Identification Of Impurities Research Articles

Comparative assessment of quality requirements for medicinal products containing diosmin

Currently, there is an increase in pre- and post-approval testing of medicinal products containing diosmin and hence a need to unify approaches to standardisation of this group of pharmaceuticals. Moreover, the State Pharmacopoeia of the Russian Federation lacks a monograph for these products.The aim of the study was to determine an approach to standardisation of medicinal products containing diosmin.Materials and methods: the study analysed scientific publications, as well as monographs of leading foreign pharmacopoeias. Experimental work was carried out using samples of diosmin-containing pharmaceuticals in the form of 500 and 1000 mg film-coated tablets produced by Russian and foreign manufacturers. The study involved high performance liquid chromatography with UV detection using an Agilent 1260 Infinity II liquid chromatography system with a diode array detector. The following reference standards were used: a diosmin RS, USP grade; a hesperidin CRS, Ph. Eur. Grade; and a diosmin CRS for testing chromatography system suitability for identification of impurities A, B, C, D, E, and F, Ph. Eur. grade.Results: the authors reviewed quality requirements for pharmaceutical products containing diosmin and analysed experimental data obtained during pre- and post-approval testing of Russian and foreign medicines. The comparison of regulatory documents for registered diosmin-containing medicinal products showed a difference in approaches to assessing the contents of related substances and active pharmaceutical ingredients. Having analysed the literature, experimental data and regulatory requirements for standardisation of diosmin-containing pharmaceuticals, the authors recommended an approach to standardisation. According to the approach, concomitant flavonoids (hesperidin, isorchoifolin, linarin, and diosmetin) contributing to the pharmacological activity of a medicinal product are specified as part of Assay, and process-related by-products (impurities A and D) are specified and evaluated as part of Related substances tests.Conclusion: the authors propose to evaluate the contents of concomitant flavonoids (hesperidin, isorchoifolin, linarin, diosmetin) under Assay and to specify impurities A and D, as well as single unidentified impurities and total amount of impurities under Related substances.

Impurity Profiling: A Review

Impurities are any substances, such as starting materials or intermediates, that coexist with the parent drug or arise from side reactions. Interest in impurities present in APIs continues to grow. Nowadays, not only purity profile but also impurity profile is mandated by various regulatory agencies. Impurity profiling is a generic name for a group of analytical working groups such as describing, quantifying and characterizing identified and unidentified impurities present in a new drug substance. Impurity profiling is a novel approach aimed at detecting, identifying, structuring and quantifying organic and inorganic impurities and residual solvents in pharmaceuticals. Various regulatory bodies, such as ICH, USFDA, UKMHRA, and India's CDSCO, focus on impurity profiling and have formulated guidelines for impurity management and restriction. Impurities are classified into different categories based on their origin, type of composition, and biological safety. The presence of these unwanted chemicals or substances may affect the safety and effectiveness of the final medicinal product. This review focuses on the sources of impurities, their classification, and various analytical methods for the identification and quantification of impurities. Terms such as residual solvent, by-product, transformation product, decomposition product, reaction product, and related products are often used to define impurities.

A Review on Impurity Profiling, Degradation Studies, and Bioanalytical Methods of Anti-diabetic Drugs

According to ICH Q3A(R), the impurity in a new drug substance is “any component of a new drug substance that is not the chemical entity defined as a new drug substance”. As Per ICH Q3B(R), the impurity in a new drug product is “any component of the drug product that is not the drug substance and excipients in the drug product. “The forced degradation studies are used to facilitate the development of analytical methodology, to achieve a better understanding of the drug substance and the drug product stability, and to determine degradation pathways and the degradation products. This study will help to get the most stable formulation. The bioanalytical method development and validation is an essential part in the drug discovery and development. There is need to develop and validate bioanalytical methods, as sponsors have to submit clinical pharmacology, bioavailability, bioequivalence, pharmacokinetic evaluation along with non-human pharmacology and toxicology studies and preclinical studies to regulatory authorities. There are number of spectroscopic methods includes Ultraviolet spectroscopy, Mass spectroscopy, Nuclear magnetic resonance spectroscopy and Chromatographic methods includes HPLC,HPTLC,GC,UPLC as well as hyphenated techniques like LC-MS, LC/ESI-MS, LC-NMR-MS used for identification and characterization of impurities in an API and the drug products forced degradation study to obtain stability data and bioanalytical methods.
 The uniqueness of this review is that it describes the detail information and background explaining impurities, forced degradation and bioanalytical method development and validation as well as all literature available regarding development and validation of all said methods for the drugs and the drug products used to treat type 2 diabetes.

