used as natural medicines by the Brazilian population. These products are susceptible to contamination by elemental impurities that are harmful to the human health. In 2017, the United States Pharmacopeia (USP) published two new chapters for elemental impurities determination. The classical methods were replaced by advanced analytical techniques such as optical emission spectrometry and inductively coupled plasma mass spectrometry (ICP OES and ICP-MS, respectively). However, these are expensive and difficult techniques to implement in small laboratories. Dispersive liquid–liquid microextraction (DLLME) contributes to improve the limit of quantification (LOQ), allowing the use of alternative analytical techniques to ICP such as capillary electrophoresis, atomic absorption and UV–Vis spectrophotometry. This work described the use a design of experiment (DoE) for the optimization of DLLME applied to the determination of metallic impurities in arnica infusions. The replacement of toxic solvents (i.e. chloroform and methanol) for a combination of organic carbonates and ionic liquids, proved to be a promising green alternative as solvent mixture in DLLME technique. The enrichment factor in infusion was between 89 and 127. The method was validated by evaluating the following parameters: selectivity, linearity, precision, accuracy, limit of detection (LOD) and LOQ. The defined range was 5.0–100.0 µg L−1 for cadmium and lead, and 1.5–30.0 µg L−1 for mercury, with accuracy varying from 94 to 107% and RSD from 1.77 to 8.51%. Therefore, DLLME employing green chemistry solvents has proved to be applicable for the analysis of elemental impurities in infusions. [ABSTRACT FROM AUTHOR]

The method of "Inductively Coupled Plasma Mass Spectrometry" (ICP-MS) may be interpreted as a trend in pharmaceutical determination of elemental impurities. The development of a specific process that is precise for all elemental impurities, however, is still a task. The ICP-MS technique using microwave acid digestion as a sample processing method was used to determine 14 elemental impurities (lithium, vanadium, chromium, manganese, iron, cobalt, nickel, copper, arsenic, molybdenum, cadmium, antimony, mercury and lead) existing in parenteral ofloxacin in this study. The strategy proposed was verified as per "United States Pharmacopeia Convention". The detection limits achieved by the proposed approach suggest that the ICP-MS technique is quite well fit for the measurement of the 14 chosen elemental impurities. Good linearity was achieved with correlation coefficient values higher than 0.99 over the range of quantification limit level concentration to 200 % level of the individual elemental impurity specification values. The values obtained for accuracy, precision, robustness, selectivity and ruggedness are also satisfactory. Six distinct batches of parenteral ofloxacin samples were subjected to analysis by the ICP-MS technique proposed. In all the batch samples, the fourteen chosen elemental impurities were noticed to be less than detection levels. [ABSTRACT FROM AUTHOR]

Elemental impurities in Active Substances: a general perspective The elemental impurities must meet high quality requirements, in order to achieve this goal several analytical parameters such as a low impurity content is the capital importance. In this situation, several types of impurities can be mentioned for example: organic and inorganic impurities, mutagenic compounds, residual solvents, and elemental impurities. The relevance of the impurities is high because these compounds are toxic for the patient and can cause adverse effects in patients therefore they should be limited. Specifically the elemental impurities are residues of metal elements that come from the unit operations used in the manufacturing process of an active substance. These contaminant are classified in the ICHQ3D guide in four groups according to their toxicity and their presence in an active substance is explained by the synthesis process (raw materials, solvents, water) or by the wear of the productive equipment (reactors, centrifuges, dryers, mills). In order to determine the quantities of these compounds analytical methods are a fundamental part, since they must be sufficiently sensitive and specific. The evaluation through a risk analysis provides the theoretical information of the potential metallic impurities present in an active substance; a case study exemplifies this section. Another important aspect to take in account is the control of the presence of metal impurities in synthetic processes, so having an overview of the control methods is a paramount importance in order to establish the appropriate control strategy. In this section, a reported case is described. Finally, general trends in purification of an active substance provide an insight into developments in this area. This paper includes a brief review of the previously mentioned topics. [ABSTRACT FROM AUTHOR]

Elemental impurities in drug samples can generate unwanted pharmacological–toxicological effects, therefore they must be carefully monitored. In order to update the elemental analysis of pharmaceutical products, new regulations for elemental impurities were published by the United States Pharmacopoeia (USP). A novel approach for the estimation of osmium was developed and evaluated. According to Regulatory necessities for the testing of Osmium content in pharmaceutical products are now included in the new general USP chapters USP232 and USP233, as well as in EP chapters. A new ICH guideline for elemental impurities Q3D was implemented. Therefore, trace elemental analysis of Osmium will be required for release testing of pharmaceutical substances and final products. In this study Osmium determination was performed by inductively coupled plasma mass spectrometry. Since osmium in an oxidising and acidic environment readily forms volatile species, there is a need for suitable analytical method to estimate the osmium in Azithromycin API. In the current research work samples were prepared with microwave assisted acid digestion and analyzed without addition of internal standard. After a multiple trials, Nitric acid: Hydrochloric acid in the ratio of (0.5 ml: 4.5 ml) with the best recovery was favoured for the digestion purpose of the Azithromycin API. The proposed method was successfully validated through ICPMS for linearity, precision, accuracy, LOD, LOQ and Ruggedness according to ICH Guidelines and USP 233. [ABSTRACT FROM AUTHOR]

