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Podcast Series\n - UPLC, QTof, HDMS, and more: A practical guide to the hottest techniques driving the future of\n biopharmaceutical science.

Resources\n - If you are looking for additional information (or terms not included in our glossary), here are some\n places to begin your search.

Bioterminology\n - A Guide to the Biopharmaceutical Lexicon, 2010 edition

Licensing of Expression Systems\n - Gaining a license can be a complex process, but a few key tips can help you avoid common pitfalls and\n patent infringements.

Rapid Process Development for High Yield Plasmid DNA Fed-batch Fermentation\n - How to reduce plasmid-mediated metabolic burden for higher yields.

Fermentation and Cell Culture\n - To assess current trends in fermentation and cell culture equipment, BioPharm International turned to\n Geoff Hodge, managing director of process technology, Xcellerex, Inc.; Günter Jagschies, senior\n director of strategic customer relations, life sciences, biotechnologies, GE Healthcare; and Rich Mirro, product\n manager, New Brunswick Scientific.

Avoiding the Regulatory Catch 22\n - Companies often wait for a critical mass before adopting new technologies. But if no one takes the\n risk, critical mass will never be reached.

Analytical Tools for Process and Product Characterization\n - Select the best approach to determine critical quality attributes.

High-Cell-Density Culture to Produce Plasmid DNA for Gene Therapy in E. coli\n - How to produce Plasmid DNA in a high-cell-density culture.

Site-Directed Engineering of Defined Chromosomal Sites for Recombinant Protein and Virus Expression\n - Method for integration of transgenes.

Using Fluorescence-Based Sensing to Accelerate Process Development\n - A prove-free system monitors accurately at very small scale.

Versatility of a Single-Use Bioreactor Platform for Culture of Diverse Cell Types\n - Are disposable bioreactors effective for cell culture?

Upcoming Technologies to Facilitate More Efficient Biologics Manufacturing\n - Choosing the right tools to enhance the process.

Biomanufacturing Capacity Quandary\n - There could be a serious glut of commercial scale mammalian cell culture capacity over the next five\n years. Then again, there could be a significant shortage. It all depends on how things develop in expression\n technology, the new product pipeline, and corporate strategies.

Detection of Cache Valley Virus in Biologics Manufactured in CHO Cells\n - Avoid manufacturing failures by effective viral inactivation.

Viral Clearance Strategy Using a Three-Tier Orthogonal Technology Platform\n - How to implement a risk-based approach to eliminating viruses.

Modeling of Biopharmaceutical Processes. Part 2: Process Chromatography Unit Operation\n - A review of some recent contributions in process chromatography.

Recombinant Protein Production Yields from Mammalian Cells: Past, Present, and Future\n - A discussion of past achievements and future expectations of recombinant protein production yields\n from mammalian cells.

Fusion Tags for Protein Expression and Purification\n - Gene fusion tags can improve the yield and solubility of many recombinant proteins. This article\n discusses the most popular fusion tags and the proteases used to remove them, with special reference to recently\n introduced technologies.

Improving Protein Production in CHO Cells\n - Using chemically defined feeds with CHO cell lines not only eliminates the variability associated with\n using plant hydrolysates, but could also improve the productivity of biopharmaceutical protein manufacture and help\n move therapeutic proteins into clinical trials more rapidly.

Maximizing Yields of Plasmid DNA Processes\n - Recombinant protein and plasmid DNA production using microbial expression systems is the cornerstone\n of many biologics manufacturing processes. HCD methods are commonly used for these processes because of the\n advantages they provide.

The Role of Media Development in Process Optimization: An Historical Perspective\n - With a variety of recombinant, animal-free, defined protein supplements such as growth factors,\n transferrin, and albumin entering the market, the biopharmaceutical industry now has innovative and safer\n alternatives to serum and other animal-derived supplements.

Modeling of Biopharmaceutical Processes—Part 1: Microbial and Mammalian Unit\n Operations\n - Process-modeling tools can ensure smooth tech transfer.

Straightforward Guidance\n - In the context of process validation, the confirmation of a belief must be checked repeatedly,\n throughout the product lifecycle.

Harvest and Recovery of Monoclonal Antibodies from Large-Scale Mammalian Cell Culture\n - A comparison of primary harvest techniques.

Leveraging Fermentation Heat Transfer Data to Better Understand Metabolic Activity\n - A simple method to leverage fermentation heat transfer data.

Disposable Bioreactors: The Next Generation\n - Disposable technologies that mimic the conventional stainless-steel bioreactor will be most readily\n adopted

How to Ensure Smooth Technology Transfer\n - A comprehensive process and analytical transfer package can speed up your product\'s time to market and\n save costs.