Identification of unknown impurities in triamcinolone acetonide palmitate

Identification of unknown impurities in triamcinolone acetonide palmitate

Identification of Process-Related Impurities and Corresponding Control Strategy in Biocatalytic Production of 2-O-α-d-Glucopyranosyl-l-ascorbic Acid Using Sucrose Phosphorylase.

2-O-α-d-Glucopyranosyl-l-ascorbic acid (AA-2G) is an ideal substitute for l-ascorbic acid because of its remarkable stability and improved biological activity, which can be easily applied in cosmetic, food, and medicine fields. However, impurity identification and control are significant procedures during the manufacturing of AA-2G. This study assessed a manufacturing routine of AA-2G synthesized by sucrose phosphorylase (SPase). First, three unknown process-related impurities were observed, which were further identified as 3-O-α-d-glucopyranosyl- l-ascorbic acid (impurity I), 2-O-α-d-glucopyranosyl-l-dehydroascorbic acid (impurity II), and 13-O-α-d-glucopyranosyl-2-O-α-d-glucopyranosyl-l-ascorbic acid (impurity III), respectively. Second, a comprehensive formation pathway of impurities was elucidated, and specific strategies corresponding to controlling each impurity were also proposed. Specifically, the content of impurity I can be reduced by 50% by fine tuning reaction conditions. The impurity II-free purification process was also achieved by applying a low concentration of alkali. Finally, a semi-rational design was introduced, and a single mutant L343F was obtained by site-directed mutagenesis, which reduced impurities I and III by 63.9 and 100%, respectively, without affecting the transglycosylation activity. It is expected that the reported impurity identification and control strategies during the AA-2G production will facilitate its industrial production.

Identification and synthesis of potential impurities of bilastine drug substance

Identification and synthesis of potential impurities of bilastine drug substance

Isolation, synthesis, identification of new process-related impurities in evocalcet

Evocalcet is a calcimimetic for the treatment of secondary hyperparathyroidism. In the preparation of evocalcet, eleven process-related impurities were detected in the reaction solution of the last step at levels of 0.05%− 2.50% by a new HPLC method. Ten impurities were separated from the enriched mother liquor and synthesized directly. These impurities were characterized and identified by HRMS and NMR spectra and then coinjected with commercial products to confirm their retention times in HPLC. The possible formation pathways and synthetic methods of ten process-related impurities ware discussed in detail.

NMR as Used in the Russian and Foreign Pharmacopoeias for Quality Control of Medicinal Products

The ongoing development of the Pharmacopoeia of the Eurasian Economic Union and the current trend for harmonisation of the Russian Pharmacopoeia with the world leading pharmacopoeias suggest the necessity of studying how different pharmacopoeias use nuclear magnetic resonance (NMR) for quality control of medicinal products. The aim of the study was to compare the extent of medicine quality characteristics assessed by NMR in the Russian and foreign pharmacopoeias. The review summarises the experience of various national and world pharmacopoeias in using the NMR method for quality control of medicines and certification of pharmacopoeial reference materials. The comparative analysis covered the following quality parameters: active ingredient identification, determination of the composition of non-stoichiometric compounds, determination of the average polymer chain length in polymers and block copolymers, determination of the absolute content of the active ingredient, identification and quantification of impurities, polymorphism, and crystallinity. It was shown that the United States and Japanese Pharmacopoeias are leading the way in introducing the NMR method into pharmacopoeial analysis. There have been some positive trends in the introduction of the NMR method in the State Pharmacopoeia of the Russian Federation as well. It was concluded that changes are needed in the general chapters “Nuclear Magnetic Resonance Spectroscopy” and “Reference Standards” of the State Pharmacopoeia of the Russian Federation, 14th ed. in order to harmonise the texts with those of the Eurasian Pharmacopoeia and the European Pharmacopoeia and to allow for the possibility of direct identification of a substance by complex analysis of NMR spectral data, without comparing the test sample and the reference standard spectra. The NMR method should be included in the list of absolute methods used for determination of purity of primary chemical reference substances during certification.