Scientific reports about elemental impurities in final pharmaceutical products are essential from a regulatory point of view; unfortunately, there is a lack of studies about this important toxicological topic. The aim of our short communication was determination of total Cr impurities in traditional herbal medicinal products (THMP) with Thymi herba (Thymus vulgaris L. and Thymus zygis L.) available in Polish pharmacies (n = 6, because only six manufacturers produce this kind of pharmaceutical products in Poland). The total content of Cr impurities was determined by atomic absorption spectrometry using electrothermal atomization (ETAAS). Applied comprehensive toxicological risk assessment was based on three main tiers: Tier 1, the comparison of raw results as total Cr impurities profile (metal per L of THMP) with ICH Q3D guideline standards; Tier 2, the estimation of total Cr exposure with a single dose; and Tier 3, the estimation of total Cr daily exposure. We confirmed that total Cr impurities were present in all analyzed THMP with thymi herba (the observed level was below 6.0 µg/L). Total Cr concentration in a single dose can be deceptively high in comparison to the raw results but is not a threat to patients (20.15–63.45 ng/single dose). Moreover, the estimation of total Cr daily exposure shows that all analyzed THMP are characterized by daily dose (40.30–181.41 ng/day) below PDE value (10,700 mg/day); hence, all products meet the standards of ICH Q3D elemental impurities guideline. [ABSTRACT FROM AUTHOR]

Plantago lanceolata L., folium (ribwort plantain) is an active pharmaceutical ingredient in traditional herbal medicinal products (THMP) available in pharmacies as a demulcent for the symptomatic treatment of oral or pharyngeal irritations and associated dry cough. This kind of THMP is widely applied among the European population; however, recently, voices have been heard in the public about alleged cadmium impurities. The idea of our study was a comprehensive risk assessment of the Cd impurity exposure and its effect on human health. Our assessment strategy was based on regulatory aspects (raw results versus limits set by FAO/WHO for herbal medicines) and toxicological risk assessment approach based on ICH Q3D guideline for elemental impurities in final pharmaceutical products. The cadmium was determined by electrothermal atomization atomic absorption spectrometry based on our previously described methodology. Obtained results show that all analysed THMP with P. lanceolata L., folium available in the Polish pharmacies contain cadmium impurities, but at a very low level (ranged 0.73 – 20.6 μg/L). The content of Cd in a single dose (ng/single dose) is also very low and is not a threat to patients. The estimated maximum daily exposure (ng/day) of Cd based on the 'worst-case scenario' (maximum concentrations by oral administration) meets the standards of ICH Q3D guideline (all results were below oral permitted daily exposure; PDE for Cd, i.e. < 5.0 µg/day). It can be concluded that all analysed samples of THMP with P. lanceolata L., folium should not represent any health hazard to the patients due to cadmium levels. To the best of our knowledge, this is the first study about Cd impurity level in THMP with P. lanceolata L., folium (ribwort plantain leaves) available in European pharmacies. [ABSTRACT FROM AUTHOR]

For elemental impurities that have been studied for transcutaneous absorption, the available data are rarely suitable for proper toxicological risk assessment — there are multiple factors that can influence this dermal absorption. Hence, in our studies, we applied generic and conservative approach — cutaneous permitted daily exposure (CPDE) described in International Conference on Harmonisation's Q3D Guideline on Elemental Impurities (ICH Q3D). The aim of this article is toxicological risk assessment (TRA) of dermal exposure of patients exposed to nickel and chromium due to application of ointments with Marjoram herb extract (Majoranae herbae extractum) available in Polish pharmacies (n = 5, because only five manufacturers produce this kind of pharmaceutical products in Poland). To make the appropriate TRA approach, we considered (1) raw results (metal per kg of ointment), (2) one-time administration of applied ointments, and (3) daily exposure versus CPDE. Due to the fact the concentrations of Ni generally present in cutaneous products as impurities are not considered sufficient to induce sensitization, the cutaneous and transcutaneous concentration limits (CTCLs) approach was applied for this element assessment. The toxicological analysis was carried out using microwave-assisted wet digestion with concentrated nitric acid and electrothermal atomization atomic absorption spectrometry. Our results show that the ointments with Marjoram herb extract from pharmacies in Poland represent a potential health hazard to patients; however, there may be a requirement for the monitoring of impurities of nickel in future. To the best of our knowledge, this paper is the first study about nickel and chromium content in ointments with Marjoram herb extract (Majoranae herbae extractum). [ABSTRACT FROM AUTHOR]

