Rapid aggregation of therapeutic monoclonal antibodies by bubbling induced air/liquid interfacial and agitation stress at different conditions

Degradation of therapeutic monoclonal antibodies (mAb) due to interfacial agitation through air bubbling was investigated. Samples containing mAb in phosphate buffered saline were subjected to rapid bubbling by using a peristaltic pump at an air flow rate of 11.5 mL/min. Samples were analyzed by visual observation, UV-Vis, fluorescence, circular dichroism and infrared spectroscopy, size-exclusion chromatography (SEC), dynamic light scattering, microscopy, and cell-based activity assays. The stressed samples showed increasing turbidity with bubbling time, with mAb1 showing a protein loss of 53% in the supernatant at the latest time point (240 min), indicating formation of sub-visible and visible aggregates. Aggregate rich samples exhibited altered secondary structure and higher hydrophobicity with 40% reduction in activity. The supernatants of the stressed samples showed unchanged secondary and tertiary structure without the presence of any oligomers in SEC. Furthermore, the impact of various factors that could affect aggregation was investigated and it was found that the extent of aggregation was affected by protein concentration, sample volume, presence of surfactants, temperature, air flow rate, and presence of silicone oil. In conclusion, exposure to air/liquid interfacial stress through bubbling into liquid mAb samples effectively generated sub-visible and visible aggregates, making air bubbling an attractive approach for interfacial stress degradation studies of mAbs.Drug Delivery Technolog

Oxidation and deamidation of monoclonal antibody products: potential impact on stability, biological activity, and efficacy

The role in human health of therapeutic proteins in general, and monoclonal antibodies (mAbs) in particular, has been significant and is continuously evolving. A considerable amount of time and resources are invested first in mAb product development and then in clinical examination of the product. Physical and chemical degradation can occur during manufacturing, processing, storage, handling, and administration. Therapeutic proteins may undergo various chemical degradation processes, including oxidation, deamidation, isomerization, hydrolysis, deglycosylation, racemization, disulfide bond breakage and formation, Maillard reaction, and beta-elimination. Oxidation and deamidation are the most common chemical degradation processes of mAbs, which may result in changes in physical properties, such as hydrophobicity, charge, secondary or/and tertiary structure, and may lower the thermodynamic or kinetic barrier to unfold. This may predispose the product to aggregation and other chemical modifications, which can alter the binding affinity, half-life, and efficacy of the product. This review summarizes major findings from the past decade on the impact of oxidation and deamidation on the stability, biological activity, and efficacy of mAb products. Mechanisms of action, influencing factors, characterization tools, clinical impact, and risk mitigation strategies have been addressed (C) 2021 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.Drug Delivery Technolog

Migration behaviour of weakly retained, charged analytes in voltage-assisted micro-high performance liquid chromatography

The application of voltage in micro-high performance liquid chromatography (micro-HPLC) creates a system where separation is governed by a hybrid differential migration process, which entails the features of both HPLC and capillary zone electrophoresis (CZE), i.e., chromatographic retention and electrophoretic migration. In this paper, we use our previously published approach to decouple these two mechanisms via analysis of the input data for estimation of electrokinetic parameters, such as conductivity, equivalent lengths, mobilities and velocities. Separation of weakly retained, charged analytes was performed via voltage-assisted micro-HPLC. Contrary to conclusions from data analysis using the conventional definitions of the retention factor, it is shown that our approach allows us to isolate the “chromatographic retention” component and thus, investigate the “modification” of the retention process upon application of voltage in micro-HPLC. It is shown that the traditional approaches of calculating retention factor would erroneously lead to conclusion that the retention behavior of these analytes changes upon application of voltage. However, the approach suggested here demonstrates that under the conditions investigated, most of the charged analytes do not show any significant retention on the columns and that all the changes in their retention times can be attributed to their electrophoretic migration

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Book of Abstracts of National Seminar on Production, Productivity & Quality of Spices held on2-3 February,2013 and Published by Director, National Research Centre on Seed Spices, Ajmer Raj. PP. 1-216.Not AvailableNot Availabl

Integration of National AIDS Control Program and Pharmacovigilance Program of India-Antiretroviral Drugs safety coactions in India

This letter describes the initiatives taken by Indian Pharmacopoeia Commission (IPC) in monitoring safety of Anti-Retroviral Therapy (ART) drugs [1, 2, 3]. The Collaboration between National AIDS control organization (NACO) & Pharmacovigilance Program of India (PvPI) is aimed to work with periphery ART centres to monitor the safety of ART drugs & also to initiate the Cohort Event Monitoring (CEM) thus to perform the benefitrisk assessment of ART drugs, however there are some technical & operational issues in implementing the program & identifying the risk related to ART drugs. Pharmacovigilance is the science and activities relating to detection, assessment, understanding and prevention adverse effects or any other possible drug related problems. It is an integral part of every public health program that uses medicines, optimizing their safety is paramount (World Health Organization–Uppsala Monitoring Centr

Grain iron and zinc densities in released and commercial cultivars of pearl millet (Pennisetum glaucum)

Crop biofortification is a cost-effective and sustainable agricultural trategy to reduce micronutrient malnutrition arising from iron (Fe) and zinc (Zn) deficiencies. A large number of hybrids and open-pollinated varieties (OPVs) of pearl millet [Pennisetum glaucum (L.) R. Br.] have been released and/or commercialized in India. Eighteen OPVs and 15 high-Fe candidate hybrids were evaluated in multi-location trials for Fe and Zn density to identify those with high density of these micronutrients. The Fe density in OPVs varied from 42 mg/kg to 67 mg/kg, and Zn density from 37 mg/kg to 52 mg/kg with ICTP 8203 having the highest Fe density (67 mg/kg) followed by ICMV 221 (61 mg/kg) and AIMP 92901 (56 mg/kg). While ICTP 8203 had also the highest level of Zn density (52 mg/kg), ICMV 221 and AIMP 92901 had 45-46 mg/kg Zn density. The Fe density in hybrids varied from 46 mg/kg to 56 mg/kg and Zn density from 37 mg/kg to 44 mg/kg. Four hybrids, viz. Ajeet 38, Proagro XL 51, AC 903 and 86M86 had the highest Fe density of 55-56 mg/kg and 39-41 mg/kg Zn density. The six commercial cultivars (2 OPVs and 4 hybrids) identified in this study with high Fe and Zn densities can be undertaken for expanded cultivation in their recommended ecologies to specifically address the Fe and Zn deficiencies in India. This study also enabled to re-define base line for Fe density at 42 mg/kg for hybrids, the most ominant cultivar type grown in India