Classification of Adulterated Particle Images in Coconut Oil Using Deep Learning Approaches

In the production of coconut oil for consumption, cleanliness and safety are the first priorities for meeting the standard in Thailand. The presence of color, sediment, or impurities is an important element that affects consumers’ or buyers’ decision to buy coconut oil. Coconut oil contains impurities that are revealed during the process of compressing the coconut pulp to extract the oil. Therefore, the oil must be filtered by centrifugation and passed through a fine filter. When the oil filtration process is finished, staff inspect the turbidity of coconut oil by examining the color with the naked eye and should detect only the color of the coconut oil. However, this method cannot detect small impurities, suspended particles that take time to settle and become sediment. Studies have shown that the turbidity of coconut oil can be measured by passing light through the oil and applying image processing techniques. This method makes it possible to detect impurities using a microscopic camera that photographs the coconut oil. This study proposes a method for detecting impurities that cause the turbidity in coconut oil using a deep learning approach called a convolutional neural network (CNN) to solve the problem of impurity identification and image analysis. In the experiments, this paper used two coconut oil impurity datasets, PiCO_V1 and PiCO_V2, containing 1000 and 6861 images, respectively. A total of 10 CNN architectures were tested on these two datasets to determine the accuracy of the best architecture. The experimental results indicated that the MobileNetV2 architecture had the best performance, with the highest training accuracy rate, 94.05%, and testing accuracy rate, 80.20%.

Исследование примесного состава изотопно обогащенного германа 70GeH4 методом хромато-масс-спектрометрии

For the first time, the impurity composition of isotopically enriched germane 70GeH4 has been studied by gas chromatography-mass spectrometry. To separate impurities, we used a GS-GasPro capillary adsorption column 60 m × 0,32 mm with silica gel as a sorbent, GS-CarbonPLOT 25 m × 0,32 mm × 0,25 μm with a carbon sorbent and 25 m × 0,26 mm × 0,25 μm with sorbent polytrimethylsilylpropine. It has been shown that their use makes it possible to achieve a high resolution of the chromatographed substances. The identification of impurities was carried out by comparing their mass spectra with the data of the NIST library. Gases are found in germane, which are part of the atmosphere, C1 – C7 hydrocarbons, chlorine and oxygenated hydrocarbons, sulfur-containing substances, homologues and alkyl derivatives of germane. As a result of studying the composition of their mass spectra, the mass spectra of impurities 70GeC3H10 and 70GeC4H12, which are absent in the literature sources, were obtained and described for the first time. Concentrations of impurities in high-purity germane, as well as their distribution over fractions isolated during its rectification purification, have been determined. The detection limits of the identified substances were 2·10–7 – 1·10–4 mol. %.

Identification of the Organic Volatile Impurities in Telmisartan Active Pharmaceutical Ingredient and Its Pharmaceutical dosage forms by using Head Space Gas Chromatography Technique

Identification of the Organic Volatile Impurities in Telmisartan Active Pharmaceutical Ingredient and Its Pharmaceutical dosage forms by using Head Space Gas Chromatography Technique

Identification, synthesis and characterization of avanafil process impurities and determination by UPLC.