The toxicological risk assessment (TRA) of elemental impurities (EI) in especially herbal medicinal products (HMP) is a significant challenge for pharmaceutical industry. In Europe, very popular are traditional HMP with valerian root (Valeriana officinalis L., radix) for relief of mild symptoms of mental stress and to aid sleep. The aim of our unique article is the comprehensive TRA of Cu, Mn, and Zn as EI in HMP with V. officinalis L., radix available in Polish pharmacies. This article is a continuation of our previously conducted studies about TRA of heavy metals (Pb and Cd) in these same samples. Investigated elements were determined by flame atomic absorption spectrometry (F AAS). The values of the correlation coefficients (R > 0.998) confirm the linearity of the applied instrument for precision and accuracy of results. The recoveries, LOD and LOQ values were acceptable. Our results show that all investigated HMP with valerian root available in Polish pharmacies contain Cu (0.16–0.23 mg/L), Mn (0.11–0.76 mg/L), and Zn (0.22–0.48 mg/L) at a very low level. Based on our estimation of EI including single dose (µg/20 mL) and estimated daily intake (µg/day), our results confirm the safety of all pharmaceuticals. To the best of our knowledge, the Cu, Mn, and Zn impurity profile in HMP with V. officinalis L., radix is described for the first time. The applied methodology and results are extremely important from regulatory toxicology point of view (ICH Q3D elemental impurities guideline for pharmaceuticals). [ABSTRACT FROM AUTHOR]

Abstract Background The aim of the present study was to develop and validate an inductively coupled plasma optical emission spectroscopic (ICP–OES) method for quantification of elemental impurities, i.e., Lead, Palladium, and Zinc, in voriconazole drug substance, and this method was employed for the regular sample analysis of Lead, Palladium, and Zinc in voriconazole drug substance for pharmaceutical use. The method has been validated using RF power of 1150 W, auxiliary gas of 0.5 L/min, and nebulizer flow of 0.4 L/min and plasma view at axial mode for Lead and Palladium and radial mode for Zinc. The wavelength was monitored for Lead, Palladium, and Zinc at 220.3 nm, 340.4 nm, and 213.8 nm respectively. Results The method is selective and is capable of detecting desired elemental impurities with regulatory acceptance limits in the presence of other elements. The validation experiments involve the demonstration of system suitability, specificity, LOD and LOQ, linearity, precision, and accuracy experiments. The linearity results obtained ˃ 0.9990 for all three impurities. Conclusion The proposed method is simple, sensitive quality control tool for the simultaneous quantitative determination of Lead, Palladium, and Zinc at low levels in voriconazole drug substance. Graphical abstract

An inductively coupled plasma mass spectrometric (ICP‐MS) technique method is developed for simultaneous determination of Li, Cr, Mn, Fe, Ni, Co, Cu, Sr, Ag, Cd, Ba, and Pb at trace level in caustic soda. Operational parameters of the instrument were optimized and suitable accessory (argon gas dilution) was used in the method. Direct aspiration of high total dissolved solids (TDS) samples (beyond 0.2% TDS) and highly alkaline NaOH is not suitable for the instrument; therefore, strategy of neutralization of NaOH by HNO3 was adopted to handle its high alkalinity. Suitable internal standards of low, mid, and high atomic masses were used with external calibration. Features such as matrix matching, calibration verification, interference correction, etc. were undertaken in this work. Neutralized caustic soda samples were spiked with the analytes with lower, middle, and higher concentration. The results of spiking with 30, 70, 140, and 200 ppb were examined. The method exhibited excellent accuracy and precision. [ABSTRACT FROM AUTHOR]

Studies related to the toxicological risk assessment (TRA) of heavy metal impurities (HMIs) in pharmaceuticals are an important issue but there is a lack of refereed literature around the safety of Valeriana officinalis L., radix (Valerian root) as herbal medicinal product (HMP) for the relief of mild nervous tension and sleep disorders according to lead and cadmium impurities. The aim of the study was to estimate the TRA of lead and cadmium in Valeriana officinalis L., radix (Valerian root) as HMP (n = 5) available in Polish pharmacies. In the case of herbal pharmaceuticals, it is particularly important to control the level of HMIs accumulated during the plant's growth. Perhaps, the exposure for a single dose is not relevant; however, justification of our studies is a fact that herbal therapies are usually long term. Therefore, even small HMI doses as present in particular plant may accumulate in patient body over a long period of time. Levels of lead and cadmium were measured by electrothermal atomization atomic absorption spectrometry. The levels of lead and cadmium as HMIs (independently of the producer and declared composition) are quite similar. Our results are satisfactory, confirming the safety of Valeriana officinalis L., radix (Valerian root) as herbal medicinal product for the relief of mild nervous tension and sleep disorders available in Polish pharmacies according to ICH guideline Q3D. To the best of our knowledge, this paper is the first study about lead and cadmium content as HMIs in HMP containing Valeriana officinalis L., radix (Valerian root). [ABSTRACT FROM AUTHOR]

