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European Biopharmaceutical Review

Biologics Process Analysis

Over the past 15-20 years, the production of biological drugs – in particular, therapeutic antibodies – has rapidly increased. Host cell proteins (HCPs) represent a major group of process-related impurities of biological drugs produced using cell culture technologies. Even at nanogram per milligram concentrations of HCP to drug substance (DS), HCPs can elicit undesired immune response and interfere with drug efficacy. Additionally, some host cell impurities, such as proteases, have been shown to reduce the stability and efficacy of the drug substance. Given the potential adverse reactions and reduction of product activity, HCPs must be adequately removed in downstream purification processes. Sponsors are responsible to use broadly reactive HCP ELISA to track the removal of HCPs during the purification processes to ensure process consistency and final DS purity.

Biopharmaceutical manufacturers routinely use ELISA for the quantification of HCPs during downstream purification. Two types of HCP ELISA, ‘process-specific’ and ‘generic’, are commonly used in scientific publications and regulatory guidelines. The terminology distinction is based on theoretical concerns that generic assays could potentially fail to detect HCPs specific to a given culture and purification process. This concern has led to an arguable belief among many in the biopharma industry that a process-specific assay should always be developed. This belief is often contradicted by comprehensive qualification data across multiple drug products using well-developed generic assays that fulfil the analytical requirements for a final product release test. This article is intended to provide a clearer definition of the terminology and to propose how an assay, regardless of the terminology used to describe it, should be comprehensively qualified to show it is fit for purpose of HCP detection in samples throughout the purification process. When a generic assay can be comprehensively qualified across multiple cell lines and cell culture processes, companies will be able to save the cost and time of developing a redundant process-specific method.

Given the variables in antigen selection, methods employed in antibody generation and purification, and, finally, in assay development, one cannot guarantee that a process-specific antibody generated to a particular strain or growth process will be superior to antibodies generated to an essentially identical strain and process. Effective generation of antibodies to the relevant downstream HCPs must incorporate multiple elements beyond proper antigen selection. A truly process-specific assay cannot be assured by simply immunising animals with an arbitrary choice of upstream antigen. With proper methods in antigen selection, antigen preparation, and effective immunisation protocols, the generated antibodies will be reactive to those HCPs constituting more than 95% of the total mass of HCP in harvest material.

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Ken Hoffman, President at Cygnus Technologies, founded the company in 1996 to provide analytical solutions to the rapidly growing biopharma industry. Prior to starting Cygnus, he worked in the clinical diagnostics field for three different companies, developing automated systems and extensive menus of assays for infectious disease, metabolic disease, drugs, and hormones. Ken has his Master of Science in radiation biology/immunology from University of Iowa, US. In addition to his MS degree, he also holds a certificate in biomedical research management from The Harvard School of Public Health, US.

Eric Bishop, Vice President of R&D at Cygnus Technologies, has worked within the biotechnology industry for 18 years. His current responsibilities at the company include business development, technical support, developing new products, and developing new services, along with being the Head of Research and Development Laboratory. Prior to joining Cygnus, Eric worked for MedImmune and CropTech Development. He has multiple degrees, including a Master of Business Administration from Hood College in Fredrick, US; a Master of Science in biotechnology from The Johns Hopkins University in Baltimore, US; and a Bachelor of Science in biology, with a minor in chemistry, from Radford University, US.

Dr Alla Zilberman leads technical marketing efforts at Cygnus Technologies. Prior to her position with Cygnus Technologies, she spent a number of years at Semba Biosciences, working on continuous downstream bioprocessing, and at Novagen/EMD Biosciences, where she led the development and marketing of products used for protein expression, purification, and proteomics research. Alla earned her PhD in biochemistry at the First Medical Academy of Moscow, Russia, and her MBA degree at the University of Cincinnati, US.

Dr Jared Isaac earned his PhD in biomedical research from the University of Cincinnati, US, and his MBA from Western Michigan University, US. He has six years of industry experience in oncology, molecular diagnostics, medical devices, and biopharma markets. Trained in both genomics and proteomics, Jared is an expert in qualitative and quantitative mass spectrometry methods of cancer biomarkers. He is currently leading Cygnus Technologies’ mass spectrometry service for identification and quantification of biopharmaceutical process impurities. Jared seeks to partner Cygnus Technologies with biopharma companies to ensure biological drugs are safe and effective.
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Ken Hoffman
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Eric Bishop
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Dr Alla Zilberman
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Dr Jared Isaac
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