Extractables and Leachables Study Approach for Disposable Materials Used in Bioprocessing\n - Two case studies illustrate a systematic approach.

The Disposables Revolution\n - The use of disposables has changed significantly in the biopharmaceutical industry.

Elements of Quality by Design in Development and Scale-Up of Freeze-Dried Parenterals\n - Design space concepts are key to a successful technology transfer.

Rapid Development and Optimization of Cell Culture Media\n - Chinese hamster ovary (CHO) cells are used extensively in the biopharmaceutical industry to produce\n recombinant proteins that require post-translation modification for full biological functionality. Optimization of\n culture conditions for recombinant CHO cell lines presents challenges in light of the diverse nutritional\n requirements observed with different clonally derived cell lines.

Engineering Biopharmaceuticals\n - An overall increasing proportion of future product approvals will be engineered in some way, either\n directly or indirectly.

SAFC Expands Fermentation Capabilities with Upgrade of Israel Site\n - SAFC (St. Louis, MO), a member of the Sigma-Aldrich Group, has announced a $29-million investment to\n significantly expand its drug substance capabilities in high-potency biologics at the Sigma-Aldrich facility in\n Jerusalem, Israel

The Evolution of Protein Expression and Cell Culture\n - It is commonly believed that technologies in the next 10–15 years will enable sequencing\n an individualized human genome for less than $1,000. With innovations like these, the twenty-first century will\n certainly belong to biotechnology. From an industrial standpoint, the discovery of therapeutic molecules and the\n development of cell lines and processes to produce these molecules will be of paramount importance. This article\n describes various approaches that have been prevalent in the industry or are likely to be used in the future for\n generating cell lines with desirable traits and developing high titer cell culture processes.

Applications of Multivariate Data Analysis in Biotech Processing\n - Multivariate data analysis can help biotech manufacturers deepen their process\n understanding.

On the Biotechnology Frontier: Personalized Medicine, A Discussion with E.J. Brandreth\n - Favrille, a San Diego-based biopharmaceutical company, is one of a handful of firms on the forefront\n of personalized medicine. Because personalized treatment is tailored to an individual\'s biology, it has the\n potential to be far more effective than current approaches to disease management.

Protein Therapeutics and the Regulation of Quality: A Brief History\n - Regulatory agencies have evolved along with the biotechnology industry to define quality\n standards.

Biotech Manufacturing Grows Up\n - It became a strategic imperative to find a better, more efficient way to manufacture our products. To\n continue with the status quo was untenable.

Glycosylation and the Demands of Antibody Engineering\n - In one series of experiments, the glycosylation site of IgG1 was removed and an IgA glycosylation site\n was introduced—resulting in a total loss of biological function.

Final Word: In the Quest to Manage Capacity, Biology Trumps Stainless Steel\n - From the earliest days of the biotechnology industry, companies have grappled with the complexities of\n making innovative biopharmaceuticals on a large scale. Success in manufacturing begins with process science, since\n biotech production requires perfection in maintaining living organisms in a sterile environment under controlled\n physiological conditions. But unless companies can solve the challenge of planning for and managing manufacturing\n capacity, they will not be able to achieve the full potential of promising biotech products.

Biopharmecuticals: Approval Trends in 2006\n - There were notable approvals in nonparenteral delivery systems and biosimiliars in 2006.

From the Editor: Issues of Scale\n - In analyzing the industry\'s current challenges, let\'s be careful before extrapolating about what they\n mean.

SemBioSys Produces Commercial Levels of Recombinant Apo AI Using Plants\n - SemBioSys Genetics, Inc. (Calgary, Canada, www.sembiosys.com) announced that it has successfully\n produced commercial levels of apolipoprotein AI and its variant apolipoprotein AI(Milano), collectively referred to\n as Apo AI, in safflower seed lines.

Regulatory Issues: Pandemic Preparedness Pacing Up\n - Any endpoint considered appropriate to support approval, whether a surrogate or a clinical endpoint,\n must be supported by substantial evidence of effectiveness.

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

Pandemic Flu Preparedness: A Manufacturing Perspective\n - For pandemic vaccine processing, single-use filter cartridges and membrane chromatography technologies\n could offer significant time- and cost-reduction advantages.

New-Age Vaccine Adjuvants: Friend or Foe?\n - Adjuvant-caused vaccine reactions are one of the most important barriers to better acceptance of\n routine prophylactic vaccination.

Cancer Vaccines: Asymptotically Approaching Product Approval\n - For many cell-based vaccines, the precursor monocytes or CD34+ cells are cultured with cytokines to\n obtain dendritic cells, which are very potent antigen-presenting cells (APCs).