Objectives: Primary objective of the present study is to develop and validate an accurate and linear analytical method for precise estimation of Vanadium, Cobalt, Nickel, Arsenic, Cadmium, Mercury, Thallium and Lead elemental impurities present in the Dobutamine Hydrochloride active pharmaceutical ingredient using inductively coupled plasma mass spectrometry. Materials and Methods: Argon gas is used as carrier gas and helium gas as collision gas, 5% nitric acid is used as diluent, plasma gas flow rate is 15 l/m, spray chamber temperature is 2°C, helium gas flow rate is 5 ml/m, integration time is 0.3 s and tune mode is He gas. Microwave digester is used to extract the elemental impurities. The developed method was validated according to the Q3D guidelines provided by the International Conference on Harmonization. Results: The correlation coefficients for all the eight metals were found to be 1, and their concentration variation (%) in standard check solution was estimated to be less than 20. The system precession was found to be less than 20% of relative standard deviation and the linearity calibration curve was linear over the concentration range of 0.25J to 2.50J specification level. The obtained recoveries are well within the acceptance criteria of 70%-150%. Conclusion: The low relative standard deviation and high recoveries of the method confirm the suitability of the method for precise estimation of the above metal impurities in Dobutamine Hydrochloride active pharmaceutical ingredient. [ABSTRACT FROM AUTHOR]

Comprehensive studies, control strategies and management of elemental impurities (EIs) in pharmaceutical products are provided by ICH in its Quality Guidelines (ICH Q3D) considering Safety and Quality of drug product for human use. Replacement of historical 'Heavy Metal Test' by introducing more sophisticated analytical methodologies such as AAS, ICP-OES, ICP-MS etc. opened the doors for the quantitative determination of EIs with stringent limits. Performing EI estimation requires sound scientific knowledge and sensitive analytical techniques that can deliver accurate results of each toxic EI present in targeted products. Continuous monitoring of EIs in manufacturing of pharmaceutical products with GLP/GMP compliance in line with regulatory guidelines helps to generate scientific-based risk assessments for over all possibilities for the presence of EIs from different sources (i.e. Drug Substance, Excipients, Solvents, Regents and Chemicals etc). For testing ICH Class 1, Class 2A, Class 2B and Class 3 EIs in single analytical method required samples prepared using microwave digestion technique. Developed methods were validated in-house as per ICH and USP <233>. [ABSTRACT FROM AUTHOR]

Introduction. When developing drugs it is necessary to use laboratory equipment that simulates pilot and industrial equipment. For the production of semi-solid preparations the key equipment are rotor-stator dispersers and vacuum reactors-homogenizers.Aim. Investigation of the functional characteristics of laboratory equipment: Megatron® MT 1-50 dispersant SHS F/2 (Kinematica AG, Switzerland) and the RP-5 vacuum homogenizer reactor (Promvit, Ukraine).Materials and methods. During development a generic product Penciclovir cream 1% the initial particle size in suspension of penciclovir and particle size after grinding were studied by optical microscopy and laser diffraction methods. In a cream made in the reactor, the particle size of the dispersed phase of the o/w emulsion and suspension, as well as the absence of air bubbles, were determined by optical microscopy. The assay of penciclovir in 9 samples of the cream taken from the reactor-homogenizer was performed by liquid chromatography. By the of rotational viscometry method the rheological properties of the cream were studied. By the inductively coupled plasma atomic emission spectroscopy the getting of metal impurities from the disperser and the reactor-homogenizer into the suspension and cream were investigated.Results and discussion. With an increase in the rotor speed, the particle size of penciclovir in suspension decreases. The disperser effectively performs its function at a rotor speed of 25,000 rpm. In a cream made in the reactor, the deviations in the quantitative content of penciclovir from the average value in each sample are within the uncertainty of the analytical procedure, which indicates its uniform distribution. The reactor provides effective dispersion and uniform distribution of the oil phase, prevents the formation of a gas emulsion and allows getting a cream that, according to its rheological properties, corresponds to the reference preparation Fenistil® Pencivir cream 1%. In the production process metal impurities were not emitted into the suspension and the cream from the equipment.Conclusion. The disperser and the reactor during the production of cream with penciclovir are suitable for their intended use. It is rational to combine these two types of equipment at the sites for the production of semi-solid preparations. The disperser can also be used to produce emulsions with a very small particle size of the dispersed phase.

Fast and simple closed-vessel microwave-assisted digestion procedure was developed for decomposition of three pharmaceutical dosage forms of ibuprofen such as tablets, suspension and gel, prior to elemental impurity analysis by one robust and precise ICP-OES method. Samples were digested by four-step microwave program consisting of a 10 min temperature gradient to 180°C, maintained at 180°C for 10 min, followed by 5 min ramping time to 210°C with holding time of 10 min on 210°C. Subsequently, ICP-OES method was developed and validated for simultaneous determination of selected elemental impurities. Results of recovery studies range between 77% and 105% for each element in all analyzed formulations. Correlation coefficients of the regression equations were higher than 0.999 for all analyzed elements. Validation results reveal that the proposed method is specific, accurate, and precise and could be applied for simultaneous quantitative analysis of multi element solutions in different pharmaceutical dosage forms of ibuprofen.