Avanafil is a phosphodiesterase type 5 inhibitor which is used to treat erectile dysfunction in men. The process-related impurities of avanafil were investigated, and four kinds of impurities in several laboratory batches with a content of 0.29–1.63% were detected by the newly developed gradient ultra-high performance liquid chromatography (UPLC). Based on the synthesis route and UPLC-MS research, the impurities are inferred as Imp-A, Imp-B, Imp-C and Imp-D. The structures of the impurities were inferred from LC-MS studies and confirmed by synthesis, followed by spectroscopic characterization such as NMR and mass spectrometry. Especially, the synthesis of Imp-D is firstly reported. The drug-related substances can be separated well by efficient and selective ultra-high performance liquid chromatography on a Waters ACQUITY HSS C18 (50 × 2.1 mm, particle size 1.8 μm) column at 35 °C, with the mobile phase consisting of ammonium formate (20 mM) and acetonitrile, and the detection at 239 nm with a DAD detector. The method was validated in terms of specificity, linearity, precision, accuracy and sensitivity, and satisfactory results were obtained. The results indicated this developed UPLC method for avanafil and the proposed synthesis mechanism can be used for quality control purposes as required by regulatory agencies to ensure the safety and efficacy of the product.

Key comparison study on peptide purity - hexapeptide of HbA0

Main textUnder the auspices of the Protein Analysis Working Group (PAWG) of the Comité Consultatif pour la Quantité de Matière (CCQM) a key comparison, CCQM-K115.2018, was coordinated by the Bureau International des Poids et Mesures (BIPM), the Health Sciences Authority (HSA) of Singapore and the Chinese National Institute of Metrology (NIM). Ten Metrology Institutes or Designated Institutes and the BIPM participated. Participants were required to assign the mass fraction of the hexapeptide of HbA0 (VE) present as the main component in the comparison sample for CCQM-K115.2018. The comparison samples were prepared by HSA/BIPM from synthetic VE purchased from a commercial supplier and used as provided without further treatment or purification.VE was selected to be representative of the performance of a laboratory's measurement capability for the purity assignment of chemically synthesized peptides of known sequence, without cross-links, up to 5 kDa and without modification. It was anticipated to provide an analytical measurement challenge representative for the value-assignment of compounds of broadly similar structural characteristics.The majority of participants used amino acid analysis (PICAA) with a correction for structurally-related peptide impurities approach as the amount of material that had been provided to each participant (25 mg) was insufficient to perform a full mass balance based characterization of the material by a participating laboratory. The coordinators, the BIPM, the HSA and the NIM, were the laboratories to use the mass balance approach as they had more material available.It was decided to propose KCRVs for both the VE mass fraction and the mass fraction of the peptide related impurities as indispensable contributor regardless of the use of PICAA, mass balance or any other approach to determine the VE purity. This allowed participants to demonstrate the efficacy of their implementation of the approaches used to determine the VE mass fraction. In particular, it allowed participants to demonstrate the efficacy of their implementation of peptide related impurity identification and quantification.More detailed studies on the identification/quantification of peptide related impurities revealed that the integrity of the impurity profile of the related peptide impurities obtained by the participant is crucial for the impact on accuracy of the VE mass fraction assignment.The assessment of the mass fraction of peptide impurities is based on the assumption that only the most consistent set of results is taken for the calculation of the KCRVPepImp. The sum of the combined cis/trans VE depsipeptide impurities (only identified/quantified by NRC and confirmed by BIPM and HSA) and mass fractions of peptide related impurities that have been identified by at least two participants have been used to establish the KCRVPepImp. The KCRVPepImp of 53.0 mg/g is associated with a corresponding expanded uncertainty of 17.3 mg/g (k = 2) providing a more realistic basis of evaluation for the capabilities of the participants to identify/quantify peptide related impurities. Inspection of the degree of equivalence plots for the mass fraction of peptide impurities and additional information obtained from the peptide related impurity profile indicates that in all cases the major related peptide impurity, VE depsipeptide, has not been identified. The VE depsipeptide impurity was initially and uniquely identified and quantified by the NRC by the use of 1H-NMR. The related peptide impurity mass fraction results of only four participants (NRC, LGC, LNE and HSA) are in agreement with the KCRVPepImp. The NRC has identified and quantified the VE depsipeptide whereas the LGC, LNE and HSA have not identified the VE depsipeptide but accounted for that contribution.The approach selected to obtain a KCRVVE for the mass fraction of VE is based on a mass balance calculation that takes into account the most consistent set of results for the peptide related impurities KCRVPepImp, TFA mass fraction and the water mass fraction. The KCRVVE for CCQM-K115.2018 is 613 mg/g with a corresponding expanded uncertainty of the KCRVVE of 20 mg/g (k = 2).To reach the main text of this paper, click on Final Report. Note that this text is that which appears in Appendix B of the BIPM key comparison database https://www.bipm.org/kcdb/.The final report has been peer-reviewed and approved for publication by the CCQM, according to the provisions of the CIPM Mutual Recognition Arrangement (CIPM MRA).

