Upstream Development

Developing an Integrated Continuous Bioprocessing Platform

    Continuous upstream processing (perfusion) is not a new concept in the bioprocessing industry. Genzyme, Bayer, Centocor, and other companies have been implementing perfusion processes for many years. However, interest is now growing for extending this concept to downstream operations to create fully integrated continuous processing. During the past year, Genzyme has presented on and published about its advancement toward the development of an integrated continuous system (1). The company has completed proof-of-principle development at laboratory scale with different…

Managing Cost Without Sacrificing Quality

    Over the past decade, significant pressures have threatened the future of many pharmaceutical and biopharmaceutical companies. Increasing drug development costs, declining research and development (R&D) productivity, mounting regulatory setbacks, and looming patent expirations — with fewer blockbuster therapies on the horizon — are collectively challenging many businesses to stay profitable and competitive within the industry. Many companies are intensifying their focus on reducing operating costs, particularly within manufacturing operations. This trend is almost an omnipresent feature of management…

Attaining Next-Level Titers in CHO Fed-Batch Cultures

    Taking full advantage of high cell-specific productivity of recombinant proteins requires use of robust fed-batch processes involving addition of one or more concentrated nutrient solutions. Proportionately large amounts of concentrated nutrient supplements are often needed to support the stoichiometrically balanced metabolic requirements of high-density cell cultures. Large feed additions ultimately dilute the final product at harvest, but attempts to minimize feed volumes often lead to multiple concentrated acidic and basic subgroups. Those impart additional complexity to manufacturing processes.…

A New Kinetic Structured Model for Cell Cultivation in a Chemostat

    Mathematically modeling the kinetics of batch and continuous cultivation allows you to not only calculate and evaluate the effects of process parameters, but also to forecast those parameters and duration of cultivation to develop a cost-effective production process. Mathematical modeling microorganism cultivation was intensively developed in the second half of the last century. Equations 1–6: ()   Monod proposed Equation 1 for batch processes in 1942 (1). In that equation, µ and µmax are the specific and maximum…

Enhancing Data Quality with a Partly Controllable System at Shake Flask Scale

    In bioprocess development, small-scale systems are used to identify appropriate cell lines, media, and feeds before applying more expensive, controlled cultivation systems at larger scales. Process development relies on data generated in such uncontrolled small-scale cultivation systems, so comparability is an issue. Shake flasks are commonly used for small-scale culture of mammalian suspensions. Incubators provide a suitable environment with carbon dioxide (CO2) supply and humidity control and ensure sufficient oxygen transfer and homogenization of cell suspension by appropriate…

QbD for Biologics: Learning from the Product Development and Realization (A-MAb) Case Study and the FDA OBP Pilot Program

    Cosponsored by CASSS (an international separation society) and the FDA, the 23rd CMC Strategy Forum was held in Bethesda, MD, on 19–20 July 2010. For the third time, this forum explored the topic of quality by design (QbD) for biologics. The first such forum was held in July 2007 and focused on establishing a general understanding of QbD terminology and concepts. In July 2008, the second discussed approaches for submission of QbD data and associated regulatory implications. Building…

Bioreactor Design and Bioprocess Controls for Industrialized Cell Processing

It’s official: The “Age of Cell Therapy” has arrived. A robust pipeline of cell therapies, with increasing numbers of both early- and late-stage clinical trials as well as FDA-approved commercial products that have entered the market already, strongly indicates that the cell therapy industry is poised to emerge as a distinct healthcare sector (1). Renewed investor interest and recent activity among major pharmaceutical companies suggest that this industry will rapidly develop the capability and capacity to be a highly competitive,…

A Decade of Bioreactor and Upstream Technologies

A high-quality product begins with efficient upstream process equipment. Ten years ago, manufacturers were still warming up to single-use bioreactors, which were mainly rocking-bag–based solutions. The benefits relating to cleaning and validation were clear, but their use as bioreactor vessels was still new, and stainless steel systems up to 20,000 L in scale were still needed. Today’s facilities are a hybrid of sophisticated single-use components and stainless steel equipment, the mechanisms of both having undergone improvement during the past decade.…

A Decade of Microbial Fermentation

Microorganisms play a vital role in modern life — with applications ranging from wine fermentation to biofuel production to solutions for complex mathematical problems (1). During the past decade, microbial fermentation for protein production reached a higher level of sophistication and wider adoption. When BPI was first published in 2003, the physical and biological characteristics of many microbial cells and the attributes of their fermentation processes were well known. Nonetheless, the economic environment at that time created immense pressure on…

A Decade of Process Development

    Our “manufacturing ” theme could be considered a sort of catch-all, encompassing much of what BioProcess International covers. You could argue that “the whole development process” is all about manufacturing biotherapeutics. But we instead consider this “pillar” of bioprocessing to include everything that isn’t strictly “upstream” (production) or “downstream” (processing) of biomolecules. Facility and supply-chain isssues come into play here, as do formulation and fill–finish (and of course, outsourcing). We discuss quality systems and their associated analytics in…