Background: The complex regulatory framework for the quality of herbal medicinal products, in particular with regard to potential contaminants, consists of legal provisions including Pharmacopoeia requirements, relating to limits as well as in most cases to methods for determination. Objective: This review intends to provide an overview on the legal requirements for testing potential contaminants in herbal drugs used for the production of herbal medicinal products. Methodology: The following issues are described and discussed: For the assessment of pesticide residues, Chapter 2.8.13 of the European Pharmacopoeia and Regulation (EC) 396/2005 applies, for heavy metals the general Pharmacopoeia monograph as well as the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Q3D guideline on elemental impurities. The Pharmacopoeia also includes limits and acceptance criteria for microbiological purity and aflatoxins, respectively. Polycyclic aromatic hydrocarbons are mentioned in Regulation (EC) 1881/2006 for food as well as in a Reflection Paper on herbal medicinal products. For several years, a potential contamination with pyrrolizidine alkaloids was discussed which led to measures being imposed on industry and health authorities. Results: Various examples demonstrate that the evaluation of data from daily analytical practice is extremely useful to gain an overview on the occurrence of residues and/or contaminants in herbal drugs and herbal preparations. Such evaluations might assist manufacturers in their individual risk assessment and the definition of their testing strategies and contribute to guarantee the quality and safety of the marketed products. Conclusion: Annual data evaluations demonstrate that a remarkable decrease of the pyrrolizidine alkaloid content burden in herbal drugs and extracts used for the production of herbal medicinal products has been achieved over the past few years. However, it has also become clear that this issue cannot be completely solved in the near future. This review summarizes the legal requirements for testing potential contaminants in herbal drugs used for the production of herbal medicinal products. Respective substances comprise e.g. pesticides, heavy metals, mycotoxins and pyrrolizidine alkaloids. Various examples of data evaluations from daily analytical practice are given which present an overview on the actual situation and might assist manufacturers in defining their testing strategies. [ABSTRACT FROM AUTHOR]

A fast and simple closed-vessel microwave-assisted digestion procedure was developed for decomposition of three pharmaceutical dosage forms of ibuprofen, including tablets, suspension and gel, prior to elemental impurity analysis by one robust and precise ICP-OES method. Samples were digested by a four-step microwave program consisting of a 10 min temperature gradient to 180 °C, maintaining at 180 °C for 10 min, followed by 5 min ramping time to 210 °C with a holding time of 10 min at 210 °C. Subsequently, an ICP-OES method was developed and validated for simultaneous determination of selected elemental impurities. Results of recovery studies ranged between 77 % and 105 % for each element in all analyzed formulations. Coefficients of determination of the regression equations were higher than 0.999 for all analyzed elements. Validation results reveal that the proposed method is specific, accurate, and precise and could be applied for simultaneous quantitative analysis of multi-element solutions in different pharmaceutical dosage forms of ibuprofen. [ABSTRACT FROM AUTHOR]

The standardisation of plant raw materials is among the most important problems of the production of herbal medicines. Medicinal plant raw materials are of complex nature and can be contaminated with impurity elements. Therefore, the content of elemental impurities typical for plants should be controlled in comparison with the existing conceptions of recommended or permitted daily exposures of human consumption of some chemical elements. The paper goal was to study the existing approaches in the world to the fixing of elemental impurity content in herbal medicines and comparative analysis of their permitted daily exposures. The following methods were used to implement the research goal: system approach, bibliographic and information search, statistical methods, as well as generalisation and analysis. The work is based on the analysis of documents of World Health Organisation and appropriate organisations of leading countries. The contents of 28 elements were shown to normalise in these documents. Depending on their toxicity and probability of ingress into drugs, the elements are divided into four classes. This approach creates a clear idea of the potential effects of elements on the human organism and also illustrates the sensitivity requirements for analytical methods to be used for elemental control. In medicinal plants as well as in plants that are used as food additives and spices, the content of the five most toxic elements (As, Hg, Cd, Pb and Cr) is fixed. For other impurities in medicinal plants, there are no universally recognised limit values in contrast to medicinal products. Therefore, when analysing the quality of herbal medicines, one should take into account permitted daily exposures of human consumption of individual chemical elements used for the quality control of foodstuff and drinking water as well as environmental protection.