Key comparison study on peptide purity - glycated hexapeptide of HbA1c

Main textUnder the auspices of the Protein Analysis Working Group (PAWG) of the Comité Consultatif pour la Quantité de Matière (CCQM) a key comparison, CCQM-K115.c, was coordinated by the Bureau International des Poids et Mesures (BIPM), the Health Sciences Authority (HSA) of Singapore and the Chinese National Institute of Metrology (NIM). Nine Metrology Institutes or Designated Institutes and the BIPM participated. Participants were required to assign the mass fraction of the glycated hexapeptide of HbA1c (GE) present as the main component in the comparison sample for CCQM-K115.c. The comparison samples were prepared by HSA/BIPM from synthetic GE purchased from a commercial supplier and used as provided without further treatment or purification.GE was selected to be representative of the performance of a laboratory's measurement capability for the purity assignment of chemically synthesized peptides of known sequence, without cross-links, up to 5 kDa and modification (mono-glycation). It was anticipated to provide an analytical measurement challenge representative for the value-assignment of compounds of broadly similar structural characteristics.The majority of participants used amino acid analysis (PICAA) or quantitative nuclear magnetic resonance (PICqNMR) spectroscopy with a correction for structurally-related peptide impurities approach as the amount of material that has been provided to each participant (25 mg) is insufficient to perform a full mass balance based characterization of the material by a participating laboratory. The coordinators, the BIPM, the HSA and the NIM, were the laboratories to use the mass balance approach as they had more material available.It was decided to propose KCRVs for both the GE mass fraction and the mass fraction of the peptide-related impurities as indispensable contributor regardless of the use of PICAA, PICqNMR or mass balance to determine the GE purity. This allowed participants to demonstrate the efficacy of their implementation of the approaches used to determine the GE mass fraction. In particular, it allows participants to demonstrate the efficacy of their implementation of peptide-related impurity identification and quantification.More detailed studies on the identification/quantification of peptide-related impurities revealed that the integrity of the impurity profile of the related peptide impurities obtained by the participant is crucial for the impact on accuracy of the GE mass fraction assignment.The assessment of the mass fraction of peptide impurities is based on the assumption that that all results are directly taken for the calculation of the KCRVPepImp by use of random-effects meta-analysis (DerSimonian-Laird (DSL) variance-weighted mean). The KCRVPepImp of 45.4 mg/g is associated with a corresponding expanded uncertainty of 9.5 mg/g (k =2.26) providing a more realistic basis of evaluation for the capabilities of the participants to identify/quantify peptide-related impurities. Inspection of the degree of equivalence plots for the mass fraction of peptide impurities and additional information obtained from the peptide-related impurity profile indicates that in most cases the major related peptide impurities have been identified and quantified.The approach selected to obtain a KCRVGE for the mass fraction of GE is based on the DerSimonian-Laird (DSL) variance-weighted mean. The DSL mean takes into account the uncertainties of the results while introducing sufficient excess variance to allow for their observed dispersion resulting in a larger expanded uncertainty U(KCRVGE). The KCRVGE for CCQM-K115.c is 628 mg/g with a corresponding expanded uncertainty of the KCRVGE of 27 mg/g (k =2.26). All GE mass fraction results are in agreement with the KCRVGE.To reach the main text of this paper, click on Final Report. Note that this text is that which appears in Appendix B of the BIPM key comparison database https://www.bipm.org/kcdb/.The final report has been peer-reviewed and approved for publication by the CCQM, according to the provisions of the CIPM Mutual Recognition Arrangement (CIPM MRA).