The Adjuvant Patch: A Universal Dose Sparing Approach for Pandemic and Conventional Vaccines\n - In animal studies, we have demonstrated that the dose of an injected H5N1 vaccine candidate can be\n significantly reduced by using a skin patch containing E. coli heat-labile enterotoxin (LT) applied over the\n injection site. LT-activated epidermal Langerhans cells migrate to the nearby draining lymph node and enhance the\n immune response to the injected antigen. A dry patch formulation has been optimized as a dose sparing strategy for\n pandemic flu and other vaccines. Iomai Corporation has developed a proprietary stabilizing formulation for the\n patch that allows use and storage at ambient temperature. The patch withstands temperature extremes during\n shipment, and is suitable for stockpiling.

Plasmid DNA–Based Vaccines: Combating Infectious Diseases\n - Like the egg-based vaccine production process, producing a vaccine under cGMP conditions using\n mammalian cells can be a lengthy process, taking a minimum of six to 12 months.

Cell-Culture–Based Manufacturing: Meeting the Challenge of 21st Century Influenza\n - Vaccines against strains originating from avian flu may achieve poor yields in egg-based systems.\n Consequently, both public and private interest in alternative systems is high.

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

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

Upstream Processing: Regulatory Considerations Regarding Quality Aspects of Monoclonal Antibodies\n -

FDA Finalizes Guidances For Pandemic and Seasonal Influenza Vaccines\n - The US Food and Drug Administration (FDA, Rockville, MD, www.fda.gov) has issued final recommendations\n for increasing the supply of safe and effective influenza vaccines for both seasonal and pandemic\n use.

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

Applying Fusion Protein Technology to E. coli\n - Protein expression remains an arduous task that involves a complex decision tree. Establishing tools\n and optimal conditions for each protein remains an empirical exercise.

Advances in Animal-Free Manufacturing of Biopharmaceuticals\n - In addition to existing guidance, in January 2007 the FDA announced further proposals to prohibit the\n use of certain bovine materials as ingredients in some medical products or as elements of product\n manufacturing.

Disposable Bioreactors Based on Wave Agitation Technology\n - Energy input is affected by rocking the chamber back and forth, generating a fluid movement in the\n cell culture and medium.

Rapid High-Throughput Feed Optimization\n - Growth of CHO cell cultures in a shaker plate model system was demonstrated to be comparable to growth\n in shake flasks.

From the Editor: Score One for Preparedness\n - Fortunately for all of us, not everyone\'s head is in the sand.

Pandemic Preparedness Picks Up Pace with First Flu Vaccine Approval\n - The FDA\'s (Rockville, MD, www.fda.gov) first approval in the United States of a vaccine for humans\n against the H5N1 influenza virus marks an important step forward in protecting the public against a pandemic\n influenza outbreak.

Companies Share CHO Genomic Sequences to Improve Drug Development\n - Major pharmaceutical and biotechnology companies have joined forces under the auspices of the Society\n for Biological Engineering (SBE, New York, NY, www.aiche.org/SBE) to make use of cell line research that is\n expected to increase the efficiencies of drug development.

The Importance of Project Management\n - Are the deadlines for your outsourced projects often not met? Are you unsure of the status of your\n project at any given time? Is the original budget of your study typically exceeded?

Disposables: Keeping Pace with Today\'s Disposable Processing Applications\n - Frequently asked questions on implementing and using single-use technologies

China Today: Vaccine Development in China\n - The Chinese vaccine market competition is now transferring from the former price-competition model to\n a technology- competition model.

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

Hylenex Accelerates Time to Peak Blood Concentration for Subcutaneous Morphine\n - Patients receiving palliative care in hospices, hospitals, and other settings can benefit from a\n subcutaneous injection of morphine with Hylenex recombinant (hyaluronidase human injection).

Outstourcing Insights: Ferment in Biomanufacturing\n - The three largest players have accumulated, or are in the process of accumulating, nearly a million\n liters of capacity between them.

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

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

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

Technology Transfer: How to Make It a Competitive Advantage\n - If a company wants to reduce costs, it should consider outsourcing some manufacturing and analytical\n testing to low-cost sites.

Successful Technology Transfer Requires More Than Technical Know-How\n - We often assume we know what success looks like for our partner, but we never ask them, or take the\n time to write it down.

Writing Effective Development Reports\n - Development reports document process development and support the design of validation experiments, yet\n in many firms training is not provided nor are expectations established. This article describes how project\n managers can help scientists master the art of report-writing.

Expediting the Technical Transfer of Biopharmaceutical Products\n - Established, fully validated methodology and SOPs are required prior to initiation of any training\n activities.

Designing a Shorter Vertical Leg for Sanitary Steam Traps\n - Steam traps are part of a steam-in-place system. The current design allots 18 in. of vertical leg for\n condensate backup. A design with a sensitive bellows has been proven in laboratory tests to need only 6 in. of\n vertical leg during the 15 min. of 121?C sterilization. Loads of 1 to 27 lb/h are covered by the capability of the\n new trap, equivalent to required steam for vessels 20 to 40,000 L.