The article is devoted to the problem of quality assurance of medicinal products, namely the determination of elemental impurity concentration compared to permitted daily exposures for and the correct choice analytical methods that are adequate to the formulated tasks. The paper goal is to compare characteristics of four analytical methods recommended by the Pharmacopoeia of various countries to control the content of elemental impurities in medicines, including medicinal plant raw materials and herbal medicines. Both advantages and disadvantages were described for atomic absorption spectroscopy with various atomising techniques, as well as atomic emission spectroscopy and mass spectrometry with inductively coupled plasma. The choice of the most rational analysis method depends on a research task and is reasoned from the viewpoint of analytical objectives, possible complications, performance attributes, and economic considerations. The methods of ICP-MS and GFAAS were shown to provide the greatest potential for determining the low and ultra-low concentrations of chemical elements in medicinal plants and herbal medicinal products. The other two methods, FAAS and ICP-AES, are limited to the analysis of the main essential elements and the largest impurities. The ICP-MS is the most efficient method for determining ultra-low concentrations. However, the interference of mass peaks is typical for ICP-MS. It is formed not only by impurities but also by polyatomic ions with the participation of argon, as well as atoms of gases from the air (C, N and O) or matrices (O, N, H, P, S and Cl). Therefore, a correct sample preparation, which guarantees minimisation of impurity contamination and loss of analytes becomes the most crucial stage of analytical applications of ICP-MS. The detections limits for some chemical elements, which content is regulated in modern Pharmacopoeia, were estimated for each method and analysis conditions of medicinal plant raw materials and herbal medicinal products.

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. [ABSTRACT FROM AUTHOR]

Guideline for Elemental Impurities-Q3D of the International Conference on Harmonisation represents a new paradigm in the control of elemental impurities (EIs) in pharmaceuticals. It changes the approach toward control of EIs from the historical 'heavy metals test', to a scientific-based risk assessment and testing by modern analytical instrumentation such as inductively coupled plasma-optical emission spectroscopy (ICP-OES) and inductively coupled plasma-mass spectrometry (ICP-MS). Management of EIs related to all finished drug products must be implemented in strict compliance with the regulatory requirements of pharmaceutical industry due to their quality and safety concerns. Testing for presence of EIs from Class 1 and Class 2a in methadone hydrochloride 1 mg/ml oral solution with recommended daily intake of 150 mg methadone hydrochloride was initially performed on ICP-OES using in-house validated method according to the requirements of pharmacopoeias, in line with Q3D. During the procedure, it became apparent that ICP-OES has its own limitations, especially when it comes to testing arsenic and lead in low concentrations. ICP-MS in-house validated method was developed and employed for determination of trace concentrations of arsenic and lead, providing resourceful information that were compared and correlated to the data obtained by ICP-OES analysis. Sample preparation using microwave digestion technique was applied for the analyses by both techniques. Although the applied ICP-OES in-house method is suitable for determination of Hg, Cd, Co, V, and Ni, more sensitive technique such as ICP-MS is required for accurate determination of As and Pb concerning pharmaceuticals with high daily intakes. [ABSTRACT FROM AUTHOR]

The objective of the present paper is to provide a practical example of risk assessment of elemental impurities (EIs) in final drug product according to the new ICH guideline Q3D on EIs. This EIs may arises from various potential sources such as excipients, water, APIs, container systems and manufacturing processes. The assessment strategy is performed on four steps: Identification of the potential sources, analysis of EIs that may be introduced by each source, evaluation of predicted levels of EIs and comparison against the established values and definition of the control strategy. The Haloperidol 2% oral solution served as model. For this pharmaceutical form, five elements were considered: cadmium, lead, cobalt, vanadium, nickel and intentionally added elements. The amount of EIs more than 30% of the permitted daily exposure (PDE) should be monitored. Our outcome indicates that the test results of studied EIs are maintained below 30% of PDE and are within the acceptance criteria as per ICH Q3D. As a result, no additional control over the finished product is needed. The haloperidol 2% oral solution was safe for human consumption. This approach has allowed to reduce and even more to eliminate the control of EIs in the drug product. [ABSTRACT FROM AUTHOR]

In this paper, we discuss general aspects of the impurity composition of high-purity solid halides, which are exemplified by an array of samples in the Permanent Exhibition–Collection of Extrapure Substances. We estimate the average and total concentrations of elemental impurities in the purest samples and assess the contributions of individual impurity classes to the total impurity concentration, which makes it possible to more accurately characterize the impurity composition of solid halides and statistic characteristics used to describe it. [ABSTRACT FROM AUTHOR]

Prescription food for special medical purposes (FSMPs) and modified milk products (MMPs) for babies in the infancy period available in pharmacies are increasingly frequently used for newborns and infants—especially in cases where allergies and food-borne diseases are diagnosed. However, there is a lack of scientific study around the safety assessment of the elemental impurities in these products. Importantly, the allergen Ni and the problematic metal Cr are little considered. Hence, the aim of this article was the toxicological analysis of Ni and Cr impurities in prescription FSMPs (n = 6) and MMPs (n = 6) for newborns and infants available in Polish pharmacies. For the best safety assessment, we include three approaches including (1) the levels of Ni and Cr in powdered products, (2) assessment of the daily dose depending on age and body weight of newborns and infants, and (3) the weekly intake of Ni and Cr in samples in comparison to provisional tolerable weekly intake (PTWI). Our results show that, on the basis of our data, the products from pharmacies in Poland investigated in this study do not represent a real health hazard to newborns and infants, although there may be a requirement for the monitoring of levels of Ni. Our results are pioneer and provide valuable data for other scientists and manufacturers. [ABSTRACT FROM AUTHOR]

