Downstream Processing

Viral Safety for Biotechnology Products, Including Viral Vectors: ICH Q5A Revision 2 Brings Updated and More Comprehensive Guidance

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The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) provides guidance on the testing and evaluation of viral safety of biotechnological products derived from characterized cell lines of human or animal origin through its harmonized guideline ICH Q5A (1). The latest revision, released for consultation in October 2022, maintains the key principles of previous versions while introducing key changes in response to important advances in the field. Those advances are covered in new sections that…

May 17, 2023

Understanding Viral Clearance During Anion-Exchange Chromatography: A Novel Design of Experiments Approach

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Anion-exchange (AEX) chromatography is a well-established polishing step for removal of viruses and other impurities during downstream processing of biotherapeutics. Before initiating phase 1 clinical trials, a representative scaled-down model of the final process must be available for use in viral-clearance studies. At that point, however, scientists usually have no way of knowing how effective a process will be for removing viruses. In this article, scientists from Thermo Fisher Scientific and Bristol Myers Squibb (BMS) describe their efforts to define…

May 2, 2023

Purification of Hepatitis B Virus Surface Antigen for Vaccine Products: Impact of Ligand Density on HBsAg Purification By Immunoaffinity Chromatography

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According to the World Health Organization (WHO), more than 350 million people worldwide are chronic carriers of hepatitis B virus (HBV) (1). Around 25% of carriers develop liver cirrhosis and/or carcinoma, making HBV responsible for the deaths of one million people annually (1). The virus has a spherical shape with a lipoprotein coating mostly of HBV surface antigen (HBsAg) (2). Knowing that, drug developers have created recombinant HBV vaccines based on HBsAg synthesized in yeast or mammalian cells (3, 4).…

March 21, 2023

Production and Purification of Newcastle Disease Virus: A High-Yield Platform Process Based on a Novel Avian Cell Line and Monolith Chromatography

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Newcastle disease is an extremely infectious condition among domesticated poultry and other avian species. Its high morbidity and mortality rates among infected birds give the disease significant economic importance. Thus, many commercially available vaccines based on live or inactivated virions are used globally to protect against Newcastle disease infection. The causative agent is Newcastle disease virus (NDV), which belongs to the Paramyxoviridae family. NDV is a single-stranded, negative-sense, enveloped RNA virus of avian origin that is highly attenuated in humans…

February 9, 2023

Triton X-100 Elimination: The Road Ahead for Viral Inactivation

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The nonionic surfactant Triton X-100 (C14H22O(C2H4O)n) is a key chemical used in ensuring the viral safety of biological medicinal products. Two pharmaceutical sectors share an extensive historical background with it: biopharmaceuticals and plasma-derived products, for which it is used to inactivate lipid-enveloped viruses. Recently, environmental regulations in the European Union have encouraged or mandated a phase-out of this surfactant (1). The goal of the ruling is to protect aquatic ecosystems from potential Triton X-100 degradation products that can function as…

December 12, 2022

Hollow-Fiber Nanofiltration for Robust Viral Clearance of Non-MAb Biologics

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Monoclonal antibody (MAb) and other therapeutic biologics produced by mammalian cells have the potential to introduce endogenous retroviruses and can be infected with adventitious viruses through raw materials or other parts of the biomanufacturing process (1–3). Based on regulatory guidelines, products derived from mammalian cells must contain less than one virus particle per million doses, which requires purification processes to demonstrate virus removal capabilities of about 12–18 log10 clearance of endogenous retroviruses and 6 log10 clearance for adventitious viruses (4).…

December 12, 2022

Opportunities in the Field of Host Cell Proteins Part 3: Case Studies in Impurity Detection and Identification

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Rigorous physicochemical and bioanalytical methods must be performed on biological products to ensure that they contain minimal levels of host cell proteins (HCPs) and other process-related impurities. In the first and second parts of our article, we surveyed literature about HCPs of concern, the mechanisms behind their immunogenicity, and ultimately, their consequences for patient safety. Herein, we highlight published case studies to explore difficulties with detecting, identifying, and quantifying such impurities. These examples demonstrate that much remains to be learned…

December 6, 2022

Tangential-Flow Filtration Process Control and Data Acquisition System for Process Development

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PendoTECH tangential-flow filtration (TFF) process control systems have been widely adopted in the filtration community. The system’s features enable its implementation in multiple unit operations and biopharmaceutical processing applications, including ultrafiltration–diafiltration (UF–DF) of proteins, viruses, and compounds such as oligonucleotides and antibody–drug conjugates (ADCs). The control system can be used to develop process parameters for UF–DF processes that have different membrane formats (e.g., flat-sheet cassette and hollow fiber). TFF laboratory setups often are manual or semiautomated processes that use pumps,…

December 6, 2022

Using 3D Imaging To Understand Sterilizing-Grade Filtration of Liposomes

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Sterilizing-grade filtration is an essential operation for biomanufacturing. It ensures that drug substances are free from microorganisms at the end of a downstream process. The COVID-19 pandemic has highlighted the need for high-quality therapies to be manufactured efficiently at scale, with particular focus on the need for multiple vaccines to be developed, produced, and distributed globally (1). Some vaccines have used lipid nanoparticle encapsulation technology, which also has potential for use in gene therapy development in the near future. Lipid…

October 20, 2022

Optimizing and Intensifying ADC Aggregate Removal: A DoE Approach to Membrane Chromatography and Rapid Cycling

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Antibody–drug conjugates (ADCs) represent a growing therapeutic segment of the oncology field. Five such treatments received market approval from the US Food and Drug Administration (FDA) between 2008 and 2018, whereas three were approved in 2019 and two each were approved in 2020 and 2021 (1). This disruptive technology combines highly potent small-molecule payloads with monoclonal antibodies (MAbs) to improve their specificity as cancer treatment. The antibodies deliver those toxic compounds directly to cancer cells but not to healthy cells,…

October 20, 2022