Impurity Control Research Articles

The Control and Comprehensive Safety Assessment of Heavy Metal Impurities (As, Pb, and Cd) in Green Tea Camellia sinensis (L.) Samples (Infusions) Available in Poland

Tea is the world’s most common drink after water, and the world’s annual sales exceed $43 billion, of which more than $11 billion is green tea (Camellia sinensis (L.)). Increasing evidence continues to show that green tea consumption and its ingredients have a variety of potential health benefits. The aim of the study was to control and assess the toxicological risk (TRA) of three heavy metals (As, Pb, and Cd) in infusions of green tea (n = 12) from Polish markets. We applied the method of inductive coupled plasma mass spectrometry (ICP-MS) to determine the selected heavy metal and designed a specific toxicological risk assessment with three crucial tiers. The first tier of our strategy was to determine the elements investigated (heavy metal impurities, µg/L). The second step was to estimate the weekly intake of green tea infusions (µg/week) based on weekly consumption. The third tier was to estimate the weekly intake per weight (µg/L/week/bw), based on the average weekly intake of green tea infusion per adult compared to the provisional weekly intake (PTWI) established by the FAO/WHO Joint Food Additives Expert Committee (JECFA). The levels of the investigated heavy metals occur at different levels in all of the investigated green tea infusions. The heavy metal profile indicated that As (0.0721–10.585 µg/L), Pb (0.386–1.695 µg/L), and Cd (0.126–0.346 µg/L) were present in all samples. Basic analysis of general content shows that As (average = 0.325 µg/L) was at a level similar to Cd (average = 0.214 µg/L). Surprisingly, the Pb content (average 0.891 µg/L) was approximately 2.75–4 times higher than that of As and Cd, respectively. The application of our proposed safety assessment methodology (three tiers) provides satisfactory results for regulatory purposes. The evaluation of the investigated heavy metals in all products analysed from green tea samples (infusions) showed that there were no health hazards to consumers due to weekly exposure. The results indicated that after drinking green tea infusions from Polish markets, the amount of investigated elements in weekly doses does not represent any health risks to consumers.

Case Studies in the Application of a Workflow-Based Crystallization Design for Optimized Impurity Rejection in Pharmaceutical Development

Crystallization is an important unit operation in pharmaceutical drug substance manufacturing for the isolation of organic products. Impurity control is a recurring critical quality attribute in most commercial pharmaceutical crystallization processes. A systematic workflow that can reveal the incorporation mechanism of various impurities during crystallization and guide us to understand impurity rejection is useful for crystallization process design. Such a workflow was recently published by Urwin et al. Herein, we present three case studies implementing this workflow, covering surface deposition, conglomerate formation, and agglomeration as principal routes for impurity incorporation during crystallization of a drug substance’s active pharmaceutical ingredient and its intermediates. We demonstrate the experimental steps to identify various impurity incorporation mechanisms and discuss the strategy for impurity rejection in each case. We built upon the previous approach to demonstrate a material sparing approach through our case studies. We highlight the value of stepwise dissolution and show the importance of doing it early in the impurity incorporation identification stage. At this stage, we introduce a missing incorporation mechanism in prior work, namely, conglomerate systems. We show how to identify and resolve this mode of incorporation mechanism through stepwise dissolution and solubility-limited rejection maps.

Superior tensile and recovery properties of hydride-dehydride elemental NiTi alloys homogenized using high-temperature sintering

Elemental powder (EP) sintering is attractive for use in fabricating the NiTi shape memory alloys due to its low cost and compositional flexibility. However, because of sintering challenges that are not adequately resolved, current EP NiTi alloys exhibit zero or trace tensile properties. In this study, a 10−4 Pa vacuum system was used to optimize the sintering of EP NiTi alloys. The unavoidable liquid phase and high-temperature sintering promoted elemental homogenization, which substantially improved the engineering properties of EP NiTi. Compared to previous studies, increasing the vacuum level caused deflagration reactions at a low temperature of 700 °C. It also rendered the materials more susceptible to macroscopic millimeter-scale defects at > 1050 °C due to the loss of the liquid phase. These problems could be avoided by optimizing the sintering process and completing high-temperature sintering at 1250 °C. High-temperature sintering promoted local elemental homogenization rather than extensive elemental migration. 3D–Computed Tomography reconstruction revealed that high-temperature sintering promoted shrinkage of the pore volumes and homogeneity of pore size distribution. This sintering process considerably improved the mechanical properties of the EP NiTi alloy. The tensile strength and related elongation were 701–763 MPa and 16.54–21.97%, respectively, and the alloy exhibited a shape memory of >90% in an 8% tensile evaluation. This optimization strategy, which integrates impurity control and the intermetallic phase sequence, promotes the practical applications of EP NiTi alloys.

