Upstream Processing

eBook: The Commercial Expression Systems Market — What Has Changed in the Past Decade

A decade ago, BioPlan Associates prepared the findings of its 2008 directory of expression system technologies that were being promoted or considered likely to be suitable for commercial licensing for biopharmaceutical manufacturing (1). Due in part to the relatively slow advances in this critical area of bioprocessing, this study remains perhaps the only directory of biopharmaceutical-relevant expression systems available for licensing. Here I discuss aspects of related bioprocessing technologies that have and have not changed in the past decade. Expression…

Data Science, Modeling, and Advanced PAT Tools Enable Continuous Culture

Bioprocesses traditionally use (fed-)batch cell culture processes for production of recombinant proteins and therapeutics. In batch bioprocessing, material flow is discrete, with a hold step between two unit operations, and product is harvested only once for each unit operation. Batch processes have been studied extensively and optimized through numerous advancements in experimental design (1, 2), monitoring (3–5), measurement techniques (6–9), and control strategies (10–12). However, such processes require large facility footprints for equipment (13) as well as sterilization, load, and…

Cell Expansion with Dissolvable Microcarriers

In recent years we have seen an exponential increase in the number of companies testing and validating new regenerative medicine products. Many of these products are reaching late-phase trials with the potential to receive final approval and marketing authorization from regulatory agencies such as the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA). In the past several years, we have seen successful launches of regenerative medicine products, including Holoclar (Holostem Advanced Therapies), Kymriah (tisagenlecleucel, Novartis), Yescarta…

Enhanced Galactosylation of Monoclonal Antibodies: Using Medium Supplements and Precursors of UDP-Galactose, Part 2

In Part 1 of this report, we described our development of a high-throughput assay for analyzing monoclonal antibody (MAb) glycans and how we used it to evaluate the effects of medium supplements on galactosylation of MAbs produced by two different cell lines (1). This month, we examine galactosylation of a MAb produced by a third cell line. A discussion follows on the benefits of this high-throughput assay before we highlight the similarities and differences in galactosylation among the three MAbs…

Reducing Variability in Cell-Specific Productivity in Perfusion Culture: A Case Study

Variation in bioproduction is recognized in the industry and often attributed to one or more of four sources: raw materials (including consumables), operational inputs (measurements, methods, personnel, equipment), environmental factors, and biological variation inherent to living cells (1). Variability can occur even among replicate units regardless of production mode (e.g., fed-batch or perfusion), and it can manifest as variability in productivity, cell metabolism, and/or product quality (2–4). In commercial biomanufacturing, meeting all product quality attributes is a requirement for regulatory…

Enhanced Galactosylation of Monoclonal Antibodies: Using Medium Supplements and Precursors of UDP-Galactose, Part 1

The biopharmaceutical industry needs better understanding of how monoclonal antibody (MAb) glycosylation is influenced by components in cultivation media — and it needs methods to exert some control over the structure of MAb glycans. That structure can affect MAb function. Thus, a high-throughput (HTP) assay is needed for characterizing MAb glycosylation so that developers can observe the effects of cultivation conditions on MAb glycosylation rapidly, with a goal of producing MAbs that have a desired glycan structure. The method also…

eBook: Addressing Quality in Cell-Line Development — Direct Analysis of Bioreactor Harvest for Clone Selection and Process Optimization

Using Direct Analysis of Bioreactor Harvest for Clone Selection and Process Optimization Therapeutic monoclonal antibodies (MAbs) mostly are manufactured using bioengineered mammalian cells cultured in a bioreactor for two to three weeks. High temperatures and an altered redox environment may compromise the quality of MAbs produced (e.g., fragmentation, truncation), as can the presence of proteases, reductases, and other chemicals released from dead cells. Thus, it would be valuable to establish analytical methods that can help cell culture groups monitor immunoglobulin…

An Approach to Generating Better Biosimilars: Considerations in Controlling Glycosylation Variability in Protein Therapeutics

The global market for biotherapeutics has expanded extensively over the past decade and is projected to account for more than a quarter of the pharmaceutical market by 2020, with sales exceeding US$290 billion (1). Continued expansion of the biosimilar marketplace has led to many commercial opportunities and technical challenges. The biological systems used to manufacture such drug products are inherently variable — a feature that has important consequences for the reproducibility, safety, and efficacy of the resulting products. Therefore, a…

eBook: Of Microbrews and Medicines — Understanding Their Similarities and Differences in Bioprocessing Can Help Improve Yields and Quality While Reducing Cost

Meeting a biopharmaceutical scientist or engineer who proclaims a love for brewing is not surprising. Perhaps it’s because of the challenge of mixing raw ingredients together and waiting patiently for the final product, maybe it’s the hands-on nature of the equipment or the data analytics entertainment, or it just might be the simple joy of creating something. Whatever attracts a scientist or engineer to making medicines and/or craft brews, a surprising number of principles hold true for both bioprocesses despite…

Simplify Upstream Process Development and Scale-Up: Single-Use 5:1 Turndown-Ratio Bioreactor Technology

Single-use technologies (SUTs) have been adopted widely in the biopharmaceutical industry for product development as well as clinical- and commercial-scale manufacturing. Over the years, suppliers of such equipment have addressed concerns about waste management, extractables and leachables, and reliability of supply — and as a result, end users have gained confidence in SUTs. Recognizing potential benefits that can be realized for both clinical and commercial operations, biomanufacturers increasingly are implementing SU solutions at larger scales in both upstream production and…