Successful Bioreactor Installation: What it Takes\n - Understand your company\'s requirements, define responsibilities,and manage your team\n effectively.

Production of Recombinant Therapeutic Proteins in the Milk of Transgenic Animals\n - Capital investments in production plants represent a significant portion of the cost of new\n recombinant drugs

From the Editor in Chief: A Shot In The Arm\n - The approvals of two groundbreaking vaccines in the last month is encouraging news. Vaccines have long\n been undervalued because they haven\'t been as profitable as other pharmaceuticals. So it\'s good to see them getting\n deserved attention that goes beyond fears of flu outbreaks.

Disposables: A Solution for Efficient Biopharmaceutical Production\n - Disposables require less space than conventional equipment, and they can be assembled offsite into\n complete process trains.

Linking Manufacturing Specifications to Clinical Results Often Challenging\n - "Clinical data is the gold standard" for setting manufacturing specifications, said\n Patrick Swann, PhD, acting deputy director of the Division of Monoclonal Antibodies at FDA, at a session on\n specification setting at the AAPS National Biotechnology Conference that was held June 19-21 in\n Boston.

Iontophoresis, Sonophoresis, and Microneedles Permit Effective Transdermal Delivery of Biologics\n - The transdermal delivery of biologics-as well as of conventional drugs-is growing in popularity\n because the technique offers numerous advantages.

Promise and Challenges of Biotech Vaccines\n - Several recent approvals highlight progress in developing both prophylactic and therapeutic\n vaccines.

From the Editor in Chief: When Does Glycosylation Matter?\n - The belief that glycosylation is critical to ensuring the functionality of protein\n therapeutics—and preventing immunogenicity—drives many manufacturing decisions. But is\n it time to question this industry tenet?

Producing Proteins Using Transgenic Oilbody-Oleosin Technology\n - Transgenics can substantially reduce capital investment and lower production costs through economies\n of scale and more flexible scale-up.

From the Editor in Chief: Engineering Oneself Out of a Job\n - Alexander Fleming\'s original process for making penicillin was a low-volume, and presumably,\n labor-intensive affair. Today, it is a highly optimized, low-budget operation that is carried out only overseas. In\n other words, says Wei-Shou Hu, PhD, of the University of Minnesota, we engineered ourselves out of a job. Could we\n do the same with mammalian cell culture? Hu posed this question during a presentation at the BIO conference in\n April.

StreetTalk: Investments in Avian Flu Soar\n - The federal government plans to spend $3.3 billion on bird flu initiatives, about half of that on a\n vaccine.

Accept No Limits on Mammalian Cell Expression\n - Instead of investing in new facilities, the industry should focus on improving manufacturing\n technology to increase yields, says Timothy Charlebois, PhD, director of cell and molecular sciences for Wyeth\n (Madison, NJ, www.wyeth.com). Charlebois made these remarks in his introduction to the session, "Frontiers\n and Economics of Mammalian Cell Expression," at the BIO 2006 convention."I\'ve seen examples where\n we took a process that produced 3 grams of protein per liter, and were able to optimize it so that it produced 9.6\n g/L," he said, adding that future yields are likely to be above 10 g/L.

Final Word: Creative Solutions Can Ensure Pandemic Flu Preparedness\n - Certain areas of the vaccine market appear to be in vogue again, revitalized by blockbusters such as\n Prevnar, the pneumococcal pneumonia vaccine that reaped $1.5 billion in sales last year, and the human papilloma\n virus vaccines, which are projected to reach $4 billion per year.

Maximizing Protein Expression in Filamentous Fungi\n - One of the major challenges in fungal biotechnology is preventing proteases of the fungi from\n degrading recombinant proteins.

The Science\n - At the heart of modern biotechnology is the ability to manipulate DNA, the astonishing molecule that\n contains the genetic code of all life on earth. But fermentation and cell culture are also the practical art of\n keeping cells alive and growing in an artificial environment. As a result, the science of cell culture also\n includes a healthy focus on the natural processes that keep cells alive.

Introduction\n - Anyone who has ever hoisted a glass of a local microbrew has experienced the results of the oldest\n form of biotechnology?fermentation, the process by which living cells obtain energy through the breakdown of\n glucose and other molecules. The basic technique of brewing has not changed much in the past 6,000 years, but it is\n still an excellent illustration of the principles that underlie some of today\'s most sophisticated biotech\n production.

References and Resources\n - To learn more about the processes of fermentation and cell culture used in the production of\n biopharmaceuticals, you can refer to our advertisers or to the following publications, organizations, and web\n sites.