February 2011

Personalized medicine is a catch phrase of the 21st century — and with good reason. Advances in genetics and biochemistry promise to tease apart factors that explain why some patients benefit dramatically from a therapy whereas others receive no benefit at all. They also help explain side-effect profiles. To accomplish such lofty goals, drug makers are increasingly partnering with diagnostics companies to develop companion biomarkers. But these companies operate in very different business and regulatory environments, so partnerships can be complicated by contrary goals and misunderstandings. Before entering such a relationship, each participant should understand a potential partner’s world view and economic incentives, as well as recognize potential difficulties. Seven Questions Here are seven questions for biopharmaceutical companies to consider when evaluating a partnership with a diagnostics company. Do you understand the value proposition? Companion diagnostics both enable and limit opportunities. T...

The 13th WCBP CMC Strategy Forum on extractables and leachables was held in Bethesda, MD, in January 2008. The purpose of this forum, cosponsored by CASSS (an international separations society) and the FDA, was to discuss questions related to extractables and leachables in the context of biopharmaceutical manufacturing and find consensus on some of those topics. Morning sessions began with “Extractables and Leachables: Challenges and Strategies in Biopharmaceutical Development” with program cochairs Stacey Ma of Genentech, Inc., Ingrid Markovic of FDA CDER, Edwin Moore of Baxter Healthcare Corporation, and Susan Yu of FDA CBER, FDA. “Analytical Tools for Testing Extractables and Leachables” followed, with session chair Edwin Moore. Presentations included Susan Yu defined extractables and leachables. Extractables are chemicals generated under exaggerated temperature and time conditions in the presence of an appropriate solvent. Leachables are chemicals that migrate spontaneously from a container–closure...

Combination products (see the “Definition” box) are experiencing steady growth in the pharmaceutical industry. According to one report, about 30% of products currently in development are combination products ( 1 ). Expanding interest in such products can be attributed to manufacturers’ need to generate new market value for current products that will soon lose patent, requirements for long-term patient care, pressure to reduce healthcare costs, and consumer interest in localized drug delivery with improved therapeutic effectiveness ( 2 ). During the 2008 fiscal year (the most recent performance report available) the US FDA’s Office of Combination Products (OCP) received 330 products for review. Regulatory flexibility and clarity, updated FDA guidances (e.g., see the “2009 Proposed Rule” box), and continued innovations in delivery mechanisms and formulations will continue to drive commercialization for combination products. Center Designation and CGMPS OCP does not regulate combination products but is respo...

Polishing with membrane chromatography (MC) has achieved acceptance as state-of- the-art technology for charged impurities. Traditionally, anion-exchange (AEX) and cation-exchange (CEX) membrane chromatography have been used to remove charged contaminants such as host-cell proteins (HCPs), recombinant DNA, protein A, endotoxins, and viruses. In monoclonal antibody (MAb) processes, polishing steps usually follow a protein A affinity column step. In some cases, CEX capture is applied, either with at least one AEX or a combined AEX and CEX step. The latter may be replaced by a hydrophobic-interaction chromatography (HIC) step. Ceramic hydroxyapatite is also used, though less frequently. Hydrophobic antibody aggregates formed during MAb manufacturing are frequent process-related impurities that must be removed during downstream processing because they can cause loss of activity as well as toxicity and immunogenicity. Because of their toxic potential, such aggregates can cause an unwanted response or even over...

As regulators become increasingly stringent in demanding a fuller understanding of whole virus preparations, researchers and manufacturers are looking beyond well-known characterization methodologies. Existing technologies for quantifying and characterizing viral preparations such as infectivity assays, quantitative polymerase chain reaction (qPCR), and protein assays provide crucial information but tell only half the story. We evaluated a unique technology developed by NanoSight Ltd. ( www.nanosight.com ) for visualizing viruses in liquid suspensions, measuring their approximate concentration, and characterizing their state of aggregation. Information generated by this technology provides complementary data and helps fill in knowledge gaps left after using traditional technologies. PRODUCT FOCUS: ALL BIOLOGICS PROCESS FOCUS: DOWNSTREAM PROCESSING AND FORMULATIONS WHO SHOULD READ: PROCESS DEVELOPMENT, QA/QC, FORMULATIONS, AND ANALYTICAL PERSONNEL KEYWORDS: VIRAL SAFETY, QPCR, LIGHT-SCATTERING, AGGREGATION...

Perfusion processes are considered more difficult to model than batch-based fermentation processes because up to a third of a perfusion-based campaign is spent outside “steady-state” production mode. Variabilities in cell density, titer, and harvest rate (HR) during ramp-up necessitate planning and explicit modeling of variabilities in these processes and their subsequent downstream operations. Longer continuous fermentation times require more rigorous attention to risk than do batch-based systems. A flexible purification platform must respond to changing fermentation conditions. Here we discuss strategies for modeling perfusion at our company and how simulation models can be used to create flexible, “just-in-time” facilities that respond to manufacturing conditions. Background Perfusion processes are well established in food and other life-science industries, in which continuous production can create relatively high product concentrations and volumetric throughput. However, biopharmaceutical manufacturin...

Chromatographic purification remains the most critical step in biopharmaceutical downstream processing. Its purpose is to separate biologic impurities such as host-cell proteins (HCPs), nucleic acids, and oligomers from a target biologic, which must be purified to very high levels (often >99%). Biological separations usually require medium to high salt concentrations and bear inherent risks of microbial contamination in waterbased process streams. Thus they require specifically designed equipment. Depending on process constraints, chromatographic media, and equipment limitations, biochromatographic separations may be run at low to very high velocities (e.g., 75 to >500 cm/h). Photos 1: Photos 1: () Columns are the most critical part of biochromatography systems because they are where the separation takes place. When choosing a column, several points should be taken into account, depending on process constraints and plant design: scale of operation (current and projected), whether it occurs in a dedicated ...

Tubing/Hose Clamps Product: Overmolded Tri-Clamp ends Applications: Sanitary fluid management, single-use processing Features: AdvantaPure Overmolded Tri-Clamp ends for PVC, TPE, and TPR tubing and hoses are injection molded from USP Class VI Hytrel material or polypropylene in Tri-Clamp and Mini Tri-Clamp styles. A smooth transition from tubing to clamp reduces bacteria entrapment potential for cleaner connections. The clamp materials are mated thermally (no leachable adhesives) to PVC, TPR, or TPE hoses and certified free of animal-derived ingredients. Miniature through1.5-in. Tri-Clamp sizes are available, as well as made-to-order assemblies, with documented quality control. Contact New Age Industries www.advantapure.com Automation Guide Literature: GAMP Good Practice Guide: Calibration Management Applications: Analytical laboratories Features: For its second edition, ISPE’s GAMP guide to calibration management provides insight into a risk-based approach to validation and regulatory compliance. ...