Early Clinical Development of Lufotrelvir as a Potential Therapy for COVID-19.

Lufotrelvir was designed as a first in class 3CL protease inhibitor to treat COVID-19. Development of lufotrelvir was challenged by its relatively poor stability due to its propensity to epimerize and degrade. Key elements of process development included improvement of the supply routes to the indole and lactam fragments, a Claisen addition to homologate the lactam, and a subsequent phosphorylation reaction to prepare the prodrug as well as identification of a DMSO solvated form of lufotrelvir to enable long-term storage. As a new approach to preparing the indole fragment, a Cu-catalyzed C-O coupling using oxalamide ligands was demonstrated. The control of process-related impurities was essential to accommodate the parenteral formulation. Isolation of an MEK solvate followed by the DMSO solvate ensured that all impurities were controlled appropriately.

A Bioanalytical Method for Quantification of N-nitrosodimethylamine (NDMA) in Human Plasma and Urine with Different Meals and following Administration of Ranitidine

Control of N-nitrosoamine impurities is important for ensuring the safety of drug products. Findings of nitrosamine impurities in some drug products led FDA to develop new guidance providing recommendations for manufacturers towards prevention and detection of nitrosamine impurities in pharmaceutical products. One of these products, ranitidine, also had a published in vivo study, which has since been retracted by its authors, suggesting a potential for in vivo conversion of ranitidine to the probable human carcinogen, N-nitrosodimethylamine (NDMA). FDA subsequently initiated a randomized, double-blind, placebo-controlled, crossover clinical investigation to assess the potential for in vivo conversion of ranitidine to NDMA with different meals. A bioanalytical method toward characterization of NDMA formation was needed as previously published methods did not address potential NDMA formation after biofluid collection. Therefore, a bioanalytical method was developed and validated as per FDA's Bioanalytical Method Validation guidance. An appropriate surrogate matrix for calibration standards and quality control sample preparation for both liquid matrices (human plasma and urine) was optimized to minimize the artifacts of assay measurements and monitor basal NDMA levels. Interconversion potential of ranitidine to NDMA was monitored during method validation by incorporating the appropriate quality control samples. The validated methods for NDMA were linear from 15.6 pg/mL to 2000 pg/mL. Low sample volumes (2 mL for urine and 1 mL for plasma) made this method suitable for clinical study samples and helped to evaluate the influence of ranitidine administration and meal types on urinary excretion of NDMA in human subjects.

The effect of impurity seeding into the closed divertor on plasma detachment in the HL-2A tokamak

Recent progress towards an increased understanding of detached divertor physics has been made with the highly closed divertor geometry in HL-2A. Non-intrinsic impurities were injected into the outer divertor chamber, and increased divertor neutral pressure and enhanced volumetric energy loss in the divertor were observed. Meanwhile the neutral pressure in the main chamber decreased slightly, and neutral compression between the divertor and main chamber increased greatly. This led to divertor detachment with a low upstream plasma line-averaged electron density (). In the H-mode, slight degradation of the core confinement, characterized by a decrease in plasma stored energy and pedestal pressure and an increase in edge-localized mode frequency, was observed, but the H-mode was still sustained well with H98 > 1. Pedestal density fluctuation was increased during detachment, implying that the enhanced pedestal transport might be responsible for the degradation. During the divertor detachment phase, the impurities were well controlled in the divertor without strong radiation near the X-point region, and the main plasma density did not increase but decreased slightly; this could be a benefit of the highly closed divertor geometry. The experimental results suggest that a closed divertor geometry has the advantages of volumetric energy loss, gas pumping and impurity control in the divertor without significant effects on the plasma confinement, thus giving a wider operating window for divertor detachment.

