Pistacchio, Alessandra (2021) Impact of four inorganic impurities – iron, copper, nickel and zinc - on the quality attributes of a Fc-fusion protein upon incubation at different temperatures. [Tesi di dottorato]

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Item Type:	Tesi di dottorato
Resource language:	English
Title:	Impact of four inorganic impurities – iron, copper, nickel and zinc - on the quality attributes of a Fc-fusion protein upon incubation at different temperatures
Creators:	Creators Email Pistacchio, Alessandra alessandra.pistacchio@unina.it
Date:	15 July 2021
Number of Pages:	145
Institution:	Università degli Studi di Napoli Federico II
Department:	Farmacia
Dottorato:	Scienza del farmaco
Ciclo di dottorato:	33
Coordinatore del Corso di dottorato:	nome email D'Auria, Maria Valeria mariavaleria.dauria@unina.it
Tutor:	nome email Stornaiuolo, Mariano UNSPECIFIED
Date:	15 July 2021
Number of Pages:	145
Keywords:	biopharmaceutical characterization; Fc-fusion protein; protein structure; protein aggregation; oxidation; fragmentation; physicochemical properties; stability; chromatography; spectroscopy; leachables; metal ions.
Settori scientifico-disciplinari del MIUR:	Area 03 - Scienze chimiche > CHIM/01 - Chimica analitica Area 03 - Scienze chimiche > CHIM/09 - Farmaceutico tecnologico applicativo
Date Deposited:	20 Jul 2021 14:38
Last Modified:	07 Jun 2023 10:17
URI:	http://www.fedoa.unina.it/id/eprint/13586

Collection description

A key aspect that must be supervised during the development of a biotherapeutic is the presence of elemental impurities in the final drug product: they must be quantified as to ensure that their concentrations does not affect patients' safety. Regulatory guidelines such as ICH Q3D provides Permitted Daily Exposure (PDE) limits for those impurities considered having a higher potential safety risk. However, one of the limits of such PDE values is that they account for the safety risk, without considering the "quality" one, intended as which are the alterations to the Quality Attributes (QA) of a biologic. The aim of this Ph.D. project was to examine how four commonly observed elemental impurities could impact the QAs of a Fc-fusion protein, in order to understand how they could affect not only the safety of patients, but also the physicochemical properties of biotherapeutics. To this aim a Fc-fusion protein was treated with increasing concentrations of Ni2+, Cu2+, Zn2+ and Fe3+ and analysed under normal storage conditions, after 6 and 44 weeks of incubation at different temperatures (+5°C, +25°C, +40°C). The potential changes in conformation, oxidation, aggregation, and fragmentation were monitored. Our data suggest that keeping the levels of these impurities under the safety threshold limits does not guarantee the product quality. While nickel and zinc slightly altered the physicochemical properties of our Fc-fusion protein, iron and copper appeared to be more harmful for the QAs stability. Indeed, these latter elements might cause significant alterations of the product quality such as to potentially alter its efficacy.

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