February 2009

Medium and Process Optimization for High Yield, High Density Suspension Cultures: From Low Throughput Spinner Flasks to High Throughput Millilitre Reactors

    The most important contributions to high-yield manufacturing processes for the production of recombinant proteins from cultivated mammalian cells have come from the identification of highly enriched and well-balanced media formulations, and fine tuning the process conditions that support high cell culture densities with high specific productivity. The industry standard yield for immunoglobulins or similar molecules derived from suspension-cultivated mammalian cells in bioreactors has risen during the past 20 years from the tens of mg/L to g/L. The more…

Supplier Innovation is an Imperative

    As organizations begin their annual budgeting meetings, the question will inevitably arise: How can we reduce costs and still retain or improve our quality? For some, the answer to the first part may seem easy, but to have a packaged improvement plan that includes both aspects appears to be more indefinable. So what can the biopharm industry do to counter these daily pressures? The answer may not be as elusive as you think. Companies need to drive innovation…

Rapid Purification of Lys-C from Cultures

Endoproteases specific for cleavage of peptidyl bonds on the C-terminal side of lysine residues (e.g., Lys-C) are produced from a number of bacterial species, including Achromobacter lyticus (1), Pseudomonas aeruginosa (2), and Lysobacter enzymogenes (3). The Achromobacter protease 1 (API) protein has been substantially characterized (4,5,6) and shown to be a resilient enzyme that can specifically cleave after lysine residues under a wide range of buffer conditions, including high concentrations of denaturing agents such as urea and sodium dodecyl sulphate…

Disposable Factory or Tailor Made Integration of Single-Use Systems?

    The use of disposables in biopharmaceutical manufacturing has increased significantly during the last few years and is expected to grow substantially in the near future. Bioplan Associates report in their 2007 “Report and Survey of Biopharmaceutical Manufacturing Capacity and Production” that the main drivers for this ongoing trend continue to be the elimination of cleaning followed by the reduction of capital investment in facilities and the required equipment. However, with the further penetration of disposables into larger volumes…

Disposable Bioreactors in Cell Culture-Based Upstream Processing

    During the last 10 years, cost pressures and the changing requirements for bioreactors in the modern pharmaceutical industry have resulted in the increased use of disposable bioreactors in both R&D and manufacturing. Numerous studies have demonstrated their efficiency in cell culture-based upstream processing at small- and middle-volume scales. As shown in Figure 1, disposable bioreactors with culture volumes between 10 mL and 2 m3 are most widely used for cell proliferation, screening experiments, the production of therapeutic agents…

Quality by Design: Current Regulatory Status and Future Challenges

    Drug manufacturers face the very real challenge of being both innovative and efficient — having to get products to market quickly — whilst at the same time facing existing hurdles that can limit both of these goals. To manufacture products innovatively and quickly, while at the same time reducing costs and ensuring quality, drug manufacturers must find ways to build quality into their processes. Doing so will aid in product approvals, cut down on poor design issues and…

Purifying a Recalcitrant Therapeutic Recombinant Protein with a Mixed-Mode Chromatography Sorbent

Mixed-mode chromatography sorbents can save time and money by reducing the number of steps required to purify recombinant proteins. They also have the potential to purify proteins that single-mode sorbents cannot. As the term mixed mode suggests, these sorbents contain ligands that offer multiple modes of interaction. Although mixed-mode sorbents are used extensively in solid-phase extraction for high-pressure liquid chromatography (HPLC) sample preparation — and to a more limited extent in analytical HPLC — these resins are generally unsuitable for…

Extractables and Leachables from Single-Use Disposables

Evaluating single-use systems for extractables and leachables is new territory for many end-users. This paper presents a risk-based approach for evaluating extractables and leachables from single-use systems. Approaches are described that have been accepted by various regulatory agencies utilizing risk assessments and sound scientific principles. Biopharmaceutical processing materials must be evaluated to determine whether they impact the final drug product with regard to safety and efficacy. For single-use and reusable systems, this usually leads to evaluations that demonstrate compatibility with…

Non-Invasive Sensors as Enablers of “Smart” Disposables

    Disposable bioprocessing has come of age. Economic and regulatory conditions are driving the widespread adoption of disposable equipment at all stages of bioprocessing. This review considers the entire bioprocess chain and assesses the status of disposables. In particular, we focus on the current availability and need for additional sensors that will enable the disposable process to be integrated — in compliance — with the latest Process Analytical Technologies. Traditional bioprocessing is highly compartmentalized into upstream and downstream operations.…

The Maturation of the Biomanufacturing Industry

    In my opening editorial, I referred to an industry in transition. This is being driven by challenges that are by no means unique to biotech: all other industry sectors are experiencing similar pressures. We are seeing the impact in terms of factory design, manufacturing technologies, validation and business processes; these are all themes that have been addressed in this supplement. The big innovation in terms of manufacturing systems has been the wholesale acceptance of disposable manufacturing technologies during…