Determination of elemental impurities in lomefloxacin hydrochloride ear drops by ICP-MS Using Oxygen Reaction Mode and study of their catalytic effect on photodegradation reaction.

According to the requirements of ICH Q3D, a method for simultaneous determination of 12 element impurities in lomefloxacin hydrochloride ear drops by inductively coupled plasma mass spectrometry (ICP-MS) was established. However, this product contains high concentrations of organic compounds such as glycerol and ethanol, and there will be interference of soluble carbon when it is determined by direct injection method. Therefore, we applied ICP-MS using oxygen reaction mode to reduce the effect of high organic matter on plasma body. The catalytic effect of trace metal ions on the photodegradation of lomefloxacin hydrochloride was also investigated. The sample was dissolved, diluted and directly determined by direct injection using oxygen reaction mode of ICP-MS with 45 Sc, 73 Ge and 115 In as the internal standards. The direct injection using oxygen reaction mode was equipped with argon-oxygen mixer. To investigate the catalytic effect of metal ions on photodegradation, a series of combinations of lomefloxacin hydrochloride mixed with different metal ions were designed. After being irradiated under ultraviolet light for 10 days, the photodegradation impurities in combinations were determined by HPLC. The linear relationships in the corresponding concentration range for 12 element impurities were good (r>0.9993). Limits of detection were between 0.002~1.294 ng·mL-1 . The average recoveries were 93.7%-108.2%, and the precision RSD were 0.04% ~ 0.55% (n=6). The experimental results showed that metal ions had a certain catalytic effect on photodegradation of lomefloxacin when EDTA, Mg2+ and Cu2+ coexisted. The ICP-MS using oxygen reaction mode is suitable to direct determination of the sample rich in organic matter without digestion, can effectively eliminate the interference of high organic matter in this product. The established method was rapid, sensitive, accurate, and can be used for the quality control of elemental impurities in lomefloxacin hydrochloride ear drops.

A Novel Validated UHPLC Method for the Estimation of Rosuvastatin and Its Complete Impurity Profile in Tablet Formulations

A key step in the development of medicinal products is the research and validation of selective and sensitive analytical methods for the control of impurities from synthesis and degradation. As most impurities are similar in structure to the drug substance, the achievement of chemo-selective conditions is usually challenging. Herein, a direct and highly selective ultra-high-performance liquid chromatographic method for determining the assay and related substances content in medicinal products containing rosuvastatin calcium salt (RSV) is presented. RSV is used to treat high cholesterol levels and prevent heart attacks and strokes. The most engaging feature of this method was the baseline separation of all organic related substances listed in the European Pharmacopoeia (EP) monograph for the RSV tablets, achieved for the first time in less than 15 min using the Acquity BEH C18 (100 mm × 2.1 mm, 1.7 μm) column under reversed-phase isocratic conditions. The mobile phase adopted for the chemo-selective analysis does not contain buffers but instead contains trifluoroacetic as an acid additive. The chromatographic method was validated according to the guidelines of the International Conference on Harmonization (ICH) and proved to be linear, precise and accurate for determining the content of RSV and related chiral substances in tablet formulations.

End-to-end approach for the characterization and control of product-related impurities in T cell bispecific antibody preparations

Antibody-based T cell-activating biologics are promising therapeutic medicines being developed for a number of indications, mainly in the oncology field. Among those, T cell bispecific antibodies are designed to bind one tumor-specific antigen and the T cell receptor at the same time, leading to a robust T cell response against the tumor. Although their unique format and the versatility of the CrossMab technology allows for the generation of safer molecules in an efficient manner, product-related variants cannot be completely avoided. Therefore, it is of extreme importance that both a manufacturing process that limits or depletes product-related impurities, as well as a thorough analytical characterization are in place, starting from the development of the manufacturing cell line until the assessment of potential toxicities. Here, we describe such an end-to-end approach to minimize, quantify and control impurities and -upon their functional characterization- derive specifications that allow for the release of clinical material.