Pilot study on peptide purity - glycated hexapeptide of HbA1c

Main textUnder the auspices of the Protein Analysis Working Group (PAWG) of the Comité Consultatif pour la Quantité de Matière (CCQM) a pilot study, CCQM-P55.2.c, was coordinated by the Bureau International des Poids et Mesures (BIPM), the Health Sciences Authority (HSA) of Singapore and the Chinese National Institute of Metrology (NIM). Three Metrology Institutes or Designated Institutes and the BIPM participated. Participants were required to assign the mass fraction of glycated hexapeptide of HbA1c (GE) present as the main component in the comparison sample for CCQM-P55.2.c. The comparison samples were prepared by HSA/BIPM from synthetic GE purchased from a commercial supplier and used as provided without further treatment or purification.GE was selected to be representative of the performance of a laboratory's measurement capability for the purity assignment of chemically synthesized peptides of known sequence, without cross-links, up to 5 kDa and modification (mono-glycation). It was anticipated to provide an analytical measurement challenge representative for the value-assignment of compounds of broadly similar structural characteristics.The majority of participants used amino acid analysis (PICAA) or quantitative nuclear magnetic resonance (PICqNMR) spectroscopy with a correction for structurally-related peptide impurities. It was decided to assign reference values (RVs) based on the KCRVs of CCQM-K115.c for both the GE mass fraction and the mass fraction of the peptide related impurities as indispensable contributor regardless of the use of PICAA, mass balance or any other approach to determine the GE purity. This allowed participants to demonstrate the efficacy of their implementation of the approaches used to determine the GE mass fraction. In particular, it allows participants to demonstrate the efficacy of their implementation of peptide related impurity identification and quantification.More detailed studies on the identification/quantification of peptide related impurities revealed that the integrity of the impurity profile of the related peptide impurities obtained by the participant is crucial for the impact on accuracy of the GE mass fraction assignment.The assessment of the mass fraction of peptide impurities is based on the assumption that all results are directly taken for the calculation of the RVPepImp by use of random-effects meta-analysis (DerSimonian-Laird (DSL) variance-weighted mean). The RVPepImp of 45.4 mg/g is associated with a corresponding expanded uncertainty of 9.5 mg/g (k =2.26) providing a more realistic basis of evaluation for the capabilities of the participants to identify/quantify peptide related impurities. Inspection of the degree of equivalence plots for the mass fraction of peptide impurities and additional information obtained from the peptide related impurity profile indicates that in all cases the major related peptide impurities have been identified and quantified.The approach selected to obtain a RVGE for the mass fraction of GE is based on the DerSimonian-Laird (DSL) variance-weighted mean. The DSL mean takes into account the uncertainties of the results while introducing sufficient excess variance to allow for their observed dispersion resulting in a larger expanded uncertainty U(RVGE). The RVGE based on CCQM-K115.c is 628 mg/g with a corresponding expanded uncertainty of the RVGE of 27 mg/g (k =2.26). All GE mass fraction results are in agreement with the RVGE.To reach the main text of this paper, click on Final Report. Note that this text is that which appears in Appendix B of the BIPM key comparison database https://www.bipm.org/kcdb/.The final report has been peer-reviewed and approved for publication by the CCQM, according to the provisions of the CIPM Mutual Recognition Arrangement (CIPM MRA).

