Upstream Processing

Accounting for the Donnan Effect in Diafiltration Optimization for High-Concentration UFDF Applications

The biopharmaceutical industry is targeting high-concentration protein formulations to enable subcutaneous administrations. Such administration can provide better patient convenience than intravenous administration. One challenge associated with high-concentration formulations is increased electrostatic interaction between proteins and excipients. That is a result of increased protein-charge density at high protein concentrations. Such interactions can create an offset between excipient levels in final products and diafiltration buffers in ultrafiltration processes. The effect of such electrostatic interactions in a membrane process is known as the…

Design of Experiments for Fed-Batch Process Development in Shaken Cultures

When designing a recombinant protein production process, a high number of parallel cultivations must be carried out. That task is typically performed using batch cultures in shake flasks or microwell plates, in which fermentation conditions are not monitored. To overcome that limitation, we combined the SensorDish Reader and Shake Flask Reader systems (from PreSens) with an enzymatic glucose delivery system (EnBase technology from BioSilta Oy) for Escherichia coli cultivations. Our objective was to determine whether SensorDish reader cultures would yield…

Cost-Effectiveness and Robustness Evaluation for Biomanufacturing

As the biotech sector has matured, it has come under increasing economic and regulatory pressures for continuous improvement in both drug development and manufacturing. As a result, assessing the value potential of alternative strategies has become critical to decision-making in areas such as bioprocess and facility design, capacity sourcing, and portfolio selection. Related decisions typically involve large cash expenditures and thus have a direct bearing on the feasibility of business units and whole companies. Figure 1:  () Making such decisions…

A Global Joint Venture Strategy for Biosimilars Development

In April 2013, biopharmaceutical company Pfenex (San Diego, CA) announced a joint venture with biologics manufacturer Stelis Biopharma, Inc. (“Stelis”), earlier known as Agila Biotech, (a wholly owned subsidiary of Strides Arcolab Limited (Bangalore, India) for the commercial development of six biosimilars. The companies will also leverage technology and global development expertise from GE Healthcare Life Sciences (Uppsala, Sweden) and Bio-XCell Malaysia (Nusajaya, Malaysia). Such international, multicompany collaboration strategies have become a growing trend in the highly competitive biosimilars industry.…

Enabling Technologies

    We hear a great deal lately about the maturation of the biopharmaceutical industry — and much advancement over the past decade or so has been in business models, financing, and product pipelines. Meanwhile, regulators around the world have become more well versed in the subject matter and have adjusted their approaches to and expectations from the industry. However, the practical side of developing, characterizing, and manufacturing biotherapeutic products cannot be overlooked — nor its importance overstated. Many technological…

Quality Risk Assessment and Management Strategies for Biopharmaceutical Companies

You’ve probably been hearing a lot about risk assessment in recent months. Indeed, some 15 times more articles have been printed referencing the concept over the past year relative to a 12-month period just three years ago. That truly represents a geometric progression. Unfortunately, very few authors have been able to disambiguate the different methods or provide insight into this time-tested, multiple-industry philosophy that at its core uses good science to make better decisions. When we undertake the challenge to…

Applying Disruptive Technologies in Mammalian Cell Line Development

Recombinant monoclonal antibodies (MAbs) maintain their ranking as the best-selling class of biologic drugs. The introduction of high titer bioprocessing for the majority of these MAb products has focused efforts towards maintaining desired quality attributes and reducing time to market. Furthermore, patents covering several blockbuster MAbs and the expression technologies, which facilitate their high-level expression, are due to expire over the next decade. A wave of second generation or “follow-on” biopharmaceuticals/bioprocesses will therefore be vying for market share and regulatory approval. Consequently, should biopharmaceutical manufacturing companies rely on traditional “platform” methods of cell line development (CLD), which are well known but yield extensive variation and unpredictable stability of expression, or invest in emerging technologies, which offer the potential of greater reproducibility and speed? Enabling technologies in this area include host cell engineering, engineered expression vectors, and rapid transient gene expression. Given the well-known mantra “the product is the process”, implementation of these disruptive technologies will require a thorough understanding of how changes at the CLD-phase affect key production process characteristics such as high cell-specific productivity, correct product processing and rapid cell proliferation. Traditionally, CLD optimisation is carried out using a lengthy trial-and-error approach where cells are treated as a “black box” and characteristics are iteratively improved. Further advancement in CLD is therefore likely to benefit from the tools of systems biology. These tools will ensure that future CLD manipulations will be informed by an understanding of the genetic, regulatory, and metabolic networks that determine key process characteristics during a production process.

Regulation of cell apoptosis by insulin and IGF-I

An increase in the number of cells growing in cell culture is the result of two opposing effects: an increase in the number of cells that traverse the cell cycle and divide into two daughter cells (mitosis), or a decrease in the number of cells that die according to different modalities, the most prominent one being apoptosis (1), or both. Insulin and IGF-I are both capable of facilitating cell progression through the cell cycle, and of inhibiting apoptotic mechanisms. In…

Process Improvements Increase Production Capacity of a Legacy Product

Implementation of postlicensure process improvements in the biopharmaceutical industry can benefit patients and drug manufacturers alike. Here we demonstrate through a case study how a change to the cell culture medium and process can be taken from proof of concept through scale-up to demonstration of feasibility. We further illustrate the scope and complexity of implementing a change in commercial manufacturing to realize significant benefits such as increased production capacity over an existing legacy process. The Importance of Postapproval Improvements Drug…

Impact of Process Interruption on Virus Retention of Small-Virus Filters

Manufacturers of biopharmaceuticals using mammalian cell culture must have processes in place to minimize the likelihood of virus contamination of their products. Regulatory agencies provide guidelines for testing strategies and best practices to assure raw-material safety and control of the manufacturing process. Safety assurance relies on an interdependent matrix of managed risks, including characterization and control of raw materials, extensive testing of process intermediates, and demonstration of the virus removal capabilities of purification unit operations Figure 1:  () A dedicated…