Rapid screening of pharmaceutical products for elemental impurities by a high-resolution portable energy dispersive X-ray fluorescence spectrometer using an efficient fundamental parameter method.

In this study, a rapid screening method for elemental impurities in pharmaceutical products has been established by portable energy dispersive X-ray fluorescence (EDXRF) spectroscopy combined with the efficient fundamental parameter method. The proposed method has been used for the screening of 22 elemental impurities (i.e., Cd, Pb, As, Hg, Co, V, Ni, Tl, Au, Pd, Ir, Os, Rh, Ru, Se, Ag, Pt, Sb, Mo, Cu, Sn, and Cr) in the International Conference on Harmonization (ICH) Q3D guideline. The verification of results could meet the acceptance criteria for accuracy, precision and linearity in the United States Pharmacopoeia 〈233〉. On the other hand, the limit of quantitation of the proposed EDXRF method for the screening of 22 elemental impurities in pharmaceutical products could meet the concentration limits of each element at 10 g maximum daily intake based on the established permitted daily exposure to oral drugs in the ICH Q3D guideline. Our findings open up new possibilities in the rapid screening of pharmaceutical products for the detection of elemental impurities by EDXRF, which can be expected to provide a novel, nondestructive, high-throughput, portable, and sensitive platform for the process control of elemental impurities to ensure the quality and safety of drugs.

Control and characterization of defects and impurities in bulk crystals

Control and characterization of defects and impurities in bulk crystals

Operational domain for the new 3MW/1000s ECRH System on WEST

The ECRH system formerly used in Tore Supra is being upgraded to start on WEST in 2023, at a power level of 1MW and frequency of 105 GHz. Its ultimate 3MW/1000s capability is expected to enlarge the WEST operational domain by increasing margins with respect to H-mode access, and by providing additional flexibility in terms of achievable scenarios using impurity and/or MHD control. This flexibility is made possible using an antenna based on three steerable mirrors for controlled power injection. In order to determine an appropriate range of EC wave injection angles for WEST scenarios, the fast and reliable ray-tracing code REMA has been interfaced with the WEST IMAS database. This allows the EC power damping rate to be quickly assessed, as well as deposition profiles to be predicted in realistic plasma conditions. Based on a typical WEST discharge at central magnetic field B0~3.6 T, central line-averaged electron density nl~4 × 1019 m−3 and central electron temperature Te0~3keV, ray-tracing calculations have been performed. Comprehensive poloidal and toroidal angle scans, as well as variations of Bt, nl and Te0 with respect to the reference parameters have allowed an adequate range of injection angles to be determined for efficient use of ECRH and/or ECCD in typical WEST scenarios, and compared with the mechanical limits set by the antenna mechanical characteristics. In order to further characterize the effect of this new power source in WEST scenarios, EC wave deposition and current profiles from ray-tracing calculations have been included in integrated simulation codes. It has been shown that this additional power source could allow central electron heating to be achieved, potentially alleviating the issue of radiative collapse caused by impurities observed in some situations.

Method for trace determination of N-nitrosamines impurities in metronidazole benzoate using high-performance liquid chromatography coupled with atmospheric-pressure chemical ionization tandem mass spectrometry.

Genotoxic impurity control has been a great concern in the pharmaceutical industry since the recall of the large round of sartans worldwide in 2018. In these sartans, N-nitrosamines were the main contaminants in active pharmaceutical ingredients and formulations. Numerous analytical methods have been developed to detect N-nitrosamines in food, drugs, and environmental samples. In this study, a sensitive method is developed for the trace determination of N-nitrosamine impurities in metronidazole benzoate pharmaceuticals using high-performance liquid chromatography/atmospheric-pressure chemical ionization tandem mass spectrometry in the multiple reaction monitoring mode. The method was validated regarding system suitability, selectivity, linearity, accuracy, precision, sensitivity, solution stability, and robustness. The method showed good linearity with R2 ≥ 0.999 and FMandel <Ftab(95%) ranging from 0.33 to 8.00ng/ml. The low limits of detection of N-nitrosamines were in the range of 0.22-0.80ng/ml (0.0014-0.0050ppm). The low limits of quantification were in the range of 0.33-1.20ng/ml (0.0021-0.0075ppm), which were lower than the acceptable limits in metronidazole benzoate pharmaceuticals and indicated the high sensitivity of the method. The recoveries of N-nitrosamines ranged from 84% to 97%. Thus, this method exhibits good selectivity, sensitivity, and accuracy. Moreover, it is a simple, convenient, and scientific strategy for detecting N-nitrosamine impurities in pharmaceuticals to support the development of the pharmaceutical industry.