Microwave-assisted wet digestion (MAWD) using only H 2 O 2 was proposed for oxidizing active pharmaceutical ingredients (APIs) for hypertension treatment and subsequent determination by inductively coupled plasma optical emission spectrometry (ICP-OES). Diltiazem hydrochloride (DIL) presented the most refractory characteristic for oxidation using MAWD-H 2 O 2. This proposed MAWD-H 2 O 2 method was validated for specificity, accuracy, and precision according to United States Pharmacopeia (USP) Chapter 233 guidelines. Regarding specificity, the most sensitive emission lines were utilized to analyze all elemental impurities in the digests, and no significant spectral interferences were observed. Sample masses of 500 mg for all APIs and a digestion temperature of 250 °C provided digests with residual carbon (RC) below 2400 mg L−1 of C. Additionally, the residual acidity of the MAWD-H 2 O 2 digests was lower than the acidity presented by the HNO 3 digests. The highest and lowest residual carbon content (RCC) for digests were observed for DIL and captopril (CAP), respectively, using MAWD-H 2 O 2. When comparing the RCC for MAWD-H 2 O 2 and MAWD-HNO 3 digests for APIs containing aromatic rings, it was evident that H 2 O 2 offered equivalent conditions for digesting these compounds. Accuracy tests showed recovery values of 91–110% for all elemental impurities, as recommended by USP chapter 233. Validation experiments for precision presented relative standard deviation (RSD) values below 6.4% and 10% under repeatability and intermediate precision conditions, respectively. The limits of quantification (LOQs) provided by MAWD-H 2 O 2 are at most half of those recommended by of USP and International Council for Harmonisation of Technical Requirements (ICH). In conclusion, MAWD-H 2 O 2 can be considered an alternative method for API digestion, aligning with green analytical chemistry principles, as it does not employ toxic reagents, minimizes waste, and the main products of H 2 O 2 oxidation are water and oxygen. Considering the analytical Eco-Scale, the MAWD-H 2 O 2 method scored 81, classifying it as an excellent green analysis. [Display omitted] • Development of eco-friendly digestion method for analysis of APIs. • H 2 O 2 considered green oxidant with production of O 2 and H 2 O. • Suitable digests for elemental impurities determination by ICP-OES. • Proposed method (MAWD-H 2 O 2) agrees with USP chapters 232 and 233 requirements. [ABSTRACT FROM AUTHOR]

The elemental impurities in pharmaceutical products have aroused widespread concern among respective supervising authorities and official pharmacopoeias since they are harmful and have no therapeutic effects. Metronidazole benzoate is used extensively to treat a variety of infections. However, impurities will inevitably be introduced in the manufacturing process of metronidazole benzoate. Hence, in this study, a sensitive method was developed for trace determination of elemental impurities in metronidazole benzoate active pharmaceutical ingredients by using inductively coupled plasma mass spectrometry in kinetic energy discrimination mode. The method was validated for system suitability, specificity, linearity, sensitivity, accuracy, and precision according to USP chapter <233> Elemental Impurities-Procedure. The method had good linearity with correlation coefficients > 0.99. The limits of detection were in the range of 0.0003-0.1411 μg/g, which was lower than the acceptable limit and indicated the high sensitivity of the method. The method was accurate with the recoveries in the range of 92%-107%. Moreover, the content of seven elemental impurities in the three batches of metronidazole benzoate active pharmaceutical ingredients by this method was originally below their limits and less than 30% of permitted daily exposure, meeting the requirement of International Council for Harmonization Q3D guidelines. Thus, this newly developed and validated method for estimating elemental impurities in metronidazole benzoate active pharmaceutical ingredients was within the permitted limit and suitable for routine use., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

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 <232/233> 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. Image 1 • A new LA-ICP-MS screening of elemental impurities in pharmaceuticals was developed. • LA-ICP-MS method meets the requirements of USP <232/233> chapters and ICH-Q3D guideline. • Simple methodology contributes to significant time, labor and pharmaceuticals saving. • Rapid quality control at different stages of pharmaceutical production. [ABSTRACT FROM AUTHOR]

