Upstream Processing

The recent growth in the vaccine market has led to renewed interest in using adherent human cell lines for vaccine production. Traditionally, small-scale adherent cell line production has been carried out in roller bottles or T-flasks. Over the past few years, however, a number of companies have found multi-tray disposable bioreactors an effective method for producing high-quality drug products using adherent cells. These disposable, expandable systems have also facilitated scale up from laboratory to clinical-scale.

Vaccines against strains originating from avian flu may achieve poor yields in egg-based systems. Consequently, both public and private interest in alternative systems is high.

Any endpoint considered appropriate to support approval, whether a surrogate or a clinical endpoint, must be supported by substantial evidence of effectiveness.

Like the egg-based vaccine production process, producing a vaccine under cGMP conditions using mammalian cells can be a lengthy process, taking a minimum of six to 12 months.

Adjuvant-caused vaccine reactions are one of the most important barriers to better acceptance of routine prophylactic vaccination.

Understanding the end-to-end management of chemistry, manufacturing, and controls (CMC) resources provides the opportunity to enhance long-term planning, leverage development options, manage resource trade offs, and track progress against plans. The goal is to improve the pharmaceutical development process to deliver the pipeline. This article provides an overview of the organizational structure of Process Research and Development (PR&D) and the CMC teams at Genentech; the alignment of resources based on CMC contracts, process development activity maps and project resource plans; and the business economic analysis for evaluating development options.

The AutovaxID is a self-contained, completely enclosed, fully automated hollow fiber bioreactor that permits rapid, efficient scale up of patient-derived cells. It is based on hollow fiber bioreactor technology and is an ideal system for high-density cell culture and the production of monoclonal antibodies or other therapeutic proteins.

Process development and manufacturing for biopharmaceuticals are often disjointed activities. Disconnects among groups are aggravated by a lack of common terminology and poor data management practices. A UK biotech consortium has initiated a collaborative development effort to address data management issues. The proposed outcome is a data model, based on the ISA-88 Standard for Batch Control, to capture process and facility data throughout the product lifecycle. A data framework that follows the ISA-88 model can simplify process scale up and enable early views of project costs and facility fit.

The US Food and Drug Administration (FDA, Rockville, MD, www.fda.gov) has issued final recommendations for increasing the supply of safe and effective influenza vaccines for both seasonal and pandemic use.

One goal of process characterization is establishing representative performance parameter ranges that can be used to set validation acceptance criteria (VAC). Characterization studies yield varying numbers of data points from multiple experiments, and may also include data generated at different scales (e.g., bench, pilot, and commercial), which add complexity to the analysis. Many statistical approaches can be used to set ranges from large data sets. As an example, we present the statistical considerations and techniques for setting validation acceptance ranges for a chromatography step used in purifying a recombinant protein. Performance parameter data from a combined data set consisting of 67 bench, six pilot, and three full-scale runs were analyzed using the statistical analysis software JMP (SAS Institute). The combined data set was used to compute tolerance intervals, so that sources such as scale and column feed material could be properly modeled. The resulting ranges were used to establish..

Viragen, Inc. (Plantation, FL, www.viragen.com), and its collaborative partners in the field of avian transgenics-Roslin Institute (Scotland, UK, www.roslin.ac.uk) and (Oxford, UK, www.oxfordbiomedica.co.uk)-have announced a significant breakthrough in the development of the OVA system, an avian transgenic protein expression technology.

Growth of CHO cell cultures in a shaker plate model system was demonstrated to be comparable to growth in shake flasks.

Energy input is affected by rocking the chamber back and forth, generating a fluid movement in the cell culture and medium.

In addition to existing guidance, in January 2007 the FDA announced further proposals to prohibit the use of certain bovine materials as ingredients in some medical products or as elements of product manufacturing.

Protein expression remains an arduous task that involves a complex decision tree. Establishing tools and optimal conditions for each protein remains an empirical exercise.

Fortunately for all of us, not everyone's head is in the sand.

Major pharmaceutical and biotechnology companies have joined forces under the auspices of the Society for Biological Engineering (SBE, New York, NY, www.aiche.org/SBE) to make use of cell line research that is expected to increase the efficiencies of drug development.

The FDA's (Rockville, MD, www.fda.gov) first approval in the United States of a vaccine for humans against the H5N1 influenza virus marks an important step forward in protecting the public against a pandemic influenza outbreak.

Are the deadlines for your outsourced projects often not met? Are you unsure of the status of your project at any given time? Is the original budget of your study typically exceeded?

Process monitoring ensures that the process performs within the defined acceptable variability that served as the basis for the filed design space.

The Chinese vaccine market competition is now transferring from the former price-competition model to a technology- competition model.

Frequently asked questions on implementing and using single-use technologies

Patients receiving palliative care in hospices, hospitals, and other settings can benefit from a subcutaneous injection of morphine with Hylenex recombinant (hyaluronidase human injection).

Cell Therapeutics, Inc. (CTI, Seattle, WA, www.ctiseattle.com), has formed a new spin-off company, Aequus BioPharma, Inc., to develop a novel process to extend the half-life of proteins.

Manufacturing recombinant proteins at industrially relevant levels requires technologies that can engineer stable, high-expressing cell lines rapidly, reproducibly, and with relative ease. Commonly used methods incorporate transfection of mammalian cell lines with plasmid DNA containing the gene of interest. Identifying stable, high-expressing transfectants is normally laborious and time consuming. To improve this process, the ACE System has been developed based on pre-engineered artificial chromosomes with multiple recombination acceptor sites. This system allows targeted integration of single or multiple gene copies and eliminates the need for random integration into native host chromosomes. To illustrate the usefulness of the ACE System in generating stable, high-expressing cell lines, we present several case studies covering CHO cell lines expressing monoclonal antibodies.

The three largest players have accumulated, or are in the process of accumulating, nearly a million liters of capacity between them.

Biopharmaceutical processes typically require a significant investment in equipment-often a substantial obstacle for start-up companies. The risk of drug development failure is often high, further limiting access to the required capital. Flexibility and lower capital outlays are required not only by start-up companies, but also by research organizations with multiple product lines and by companies requiring quick capacity increases. Disposable technologies offer the highest potential for these companies to meet their business requirements. With lower capital requirements and increased flexibility, disposables are an important part of these companies' risk management strategy.

The number of biotechnology-based human therapeutic products in the late-stage pipeline, and the average cost to commercialize a biotech product, have steadily increased. This has required biotech companies to use economic analysis as a tool during process development and for making decisions about process design. Process development efforts now aim to create processes that are economical, as well as optimal and robust.

If a company wants to reduce costs, it should consider outsourcing some manufacturing and analytical testing to low-cost sites.