Shielding analyses supporting the Lithium loop design and safety assessments in IFMIF-DONES

The assessment of radiation fields in the lithium loop pipes and dump tank during the operation were performed for International Fusion Materials Irradiation Facility – DEMO-Oriented NEutron Source (IFMIF-DONES) in order to obtain the radiation dose-rate maps in the component surroundings. Variance reduction techniques such as weight window mesh (produced with the ADVANTG code) were applied to bring the statistical uncertainty down to a reasonable level. The biological dose was given in the study, and potential shielding optimization is suggested and more thoroughly evaluated. The MCNP Monte Carlo was used to simulate a gamma particle transport for radiation shielding purposes for the current Li Systems’ design. In addition, the shielding efficiency was identified for the Impurity Control System components and the dump tank. The analysis reported in this paper takes into account the radiation decay source from and activated corrosion products (ACPs), which is created by d-Li interaction. As a consequence, the radiation (resulting from ACPs and Be-7) shielding calculations have been carried out for safety considerations.

Development and Basic Qualification Steps towards an Electrochemically Based H-Sensor for Lithium System Applications

IFMIF-DONES, or the InternationalFusionMaterialsIrradiationFacility-DEMOOrientedNeutronSource, is a facility for investigations into foreseen fusion power plant materials using the relevant neutron irradiation of 14 MeV. This special n-irradiation is generated by the interaction of deuteron beams with liquid lithium. A critical issue during the operation of IFMIF-DONES is the enrichment of dissolved impurities in the Li-melt loops. The danger occurs as a result of hydrogen-induced corrosivity and embrittlement of the loop components, as well as the security hazards associated with the radioactive tritium. Hence, the application of liquid lithium in IFMIF-DONES requires a suitable impurity control system for reliable and low-level maintenance under the operating conditions of DONES. Regarding those requirements, an electrochemical sensor for hydrogen monitoring was developed in the frame of an international EUROFusion–WPENS task, to determine H-concentrations via the electro-motive force (EMF) of Li-melts and a suitable online-monitoring system. Long-term tests demonstrated that the sensor fulfills the requirements of chemical and mechanical stability and functionality under the harsh Li environment under the planned DONES conditions. Obtained results and operational experiences will be discussed in regard to application windows, reproducibility and calibration needs. Additionally, recommendations will be outlined for upgraded systems and future qualification needs.

The Control of Novel and Traditional Elemental Impurities: Ag, Au, Co, Cs, Li, Mo, Se, Sr, and V in Mint Tea Infusions (Peppermint, Mentha piperita L.) Available in Poland: A Health Risk Assessment.

The purpose of our studies is the evaluation of the health risks of the novel elemental impurities (Ag, Au, Co, Cs, Li, Mo, Se, Sr, and V) in mint tea infusions (Mentha piperita L.) available in Poland. For this purpose, we applied ICP-MS-based methodology for content analysis (elemental profile and µg/L of the infusion) and also the specific health risk assessment for a comprehensive assessment. Our strategy was based on weekly intake (µg/L of infusion/week) considering weekly tea consumption. Then, based on the weekly consumption of tea per adult, individuals were compared to the Temporary Tolerated Weekly Intake (PTWI) designated by the Joint FAO Expert Committee on Food Additives (JECFA), and the weekly consumption per body weight (µg/L of infusion/week/bw) was estimated. Daily exposure to Co in the tested products is in a range of 0.093-0.238 µg/day. In comparison, the established PDE (oral exposure) for Co by the ICH guideline (the ICH guideline Q3D (R1), 2019) is 50 µg/day. For lithium, PDE is approximately 560 µg/day and, in our study, the estimated daily exposure for Li in investigated products is in a range of 0.226-2.41 µg/day. Our studies found also low levels of Cs (in a range of 0.0598-0.195 µg/L), Mo (in a range of 0.663-3.261 µg/L), and Sr (0.223-65.842 µg/L) in infusions. For Molybdenum, the established PDE is approximately 3400 µg/day. There are no documents about Sr and Co in the Joint FAO/WHO Expert Committee on Food Additives (JECFA) database and the ICH guideline Q3D (R1). In the case of V, the established PDE is 120 µg/day, and the level of V in analyzed infusions is in a range of 0.284-0.702 µg/L. Silver and gold were present only in a few samples, and the estimated daily exposure for Ag is approximately 0.04575 µg/day for product A and approximately 0.1885 µg/day for product O, except for Au, which is in a range of 0.000356-0.114 µg/L. The estimated daily exposure for Ag is 167 µg/day and, for Au, it is in a range of 8.9 × 105-0.0285 µg/day. It can be concluded that levels of all investigated elements (novel and also traditional elemental impurities) in the daily dose should not threaten the consumer's health after consuming mint tea infusions.