Pilot study on peptide purity - hexapeptide of HbA0

Main textUnder the auspices of the Protein Analysis Working Group (PAWG) of the Comité Consultatif pour la Quantité de Matière (CCQM) a pilot study, CCQM-P55.2.2018, was coordinated by the Bureau International des Poids et Mesures (BIPM), the Health Sciences Authority (HSA) of Singapore and the Chinese National Institute of Metrology (NIM). Three Metrology Institutes or Designated Institutes and the BIPM participated. Participants were required to assign the mass fraction of hexapeptide of HbA0 (VE) present as the main component in the comparison sample for CCQM-P55.2.2018. The comparison samples were prepared by HSA/BIPM from synthetic VE purchased from a commercial supplier and used as provided without further treatment or purification.VE was selected to be representative of the performance of a laboratory's measurement capability for the purity assignment of chemically synthesized peptides of known sequence, without cross-links, up to 5 kDa and without modification. It was anticipated to provide an analytical measurement challenge representative for the value-assignment of compounds of broadly similar structural characteristics.The majority of participants used amino acid analysis (PICAA) or quantitative nuclear magnetic resonance (PICqNMR) spectroscopy with a correction for structurally related peptide impurities. It was decided to assign reference values (RVs) based on the KCRVs of CCQM-K115.2018 for both the VE mass fraction and the mass fraction of the peptide-related impurities as indispensable contributor regardless of the use of PICAA, mass balance or any other approach to determine the VE purity. This allowed participants to demonstrate the efficacy of their implementation of the approaches used to determine the VE mass fraction. In particular, it allows participants to demonstrate the efficacy of their implementation of peptide-related impurity identification and quantification.More detailed studies on the identification/quantification of peptide related impurities revealed that the integrity of the impurity profile of the related peptide impurities obtained by the participant is crucial for the impact on accuracy of the VE mass fraction assignment.The assessment of the mass fraction of peptide impurities is based on the assumption that only the most consistent set of results is taken for the calculation of the RVPepImp. The sum of the combined cis/trans VE depsipeptide impurities (only identified/quantified by NRC and confirmed by BIPM and HSA) and mass fractions of peptide-related impurities that have been identified by at least two participants have been used to establish the RVPepImp. The RVPepImp of 53.0 mg/g is associated with a corresponding expanded uncertainty of 17.3 mg/g (k = 2) providing a more realistic basis of evaluation for the capabilities of the participants to identify/quantify peptide related impurities. Inspection of the degree of equivalence plots for the mass fraction of peptide impurities and additional information obtained from the peptide-related impurity profile indicates that in all cases the major related peptide impurity, VE depsipeptide, has not been identified. The VE depsipeptide impurity was initially and uniquely identified and quantified by the NRC by the use of 1H-NMR in the parallel CCQM-K115.2018. The related peptide impurity mass fraction results of only four participants (NRC, LGC, LNE and HSA) are in agreement with the RVPepImp. The NRC has identified and quantified the VE depsipeptide whereas the LGC, LNE and HSA have not identified the VE depsipeptide but accounted for that contribution.The approach selected to obtain a RVVE for the mass fraction of VE is based on a mass balance calculation that takes into account the most consistent set of results for the peptide-related impurities RVPepImp, TFA mass fraction and the water mass fraction. The RVVE based on CCQM-K115.2018 is 613 mg/g with a corresponding expanded uncertainty of the RVVE of 20 mg/g (k = 2). Inspection of the degree of equivalence plots for the mass fraction of VE shows that all results obtained by PICAA agree with the RVVE while the result obtained by the BIPM with PICqNMR disagrees with the RVVE.To reach the main text of this paper, click on Final Report. Note that this text is that which appears in Appendix B of the BIPM key comparison database https://www.bipm.org/kcdb/.The final report has been peer-reviewed and approved for publication by the CCQM, according to the provisions of the CIPM Mutual Recognition Arrangement (CIPM MRA).

Optimization of the Everolimus Intermediate Preparation Process: Impurity Identification Followed by One-Pot Transformation to the Desired Product

An investigation of the everolimus intermediate PG-EVR preparation process resulted in the identification of three impurities PG-D,E,F constantly formed as byproducts in large amounts. Their structures were reliably established based on two-dimensional (2D) NMR and liquid chromatography–high-resolution tandem mass spectrometry (LC–HRMS/MS) data as dialkylated rapamycin derivatives. Finding that one of these impurities PG-E is hydrolyzable to the target everolimus intermediate resulted in optimized technology based on changing the selectivity of byproduct formation to PG-E as the major one followed by its one-pot quantitative transformation to PG-EVR. The yield of the everolimus intermediate increased by 10% under mild conditions, while lower amounts of reagents and solvents were required. The active pharmaceutical ingredient (API) that meets the requirements of the European Pharmacopoeia was prepared from thus obtained intermediate with no need for high-performance liquid chromatography (HPLC) purification, indicating a significant increase in the efficiency of large-scale production using new technology.

