During biopharmaceutical manufacturing, final drug products can get contaminated with host-cell proteins (HCPs) derived from a production cell line. HCPs can elicit adverse immune responses, so regulatory authorities require accurate monitoring of their presence and concentration in final drug products. Because they are robust and offer good throughput, enzyme-linked immunosorbent assays (ELISAs) are the first choice for HCP detection to monitor product quality. Generic ELISA kits are commercially available for HCP detection with a number of commonly used…
Upstream Processing
A Novel Dry-Format Supplement for CHO Cells
The biotechnology industry is continually looking for new methods of improving titer of biotherapeutic proteins. Numerous reports show that nutrient supplementation improves productivity several-fold (1,2). Maintaining cells in a viable and productive condition is the ultimate goal and generally involves adding small volumes of concentrated nutrients to cell cultures. Important parameters for designing a nutrient supplement include ease of use, operator and site safety, and product storage footprint at a manufacturing facility. Traditionally, these supplements come as concentrated…
Think Strategically for Design of Experiments Success
Global competition fueled by the power of information technology has forced the pharmaceutical and biotechnology industries to seek new ways to compete. The US Food and Drug Administration (FDA) has promoted quality by design (QbD) as an effective approach to speed up product and process development and create manufacturing processes that produce high-quality products that are safe and effective (1,2,3). Statistical design of experiments (DoE) is a tool that is central to QbD and the development of product and process…
Development of an In-House, Process-Specific ELISA for Detecting HCP in a Therapeutic Antibody, Part 1
After production and purification of biopharmaceuticals generated by cell culture expression systems, endogenous cell line proteins — commonly referred to as host-cell proteins (HCPs) — sometimes contaminate finished products. HCPs can elicit an immune response following administration of those drugs to patients (1), and cause potentially deleterious side effects. It is therefore imperative to minimize HCP contamination in finished biologics. Regulatory health authorities require monitoring of HCP contamination. They expect validation of each purification process to demonstrate its…
Extractables and Leachables
The 13th WCBP CMC Strategy Forum on extractables and leachables was held in Bethesda, MD, in January 2008. The purpose of this forum, cosponsored by CASSS (an international separations society) and the FDA, was to discuss questions related to extractables and leachables in the context of biopharmaceutical manufacturing and find consensus on some of those topics. Morning sessions began with “Extractables and Leachables: Challenges and Strategies in Biopharmaceutical Development†with program cochairs Stacey Ma of Genentech, Inc., Ingrid…
Modeling Perfusion Processes in Biopharmaceutical Production
Biopharmaceutical manufacturing is mostly batch-based for a number of reasons: lower perceived contamination risks, batch-to-batch segregation, and historical legacy. Despite those reasons, perfusion is used by a number of biomanufacturers because it produces large product quantities using smaller bioreactors than would be possible with batch-based production.
Though perfusion-based production presents challenges that confound traditional models, it can create an environment in which many more factors can be influenced to directly optimize production. Read this case study to learn more about how perfusion can be used to create flexible, “just-in-time†facilities that respond to manufacturing conditions.
A Biomass Monitor for Disposable Bioreactors
Of the available on-line biomass assay types, radio-frequency impedance spectroscopy (RFI, often referred to as capacitance) is generally regarded as the most robust and reliable method for monitoring viable biomass during fermentation and cell culture. The first article to show that capacitance could be used to estimate microbial biomass dates back over 20 years (1). Today the technology is routinely used for monitoring and controlling mammalian cell culture processes and high-density yeast and bacterial fermentations in research, process…
The Dinosaurs Reborn: Evaluating Stainless Steel and Disposables in Large-Scale Biomanufacturing
Although a number of biomanufacturers have adopted disposable technologies for small-scale process design, there has been considerable debate over the role of single-use systems in large-scale biopharmaceutical manufacturing— particularly in retrofitting facilities. Some experts have gone so far as to suggest that large-scale stainless steel fermentors are “dinosaurs,†with their large capacities, long installation lead times, and low flexibility. I advocate a systematic approach to look holistically at possible retrofit technologies in existing (stainless steel) facilities, with particular…
Single-Use Systems As Principal Components in Bioproduction
Single-use systems (SUS) have become an accepted component of animal-cell–based bioproduction. No longer a merely exciting possibility, they have emerged as a significant and growing resource for companies to use from process development to manufacturing of approved products. Having been examined for years in less regulated environments, off-the-shelf SUS are now in regular use to some extent in nearly every segment of the production train by contract manufacturing organizations (CMOs) and biopharmaceutical companies in mid-scale production applications. For…
Linear Scale-Up of Cell Cultures
Reusable bioreactors have been the benchmark standard for many decades, during which a large knowledge base on process control and scale-up has been developed. However, single-use bioreactors are increasingly being implemented in modern bioindustrial upstream processes. Many of these bioreactors deviate from the traditional stirred-tank design, but a number of companies have expressed a strong need for single-use bioreactors based on the strirred-tank design. A traditional stirred-tank design would enable users to optimize their scale-up processes based on…