Control of elemental impurities (EIs) in pharmaceutical herbal products is currently important but not a very popular topic in modern toxicological analysis. The occurrence and concentration of EIs in the pharmaceutical herbal products should be controlled and meet the standards of directive International Conference on Harmonisation's Q3D Guideline on Elemental Impurities. An interesting area of interest is measuring EIs including toxic and allergic metals in pharmaceutical herbal products for teething. The aim of this article was determination of Ni and Cr impurities in pharmaceutical herbal products for teething available in Polish pharmacies. Justifications were (1) herbs as an important source of EIs and (2) infants may be particularly sensitive to the toxic effects of metals because they tend to absorb a higher fraction of an oral dose. The analysis was carried out using microwave-assisted wet digestion with concentrated nitric acid and electrothermal atomisation atomic absorption spectrometry. The safety assessment involved a triple approach: (1) level of Ni and Cr impurities in pharmaceutical samples; (2) level of Ni and Cr impurities including one-time administration of teething gels and (3) daily intake of metals. In all three cases, the results indicate that the standards of directive ICH Q3D are met for Ni and Cr. Overall, it can be concluded that none of the teething gels represents a health hazard to infants. [ABSTRACT FROM AUTHOR]

Abstract 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. Graphical abstract fx1 Highlights • New guidelines for elemental impurities in pharmaceutical drugs demand new methodologies for analysis. • The guidelines define permitted daily exposure (PDE) for 24 elements. • The features of the HR-CS AAS offer the possibility of sample screening to define the elements present in the sample. • Limits of detection below the PDE and spectra evaluation establish the validity of this pass/fail test. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Impurity profile of a five teething gels based on herbs available in Polish pharmacies including Cu, Mn and Zn impurities. • The level of elemental impurities in a single administration is not a threat to babies in infancy period. • The results of the daily intake of EIs are satisfactory and confirm the safety of all teething gels. • All investigated teething gels meet the standards of directive ICH Q3D. • Each of the teething gels do not represent a health hazard to the infants. Abstract The monitoring of elemental impurities (EIs) in pharmaceutical materials is often not adequately treated, although it is a very important topic because the directive ICH Q3D requires a wide range of elements, often at low concentrations, to be monitored. This article describes the quantitative toxicological analysis of copper, manganese and zinc as EIs in the pharmaceutical gels for teething containing herbs available in Poland. The levels of EIs were measured to evaluate whether the intake of these metals through the gels was within recommended levels. The flame absorption spectrometry (FAAS) following microwave induced digestion (concentrated nitric acid) was applied to determine the levels of Cu, Mn and Zn in the products. This article was motivated especially by the facts that: (i) herbs can be a potential source of EIs; (ii) Cu, Mn and Zn are essential trace elements in the infancy period; (iii) there is a general lack of data around the risk assessment associated with exposure to these EIs in this kind of pharmaceutical. Our safety assessment is based on triple approach including: (1) profile of EIs in gels; (2) the actual amount of EIs in the appropriate amount of gel applied with a single administration (one drop) and (3) the daily exposure of EIs in analysed teething pharmaceuticals due to the maximum daily dose. Our results show that all EI levels meet the standards of directive ICH Q3D. It can be concluded that all of the teething gels investigated, based on herbs, available in Polish pharmacies do not represents a health hazard to babies. [ABSTRACT FROM AUTHOR]

Abstract—: In this paper, we discuss general aspects of the impurity composition of natural monoisotopic substances, which are exemplified by samples in the Permanent Exhibition-Collection of Extrapure Substances. The entire set of natural monoisotopes is divided into subsets belonging to sets of alkali and alkaline-earth metals, transition metals, rare-earth metals (REMs), and p-block elements. We estimate the average and total concentrations of elemental impurities in subsets of the purest samples of the natural monoisotopes. The purest monoisotopes are those of the p-block elements. Next are samples of the alkali and alkaline-earth metals, transition metals, and REMs. We estimate the contributions of individual impurity classes to the total impurity concentration, which enables more accurate characterization of the impurity composition of the natural monoisotopes and statistical characteristics of its description. [ABSTRACT FROM AUTHOR]

Elemental analysis using the ppXRF (portable XRF) spectrometer is non-destructive, rapid, green, and low cost, and is suitable for different types of samples (solid or liquid). The use of pXRF for food product analysis is a promising and desired way to detect and fingerprint elements, taking into account the speed, convenience, and precision of food analysis as low-persistence samples. We focussed on the assessment of available studies with special emphasis on analytical aspects: calibration strategies, the operating mode of the pXRF device, LOD, LOQ, linearity, etc. This critical review could open up real opportunities and inspiration for food toxicologists to validate the reputation of pXRF in food elemental analysis. In this review, we suggest solutions that can improve the quality and reliability of future food research using pXRF for the in situ analysis of different types of food samples (solid and liquid). In addition, we have included a review of known pXRF spectrometers and issues related to analytical calibration strategies that can be successfully implemented in pXRF measurements for food analysis. [Display omitted] • Overview of the application of the pXRF (portable XRF) technique in food analysis. • pXRF as a powerful annalytical tool for non-destructive, inexpensive, direct, and rapid analysis of food • Food fingerprinting of elements using a handheld XRF instrument. • Screening of toxic elements and trace elements in food samples using pXRF technique. [ABSTRACT FROM AUTHOR]

Experience with the implementation of a quality management system (QMS) at the research laboratory of a public university in the Czech Republic will be presented in this talk. [...]