МОНИТОРИНГ СОДЕРЖАНИЯ СОРТОВОЙ ПРИМЕСИ В ПИТОМНИКАХ ПЕРВИЧНОГО И ЭЛИТНОГО СЕМЕНОВОДСТВА ЛЬНА-ДОЛГУНЦА

The most common reason for varietal impurities of long-stalked type in the crops of fiber flax is non-compliance with the basic requirements of internal control when working with several flax varieties on the farm or when carrying out a variety change. During field testing, the identification of biological impurity of the intermediate type is not completely carried out due to the unevenness of the crops. Due to morphological similarity of fiber flax varieties, it is impossible to determine the percentage of mechanical variety impurities of the long-stalked type. The aim of the research is to study the reproduction dynamics of variety impurity of K-7009 long- stalked form of flax, which has a yellow color of seeds, in the seeds of fiber flax contaminated with it after 6-year sowing. The aim is also to clarify the parameter of variety purity of fiber flax seeds of the following categories: genuine seeds (GS) and elite seeds (ES) in State Standard GOST R 52325-2005. The research was carried out in 2015-2020 in the field conditions of the Experimental field of the Federal State Budgetary Scientific Institution "Federal Scientific Center of Bast Cultures" in Tver region. The objects of the study were plants and seeds of Antey fiber flax variety (control). The usage of variety admixture of the long-stalked flax form with a marker trait made it possible to accurately determine its content in the crop in case of seed multiplication in nurseries of primary seed growing, superelite (GS) and elite (ES). It was found that variety contamination of fiber flax seeds with variety admixture in the amount of 0.2-1.0% did not affect the yield of seeds and straw. As a result of five-year reproduction of seeds in the crops of GS category, an increase in the amount of variety impurity was noted by 0.1-1.3%, in the ES category - by 0.3-2.1% compared to initial contamination. Based on the obtained experimental data, it was recommended to reduce variety purity index for the category of genuine fiber flax seeds in State Standard GOST R 52325-2005 to 99.5%, elite - to 90%.

QUALITATIVE AND QUANTITATIVE ASSESSMENT OF RELATED SUBSTANCES IN THE CLOBETASOL PROPIONATE IN TOPICAL CREAM DOSAGE FORM BY RP-HPLC

The identification and control of impurities in drug substance and drug product is considered as very critical factor by regulatory agency for safe and effective use of Drug product for its intended use. A specific and sensitive Reverse Phase High Performance Liquid Chromatography (RP-HPLC) method is developed and validated for the estimation of 11 specified impurities in Topical Clobetasol Propionate Cream. The chromatographic parameters for develop method are C18 column, proportion of Water: Methanol: Acetonitrile: Trifluoro acetic acid as mobile phase at flow rate of 1.2 ml/min and UV detection at 241 nm. The method is validated for parameters as specified in ICH guideline. Developed method is validated for range 0.05–0.75 μg/mL for which Linearity, accuracy and precision was proven with acceptable limits. Method is sensitive as established Limit of Detection (LOD), and Limit of Quantitation (LOQ) are 0.02% and 0.06% respectively.

Reversed-phase high-performance liquid chromatography method for impurity profiling of generic drug Calcium Orotate

New reversed-phase high-performance liquid chromatography (HPLC) method has been developed and validated for the identification of impurity in calcium orotate dihydrate (CaOD) drug. The developed analytical method has been achieved superior resolution between the impurity and CaOD using Alltima C-18 column. The method has been established by isocratic mobile phase condition comprising of 0.01 mol/L of potassium dihydrogen orthophosphate, pH adjusted to 2.7 with orthophosphoric acid and acetonitrile in a ratio of 98:2 v/v. The eluted impurity at the retention time of 6.02 min. has so far not been reported in earlier methods of analysis. Further, this method highlights that the eluted impurity in the drug is uracil and confirmed by spiking the standard uracil into CaOD sample. According to International council for harmonization (ICH) guidelines, the developed method has been validated with respect to accuracy, precision, specificity, linearity, range, robustness, system suitability, limit of detection and limit of quantification.