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Iyer, Paddy; Ostrove, Jeffrey M.; Vacante, Dominick A.

doi:10.1023/a:1008040221630

Cited by 51 publications

(6 citation statements)

References 5 publications

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“…A common approach to maintaining cell-specific productivity at increased cell density consists of infecting the cells in fresh medium (via medium exchange) instead of simply adding the virus inoculum to the medium used for cell growth. This mode of operation, which requires a cell separation step, has been frequently reported in the literature for viral vector production [164][165][166]. In the same experimental system as Fig.…”

Section: Improving Volumetric Productivity Beyond the Batch Processmentioning

confidence: 74%

Production and Formulation of Adenovirus Vectors

Altaras

Auniņš

Evans

et al. 2005

Gene Therapy and Gene Delivery Systems

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uct characterization and release, production and purification processes that are scaleable and economical, and formulations enabling sufficient stability to guarantee an acceptable shelf-life. In this review, we highlight the many advances in these areas, and identify requirements for further research. In order to capture a comprehensive and current picture, we emphasize both the published and patent literature.We begin by discussing the common methods used for analysis of both purified and unpurified adenovirus (AdV) samples. These methods are critical to both process development and the release of GMP (good manufacturing practices) supplies to be used in clinical studies, and are referred to throughout the remainder of the review. Next, we discuss the options and rationale for vector design, and we describe the common complementing cell lines. Cultivation of AdV vectors including media selection, modes of operation (suspension vs. adherent, batch vs. fed-batch, and so on), and critical optimization and control parameters are then discussed, with an emphasis on current industrial practice. Adenovirus purification methodologies are addressed similarly, with a focus on the rational selection of unit operations for a scaleable process. Current industrial practices are compared, and critical issues such as the clearance of empty capsids and host cell DNA are reviewed in detail. Next, the development of remarkably stable liquid formulations is discussed, with an emphasis on excipient selection based on the mechanisms of inactivation. Finally, we briefly recap critical developments and highlight areas in need of additional research to support the next generation of adenovirus-based gene transfer products. 2Analytical methods for process and product characterization 2.1

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Section: Improving Volumetric Productivity Beyond the Batch Processmentioning

confidence: 74%

Production and Formulation of Adenovirus Vectors

Altaras

Auniņš

Evans

et al. 2005

Gene Therapy and Gene Delivery Systems

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“…Different production methods for viral particle (vp) have been described in the literature, 19–23 including the growth of producer cells in suspension using serum-free medium. However, the production of oncolytic Ads under serum-free conditions causes a significant reduction in virus yield.…”

Section: Adenovirusesmentioning

confidence: 99%

Moving oncolytic viruses into the clinic: clinical-grade production, purification, and characterization of diverse oncolytic viruses

Ungerechts

Bossow

Leuchs

et al. 2016

Molecular Therapy - Methods & Clinical Development

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Oncolytic viruses (OVs) are unique anticancer agents based on their pleotropic modes of action, which include, besides viral tumor cell lysis, activation of antitumor immunity. A panel of diverse viruses, often genetically engineered, has advanced to clinical investigation, including phase 3 studies. This diversity of virotherapeutics not only offers interesting opportunities for the implementation of different therapeutic regimens but also poses challenges for clinical translation. Thus, manufacturing processes and regulatory approval paths need to be established for each OV individually. This review provides an overview of clinical-grade manufacturing procedures for OVs using six virus families as examples, and key challenges are discussed individually. For example, different virus features with respect to particle size, presence/absence of an envelope, and host species imply specific requirements for measures to ensure sterility, for handling, and for determination of appropriate animal models for toxicity testing, respectively. On the other hand, optimization of serum-free culture conditions, increasing virus yields, development of scalable purification strategies, and formulations guaranteeing long-term stability are challenges common to several if not all OVs. In light of the recent marketing approval of the first OV in the Western world, strategies for further upscaling OV manufacturing and optimizing product characterization will receive increasing attention.

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“…While mammalian viruses grow to high titers in tissue culture, typical yields obtained are only a few milligrams per 1 L cell culture. 31 Therefore, expression of plant viruses gives raise to yields that are 10–100 times higher. The approach is scalable; for example, Medicago Inc. already produces a product line of virus-like particles in plants.…”

Section: Introductionmentioning

confidence: 99%