Towards advanced divertor configurations on the J-TEXT tokamak

Developing advanced magnetic divertor configurations to address the coupling of heat and particle exhaust with impurity control is one of the major challenges currently constraining the further development of fusion research. It has therefore become the focus of extensive attention in recent years. In J-TEXT, several new divertor configurations, including the high-field-side single-null poloidal divertor and the island divertor, as well as their associated fundamental edge divertor plasma physics, have recently been investigated. The purpose of this paper is to briefly summarize the latest progress and achievements in this relevant research field on J-TEXT from the past few years.

A convenient route for the Synthesis of desfluoro impurity of Enzalutamide: a prostate cancer drug and its characterization

The control of impurities plays a significant role for the production of high quality drug substance. In the present study, we reported a simple four step route for the synthesis of desfluoro impurity (4-(3-(4-cyano- 3(trifluoromethyl) phenyl dimethyl-2,4- dioxoimidazolidin-1-yl)-N-methyl benzamide) of enzalutamide drug with readily available raw materials and intermediate chemicals. The synthesised compound was characterized using FT-IR, NMR and mass spectral studies. Based on the spectral analysis, it was confirmed that the compound was pure with no other bye-products or side reactions formed in the synthesis route. The purity and quantity of the compound were further evaluated using HPLC analysis. Based on the HPLC analysis, it was confirmed that the compound is having a purity of 98.58 %. Hence it can be concluded that the proposed route of methodology produces highly pure compound that can be utilized as reference substance and are useful for quality control and the validation of the analytical method in the manufacture of enzalutamide.

Thermophysical properties of FLiBe using moment tensor potentials

Fluoride salts are prospective materials for applications in some next-generation nuclear reactors and their thermophysical properties at various conditions are of interest. Experimental measurement of the properties of these salts is often difficult and, in some cases, unfeasible due to challenges from high temperatures, impurity control, and corrosivity. Therefore, accurate theoretical methods are needed for fluoride salt property prediction. In this work, we used moment tensor potentials (MTP) to approximate the potential energy surface of eutectic FLiBe (66.6% LiF – 33.3% BeF2) predicted by the ab initio (DFT-D3) method. We then used the developed potential and molecular dynamics to obtain several thermophysical properties of FLiBe, including radial distribution functions, density, self-diffusion coefficients, thermal expansion, specific heat capacity, bulk modulus, viscosity, and thermal conductivity. Our results show that the MTP potential approximates the potential energy surface accurately and the overall approach yields very good agreement with experimental values. The converged fitting can be obtained with less than 600 configurations generated from DFT calculations, which data can be generated in just 1200 core hours on today's typical processors. The MTP potential is faster than many machine learning potentials and about one order of magnitude slower than widely used empirical molten salt potentials such as Tosi/Fumi.

Phase Control of Typical Impurities in Hazardous Selenium Waste and Preparation of High-Purity Selenium During Pre-oxidation and Vacuum Distillation Process

Phase Control of Typical Impurities in Hazardous Selenium Waste and Preparation of High-Purity Selenium During Pre-oxidation and Vacuum Distillation Process